The Neurobiology of Social Recognition, Attraction and Bonding (Philosophical Transactions of the Royal Society series B)

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volume 361

. number 1476 . pages 2055–2272

The neurobiology of social recognition, attraction and bonding Papers of a Theme Issue organised and edited by Keith M. Kendrick, and including the 1998 Ferrier lecture by Jean-Pierre Changeux

Registered Charity No 207043

2061

number 1476

pages 2055–2272

In this issue

The neurobiology of social recognition, attraction and bonding Papers of a Theme Issue organised and edited by Keith M. Kendrick, and including the 1998 Ferrier lecture by Jean-Pierre Changeux

2079 2091 2109 2129 2143

2155 2173 2187 2199 2215 2229 2239 2261 2263

. 29 December 2006

Founded in 1660, the Royal Society is the independent scientific academy of the UK, dedicated to promoting excellence in science

2057

volume 361

volume 361 . number 1476 . pages 2055–2272

Introduction. The neurobiology of social recognition, attraction and bonding K. M. Kendrick Mammalian social odours: attraction and individual recognition P. A. Brennan & K. M. Kendrick Social odours, sexual arousal and pairbonding in primates C. T. Snowdon, T. E. Ziegler, N. J. Schultz-Darken & C. F. Ferris Voice processing in human and non-human primates P. Belin The fusiform face area: a cortical region specialized for the perception of faces N. Kanwisher & G. Yovel Genetic influences on the neural basis of social cognition D. Skuse Reproductive strategy, sexual development and attraction to facial characteristics R. E. Cornwell, M. J. Law Smith, L. G. Boothroyd, F. R. Moore, H. P. Davis, M. Stirrat, B. Tiddeman & D. I. Perrett Behavioural and neurophysiological evidence for face identity and face emotion processing in animals A. J. Tate, H. Fischer, A. E. Leigh & K. M. Kendrick Romantic love: a mammalian brain system for mate choice H. E. Fisher, A. Aron & L. L. Brown Oxytocin, vasopressin and pair bonding: implications for autism E. A. D. Hammock & L. J. Young Mother–infant bonding and the evolution of mammalian social relationships K. D. Broad, J. P. Curley & E. B. Keverne Social buffering: relief from stress and anxiety T. Kikusui, J. T. Winslow & Y. Mori Genomic imprinting and the social brain A. R. Isles, W. Davies & L. S. Wilkinson The Ferrier Lecture 1998 The molecular biology of consciousness investigated with genetically modified mice J.-P. Changeux Erratum Indexes Volume Title Page and Table of Contents

Philosophical Transactions of the Royal Society B

29 December 2006

ISSN 0962-8436

The world’s longest running international science journal

www.journals.royalsoc.ac.uk Published in Great Britain by the Royal Society, 6–9 Carlton House Terrace, London SW1Y 5AG

29 December 2006

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Cover image: An allegorical representation of social recognition attraction and bonding. (Design by H. Fischer. See pages 2155–2172.)

RSTB_361_1476.qxp

11/18/06

7:32 PM

Page 1

volume 361

. number 1476 . pages 2055–2272

The neurobiology of social recognition, attraction and bonding Papers of a Theme Issue organised and edited by Keith M. Kendrick, and including the 1998 Ferrier lecture by Jean-Pierre Changeux

Registered Charity No 207043

2061

number 1476

pages 2055–2272

In this issue

The neurobiology of social recognition, attraction and bonding Papers of a Theme Issue organised and edited by Keith M. Kendrick, and including the 1998 Ferrier lecture by Jean-Pierre Changeux

2079 2091 2109 2129 2143

2155 2173 2187 2199 2215 2229 2239 2261 2263

. 29 December 2006

Founded in 1660, the Royal Society is the independent scientific academy of the UK, dedicated to promoting excellence in science

2057

volume 361

volume 361 . number 1476 . pages 2055–2272

Introduction. The neurobiology of social recognition, attraction and bonding K. M. Kendrick Mammalian social odours: attraction and individual recognition P. A. Brennan & K. M. Kendrick Social odours, sexual arousal and pairbonding in primates C. T. Snowdon, T. E. Ziegler, N. J. Schultz-Darken & C. F. Ferris Voice processing in human and non-human primates P. Belin The fusiform face area: a cortical region specialized for the perception of faces N. Kanwisher & G. Yovel Genetic influences on the neural basis of social cognition D. Skuse Reproductive strategy, sexual development and attraction to facial characteristics R. E. Cornwell, M. J. Law Smith, L. G. Boothroyd, F. R. Moore, H. P. Davis, M. Stirrat, B. Tiddeman & D. I. Perrett Behavioural and neurophysiological evidence for face identity and face emotion processing in animals A. J. Tate, H. Fischer, A. E. Leigh & K. M. Kendrick Romantic love: a mammalian brain system for mate choice H. E. Fisher, A. Aron & L. L. Brown Oxytocin, vasopressin and pair bonding: implications for autism E. A. D. Hammock & L. J. Young Mother–infant bonding and the evolution of mammalian social relationships K. D. Broad, J. P. Curley & E. B. Keverne Social buffering: relief from stress and anxiety T. Kikusui, J. T. Winslow & Y. Mori Genomic imprinting and the social brain A. R. Isles, W. Davies & L. S. Wilkinson The Ferrier Lecture 1998 The molecular biology of consciousness investigated with genetically modified mice J.-P. Changeux Erratum Indexes Volume Title Page and Table of Contents

Philosophical Transactions of the Royal Society B

29 December 2006

ISSN 0962-8436

The world’s longest running international science journal

www.journals.royalsoc.ac.uk Published in Great Britain by the Royal Society, 6–9 Carlton House Terrace, London SW1Y 5AG

29 December 2006

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Phil. Trans. R. Soc. B (2006) 361, 2057–2059 doi:10.1098/rstb.2006.1930 Published online 3 November 2006

Introduction. The neurobiology of social recognition, attraction and bonding Providing an understanding of the neural, humoral and genetic factors that control social recognition and attraction, communication and interpretation of emotional state and the formation of long-term emotional bonds is of key importance for human mental health and well-being. However, unlocking the secrets of these different aspects of the social brain presents a significant challenge to Neuroscience, since a broad spectrum of different behaviours and brain systems are involved together with a multitude of complex interactions between them. The question also arises as to whether true insights into the workings of the human social brain can be gained from detailed studies of other mammalian species that have evolved a variety of different social systems. Advances in human brain imaging have provided us with far more detailed information about both social and emotional recognition pathways in the brain. We also are beginning to understand the substrates involved in romantic attraction and social bonds. Comparing this with the more extensive research that has often been carried out on other mammalian species strongly suggests extensive evolutionary conservation of many of the basic mechanisms operating within the social brain that regulate discrimination of individual identity, interpretation of emotion cues and even mate attraction. The main aim of this theme issue has been to try to bring together the major advances made in recent years in diverse areas of research on both humans and other mammalian species investigating the neurobiology of social recognition, attraction and bonding. Numerous conferences and symposia have focused on specific features of social recognition, such as identifying individuals via odours or voices or faces, although research findings from the different senses are rarely presented together. Similarly, studies investigating the processes by which individuals recognize one another are often considered separately from those investigating communication and interpretation of emotional cues. Yet again, studies investigating these identity and emotion recognition cues often do not link into those investigating the specific cues that determine sexual or social attraction and can lead to the establishment of social bonds. A number of the papers in this issue detail the present state of knowledge on the best understood area of social identity recognition in mammals, namely olfaction. The first provides a review of the nature of mammalian social chemo signals and the odorant receptors, neural pathways and neurochemical systems required for their detection by both the vomeronasal and main olfactory One contribution of 14 to a theme issue ‘The neurobiology of social recognition, attraction and bonding’.

systems (Brennan & Kendrick 2006). The importance of genes in the major histocompatibility complex for determining chemosensory individuality is discussed in the context of recognition and mate choice in both mice and humans. The review also provides insights into the nature of learning-induced changes which occur within these systems in both rodent mate recognition and sheep models of offspring recognition. The second review focuses on a recent series of brain imaging studies on pair-bonding marmosets revealing that social odours which signal reproductive state influence not only sexual arousal and brain regions mediating the sexual response, but also those associated with memory and emotional decision making as well (Snowdon et al. 2006). This paper also discusses evidence for similar roles of social odours in the control of human reproduction, although it is clear that odour plays less of a role in humans than in many other species. A later review discusses the effects of neuropeptides that promote pair-bonding in voles on recognition and memory for social odours (Hammock & Young 2006). Evolutionary aspects of the shift away from more hard-wired utilization of olfactory signals to stimulate social and reproductive behaviours in a relatively inflexible manner, towards a more multisensory-based flexible system in primates, are discussed in Broad et al. (2006). While vocal recognition may well be quite extensive among mammalian species, it remains the least investigated of the senses. However, exciting new brain imaging experiments have been carried out in humans and a single extensive review has detailed these together with a small number of behavioural and neurophysiological studies in monkeys (Belin 2006). This paper concludes that while voice identification in humans is less accurate than that for faces, the right brain hemisphere appears to be important for both, and particularly the superior temporal sulcus. Evidence is provided for the presence of specialized parts of this region for voice recognition. Interestingly, autistic humans do not seem to have these voice selective regions; their brains may process voice and non-voice sounds in the same way. This appears to contrast somewhat with the human face recognition system, where regions controlling the interpretation of face emotion rather than face identity recognition seem to be impaired in autistic individuals (Skuse 2006). By contrast with the recognition of voice identity, there have been a large number of studies carried out on processing of face identity, face emotion and face attraction cues in humans, monkeys and sheep. A number of reviews in the current issue discuss these studies (Cornwell et al. 2006; Kanwisher & Yovel 2006; Skuse 2006; Tate et al. 2006). The first of these focuses on the considerable amount of behavioural,

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Introduction

neuropsychological and brain imaging data in humans which establish a critical role for the face fusiform area of the cortex in the right brain hemisphere for face identity processing (Kanwisher & Yovel 2006). The authors argue strongly that there is a face-specific domain despite recent claims that this is just a region involved in expert recognition of any visual object. They also discuss a number of ways that this region may compute and represent faces. A further review considers brain imaging and neuropsychological experiments establishing the role of the amygdala and the different visual pathways projecting to it for processing face emotion in humans (Skuse 2006). It describes both a subcortical preconscious pathway activated by direct eye and a more cortical-based one for more detailed analysis of face emotion cues, as well as differential roles for the left and right brain hemispheres. Potential contributions of the serotonin transporter gene and X-linked genes in the integration of these two pathways and progress towards an understanding of genetic contributions to affective disorders are discussed. Staying with the theme of human face perception, a further paper describes new experiments investigating developmental influences on male preferences for highly feminized female faces and female preferences for highly masculinized ones (Cornwell et al. 2006). The authors show that the degree of this dimorphic preference is correlated with the age of first sexual experience and they discuss possible hormonal and learning factors that might contribute to this phenomenon. Experiments also demonstrate that female attraction to specific male faces can occur independent of masculinity cues. A final review on face recognition, attraction and emotion concentrates on behavioural and neurophysiological studies investigating these in non-human primates and sheep (Tate et al. 2006). This provides strong evidence for similar specialized encoding of face identity in these species and details electrophysiological experiments illustrating high-order view invariant coding by face sensitive cells both in the temporal and the frontal cortices and which may also be important for face imagery. The paper suggests that configural aspects of encoding are perhaps primarily mediated by cells which respond to faces in a view-dependent manner. Research in sheep and monkeys is also discussed which shows evidence for the use of face emotion cues and encoding of these within the temporal cortex. The findings suggest that both identity and emotion cues are processed by parts of the temporal cortex, although emotion cues may be given priority compared with those for identity. The review also describes experiments using novel multiarray electrophysiological recording approaches, which suggest the presence of population encoding of faces by temporal cortex networks combined with high-order sparse encoding. The remaining reviews in this issue deal mainly with the neurohumoral control of sociosexual behaviours, mate attraction, mate and parental bonding, and how sensory cues are used in this context. These start with a detailed consideration of how different aspects of the mammalian sexual response are controlled, focusing particularly on humans (Fisher et al. 2006). The authors propose that there are distinct, although Phil. Trans. R. Soc. B (2006)

integrated, systems in the mammalian brain for controlling the sex drive, individual mate attraction and bonding, and they provide a description of the key brain pathways that may be involved. They draw particularly on results from recent brain imaging studies and also rely on far more extensive studies carried out on other species (see Hammock & Young (2006) for bonds between mating partners). The brain imaging studies have also used faces of loved ones as a key stimulus and suggest a strong link with dopaminergic brain reward systems. Interestingly, this relationship has also been shown with female sheep viewing the faces of particularly attractive males, although in a strongly hormone-dependent fashion (Tate et al. 2006). Finally, the review provides new data showing that when a romantically rejected individual views a picture of the person who rejected them, this activates the same brain regions as in individuals performing tasks involving high risks. Indeed, one might argue that the quest for finding and reproducing with an appropriate mate represents the most high-risk social behaviour that any individual of any species engages in. The next review continues with the theme of bonds between sexual partners by providing a detailed consideration of the roles of oxytocin and vasopressin systems in the brain of pair-bonding voles and their important links with dopaminergic reward systems and noradrenergic systems involved in olfactory recognition (Hammock & Young 2006). This animal model has often been considered somewhat esoteric but it has nevertheless produced some remarkable insights into what distinguishes social brains from asocial ones. Indeed, the authors discuss a possible association between polymorphisms in the vasopressin receptor gene for autism in humans and as a possible contributor to the wide degree of individual differences in sociosexual bonding. Another paper reviews a field that has made considerable progress using animal models in recent years, namely the control of maternal offspring bonds in mammals, particularly sheep and monkeys. This again emphasizes the important role of brain oxytocin pathways as well as of the endogenous opioid peptides (Broad et al. 2006). The evolutionary approach adopted outlines a gradual shift away from a strongly hormone-dependent olfactory-based recognition system towards a more flexible multisensory-based one. The authors argue that this is what has allowed a huge increase in the importance and complexity of social learning, particularly in humans. The next two contributions discuss relatively newer areas of research in terms of behavioural and genetic aspects of social and emotional behaviours. The first presents findings in a field of growing interest, ‘social buffering’ (Kikusui et al. 2006). It describes experiments in both rodents and monkeys showing the stress/anxiety relieving effects of the social presence of a calm but not a stressed familiar conspecific. The findings once again illustrate the power of emotional communication between animals in the control of behaviour. The review also discusses ‘social buffering’ in the context of human behaviour. The final review also discusses a relatively new field, namely the importance of imprinted genes for social behaviour (Isles et al. 2006). The authors summarize how

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Introduction these monoallelically expressed genes may be used by the different sexes to promote various aspects of nurturing and social behaviours as well as growth in their offspring. This review also complements the earlier review in the issue that discussed the possible importance of X-linked genes for the control of interpretation of emotional cues (Skuse 2006). It seems likely that future research in this field of imprinted genes will reveal important new molecular candidates with key contributions to the control of the functioning of social and emotional brain, and perhaps also for the treatment of affective disorders in humans. A final review by Jean-Pierre Changeux (Changeux 2006), and based on his Ferrier lecture, describes work investigating molecular contributions to the elementary building blocks of consciousness using genetically modified mice. This focuses particularly on the role of the nicotinic acetylcholine receptor in the brain and functions such as behavioural flexibility and exploration in both social and non-social contexts. Increasing dependence upon social behaviour and interactions is widely thought to have been an important driver for the evolution of higher levels of consciousness in animals. Overall, there can be little doubt that we still have much to learn about how the brain controls different aspects of individual recognition, attraction, interpretation of emotional cues and the formation of social bonds. However, I hope that the excellent reviews in this issue will both promote debate and stimulate further research to address the significant gaps that still remain in our understanding. Rewarding social interactions and relationships are of paramount importance for humans as well as for many other mammals, and yet we humans, in particular, seem highly prone to social and emotional dysfunctions. Indeed, in many cultures, this seems to be on the increase. Not only are there a wide range of psychiatric and developmental disorders associated with problems in social interactions and interpreting emotional cues, but also the changing face of many human cultures is progressively exposing problems with forming successful social relationships and bonds. Increasing numbers of individuals are leading single lives as both social and work pressures combine to make it difficult to find suitable partners. Along with this goes the rise in more asocial pursuits, such as playing computer and electronic games. In this respect, it is perhaps interesting to speculate what evolutionary selection pressures might occur in future human populations which could promote the development of a less social species. After all, it is a remarkable observation that a polymorphism in a single gene can lead to an asocial as opposed to a social species of vole

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(Hammock & Young 2006). So, perhaps a social bonding phenotype is not that stable an adaptation in humans either? Keith M. Kendrick

February 2006

Cognitive and Behavioural Neuroscience, Babraham Institute, Cambridge CB2 4AT, UK ([email protected]) REFERENCES Belin, P. 2006 Voice processing in humans and non-human primates. Phil. Trans. R. Soc. B 361, 2091–2107. (doi:10. 1098/rstb.2006.1933) Brennan, P. A. & Kendrick, K. M. 2006 Mammalian social odours: attraction and individual recognition. Phil. Trans. R. Soc. B 361, 2061–2078. (doi:10.1098/rstb.2006.1931) Broad, K. D., Curley, J. P. & Keverne, E. B. 2006 Mother– infant bonding and the evolution of mammalian social relationships. Phil. Trans. R. Soc. B 361, 2199–2214. (doi:10.1098/rstb.2006.1940) Changeux, J.-P. 2006 The molecular biology of consciousness investigated with genetically modified mice. Phil. Trans. R. Soc. B 361, 2239–2259. (doi:10.1098/rstb.2006.1832) Cornwell, R. E., Law Smith, M. J., Boothroyd, L. G., Moore, F. R., Davis, H. P., Stirrat, M., Tiddeman, B. & Perrett, D. I. 2006 Reproductive strategy, sexual development and attraction to facial characteristics. Phil. Trans. R. Soc. B 361, 2143–2154. (doi:10.1098/rstb.2006.1936) Fisher, H. E., Arthur, A. & Brown, L. L. 2006 Romantic love: a mammalian brain system for mate choice. Phil. Trans. R. Soc. B 361, 2173–2186. (doi:10.1098/rstb.2006.1938) Hammock, E. A. D. & Young, L. J. 2006 Oxytocin, vasopressin and pair bonding: implications for autism. Phil. Trans. R. Soc. B 361, 2187–2198. (doi:10.1098/rstb. 2006.1939) Isles, A. R., Davis, W. & Wilkinson, L. S. 2006 Genomic imprinting and the social brain. Phil. Trans. R. Soc. B 361, 2229–2237. (doi:10.1098/rstb.2006.1942) Kanwisher, N. & Yovel, G. 2006 The fusiform face area: a cortical region specialized for the perception of faces. Phil. Trans. R. Soc. B 361, 2109–2128. (doi:10.1098/rstb. 2006.1934) Kikusui, T., Winslow, J. T. & Mori, Y. 2006 Social buffering: relief from stress and anxiety. Phil. Trans. R. Soc. B 361, 2215–2228. (doi:10.1098/rstb.2006.1941) Skuse, D. 2006 Genetic influences on the neural basis of social cognition. Phil. Trans. R. Soc. B 361, 2129–2141. (doi:10.1098/rstb.2006.1935) Snowdon, C. T., Ziegler, T. E., Schultz-Darken, N. J. & Ferris, C. F. 2006 Social odours, sexual arousal and pairbonding in primates. Phil. Trans. R. Soc. B 361, 2079–2089. (doi:10.1098/rstb.2006.1932) Tate, A. J., Fischer, H., Leigh, A. E. & Kendrick, K. M. 2006 Behavioural and neurophysiological evidence for face identity and face emotion processing in animals. Phil. Trans. R. Soc. B 361, 2155–2172. (doi:10.1098/rstb.2006. 1937)

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Phil. Trans. R. Soc. B (2006) 361, 2061–2078 doi:10.1098/rstb.2006.1931 Published online 8 November 2006

Mammalian social odours: attraction and individual recognition Peter A. Brennan1,* and Keith M. Kendrick2 1

Department of Physiology, University of Bristol, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK 2 Cognitive and Behavioural Neuroscience, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK Mammalian social systems rely on signals passed between individuals conveying information including sex, reproductive status, individual identity, ownership, competitive ability and health status. Many of these signals take the form of complex mixtures of molecules sensed by chemosensory systems and have important influences on a variety of behaviours that are vital for reproductive success, such as parent–offspring attachment, mate choice and territorial marking. This article aims to review the nature of these chemosensory cues and the neural pathways mediating their physiological and behavioural effects. Despite the complexities of mammalian societies, there are instances where single molecules can act as classical pheromones attracting interest and approach behaviour. Chemosignals with relatively high volatility can be used to signal at a distance and are sensed by the main olfactory system. Most mammals also possess a vomeronasal system, which is specialized to detect relatively non-volatile chemosensory cues following direct contact. Single attractant molecules are sensed by highly specific receptors using a labelled line pathway. These act alongside more complex mixtures of signals that are required to signal individual identity. There are multiple sources of such individuality chemosignals, based on the highly polymorphic genes of the major histocompatibility complex (MHC) or lipocalins such as the mouse major urinary proteins. The individual profile of volatile components that make up an individual odour signature can be sensed by the main olfactory system, as the pattern of activity across an array of broadly tuned receptor types. In addition, the vomeronasal system can respond highly selectively to non-volatile peptide ligands associated with the MHC, acting at the V2r class of vomeronasal receptor. The ability to recognize individuals or their genetic relatedness plays an important role in mammalian social behaviour. Thus robust systems for olfactory learning and recognition of chemosensory individuality have evolved, often associated with major life events, such as mating, parturition or neonatal development. These forms of learning share common features, such as increased noradrenaline evoked by somatosensory stimulation, which results in neural changes at the level of the olfactory bulb. In the main olfactory bulb, these changes are likely to refine the pattern of activity in response to the learned odour, enhancing its discrimination from those of similar odours. In the accessory olfactory bulb, memory formation is hypothesized to involve a selective inhibition, which disrupts the transmission of the learned chemosignal from the mating male. Information from the main olfactory and vomeronasal systems is integrated at the level of the corticomedial amygdala, which forms the most important pathway by which social odours mediate their behavioural and physiological effects. Recent evidence suggests that this region may also play an important role in the learning and recognition of social chemosignals. Keywords: amygdala; maternal bonding; olfactory bulb; pregnancy block; social recognition; vomeronasal

1. INTRODUCTION The mammalian lifestyle with its high degree of maternal care has led to the evolution of complex social systems in which the ability to distinguish and recognize individuals is vital for reproductive success. It is particularly important in the formation of parent–offspring bonds, enabling maternal resources to be directed to related individuals and denied to others. Individual recognition also forms the basis of territorial behaviour, identifying the individual or group, defending resources such as * Author for correspondence ([email protected]). One contribution of 14 to a theme issue ‘The neurobiology of social recognition, attraction and bonding’.

mates, food or nest sites and allowing the detection of intruders and the rejection of unfamiliar animals from a social group. It further extends to the choice of mate, in which the ability to assess the degree of relatedness of a potential mate is thought to reduce inbreeding and maximize the fitness of offspring, especially in competitive natural environments (Meagher et al. 2000). Information from a range of senses can be used for discrimination among conspecifics, including visual recognition of physical features, such as faces, or vocal cues, such as those in whale song or in human speech. However, for most mammals, olfaction is their dominant sense and their behaviour is heavily influenced by the social chemosignals secreted by individual conspecifics (Wyatt 2003).

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2. MAMMALIAN SOCIAL CHEMOSIGNALS Mammals release an enormous variety of molecules into the environment, either as specific chemosignals or as products of metabolic processes. These range from small volatile molecules to large proteins, and are released by a variety of routes including urine, faeces or the secretions of skin, reproductive tract or specialized scent glands. They provide a wealth of information about the producer, such as their sex, age, health and reproductive state which contribute to the odour profile of the animal. Some of these, such as the 5a-androst16-en-3-one and 5a-androst-16-en-3-ol produced by boars in their saliva, can act as classical pheromones in releasing a specific behavioural response (Brennan & Keverne 2004). Being volatile, these airborne steroids are sensed at a distance by the main olfactory system of sows, in which they elicit approach behaviour and lordosis, to allow mating (Dorries et al. 1997). Other chemosignals, such as those signalling individuality, are components of highly complex mixtures. The main olfactory system is able to integrate the pattern of volatile molecules produced by an animal into an overall odour signature for that individual. However, many of the constituent molecules will be subjected to environmental influences, such as changes in diet, or microbial flora, and may prove unreliable as cues for recognizing the individual on subsequent occasions. There is thus a strong argument that reliable cues for individual discrimination and recognition should be based on differences in individual genotype.

3. GENETIC DETERMINANTS OF CHEMOSENSORY INDIVIDUALITY Although many genotypic differences have the potential to affect chemosensory identity, most interest has focused on the genes of the major histocompatibility complex (MHC). This large and highly polymorphic family of genes is involved in the ability of the immune system to distinguish self from non-self at the cellular level as a defence against invading pathogens. In addition to this immunological role, MHC genotype can determine individual identity at the behavioural level (Boyse et al. 1987). For instance, there is strong evidence that MHC genotype influences the urine odour of mice. In a series of experiments, Yamazaki & Beauchamp’s group trained mice to discriminate between urine from different individuals in a Y maze to obtain a water reward. They showed that mice could discriminate between the urine odours of congenic mice that differed genetically only at the H2 locus of their MHC (Yamaguchi et al. 1981; Yamazaki et al. 1990). Although this odour conditioning procedure required extensive training, untrained mice have also been shown to be capable of similarly fine discriminations using a habituation/dishabituation test (Penn & Potts 1998c). Humans too can discriminate and recognize the odours from different individuals. Fathers, grandmothers and aunts have been shown to be able to identify the odour of a related infant compared with an unrelated one, independent of prior experience with the infant (Porter et al. 1986). Such an ability to identify genetic relatedness through social odours influences mate choice in mice. Studies by Yamazaki et al. (1976, 1988) have demonstrated Phil. Trans. R. Soc. B (2006)

MHC-dependent mate choice in congenic strains of mice differing only in their MHC genotype. When given the choice between two individuals, under laboratory conditions, mice generally choose to mate with the MHC-dissimilar individuals (Jordan & Bruford 1998). This pattern of dissassortative mating has also been observed in colonies of mice living in semi-natural enclosures, which produced fewer MHC homozygous offspring than expected from random matings (Potts et al. 1991). There is even limited evidence that MHC genotype may play a similar role in human mate choice. Genetic analysis of human leukocyte antigen (HLA) haplotype (the human MHC) in reproductively isolated Hutterite communities has found fewer HLA matches than expected, suggesting that they avoid spouses with similar HLA haplotype to their own (Ober et al. 1997). Other studies have found that on average, human subjects rate the odours of other individuals as more pleasant if they have a few matches of HLA alleles, rather than either none or a high degree of similarity (Wedekind & Furi 1997; Jacob et al. 2002). Furthermore, these preferences were based on the matches with only paternally inherited HLA type, suggesting that the preference was dependent on own genotype, rather than having been learnt during exposure to related individuals (Jacob et al. 2002). These findings are consistent with the idea of disassortative mating preferences, but human mate choice is difficult to study and much more work needs to be done in this area to establish whether HLA type plays a significant role in complex human societies. MHC genotype also influences parent–offspring interactions. For instance, although female mice nest communally with other females and nurture each other’s pups indiscriminately, they are more likely to nest with individuals of MHC-similar genotype (Manning et al. 1992). This co-operative behaviour minimizes the delivery of maternal resources to genetically unrelated individuals. Maternal recognition of offspring is not as important as in altricial mammals, such as rodents, where their young are confined to a nest, as it is in mammals that have more mobile, precocial young, such as sheep. Nevertheless, when presented with scattered pups, mice preferentially retrieve those of the same MHC type as themselves (Yamazaki et al. 2000). Furthermore, pups learn from an early age to recognize the odours to which they are exposed in the nest. When tested in a Y maze, mouse pups were found to prefer nest odours of maternal and sibling MHC type rather than an unfamiliar MHC type (Yamazaki et al. 2000).

4. CHEMOSENSORY CUES OF MHC IDENTITY Gas chromatographic analysis of the urinary volatiles from MHC-congenic mice have been shown to differ in the relative proportions of volatile carboxylic acids, which are necessary and sufficient to convey MHCchemosensory identity (Singer et al. 1997; Schaefer et al. 2002). However, despite extensive research and a range of different hypotheses, the mechanism linking the MHC’s role in conveying individuality at the immunological and behavioural levels has remained unclear (Penn & Potts 1998a). The H2 region of mouse chromosome 17 codes for MHC proteins of classical

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Mammalian social odours class I type that are expressed on the cell membrane of nearly all the cells in the body. Their immunological role is to bind peptides produced by the proteosomal degradation of endogenous and foreign proteins and present them to the cell surface, providing the immune system with a dynamic view of intracellular protein composition (Singh 2001). The immune system is able to recognize peptides of endogenous origin as self, whereas peptides derived from foreign proteins activate cytotoxic T lymphocytes and cell destruction. The MHC class I proteins belong to a highly polymorphic gene family with structurally diverse peptide binding grooves. Therefore, a particular MHC class I protein will bind a specific subset of the pool of peptides produced by proteosomal degradation. These are estimated to be up to 100 alleles at the H-2K and H-2D loci, with less polymorphism at the H-2L locus, producing greater than 109 unique phenotypes in outbred mice (Singh 2001). A similar amount of MHC diversity is believed to occur in other mammalian species, implying that each individual within a population essentially has a different MHC genotype, and consequently a unique combination of peptide ligands bound by its MHC class I proteins. The ability of mice to discriminate urine odours of MHC-congenic strains is related to the degree of amino acid divergence in the peptide-binding groove of their MHC class I proteins (Carroll et al. 2002). Several theories have been proposed as to how these differences could be related to differences in the profile of urinary volatiles (Penn & Potts 1998a). According to one hypothesis, differences in profiles of urinary volatiles could arise from endogenous and/or microbial breakdown of the individual-specific pool of MHC-bound peptides, although, as mice are able to distinguish urine odours of germ free mice, it appears that microbial processes are not essential. Another suggestion, known as the carrier hypothesis, proposes that when MHC class I proteins are cleaved from the cell surface, a conformational change causes the peptide to dissociate from the binding cleft. This would enable the MHC class I protein to bind plasma volatiles and transport them into the urine. Differences in the structure of the binding grooves would thus lead to differences in the profile of urinary volatiles. Small, 27 kDa fragments of MHC class I proteins have been found in mouse urine, albeit at low concentrations (Singh et al. 1987), although there is no evidence that they bind volatiles. More recent evidence has shown that the MHC peptide ligands themselves can function as individuality chemosignals, forming a direct link between individuality at the immunological and behavioural levels. These peptides are nine amino acids long in mice, a size determined by proteosomal processing. The major factor determining their binding is large hydrophobic side chains of particular amino acids, known as anchor residues, which occupy characteristic pockets in the MHC-binding groove. The position and shape of two, or rarely three, anchor pockets vary among different MHC class I proteins and determine the specificity of peptide binding. For example, the MHC class I Db molecule encoded by the H-2b haplotype found in C57BL/6 mice, preferentially binds to peptides having asparagine (N) at position 5, such as AAPDNRETF, whereas the Kd Phil. Trans. R. Soc. B (2006)

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Figure 1. MHC class I peptide ligands act as vomeronasal chemosignals of MHC identity owing to the binding characteristics of their anchor residues. Both endogenous and foreign proteins are degraded into nine amino acid peptides by the proteosomal degradation pathway. MHC class I proteins are loaded with the subset of peptides possessing anchor residues that specifically bind to their peptide binding groove. When these peptides are released in body secretions they can act as ligands at the V2R class of vomeronasal receptor, in which the peptide binding specificity is determined by the MHC-dependent positions of their anchor residues.

molecule encoded by the H-2d haplotype found in BALB/c mice, preferentially binds to peptides with tyrosine (Y) at position 2, such as SYFPEITHI. Therefore, any receptor system with similar binding characteristics to the MHC class I molecules will be activated specifically by peptides associated with a certain MHC type (figure 1). Receptors with these binding characteristics have been found in mouse vomeronasal sensory neurons (VSNs) of the V2R class (Leinders-Zufall et al. 2004). Synthetic peptides of BALB/c-type (SYFPEITHI) or C57BL/ 6-type (AAPDNRETF) were found to elicit selective responses from largely separate sub-populations of VSNs. Furthermore, the specificity of the responses was not affected if the amino acid residues between the anchor residues were varied. In contrast, replacement of the characteristic anchor residues with alanines or scrambling the sequence of amino acids to change the locations of the anchor residues both abolished the receptor response. These findings confirm that MHC peptides can signal individual information via the vomeronasal system. This chemosensory system is

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found in most mammals, with the notable exception of Old World primates, including humans. The vomeronasal organ (VNO) is a blind-ended tubular structure situated in the nasal septum and connected to the nasal cavity via a narrow duct (Døving & Trotier 1998). The VSNs are located in the sensory epithelium along the medial side of the lumen with a large blood sinus running laterally. Changes in the blood flow to this sinus result in pressure changes in the lumen, which pumps mucus and chemosignals into the organ (Meredith & O’Connell 1979; Meredith 1994). The vomeronasal system has been shown to convey individuality information in the pregnancy block effect (also known as the Bruce effect). This occurs when recently mated female mice are exposed to urinary chemosignals from an unfamiliar male, which elicits a high incidence of pregnancy failure (Bruce 1959). Although the mating male also produces pregnancyblocking chemosignals in its urine, they do not block its mate’s pregnancy. This is because the female learns to recognize the individual identity of her mate’s urinary chemosignals, during a sensitive period at the time of mating, which prevents them from aborting her offspring (Keverne & de la Riva 1982). Selective lesions of the VNO abolish the pregnancy block effect (Bellringer et al. 1980; Rajendren & Dominic 1984), whereas lesions of the main olfactory epithelium are without effect on pregnancy block or selective recognition of the mating male (Lloyd-Thomas & Keverne 1982; Ma et al. 2002). The biological effectiveness of MHC peptide ligands in conveying strain identity has been demonstrated in the context of the pregnancy block effect (Leinders-Zufall et al. 2004). Addition of C57BL/6 peptides was sufficient to alter the strain identity and confer pregnancy-blocking effectiveness to BALB/c urine, following mating with a BALB/c male, whereas the addition of BALB/c-specific peptides was ineffective. The converse was true for females that had mated with C57BL/6 males. Hence, the addition of BALB/c type peptides to C57BL/6 urine changed its strain identity and caused it to be treated as unfamiliar, resulting in pregnancy failure (LeindersZufall et al. 2004). These results are consistent with earlier findings (Yamazaki et al. 1983) that congenic mice differing from the mating male at only the H2 locus of the MHC were effective in blocking pregnancy. Therefore, these peptides form robust and specific chemosignals of individuality, which may be of importance in other vertebrate species and behavioural contexts. The importance of MHC peptide ligands as potential signals of individuality has been enhanced by the recent finding that they elicit responses in olfactory sensory neurons (OSNs) of the main olfactory epithelium of mice (Spehr et al. 2006). The responses of OSNs to MHC peptide ligands differ from those of VSNs in their dependence on the presence of anchor residues and their lower sensitivity of around 10K10 M, suggesting that different receptor mechanisms are involved. These peptides therefore form robust and specific chemosignals of individuality, which may be of importance in other vertebrate species. However, nine amino acid peptides are unlikely to be very volatile and probably could not account for the discriminability of urine odours at a distance. It therefore appears that there are both peptide and volatile MHC genotype Phil. Trans. R. Soc. B (2006)

signals that are sensed by separate chemosensory systems, and may be used in different behavioural contexts.

5. MAJOR URINARY PROTEINS AND COUNTERMARKING BEHAVIOUR IN MICE The MHC is not the only story when it comes to a genetic basis for chemosensory identity. Members of a lipocalin family of ligand binding proteins are found in body secretions, saliva and urine, and are thought to play a chemosensory signalling role in a variety of species and behavioural contexts. These lipocalins possess a b-barrel structure enclosing a ligand-binding calyx, and they often bind and transport small volatile chemosignals (Flower 1996). This is certainly the case for lipocalins found in rodent urine such as the major urinary proteins (MUPs). The 18–20 kDa MUPs bind small volatile urinary chemosignals including (R,R)-3,4-dehydro-exobrevicomin (DB), (S )-2-sec-butyl-4,5-dihydrothiazole (BT), E,E-a-farnesene, E-b-farnesene and 6-hydroxy-6methyl-3-heptanone (Robertson et al. 1993; Novotny 2003). These testosterone-dependent chemosignals advertize the presence of a reproductively active male. Thus, they elicit aggressive behaviour in male mice (Novotny et al. 1985) and play a role in regulating the reproductive state of females, including the acceleration of puberty (Novotny et al. 1999) and the induction and synchronization of oestrus cycles ( Jemiolo et al. 1986). Male mouse urine contains extremely high concentrations of MUPs of up to 70 mg mlK1, constituting up to 99% of its protein content (Humphries et al. 1999). Therefore, their production represents a significant energetic cost and reflects their important chemosensory role in mouse territorial behaviour. Many animals display territorial behaviour to defend a certain area and its attendant resources from competitors (Wyatt 2003). Individual mammals or groups typically identify their territory by depositing urine, faeces or marks from specialized scent glands throughout their territory, but especially at the boundaries or along major access routes. Such odour signalling has the advantage that the chemical cues are long lasting and are generally less costly than other mechanisms of advertizing their presence. The maintenance of fresh odour marks throughout the territory not only signals the fitness of the producer, but also their identity, allowing an intruder to recognize the territory owner and vice versa. For instance, dominant male mice deposit urine marks throughout their territory and will countermark any marks left by intruder males and can match a urine mark with the individual odour of the male that produced it (Hurst 1993; Hurst et al. 2005). The MUPs in male mouse urine act as a reservoir for volatile chemosignals that attract investigation from females and other males, prolonging their release from dried urine marks (Hurst et al. 1998). However, the countermarking behaviour of males is driven by the non-volatile MUPs rather than the volatiles released from urine marks. Moreover, the MUPs form a highly polymorphic family of genes of which a wild mouse produces between 4 and 15 MUP variants in its urine (Beynon & Hurst 2003). This MUP profile differs among inbred mouse strains in the laboratory and

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Mammalian social odours among individual mice in the wild, forming an identity code with diversity comparable with that of the MHC (Robertson et al. 1997). Indeed, Hurst’s group has demonstrated that MUPs convey the individual ownership of urine marks (Hurst et al. 2001). They showed that changing the MUP profile of urine marks, by the addition of artificially produced MUPs, increased the countermarking rate of territory owners. Moreover, male mouse countermarking behaviour depended on MUP profile rather than MHC genotype. The mechanism by which MUPs signal individuality remains to be resolved. They could potentially influence the profile of volatile urinary chemosignals. However, the fact that male countermarking behaviour is driven by non-volatile components of urine leads to the speculation that they may interact directly with vomeronasal receptors to provide a reliable signal of urine mark identity (Flower 1996). Mouse urine is clearly a complex chemosensory cocktail with MHC-dependent volatile and non-volatile, and MUP-dependent cues, which are each capable of signalling individual identity in different behavioural contexts.

6. CODING OF CHEMOSENSORY INDIVIDUALITY The complex mixture of molecules that constitutes the airborne odour signature of an individual appears to contain few, if any, unique compounds. Rather, it is the relative proportions of common volatiles in the odour profile that convey the information about individual identity (Singer et al. 1997; Schaefer et al. 2002). Such complex odour discrimination tasks can be readily accomplished by the main olfactory system, which is ideally suited for recognizing the profiles of airborne volatiles that constitute an individual odour signature. Each OSN expresses a single receptor protein, which typically responds to a relatively broad range of odourants with related molecular structures. Consequently, each OSN will respond to a range of related odourants, and a single odourant will stimulate OSNs expressing different receptor types. A complex profile of odourants that constitute the odour of an individual will therefore be represented as a pattern of activity across the receptor repertoire. OSNs project their axons to the glomeruli of the main olfactory bulb (MOB) where they provide input to the primary dendrites of mitral and tufted cell projection neurons. Each glomerulus receives input from a single receptor type and therefore acts as a fundamental unit of odour representation. Therefore, individual odour profiles are represented as specific patterns of glomerular activity across the MOB (figure 2; Schaefer et al. 2001, 2002). Indeed, exposure to urine from congenic mice differing in MHC at only the H-2K gene results in patterns of glomerular activity in the MOB that can be distinguished using principal components analysis (Schaefer et al. 2002). The different modes of stimulus access to the main olfactory epithelium and the VNO have the consequence that they are specialized for detecting different types of stimuli. The main olfactory epithelium senses highly volatile stimuli that are carried in the nasal airstream. In contrast, the VNO appears to be specialized to detect relatively non-volatile stimuli, such as peptides and Phil. Trans. R. Soc. B (2006)

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proteins present in skin secretions or scent marks which are only taken into the VNO following direct contact (Wysocki et al. 1985; Luo et al. 2003). The degree of this specialization has recently been called into question, as VSNs respond highly specifically and sensitively to urinary volatiles in vitro (Leinders-Zufall et al. 2000). Furthermore, calcium imaging of VSNs found that they responded to 18 out of a panel of the 82 general odourants tested. This suggests that there is at least the potential for overlap in the chemosignals that are detected by the main olfactory and vomeronasal systems (Sam et al. 2001). If this actually occurs will depend on whether such volatile stimuli gain access to the VNO under normal conditions. Evidence from type-3 adenylyl cyclase knockout mice that lack functional OSNs, but retain functional VSNs, has suggested that this could be the case (Trinh & Storm 2003). These mice show a behavioural response to volatile urinary pheromones, such as 2-heptanone and dimethylpyrazine when presented on a cotton swab without any direct contact. However, the extent to which main olfactory system function is abolished in these mice has been questioned and the behavioural discrimination of these volatile odours could be mediated by atypical OSNs using alternative transduction mechanisms (Lin et al. 2004). Therefore, the ability of volatile stimuli to gain access to the VNO in natural situations remains in doubt. The two classes of vomeronasal receptors that have been identified are seven-transmembrane-domain G-protein coupled receptors, but they share little homology with each other or with main olfactory receptors, which suggests that they may respond to different types of ligand (Herrada & Dulac 1997; Matsunami & Buck 1997; Ryba & Tirindelli 1997). The VSNs expressing receptors from each class are segregated in the vomeronasal epithelium. VSNs that express V1rs are located in the apical zone, whereas V2rexpressing VSNs are found in the deeper basal zone. At least 137 functional receptors of the V1r class have been identified in the mouse genome (Rodriguez et al. 2002) and it has been estimated that there are around 60 functional receptors in the V2r class (Yang et al. 2005). Unlike the OSNs that typically respond to a range of related odourant molecules, VSNs respond highly selectively to specific chemosignals (Leinders-Zufall et al. 2000, 2004). In vitro recordings have revealed that VSNs of the V1r class respond to small volatile molecules, such as 2-heptanone (Boschat et al. 2002) which is found in male mouse urine and extends the length of female oestrus cycles (Novotny 2003). In addition to being highly selective, V1r VSNs are highly sensitive, with typical thresholds of 10K10–10K11 M, and unlike OSNs their selectivity does not broaden as stimulus concentration is increased (Leinders-Zufall et al. 2000). The V2r class of VSNs is even more sensitive and V2rs respond specifically to MHC peptide ligands at concentrations down to 10K13 M (Leinders-Zufall et al. 2004). The structure of V2rs differs from that of the V1Rs in the presence of a large extracellular N-terminal domain (Herrada & Dulac 1997). This accounts for most of the receptor diversity and is likely to form the ligand-binding domain that interacts with MHC peptide ligands. Interestingly, the V2rs are co-expressed with nonclassical MHC Ib proteins, in VSNs in the basal zone of

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Figure 3. Accessory olfactory bulb mitral cells respond selectively to the strain identity of anaesthetized stimulus animals. Significant excitatory responses are indicated in red and significant inhibitory responses are indicated in green. Nonsignificant responses are shown in black and hatched boxes indicate stimulus animals that were not tested. Colour scale at the right represents response indices ranging from K2 to 3. Numbers to the left are identifiers of the individual neurons, some of which were excited by specific strain–sex combinations (7.11–2.8), others by animals of both sexes of a single strain (10.9 and 2.5y). Neuron 9.2x was excited by the majority of stimulus animals and did not show strain specificity. Reprinted with permission from Luo et al. (2003). Copyright 2003 AAAS.

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Figure 2. Distinct patterns of glomerular activity in the main olfactory bulb are found in response to urine odours from mice of difference MHC type. (a) The schematic shows the positional relationship between regions of the main olfactory bulb and the two-dimensional contour maps. Average c-fos glomerular activation patterns in the main olfactory bulbs of H-2d female mice in response to; (b) clean air, (c) H-2b male urine odour and (d ) H-2k male urine odour. Colour bar to the right of b shows the density of active glomeruli for b–d (number of positive glomeruli per bin). (e) Colour contour map of the difference between H-2b and H-2k odour representations assessed by Mann–Whitney U test. Colour bar to the right of e shows the p values. The black border indicates the critical value for the differences to be regarded as significant. Modified with permission from Schaefer et al. (2002). Copyright 2002 by the Society for Neuroscience.

the VNO, suggesting they may have a role in vomeronasal function. There are nine members of the non-classical MHC Ib family, M1, M9, M10.1 to M10.6 and M11 (Loconto et al. 2003; Ishii et al. 2003) with sequence variability concentrated in the region around the peptide binding pocket. Whether they bind MHC peptide ligands is unclear, as several of the amino acid residues that are normally involved in peptide binding are missing (Loconto et al. 2003). However, certain combinations of MHC Ib proteins are expressed with particular V2rs Phil. Trans. R. Soc. B (2006)

(Ishii et al. 2003), and it is tempting to speculate that they might convey innate differences in responsiveness to different MHC types. As expected from their differences in epithelial location and receptor structure, the different classes of VSN expressing either V1rs or V2rs appear to handle different types of vomeronasal information. The V1r class handles chemosensory information of a specific pheromonal nature, conveying signals such as sex, whereas the V2r class conveys information about MHC identity. These two receptor classes are not only segregated at the level of the vomeronasal epithelium, but also project to separate sub-regions of the mouse accessory olfactory bulb (AOB; Halpern et al. 1998). The V1r class of VSNs projects to the anterior subregion, while the V2r class projects to the posterior subregion. In vitro recordings from the guinea-pig AOB have demonstrated that stimulation of the afferents to one sub-regions elicits activity that propagates through that sub-region, but that does not propagate across the anatomical boundary to the other sub-region (Sugai et al. 1997). This suggests that information about MHC identity might be processed separately from other vomeronasal stimuli in the rodent AOB. Unlike the mitral cells in the MOB which project a single primary dendrite to collect information from a single glomerulus (Mombaerts et al. 1996), mitral/ tufted (M/T) projection neurons in the anterior subregion of the AOB send a branched primary dendritic tree that collects information from typically 15–30 glomeruli (Rodriguez et al. 1999; Belluscio et al. 1999). This pattern of connectivity appears to mediate the integration of different types of pheromonal information at the level of the AOB, at least for the V1r class of VSNs (Wagner et al. 2006).

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Mammalian social odours This view is consistent with electrophysiological recordings from the mouse AOB reported by Katz’s group (Luo et al. 2003). Although they found M/T neurons that responded specifically to strain identity regardless of sex of an anaesthetized mouse, many M/T neurons were found to be excited or inhibited by specific combinations of sex and inbred strain identity (figure 3). For instance, a single M/T neuron in the AOB of a CBA male was strongly excited during investigation of a BALB/c male, but did not respond to either a CBA male or a BALB/c female. The same neuron was strongly inhibited during investigation of a CBA female and weakly inhibited in response to a C57/B6 female. It is difficult to see how MHC peptide ligands could convey information about both sex and strain identity of the producer. Therefore, it appears that information about sexual and individual identity is integrated in the AOB, although whether this involves convergent input from V1r and V2r receptor types remains unclear.

7. NEURAL MECHANISMS UNDERLYING INDIVIDUAL RECOGNITION Much of what is known of the neural basis of olfactory learning in mammals has come from studying a small range of species, especially rodents and sheep, in which learning occurs in particular contexts often vital for reproductive success. These not only involve cues for individuality but occur in the context of other arousing sensory signals. Somatosensory stimulation plays an important role in many contexts of olfactory learning. However, attractant chemosignals may also play an important, if subtle, role in olfactory recognition by promoting attention towards the individuality chemosignals that have to be learned (Le´vy et al. 2004). For instance, male mouse urine contains (methylthio) methanethiol, a chemical that is partly responsible for its attractiveness to other mice (Lin et al. 2005). This attraction will promote initial investigation of urine, which will facilitate learning of the individuality cues. Attractant chemosignals are particularly important in the formation of mother offspring bonds, and chemosignals in amniotic fluid appear to play an important role in lamb odour learning in sheep. Amniotic fluid is normally unattractive to sheep but it becomes highly attractive immediately after parturition, a change that is dependent on the associated vaginocervical stimulation (Poindron & Le´vy 1990). Ewes that receive peridural anaesthetic during parturition are not attracted to amniotic fluid, but interestingly the attraction can be induced by intracerebroventricular infusion of oxytocin (OT; Le´vy et al. 1990b). This attraction to amniotic fluid promotes licking of the newborn lamb and facilitates maternal behaviour and the development of selective lamb recognition. Many species of mammal use attractant pheromones to encourage neonates to the nipples for suckling. Perhaps, the most extreme example of this is in rabbits that nurse their young for only a 3–4-min period once a day. A single molecule, identified as 2-methylbut2-enal, is produced in milk and elicits the stereotyped search behaviour that results in the rapid location of Phil. Trans. R. Soc. B (2006)

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the nipples (Schaal et al. 2003). This arousing behavioural context induces learning of the maternal odours by the rabbit pups, which reinforces the nipple search response (Kindermann et al. 1994). The breast odour of human mothers also elicits attraction of newborn babies, which will crawl towards the odour, despite the relative immaturity of their motor system development (Varendi & Porter 2001).

8. NEONATAL ODOUR LEARNING IN RODENTS The preference of mouse pups to approach maternal odours is influenced by neonatal learning, as it can be reversed by cross-fostering (Yamazaki et al. 2000). However, this learning not only forms the basis for their ability to find their way back to their nest as their mobility increases, but it also has longer term effects on their behaviour as adults. MHC-associated mate preferences in adulthood can be reversed by crossfostering neonatal mice to a mother of different MHC type (Yamazaki et al. 1988; Penn & Potts 1998b). Thus, adult mice appear to bias their choice of mate towards dissimilarity from the parental and sibling odours to which they were exposed in the nest environment. The finding that the approach of neonates to maternal odours could not be completely reversed suggests that there may be a component of introspection involved, in which behaviour is influenced by ‘knowledge of self’. Direct evidence for such phenotype matching in rodents is lacking. It has been claimed that hamsters’ investigation of scent marks from different individuals is based on preferences acquired partly through introspection (Mateo & Johnston 2000). However, the hamsters in this study were not cross-fostered until several hours following birth. Therefore, there was a chance for learning of maternal odour to occur perinatally or even in utero. Although the main olfactory system is not fully developed at birth, there is good evidence from many species, including humans, that foetuses can learn in utero about the odours of food eaten by their mothers during gestation. Thus, it is perfectly plausible that mammals could also learn odours associated with maternal MHC type in utero. The neural mechanisms underlying neonatal olfactory learning have been investigated using a conditioning procedure to artificial odours that mimics the natural learning of maternal and sibling nest odours (Wilson & Sullivan 1994). The licking and grooming of rat pups by their mother acts as a strong unconditioned stimulus for learning of maternal and sibling odours. This can be conveniently studied in a laboratory environment by placing rat pups in a beaker with peppermint scented wood shavings (conditioned stimulus) and stroking them for a few minutes with a paintbrush (unconditioned stimulus). When tested with a choice of the peppermint-scented pine shavings versus unscented pine shavings, the neonates spent more time over the conditioned peppermint odour compared with naive pups. This has features of classical conditioning, as learning does not occur in the backward pairing condition in which the stroking occurs before odour exposure. This form of learning only occurs during a developmentally determined

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sensitive period before postnatal day 10. After this time, stroking loses its ability to act as an unconditioned stimulus (Woo & Leon 1987). The unconditioned stimulus of tactile stimulation increases noradrenaline (NA) release in the MOB of neonatal rats by centrifugal fibres from the locus ceruleus (Rangel & Leon 1995). This noradrenergic transmission is necessary for learning to occur, as lesions of the noradrenergic fibres to the MOB prevent odour conditioning (Sullivan et al. 1989). Similarly, odour conditioning is prevented by local infusions of the b-noradrenergic antagonist propranolol into the MOB during the odour conditioning procedure (Sullivan et al. 1992). The association of increased NA release in the MOB and odour input results in substantial morphological and functional changes at the glomerular level, which are restricted to consistently located odour ‘hotspots’ (Coopersmith & Leon 1984). Following odour conditioning, the activity of mitral cells in these hotspots is more likely to be suppressed than excited in response to the conditioned odour. In contrast, mitral cells recorded in the hotspots of control animals were more likely to be excited rather than suppressed in response to the same odour (Wilson et al. 1987). This suggests that the inhibitory input to mitral cells from local inhibitory interneurons is increased following learning in response to the conditioned odour. Stroking results in a higher and more prolonged release of NA in the MOB prior to postnatal day 10, when tactile stimulation is effective as an unconditioned stimulus. Furthermore, whereas local infusions of acetylcholine into the locus ceruleus stimulate the release of NA in the MOB before postnatal day 10, they lose their effectiveness after this sensitive period (Moriceau & Sullivan 2004). The change in neonatal odour conditioning around postnatal day 10 coincides with an increase in the ratio of a2–a1 noradrenergic receptors in the locus ceruleus. This would act to limit the duration of locus ceruleus neuronal activity in response to tactile stimulation and consequently reduce the amount of NA released in MOB by stroking (Moriceau & Sullivan 2004). This developmental change is associated with the functional maturation of other, more sophisticated, learning systems. In adults, pairing an odour with an aversive consequence such as a mild shock leads to the subsequent avoidance of the odour. However, pairing odour and shock in neonatal rats younger than postnatal day 10 leads to a lasting odour preference. This makes sense biologically as rat pups depend on the relationship with their mother for their early survival. Even if their mother treats them roughly, they cannot afford to form an aversion to her or her odour as they depend on her maternal care and the safe environment of the nest. The developmental changes to the neonatal brain around day 10 include the onset of amygdala function and the appearance of innate fear responses and fear conditioning, so that aversive stimuli such as footshock now support aversive conditioning (Sullivan et al. 2000). These are required when their visual, auditory and motor systems have developed enough to move away from the security of the nest for short periods. Phil. Trans. R. Soc. B (2006)

9. LAMB-ODOUR RECOGNITION IN SHEEP Unlike maternal care in rodents, where their pups are born at an early stage of development and are confined to a nest, sheep give birth to precocial young that are able to stand and move within a few hours of birth. Being seasonal breeders, a large number of lambs are born over the same period. Although they show some evidence for being able to recognize their own mother within the first 12 h after birth using a combination of odour, vocal and visual cues, they need 2–4 weeks to become completely proficient at doing so and will often try to suckle from other ewes (Kendrick 1994). Therefore, the mother has to have a highly efficient system for recognizing her own lamb and allow it to suckle, while rejecting the suckling attempts of ‘strange’ lambs (Poindron & Le´ vy 1990). This discrimination of own from strange lambs is vital for restricting the ewe’s maternal resources to her own offspring and is mediated primarily by olfactory cues from their wool and skin. If the olfactory bulbs or the olfactory epithelium is lesioned, selectivity is lost and a ewe will accept any lamb. In contrast, cutting the vomeronasal nerve does not affect maternal selectivity, implying that the olfactory cues involved in lamb recognition are mediated by the main olfactory system (Le´vy et al. 1995b). The ewe learns about the odour of her newborn lamb during a sensitive period of 2–4 h following parturition. After this period, the ewe becomes increasingly selective and will accept suckling attempts from only her own lamb. This olfactory learning and the maternal acceptance behaviour are dependent on the hormonal environment of late gestation, but are triggered by the mechanical stimulation of the vagina and cervix that occurs during parturition (Keverne et al. 1983). Thus, a new sensitive period for lamb acceptance can be induced by vaginocervical stimulation 2–3 days following parturition (Kendrick & Keverne 1991). The development of maternal behaviour is facilitated by the odour of the amniotic fluid, which the ewe licks off the lamb immediately after birth. Washing lambs to remove the amniotic fluid reduces maternal licking behaviour and disrupts the acceptance of lambs by inexperienced ewes (Le´vy & Poindron 1987). Conversely, applying amniotic fluid to a 1-day-old lamb increases its chance of acceptance by a parturient ewe. Vaginocervical stimulation occurring during parturition increases the release of NA from locus ceruleus afferents in the MOB, which plays an essential role in odour learning (Le´vy et al. 1993). Both specific noradrenergic lesions of the MOB using 6-hydroxydopamine (Pissonier et al. 1985) and the infusion of the b-noradrenergic antagonist propranolol into the MOB, during the sensitive period, prevent the selective recognition of the ewe’s own lamb (Le´vy et al. 1990a). Oxytocin release in the MOB also increases at birth and is likely to facilitate the learning process by enhancing the release of NA in the MOB (Kendrick 2000). There is also a role for the nitric oxide signalling pathway in the development of the selective response to own lamb odour. Neuronal nitric oxide synthase (nNOS) is present in the granule cells of the sheep MOB and can act as a retrograde messenger to enhance

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Mammalian social odours glutamate release from the mitral cells via soluble guanylyl cyclase (SGC). Inhibition of this pathway by MOB infusions of inhibitors of nNOS or SGC prevents the selective recognition of own lamb odours (Kendrick et al. 1997). The effects of NOS, but not SGC inhibition, can then be reversed by localized infusions of nitric oxide donors (Kendrick et al. 1997). Lamb odour learning is associated with dramatic changes in the electrophysiology and neurochemistry of the MOB. Kendrick et al. (1992) found that before parturition, the majority of mitral cells in a defined area of the MOB responded most strongly to food odours and none responded preferentially to lamb odours. However, when mitral cell responses were recorded from the same region of the MOB following parturition, the vast majority (60%) of them now showed a preferential response to lamb odours with some showing a preferential response to own lamb odour. Furthermore, in vivo microdialysis monitoring of neurotransmitter levels in the MOB showed that before parturition lamb odours have little effect on the release of any bulbar neurotransmitters. However, following parturition and the establishment of maternal selectivity, own lamb odour, but not the odour of a strange lamb, induced a significant increase in the release of both the excitatory amino acid glutamate and the inhibitory transmitter g-aminobutyric acid (GABA) (Kendrick et al. 1992). Moreover, the ratio of glutamate to GABA was significantly lower in response to own lamb odour compared with strange lamb odour, suggesting that inhibitory neurotransmission in the MOB is increased in response to own lamb odour. The first maternal experience has lasting consequences, as the development of selective recognition of the ewe’s own lamb occurs more rapidly for subsequent births (Keverne et al. 1993; Kendrick 1994). This is reflected in the release of intrinsic MOB neurotransmitters (dopamine, GABA and glutamate), as well as modulatory neurotransmitters (acetylcholine and NA), and peptides (OT and vasopressin), which depends on previous maternal experience (Le´vy et al. 1993, 1995a). In particular, NA levels only increase around 2 h following the first birth, suggesting that vaginocervical stimulation is not as efficient at stimulating NA release as it is in experienced ewes (Le´vy et al. 1995a). The process of bonding with their offspring after the first birth therefore induces lasting changes in the MOB circuitry. This may well involve up regulation of OT receptors (Le´vy et al. 1993) thereby sensitizing the system to vaginocervical stimulation and shortening the time taken to develop a selective response at subsequent births. Certainly, mRNA expression for the OT receptor is significantly enhanced in a number of brain regions as a function of maternal experience (Broad et al. 1999).

10. THE ROLE OF THE MOB IN SOCIAL RECOGNITION Neonatal odour conditioning in rats and lamb odour learning in sheep occur in behavioural contexts that are vital for reproductive success. In both cases learning is contingent on somatosensory stimulation, which evokes increased NA release in the MOB, and is associated with extensive neural changes at the level of Phil. Trans. R. Soc. B (2006)

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AON PIR

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hypothalamus Figure 4. Schematic of the major projections of the main olfactory system and the vomeronasal system in the rat. Selected second order connections are shown to highlight the interconnectivity of the two chemosensory pathways at the level of the amygdala and their convergence on outputs to the hypothalamus and BNST (Pitka¨nen 2000). Abbreviations: ACo, anterior cortical nucleus; AOB, accessory olfactory bulb; AON, anterior olfactory nucleus; BAOT, bed nucleus of the accessory olfactory tract; BNST, bed nucleus of the stria terminalis; ENT, entorhinal cortex; Me, medial nucleus; MOB, main olfactory bulb; MOE, main olfactory epithelium; NLOT, nucleus of the lateral olfactory tract; OT, olfactory tubercle; PIR, piriform cortex; PMCo, posterior medial cortical nucleus; PLCo, posterior lateral cortical nucleus; VNO, vomeronasal organ.

the MOB. A common feature of these changes is the increased inhibitory control of MOB mitral cells in response to the learned olfactory stimulus (Brennan & Keverne 2000). These forms of olfactory learning are somewhat specialized in that they occur during a defined sensitive period. However, similar neurochemical changes have been reported to occur in the MOB following a simple appetitive odour conditioning procedure in adult mice (Brennan et al. 1998). Changes in the inhibitory control of mitral cells in the MOB therefore appear to be a general feature of odour learning, but an understanding of how these changes are involved in odour recognition requires a consideration of the network properties of the MOB. In addition to their single primary dendrite, mitral cells in the vertebrate MOB possess an extensive secondary dendritic tree. This extends tangentially over a large area of the MOB making reciprocal dendrodendritic synapses at spines on granule cell inhibitory interneurons (Mori et al. 1983). This neural architecture is highly suited for mediating lateral inhibitory interactions with the surrounding mitral cells, as has been demonstrated in the rabbit MOB (Yokoi et al. 1995). Lateral inhibition is further

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facilitated by the presence of mGluR2 receptors on the granule cell side of reciprocal synapses which locally inhibit GABA release at spines receiving mitral cell input (Bischofberger & Schild 1996). These reduce selfinhibition while permitting lateral inhibition onto neighbouring mitral cells that are less active. Electroencephalogram (EEG) recordings from the surface of the rabbit MOB have provided evidence for learningdependent changes in the pattern of activity in the MOB (Freeman & Schneider 1982). The global pattern of EEG activity across the MOB was observed to change during learning. However, once an odour had become specifically associated with a behavioural response, the pattern was invariant for succeeding odour presentations. Moreover, when the reward contingencies of the odour changed, the pattern of EEG activity elicited by the odour also changed, generating a new odour response pattern specific for the learned odour. There is also evidence for a role of the granule cells in synchronizing the activity of mitral cells activated by different odourant features, which could facilitate their binding as a single odour representation at the level of the piriform cortex (Kashiwadani et al. 1999; Wilson & Stevenson 2003). Changes in the efficacy of inhibitory control of mitral neurons by granule inhibitory interneurons could therefore change the spatial pattern, temporal pattern or synchrony of the mitral cells that respond to an odour. This is hypothesized to play an important role in odour learning by pulling apart the bulbar representations of similar odours, enabling them to be discriminated more reliably. For example, prior to parturition sheep do not have to make fine discriminations between lamb odours, as they have the same meaning to the animal and are largely ignored. However, following parturition, the failure to discriminate between the odours of her own and alien lambs would be highly undesirable. The change in the MOB representation of own lamb odour following parturition, would differentiate it from representations of the highly similar odours of alien lambs, and increase the reliability with which it is linked to a different behavioural response by more central brain areas.

11. VOMERONASAL MECHANISMS OF MATE RECOGNITION The ability of a female mouse to recognize the pheromones of the male with which she has mated is one of the simplest examples of social recognition (Brennan et al. 1990; Brennan & Keverne 1997). Exposure of a recently mated female mouse to the urinary chemosignals of an unfamiliar male causes a high rate of pregnancy failure, but this does not occur when she is exposed to the pheromones of the mating male, as she is able to recognize her mate’s chemosignals (Bruce 1961). Learning her mate’s identity occurs during a sensitive period lasting a few hours immediately after mating and is contingent on the vaginocervical stimulation of coitus (Rosser & Keverne 1985). The pregnancy block effect depends on a testosterone-dependent chemosignal in male mouse urine, as pregnancy-blocking effectiveness is lost following castration (Bruce 1965) and restored by testosterone injections (Hoppe 1975). Such hormonal Phil. Trans. R. Soc. B (2006)

manipulations would not be expected to affect the production of MHC peptide ligands, suggesting that pregnancy-blocking effectiveness and the individual identity are likely to be conveyed by separate chemosignals. Both the pregnancy block effect and ability of females to recognize the male with which they mated are mediated solely by the vomeronasal system (LloydThomas & Keverne 1982; Ma et al. 2002). However, there is also evidence for a luteotrophic effect of male exposure, which lasts up to 7 days following mating and is mediated by the main olfactory system (Archunan & Dominic 1990; Acharya & Dominic 1997). This cannot explain the mate recognition in the pregnancy block effect which lasts for at least 30 days after mating (Kaba et al. 1988), far longer than the recognition underlying the luteotrophic effect. Nevertheless, it suggests that the main olfactory and vomeronasal systems may have synergistic roles in mediating mate recognition in mice. The vomeronasal pathway forms a relatively direct route by which chemosensory stimuli mediate effects on endocrine state and reflexive behaviour. The M/T neurons of the AOB receive input from the VSNs and project on to the cortico-medial regions of the amygdala, then via the medial hypothalamus to the tuberoinfundibular dopaminergic (TIDA) neurons in the arcuate nucleus of the hypothalamus (Li et al. 1989, 1990, 1992). Activation of this pathway by pregnancyblocking chemosignals results in dopamine release from the TIDA neurons, which inhibits prolactin production by the anterior pituitary (Reynolds & Keverne 1979; Ryan & Schwartz 1980; Marchelwska-Koj 1983). As prolactin is luteotrophic in mice, the fall in serum prolactin withdraws luteotrophic support, leading to the failure of progesterone production by the corpora lutea. This change in hormonal state prevents implantation of the developing embryos and causes the female to return to oestrus (Parkes & Bruce 1961; Dominic 1966). Thus, male chemosignals are only effective at blocking pregnancy when the exposure is coincident with the twice-daily peaks of prolactin during the vulnerable preimplantation period (Rosser et al. 1989). Similarly, electrical stimulation of the AOB is effective in blocking pregnancy, but again only when it is timed to coincide with the prolactin surges (Li et al. 1994). The locus for the neural changes underlying mate recognition has been established by infusing the local anaesthetic lignocaine into each site along the vomeronasal pathway, to temporarily disrupt neural activity during the sensitive period for memory formation (Kaba et al. 1989). Infusions of lignocaine into the corticomedial amygdala were without effect on memory formation, whereas recognition of the mating male was prevented when lignocaine was infused into the AOB. Along with the necessary control procedures, these experiments imply that the neural changes underlying mate recognition occur in the AOB, at the first level of processing of the chemosensory information. The synaptic circuitry of the AOB is comparatively simple (Mori 1987). M/T cells receive vomeronasal nerve input from multiple glomeruli and project to the cortico-medial amygdala. They form reciprocal dendrodendritic synapses with inhibitory interneurons at two levels in the AOB. Periglomerular interneurons

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Mammalian social odours provide feedback inhibition onto M/T neurons at the glomerular level, while granule cell interneurons provide feedback inhibition on their primary dendritic tree. Granule cell dendritic spines are depolarized by excitatory glutamatergic input from M/T neurons, providing lateral inhibition between M/T neurons and feedback inhibition onto the same M/T neurons via GABA release at their reciprocal synapses. Mate recognition can therefore be explained by an increased efficacy of the reciprocal synapses of the sub-population of M/T neurons responding to the mating male (Brennan et al. 1990; Kaba & Nakanishi 1995). This would result in a long-lasting increase in feedback inhibition onto the sub-population of M/T neurons receiving the mating male’s chemosignal. The outcome would be to selectively disrupt the mating male’s pheromonal signal at the level of the AOB, preventing it from reaching the hypothalamus and blocking pregnancy. Chemosignals from an unfamiliar male would activate a different sub-population of M/T neurons that were not subjected to the enhanced feedback inhibition and would convey the pregnancyblocking signal unimpeded. This long-standing hypothesis is consistent with recent findings that M/T neurons in the AOB are excited highly selectively in response to males of individual inbred strains (figure 3). Furthermore, M/T neurons are subjected to powerful and highly selective inhibition (Luo et al. 2003). This may be a consequence of the morphology of AOB M/T neurons, which differ from MOB mitral cells both in their highly branched primary dendritic tree and in lacking an extensive lateral dendritic tree. Inhibitory feedback is provided by granule cell inhibitory neurons at reciprocal synapses on the primary dendritic tree of the M/T neurons, where it is ideally located to inhibit the transmission of information from individual glomeruli (Mori et al. 1987). The external plexiform and granule cell layers of the AOB receive a dense noradrenergic innervation from the locus ceruleus, which is activated by the vaginocervical stimulation at mating. This increases NA release in the AOB for at least 4 h following mating, signalling that mating has occurred (Rosser & Keverne 1985; Brennan et al. 1995). 6-Hydroxydopamine lesions of NA fibres or local infusions of the a-noradrenergic antagonist phentolamine into the AOB have demonstrated a vital role for NA in this learning. Both of these treatments prevent memory formation and subsequent recognition of the mating male (Rosser & Keverne 1985; Kaba & Keverne 1988). Although NA plays a vital role in olfactory learning in both the MOB and AOB, the pharmacology of its effects differs. The primary role of NA in the AOB is likely to be an a2 mediated suppression of the GABAmediated granule cell inhibition of M/T neurons, similar to that observed in cultured MOB neurons (Trombley & Shepherd 1992). This would be consistent with the effect of vaginocervical stimulation in causing disinhibition of spontaneous M/T neuron activity in the AOB of anaesthetized mice (Otsuka et al. 2001). The NA-induced disinhibition of M/T neurons is hypothesized to result in a long-lasting enhancement of Phil. Trans. R. Soc. B (2006)

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the glutamatergic synapses onto granule cells. This can be mimicked by local infusions of the GABAA-receptor antagonist bicuculline into the AOB, which disinhibit M/T neurons by blocking the feedback inhibition from granule cells. This widespread pharmacological disinhibition of M/T neurons leads to the formation of a non-specific memory without mating, so that all males are recognized as familiar (Kaba et al. 1989). In the natural memory formation process, the disinhibition of M/T cells is likely to be more selective owing to the action of mGluR2 metabotropic glutamate receptors, which are expressed at high levels by granule cells. These mGluR2 receptors presynaptically inhibit the release of GABA from granule cells receiving M/T input and therefore selectively disinhibit the M/T neurons responding to the mating male chemosignals (Hayashi et al. 1993). Hence, local infusions of the mGluR2 agonist (2S,1 0 R,2 0 R,3 0 R)-2-(2,3-dicarboxycyclopropyl) glycine (DCG-IV) into the AOB, during exposure to male chemosignals, promote the formation of a selective memory for that male without mating having occurred (Kaba et al. 1994). The importance of the granule cell side of the reciprocal synapses as the locus for memory induction is supported by experiments involving infusions of nonselective ionotropic glutamate antagonists into the AOB during the sensitive period after mating. These prevent memory formation, despite causing the disinhibition of M/T neurons, as they prevent ionotropic glutamatergic input to granule cells (Brennan & Keverne 1989; Brennan 1994). Memory formation can also be prevented by local infusions the calmodulin inhibitor calmidazolium into the AOB (Nakazawa et al. 1995), suggesting that in common with other examples of synaptic plasticity, the level of Ca2C within the spine is likely to be the important trigger for memory induction. Nitric oxide is also likely to play a role in memory formation, as granule cells of the AOB have one of the highest levels of NOS of any region of the mouse brain (Bredt et al. 1991). Inhibition of NOS activity does not disrupt memory formation as it does in the sheep MOB (Brennan & Kishomoto 1993; Okere et al. 1995). However, infusions of the nitric oxide donor sodium nitroprusside into the AOB during exposure to male chemosignals result in the formation of a selective memory without mating (Okere et al. 1996). Therefore, although nitric oxide is not essential, it does appear to facilitate memory formation in the AOB. The hypothesis that mate recognition involves an increase in the inhibitory feedback onto M/T neurons at reciprocal synapses is supported by investigations of the neurochemical changes in the AOB following learning (Brennan et al. 1995; Brennan & Binns 2005). Following mating, exposure chemosignals from the mating male resulted in a significant decrease in the ratio of excitatory to inhibitory neurotransmitters, compared with females that had received the same chemosensory exposure without mating. Consistent with this, the length of postsynaptic densities of the glutamatergic synapses on granule cells has been found to increase following learning (Matsuoka et al. 1997). Interestingly, this change in the glutamatergic side of the reciprocal synapse is only apparent during the first

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5 days after mating, after which the length of the GABAergic postsynaptic densities onto M/T neurons increased (Matsuoka et al. 2004). These changes lasted until day 20 following mating but had declined by day 50, mirroring the time course of the memory for the mating male. Increases in efficacy of both the excitatory and inhibitory sides of the reciprocal synapses have the same overall effect of increasing the inhibitory feedback to M/T neurons. As in the MOB, this tight inhibitory feedback in the AOB results in oscillatory properties of the network, which would be expected to have the effect of synchronizing M/T activity and their output to central brain areas. Oscillations in the gamma frequency range have been observed in recordings from slices of guinea pig AOB in vitro, which were mediated by GABAergic inhibition from local interneurons (Sugai et al. 1999). Changes in the inhibitory gain of the reciprocal synapses in the AOB associated with learning might therefore be speculated to involve changes in the synchrony or frequency of such network activity, which could impair the activation of neurons downstream in the cortico-medial amygdala. This might provide a subtle way of disrupting the transmission of the pregnancy-blocking signal without completely inhibiting M/T neuron activity at the level of the AOB (Taylor & Keverne 1991). Recent evidence has shown that oscillations of the local field potential recorded from the AOB do change following learning (Binns & Brennan 2005). The differential responses to chemosignals from the mating compared with an unfamiliar male, are consistent with increased granule cell inhibition of the mate’s signal. Furthermore, individual neurons in the medial amygdala were found to respond more strongly to urine from an unfamiliar male than the mating male (Binns & Brennan 2005). This is consistent with the reduced c-Fos expression found in the medial amygdala in response to the mating male chemosignals compared with those from an unfamiliar male (Halem et al. 2001). These findings provide further support for the hypothesis that the pregnancy-blocking signal from the mating male is selectively suppressed at the level of the AOB and therefore less effective in activating neurons at the level of the corticomedial amygdala that elicit pregnancy block.

12. CENTRAL AREAS INVOLVED IN OLFACTORY RECOGNITION OF INDIVIDUALS The importance of the corticomedial amygdala and the peptide OT in handling social information in adult animals is apparent from tests of social recognition in rodents. Many variants of this test are used in a variety of rodent species. They generally involve an adult male, which will readily investigate a juvenile or ovariectomized female that is introduced to its cage for a period of ca 5 min. The stimulus animal is then removed and reintroduced after a delay of ca 30 min. If the male is able to recognize the reintroduced animal as familiar, it shows a decreased amount of investigation compared with the first encounter with the animal or to the high level of investigation to a novel animal. In rats, this is a relatively short-term memory Phil. Trans. R. Soc. B (2006)

that decays over a period of around an hour, so that by ca 120 min, following the first exposure, the reintroduced animal is investigated as intensively as a novel animal. However, in mice kept in a social environment, the memory can be maintained for a week or more (Kogan et al. 2000). OT is crucial for the processing of these social odours, as OT knockout mice fail to recognize the reintroduced animal as familiar (Ferguson et al. 2000). However, this ability to recognize the familiar animal is rescued by infusions of OT into the medial amygdala (Ferguson et al. 2001). Furthermore, infusions of an OT antagonist into the medial amygdala but not the MOB of wild-type mice prevent recognition. Although these findings point to the important role played by the OT in the corticomedial amydgala in social recognition, the duration of the memory in rats can be extended to 120 min by infusing OT into the MOB (Dluzen et al. 2000). This effect of oxytocin is likely to be mediated by enhancing the release of NA in the MOB, which acts to prolong the duration of the memory via a-noradrenergic receptors, perhaps involving a disinhibition of mitral cell activity. Therefore, although OT release in the MOB appears to enhance social recognition, the crucial site for its action is the medial amygdala. The importance of the corticomedial amygdala has also been shown in the context of selective maternal bonding in sheep. Medial and corticomedial amygdala infusions of lignocaine were found to disrupt lamb recognition in ewes, in that they were still maternal but no longer selective (Keller et al. 2004). These findings reflect the fact that the cortical and medial nuclei of the amygdala form a hub in the networks governing mammalian social behaviour. Although c-Fos expression has been found to increase in the anterior medial amygdala of hamsters in response to both conspecific and heterospecific chemosensory stimuli, the posterior medial amygdala was found to respond only to socially relevant conspecific stimuli (Meredith & Westberry 2004). There are considerable species differences in the afferent projections to the medial amygdala, but in most mammals they receive a predominantly chemosensory input. In mice, the separate streams of vomeronasal information from anterior and posterior sub-regions of the AOB converge in completely overlapping projections to the corticomedial amygdala, the bed nucleus of the accessory olfactory tract and the bed nucleus of the stria terminalis (von Campenhausen & Mori 2000). The corticomedial amygdala is interconnected with the main olfactory pathway and is therefore a major site for the integration of V1r, V2r and main olfactory information (figure 4). Moreover, the high levels of expression of steroid receptors in this area also make it sensitive to hormonal state. Consequently, whereas VNO lesions disrupt mating behaviour in sexually naive hamsters, such lesions are ineffective following sexual experience as mating behaviour can be sustained by the main olfactory system. Thus, odours conveyed by the main olfactory system may become associated with vomeronasal stimuli, at the level of the medial amygdala, and may

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subsequently become sufficient to drive the same behavioural response (Meredith 1998). The main olfactory system also sends projections to the hippocampus via the entorhinal cortex and to the frontal cortex. These regions, together with the piriform cortex, show enhanced expression of genes associated with neural plasticity, such as brain-derived nerve growth factor (BDNF) and its receptor trk-B following the development of lamb recognition in sheep (Broad et al. 2002). A number of studies in rodents have reported that formation of long-term social and nonsocial recognition memories requires an intact hippocampus or pathways projecting to it (Maaswinkel et al. 1996; Kogan et al. 2000). However, individual recognition by male hamsters in the context of the Coolidge effect (i.e. ability to distinguish a novel from a familiar female) has been found to be disrupted by lesions of the perirhinal and entorhinal cortices but not the hippocampus (Petrulis & Eichenbaum 2003). Neurons in the entorhinal cortex of hamsters have been reported to be responsive to individual social odours (Petrulis et al. 2005). Furthermore, temporary inactivation of the entorhinal cortex using the anaesthetic tetracaine prevents selective recognition of lambs by maternal ewes but without disrupting maternal behaviour. However, after consolidation of the memory, similar inactivation of the entorhinal cortex does not prevent recognition (Sa´nchez-Andrade et al. 2005). There is enhanced activation (c-Fos protein expression) in the frontal cortex of maternal ewes in response to their own lambs after memory consolidation (Keller et al. 2004). However, this may have more to do with strengthening of perception-action patterns, since temporary inactivation of the medial prefrontal cortex has been found to disrupt a maternal ewe’s ability to show selective recognition, in terms of her motor response (aggression towards strange lambs), but not to prevent memory formation per se (Broad et al. 2002). While the role of central projections of the main olfactory system in social recognition memory still requires further clarification, it is clear at this stage that multiple systems downstream of the olfactory bulbs and piriform cortex are initially involved, including the corticomedial amygdala, entorhinal, perirhinal and frontal cortex, and possibly the hippocampus as well. Post-consolidation maintenance of the recognition memory seems to become restricted to the olfactory bulb and piriform cortex, and the links between the frontal cortex and systems controlling motor and motivational responses. In contrast, in the vomeronasal system only the AOB seems to be of importance in all phases of the social recognition process. However, it seems probable that with recognition systems involving both vomeronasal and main olfactory systems, AOB projections to the corticomedial amygdala may also be important.

recognition of individuals. There is no single means of signalling this individuality information, but rather a variety of complementary systems, based on highly polymorphic genetic loci that are adapted for use in different behavioural contexts, such as mate choice or territorial marking. The vomeronasal system has long been thought of as specialized to sense pheromonal signals using labelled line systems to engage relatively simple stereotyped responses. However, this view has been rethought in light of the evidence that the main olfactory system also conveys highly specific pheromonal information via labelled lines. Conversely, the vomeronasal system is able to convey information about MHC individuality as effectively as the main olfactory system. So can the roles of the main olfactory and vomeronasal systems be neatly summarized? Maybe not presently, but there do at least seem to be common themes related to the means of stimulus access. The main olfactory system is specialized to sense volatile molecules present in the nasal airstream and therefore at a distance. In contrast, the vomeronasal system is specialized to pump in relatively non-volatile stimuli following direct contact with the stimulus source. Of course, individual chemosignals may be able to stimulate both systems, such as the mouse urinary volatiles that when dissociated from MUPs can be sensed as volatile signals by the main olfactory system, but that can be taken up into the VNO when tightly bound by MUPs. The two systems have complimentary roles in mediating the effects of social chemosignals. Volatile attractant chemosignals, sensed via the main olfactory system, drive more direct investigation that enables non-volatile cues to be taken up and analysed by the vomeronasal system. The recognition of individuals depends on learning their chemosensory profile, which involves changes at all levels of neural processing. The involvement of noradrenaline release in the olfactory bulb in inducing sensitive periods is a common feature of olfactory learning across different species and different behavioural contexts. Changes in the inhibitory control of the mitral cell projection neurons following learning may be a common feature to differentiate odour representations that need to be reliably discriminated. However, olfactory learning must also involve changes in odour processing at more central levels, including the pivotal role of the corticomedial amygdala in integrating social information from different sensory systems and hormonal states. Finally, although the sense of smell is often relegated to a minor role in human social communication, evidence is starting to accumulate that odours have not lost the ability to influence human behaviour. The extent to which social odours play a role in modern human society is an open but intriguing question for future research.

13. CONCLUSIONS Mammals produce complex mixtures of social chemosignals that are still poorly understood. Single molecules can act as pheromones exerting specific control over physiology and behaviour, while genetically determined cocktails of molecules enable the

REFERENCES

Phil. Trans. R. Soc. B (2006)

Acharya, K. K. & Dominic, C. J. 1997 Duration of the luteotrophic memory of the stud male odors formed in the female mouse. J. Exp. Zool. 279, 626–632. (doi:10.1002/ (SICI)1097-010X(19971215)279:6!626::AID-JEZ11O 3.0.CO;2-)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2074

P. A. Brennan & K. M. Kendrick

Mammalian social odours

Archunan, G. & Dominic, C. J. 1990 Stud male protection of implantation food-deprived mice: evaluation of the involvement of olfactory–vomeronasal systems. Exp. Clin. Endocrinol. 96, 30–36. Bellringer, J. F., Pratt, H. P. M. & Keverne, E. B. 1980 Involvement of the vomeronasal organ and prolactin in pheromonal induction of delayed implantation in mice. J. Reprod. Fert. 59, 223–228. Belluscio, L., Koentges, G., Axel, R. & Dulac, C. 1999 A map of pheromone receptor activation in the mammalian brain. Cell 97, 209–220. (doi:10.1016/S0092-8674(00)80731-X) Beynon, R. J. & Hurst, J. L. 2003 Multiple roles of major urinary proteins in the house mouse, Mus domesticus. Biochem. Soc. Trans. 31, 142–146. Binns, K. E. & Brennan, P. A. 2005 Changes in electrophysiological activity in the accessory olfactory bulb and medial amygdala associated with mate recognition in mice. Eur. J. Neurosci. 21, 2529–2537. (doi:10.1111/ j.1460-9568.2005.04090.x) Bischofberger, J. & Schild, D. 1996 Glutamate and N-acetylaspartylglutamate block HVA calcium currents in frog olfactory bulb interneurons via an mGluR2/3-like receptor. J. Neurophysiol. 76, 2089–2092. Boschat, C., Pe´lofi, C., Randin, O., Roppolo, D., Lu¨scher, C., Broillet, M. & Rodriguez, I. 2002 Pheromone detection mediated by a V1r vomeronasal receptor. Nat. Neurosci. 5, 1261–1262. (doi:10.1038/nn978) Boyse, E. A., Beauchamp, G. K. & Yamazaki, K. 1987 The genetics of body scent. Trends Genet. 3, 97–102. (doi:10. 1016/0168-9525(87)90192-2) Bredt, D. S., Glatt, C. E., Hwang, P. M., Fotuhi, M., Dawson, T. M. & Snyder, S. H. 1991 Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 7, 615–624. (doi:10. 1016/0896-6273(91)90374-9) Brennan, P. A. 1994 The effects of local inhibition of N-methyl-D-aspartate and AMPA/kainate receptors in the accessory olfactory bulb on the formation of an olfactory memory in mice. Neuroscience 60, 701–708. (doi:10.1016/0306-4522(94)90498-7) Brennan, P. A. & Binns, E. K. 2005 Vomeronasal mechanisms of mate recognition in mice. Chem. Senses 30, i148–i149. (doi:10.1093/chemse/bjh157) Brennan, P. A. & Keverne, E. B. 1989 Impairment of olfactory memory by local infusions of non-selective excitatory amino acid receptor antagonists into the accessory olfactory bulb. Neuroscience 33, 463–468. (doi:10.1016/0306-4522(89)90398-9) Brennan, P. A. & Keverne, E. B. 1997 Neural mechanisms of mammalian olfactory learning. Prog. Neurobiol. 51, 457–481. (doi:10.1016/S0301-0082(96)00069-X) Brennan, P. A. & Keverne, E. B. 2000 Neural mechanisms of olfactory recognition memory. In Brain, perception, memory. Advances in cognitive neuroscience (ed. J. J. Bolhuis), pp. 93–112. Oxford, UK: Oxford University Press. Brennan, P. A. & Keverne, E. B. 2004 Something in the air? New insights into mammalian pheromones. Curr. Biol. 14, R81–R89. (doi:10.1016/j.cub.2003.12.052) Brennan, P. A. & Kishomoto, J. 1993 Local inhibition of nitric oxide synthase activity in the accessory olfactory bulb does not prevent the formation of an olfactory memory in mice. Brain Res. 619, 306–312. (doi:10.1016/ 0006-8993(93)91625-3) Brennan, P., Kaba, H. & Keverne, E. B. 1990 Olfactory recognition: a simple memory system. Science 250, 1223–1226. (doi:10.1126/science.2147078) Brennan, P. A., Kendrick, K. M. & Keverne, E. B. 1995 Neurotransmitter release in the accessory olfactory bulb Phil. Trans. R. Soc. B (2006)

during and after the formation of an olfactory memory in mice. Neuroscience 69, 1075–1086. (doi:10.1016/03064522(95)00309-7) Brennan, P. A., Schellinck, H. M., de la Riva, C., Kendrick, K. M. & Keverne, E. B. 1998 Changes in neurotransmitter release in the main olfactory bulb following an olfactory conditioning procedure in mice. Neuroscience 87, 583–590. (doi:10.1016/S0306-4522(98)00182-1) Broad, K. D., Le´vy, F., Evans, G., Kimura, T., Keverne, E. B. & Kendrick, K. M. 1999 Previous maternal experience potentiates the effect of parturition on oxytocin receptor mRNA expression in the paraventricular nucleus. Eur. J. Neurosci. 11, 3725–3737. (doi:10.1046/j.1460-9568. 1999.00782.x) Broad, K. D., Hinton, M. R., Keverne, E. B. & Kendrick, K. M. 2002 Involvement of the medial prefrontal cortex in mediating behavioural responses to odour cues rather than olfactory recognition memory. Neuroscience 114, 715–729. (doi:10.1016/S0306-4522(02)00231-2) Bruce, H. 1959 An exteroceptive block to pregnancy in the mouse. Nature 184, 105. (doi:10.1038/184105a0) Bruce, H. M. 1961 Time relations in the pregnancy-block induced in mice by strange males. J. Reprod. Fert. 2, 138–142. Bruce, H. M. 1965 Effect of castration on the reproductive pheromones of male mice. J. Reprod. Fert. 10, 141–143. Carroll, L. S., Penn, D. J. & Potts, W. K. 2002 Discrimination of MHC-derived odors by untrained mice is consistent with divergence in peptide-binding region residues. Proc. Natl Acad. Sci. USA 99, 2187–2192. (doi:10.1073/pnas. 042244899) Coopersmith, R. & Leon, M. 1984 Enhanced neural responses to familiar olfactory cues. Science 225, 849–851. (doi:10.1126/science.6474157) Dluzen, D. E., Muraoka, S., Engelmann, M., Ebner, K. & Landgraf, R. 2000 Oxytocin induces preservation of social recognition in male rats by activating alpha adrenoreceptors of the olfactory bulb. Eur. J. Neurosci. 12, 760–766. (doi:10.1046/j.1460-9568.2000.00952.x) Dominic, C. J. 1966 Observations on the reproductive pheromones of mice: II neuroendocrine mechanisms involved in the olfactory block to pregnancy. J. Reprod. Fert. 11, 415–421. Dorries, K. M., Adkins, R. E. & Halpern, B. P. 1997 Sensitivity and behavioral responses to the pheromone androstenone are not mediated by the vomeronasal organ in domestic pigs. Brain Behav. Evol. 49, 53–62. Døving, K. B. & Trotier, D. 1998 Structure and function of the vomeronasal organ. J. Exp. Biol. 21, 2913–2925. Ferguson, J. N., Young, L. J., Hearn, E. F., Matzuk, M. M., Insel, T. R. & Winslow, J. T. 2000 Social amnesia in mice lacking the oxytocin gene. Nat. Genet. 25, 284–288. (doi:10.1038/77040) Ferguson, J. N., Aldag, J. M., Insel, T. R. & Young, L. J. 2001 Oxytocin in the medial amygdala is essential for social recognition in the mouse. J. Neurosci. 21, 8278–8285. Flower, D. R. 1996 The lipocalin protein family: structure and function. Biochem. J. 318, 1–14. Freeman, W. J. & Schneider, W. 1982 Changes in spatial patterns of rabbit olfactory EEG with conditioning to odours. Psychophysiology 19, 44. Halem, H. A., Cherry, J. A. & Baum, M. J. 2001 Central forebrain responses to familiar male odors are attenuated in recently mated female mice. Eur. J. Neurosci. 13, 389–399. (doi:10.1046/j.1460-9568.2001.01382.x) Halpern, M., Jia, C. P. & Shapiro, L. S. 1998 Segregated pathways in the vomeronasal system. Micros. Res. Tech. 41, 519–529. (doi:10.1002/(SICI)1097-0029(19980615)41:6 !519::AID-JEMT7O3.0.CO;2-H)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Mammalian social odours Hayashi, Y., Momiyama, A., Takahashi, T., Ohishi, H., Ogawa, M. R., Shigemoto, R., Mizuno, N. & Nakanishi, S. 1993 Role of a metabotropic glutamate receptor in synaptic modulation in the accessory olfactory bulb. Nature 366, 687–690. (doi:10.1038/366687a0) Herrada, G. & Dulac, C. 1997 A novel family of putative pheromone receptors in mammals with a topographically organized and sexually dimorphic distribution. Cell 90, 763–773. (doi:10.1016/S0092-8674(00)80536-X) Hoppe, P. C. 1975 Genetic and endocrine studies of the pregnancy-blocking pheromone of mice. J. Reprod. Fert. 45, 109–115. Humphries, R. E., Robertson, D. H. L., Beynon, R. J. & Hurst, J. L. 1999 Unravelling the chemical basis of competitive scent marking in house mice. Anim. Behav. 58, 1177–1190. (doi:10.1006/anbe.1999.1252) Hurst, J. L. 1993 The priming effects of urine substrate marks on interactions between male house mice Mus musculus domesticus Schwarz & Schwarz. Anim. Behav. 45, 55–81. (doi:10.1006/anbe.1993.1007) Hurst, J. L., Robertson, D. H. L., Tolladay, U. & Beynon, R. J. 1998 Proteins in urine scent marks of male house mice extend the longevity of olfactory signals. Anim. Behav. 55, 1289–1297. (doi:10.1006/anbe.1997.0650) Hurst, J. L., Payne, C. E., Nevison, C. M., Marie, A. D., Humphries, R. E., Robertson, D. H. L., Cavaggioni, A. & Beynon, R. J. 2001 Individual recognition in mice mediated by major urinary proteins. Nature 414, 631–634. (doi:10.1038/414631a) Hurst, J. L., Thom, M. D., Nevison, C. M., Humphries, R. E. & Beynon, R. J. 2005 MHC odours are not required or sufficient for recognition of individual scent owners. Proc. R. Soc. B 272, 715–724. (doi:10.1098/rspb.2004. 3004) Ishii, T., Hirota, J. & Mombaerts, P. 2003 Combinational coexpression of neural and immune multigene families in mouse vomeronasal sensory systems. Curr. Biol. 13, 394–400. (doi:10.1016/S0960-9822(03)00092-7) Jacob, S., McClintock, M. K., Zelano, B. & Ober, C. 2002 Paternally inherited HLA alleles are associated with women’s choice of male odor. Nat. Genet. 30, 175–179. (doi:10.1038/ng830) Jemiolo, B., Harvey, S. & Novotny, M. 1986 Promotion of the Whitten effect in female mice by synthetic analogs of male urinary constituents. Proc. Natl Acad. Sci. USA 83, 4576–4579. (doi:10.1073/pnas.83.12.4576) Jordan, W. C. & Bruford, M. W. 1998 New perspectives on mate choice and the MHC. Heredity 81, 127–133. (doi:10. 1046/j.1365-2540.1998.00428.x) Kaba, H. & Keverne, E. B. 1988 The effect of microinfusions of drugs into the accessory olfactory bulb on the olfactory block to pregnancy. Neuroscience 25, 1007–1011. (doi:10. 1016/0306-4522(88)90053-X) Kaba, H. & Nakanishi, S. 1995 Synaptic mechanisms of olfactory recognition memory. Rev. Neurosci. 6, 125–141. Kaba, H., Rosser, A. E. & Keverne, E. B. 1988 Hormonal enhancement of neurogenesis and its relationship to the duration of olfactory memory. Neuroscience 24, 93–98. (doi:10.1016/0306-4522(88)90314-4) Kaba, H., Rosser, A. & Keverne, E. B. 1989 Neural basis of olfactory memory in the context of pregnancy block. Neuroscience 32, 657–662. (doi:10.1016/0306-4522(89) 90287-X) Kaba, H., Hayashi, Y., Higuchi, T. & Nakanishi, S. 1994 Induction of an olfactory memory by the activation of a metabotropic glutamate receptor. Science 265, 262–264. (doi:10.1126/science.8023145) Kashiwadani, H., Sasaki, Y. F., Uchida, N. & Mori, K. 1999 Synchronized oscillatory discharges of mitral/tufted cells Phil. Trans. R. Soc. B (2006)

P. A. Brennan & K. M. Kendrick

2075

with different molecular receptive ranges in the rabbit olfactory bulb. J. Neurophysiol. 82, 1786–1792. Keller, M., Perrin, G., Meurisse, M., Ferreira, G. & Le´vy, F. 2004 Cortical and medial amygdala are both involved in the formation of olfactory offspring memory in sheep. Eur. J. Neurosci. 20, 3433–3441. (doi:10.1111/j.1460-9568. 2004.03812.x) Kendrick, K. M. 1994 Neurobiological correlates of visual and olfactory recognition in sheep. Behav. Processes 33, 89–112. (doi:10.1016/0376-6357(94)90061-2) Kendrick, K. M. 2000 Oxytocin, motherhood and bonding. Exp. Physiol. 85S, 111S–124S. Kendrick, K. M. & Keverne, E. B. 1991 Importance of vaginocervical stimulation for the formation of maternal bonding in primiparous and multiparous parturient ewes. Physiol. Behav. 50, 595–600. (doi:10.1016/0031-9384(91) 90551-X) Kendrick, K. M., Levy, F. & Keverne, E. B. 1992 Changes in sensory processing of olfactory signals induced by birth in sheep. Science 256, 833–836. (doi:10.1126/ science.1589766) Kendrick, K. M., Guevara-Guzman, R., Zorilla, J., Hinton, M. R., Broad, K. D., Mimmack, M. & Ohkura, S. 1997 Formation of olfactory memories mediated by nitric oxide. Nature 388, 670–674. (doi:10.1038/41765) Keverne, E. B. & de la Riva, C. 1982 Pheromones in mice: reciprocal interaction between the nose and brain. Nature 296, 148–150. (doi:10.1038/296148a0) Keverne, E. B., Le´vy, F., Poindron, P. & Lindsay, D. R. 1983 Vaginal stimulation: an important determinant of maternal bonding in sheep. Science 219, 81–83. (doi:10. 1126/science.6849123) Keverne, E. B., Le´vy, F., Guevara-Guzman, R. & Kendrick, K. M. 1993 Influence of birth and maternal experience on olfactory bulb neurotransmitter release. Neuroscience 56, 557–565. (doi:10.1016/0306-4522(93)90356-K) Kindermann, U., Hudson, R. & Distel, H. 1994 Learning of suckling odors by newborn rabbits declines with age and suckling experience. Dev. Psychobiol. 27, 111–122. (doi:10.1002/dev.420270205) Kogan, J. H., Frankland, P. W. & Silva, A. J. 2000 Longterm memory underlying hippocampus-dependent social recognition in mice. Hippocampus 10, 45–56. (doi:10. 1002/(SICI)1098-1063(2000)10:1!47::AID-HIPO5O 3.0.CO;2-6) Leinders-Zufall, T., Lane, A. P., Puche, A. C., Ma, W., Novotny, M. V., Shipley, M. T. & Zufall, F. 2000 Ultrasensitive pheromone detection by mammalian vomeronasal neurons. Nature 405, 792–796. (doi:10. 1038/35015572) Leinders-Zufall, T. et al. 2004 MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306, 1033–1037. (doi:10.1126/science.1102818) Le´vy, F. & Poindron, P. 1987 The importance of amniotic fluids for the establishments of maternal behavior in experienced and inexperienced ewes. Anim. Behav. 35, 1188–1192. (doi:10.1016/S0003-3472(87)80175-6) Le´vy, F., Gervais, R., Kindermann, U., Orgeur, P. & Piketty, V. 1990a Importance of b-noradrenergic receptors in the olfactory bulb of sheep for recognition of lambs. Behav. Neurosci. 104, 464–469. (doi:10.1037/0735-7044.104.3.464) Le´vy, F., Keverne, E. B., Piketty, V. & Poindron, P. 1990b Physiological determinism of olfactory attraction for amniotic fluids in sheep. In Chemical signals in vertbrates, vol. 5 (ed. D. W. MacDonald, D. Mu¨ller-Schwartze & S. E. Natynczuck), pp. 162–165. Oxford, UK: Oxford University Press. Le´vy, F., Guevara, G. R., Hinton, M. R., Kendrick, K. M. & Keverne, E. B. 1993 Effects of parturition and maternal

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2076

P. A. Brennan & K. M. Kendrick

Mammalian social odours

experience on noradrenaline and acetylcholine release in the olfactory bulb of sheep. Behav. Neurosci. 107, 662–668. (doi:10.1037/0735-7044.107.4.662) Le´vy, F., Kendrick, K. M., Goode, J. A., Guevara-Guzman, R. & Keverne, E. B. 1995a Oxytocin and vasopressin release in the olfactory bulb of parurient ewes: changes with maternal experience and effects of acetylcholine, g-aminobutyric acid, glutamate and noradrenaline release. Brain Res. 669, 197–206. (doi:10.1016/00068993(94)01236-B) Le´vy, F., Locatelli, A., Piketty, V., Tillet, Y. & Poindron, P. 1995b Involvement of the main but not the accessory olfactory system in maternal behaviour of primiparous and multiparous ewes. Physiol. Behav. 57, 97–104. (doi:10. 1016/0031-9384(94)00200-O) Le´vy, F., Keller, M. & Poindron, P. 2004 Olfactory regulation of maternal behavior in mammals. Horm. Behav. 46, 284–302. (doi:10.1016/j.yhbeh.2004.02.005) Li, C. S., Kaba, H., Saito, H. & Seto, K. 1989 Excitatory influence of the accessory olfactory bulb on tuberoinfundibular arcuate neurons of female mice and its modulation by oestrogen. Neuroscience 29, 201–208. (doi:10.1016/ 0306-4522(89)90343-6) Li, C. S., Kaba, H., Saito, H. & Seto, K. 1990 Neural mechanisms underlying the action of primer pheromones in mice. Neuroscience 36, 773–778. (doi:10.1016/03064522(90)90019-Z) Li, C. S., Kaba, H., Saito, H. & Seto, K. 1992 Cholecystokinin: critical role in mediating olfactory influences on reproduction. Neuroscience 48, 707–713. (doi:10.1016/ 0306-4522(92)90413-V) Li, C. S., Kaba, H. & Seto, K. 1994 Effective induction of pregnancy block by electrical stimulation of the mouse accessory olfactory bulb coincident with prolactin surges. Neurosci. Lett. 176, 5–8. (doi:10.1016/0304-3940(94) 90857-5) Lin, W., Arellano, J., Slotnick, B. & Restrepo, D. 2004 Odors detected by mice deficient in cyclic nucleotide-gated channel subunit A2 stimulate the main olfactory system. J. Neurosci. 24, 3703–3710. (doi:10.1523/JNEUROSCI. 0188-04.2004) Lin, D. Y., Zhang, S.-Z., Block, E. & Katz, L. C. 2005 Encoding social signals in the mouse main olfactory bulb. Nature 434, 470–477. (doi:10.1038/nature03414) Lloyd-Thomas, A. & Keverne, E. B. 1982 Role of the brain and accessory olfactory system in the block to pregnancy in mice. Neuroscience 7, 907–913. (doi:10.1016/03064522(82)90051-3) Loconto, J., Papes, F., Chang, E., Stowers, L., Jones, E. P., Takada, T., Kumanovics, A., Fischer-Lindahl, K. & Dulac, C. 2003 Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class 1b molecules. Cell 112, 607–618. (doi:10.1016/S0092-8674(03)00153-3) Luo, M. M., Fee, M. S. & Katz, L. C. 2003 Encoding pheromonal signals in the accessory olfactory bulb of behaving mice. Science 299, 1196–1201. (doi:10.1126/ science.1082133) Ma, D., Allen, N. D., Van Bergen, Y. C. H., Jones, C. M. E., Baum, M. J., Keverne, E. B. & Brennan, P. A. 2002 Selective ablation of olfactory receptor neurons without functional impairment of vomeronasal receptor neurons in OMP-ntr transgenic mice. Eur. J. Neurosci. 16, 2317–2323. (doi:10.1046/j.1460-9568.2002.02303.x) Maaswinkel, H., Baars, A.-M., Gispen, W.-H. & Spruijt, B. M. 1996 Roles of the basolateral amygdala and hippocampus in social recognition in rats. Physiol. Behav. 60, 55–63. (doi:10.1016/0031-9384(95)02233-3) Phil. Trans. R. Soc. B (2006)

Manning, C. J., Wakeland, E. K. & Potts, W. K. 1992 Communal nesting patterns in mice implicate MHC genes in kin recognition. Nature 360, 581–583. (doi:10.1038/ 360581a0) Marchelwska-Koj, A. 1983 Pregnancy blocking by pheromones. In Pheromones and reproduction in mammals (ed. J. G. Vandenbergh), pp. 113–174. New York, NY: Academic Press. Mateo, J. M. & Johnston, R. E. 2000 Kin recognition and the “armpit effect”: evidence of self-referent phenotype matching. Proc. R. Soc. B 267, 695–700. (doi:10.1098/ rspb.2000.1058) Matsunami, H. & Buck, L. B. 1997 A multigene family encoding a diverse array of putative pheromone receptors in mammals. Cell 90, 775–784. (doi:10.1016/S00928674(00)80537-1) Matsuoka, M., Kaba, H., Mori, Y. & Ichikawa, M. 1997 Synaptic plasticity in olfactory memory formation in female mice. Neuroreport 8, 2501–2504. Matsuoka, M., Kaba, H., Moriya, K., Yoshida-Matsuoka, J., Costanzo, R. M., Norita, M. & Kchikawa, M. 2004 Remodeling of reciprocal synapses associated with persistence of long-term memory. Eur. J. Neurosci. 19, 1668–1672. (doi:10.1111/j.1460-9568.2004.03271.x) Meagher, S., Penn, D. J. & Potts, W. K. 2000 Male-male competition magnifies inbreeding depression in wild house mice. Proc. Natl Acad. Sci. USA 97, 3324–3329. (doi:10.1073/pnas.060284797) Meredith, M. & O’Connell, R. J. 1979 Efferent control of stimulus access to the hamster vomeronasal organ. J. Physiol. 286, 301–316. Meredith, M. & Westberry, J. M. 2004 Distinctive responses in the medial amygdala to same-species and differentspecies pheromones. J. Neurosci. 24, 5719–5725. (doi:10. 1523/JNEUROSCI.1139-04.2004) Meredith, M. 1994 Chronic recording of vomeronasal pump activation in awake behaving hamsters. Physiol. Behav. 56, 345–354. (doi:10.1016/0031-9384(94)90205-4) Meredith, M. 1998 Vomeronasal, olfactory, hormonal convergence in the brain. Ann. NY Acad. Sci. 855, 349–361. (doi:10.1111/j.1749-6632.1998.tb10593.x) Mombaerts, P., Wang, F., Dulac, C., Chao, S. K., Nemes, A., Mendelsohn, M., Edmondson, J. & Axel, R. 1996 Visualizing an olfactory sensory map. Cell 87, 675–686. (doi:10.1016/S0092-8674(00)81387-2) Mori, K. 1987 Membrane and synaptic properties of identified neurons in the olfactory bulb. Prog. Neurobiol. 29, 275–320. (doi:10.1016/0301-0082(87)90024-4) Mori, K., Kishi, K. & Ojima, H. 1983 Distribution of dendrites of mitral, displaced mitral, tufted, and granule cells in the rabbit olfactory bulb. J. Comp. Neurol. 219, 339–335. (doi:10.1002/cne.902190308) Mori, K., Imamura, K., Fujita, S. C. & Obuta, K. 1987 Projections of two subclasses of vomeronasal nerve fibers to the accessory olfactory bulb in the rabbit. Neuroscience 20, 259–278. (doi:10.1016/0306-4522(87)90018-2) Moriceau, S. & Sullivan, R. M. 2004 Unique neural circuitry for neonatal olfactory learning. J. Neurosci. 24, 1182–1189. (doi:10.1523/JNEUROSCI.4578-03.2004) Nakazawa, H., Kaba, H., Higuchi, T. & Inoue, S. 1995 The importance of calmodulin in the accessory olfactory bulb in the formation of an olfactory memory in mice. Neuroscience 69, 585–589. (doi:10.1016/0306-4522(95) 00293-R) Novotny, M. V. 2003 Pheromones, binding proteins and receptor responses in rodents. Biochem. Soc. Trans. 31, 117–122. Novotny, M., Harvey, S., Jemiolo, B. & Alberts, J. 1985 Synthetic pheromones that promote inter-male aggression

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Mammalian social odours in mice. Proc. Natl Acad. Sci. USA 82, 2059–2061. (doi:10.1073/pnas.82.7.2059) Novotny, M. V., Weidong, M., Wiesler, D. & Zidek, L. 1999 Positive identification of the puberty-accelerating pheromone of the house mouse: the volatile ligands associating with the major urinary protein. Proc. R. Soc. B 266, 2017–2022. (doi:10.1098/rspb.1999.0880) Ober, C., Weitkamp, L. R., Cox, N., Dytch, H., Kostyu, D. & Elias, S. 1997 HLA and mate choice in humans. Am. J. Hum. Genet. 61, 497–504. (doi:10.1017/S00034800 97006532) Okere, C. O., Kaba, H. & Higuchi, T. 1995 Failure of intrabulbar and peripheral administration of N u-nitro-Larginine to prevent the formation of an olfactory memory in mice. Physiol. Behav. 58, 387–391. (doi:10.1016/00319384(95)00074-S) Okere, C. O., Kaba, H. & Higuchi, T. 1996 Formation of an olfactory recognition memory in mice: reassessment of the role of nitric oxide. Neuroscience 71, 349–354. (doi:10. 1016/0306-4522(95)00467-X) Otsuka, T., Ishii, K., Osako, Y., Okutani, F., Taniguchi, M., Oka, T. & Kaba, H. 2001 Modulation of dendrodendritic interactions and mitral cell excitability in the mouse accessory olfactory bulb by vaginocervical stimulation. Eur. J. Neurosci. 13, 1833–1838. (doi:10.1046/j.0953816x.2001.01557.x) Parkes, A. S. & Bruce, H. M. 1961 Olfactory stimuli in mammalian reproduction. Science 134, 1049–1054. (doi:10.1126/science.134.3485.1049) Penn, D. & Potts, W. 1998a How do major histocompatibility complex genes influence odor and mating preferences? Adv. Immunol. 69, 411–436. Penn, D. & Potts, W. 1998b MHC-disassortative mating preferences reversed by cross-fostering. Proc. R. Soc. B 265, 1299–1306. (doi:10.1098/rspb.1998.0433) Penn, D. & Potts, W. K. 1998c Untrained mice discriminate MHC-determined odors. Physiol. Behav. 63, 235–243. (doi:10.1016/S0031-9384(98)00052-3) Petrulis, A. & Eichenbaum, H. 2003 The perirhinal–entorhinal cortex, but not the hippocampus, is critical for expression of individual recognition in the context of the Coolidge effect. Neuroscience 122, 599–607. (doi:10.1016/ j.neuroscience.2003.08.009) Petrulis, A., Alvarez, P. & Eichenbaum, H. 2005 Neural correlates of social odor recognition and the representation of individual distinctive social odors within entorhinal cortex and ventral subiculum. Neuroscience 130, 259–274. (doi:10.1016/j.neuroscience.2004.09.001) Pissonier, D., Thiery, J. C., Fabre-Nys, C., Poindron, P. & Keverne, E. B. 1985 The importance of olfactory bulb noradrenalin for maternal recognition in sheep. Physiol. Behav. 35, 361–363. (doi:10.1016/0031-9384(85)90309-9) Pitka¨nen, A. 2000 Connectivity of the rat amygdaloid complex. In The amygdala (ed. J. P. Aggleton), pp. 31–115. Oxford, UK: Oxford University Press. Poindron, P. & Le´vy, F. 1990 Physiological, sensory, and experiential determinants of maternal behavior in sheep. In Mammalian parenting (ed. N. A. Krasnegor & R. S. Bridges), pp. 133–156. Oxford, UK: Oxford University Press. Porter, R. H., Balogh, R. D., Cernoch, J. M. & Franchi, C. 1986 Recognition of kin through characteristic body odors. Chem. Sens. 11, 389–395. Potts, W. K., Manning, C. J. & Wakeland, E. K. 1991 Mating patterns in seminatural populations of mice influenced by MHC genotype. Nature 352, 619–621. (doi:10.1038/ 352619a0) Rajendren, G. & Dominic, C. J. 1984 Role of the vomeronasal organ in the male-induced implantation Phil. Trans. R. Soc. B (2006)

P. A. Brennan & K. M. Kendrick

2077

failure (the Bruce effect) in mice. Arch. Biol. (Bruxelles) 95, 1–9. Rangel, S. & Leon, M. 1995 Early odor preference training increases olfactory bulb norepinephrine. Dev. Brain Res. 85, 187–191. (doi:10.1016/0165-3806(94)00211-H) Reynolds, J. & Keverne, E. B. 1979 The accessory olfactory system and its role in the pheromonally mediated suppression of oestrus in grouped mice. J. Reprod. Fert. 57, 31–55. Robertson, D. H. L., Beynon, R. J. & Evershed, R. P. 1993 Extraction, characterization and binding analysis of two pheromonally active ligands associated with major urinary proteins of house mouse (Mus Musculus). J. Chem. Ecol. 19, 1405–1416. (doi:10.1007/BF00984885) Robertson, D. H. L., Hurst, J. L., Bolgar, M. S., Gaskell, S. J. & Beynon, R. J. 1997 Molecular heterogeneity of urinary proteins in wild house mouse populations. Rap. Comm. Mass Spec. 11, 786–790. (doi:10.1002/(SICI)1097-0231 (19970422)11:7!786::AID-RCM876O3.0.CO;2-8) Rodriguez, I., Feinstein, P. & Mombaerts, P. 1999 Variable patterns of axonal projections of sensory neurons in the mouse vomeronasal system. Cell 97, 199–208. (doi:10. 1016/S0092-8674(00)80730-8) Rodriguez, I., Del Punta, K., Rothman, A., Ishii, T. & Mombaerts, P. 2002 Multiple new and isolated families within the mouse superfamily of V1r vomeronasal receptors. Nat. Neurosci. 5, 134–140. (doi:10.1038/nn795) Rosser, A. & Keverne, E. B. 1985 The importance of central noradrenergic neurones in the formulation of an olfactory memory in the prevention of pregnancy block. Neuroscience 15, 1141–1147. (doi:10.1016/0306-4522(85)90258-1) Rosser, A. E., Remfry, C. J. & Keverne, E. B. 1989 Restricted exposure of mice to primer pheromones coincident with prolactin surges blocks pregnancy by changing hypothalamic dopamine release. J. Reprod. Fert. 87, 553–559. Ryan, K. D. & Schwartz, N. B. 1980 Changes in serum hormone levels associated with male-induced ovulation in group housed female mice. Endocrinology 105, 959–966. Ryba, N. J. P. & Tirindelli, R. 1997 A new multigene family of putative pheromone receptors. Neuron 19, 371–379. (doi:10.1016/S0896-6273(00)80946-0) Sam, M., Vora, S., Malnic, B., Ma, W., Novotny, M. V. & Buck, L. B. 2001 Odorants may arouse instinctive behaviours. Nature 412, 142. (doi:10.1038/35084137) Sa´nchez-Andrade, G., James, B. M. & Kendrick, K. M. 2005 Neural encoding of olfactory recognition memory. J. Reprod. Dev. 51, 547–558. Schaal, B., Coureaud, G., Langlois, D., Ginie`s, C., Se´mon, E. & Perrier, G. 2003 Chemical and behavioural characterization of the rabbit mammary pheromone. Nature 424, 68–72. (doi:10.1038/nature01739) Schaefer, M. L., Young, D. A. & Restrepo, D. 2001 Olfactory fingerprints for major histocompatibility complexdetermined body odors. J. Neurosci. 21, 2481–2487. Schaefer, M. L., Yamazaki, K., Osada, K., Restrepo, D. & Beauchamp, G. K. 2002 Olfactory fingerprints for major histocompatibility complex-determined body odors II: relationship among odor maps, genetics, odor composition, and behavior. J. Neurosci. 22, 9513–9521. Singer, A. G., Beauchamp, G. K. & Yamazaki, K. 1997 Volatile signals of the major histocompatibility complex in male mouse urine. Proc. Natl Acad. Sci. USA 94, 2210–2214. (doi:10.1073/pnas.94.6.2210) Singh, P. B. 2001 Chemosensation and genetic individuality. Reproduction 121, 529–539. (doi:10.1530/rep.0.1210529) Singh, P. B., Brown, R. E. & Roser, B. 1987 MHC antigens in urine as olfactory recognition cues. Nature 327, 161–164. (doi:10.1038/327161a0) Spehr, M., Kelliher, K. R., Li, X.-H., Boehm, T., LeindersZufall, T. & Zufall, F. 2006 Essential role of the main

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2078

P. A. Brennan & K. M. Kendrick

Mammalian social odours

olfactory system in social recognition of major histocompatibility complex peptide ligands. J. Neurosci. 26, 1961–1970. Sugai, T., Sugitani, M. & Onoda, N. 1997 Subdivisions of the guinea pig accessory olfactory bulb revealed by the combined method with immunohistochemistry, electrophysiological, and optical recordings. Neuroscience 79, 871–885. (doi:10.1016/S0306-4522(96)00690-2) Sugai, T., Sugitani, M. & Onoda, N. 1999 Effects of GABAergic agonists and antagonists on oscillatory signal propagation in the guinea pig accessory olfactory bulb slice revealed by optical recording. Eur. J. Neurosci. 11, 2773–2782. (doi:10.1046/j.1460-9568.1999.00694.x) Sullivan, R. M., Wilson, D. A. & Leon, M. 1989 Norepinephrine and learning-induced plasticity in infant rat olfactory system. J. Neurosci. 9, 3998–4006. Sullivan, R. M., Zyzak, D. R., Skierkowski, P. & Wilson, D. A. 1992 The role of olfactory bulb norepinephrine in early olfactory learning. Dev. Brain Res. 70, 279–282. (doi:10. 1016/0165-3806(92)90207-D) Sullivan, R. M., Landers, M., Yeaman, B. & Wilson, D. A. 2000 Good memories of bad events in infancy: ontogeny of conditioned fear and the amygdala. Nature 407, 38–39. (doi:10.1038/35024156) Taylor, J. G. & Keverne, E. B. 1991 Accessory olfactory learning. Biol. Cybern. 64, 301–306. (doi:10.1007/BF00 199593) Trinh, K. & Storm, D. R. 2003 Vomeronasal organ detects odorants in absence of signaling through main olfactory epithelium. Nat. Neurosci. 6, 519–525. Trombley, P. Q. & Shepherd, G. M. 1992 Noradrenergic inhibition of synaptic transmission between mitral and granule cells in mammalian olfactory bulb cultures. J. Neurosci. 12, 3985–3991. Varendi, H. & Porter, R. H. 2001 Breast odour as the only maternal stimulus elicits crawling towards the odour source. Acta Paediatr. 90, 372–375. (doi:10.1080/080352501750 126131) von Campenhausen, H. & Mori, K. 2000 Convergence of segregated pheromonal pathways from the accessory olfactory bulb to the cortex in the mouse. Eur. J. Neurosci. 12, 33–46. (doi:10.1046/j.1460-9568.2000. 00879.x) Wagner, S., Gresser, A. L., Torello, A. T. & Dulac, C. 2006 A multireceptor genetic approach uncovers an ordered integration of VNO sensory inputs in the accessory olfactory bulb. Neuron 50, 679–709. Wedekind, C. & Furi, S. 1997 Body odour preferences in men and women: do they aim for specific MHC combinations or simply heterozygosity? Proc. R. Soc. B 264, 1471–1479. (doi:10.1098/rspb.1997.0204) Wilson, D. A. & Stevenson, R. J. 2003 The fundamental role of memory in olfactory perception. Trends Neurosci. 26, 243–247. (doi:10.1016/S0166-2236(03)00076-6)

Phil. Trans. R. Soc. B (2006)

Wilson, D. A. & Sullivan, R. M. 1994 Neurobiology of associative learning in the neonate: early olfactory learning. Behav. Neural Biol. 61, 1–18. (doi:10.1016/S0163-1047(05) 80039-1) Wilson, D. A., Sullivan, R. M. & Leon, M. 1987 Single-unit analysis of postnatal olfactory learning: modified olfactory bulb output response patterns to learned attractive odors. J. Neurosci. 7, 3154–3162. Woo, C. C. & Leon, M. 1987 Sensitive period for neural and behavioral response development to learned odors. Dev. Brain Res. 36, 309–313. (doi:10.1016/0165-3806(87) 90038-1) Wyatt, T. D. 2003 Pheromones and animal behaviour. Cambridge, UK: Cambridge University Press. Wysocki, C. J., Beauchamp, G. K., Reidinger, R. R. & Wellington, J. L. 1985 Access of large and nonvolatile molecules to the vomeronasal organ of mammals during social and feeding behaviours. J. Chem. Ecol. 11, 1147–1159. (doi:10.1007/BF01024105) Yamaguchi, M., Yamazaki, K., Beauchamp, G. K., Bard, J., Thomas, L. & Boyse, E. A. 1981 Distinctive urinary odors governed by the major histocompatibility locus of the mouse. Proc. Natl Acad. Sci. USA 78, 5817–5820. (doi:10. 1073/pnas.78.9.5817) Yamazaki, K., Boyse, E. A., Mike´, V., Thaler, H. T., Mathieson, B. J., Abbott, J., Boyse, J., Zayas, Z. A. & Thomas, L. 1976 Control of mating preferences in mice by genes in the major histocompatibility complex. J. Exp. Med. 144, 1324–1335. (doi:10.1084/jem.144.5.1324) Yamazaki, K., Beauchamp, G. K., Wysocki, C. J., Bard, J., Thomas, L. & Boyse, E. A. 1983 Recognition of H-2 types in relation to the blocking of pregnancy in mice. Science 221, 186–188. (doi:10.1126/science.6857281) Yamazaki, K., Beauchamp, G. K., Kupniewski, D., Bard, J., Thomas, L. & Boyse, E. A. 1988 Familial imprinting determines H-2 selective mating preferences. Science 240, 1331–1332. (doi:10.1126/science.3375818) Yamazaki, K., Beauchamp, G. K., Imai, Y., Bard, J., Phelan, S. P., Thomas, L. & Boyse, E. A. 1990 Odortypes determined by the major histocompatibility complex in germfree mice. Proc. Natl Acad. Sci. USA 87, 8413–8416. (doi:10.1073/pnas.87.21.8413) Yamazaki, K., Beauchamp, G. K., Curran, M. & Boyse, E. A. 2000 Parent-progeny recognition as a function of MHC odotype identity. Proc. Natl Acad. Sci. USA 97, 10 500–10 502. (doi:10.1073/pnas.180320997) Yang, H., Shi, P., Zhang, Y. & Zhang, J. 2005 Composition and evolution of the V2r vomeronasal receptor gene repertoire in mice and rats. Genomics 86, 306–315. Yokoi, I., Mori, K. & Nakanishi, S. 1995 Refinement of odor molecules tuning by dendrodendritic synaptic inhibition in the olfactory bulb. Proc. Natl Acad. Sci. USA 92, 3371–3375. (doi:10.1073/pnas.92.8.3371)

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Phil. Trans. R. Soc. B (2006) 361, 2079–2089 doi:10.1098/rstb.2006.1932 Published online 6 November 2006

Social odours, sexual arousal and pairbonding in primates Charles T. Snowdon1,*, Toni E. Ziegler1,2, Nancy J. Schultz-Darken2 and Craig F. Ferris3 1

Department of Psychology, University of Wisconsin, 1202 West Johnson Street, Madison, WI 53706, USA 2 Wisconin National Primate Research Center, 1220 Capitol Court, Madison , WI 53715-1299, USA 3 Department of Psychiatry, University of Massachusetts School of Medicine, Worcester, MA 01655, USA

We describe the role of social odours in sexual arousal and maintaining pairbonds in biparental and cooperatively breeding primates. Social odours are complex chemical mixtures produced by an organism that can simultaneously provide information about species, kinship, sex, individuality and reproductive state. They are long lasting and have advantages over other modalities. Both sexes are sensitive to changes in odours over the reproductive cycle and experimental disruption of signals can lead to altered sexual behaviour within a pair. We demonstrate, using functional magnetic resonance imaging (fMRI), that social odours indicating reproductive state directly influence the brain areas responsible for sexual behaviour. Social odours also influence other brain areas typically involved in motivation, memory and decision making, suggesting that these signals have more complex functions in primates than mere sexual arousal. We demonstrate a rapid link between social odours and neuroendocrine responses that are modulated by a male’s social status. Recent work on humans shows similar responses to social odours. We conclude with an integration of the importance of social odours on sexual arousal and maintaining pairbonds in socially biparental and cooperatively breeding species, suggesting new research directions to integrate social behaviour, neural activation and neuroendocrine responses. Keywords: social odours; sexual arousal; pairbonds; primates; functional magnetic resonance imaging; neuroendocrine responses

1. INTRODUCTION Evolutionary theorists have argued that in mammals, the sexes have fundamentally different reproductive strategies. Mammalian females have a greater certainty of maternity and greater energetic investment than do males, owing to gestation and lactation. Males can benefit from reduced post-conception energetic investment, but have a low certainty of paternity. As a result, females should be very choosy of mates, whereas males should compete with one another for as many conceptions as possible. However, in some mammalian species, including humans, mothers cannot rear infants successfully without some help from others. In such situations, either biparental care or infant care from a broader range of caregivers becomes essential. In these species, males and females have more congruent interests in reproduction. Some mechanisms become necessary not only to maintain a close social relationship between the breeding pair for infant care, but also to provide the male with confidence that the infant he is caring for is likely to be his. It has been argued (Snowdon 2001) that non-conceptive sex may be one proximal mechanism to form and sustain a pairbond. In this paper, we examine how social odours affect brain mechanisms and the neuroendocrine system to stimulate sexual behaviour, and how these odours may serve to sustain a relationship. * Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘The neurobiology of social recognition, attraction and bonding’.

We first present the cooperatively breeding primates that we study, where both sexes are critical for infant survival and thus a close relationship between mates is critical. We then examine the features of olfactory signals and the potential role of these signals in regulating sexual behaviour and pairbonding along with the techniques available to study olfactory signals. We review behavioural evidence indicating the importance of social odours in reproduction in marmosets and tamarins and follow with our research on how social odours influence brain activity using functional magnetic resonance imaging (fMRI) as well as endocrine function and behaviour. We discuss some recent parallel studies on human responses to social odours and conclude with suggestions for future research to firmly link social odours, sexual arousal and pairbonding.

2. MARMOSETS AND TAMARINS: PRIMATES WITH OBLIGATE PAIRBONDING As noted above, a close social relationship between mates is essential in those species where females are unable to rear infants successfully alone. Biparental species are those in which both parents are involved in taking care of infants. Cooperative breeders require not only both parents, but also additional helpers or alloparents which suppress their own reproduction to assist in the care of infants. Callitrichid primates (marmosets and tamarins) are small monkeys (120–700 g) distributed throughout the

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Neotropics from Panama to southern Brazil. Characteristic of all of the species is a preponderance of giving birth to twins. In many natural habitats, as well as in captivity, females give birth twice a year. Gestation time is long compared with other small mammals, ranging from 4.5 to 6 months, which means that females generally become pregnant shortly after parturition while they are still nursing the current infants. Unlike birds, marmosets and tamarins do not build nests and so infants must be carried throughout the day as the group forages. Under such conditions, females are unlikely to be able to provide for all infants’ care alone. In both field and captive environments, fathers and other group members are actively involved in transporting infants, share food with them as they are weaned, and probably assist infants with thermoregulation (Snowdon 1996). Fathers and other helpers are essential for infant survival (Snowdon 1996), and infant care is a significant energetic cost to males (Sanchez et al. 1999; Achenbach & Snowdon 2002). Thus, in marmosets and tamarins both females and males have high stakes in maintaining a close social relationship. If a female is to be successful, she must keep her mate (and other helpers) with her during pregnancy and into the infant care period. In contrast with most other primate species, female marmosets and tamarins cannot rear infants alone and must maintain social ties with other animals to provide infant care. Similarly, if a male is to be reproductively successful, he must remain with his mate and invest significant energy in infant care. In order to do this, the father must have a high degree of confidence of paternity. Males would not benefit from providing infant care for infants they have not sired. Thus, it is critical to the self-interest of both females and males to develop and maintain a strong social relationship (or pairbond). We know relatively little about the mechanisms that lead to the formation and maintenance of bonds, but social odours appear to be one of the mechanisms by which bonds are maintained.

3. SOCIAL ODOURS Olfaction is a sensory modality that is important in social communication in a wide array of species from insects to humans. There are many virtues of olfactory signals relative to other sensory modalities. Olfaction is useful where visual cues are difficult to detect and can be used at night and in visually obscured habitats. Olfactory signals may be energetically less expensive to produce than other types of signals and are long lasting relative to social signals. Olfactory cues have the advantage that they may be dissociated from the signaller if needed. Many species mark territorial boundaries through olfactory cues. This is an efficient way of defending a boundary since the odours will last after the producer has left. An organism can communicate without being directly located, providing reduced risk of detection by predators. Odours used specifically for communication between animals within a species are called ‘pheromones’ in analogy to ‘hormones’. Hormones are chemical signals that communicate from one part of the body to another, whereas pheromones are chemical signals that communicate from one organism to another. The original Phil. Trans. R. Soc. B (2006)

research on pheromones was done with invertebrate species where there often appeared to be a fixed response to a signal. However, we take a broader view here (following Wyatt 2003). Pheromones are highly complex and variable mixtures of different chemicals and as a result will lead to different responses in recipients according to environmental and social variables. However, because discussion remains about the definition of a pheromone, here we use ‘social odours’ to describe chemical signals involved in regulating social interactions. Social odours have a broad range of functions that vary within and between species. Odours can provide directional cues for orientation, serve as signals of alarm, mark territory boundaries, unify groups, direct foraging behaviour, attract mates, indicate reproductive and social status and provide information about species, subspecies, group, kin and individual identity (Wyatt 2003). Factors involved in mate choice and coordination of reproduction are of importance here. Social odours that serve to attract mates and communicate reproductive status are important for the coordination of reproductive behaviour, and odours that communicate species identity could limit reproduction to the appropriate species. Individual specific odours could be used to identify specific mates (Smith et al. 1997) and therefore be of value in maintaining relationships between mates. Since social odours are usually a mixture of many substances, multiple levels of information can be provided simultaneously. Analyses of scent marks from Callitrichid primates (marmosets and tamarins) have revealed literally hundreds of chemical forms within a signal (Smith et al. 1976; Epple et al. 1993). There are several implications to this finding. First, social odours have the complexity to encode multiple levels of information. The same signal might provide invariant information about the identity of species, subspecies, sex and individual while at the same time providing varying information such as the ovulatory state of a female. Chemicals of different molecular weight and molecular structure have different properties of diffusion. Thus, some components of a chemical signal may diffuse widely and attract a conspecific to the location of the signaller whereas larger, less well-diffusing molecules at the site of a scent mark can have a different effect once the receiver is attracted to the source. In addition, there are two receptor pathways by which social odours can influence brain function. Each pathway can function simultaneously. The main olfactory system provides for transduction of airborne molecules at the nasal epithelium. Nerves from the nasal epithelium transmit information to the olfactory bulb, which in turn projects to the piriform and entorhinal cortices and subsequently to other cortical and subcortical areas, particularly the hippocampus. Some information may also be sent to the amygdala. The accessory olfactory system begins with chemicals transduced in the vomeronasal organ (VNO), which in many species is accessed via an aperture in the roof of the mouth. However, vomeronasal chemosignals can be taken into the VNO following direct contact by oral or nasal routes. Neurons from the VNO project to the accessory olfactory bulb, which connects directly to the amygdala and projects from there to other subcortical areas (Wyatt 2003).

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Social odours, sexual arousal and pairbonding C. T. Snowdon and others There are several interesting and important points that emerge from a comparison of these two different systems for processing social odours. First, the main olfactory system is more likely to process volatile chemicals that can diffuse passively to the nasal epithelium, whereas the vomeronasal system appears better adapted to process less volatile chemicals that make direct contact by oral or nasal routes. Second, the somewhat different brain pathways from the main olfactory bulb and the accessory olfactory bulb suggest that each area may process different potential functions of odours. Information from the accessory olfactory bulb goes directly to subcortical areas involved in sexual behaviour and neuroendocrine function, whereas information from the main olfactory bulb generally projects to many cortical areas and hippocampus first before being relayed to subcortical areas, although direct projections from the main olfactory bulb to the amygdala can be seen in rodents and probably in other species. Nonetheless, the main olfactory system provides greater flexibility in linking complex odours to different responses, including information requiring evaluation or cognitive processing.

4. TECHNIQUES TO STUDY SOCIAL ODOURS It is difficult to study a sensory modality that we cannot perceive directly, and so determination of the role of olfactory signals requires careful methodology to (i) determine that odours are perceived, (ii) be certain that different odours may be discriminated, and (iii) know that odours have different functional effects. There are two major methods that have been used in studies of olfactory stimuli in mammals. First, one can use a behavioural bioassay to see if a participant can discriminate between different odours through preferences or other differential expression of behaviour. Second, one can look for a differential physiological response to different odours, either through peripheral measures or through changes in neural activity. We have used both methods in our research. As an example of a behavioural bioassay, Ziegler et al. (1993) were interested in whether cotton-top tamarin males could detect signs of ovulation in their mates. Some authors (e.g. Burley 1979) had proposed that females manage monogamy by concealing the time of ovulation from their mate. Since the male cannot know when the female ovulates, he is prevented from seeking other mates. As noted, tamarins are cooperative breeders and male care of infants is critical to their survival. We had been unable to detect any changes in female behaviour or external physical changes that are related to ovulation. Thus, cotton-top tamarins appeared superficially to be a model of concealed ovulation. However, by monitoring hormonal states of females, we discovered that approximately 85% of ovulations resulted in conception (Ziegler et al. 1987). This suggested that some sort of communication of ovulatory status was happening. To test whether males could detect signs of ovulation, we collected daily scent marks (on ground glass stoppers) throughout the ovulatory cycle of a female and transferred the stoppers to cages housing pairs where the female was pregnant and not ovulating herself. In the periovulatory period of Phil. Trans. R. Soc. B (2006)

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the donor female, recipient males demonstrated increased rates and durations of erections and increased mounting of their own mates compared with days when the donor female was not ovulating. Although ovulation was concealed to human investigators, it was clearly not concealed to the tamarins. An example of using a physiological response to determine if odours are perceived and have a functional effect comes from Ziegler et al. (2005). Male common marmosets were presented with small wooden disks containing odours from novel, ovulating females or of vehicle only, and a blood sample was taken 30 min later. Males had increased levels of testosterone following exposure to the odour of an ovulating female compared with exposure to the disk containing the vehicle.

5. THE ROLE OF SOCIAL ODOURS IN MARMOSETS AND TAMARINS Owing to the importance of careful mate choice by both the sexes, each sex must evaluate carefully the quality and potential for a long-term relationship with the other. Social odours may play an important role in the evaluation of potential mates. Lazaro-Perea et al. (1999) studied the patterns of scent marking in wild groups of common marmosets and found that scent marking occurred in a variety of contexts in addition to the expected marking of territorial boundaries and food resources. Studies on marmosets and tamarins in captivity have found that common marmosets of both the sexes and female cotton-top tamarins scent mark in response to presentation of a novel intruder (e.g. French & Snowdon 1981; Evans 1983). Lazaro-Perea et al. (1999) also found increased scent marking during intergroup encounters in wild common marmosets. In captive marmosets and tamarins, odours from reproductive females suppress ovulation in other females, providing a mechanism that could limit reproduction to a single female in a group (Epple & Katz 1984; Savage et al. 1988; Barrett et al. 1990). Although not reproductively active in the context of the family unit, subordinate females in the wild will scent mark at higher rates than reproductive females, particularly at territorial boundaries (Lazaro-Perea et al. 1999). Subsequent research on the details of territorial interactions (Lazaro-Perea 2001) suggested that these interactions did not function solely to display aggression towards others, but also allowed marmosets to assess potential mates in other groups. In nearly every territorial encounter, a male from one group and a female from another group would cease behaving aggressively towards each other, move away from the rest of the group and copulate before returning to be aggressive to each other again. When a breeding animal disappeared from a group, the vacancy was filled rapidly, often by an animal previously seen engaged in territorial and assessment behaviour (Lazaro-Perea et al. 2000). Scent marks produced by non-reproductive males and females at territory boundaries may provide information about quality (physical health, stamina, reproductive competence) and also individual identity, information that can influence mate choice decisions.

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These results suggest that social odours may serve as sexually selected traits in marmosets and tamarins by providing honest cues about the quality of the mate. This would be especially important in species that are dependent upon male infant care. Heymann (2003) has argued that scent marks are sexually selected traits, and he calls attention to an interesting sexual dimorphism in scent marking across different genera of Callitrichids. Scent marking is equally common in male and female marmosets, whereas it is rare among male tamarins. Male cotton-top tamarins scent mark when they are aggressive but not during sexual displays as common marmosets do. Evidence from both field and captivity has indicated that in Saguinus tamarins male care of infants is much more critical than in other species. Heymann (2003) argues that the sexual dimorphism in tamarin scent marking is functional because males will have a greater investment in infant care than in other genera and thus males rely on social odours from females to evaluate mate quality. In addition to the evidence of intersexual selection based on social odours, the evidence of olfactory suppression of reproduction in subordinate females cited above indicates that there is intrasexual selection in females based on social odours. Another important function of social odours in marmosets and tamarins is in regulating sexual behaviour. These monkeys copulate throughout the ovarian cycle, as well as during pregnancy. This continuous receptivity is not an artefact of confined spaces that has been reported for other species (Wallen 1982). When we observed that the majority of ovulations that occurred in our captive tamarins resulted in conception, we began to look for potential signals by which females could communicate ovulation time to their mates. None of the traditional measures correlated. There was no obvious change in physical appearance, unlike the sexual swellings found in many old world primates (Zinner et al. 2004), and no changes in coloration. We find no evidence of menstruation, so males cannot be using menstruation to estimate when the next ovulation will occur. Given the importance of social odours already described, odours seemed a natural ovulatory signal, but we could find no changes in rates of scent marking by females that correlated with ovulation. However, it seemed likely that changes in odour quality might be an important cue. Using the behavioural bioassay described above, Ziegler et al. (1993) collected scent marks deposited daily from an ovulating female on glass stoppers. The stoppers were then introduced to the cages of several mated pairs of tamarins where the females were pregnant and thus not ovulating themselves. We observed the behaviour of each pair in response to the odour and recorded all social and sexual behaviour that occurred during 10-min scent presentation. After all the behavioural data were gathered, we analysed the daily urine samples collected from the donor to determine when she had ovulated. We defined a periovulatory period as the day before, the day of and the day following the rise in luteinizing hormone (LH) that signals ovulation. Males showed increased frequency and duration of erection and increased rates of mounting their own mates on days of the donor’s Phil. Trans. R. Soc. B (2006)

periovulatory period. Females showed increased exploration of the platform containing the donor’s periovulatory odours. Interestingly, males did not differ in rates of investigating, sniffing or licking at the donor’s odours as a function of her cycle. This suggests that males are constantly monitoring social odours. Thus, female tamarins do communicate ovulatory status to males, but through changes in quality of the odour rather than frequency of marking. A different type of experiment by Smith & Abbott (1998) found that male common marmosets could discriminate between odours of ovulatory versus anovulatory females. In an observational study on pygmy marmosets, Converse et al. (1995) described sexual behaviour occurring throughout the ovulatory cycle and found no changes in the rates of female scentmarking behaviour. However, males demonstrated increased rates of investigating scent marks from their mates at the time of ovulation as well as increased rates of courtship behaviour and mounting at ovulation. Female pygmy marmosets often displayed aggression towards male mounting attempts during the ovulatory cycle, but female aggression was never observed in the periovulatory period. Evidence from these three species taken together suggests strongly that social odours of females change through the ovulatory cycle and that males detect these cues. Ziegler et al. (1993) demonstrated that the periovulatory odours of novel females could stimulate sexual arousal (erection and mounting behaviour) by males. The same result is found in common marmosets. Ziegler et al. (2005) presented male common marmosets with odours of novel ovulating females and compared behavioural response to this odour versus a vehicle control. Males showed increased rates of sniffing at the ovulatory odour as well as increased duration of erections during the 10-min tests. Although not significant, there were also decreases in latency to sniff at the odour, increases in licking, touching and male scent marking. Taken together, the results suggest the ability of odours of ovulating females to induce sexual arousal in males. Washabaugh & Snowdon (1998) tested pairs of cotton-top tamarins with odours of the (i) resident female, (ii) unfamiliar females undergoing reproductive cycling, and (iii) unfamiliar females which were reproductively suppressed. The study was designed specifically to evaluate the response to odours independent of the ovarian cycle, by testing animals once each week for three weeks, with samples from the same females. The ovulatory cycle in tamarins is 23 days (French et al. 1984). Thus, by averaging observations across three weekly tests, the data represented responses to females in different reproductive conditions independent of ovulation. Males did not show increased sexual behaviour, but spent more time approaching and sniffing scents from the unfamiliar reproductive female. In contrast, females not only spent increased time investigating the odours of both unfamiliar reproductive females and unfamiliar noncycling females, but also showed greatly increased rates of proceptive behaviour towards their mates in response to odours of unfamiliar reproductive females. These results taken together with those of Ziegler et al.

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Social odours, sexual arousal and pairbonding C. T. Snowdon and others (1993) suggest that males respond with sexual arousal to novel females only at the time of ovulation, whereas females respond to odours of novel females at all stages of their cycle. Not only is information about ovulation conveyed, but there must also be some information in social odours independent of ovulation that allow females to recognize a reproductive female as novel at any stage in her cycle.

6. HOW SOCIAL ODOURS AFFECT THE BRAIN AND NEUROENDOCRINE SYSTEMS How do odours affect the brain? Until recently, there has been no direct information directly linking olfactory stimuli to the specific brain areas known to be involved in sexual arousal. Given that there are direct pathways from the accessory olfactory system to the limbic system and other subcortical areas, the logical place to look for a direct influence of social odours is in these areas. Several studies implicate the anterior hypothalamus (AH) and medial preoptic areas (MPOA) as likely targets owing to their involvement in sexual arousal. In common marmosets, Dixson & Lloyd (1988) and Lloyd & Dixson (1988) lesioned the AH and MPOA in male common marmosets and found that the lesions reduced copulatory behaviour and male sexual interest in females without affecting grooming or affiliative behaviour with mates. In other species, the AH/MPOA has been implicated in sexual behaviour. Paredes & Baum (1995) studied ferrets and found that castrated females treated with oestradiol and tested in a T-maze preferred to approach a male and accept sexual behaviour, whereas intact males approached females and initiated sexual behaviour. However, castrated, oestrogen-treated males with AH/ MPOA lesions showed reduced sexual behaviour towards females, and these castrated and lesioned males chose to approach sexually active males at the same rate as did control females. In a study on rats, Paredes et al. (1998) made lesions in the AH/MPOA of males and females and found no changes in female preferences for males as a function of either hormonal treatment or lesion condition. However, after AH/ MPOA lesions, males changed partner preference and spent significantly more time in contact with sexually active males. Thus in rats and ferrets, AH/MPOA lesions in males, but not in females, can change preferences for sexual partners. Based on these studies, we predicted that the odours of ovulating females would have a direct stimulatory effect on neurons in the AH and MPOA of males. To test this notion, we developed the technology and methods to image odour-evoked changes in brain activity of fully conscious monkeys using fMRI. First and foremost, we developed a restraint system that would keep the marmoset’s head immobile during imaging. Built into the chassis of the marmoset restrainer were radiofrequency electronics for detecting subtle changes in MR signal from localized areas of the brain. Animals were lightly anaesthetized so that they could be placed in the restraints and then they were administered an antidote to the anaesthesia. We determined that each individual monkey recovered completely within 12–30 min after being given the Phil. Trans. R. Soc. B (2006)

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antidote. We took heart rate, respiratory rate and EEG data to demonstrate that animals were completely alert in the magnet, and documented normal physiological responses to the presentation of odours from ovulating females (increased heart rate and decreased respiration). In every session we compared images at the beginning and end of imaging and rejected any sessions where there was evidence of motion artefact. Since we were concerned about possible stress effects on the subjects owing to the procedure, we habituated monkeys to the procedures three times before testing. Measures of serum cortisol before and after imaging indicated some elevation of cortisol, but the elevation remained within the normal acceptable range for unrestrained controls. For more details on the methodology and the controls that are necessary see Ferris & Snowdon (2005). We presented four male common marmosets with odours of novel females. Two types of odours were presented: scent marks of novel ovulating females and scent marks from novel ovariectomized females. The female scent marks were collected on glass stoppers, the scents were dissolved in a mixture of alcohol and deoxygenated water, and the extracts were stored at K808C until they were used as a stimulus. Within each imaging session, the males were tested with an ovulatory odour, an ovariectomized odour and a vehicle control. Prior to each stimulus presentation, we also gathered data in the absence of any stimuli. We found support for our hypothesis (Ferris et al. 2001). There was a significantly increased activation of both the MPOA and AH in response to odours of both ovulatory and anovulatory females relative to vehicle control and no stimulus controls (figure 1). In addition, the activation in response to the ovulatory odour was significantly greater than the response to the anovulatory odour. Thus, social odours by themselves in the absence of any other sensory cues led to increased activation of the AH and MPOA, areas known to be involved in male sexual arousal. There are many benefits in using fMRI. The technique is minimally invasive and thus the same animals can be tested repeatedly under different developmental and social conditions. Furthermore, one can carry out hypothesis-driven research such as described above, and at the same time, by collecting images from the entire brain, one can use fMRI for exploratory research as well. We further analysed the data from our marmosets to determine what other brain areas were involved in responding to sexual odours (Ferris et al. 2004). We specifically compared responses to the odours from novel ovulating females with responses to the odours from novel ovariectomized females. We found significant differences in positive MR signal in prefrontal cortex, temporal cortex, somatosensory cortex, insular cortex, cingulate cortex, caudate nucleus, putamen, hippocampus, septum, medial preoptic, AH, periaqueductal grey, Raphe nucleus and cerebellum. We also found significant differences between stimuli in reduced or negative MR signal in temporal cortex, cingulate cortex, putamen, substantia nigra, hippocampus, medial preoptic and cerebellum. In general, most of these areas have greater activation (positive signal) to the ovulatory odours (compared with the anovulatory

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Social odours, sexual arousal and pairbonding

ovulate scent positive BOLD

OVX scent

ovulate scent positive BOLD

negative BOLD negative BOLD

high resolution MR image

INS PU

CD

CG SP

high resolution MR image SMC CG PT MT

mPOA TP

AM HIP TP

Figure 1. Activational maps at the level of the amygdala taken from a single animal. Significant changes in positive and negative BOLD signal are shown for presentation of the scent of novel, ovariectomized (OVX) females and those of novel, ovulating females. Regions of interest are delineated in the upper right-hand image. Note the greater overall degree of positive BOLD signal in response to the scent of ovulating females and the greater degree of negative BOLD signal in response to odours of ovariectomized females. Abbreviations: INS, insular cortex; CG, cingulate cortex; CD, caudate; SP, septum; PU, putamen; TP, temporal cortex; AM, amygdala; mPOA, medial preoptic area. (Reprinted from fig. 2, Ferris et al. 2004 Journal of Magnetic Resonance Imaging 2004, Wiley Liss.)

odours) and greater deactivation (negative signal) to anovulatory odours (figures 1 and 2). These results indicate that sexual odours are not merely having an effect on areas directly involved in male sexual behaviour (AH/MPOA), but are also influencing the areas involved in memory (hippocampus, temporal cortex), emotional decision making (cingulate cortex), motivational systems (caudate, putamen, substantia nigra) and sensory integration (cerebellum, somatosensory cortex). If all of these areas are differentially involved in reaction to ovulatory versus anovulatory odours, then the odours cannot just be activating some sort of reflexive process, but some evaluative and recognition processes as well. These results lead us to hypothesize that male marmosets are using memory and decision-making processes to identify the source of the odour. For maintaining a pairbond, individual recognition of the mate becomes important and a male’s mating decision may be based on the value of the relationship as well as whether the mate is detected or not. Phil. Trans. R. Soc. B (2006)

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Figure 2. Activational maps at the level of the thalamus. Images taken from a single animal. See figure 1 for detailed description. Abbreviations: SMC, sensory motor cortex; PT, posterior thalamus; MT, medial thalamus; HIP, hippocampus; SN, substantia nigra. (Reprinted from fig. 3, Ferris et al. 2004 Journal of Magnetic Resonance Imaging 2004, Wiley Liss.)

The hypothalamus including the AH and MPOA is intimately involved in regulating the neuroendocrine system. Is it possible to demonstrate that olfactory cues influence male neuroendocrine function? A few studies on rodents have shown an increase in LH or testosterone within a brief time of being presented with female odours. But in primates, only chronic exposure to odours over a few weeks has so far been related to increased hormonal activity. In a direct test of the hypothesis that female odours could have a rapid effect on endocrine responses, Ziegler et al. (2005) tested male common marmosets with odours of novel, ovulating females and compared these with responses to vehicle alone. Male marmosets showed increased erection rates and sniffing at the ovulatory scent. At the same time, Ziegler et al. (2005) took blood samples from males 30 min later and analysed these for testosterone and cortisol. The males were grouped according to their social condition (single, newly paired or fathers taking care of infants). Within 30 min of presenting the odour of a novel, ovulating female, single males and non-reproducing, paired males demonstrated a significant increase in testosterone levels but with no changes in cortisol levels. However, fathers showed no change in testosterone levels, reacting to the ovulatory odour as they did to the control. Something about being a father and caring for

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Social odours, sexual arousal and pairbonding C. T. Snowdon and others infants prevented these marmosets from responding physiologically to ovulatory scents of a novel female. Ziegler et al. (2004b) studied cotton-top tamarin males in the period around the post-partum ovulation of their mates. Females varied considerably in when they ovulated after giving birth (range 13–25 days), but males demonstrated significant increases in testosterone and dihydrotestosterone during the 5 days prior to the mate’s ovulation. This hormonal anticipation of a mate’s ovulation may prepare the male for copulation and mate guarding. The fact that the timing of increased hormonal levels in males anticipated precisely the timing of the mate’s ovulation implies some sort of communication, and social odours appear the most likely modality.

7. SOCIAL ODOURS AND HUMAN REPRODUCTION Do olfactory stimuli have any relationship to human reproductive behaviour? Hrdy (1999) has argued that humans are also cooperative breeders, since a single female is typically unable to rear an infant to adulthood without substantial support from others either in caregiving or financial support. Thus, we might expect to find similar importance in forming and maintaining pairbonds in humans, and it would not be surprising to find some similar mechanisms involved. However, there are similar difficulties in studying social odours in humans as in monkeys. We often cannot perceive social odours at a conscious level. Sobel et al. (1999) used fMRI to measure response of subjects to oestra-2,3,5 (10), 16 tetraen-3yl acetate, an odour none of the subjects could consciously detect. At a low concentration, participants could not discriminate between the odour and a control but at high concentrations, they could discriminate despite being unaware of the presence of an odour. Nonetheless, fMRI revealed increased activation in the anterior medial thalamus and inferior frontal gyrus in response to both odours. Thus, although subjects were unaware of the odour at both the concentrations, they could discriminate between high concentrations and a control odour and had increased brain activation to both concentrations. There has been considerable controversy over whether humans have a functional VNO. Trotier et al. (2000) found evidence of a vomeronasal pit bilaterally in 13% of more than 1800 subjects and unilaterally in another 26%. However, repeated sampling of a subset of 764 subjects found changes over time in whether a vomeronasal pit could be detected. There was no evidence of any nerve tract leaving the VNO, and the proteins expressed in the organ were different from those seen in other species. Although the VNO may be vestigial and ephemeral in humans, social odours may still be detected and processed by the nasal mucosa and main olfactory bulb. As with non-human animals, behavioural and physiological bioassays are used to determine the presence and the effects of social odours in humans. Singh & Bronstad (2001) provide a typical example of a behavioural bioassay. Women wore clean T-shirts for three nights before menstruation (luteal phase) and another clean T-shirt for three nights at mid-cycle. Men were asked to smell the T-shirts and rate them on Phil. Trans. R. Soc. B (2006)

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qualities of pleasantness, attractiveness and sexiness. The T-shirts worn during ovulation were ranked higher than those worn during the luteal phase. Stern & McClintick (1998) illustrate a physiological bioassay. Axillary secretions were collected from women at either the early follicular phase or ovulation. Extracts of these odours were placed on the skin of recipient females between the upper lip and the nose. Over the subsequent two menstrual cycles, women receiving odours from ovulating women increased cycle length by 1.5 days and women receiving follicular odours shortened their cycles by a mean of 2 days. Thus, odours from women at different stages of their cycles can produce physiological effects on recipients. Stern & McClintick (1998) use these results to suggest a mechanism for menstrual synchrony. In another study, Preti et al. (2003) collected axillary extracts from men and placed them under the noses of women who were being monitored for serum LH levels and mood. When presented with male axillary extracts, women showed more frequent LH pulses, reduced tension and increased relaxation, indicating both a physiological and emotional effect of male social odours. The fact that axillary extracts of men and women have effects on physiology and mood led to a search for what might be key olfactory compounds. One compound of male axillary secretions is an androgen (4,16 androstadien-3-one; AND), and a less welldocumented female equivalent is an oestrogen (1,3,5(10), 16-oestratetraen-3-ol; EST). How do these compounds influence behaviour and physiology in humans? Bensafi et al. (2003) presented AND and EST to heterosexual men and women while recording several measures of physiology and mood. The steroid, AND, affected the sexes differently, increasing physiological arousal in women, but decreasing arousal in men. EST, however, had no effect on either sex. Neither compound had a significant effect on mood. In contrast, Savic et al. (2001) reported a double dissociation between AND and EST. They used positron emission tomography to measure neural activation in response to each compound. Women demonstrated a strong activation to AND and men demonstrated a strong activation to EST. There was a sex difference in the activated regions of the hypothalamus. AND activated the MPOA/AH and ventromedial hypothalamus in women, whereas EST activated the paraventicular and dorsomedial hypothalamus in men, although there was some overlap. The MPOA/AH was not activated in men in contrast to our results with marmosets, but the anterior cingulate and insula were activated in both sexes (men by EST and women by AND), comparable to our results with male marmosets. EST in men and AND in women also activated both left and right amygdala, but we found no differential responses in the amygdala of marmosets. In addition, EST increased activation in the fusiform and lingual gyrus in men, and AND activated the same areas in women. The fusiform gyrus is involved in individual face recognition and its activation by odours suggests a potential involvement in individual odour recognition as well. Neither men nor women rated the odours differently in terms of pleasantness, familiarity, intensity or irritability.

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Savic et al. (2005) have extended their work with AND and EST to include homosexual men. They reported that EST did not produce increased neural activation in homosexual men, but AND did lead to increased activation in homosexual men in the same hypothalamic areas that were activated by AND in women. There were no differences between heterosexual and homosexual men to any of a variety of other steroid and peptide hormones that were sampled. Research on determining putative social odours that affect reproductive behaviour in humans and identifying the relevant compounds is in its infancy, but it is becoming clear that human social odours may have influences on neural activity, neuroendocrine function and behaviour, somewhat similar to what we have documented in marmosets and tamarins.

8. RELATIONSHIP BETWEEN SEXUAL AROUSAL AND PAIRBONDS Almost all of the studies we have reported so far have measured responses to odours of novel females. But this leads to a serious problem with respect to our initial arguments. We have shown that only ovulatory odours from novel females (and in women from novel males) can lead to sexual arousal, AH/MPOA activation and neuroendocrine responses, but how could odours work to maintain a pairbond that is essential for cooperative breeding? Remember that (i) both male and female tamarins initiated sex with their mates when they are exposed to the odours of novel reproductive females (Ziegler et al. 1993; Washabaugh & Snowdon 1998), (ii) in common marmosets, fathers do not display an increased testosterone response to odours of novel females (Ziegler et al. 2005), and (iii) a variety of neural areas associated with recognition and memory are also activated by female odours (Ferris et al. 2004). Therefore, male marmosets and tamarins are not responding reflexively to sexual odours. If males can distinguish between odours from their own mate and that of a novel female and make decisions based on the value of the current mate versus the potential value of a novel female, we should be able to model this through a study of sexual conditioning to show that animals can learn specific olfactory cues associated with sexual activity. We are completing a study on sexual conditioning in common marmosets. In our fMRI studies, we also used lemon extract as a non-sexual olfactory cue and as an additional control for novel female odours. Subsequently, these same males were trained to anticipate the opportunity of sex whenever they smelled lemon. In other words, on conditioning trials, males would receive lemon odour in the presence of a caged ovulating female and 3 min later the males had access to the female with whom they could copulate. On alternating trials, the males were presented with the vehicle, in the presence of a caged ovulating female, but the female was not released. The males rapidly displayed anticipatory sexual behaviour only when lemon was present. We are currently analysing the results from fMRI imaging to lemon before and after conditioning (Schultz-Darken et al. 2003, unpublished data). The demonstration of sexual conditioning to an arbitrary odour indicates that males can Phil. Trans. R. Soc. B (2006)

learn to target sexual activity to those females associated with that odour. This, in turn, suggests that males can rapidly learn about the individual odours of their mates and thus limit their sexual reactions to their mates (or at least inhibit responses to other females in the presence of their mates). How does this work to maintain a pairbond? Data from a variety of studies suggest that non-conceptive sex is important in forming and maintaining pairbonds (Snowdon 2001). Not only is sexual activity greater at the beginning of a relationship than later on, but also various experimental disruptions to a relationship, such as brief separation from mate, presenting a novel animal, either directly or indirectly through odour cues, lead to increased levels of sexual activity among mated pairs as though non-conceptive sex was acting to reaffirm or restore the relationship. We hypothesize that the rewards of non-conceptive sex condition mates to the individualspecific cues of one another and that these cues may serve as secondary reinforcement for maintaining a close relationship. Thus, social odours lead to sexual arousal and conceptive or non-conceptive sex with the mate. This, in turn, leads to learning about mate-specific cues that may then serve to maintain a strong relationship.

9. FUTURE DIRECTIONS Our research to date suggests several interesting future studies. We know that male common marmosets are likely to be interested in and copulate with novel females at the time of ovulation, but males appear to be much less interested in novel, non-ovulating females. However, mated pairs of common marmosets engage in sexual activity throughout the cycle. This suggests that the sexual arousal of male marmosets by novel females is much more sensitive to their reproductive condition, whereas arousal to their own mates is less linked to ovulation. It follows then that males should display equal interest in the odours of their mates throughout the ovarian cycle. Thus, although activation of the MPOA and AH is clear to novel, ovulating females, we predict that activation of the MPOA and AH would be equally strong to the mate’s odour at all phases of the ovarian cycle. Alternatively, owing to long-term habituation to odours of the mate, the mate’s odours alone might not induce as much activation at any time in the reproductive cycle, compared with a novel female’s odours. Several studies have shown that male marmosets react differently to a novel female depending on whether his mate is present or not. Evans (1983) showed that when a novel female intruder was presented to paired common marmosets, both male and female engaged in aggressive behaviour towards the intruder. However, when the male of the pair was tested alone with a novel female, he demonstrated affiliative behaviour with little aggressive behaviour. In an extension of this paradigm, Anzenberger (1985) tested males separately from their mates but with the mates visible behind a one-way window. In this condition, males displayed much more aggression and less affiliation towards a novel female than when they were tested in an environment where they could not see their mates. Clearly, some aspect about the presence of

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Social odours, sexual arousal and pairbonding C. T. Snowdon and others the mate inhibits a male from demonstrating sexual interest in a novel female. Could this be done with odours as well and what effect might these have on brain activity? In parallel with the studies using visual cues, we predict that a male should demonstrate a much lower level of sexual interest when tested with odours of a novel female in the presence of olfactory cues from his mate. Erection rates would be lower and sniffs and licks at the novel female odour would be fewer and latency to approach the odour would be less in the presence of odours from the mate. With respect to neural activity, we predict that the presence of the mate’s odour along with the odour of a novel ovulating female should suppress the response of the AH and MPOA. We have preliminary data suggesting that this is the case (C. F. Ferris et al. 2004, unpublished data). The males were presented with odours from a novel, ovulating female and displayed the robust neural response in AH/MPOA described earlier. However, when an odour from the male’s mate was presented in addition to that of the novel female, there was an immediate inhibition of AH and MPOA activation suggesting that, as with visual stimuli, olfactory stimuli can inhibit a male’s sexual reaction to a novel female. Since odours last a relatively long time and can be effective even in the absence of the animal producing the odour, an inhibition of a male’s sexual response suggests that females can control the sexual behaviour of the mate even without being visible or present. We found a rapid increase in serum testosterone within 30 min of presenting the odour of an ovulating novel female, but this hormonal response was limited to singly housed and non-reproducing, paired males and not to fathers (Ziegler et al. 2005). Thus, the sexual response to social odours varies with the male’s reproductive history. One of the great advantages of fMRI as a tool to study the nervous system is that the same individuals can be tested repeatedly. All of the males that we have studied with fMRI to date have been either sexually naive males living together or nonreproductive pairs. We predict that virgin males and non-reproductive paired males should continue to demonstrate a robust response of AH and MPOA, but that the same males, when retested as fathers, should display a muted response or no response. Furthermore, since Ziegler et al. (2004a) showed that male cotton-top tamarins begin to exhibit a hormonal cascade halfway through pregnancy, shortly after the foetal adrenal begins to become active, it is possible that males tested late in their mate’s pregnancy would also demonstrate neural inhibition to odours of novel females. All of the research to date on neural and endocrine changes on common marmosets in response to odours of novel animals has involved the study of males. However, we have shown in the related cotton-top tamarins that females also reacted to the odours of novel females by increasing proceptive behaviour towards their mate (Ziegler et al. 1993; Washabaugh & Snowdon 1998). In a monogamous or cooperatively breeding species, both the sexes should be involved in the maintenance of the relationship if infant care is to be successful. The cottontop tamarin males rarely scent mark (French & Cleveland Phil. Trans. R. Soc. B (2006)

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1984), and we cannot study how female tamarins react to male odours. However, in common marmosets, both the sexes use social odours about equally and therefore a parallel series of studies could be done with females in response to male social odours. Single and newly paired females should be much more interested in odours of novel males and should demonstrate greater neural activation than females either late in pregnancy or with dependent infants.

10. CONCLUSIONS Social odours play an important role in regulating sexual behaviour in cooperatively breeding primates, marmosets and tamarins. Odours appear to be important in marking territories, suppressing the fertility in subordinate females and, possibly, evaluating potential mates. Mated marmosets and tamarins engage in pair maintenance behaviour in the presence of odours from novel, reproductive females and males are sensitive to odour cues of ovulation. We have shown that it is feasible to use fMRI in conscious marmosets as a tool to study odourinduced changes in brain activity in response to signals inducing sexual arousal. fMRI indicated activation, not only of areas involved in sexual arousal, but also brain areas involved in motivational processes, memory and decision making. Odour cues from novel ovulating females also elicit a rapid increase in testosterone secretion in single and non-reproducing, paired males, but not in fathers, suggesting that male reproductive status affects how he responds to female odours. These findings taken together illustrate the importance of social odours not only in sexual arousal, but also in identifying a mate and regulating neuroendocrine function. Since fMRI allows one to study activation throughout the brain and over the course of an animal’s reproductive life, the technique holds great promise when used in conjunction with behavioural and neuroendocrine methods for understanding the brain mechanisms involved in linking sexual arousal with forming and maintaining the strong pair relationship needed to rear infants successfully. The finding of somewhat similar effects in humans suggests the potential importance of this research to better understand the formation and maintenance of human relationships. We thank Kate Washabaugh for leading us to some of the literature on human responses to social odours, Anita J. Ginther for critical comments, and Pamela Tannenbaum, Jean King, Reinhold Ludwig, David Olsen, John Sullivan and Jillian Scott for their collaboration on our research. This work was supported by grants MH 35215 to C.T.S. and T.E.Z., MH 58700 to C.F.F. and RR000167 to the Wisconsin National Primate Research Center.

REFERENCES Achenbach, G. G. & Snowdon, C. T. 2002 Costs of caregiving: weight loss in captive adult male cotton-top tamarins (Saguinus oedipus) following the birth of infants. Int. J. Primatol. 23, 179–189. (doi:10.1023/A:1013210226793) Anzenberger, G. 1985 How stranger encounters of common marmosets (Callithrix jacchus jacchus) are influenced by family members: the quality of behavior. Fol. Primatol. 45, 204–224.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

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Barrett, J., Abbott, D. H. & George, L. M. 1990 Extension of reproductive suppression by pheromonal cues in subordinate female marmoset monkeys, Callithrix jacchus. J. Reprod. Fert. 90, 411–418. Bensafi, M. et al. 2003 Sex-steroid derived compounds induce sex-specific effects on autonomic nervous system functions in humans. Behav. Neurosci. 117, 1125–1134. (doi:10.1037/0735-7044.117.6.1125) Burley, N. 1979 The evolution of concealed ovulation. Am. Nat. 114, 835–858. (doi:10.1086/283532) Converse, L. J., Carlson, A. A., Ziegler, T. E. & Snowdon, C. T. 1995 Communication of ovulatory state to mates by female pygmy marmosets (Cebuella pygmaea). Anim. Behav. 49, 615–621. Dixson, A. F. & Lloyd, S. A. C. 1988 The hormonal and hypothalamic control of primate sexual behaviour. Symp. Zool. Soc. Lond. 60, 81–117. Epple, G. & Katz, Y. 1984 Social influences on estrogen excretion and ovarian cyclicity in saddleback tamarins (Saguinus fuscicollis). Am. J. Primatol. 6, 215–227. (doi:10. 1002/ajp.1350060309) Epple, G., Belcher, A. M., Kuderling, I., Seller, U., Scolnick, L., Greenfield, K. L. & Smith III, A. B. 1993 Making sense out of scents: species differences in scent glands, scent marking behaviour, and scent mark composition in the Callitrichidae. In Marmosets and tamarins: systematics, behaviour and ecology (ed. A. B. Rylands), pp. 123–151. Oxford, UK: Oxford University Press. Evans, S. 1983 The pair-bond of the common marmoset, (Callithrix jacchus jacchus): an experimental investigation. Anim. Behav. 31, 651–658. (doi:10.1016/S0003-3472(83) 80220-6) Ferris, C. F. & Snowdon, C. T. 2005 Functional magnetic resonance imaging in conscious marmoset monkeys: methods and applications in neuroscience research. In The laboratory primate (ed. S. Wolfe-Coate). Handbook of experimental animals. London, UK: Academic Press. Ferris, C. F. et al. 2001 Functional imaging of brain activity in conscious monkeys responding to sexually arousing cues. NeuroReport 12, 2231–2236. (doi:10.1097/00001756200107200-00037) Ferris, C. F. et al. 2004 Imaging neural pathways associated with stimuli for sexual arousal in nonhuman primates. J. Mag. Res. Imag. 19, 168–175. (doi:10.1002/jmri.10456) French, J. A. & Cleveland, J. 1984 Scent marking in the tamarin, Saguinus oedipus: sex differences and ontogeny. Anim. Behav. 32, 615–623. (doi:10.1016/S0003-3472(84) 80299-7) French, J. A. & Snowdon, C. T. 1981 Sexual dimorphism in responses to unfamiliar intruders in the tamarin (Saguinus oedipus). Anim. Behav. 29, 822–829. (doi:10.1016/S00033472(81)80016-4) French, J. A., Abbott, D. H. & Snowdon, C. T. 1984 The effect of social environment on estrogen secretion, scent marking and sociosexual behavior in tamarins (Saguinus oedipus). Am. J. Primatol. 6, 155–167. (doi:10.1002/ajp. 1350060304) Heymann, E. W. 2003 Scent marking paternal care and sexual selection in Callitrichines. In Sexual selection and reproductive competition in primates; new perspectives and directions (ed. C. Jones), pp. 305–325. New York, NY: Wiley Liss. Hrdy, S. 1999 Mother nature, maternal instincts and how they shape the human species. New York, NY: Ballantine. Lazaro-Perea, C. 2001 Intergroup interactions in wild common marmosets, Callithrix jacchus; territorial defence and assessment of neighbours. Anim. Behav. 62, 11–21. (doi:10.1006/anbe.2000.1726) Phil. Trans. R. Soc. B (2006)

Lazaro-Perea, C., Snowdon, C. T. & Arruda, M. F. 1999 Scent-marking behavior in wild groups of common marmosets (Callithrix jacchus). Behav. Ecol. Sociobiol. 46, 313–324. (doi:10.1007/s002650050625) Lazaro-Perea, C., Castro, C. S. S., Harrison, R., Araujo, A., Arruda, M. F. & Snowdon, C. T. 2000 Behavioral and demographic changes following the loss of the breeding female in cooperatively breeding marmosets. Behav. Ecol. Sociobiol. 48, 137–146. (doi:10.1007/s002650000215) Lloyd, S. A. C. & Dixson, A. F. 1988 Effects of hypothalamic lesions upon the sexual and social behaviour of the male common marmoset (Callithrix jacchus). Brain Res. 463, 317–329. (doi:10.1016/0006-8993(88)90405-2) Paredes, R. G. & Baum, M. J. 1995 Altered sexual partner preference in male ferrets given excitotoxic lesions of the preoptic area/anterior hypothalamus. J. Neurosci. 15, 6619–6630. Paredes, R. G., Tzschentke, T. & Nakach, N. 1998 Lesions of the medial preoptic area/anterior hypothalamus (MPOA/AH) modify partner preference in male rats. Brain Res. 813, 1–8. (doi:10.1016/S0006-8993(98)00914-7) Preti, G., Wysocki, C. J., Barnhart, K. T., Sondheimer, S. J. & Leyden, J. L. 2003 Male axillary extracts contain pheromones that affect pulsatile secretion of luteinizing hormone and mood in women recipients. Biol. Reprod. 68, 2107–2113. (doi:10.1095/biolreprod.102.008268) Sanchez, S., Peleaz, F., Gil-Burmann, C. & Kaumanns, W. 1999 Costs of infant carrying in the cotton-top tamarin. Am. J. Primatol. 48, 99–111. (doi:10.1002/(SICI)10982345(1999)48:2!99::AID-AJP2O3.0.CO;2-6) Savic, I., Berglund, P., Gulyas, B. & Roland, P. 2001 Smelling of odorous sex hormone-like compounds causes sex differentiated hypothalamic activations in humans. Neuron 31, 661–668. (doi:10.1016/S0896-6273(01)00390-7) Savic, I., Berglund, H. & Lindstrom, P. 2005 Brain responses to putative pheromones in homosexual men. Proc. Natl Acad. Sci. USA 102, 7356–7361. (doi:10.1073/pnas. 0407998102) Savage, A., Ziegler, T. E. & Snowdon, C. T. 1988 Sociosexual development, pairbond formation and mechanisms of fertility suppression in female cotton-top tamarins (Saguinus oedipus oedipus). Am. J. Primatol. 14, 345–359. (doi:10.1002/ajp.1350140404) Singh, D. & Bronstad, P. M. 2001 Female body odour is a potential cue for ovulation. Proc. R. Soc. B 268, 797–801. (doi:10.1098/rspb.2001.1589) Smith, T. E. & Abbott, D. H. 1998 Behavioral discrimination between circumgenital odor from periovulatory dominant and anovulatory female common marmosets (Callithrix jacchus). Am. J. Primatol. 46, 265–284. (doi:10.1002/(SICI) 1098-2345(1998)46:4!265::AID-AJP1O3.0.CO;2-D) Smith, A. B., Yarger, R. G. & Epple, G. 1976 The major volatile constituents of the marmoset (Saguinus fuscicollis) scent mark. Tetrahedron Lett. 17, 983–986. (doi:10.1016/ S0040-4039(00)77984-6) Smith, T. E., Abbott, D. H., Tomlinson, A. J. & Mlotkewicz, J. A. 1997 Differential display of investigative behavior permits discrimination of scent signatures from familiar and unfamiliar socially dominant female marmoset monkeys (Callithrix jacchus). J. Chem. Ecol. 23, 2523–2546. (doi:10. 1023/B:JOEC.0000006664.38169.e5) Snowdon, C. T. 1996 Parental care in cooperatively breeding species. In Parental care: evolution, mechanisms and adaptive significance (ed. J. S. Rosenblatt & C. T. Snowdon), pp. 643–689. San Diego, CA: Academic Press. Snowdon, C. T. 2001 Sexe, attachement et monogamie chez les primates (sex, pairbonds and monogamy in primates). Primatologie 3, 387–420. Sobel, N., Prabhakaran, V., Hartley, C. A., Desmond, J. E., Glover, G. H., Sullivan, E. V. & Gabrielli, J. D. E. 1999

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Social odours, sexual arousal and pairbonding C. T. Snowdon and others Blind smell: brain activation induced by an undetected airborne chemical. Brain 122, 209–217. (doi:10.1093/brain/ 122.2.209) Stern, K. & McClintick, M. K. 1998 Regulation of ovulation by human pheromones. Nature 392, 177–179. (doi:10. 1038/32408) Trotier, D., Eliot, C., Wassef, M., Talman, G., Bensimon, J. L., Doving, K. B. & Ferrand, J. 2000 The vomeronasal cavity in adult humans. Chem. Senses 25, 369–380. (doi:10.1093/chemse/25.4.369) Wallen, K. 1982 Influence of female hormonal state on rhesus sexual behavior varies with space for social interactions. Science 217, 375–377. (doi:10.1126/science.7201164) Washabaugh, K. & Snowdon, C. T. 1998 Chemical communication of reproductive status in female cotton-top tamarins (Saguinus o. oedipus). Am. J. Primat. 45, 337–349. (doi:10. 1002/(SICI)1098-2345(1998)45:4!337::AID-AJP2O3.0. CO;2-X) Wyatt, T. D. 2003 Pheromones and animal behaviour, communication by smell and taste. Cambridge, UK: Cambridge University Press. Ziegler, T. E., Bridson, W. E., Snowdon, C. T. & Eman, S. 1987 Urinary gonadotropin and estrogen excretion during the post-partum estrous, conception and pregnancy in the cotton-top tamarin. Am. J. Primatol. 12, 127–140. (doi:10. 1002/ajp.1350120202)

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Ziegler, T. E., Epple, G., Snowdon, C. T., Porter, T. A., Belcher, A. & Kuederling, I. 1993 Detection of the chemical signals of ovulation in the cotton-top tamarin, Saguinus oedipus. Anim. Behav. 45, 313–322. (doi:10. 1006/anbe.1993.1036) Ziegler, T. E., Washabaugh, K. F. & Snowdon, C. T. 2004a Responsiveness of expectant male cotton-top tamarins, Saguinus oedipus, to mate’s pregnancy. Horm. Behav. 45, 84–92. (doi:10.1016/j.yhbeh.2003.09.003) Ziegler, T. E., Jacoris, S. & Snowdon, C. T. 2004b Sexual communication between breeding male and female cotton-top tamarins (Saguinus oedipus) and its relationship to infant care. Am. J. Primatol. 64, 57–69. (doi:10.1002/ ajp.20061) Ziegler, T. E., Schultz-Darken, N. J., Scott, J. J., Snowdon, C. T. & Ferris, C. F. 2005 Neuroendocrine response to female ovulatory odors depends upon social condition in male common marmosets, Callithrix jacchus. Horm. Behav. 47, 56–64. (doi:10.1016/j.yhbeh.2004.08.009) Zinner, D. P., Nunn, C. L., Van Schaik, C. & Kappeler, P. 2004 Sexual selection and exaggerated sexual swelling in female primates. In Sexual selection in primates: new and comparative perspectives (ed. P. Kappeler & C. Van Schaik), pp. 71–89. Cambridge, UK: Cambridge University Press.

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Phil. Trans. R. Soc. B (2006) 361, 2091–2107 doi:10.1098/rstb.2006.1933 Published online 3 November 2006

Voice processing in human and non-human primates Pascal Belin1,2,* 1

Centre for Brain, Music and Sound (BRAMS), De´partement de Psychologie, Universite´ de Montre´al, CP 6128 Succ Centre-Ville, Montre´al, Que´bec, H3C 3J7 Canada 2 Centre for Cognitive Neuroimaging (CCNi), Department of Psychology, University of Glasgow, 58 Hillhead Street, Glasgow G12 8QB, UK

Humans share with non-human primates a number of voice perception abilities of crucial importance in social interactions, such as the ability to identify a conspecific individual from its vocalizations. Speech perception is likely to have evolved in our ancestors on the basis of pre-existing neural mechanisms involved in extracting behaviourally relevant information from conspecific vocalizations (CVs). Studying the neural bases of voice perception in primates thus not only has the potential to shed light on cerebral mechanisms that may be—unlike those involved in speech perception—directly homologous between species, but also has direct implications for our understanding of how speech appeared in humans. In this comparative review, we focus on behavioural and neurobiological evidence relative to two issues central to voice perception in human and non-human primates: (i) are CVs ‘special’, i.e. are they analysed using dedicated cerebral mechanisms not used for other sound categories, and (ii) to what extent and using what neural mechanisms do primates identify conspecific individuals from their vocalizations? Keywords: voice; speech; conspecific vocalizations; speaker recognition; auditory cortex; social cognition

1. INTRODUCTION In the auditory environment of primates, vocalizations produced by a conspecific individual—conspecific vocalizations (CVs)—are sounds of overriding importance. Most non-human primates possess a rich vocal repertoire, which they use in many different contexts, such as agonistic or affiliative interactions with members of their social group, territorial calls and alarm calls, many of them loud enough to be heard at a distance (e.g. Winter et al. 1966; Green 1975). Thus, each individual is daily exposed to a large number of CVs from several callers (Snowdon 1986; Hauser 1996). In humans, particularly in modern societies, voices are everywhere, from physically present individuals as well as increasingly from virtual sources such as radios, TVs, etc., and we spend a large part of our time listening to these voices. CVs are extremely rich in information. The clearest example is human speech, a uniquely human adaptation to transmit symbolic information in a highly efficient manner—although precursors of speech may exist in non-human primates as well (Seyfarth et al. 1980; Hauser et al. 2002). Speech played a major role in our global domination of other species. Accordingly, much research effort in auditory perception has focused on speech perception. Yet, speech perception constitutes the tip of an iceberg of pre-existing cognitive abilities to extract information contained in CVs. Primate vocalizations—human as well as nonhuman—can be thought of as ‘auditory faces’ (Belin et al. 2004) that carry in their acoustic structure a *[email protected] One contribution of 14 to a theme issue ‘The neurobiology of social recognition, attraction and bonding’.

wealth of paralinguistic information. As our face, the human voice carries much information on our physical characteristics and our affective state; for example, allowing recognition of a person over the telephone. Accurate perception of this information plays a major role in our social interactions. Similarly, the cooperative structure and frequent social interactions of most non-human primates emphasize the importance of good abilities to accurately extract information in CVs. Examples of increased chances of mating success and survival related to accurate perception of vocal information include: accurate perception and appropriate response to predators’ alarm calls; rapid recognition by a mother that the distress calls she hears are from her infant; accurate evaluation of reproductive fitness in the call of a potential mate during courtship, etc. The nervous system of our primate ancestors has therefore been subject to high evolutionary pressure to develop neural mechanisms endowing primates with abilities to rapidly and accurately categorize relevant information in CVs, turning them into ‘auditory specialists’ (Ghazanfar & Santos 2003). Many of these ‘voice perception’ abilities are probably shared to a large extent between human and non-human primates—unlike speech perception. Our understanding of the communicative brain can only be increased by a closer study of vocal cognitive abilities having emerged in all primates as similar solutions to common ecological problems, perhaps based on similar cerebral mechanisms as well. This review adopts a comparative perspective to examine behavioural and neurobiological evidence relative to two main questions that can be posed in

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Voice processing in primates (a)

(b)

larynx (source) (c)

vocal tract (filter)

+

(d)

=

output

(e)

Figure 1. Voice production mechanism in primates. (a) Sagittal views depicting vocal tract anatomy in an (i) orang-utan, (ii) a chimpanzee and (iii) a human. Red colour, the tongue body; yellow, the larynx; blue, the air sacs (apes only). Note the longer oral cavity and much lower larynx in the humans, with concomitant distortion of tongue shape compared with orang-utans and chimpanzees. These differences allow a much greater range of sounds to be produced by humans, which would have been significant in the evolution of speech (Fitch 2000). Adapted with permission from Fitch (2000). (b) The source/filter theory. The source/filter theory of vocal production, originally proposed for speech, appears to apply to vocal production in all mammals studied so far. The theory holds that vocalizations result from a sound source (typically produced at the larynx) combined with a vocal tract filter (which consists of a number of formants). This filtering action applies regardless of the type(s) of sound produced at the larynx. Reproduced with permission from Fitch (2000). (c)–(e) Spectrograms (0–5500 Hz) of a rhesus coo (c), a chimp pan-hoot excerpt (d ) and human speech (e ). Note the similarities in structure, with harmonics and formants visible in each case.

similar terms for human and non-human primates. The first question is whether the perception of CVs involves specific neuronal processes or not compared with non-vocal sounds or heterospecific vocalizations. In other words, are CVs ‘special’? The second question concerns the ability to extract identity information in voices. Can our non-human relatives recognize callers by their vocalizations? What are the neuronal correlates of these voice recognition abilities? Before addressing these two issues, we will begin with a rapid overview of similarities and differences in the voice production mechanisms of human and non-human primates. Phil. Trans. R. Soc. B (2006)

2. HUMAN VOICE AND PRIMATE VOCALIZATIONS The human voice and non-human primate vocalizations share a number of similarities in their acoustic structure, but are also characterized by important differences (Fitch 2000, 2003). The basic mechanism of voice production is similar across primates (figure 1); the ‘source/filter theory’ developed by Fant (1960) in the context of human speech production (Fant 1960) also largely applies to non-human primate vocalizations (Owren & Linker 1995; Fitch 2000). Briefly, the sound source produced in the larynx generally consists of quasi-periodic series of pulses generated by the successive openings and closings of the vocal folds

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Voice processing in primates (the ‘mucosal wave’; Titze 1993). The rate of vibration of the vocal folds determines the fundamental frequency of phonation (f0). The frequency spectrum of this sound source contains energy not only at the f0, but also at all integer multiples of the f0 (harmonics). In addition to this quasi-periodic component, the source contains some proportion of inharmonicity, such as temporal irregularities in vocal fold vibration (contributing to the ‘rough’ quality of voice) or noise caused by aerodynamic turbulences (contributing to the ‘breathy’ quality of voice; the source exclusively consists of turbulent noise in the case of whispered speech). Besides the ‘modal’ register described above, humans as well as monkeys and apes are also able to use the larynx in different modes with varying degrees of nonlinearity, such as the ‘falsetto’ and the ‘vocal fry’ registers in humans (Eskenazi et al. 1990). The sound emitted by the larynx is modified by the cavities and tissues located above the larynx (supralaryngeal vocal tract), which act as an acoustic filter relatively independent of the source characteristics— for example, unlike in wind instruments (Fant 1960; Fitch 2003). The vocal tract causes resonances—the ‘formants’—that reinforce energy at certain frequencies depending on the shape of the vocal tract (figure 1). In humans, different vowels correspond to different configurations of the articulators that yield different resonant properties of the vocal tract, and thus induce formants at different frequencies. These formant frequencies constitute a critical acoustic cue for the identification of vowels: speech synthesizers based on formant synthesis achieve a high degree of realism in vowel production using a single source and as little as three formants (e.g. Klatt 1980); reasonable rates of speech recognition can even be obtained from sinewave analogues of speech composed only of three pure tones following the frequencies of the first three formants (Remez et al. 1981). In non-human primates, there is now ample evidence in several species that the laryngeal sound source is also subject to spectral patterning by the supralaryngeal vocal tract, resulting in formants clearly visible on sonograms (Owren et al. 1997; figure 1). Thus, monkeys and apes use vocalizations that combine source due to vocal fold movement with filtering by vocal tract—comparable to our vowels (Rendall et al. 1998). For example, baboon grunts are very similar to our neutral, central vowel pronounced with a relaxed vocal tract (Owren et al. 1997). Apart from these similarities, the human voice differs from non-human vocalizations on several important aspects. There are a number of morphological differences in the vocal apparatus of human and non-human primates (Fitch 2000, 2003). Comparative studies of the anatomy of the vocal folds show that several species of monkeys possess vocal membranes (or vocal lips), consisting of thin extensions of the vocal folds lacking in humans (Scho¨n Ybarra 1995). Although the issue needs further investigation, the very low mass of these vocal membranes is thought to enable the production of vocalizations with high pitch (Fitch 2003). Another difference is that many primates possess air sacs in the larynx—out-pouchings of the epithelium lining the larynx—not present in humans. The exact role of these sacs is still unclear, although Phil. Trans. R. Soc. B (2006)

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they are thought to be involved in the loud calls of some species (Scho¨n Ybarra 1995; Fitch 2003). A more important difference in vocal tract anatomy between human and non-human primates concerns the position of the larynx; the human larynx is much lower than its non-human counterpart (except in very young infants). This particularity has the rather harmful consequence of forcing particles of food or water to pass in front of the trachea before reaching the entrance of the oesophagus, at significant risk of entering into the lungs—causing hundreds of accidental deaths every year. The exact nature of the evolutionary advantage provided by this ‘descent of the larynx’ is still debated, but it must have been quite important to compensate for the associated significant increase in risk of choking. One clear advantage conferred by the descended larynx is the increased space for the tongue, which as a consequence is much less elongated and more flexible in humans (Scho¨n Ybarra 1995). Another possible advantage is that a descended larynx directly lengthens the vocal tract, thus lowering formant frequencies. Since vocal tract length is generally well correlated with body size, the descended larynx could contribute to convey an exaggerated perceptual impression of size in listeners (Fitch 2000, 2003). Especially important consequences of the lowered larynx in humans are an increased flexibility of the tongue and an important angle in the vocal tract, both yielding an increased range of variation in formant frequencies. The typical ‘vowel space’ of non-human primates is smaller (corresponding to less formant variations) due to the relatively inflexible nature of their vocal tract (Lieberman et al. 1969). Thus, non-human primates have a lesser ability to create several acoustically distinctive sounds from a same source through supralaryngeal vocal tract filtering. In sum, the human vocal tract is characterized by several morphological differences that probably contributed to/accompanied the emergence of speech. Yet, the basic mechanisms of voice production are largely similar between humans and our non-human relatives, yielding similar acoustic structures (figure 1) and comparable influence of inter- and within-individual variability. This in turn posed similar ecological problems to the brain of the receiver, which may have been solved using similar cerebral mechanisms across species of primates.

3. ARE CONSPECIFIC VOCALIZATIONS SPECIAL? One essential question relative to the cerebral organization underlying voice perception abilities is whether these neural mechanisms are exclusively dedicated to process CVs or are also involved analysing other classes of sounds. In other words: ‘are primate CVs special’?—or in the case of humans, ‘are voices special?’ (This question has been asked many times in the domain of face perception: the ‘are faces special?’ question still generates much argument and research; Farah 1996; Kanwisher et al. 1997; Gauthier et al. 2000; Haxby et al. 2001). In this section, we review behavioural and neurobiological evidence for species-specific mechanisms in the perception of vocalizations, in non-human primates as well as in humans.

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(a) Behavioural evidence in non-human primates It is clear from observing the behaviour of non-human primates that they are particularly influenced by hearing CVs. One relevant question is whether the special status of these sounds is associated with enhanced measures of perceptual sensitivity for discriminating CVs. Zoloth et al. (1979) used an operant paradigm with food rewards to train several species of Old World monkeys to discriminate between variants of ‘coo’ calls from Japanese macaques (Macaca fuscata). The discrimination could be based either on the temporal position of the f0 peak in the call (‘smooth early’, SE, versus ‘smooth late’, SL), an acoustic cue of behavioural relevance for Japanese macaques, since it distinguishes between variants used in different contexts, or on the starting pitch of the call, an acoustic cue with no particular relevance. Japanese macaques were found to perform much better than the comparison species when the discrimination task was based on the behaviourally relevant temporal cue; in contrast, they were worse than the other monkeys when the discrimination was based on the irrelevant dimension and pitch (Zoloth et al. 1979). Thus, this study provides strong evidence in one species of Old World monkeys for an enhanced perceptual discrimination of CVs compared with other species; however, this seems to hold only if the discrimination is based on an ecologically valid contrast. A connected question is how do non-human primates perceive human speech sounds. Many studies have used speech material to probe auditory perceptual abilities of non-human primates. One study compared difference limens of humans and monkeys at a discrimination task using synthetic consonant–vowel English syllables. The syllables were arranged in a continuum of voice onset time (VOT), an important cue for a place of articulation (Sinnott & Adams 1987). Humans were found to discriminate pairs of syllables with differences in VOT two to four times smaller than the monkeys. Sinnot (1989) also found that monkeys were less accurate than human listeners to discriminate synthetic English vowels. However, the pairs with which the monkeys had most difficulties were also the ones that led to the longest reaction times in humans, suggesting comparable analysis mechanisms (Sinnott 1989). Ramus et al. (2000) found that both cotton-top tamarins as well as human babies were able to discriminate speech sentences in two different languages, but not if the sentences were played backwards (Ramus et al. 2000). Conversely, Hopp et al. (1992) found that Japanese macaques were less accurate than human listeners in a discrimination task along a continuum of synthetic ‘coos’ varying on the temporal position of the f0 peak—although humans also generally perform better at discrimination tasks involving lower-level acoustic cues (Owren et al. 1992). (b) Neurobiological evidence in non-human primates Does the nervous system of non-human primates show a specialization for processing CVs? One possible sign of species specificity in the processing of vocalizations is that primates seem to have increased sensitivity at Phil. Trans. R. Soc. B (2006)

frequencies corresponding to the range found in their species-specific vocalizations (Aitkin et al. 1986; Wang 2000). For example, monkeys have better sensitivity (smaller absolute auditory thresholds) than humans in high, but not in low frequencies (Owren et al. 1988), consistent with the higher frequency range of monkey vocalizations compared with human voice. More evidence is needed to allow the generalization of this observation to all primates. Several teams have used electrophysiological recordings in awake non-human primates to investigate the response of auditory cortex to various sound categories, including conspecific calls. One of the first set of studies was performed in the squirrel monkey, a highly vocal New World primate whose vocal behaviour is well documented (Newman 2003). Winter & Funkenstein (1973) found that more units responded to pure tones than to conspecific calls in auditory cortex, but for the first time evidenced a small number of cells that responded only to CVs. In a subsequent study using a larger set of conspecific calls, they found that more than half the cells that responded to CVs displayed some selectivity in responding only to no more than two acoustically similar calls (Winter & Funkenstein 1973). These results initially suggested the existence of ‘call detectors’, i.e. specialized neurons responding only to CVs. However, subsequent experiments using more repetitions of the same calls found that vocalization-responsive neurons of auditory cortex typically responded to more than one call or to various features of calls (Wollberg & Newman 1972); moreover, their response properties were in fact quite variable and were found to change significantly over the course of an hour (Manley & Muller-Preuss 1978). More recently, Wang et al. (1995) suggested that cells in the primary auditory cortex (A1) of the marmoset could be categorized into two general classes: one responding to call types and another to a wider range of sounds, including vocalizations as well as non-vocal sounds (Wang et al. 1995). Thus, at least at the primary stages of auditory cortex, CVs typically elicit strong responses in a large proportion of cells; however, the notion of ‘call detectors’ or neurons highly specialized for processing CVs now seems doubtful, and this is progressively replaced by the idea of population coding where features of the vocal signal are coded by the distributed activity of a large number of cells (Wang 2000; Newman 2003). One way to better characterize the specificity of response to CVs is to compare the cellular responses to CVs and time-reversed versions of the same calls, i.e. stimuli with the same spectral structure but a different temporal structure and lacking the natural behavioural meaning of these calls. Glass & Wollberg (1983) found in the awake squirrel monkey that the responsiveness of cells of both primary and secondary auditory cortices was not significantly different from calls or their timereversed versions; very few cells were found to show ‘reversed responses’ to the time-reversed vocalizations (Glass & Wollberg 1983). However, a more recent study in the anaesthetized common marmoset found that a majority of A1 neurons showed stronger responses to natural marmoset twitter calls than to

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Voice processing in primates their time-reversed version (Wang et al. 1995). While this finding is consistent with similar recent findings in other species, it may simply reflect the lack of naturalness of the reversed calls and not species specificity per se in the processing of CVs; other stimuli such as heterospecific vocalizations or other natural sounds might very well yield the same result. Some of the strongest evidence against this alternative explanation has been obtained by Wang & Kadia (2001), who compared the responses elicited by natural and time-reversed marmoset twitter calls in A1 neurons of the cat, a species for which neither the natural nor the reversed version of the twitter call have ecological relevance. They found that contrary to marmoset neurons, cat A1 neurons did not respond differently to the natural and time-reversed versions of the call (whereas they were found to do so for cat vocalizations; Wang & Kadia 2001). Moreover, this lack of preference appeared to be due to weaker responses to the natural calls in the cat than in the marmoset A1, whereas responses to the time-reversed calls were comparable in the two species (Wang & Kadia 2001). The diminished response of A1 neurons to time-reversed calls in marmosets is thus not only related to their lack of naturalness, as it was not observed in another species for which the time-reversed call would be presumably as unnatural. However, the stronger response to natural than time-reversed stimuli is not necessarily the signature of a species-specific mechanism, as it could also be related to the ecological value of the call; behaviourally relevant sounds from other species (such as predators or humans) might also induce a similar pattern of response. A stronger test of species specificity in the processing of CVs thus will ultimately require comparison of CVs with a larger array of natural sounds. Thus, there is no clear demonstration yet of neuronal mechanisms selectively engaged by CVs in a non-human primate A1. What is the present evidence in other parts of auditory cortex? Tian et al. (2001) recorded from neurons in the lateral belt of lightly anaesthetized rhesus monkeys in response to the presentation of seven conspecific calls presented at seven azimuthal locations (Tian et al. 2001). In all three regions of the lateral belt (anterolateral, AL; mediolateral, ML; caudolateral, CL), neurons were found to display some call selectivity (i.e. more than half of the cells responding with more than 50% of their maximal firing rate to three calls or less out of the seven calls; Tian et al. 2001). In particular, selectivity was found to be significantly better in the AL field, which the authors interpreted as evidence for a ‘what’ (object identification) versus ‘where’ (spatial localization) functional segregation between anterior and posterior fields, as in primate visual cortex (Ungerleider & Haxby 1994; Kaas & Hackett 1999; Rauschecker & Tian 2000). Neurons responding to sounds and, in particular, CVs have also been observed outside auditory cortex. Romanski & Goldman-Rakic (2002) identified what seems to constitute an auditory responsive region in the prefrontal cortex of awake-behaving rhesus macaques. Neurons in a discrete region of ventrolateral prefrontal cortex were found to respond to complex sounds, including CVs and human vocalizations. Most neurons in this auditory domain responded to both vocalizations Phil. Trans. R. Soc. B (2006)

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and non-vocalization stimuli, but most (nZ52/70) responded more strongly to vocalizations, and a small subset of cells (nZ3) responded only to macaque or human vocalizations, with at least one cell responding only to a CV (Romanski & Goldman-Rakic 2002). More recently, Romanski et al. (2004) investigated in greater detail the response of these auditory prefrontal cells to CVs, using a large set of CVs from several different callers. The majority of the recorded cells was found to respond to between two and five vocalizations, with 2/301 cells being caller-selective. However, because this last study focused on the response to CVs, cells responsive to CVs were not tested with non-vocalization stimuli, not allowing any conclusion to be drawn on the possible vocalization specificity of these cells. In sum, a large body of electrophysiological studies in non-human primates has evidenced many cells with significant responses to CVs in primary and secondary auditory cortices, as well as in ventrolateral prefrontal cortex. Yet, few studies to date have systematically compared responses elicited by CVs with those elicited by heterospecific vocalizations or by equally complex, non-vocalization stimuli. Only one study so far has reported cells that seemed to respond only to CVs (Romanski & Goldman-Rakic 2002), although in very small proportion (one or two on 400 recorded cells). Thus, it seems too early to conclude unequivocally on the species specificity of the mechanisms involved in processing CVs in non-human primates. (c) Functional lateralization in processing CVs Several studies have measured indexes of functional lateralization in the processing of CVs by non-human primates seeking to demonstrate an advantage of the left hemisphere. The rationale behind these studies is that left-lateralized processing of CVs in non-human primates might provide an evolutionary precursor of the lefthemisphere advantage for speech processing in humans. Petersen et al. (1978) used a psychophysical paradigm similar to the one used by Zoloth and colleagues (see §3a) to train several species of Old World monkeys to discriminate between variants of ‘coo’ calls from Japanese macaques (M. fuscata), except that stimuli were presented monaurally either to the left or to the right ear. When the discrimination was based on the communicatively relevant peak position (SE versus SL), they found that all five Japanese macaques they had trained made less errors when CVs were presented to the right as compared with the left ear; such a right-ear advantage was only observed in one out of five of the animals from comparison species. In contrast, Japanese macaques trained to perform the discrimination based on the pitch dimension showed either a left-ear advantage or no advantage. A follow-up study by the same group replicated the findings of a right-ear advantage in Japanese macaques in the discrimination of SE versus SL versions of their coos, and further confirmed that comparison animals failed to show lateralized processing although they were using similar acoustic dimension in their judgement (Petersen et al. 1984). These results provide strong evidence that leftlateralized neural mechanisms analogous to those observed in human speech processing can be engaged

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in Japanese macaques when they attend selectively to the temporal position of the f0 peak in their coo (SE versus SL). The lack of lateralization in comparison animals in two consecutive studies is particularly interesting, since it suggests that these lateralized processes could be observed only for conspecific calls; yet a complete verification of this hypothesis would have required animals to be tested with vocalizations from the comparison species as well. The fact that Petersen et al. (1978) did not observe a right-ear advantage when the same sounds were discriminated by pitch—although only in two animals—could be interpreted along with the authors as suggesting that only the communicatively relevant features of the call might engage lateralized processes. Alternatively, different features of the same call could be processed using partially distinct, differentially lateralized neural networks, as seems to be the case in humans; speech processing engages left-lateralized networks in most right-handed human subjects, but processing of pitch or identity from the same vocal input reverses this pattern and yields a right-hemisphere advantage (Zatorre et al. 1992; von Kriegstein et al. 2003). Another method used to measure functional asymmetries in non-human primates involves unilateral cortical lesions. Heffner & Heffner (1984) used a variant of the paradigm used by Petersen et al. (1984) to train Japanese macaques to perform the discrimination of SE versus SL among 15 different coos. Then they performed unilateral lesions in the superior temporal gyrus encompassing primary as well as secondary auditory cortices and measured the effects of the lesions on performance at the coo discrimination according to whether the lesion had been performed in the left (five animals) or in the right (five animals) hemisphere. A striking pattern of lateralization emerged: the animals having received a lesion in the right hemisphere showed no noticeable deficit when tested within 3–8 days of the lesion, whereas the animals with a lesion in the left hemisphere showed a marked initial deficit followed by a progressive recovery over the following days. A second lesion to the remaining auditory cortex of the other hemisphere then completely abolished the ability to discriminate the coos (Heffner & Heffner 1984). The monkeys were still able to perform simpler discrimination of coos from noise or tones outside the frequency range of coos (2 and 4 kHz; Heffner & Heffener 1986). Thus, these results are consistent with the findings of Petersen et al. (1978, 1984) in suggesting that the discrimination of SE and SL coos primarily engages the left hemisphere in Japanese macaques. Playback experiment in field studies has also yielded useful information on the cerebral lateralization of the processing of CVs. Hauser & Andersson (1994) monitored the orienting response to CVs in a large number of free-ranging rhesus macaques in the colony of Cayo Santiago. The sounds were played exactly 1808 behind the experimental animal while feeding on one of the three food dispensers of the island, so that the target animal could choose to orient to the source by turning the head either to the left or to the right. The majority of adult macaques (61 out of 80) was found to orient to the sound source by turning their head to the right, thus Phil. Trans. R. Soc. B (2006)

seeking to increase sound amplitude in the right ear, or the left hemisphere, whereas they tended to present the left ear to the source when a familiar, but heterospecific alarm call was played. Infants tested using the same paradigm failed to show any head-turning preference. The authors interpreted this finding as evidence for left-biased cerebral lateralization for processing CVs in the rhesus macaque, as for human speech, but only once a certain stage of maturation is reached. Followup studies using the same paradigm but acoustically modified CVs replicated the right-ear orienting bias in the adult rhesus monkeys, and further showed that temporal modifications such as expansion of contraction (Hauser et al. 1998) or temporal inversion (Ghazanfar et al. 2001) could eliminate or reverse the right-ear advantage. (d) Neuroimaging studies in non-human primates More recently, several teams used neuroimaging techniques generally used in humans to measure cerebral activity during processing of CVs in awake monkeys. Poremba et al. (2004) used positron emission tomography (PET) to measure metabolic activity in rhesus macaques during passive listening to several classes of complex sounds, including CVs, human vocalizations, as well as non-vocal sounds from the environment (Poremba et al. 2004). Each superior temporal gyrus was divided into five regions of interest, and metabolic activity in each region was compared across hemispheres. Unexpectedly, all sound categories elicited stronger activity in the right than in the left hemisphere in the posterior parts of the superior temporal gyrus corresponding to auditory cortex. Yet, a left-lateralized pattern of activity was found in the dorsal temporal pole, the most anterior region of interest, only for the conditions where CVs were present (CVs or CVs mixed with other sounds). These findings were interpreted as suggesting that the temporal pole might constitute a precursor of a human acoustic language area (Poremba et al. 2004). Of particular interest would have been a comparison of activity across the different classes of sounds within a same region. This comparison, unfortunately not provided, would have had the potential to uncover possible regions of specific response to CVs in non-human primates. Gil-da-Costa et al. (2004) used PET in awake macaques to measure cerebral blood flow during auditory stimulation with CVs (coos and screams) and non-biological sounds. They found that CVs elicited greater activity than non-biological sounds in several posterior visual-processing regions extending from early to higher-order areas in the ventral object-processing stream and in visual motion-processing areas extending to posterior superior temporal sulcus (STS; Gil-da-Costa et al. 2004). Interestingly, they also found CVs to elicit greater activation than the non-biological sounds in several peri-sylvian areas, including area Tpt in the posterior superior temporal gyrus, as well as in the ventrolateral portions of the STS (Ricardo Gil-da-Costa, personal communication). Unfortunately, however, neuronal activity was not measured during stimulation with intermediate control categories, such as biological sounds or heterospecific vocalizations. Thus, the species

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(a)

(b)

Figure 2. STS voice-selective areas in humans. (a) Spectrograms (0–5000 Hz) of examples of (i) non-vocal and (ii) vocal sounds used by Belin et al. (2000). Note their similar apparent complexity. (b) Cortical rendering of regions showing greater response to vocal compared with non-vocal sounds in eight subjects, located in the anterior part of the STS. Reproduced with permission from Belin et al. (2004).

specificity of these activations remains to be demonstrated in future studies. (e) Specialization for voice perception in humans Humans have presumably been subject to similar evolutionary pressure as non-human primates to develop mechanisms specialized in accurately extracting information in CVs (voice). The paramount importance of speech in all human societies makes it even more probable that specific mechanisms have evolved in the human brain to process sounds of voice. What is the present evidence for such voice-selective mechanisms in humans? Studies of patients with cerebral lesions constitute one crucial source of information. It is well known that lesions in the region of the left posterior superior temporal gyrus lead to the syndrome known as ‘Wernicke’s aphasia’, which is characterized among other things by a severe deficit in speech comprehension (Wernicke 1874; Damasio 1992). Another syndrome known as ‘pure Phil. Trans. R. Soc. B (2006)

word deafness’, reported to occur after lesions involving the primary auditory cortex bilaterally (Shoumaker et al. 1977; Coslett et al. 1984), is characterized by a deficit that appears restricted to sounds of speech. In these two syndromes, the perception and recognition of other sounds such as music or sounds from the environment appear essentially preserved, which suggests that the deficits are restricted to human speech and makes a strong case for species specificity in humans’ auditory processing. However, this is not very surprising since speech is unique to humans. Is there evidence for other acquired deficits restricted to human voice perception but not to speech? As noted by several authors, speech is but only one type of information contained in voice. The human voice contains a wealth of paralinguistic information, such as information on the speaker’s identity (gender, approximate age, etc.) and affective state, and a sound of voice may very well contain no speech at all (e.g. laughs, cries). These types of information are also present

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to some extent in the vocalizations of non-human primates. Thus, evidence for human mechanisms selectively involved in extracting paralinguistic information in voice would be particularly useful, given our comparative perspective. Such evidence exists and comes from the study of patients with deficits in voice discrimination or recognition, a deficit termed ‘phonagnosia’ (Van Lancker & Canter 1982). The first report of such patients was by Assal and colleagues (Assal et al. 1976) and has been followed by several others in the same decade (Assal et al. 1981; Landis et al. 1982; Van Lancker & Canter 1982; Van Lancker & Kreiman 1987; Van Lancker et al. 1988, 1989). Then, all interest in phonagnosia seems to have vanished (but see Peretz et al. 1994; Neuner & Schweinberger 2000) probably due to the lack of a standardized battery of voice discrimination and recognition, forcing interested researchers to devise their own tests. Briefly, phonagnosia, like prosopagnosia the equivalent deficit for faces, has been found to occur most often after posterior right-hemisphere lesions. Phonagnosia has been dissociated from voice discrimination deficits (Van Lancker & Kreiman 1987) and doubly dissociated from aphasia; patients with receptive aphasia but unimpaired voice recognition have been reported, as well as patients with phonagnosia but normal speech perception (Van Lancker & Canter 1982). Most importantly for our discussion, at least one case of phonagnosia with preserved recognition of environmental sounds has been reported (Peretz et al. 1994), suggesting that voice recognition might rely on a different neural substrate than recognition of other sound sources, an argument for species specificity in the processing of voice. However, the poor resolution of the scanner used for lesion localization in most reported cases of phonagnosia prevents the precise neuroanatomical identification of these putative voicespecific mechanisms. (f ) Neuroimaging evidence for voice-selective mechanisms in humans Neuroimaging studies using PET or functional magnetic resonance imaging (fMRI), by measuring noninvasively the cerebral activity of awake, behaving normal humans, have allowed substantial progress in our understanding of the functional organization of human auditory cortex (Zatorre & Binder 2000). In particular, a number of studies have investigated the neural correlates of speech perception and highlighted a large-scale network of parallel, distributed neuronal activity involving cortical regions, such as inferior prefrontal cortex, posterior temporal cortex, inferior parietal lobule and anterior STS with a predominance of the left hemisphere (De´monet et al. 1992; Binder et al. 2000; Scott et al. 2000; Crinion et al. 2003; Scott & Johnsrude 2003; but see Poeppel 1996; Price et al. 2005). However, these studies typically contrasted speech stimuli with much lower-level control stimuli, such as tones, noise or amplitude-modulated noise. The lack of control stimuli of intermediary complexity makes it hard to understand exactly which features of the speech signal are responsible for the different components of Phil. Trans. R. Soc. B (2006)

the pattern of cortical activation. Are these active regions really all involved in processing speech information? One troubling observation is that timereversed speech—a signal which carries no linguistic content, although it essentially preserves the timbre and pitch variations of the voice—yields a pattern of activation quite similar to the one induced by the original speech signal in a large part of auditory cortex (Binder et al. 2000). Hence, could some lowerlevel features of the signal be determinant regardless of the speech content, for example, such as the signal’s ‘voiceness’? (g) Voice-selective areas along anterior STS Belin and colleagues used fMRI to compare the cortical activation patterns induced by vocal versus non-vocal sounds in normal adult volunteers (Belin et al. 2000, 2002; Fecteau et al. 2004, 2005). The vocal sounds were from a large variety of speakers spanning a large age range; they consisted of either speech sounds, such as syllables, words or connected speech in several languages, or non-speech vocal sounds, such as coughs, cries, laughs, various interjections, etc. The non-vocal sounds were matched in number, duration and energy, and consisted of instrumental, mechanical and environmental sounds or animal vocalizations. A first experiment used a block design and a passive listening task with only two categories: vocal and non-vocal. In all participants, discrete regions of auditory cortex were found to respond significantly more to the vocal than to the non-vocal sounds (Belin et al. 2000). No region of auditory cortex was found to respond more to the non-vocal sounds. The anatomical localization of the voice-sensitive cortex was quite variable across subjects, unilateral on the left in some subjects, on the right in some others and bilateral in some (Belin et al. 2002), yet these regions were consistently located along the upper bank of the STS. The predominance of middle and anterior STS regions was confirmed in the group-level analysis. Interestingly, the voice-sensitive activity was the strongest on the right side, which appeared counter-intuitive at first, given the well-established advantage of the left hemisphere for speech (Belin et al. 2000; figure 2). Follow-up experiments confirmed and extended the finding of voice-sensitivity along anterior STS. The voice-sensitive anterior STS regions were found to respond more strongly to voice than to control categories, such as a homogeneous category consisting of only bells or to acoustic control sounds equated in amplitude waveform or in an average long-term frequency (Belin et al. 2000). The STS voice-sensitive response therefore also proved to be quite selective. Fecteau et al. (2004) tested the species specificity of this response by comparing, using an event-related design, vocal and non-vocal sounds to a category of only cat vocalizations and a category of mixed animal vocalizations. The comparison of the human vocal with the non-vocal sounds again yielded bilateral activation along the middle and anterior STS; in contrast, the animal vocalizations, although matched in number and overall energy to the human vocalizations, only yielded marginal activation of the STS when compared with the non-vocal sounds (Fecteau et al. 2004).

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Voice processing in primates (h) Electrophysiological evidence in humans Electrophysiological techniques also proved useful in investigating the ‘special’ status of voice in the auditory cortical activity of normal, behaving adult humans. Levy et al. (2001) compared the evoked response potentials elicited by a sung voice and by pitch-matched notes played on different musical instruments. A late positive component peaking about 320 ms after sound onset was observed only in response to the sung voice (Levy et al. 2001). However, this ‘voice-specific response’ was not observed when participants did not attend to the auditory stimuli, or when they attended to features other than timbre. Thus, the ‘voice-specific response’ might reflect attentional processes related to the overriding salience of voice stimuli (Levy et al. 2003). This important finding suggests an electrophysiological counterpart for the STS activations observed with fMRI. It is tempting to suggest that the generators of this late positivity may be located along anterior STS bilaterally. Yet 320 ms is a considerable time to show a differential response to such a biologically important sound category. It is a much longer time, for example, than the 170 ms that the visual cortex needs to differentiate faces from non-face objects, despite the later arrival of the sensory wave of information in visual compared with auditory cortex. Thus, one might reasonably make the hypothesis that components differentially sensitive to vocal and non-vocal information might be observed with earlier latencies, comparable to the face-selective N170. Such a putative early response remains to be discovered. Overall, there is converging evidence from a variety of experimental techniques that a normal human brain contains several cortical areas selectively activated by sounds of human voice. This finding is very similar to the observations that several face-selective regions can be found in visual cortex (Puce et al. 1995; Kanwisher et al. 1997; Haxby et al. 2001), and suggests that face and voice processing could be organized following similar principles of cortical organizations (Belin et al. 2004). As for face processing, an important question arises: what is the functional role of the voice-selective cortical areas? Are they truly voice-selective? Or are they associated with our expertise for voices, and could be activated for other categories of expertise? This important question, still actively debated in the domain of face processing (Gauthier et al. 2000), is at present virtually unexplored in the domain of voice processing. (i) Abnormal cortical response to voice in autism Gervais et al. (2004) investigated the voice-sensitive cortical activity in autistic individuals. They used fMRI and the same protocol as Belin et al. (2000) to compare a group of five adults with autism with a group of eight age-matched controls. The control group showed an enhanced activation along anterior STS regions when vocal sounds were compared with non-vocal sounds, consistent with the previous experiments. In contrast, no voice-sensitive response could be observed in the autistic group (Gervais et al. 2004). When the responses to the vocal and non-vocal sounds were independently analysed, the response of the autistic group to the non-vocal sounds was found to be essentially normal, i.e. no different from that of the Phil. Trans. R. Soc. B (2006)

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control group. It is only for the vocal sounds that an abnormality appeared; the autistic participants failed to show additional STS activation for the sounds of voice. Their pattern of cerebral activation for the vocal sounds was essentially similar to that for the non-vocal sounds. In other words, for the auditory cortex of the autistic participants, voices had nothing special, they were just another sound category (Gervais et al. 2004). The findings of Gervais et al. (2004) are interesting, in that the abnormal response of the cortex to sounds of voice is consistent with behaviour of autism and parallels recent findings of abnormal activation of face-processing networks in autism (Schultz et al. 2000). They also raise many questions that remain to be answered. One important question is whether the abnormal cortical response to voice can be generalized to all classes of vocal sounds and all groups of autistic subjects. Pelletier et al. (2005) recently investigated a small group of ‘high functioning’ autistic subjects, using the same experimental procedure as Gervais et al. (2004). This time, each autistic subject in whom functional images were successfully obtained showed activation of the STS in the vocal versus non-vocal comparison, comparable to the control subjects (Pelletier et al. 2005). Again, the small number of subjects calls for replication, but is seems that autism may not be automatically associated with abnormal cortical response to voice, and that variables such as performance IQ may prove to play a critical role. Future experiments need to investigate this possible relationship in more details and to relate cortical activity to measures of behavioural performance at voice perception tasks. In sum, the study of the neural correlates of voice perception in autism is a young but promising area of research which deserves as much attention as its counterpart in the domain of face processing.

4. PERCEPTION OF IDENTITY INFORMATION IN VOICE It is a common observation that we can discriminate voices from different persons, extract much information on the physical characteristics of a speaker and often recognize familiar individuals from their voice alone. Do we share this ability to extract identity cues from voice with our non-human relatives? To begin with, are calls from different primates of a same species distinctive? If yes, do monkeys and apes actually use this identity information in their behaviour? And what are the neural correlates of these abilities? (a) Identity information in primate vocalizations The vocal production mechanism of primates allows a fair degree of variation in the acoustic structure of vocalizations, both inter-individually and across individuals. Slight differences in physical morphology between individuals of a same species have the potential to yield consistent acoustic differences. As discussed by Rendall et al. (1998), three main sources of individual variation that can lead to acoustic differences in a vocalization are as follows. (i) Variation in laryngeal anatomy, such as overall size of the larynx, size and relative proportion of

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the vocal folds, amount of lubrication, presence of abnormalities, pattern of glottal closure, etc. Such variation in the source of the vocal tract can lead to differences in the fundamental frequency of phonation (f0). Babies tend to have higher-pitched voice than adult females who tend to have higher-pitched voices than adult males (Titze 1989). Yet, the f0 can also vary substantially in each individual, such that there is considerable overlap in f0 range between these groups (Hillenbrand et al. 1995). Thus, f0 alone is not a really good indicator of vocal identity (Kunzel 1989). (ii) Variation in supralaryngeal anatomy, such as in the shape and length of the vocal tract, elasticity of the tissues, etc. One particularly important parameter is the length of vocal tract, which is tightly related to the body size and largely determines the frequencies of the formants (Fitch 2000). However, the vocal tract length is not an absolute indicator of identity, since it can also show some degree of within-individual variability, particularly in humans; speech is essentially a rapid succession of fast changes of vocal tract shape that induce associated changes in formant frequencies. (Yet, individuals can be identified from sine-wave versions of their speech in which only formant frequencies are represented; Remez et al. 1997). Modifications of formant frequencies by alteration of the vocal tract length—such as by protruding lips—have also been observed in non-human primates, although the range of formant variation (the ‘vowel space’) is much smaller in non-human primates than in humans (Lieberman et al. 1969; Owren & Rendall 2003). The effect of the supralaryngeal filtering, and thus the perceptual salience of inter-individual variability, is the strongest for harmonically rich sounds, such as the coos or grunts of baboons (Owren et al. 1997) or the human vowels. (iii) Variation in temporal patterning, i.e. variations in the timing and duration of the vocalization that can be quite idiosyncratic and sometimes allow recognition, such as in some characteristic laughs that unmistakably identify their human owner. Variations in voice production between individuals induce variations in the spectro-temporal distribution of acoustic energy, which in turn may or not have the potential to lead to successful discrimination or identification. In order to discriminate and eventually identify individuals based on their vocalizations, nonhuman primates as well as humans need to construct some sort of ‘vocal signature’, representation of an individual’s voice based on a combination of acoustic features that maximizes inter-individual variation while minimizing within-individual variation. It is clear to us that the human voice contains such combination of features, otherwise we would not be able to identify persons on the telephone. Is this the case as well for our non-human relatives? Can vocalizations from nonhuman primates be individually distinctive? Phil. Trans. R. Soc. B (2006)

The information to discriminate speakers is indeed present in the vocalizations of many species of apes and monkeys as shown by several methods, in particular by statistical studies using clustering methods (reviewed in Snowdon 1986). Recent evidence for individual distinctiveness in vocalizations was obtained in the squirrel monkey (Boinski & Mitchell 1997), in the baboon (Owren et al. 1997), the rhesus monkey (Rendall et al. 1996, 1998; Owren & Rendall 2003), the Japanese macaque (Ceugniet & Izumi 2004a) and the cotton-top tamarin (Weiss et al. 2001). Owren et al. (1997) showed that the spectral energy peak (formant) patterning varied with caller identity in baboon grunts, and constituted the strongest grouping variable. The amplitude and frequency of the formants was found to emerge as a ‘predominant source of identity-based classificatory power’ (Owren et al. 1997). However, this information can be more present in some vocalizations than in others. Thus, the screams of rhesus monkeys appear to be less discriminative than the coos (Rendall et al. 1998), consistent with the idea that harmonically rich, low-frequency sounds comparable to our vowels are especially well suited to provide good estimates of vocal tract filtering effects. It has been suggested that these characteristics of the call may have been selected in the evolution partly owing to this reason (Brown 2003). Thus, vocalizations by non-human primates can contain information that allows distinction of individuals. Can non-human primates use this information? Again, evidence using different methods in several species suggests that non-human primates, as humans, are able to use the idiosyncratic information in calls to discriminate or identify callers. (b) Behavioural evidence in non-human primates The ability to signal and perceive kin and identity at a distance through vocalizations—monkeys seem to avoid visual contacts in their social interactions—plays an important role in the social life of primates. It may constitute an adaptation of extreme importance in facilitating intra-group social cohesion (Rendall et al. 1996). Indeed, complex social interactions of most primates call for a good ability to discriminate between other group members from vocal cues alone, to extract kin relations, or even to explicitly recognize each other (Rendall et al. 1996, 1998). Several studies investigated one particularly important example of vocal identification: the vocal recognition of infants by their mothers. The ability to accurately recognize her infant by his cries indeed provides a clear selective advantage by allowing the mother to respond appropriately to potentially dangerous situations, thus increasing offspring’s chances of survival. Kaplan et al. (1978) examined the responses of captive squirrel monkeys to vocalizations produced by their infants as well as by infants from other females. The responses of mothers to their own infant’s cries were clearly different from responses to cries from other infants, with a large increase in number of maternal vocalizations (Kaplan et al. 1978). Cheney & Seyfarth (1980), using playback of juvenile cries in a group of free-ranging vervet monkeys, found that the

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Voice processing in primates mothers responded significantly faster and were more likely to approach the crying infant than other females (Cheney & Seyfarth 1980). Similar evidence was obtained in a group of three Japanese macaques mothers (Pereira 1986). Other studies have investigated vocal recognition outside the mother–infant context. In an important study, Rendall et al. (1996) used single-trial playbacks in free-ranging rhesus macaques and showed that female rhesus responded faster and longer to contact ‘coo’ calls produced by a matrilineal relative than by a familiar, but non-kin individual (Rendall et al. 1996). Moreover, when tested with a habituation paradigm, the macaques showed a significant recovery from adaptation when the identity of the caller changed. Thus, these data suggest that monkey can extract enough information from a call to discriminate kin from non-kin individuals and discriminate between individuals. However, this ability does not generalize to all vocalizations, since screams were not found to allow accurate discrimination of kin or identity in a subsequent study (Rendall et al. 1998). Comparable results were obtained in captive monkeys from several species. Weiss et al. (2001) used a habituation–dishabituation paradigm in the cotton-top tamarin and showed that habituation transferred when a different call was played but from the same individual, whereas they dishabituated when caller identity changed ( Weiss et al. 2001). Ceugniet & Izumi (2004a,b) used an operant conditioning procedure to train two captive Japanese macaques to discriminate the calls from three conspecific callers (30 vocalizations each). The macaques then were able to successfully transfer discrimination of identity when new calls from these three callers were introduced (Ceugniet & Izumi 2004b). Interestingly, the monkeys performed less well, but still above chance, when the calls had been low-pass filtered to preserve only the first harmonic, thereby eliminating cues to vocal tract filtering. Thus, the patterning of source harmonics by the vocal tract is an important, but not essential cue to vocal identity; interindividual variation related to the source or temporal patterning, which are comparatively preserved in the low-passed vocal stimuli, also allow above-than-chance identification of the ‘speaker’. Evidence for identification of individual by vocal cues alone has also recently been obtained in greater apes. A captive female chimpanzee was shown to successfully match various calls (pan hoots, pan grunts and screams) from 10 different chimpanzee callers to the photograph of these callers (Kojima et al. 2003). She was also able to identify both callers of a duet of pan-hoots, suggesting that abilities of caller identification are present to a remarkable degree in chimpanzees. Thus, the available data show that non-human primates appear to be able to use the individually distinctive information present in voice to discriminate and recognize individuals. (c) Behavioural evidence in humans As we all can experience it each time we hear a voice, we are able to extract rich information on the physical characteristics and identity of a speaker/caller. An important corpus of studies has measured the accuracy Phil. Trans. R. Soc. B (2006)

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with which normal human listeners can extract different types of identity information (reviewed in Kreiman 1997). The first physical characteristic we judge easily and relatively accurately is gender (Lass et al. 1976; Childers & Wu 1991; Wu & Childers 1991; Mullennix et al. 1995; Andrews & Schmidt 1997; Whiteside 1998a,b; Bachorowski & Owren 1999). Not very surprisingly, judgment of gender is quite accurate even in brief (Bachorowski & Owren 1999) or much degraded signals, such as in whispered speech (Tartter 1989) or sine-wave analogues of speech (Fellowes et al. 1997). The importance of not mistaking the gender of a potential mate clearly puts some evolutionary pressure to solve this particular ecological problem well. Childers & Wu (1991) and Bachorowski & Owren (1999) used statistical analyses of gender-related acoustical differences in voices, and showed that cues related both to the source (f0) and to vocal tract characteristics (such as frequency of the second formant) were combined in an accurate representation of voice gender (Childers & Wu 1991; Bachorowski & Owren 1999). Other physical characteristics can also be extracted with relatively good accuracy, although there is significant variation across listeners (Kreiman 1997). Estimated age is generally accurate within a decade, although listeners seem to underestimate the age of speakers (Hartman & Danahuer 1976; Hartman 1979). Body size estimates have been found to be quite inaccurate, with a very small proportion of judgements actually correlating with the speakers’ height and weight (Lass & Davis 1976; Van Dommelen & Moxness 1995). Yet, listeners are found to be quite consistent in their judgement across several listening conditions, suggesting that vocal stereotypes are used to estimate body size, although these stereotypes are wrong (Gonzalez 2003). This inaccuracy is quite surprising as vocal tract length is well correlated with body size (at least in adult male humans; Rendall et al. 2005) and is tightly associated with formant frequencies (Fitch 1997), unlike the f0 (Kunzel 1989; Rendall et al. 2005). The ability to extract physical characteristics from voice peaks with identification of a speaker by the voice alone. A common finding is that some voices are easier to identify than others (Papcun et al. 1989; Kreiman 1997). Abberton & Fourcin (1978) reported abovethan-chance accuracy in recognition of speakers from the output of a laryngograph, eliminating vocal tract contribution (cited in Kreiman 1997). Conversely, reliable speaker identification can be obtained from whispered speech (Tartter 1991), or sine-wave analogues of speech (Remez et al. 1997), demonstrating that, as for gender identification, acoustic cues related to both the laryngeal source and the supralaryngeal vocal tract are used to identify speakers. More research is now needed to understand how our perception of familiar and unfamiliar voices is organized in the brain, and which acoustic features are the most important in these processes. As we have seen previously, the ability to extract information on the caller/speaker’s physical characteristics in voice is phylogenetically older than speech

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perception, since we share it with other species, in particular other primates. There is also a strong evidence that voice perception abilities develop earlier than speech perception in ontogeny. Studies using measures of sucking preference or heart rate show that one-month-old infants prefer their mother’s voice to voices from other persons (Mehler et al. 1978). This ability is even present in newborn babies (DeCasper & Fifer 1980) and extends to the father’s voice (Ockleford et al. 1988). Recent measures in foetuses suggest that his ability is even present before birth (Kisilevsky et al. 2003). Thus, long before being able to discriminate and categorize the sounds of their maternal tongue, babies show impressive voice perception abilities. In sum, humans clearly possess the ability to extract information on the physical characteristics and identity of a speaker from the voice alone. The voice recognition abilities of most normal listeners are clearly less accurate than face recognition, but still sufficient to extract useful information from an individual who is even out of sight. What are the neural correlates of the socially useful ability to recognize speakers? (d) Neurobiological evidence in non-human primates There are virtually no published data on the neural correlates of this ability to identify callers in nonhuman primates. Most researchers investigating neuronal responses to conspecific calls have focused on the issue of call selectivity (cf. §3b). The only evidence for neuronal mechanisms possibly involved in extracting vocal signatures of individual callers comes from outside of auditory cortex in the recent work by Romanski et al. (2004). These authors found that on the 301 auditory-responsive cells they recorded in macaque prefrontal cortex, two cells were found to be caller selective, i.e. to respond best to vocalizations from one caller and not to vocalizations from other callers (Romanski et al. 2004). (e) Neurobiological evidence in humans Despite the social importance of voice recognition abilities and the fact that they appeared earlier than speech in both phylogeny and ontogeny, little is know on their functional organization in the human brain. However, this ability has been the focus of several recent neuroimaging studies, and their results start shedding light on cortical regions involved in voice recognition abilities—which is comparatively much more than what is known in non-human primates (figure 3). Imaimuzi and colleagues used PET to scan normal volunteers while listening to words pronounced by several actors and performing forced-choice identification of either the speaker pronouncing the words or the emotion that was portrayed in saying the word. The main finding was that the anterior temporal lobes were more active bilaterally during speaker identification than during emotion identification (Imaizumi et al. 1997). A follow-up study compared a familiarity decision task on voices that were either familiar or unknown to the participants with a control phonetic decision task. Several cortical regions, including the Phil. Trans. R. Soc. B (2006)

enthorinal cortex and the anterior part of the right temporal lobe, were found to be more active during the voice familiarity task. Moreover, cerebral blood flow in the right anterior temporal pole was correlated with the subjects’ performance at a speaker identification task administered after scanning (Nakamura et al. 2001). Belin & Zatorre (2003) used fMRI and a paradigm based on neuronal adaptation to investigate a putative representation of vocal signature in human auditory cortex. The reasoning was as follows: if a cortical region is involved in representing a speaker’s vocal signature, then it should show adaptation or repetition-induced decrease in activity, in response to vocal samples produced by the same speaker—even if the samples correspond to different words. Normal volunteers were scanned while passively listening to auditory blocks corresponding to two conditions: in one condition (adapt-speaker), blocks were composed of 12 different syllables pronounced by a same speaker; in the control condition (adapt-syllable), blocks were composed of a same syllable spoken by 12 different speakers. The same 144 stimuli (12 syllables!12 speakers) were used in the two conditions, only the order of presentation changed. Owing to the similarities between the two conditions, most of the auditory cortices, including left and right A1, showed similar activation to the two conditions (Belin & Zatorre 2003). Only one region of auditory cortex showed a difference in activity between the two conditions; as predicted, this region showed significantly less activity in the adapt-speaker condition. Interestingly, it was located along the anterior STS in the right hemisphere, just a few millimetres away from one of the maxima of voice-selectivity previously observed (Belin et al. 2000). A remarkably convergent finding was obtained by another team using a nearly opposite design: whereas Belin & Zatorre (2003) used a bottom-up design, manipulating stimuli but not task, von Kriegstein et al. (2003) scanned normal volunteers while they were attending either to the linguistic content of German utterances or to the speaker of these same utterances (von Kriegstein et al. 2003). They found that the right anterior STS and a part of the right precuneus were more active when the identification task was focused on the speaker’s identity, whereas a left middle STS region was more active in the reverse comparison. Thus, although the vocal stimuli were similar in the two conditions, directing attention to vocal identity was found to increase activity in a region of right anterior STS very close to that observed by Belin & Zatorre (2003). Using complementary analyses, von Kriegstein & Giraud (2004) further documented the functional organization of right STS. When comparing the responses to familiar versus unfamiliar voices, they outlined a region of the posterior part of the STS that responded more during speaker recognition when the voices were unfamiliar (von Kriegstein & Giraud 2004). Functional connectivity analyses showed that both anterior and posterior regions of the right STS interacted with a more central part of right STS located close to the maxima of sensitivity to the acoustic structure of voice (von Kriegstein & Giraud 2004).

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adapt-speaker

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Figure 3. Cortical sensitivity to vocal identity. (a) Spectrograms (0–5000 Hz) of examples of auditory blocks used by Belin & Zatorre (2003). Adapt-speaker: different syllables spoken by a same speaker. Adapt-syllable: a same syllable spoken by several different speakers. (b) Cortical regions showing decrease in neuronal activity with repetition of the speaker’s voice, shown in colour scale on axial (top) and sagittal (middle) slices through the subjects’ mean anatomical image. Reproduced with permission from Belin & Zatorre (2003).

5. CONCLUSIONS Converging evidence from human studies clearly points to an important role of anterior STS regions in processing voice information, particularly related to speaker’s identity, with a clear functional lateralization to the right hemisphere. These findings in humans allow two important conclusions for studies in nonhuman primates. Phil. Trans. R. Soc. B (2006)

First, single-cell recordings focusing on anterior STS regions would probably yield highly interesting findings. The STS regions play a clear role in human voice perception in particular and social cognition in general (Allison et al. 2000). Evidence in the macaque shows that these regions also contain neurons selectively tuned to faces (Perrett et al. 1992) and to sounds of actions (Barraclough et al. 2005). Recent data

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suggest that some of these STS regions (particularly, area TAa) may send direct projections to the auditory prefrontal domain identified in the macaque brain (L. M. Romanski 2006, personal communication), further suggesting that STS regions would be particularly well suited to combine information from vocalizations and face displays, and yield a supra-modal representation of conspecific individuals. A second important conclusion relates to the patterns of functional lateralization. The well-known advantage of the left hemisphere in processing speech information has pushed researchers to look for a comparable left-hemisphere advantage for processing communication sounds in non-human animals. Yet what the human studies suggest is that the lefthemisphere advantage only holds when processing speech information. Human studies having manipulated subject’s attention towards non-linguistic features of the vocal signal, such as prosody (Zatorre et al. 1992) or speaker identity (von Kriegstein et al. 2003), clearly showed that a right-hemisphere advantage can be obtained. Thus, patterns of functional lateralization in non-human primates may also not be exclusively biased towards the left hemisphere, particularly when attending to caller affect or identity. REFERENCES Abberton, E. & Fourcin, A. 1978 Intonation and speaker identification. Lang. Speech 21, 305–318. Aitkin, L. M., Merzenich, M. M., Irvine, D. R., Clarey, J. C. & Nelson, J. E. 1986 Frequency representation in auditory cortex of the common marmoset (Callithrix jacchus jacchus). J. Comp. Neurol. 252, 175–185. (doi:10.1002/ cne.902520204) Allison, T., Puce, A. & McCarthy, G. 2000 Social perception from visual cues: role of the STS region. Trends Cogn. Sci. 4, 267–278. (doi:10.1016/S1364-6613(00)01501-1) Andrews, M. L. & Schmidt, C. P. 1997 Gender presentation: perceptual and acoustical analyses of voice. J. Voice 11, 307–313. (doi:10.1016/S0892-1997(97)80009-4) Assal, G., Zander, E., Kremin, H. & Buttet, J. 1976 Discrimination des voix lors des lesions du cortex cerebral. Arch. Suisses Neurol. Neurochir. Psychiatry 119, 307–315. Assal, G., Aubert, C. & Buttet, J. 1981 Asyme´trie ce´re´brale et reconnaissance de la voix. Revue Neurolog. 137, 255–268. Bachorowski, J. A. & Owren, M. J. 1999 Acoustic correlates of talker sex and individual talker identity are present in a short vowel segment produced in running speech. J. Acoust. Soc. Am. 106, 1054–1063. (doi:10.1121/ 1.427115) Barraclough, N. E., Xiao, D., Baker, C. I., Oram, M. W. & Perrett, D. I. 2005 Integration of visual and auditory information by superior temporal sulcus neurons responsive to the sight of actions. J. Cogn. Neurosci. 17, 377–391. (doi:10.1162/0898929053279586) Belin, P. & Zatorre, R. J. 2003 Adaptation to speaker’s voice in right anterior temporal-lobe. Neuroreport 14, 2105–2109. (doi:10.1097/00001756-200311140-00019) Belin, P., Zatorre, R. J., Lafaille, P., Ahad, P. & Pike, B. 2000 Voice-selective areas in human auditory cortex. Nature 403, 309–312. Belin, P., Zatorre, R. J. & Ahad, P. 2002 Human temporallobe response to vocal sounds. Cogn. Brain Res. 13, 17–26. (doi:10.1016/S0926-6410(01)00084-2) Belin, P., Fecteau, S. & Be´dard, C. 2004 Thinking the voice: neural correlates of voice perception. Trends Cogn. Sci. 8, 129–135. (doi:10.1016/j.tics.2004.01.008) Phil. Trans. R. Soc. B (2006)

Binder, J. R. et al. 2000 Human temporal lobe activation by speech and nonspeech sounds. Cereb. Cortex 10, 512–528. Boinski, S. & Mitchell, C. L. 1997 Chuck vocalizations of wild female squirrel monkeys (Saimiri sciureus) contain information on caller identity and foraging acitivity. Int. J. Primatol. 18, 975–993. (doi:10.1023/A:1026300314739) Brown, C. H. 2003 Ecological and physiological constraints for primate vocal communication. In Primate audition. Ethology and neurobiology (ed. A. A. Ghazanfar), pp. 127–149. Boca Raton, FL: CRC Press. Ceugniet, M. & Izumi, A. 2004a Individual vocal differences of the coo call in Japanese monkeys. CR Biol. 327, 149–157. Ceugniet, M. & Izumi, A. 2004b Vocal individual discrimination in Japanese monkeys. Primates 45, 119–128. Cheney, D. L. & Seyfarth, R. M. 1980 Vocal recognition in free-ranging vervet monkeys. Anim. Behav. 28, 362–367. (doi:10.1016/S0003-3472(80)80044-3) Childers, D. G. & Wu, K. 1991 Gender recognition from speech. Part II: fine analysis. J. Acoust. Soc. Am. 90, 1841–1856. (doi:10.1121/1.401664) Coslett, H. B., Brashear, H. R. & Heilman, K. M. 1984 Pure word deafness after bilateral primary auditory cortex infarcts. Neurology 34, 347–352. Crinion, J. T., Lambon-Ralph, M. A., Warburton, E. A., Howard, D. & Wise, R. J. 2003 Temporal lobe regions engaged during normal speech comprehension. Brain 126, 1193–1201. (doi:10.1093/brain/awg104) Damasio, A. R. 1992 Aphasia. N. Engl. J. Med. 326, 531–539. DeCasper, A. J. & Fifer, W. P. 1980 Of human bonding: newborns prefer their mothers’ voices. Science 208, 1174–1176. (doi:10.1126/science.7375928) De´monet, J. F. et al. 1992 The anatomy of phonological and semantic processing in normal subjects. Brain 115, 1753–1768. Eskenazi, L., Childers, D. G. & Hicks, D. M. 1990 Acoustic correlates of vocal quality. J. Speech Hear Res. 33, 298–306. Fant, G. 1960 Acoustic theory of speech production. The Hague, The Netherlands: Mouton. Farah, M. J. 1996 Is face recognition ‘special’? Evidence from neuropsychology. Behav. Brain Res. 76, 181–189. Fecteau, S., Armony, J., Joanette, Y. & Belin, P. 2004 Is voice processing species-specific in human auditory cortex? An fMRI study. Neuroimage 23, 840–848. (doi:10.1016/ j.neuroimage.2004.09.019) Fecteau, S., Armony, J., Joanette, Y. & Belin, P. 2005 Sensitivity to voice in human prefrontal cortex. J. Neurophysiol. 94, 2251–2254. (doi:10.1152/jn.00329. 2005) Fellowes, J. M., Remez, R. E. & Rubin, P. E. 1997 Perceiving the sex and identity of a talker without natural vocal timbre. Percept. Psychophys. 59, 839–849. Fitch, W. T. 1997 Vocal tract length and formant frequency dispersion correlate with body size in rhesus macaques. J. Acoust. Soc. Am. 102, 1213–1222. (doi:10.1121/ 1.421048) Fitch, W. T. 2000 The evolution of speech: a comparative review. Trends Cogn. Sci. 4, 258–267. (doi:10.1016/S13646613(00)01494-7) Fitch, W. T. 2003 Primate vocal production and its implications for auditory research. In Primate audition. Ethology and neurobiology (ed. A. A. Ghazanfar), pp. 1–12. Boca Raton, FL: CRC Press. Gauthier, I., Tarr, M. J., Moylan, J., Skudlarski, P., Gore, J. C. & Anderson, A. W. 2000 The fusiform “face area” is part of a network that processes faces at the individual level. J. Cogn. Neurosci. 12, 495–504. (doi:10.1162/ 089892900562165)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Voice processing in primates Gervais, H. et al. 2004 Abnormal voice processing in autism: a fMRI study. Nat. Neurosci. 7, 801–802. (doi:10.1038/ nn1291) Ghazanfar, A. A. & Santos, L. R. 2003 Primates as auditory specialists. In Primate audition. Ethology and neurobiology (ed. A. A. Ghazanfar), pp. 1–12. Boca Raton, FL: CRC Press. Ghazanfar, A. A., Smith-Rohrberg, D. & Hauser, M. D. 2001 The role of temporal cues in rhesus monkey vocal recognition: orienting asymmetries to reversed calls. Brain Behav. Evol. 58, 163–172. (doi:10.1159/000047270) Gil-da-Costa, R., Braun, A., Lopes, M., Hauser, M. D., Carson, R. E., Herscovitch, P. & Martin, A. 2004 Toward an evolutionary perspective on conceptual representation: species-specific calls activate visual and affective processing systems in the macaque. Proc. Natl Acad. Sci. USA 101, 17 516–17 521. (doi:10.1073/pnas.0408077101) Glass, I. & Wollberg, Z. 1983 Responses of cells in the auditory cortex of awake squirrel monkeys to normal and reversed species-specific vocalizations. Hear Res. 9, 27–33. (doi:10.1016/0378-5955(83)90131-4) Gonzalez, J. 2003 Estimation of speakers’ weight and height from speech: a re-analysis of data from multiple studies by Lass and colleagues. Percept. Mot. Skills 96, 297–304. (doi:10.2466/PMS.96.1.297-304) Green, S. 1975 Variation of vocal pattern with social situation in the Japanese monkey (Macaca fuscata): a field study. In Primate behavior, vol. 4 (ed. E. L. A. Rosenblum), pp. 1–102. New York, NY: Academic Press. Hartman, D. E. 1979 The perceptual identity and characteristics of aging in normal male adult speakers. J. Commun. Disord. 12, 53–61. (doi:10.1016/0021-9924(79)90021-2) Hartman, D. E. & Danahuer, J. L. 1976 Perceptual features of speech for males in four perceived age decades. J. Acoust. Soc. Am. 59, 713–715. Hauser, M. 1996 The evolution of communication. Cambridge, MA: MIT Press. Hauser, M. D. & Andersson, K. 1994 Left hemisphere dominance for processing vocalizations in adult, but not infant, rhesus monkeys: field experiments. Proc. Natl Acad. Sci. USA 91, 3946–3948. (doi:10.1073/pnas.91.9. 3946) Hauser, M. D., Agnetta, B. & Perez, C. 1998 Orienting asymmetries in rhesus monkeys: the effect of time-domain changes on acoustic perception. Anim. Behav. 56, 41–47. (doi:10.1006/anbe.1998.0738) Hauser, M. D., Chomsky, N. & Fitch, W. T. 2002 The faculty of language: what is it, who has it, and how did it evolve? Science 298, 1569–1579. Haxby, J. V., Gobbini, M. I., Furey, M. L., Ishai, A., Schouten, J. L. & Pietrini, P. 2001 Distributed and overlapping representations of faces and objects in ventral temporal cortex. Science 293, 2425–2430. (doi:10.1126/ science.1063736) Heffner, H. E. & Heffner, R. S. 1984 Temporal lobe lesions and perception of species-specific vocalizations by macaques. Science 226, 75–76. (doi:10.1126/science.6474192) Heffner, H. E. & Heffener, R. S. 1986 Effect of unilateral and bilateral auditory cortex lesions on the discrimination of vocalizations by japanese macaques. J. Neurophysiol. 56, 683–701. Hillenbrand, J. M., Getty, L. A., Clark, M. J. & Wheeler, K. 1995 Acoustic characteristics of American English vowels. J. Acoust. Soc. Am. 97, 1300–1313. Hopp, S. L., Sinnott, J. M., Owren, M. J. & Petersen, M. R. 1992 Differential sensitivity of Japanese macaques (Macaca fuscata) and humans (Homo sapiens) to peak position along a synthetic coo call continuum. J. Comp. Psychol. 106, 128–136. (doi:10.1037/0735-7036.106.2.128) Phil. Trans. R. Soc. B (2006)

P. Belin

2105

Imaizumi, S. et al. 1997 Vocal identification of speaker and emotion activates different brain regions. Neuroreport 8, 2809–2812. Kaas, J. H. & Hackett, T. A. 1999 ‘What’ and ‘where’ processing in auditory cortex. Nat. Neurosci 2, 1045–1047. (doi:10.1038/15967) Kanwisher, N., McDermott, J. & Chun, M. M. 1997 The fusiform face area: a module in human extrastriate cortex specialized for face perception. J. Neurosci. 17, 4302–4311. Kaplan, J. N., Winship-Ball, A. & Sim, L. 1978 Maternal discrimination of infant vocalizations in squirrel monkeys. Primates 19, 187–193. Kisilevsky, B. S. et al. 2003 Effects of experience on fetal voice recognition. Psychol. Sci. 14, 220–224. (doi:10.1111/ 1467-9280.02435) Klatt, D. H. 1980 Software for a cascade/parallel formant synthesizer. J. Acoust. Soc. Am. 67, 971–995. (doi:10. 1121/1.383940) Kojima, S., Izumi, A. & Ceugniet, M. 2003 Identification of vocalizers by pant hoots, pant grunts and screams in a chimpanzee. Primates 44, 225–230. Kreiman, J. 1997 Listening to voices: theory and practice in voice perception research. In Talker variability in speech research (ed. K. Johnson & J. Mullenix), pp. 85–108. New York, NY: Academic Press. Kunzel, H. J. 1989 How well does average fundamental frequency correlate with speaker height and weight? Phonetica 46, 117–125. Landis, T., Buttet, J., Assal, G. & Graves, R. 1982 Dissociation of ear preference in monaural word and voice recognition. Neuropsychologia 20, 501–504. (doi:10. 1016/0028-3932(82)90049-5) Lass, N. J. & Davis, M. 1976 An investigation of speaker height and weight identification. J. Acoust. Soc. Am. 60, 700–703. Lass, N. J., Hughes, K. R., Bowyer, M. D., Waters, L. T. & Bourne, V. T. 1976 Speaker sex identification from voiced, whispered, and filtered isolated vowels. J. Acoust. Soc. Am. 59, 675–678. (doi:10.1121/1.380917) Levy, D. A., Granot, R. & Bentin, S. 2001 Processing specificity for human voice stimuli: electrophysiological evidence. Neuroreport 12, 2653–2657. (doi:10.1097/ 00001756-200108280-00013) Levy, D. A., Granot, R. & Bentin, S. 2003 Neural sensitivity to human voices: ERP evidence of task and attentional influences. Psychophysiology 40, 291–305. Lieberman, P. H., Klatt, D. H. & Wilson, W. H. 1969 Vocal tract limitations on the vowel repertoires of rhesus monkey and other nonhuman primates. Science 164, 1185–1187. (doi:10.1126/science.164.3884.1185) Manley, J. A. & Muller-Preuss, P. 1978 Response variability of auditory cortex cells in the squirrel monkey to constant acoustic stimuli. Exp. Brain Res. 32, 171–180. (doi:10. 1007/BF00239725) Mehler, J., Bertoncini, J. & Barriere, M. 1978 Infant recognition of mother’s voice. Perception 7, 491–497. Mullennix, J. W., Johnson, K. A., Topcu-Durgun, M. & Farnsworth, L. M. 1995 The perceptual representation of voice gender. J. Acoust. Soc. Am. 98, 3080–3095. (doi:10. 1121/1.413832) Nakamura, K. et al. 2001 Neural substrates for recognition of familiar voices: a PET study. Neuropsychologia 39, 1047–1054. (doi:10.1016/S0028-3932(01)00037-9) Neuner, F. & Schweinberger, S. R. 2000 Neuropsychological impairments in the recognition of faces, voices, and personal names. Brain Cogn. 44, 342–366.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2106

P. Belin

Voice processing in primates

Newman, J. D. 2003 Auditory communication and mechanisms in the Squirrel monkey. In Primate audition. Ethology and neurobiology (ed. A. A. Ghazanfar), pp. 27–246. Boca Raton, FL: CRC Press. Ockleford, E. M., Vince, M. A., Layton, C. & Reader, M. R. 1988 Responses of neonates to parents’ and others’ voices. Early Hum. Dev. 18, 27–36. (doi:10.1016/0378-3782(88) 90040-0) Owren, M. J. & Linker, C. D. 1995 Some analysis methods that may be useful to acoustic primatologists. In Current topics in primate vocal communication (ed. E. Zimmermann, J. D. Newman & U. Jurgens), pp. 1–27. New York, NY: Plenum. Owren, M. J. & Rendall, D. 2003 Salience of caller identity in rhesus monkey (Macaca mulatta) coos and screams: perceptual experiments with human (Homo sapiens) listeners. J. Comp. Psychol. 117, 380–390. (doi:10.1037/ 0735-7036.117.4.380) Owren, M. J., Hopp, S. L., Sinnott, J. M. & Petersen, M. R. 1988 Absolute auditory thresholds in three Old World monkey species (Cercopithecus aethiops, C. neglectus, Macaca fuscata) and humans (Homo sapiens). J. Comp. Psychol. 102, 99–107. (doi:10.1037/0735-7036.102.2.99) Owren, M. J., Seyfarth, R. M. & Hopp, S. L. 1992 Categorical vocal signaling in nonhuman primates. In Nonverbal vocal communication. Comparative and developmental approaches (ed. H. Papousek, U. Ju¨rgens & M. Papousek), pp. 102–122. Cambridge, UK: Cambridge University Press. Editions de la Maison des Sciences de l’Homme Owren, M. J., Seyfarth, R. M. & Cheney, D. L. 1997 The acoustic features of vowel-like grunt calls in chacma baboons (Papio cyncephalus ursinus): implications for production processes and functions. J. Acoust. Soc. Am. 101, 2951–2963. (doi:10.1121/1.418523) Papcun, G., Kreiman, J. & Davis, A. 1989 Long-term memory for unfamiliar voices. J. Acoust. Soc. Am. 85, 913–925. (doi:10.1121/1.397564) Pelletier, I., Belin, P., Gervais, H., Jemel, B., Mottron, L. & Zilbovicius, M. 2005 Typical brain activation for voices in high functioning autistic individuals; a preliminary study. Paper presented at the International Meeting for Autism Research, Boston, MA. Pereira, M. E. 1986 Maternal recognition of juvenile offspring coo vocalizations in Japanese macaques. Anim. Behav. 34, 935–937. (doi:10.1016/S0003-3472(86) 80084-7) Peretz, I. et al. 1994 Functional dissociations following bilateral lesions of auditory cortex. Brain 117, 1283–1301. Perrett, D. I., Hietanen, J. K., Oram, M. W. & Benson, P. J. 1992 Organization and functions of cells responsive to faces in the temporal cortex. Phil. Trans. R. Soc. B 335, 23–30. Petersen, M. R., Beecher, M. D., Zoloth, S. R., Moody, D. B. & Stebbins, W. C. 1978 Neural lateralization of speciesspecific vocalizations by Japanese macaques (Macaca fuscata). Science 202(4365), 324–327. (doi:10.1126/ science.99817) Petersen, M. R. et al. 1984 Neural lateralization of vocalizations by Japanese macaques: communicative significance is more important than acoustic structure. Behav. Neurosci. 98, 779–790. (doi:10.1037/0735-7044. 98.5.779) Poeppel, D. 1996 A critical review of PET studies of phonological processing. Brain Lang. 55, 317–351. (doi:10.1006/brln.1996.0108) Poremba, A., Malloy, M., Saunders, R. C., Carson, R. E., Herscovitch, P. & Mishkin, M. 2004 Species-specific calls evoke asymmetric activity in the monkey’s temporal poles. Nature 427, 448–451. (doi:10.1038/nature02268) Phil. Trans. R. Soc. B (2006)

Price, C., Thierry, G. & Griffiths, T. D. 2005 Speech-specific auditory processing: where is it? Trends Cogn. Sci. 9, 271–276. (doi:10.1016/j.tics.2005.03.009) Puce, A., Allison, T., Gore, J. C. & McCarthy, G. 1995 Facesensitive regions in human extrastriate cortex studied by functional MRI. J. Neurophysiol. 74, 1192–1199. Ramus, F., Hauser, M. D., Miller, C., Morris, D. & Mehler, J. 2000 Language discrimination by human newborns and by cotton-top tamarin monkeys. Science 288, 349–351. (doi:10.1126/science.288.5464.349) Rauschecker, J. P. & Tian, B. 2000 Mechanisms and streams for processing of “what” and “where” in auditory cortex. Proc. Natl Acad. Sci. USA 97, 11 800–11 806. (doi:10. 1073/pnas.97.22.11800) Remez, R. E., Rubin, P. E., Pisoni, D. B. & Carrel, T. D. 1981 Speech perception without traditional speech cues. Science 212, 947–950. (doi:10.1126/science.7233191) Remez, R. E., Fellowes, J. M. & Rubin, P. E. 1997 Talker identification based on phonetic information. Exp. Psychol. Hum. Percept. Perform. 23, 651–666. (doi:10.1037/00961523.23.3.651) Rendall, D., Rodman, P. S. & Edmond, R. E. 1996 Vocal recognition of individuals and kin in free-ranging rhesus monkeys. Anim. Behav. 51, 1007–1015. (doi:10.1006/ anbe.1996.0103) Rendall, D., Owren, M. J. & Rodman, P. S. 1998 The role of vocal tract filtering in identity cueing in rhesus monkey (Macaca mulatta) vocalizations. J. Acoust. Soc. Am. 103, 602–614. (doi:10.1121/1.421104) Rendall, D., Kollias, S., Ney, C. & Lloyd, P. 2005 Pitch (F0) and formant profiles of human vowels and vowel-like baboon grunts: the role of vocalizer body size and voiceacoustic allometry. J. Acoust. Soc. Am. 117, 944–955. (doi:10.1121/1.1848011) Romanski, L. M. & Goldman-Rakic, P. S. 2002 An auditory domain in primate prefrontal cortex. Nat. Neurosci. 5, 15–16. (doi:10.1038/nn781) Romanski, L. M., Averbeck, B. B. & Diltz, M. 2004 Neural representation of vocalizations in the primate ventrolateral prefrontal cortex. J. Neurophysiol. 93, 734–747. (doi:10. 1152/jn.00675.2004) Scho¨n Ybarra, M. A. 1995 A comparative approach to the non-human primate vocal tract: implications for sound production. In Current topics in primate vocal communication (ed. E. Zimmermann, J. D. Newman & U. Jurgens), pp. 185–198. New York, NY: Plenum Press. Schultz, R. T. et al. 2000 Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. Arch. Gen. Psychiatry 57, 331–340. (doi:10.1001/archpsyc.57.4.331) Scott, S. K. & Johnsrude, I. S. 2003 The neuroanatomical and functional organization of speech perception. Trends Neurosci. 26, 100–107. (doi:10.1016/S0166-2236(02) 00037-1) Scott, S. K., Blank, C. C., Rosen, S. & Wise, R. J. 2000 Identification of a pathway for intelligible speech in the left temporal lobe. Brain 123, 2400–2406. (doi:10.1093/brain/ 123.12.2400) Seyfarth, R. M., Cheney, D. L. & Marler, P. 1980 Monkey responses to three different alarm calls: evidence of predator classification and semantic communication. Science 210, 801–803. (doi:10.1126/science.7433999) Shoumaker, R. D., Ajax, E. T. & Schenkenberg, T. 1977 Pure word deafness. (Auditory verbal agnosia). Dis. Nerv. Syst. 38, 293–299. Sinnott, J. M. 1989 Detection and discrimination of synthetic english vowels by old world monkeys (Cercopithecus, Macaca) and humans. J. Acoust. Soc. Am. 86, 557–565. (doi:10.1121/1.398235)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Voice processing in primates Sinnott, J. M. & Adams, F. S. 1987 Differences in human and monkey sensitivity to acoustic cues underlying voicing contrasts. J. Acoust. Soc. Am. 82, 1539–1547. (doi:10. 1121/1.395144) Snowdon, C. T. 1986 Vocal communication. In Comparative primate biology: behaviour, conservation and ecology (ed. G. Mitchell & J. Erwin), pp. 495–530. New York, NY: Alan R. Liss. Tartter, V. C. 1989 What’s in a whisper? J. Acoust. Soc. Am. 86, 1678–1683. (doi:10.1121/1.398598) Tartter, V. C. 1991 Identifiability of vowels and speakers from whispered syllables. Percept. Psychophys. 49, 365–372. Tian, B., Reser, D., Durham, A., Kustov, A. & Rauschecker, J. P. 2001 Functional specialization in rhesus monkey auditory cortex. Science 292, 290–293. (doi:10.1126/ science.1058911) Titze, I. R. 1989 Physiologic and acoustic differences between malen and female voices. J. Acoust. Soc. Am. 85, 1699–1707. (doi:10.1121/1.397959) Titze, I. R. 1993 Current topics in voice production mechanisms. Acta Otolaryngol. 113, 421–427. Ungerleider, L. G. & Haxby, J. V. 1994 ‘What’ and ‘where’ in the human brain. Curr. Opin. Neurobiol. 4, 157–165. (doi:10.1016/0959-4388(94)90066-3) Van Dommelen, W. A. & Moxness, B. H. 1995 Acoustic parameters in speaker height and weight identification: sex-specific behaviour. Lang. Speech 38, 267–287. Van Lancker, D. R. & Canter, G. J. 1982 Impairment of voice and face recognition in patients with hemispheric damage. Brain Cogn. 1, 185–195. (doi:10.1016/0278-2626(82) 90016-1) Van Lancker, D. & Kreiman, J. 1987 Voice discrimination and recognition are separate abilities. Neuropsychologia 25, 829–834. (doi:10.1016/0028-3932(87)90120-5) Van Lancker, D. R., Cummings, J. L., Kreiman, J. & Dobkin, B. H. 1988 Phonagnosia: a dissociation between familiar and unfamiliar voices. Cortex 24, 195–209. Van Lancker, D. R., Kreiman, J. & Cummings, J. 1989 Voice perception deficits: neuroanatomical correlates of phonagnosia. J. Clin. Exp. Neuropsychol. 11, 665–674. von Kriegstein, K. & Giraud, A. L. 2004 Distinct functional substrates along the right superior temporal sulcus for the processing of voices. Neuroimage 22, 948–955. (doi:10. 1016/j.neuroimage.2004.02.020) von Kriegstein, K., Eger, E., Kleinschmidt, A. & Giraud, A. L. 2003 Modulation of neural responses to speech by directing attention to voices or verbal content. Brain Res. Cogn. Brain Res. 17, 48–55. (doi:10.1016/S0926-6410(03)00079-X)

Phil. Trans. R. Soc. B (2006)

P. Belin

2107

Wang, X. 2000 On cortical coding of vocal communication sounds in primates. Proc. Natl Acad. Sci. USA 97, 11 843–11 849. (doi:10.1073/pnas.97.22.11843) Wang, X. & Kadia, S. C. 2001 Differential representation of species-specific primate vocalizations in the auditory cortices of marmoset and cat. J. Neurophysiol. 86, 2616–2620. Wang, X., Merzenich, M. M., Beitel, R. & Schreiner, C. E. 1995 Representation of a species-specific vocalization in the primary auditory cortex of the common marmoset: temporal and spectral characteristics. J. Neurophysiol. 74, 2685–2706. Weiss, D. J., Garibaldi, B. T. & Hauser, M. D. 2001 The production and perception of long calls by cotton-top tamarins (Saguinus oedipus): acoustic analyses and playback experiments. J. Comp. Psychol. 115, 258–271. (doi:10.1037/0735-7036.115.3.258) Wernicke, C. 1874 Der aphasische Symptomencomplex. Breslau, Germany: Cohn & Weigert. Whiteside, S. P. 1998a Identification of a speaker’s sex: a fricative study. Percept. Mot. Skills 86, 587–591. Whiteside, S. P. 1998b Identification of a speaker’s sex: a study of vowels. Percept. Mot. Skills 86, 579–584. Winter, P. & Funkenstein, H. H. 1973 The effect of speciesspecific vocalization on the discharge of auditory cortical cells in the awake squirrel monkey (Saimiri sciureus). Exp. Brain Res. 18, 489–504. (doi:10.1007/BF00234133) Winter, P., Ploog, D. & Latta, J. 1966 Vocal repertoire of the squirrel monkey (Saimiri sciureus), its analysis and significance. Exp. Brain Res. 1, 359–384. (doi:10.1007/ BF00237707) Wollberg, Z. & Newman, J. D. 1972 Auditory cortex of squirrel monkey: response patterns of single cells to species-specific vocalizations. Science 175, 212–214. Wu, K. & Childers, D. G. 1991 Gender recognition from speech. Part I: coarse analysis. J. Acoust. Soc. Am. 90, 1828–1840. (doi:10.1121/1.401663) Zatorre, R. J. & Binder, J. R. 2000 Functional and structural imaging of the human auditory system. In Brain mapping: the systems (ed. A. Toga & J. Mazziota), pp. 365–402. Los Angeles, CA: Academic Press. Zatorre, R. J., Evans, A. C., Meyer, E. & Gjedde, A. 1992 Lateralisation of phonetic and pitch discrimination in speech processing. Science 256, 846–849. (doi:10.1126/ science.1589767) Zoloth, S. R. et al. 1979 Species-specific perceptual processing of vocal sounds by monkeys. Science 204, 870–873. (doi:10.1126/science.108805)

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Phil. Trans. R. Soc. B (2006) 361, 2109–2128 doi:10.1098/rstb.2006.1934 Published online 8 November 2006

The fusiform face area: a cortical region specialized for the perception of faces Nancy Kanwisher1,* and Galit Yovel2 1

McGovern Institute for Brain Research and Department of Brain & Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 2 Department of Psychology, Tel Aviv University, PO Box 39040, Tel Aviv 69978, Israel

Faces are among the most important visual stimuli we perceive, informing us not only about a person’s identity, but also about their mood, sex, age and direction of gaze. The ability to extract this information within a fraction of a second of viewing a face is important for normal social interactions and has probably played a critical role in the survival of our primate ancestors. Considerable evidence from behavioural, neuropsychological and neurophysiological investigations supports the hypothesis that humans have specialized cognitive and neural mechanisms dedicated to the perception of faces (the face-specificity hypothesis). Here, we review the literature on a region of the human brain that appears to play a key role in face perception, known as the fusiform face area (FFA). Section 1 outlines the theoretical background for much of this work. The face-specificity hypothesis falls squarely on one side of a longstanding debate in the fields of cognitive science and cognitive neuroscience concerning the extent to which the mind/brain is composed of: (i) special-purpose (‘domain-specific’) mechanisms, each dedicated to processing a specific kind of information (e.g. faces, according to the face-specificity hypothesis), versus (ii) general-purpose (‘domain-general’) mechanisms, each capable of operating on any kind of information. Face perception has long served both as one of the prime candidates of a domain-specific process and as a key target for attack by proponents of domain-general theories of brain and mind. Section 2 briefly reviews the prior literature on face perception from behaviour and neurophysiology. This work supports the face-specificity hypothesis and argues against its domain-general alternatives (the individuation hypothesis, the expertise hypothesis and others). Section 3 outlines the more recent evidence on this debate from brain imaging, focusing particularly on the FFA. We review the evidence that the FFA is selectively engaged in face perception, by addressing (and rebutting) five of the most widely discussed alternatives to this hypothesis. In §4, we consider recent findings that are beginning to provide clues into the computations conducted in the FFA and the nature of the representations the FFA extracts from faces. We argue that the FFA is engaged both in detecting faces and in extracting the necessary perceptual information to recognize them, and that the properties of the FFA mirror previously identified behavioural signatures of face-specific processing (e.g. the face-inversion effect). Section 5 asks how the computations and representations in the FFA differ from those occurring in other nearby regions of cortex that respond strongly to faces and objects. The evidence indicates clear functional dissociations between these regions, demonstrating that the FFA shows not only functional specificity but also area specificity. We end by speculating in §6 on some of the broader questions raised by current research on the FFA, including the developmental origins of this region and the question of whether faces are unique versus whether similarly specialized mechanisms also exist for other domains of high-level perception and cognition. Keywords: face perception; fusiform face area; functional magnetic resonance imaging; domain specificity

1. FACE PERCEPTION: DOMAIN-SPECIFIC VERSUS DOMAIN-GENERAL HYPOTHESES One of the longest running debates in the history of neuroscience concerns the degree to which specific high-level cognitive functions are implemented in * Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘The neurobiology of social recognition, attraction and bonding’.

discrete regions of the brain specialized for just that function. The current consensus view was recently synopsized in a respected textbook of neuroimaging as follows: ‘unlike the phrenologists, who believed that very complex traits were associated with discrete brain regions, modern researchers recognize that . a single brain region may participate in more than one function’ (Huettel et al. 2004). Despite this currently popular view that complex cognitive functions are conducted in

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distributed and overlapping neural networks, substantial evidence supports the hypothesis that at least one complex cognitive function—face perception—is implemented in its own specialized cortical network that is not shared with many if any other cognitive functions. Here, we review the evidence for this hypothesis, focusing particularly on functional magnetic resonance imaging (fMRI) investigations of a region of human extrastriate cortex called the fusiform face area (FFA; Kanwisher et al. 1997). Face perception has long served as a parade case of functional specificity, i.e. as a process that is implemented in specialized cognitive and neural mechanisms dedicated to face perception per se. This ‘face-specificity hypothesis’ has a certain intuitive appeal, given the enormous importance of face perception in our daily lives (and in the lives of our primate ancestors), the unique computational challenges posed by the task of face recognition and the processing advantages that can result from the use of dedicated neural hardware specialized for a specific task. Yet the face-specificity hypothesis has remained controversial, and many researchers have favoured alternative ‘domain-general’ hypotheses which argue that the mechanisms engaged by faces are not specific for a particular stimulus class (i.e. faces), but for a particular process that may run on multiple stimulus classes. For example, according to the individuation hypothesis, putative face-specific mechanisms can be engaged whenever fine-grained discriminations must be made between exemplars within a category (Gauthier et al. 1999a, 2000b). The idea here is that when we look at faces, we do not merely decide that the stimulus is a face, but we also automatically identify which face it is, whereas with cars or tables or mugs we may often extract only the general category of each stimulus (car versus table) without identifying the specific individual (which car). Thus, according to the individuation hypothesis, faces automatically recruit a domain-general mechanism for individuating exemplars within a category, which can be recruited in a task-dependent fashion by non-faces. According to the expertise hypothesis (which is a special case of the individuation hypothesis), putative face-specific mechanisms are specialized not for processing faces per se, but rather for distinguishing between exemplars of a category that share the same basic configuration and for which the subject has gained substantial expertise. The idea here is that we are all experts at recognizing faces, and if we had similar expertise discriminating exemplars of a non-face category, then the same processing mechanisms would be engaged. This idea originates from a seminal study by Diamond & Carey (1986) who reported that people with many years of experience judging dogs (‘dog experts’) exhibit behavioural signatures of facelike processing when perceiving dogs, as well as from more recent studies in which it has been claimed that just 10 h of laboratory training on novel stimuli can lead to ‘face-like’ processing of those stimuli (Gauthier et al. 1998; Tarr & Gauthier 2000). We argue here that substantial evidence favours the face-specificity hypothesis over these and other domain-general alternatives. Before reviewing the Phil. Trans. R. Soc. B (2006)

relevant literature on the FFA, we briefly synopsize the evidence for the face-specificity hypothesis from other methods.

2. SPECIALIZED MECHANISMS FOR FACE PERCEPTION: EVIDENCE FROM NEUROPSYCHOLOGY, BEHAVIOUR AND ELECTROPHYSIOLOGY Evidence from neuropsychology, behaviour and electrophysiology has long been marshalled in the debate over the nature of face-processing mechanisms. (a) Evidence from neuropsychology: prosopagnosia and agnosia The first evidence that face perception engages specialized machinery distinct from that engaged during object perception came from the syndrome of acquired prosopagnosia, in which neurological patients lose the ability to recognize faces after brain damage. Prosopagnosia is not a general loss of the concept of the person, because prosopagnosic subjects can easily identify individuals on the basis of their voice or a verbal description of the person. Impairments in face recognition are often accompanied by deficits in other related tasks such as object recognition, as expected, given the usually large size of lesions relative to functional subdivisions of the cortex. However, a few prosopagnosic patients have been described who show very selective impairments in which face-recognition abilities are devastated despite the lack of discernible deficits in the recognition of non-face objects (Wada & Yamamoto 2001). Some prosopagnosic subjects have preserved abilities to discriminate between exemplars within a category (McNeil & Warrington 1993; Henke et al. 1998; Duchaine et al. 2006), arguing against the individuation hypothesis. Normal acquisition of expertise for novel stimuli (‘Greebles’) was found in an individual with ‘developmental prosopagnosia’ (Duchaine et al. 2004), a lifelong impairment in face recognition (Behrmann & Avidan 2005) with no apparent neurological lesion (see §6a). A recent report tested each of the domain-general hypotheses that have been discussed in the literature in a highly selective case of developmental prosopagnosia. Findings from six experiments ruled out each of the domain-general hypotheses in favour of the face-selective hypothesis (Duchaine et al. 2006). Taken together, studies of prosopagnosic individuals support the face-specificity hypothesis. Is face recognition just the most difficult visual recognition task we perform, and hence the most susceptible to brain damage? Apparently not: the striking case of patient CK (Moscovitch et al. 1997; see also McMullen et al. 2000) showed severe deficits in object recognition, but normal face recognition, indicating a double dissociation between the recognition of faces and objects. Further, patient CK, who had been a collector of toy soldiers, lost the ability to discriminate these stimuli, showing a further dissociation between face recognition (preserved) and visual expertise (impaired). Thus, taken together, these selective cases of prosopagnosia and agnosia support

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The fusiform face area the face-specificity hypothesis and are inconsistent with its domain-general alternatives. (b) Behavioural signatures of face-specific processing Classic behavioural work in normal subjects has also shown dissociations between the recognition of faces and objects by demonstrating a number of differences in the ways that faces and objects are processed. Best known among these signatures of face-specific processing is the face-inversion effect, in which the decrement in performance that occurs when stimuli are inverted (i.e. turned upside-down) is greater for faces than for non-face stimuli (Yin 1969). Other behavioural markers include the ‘part–whole’ effect (Tanaka & Farah 1993), in which subjects are better able to distinguish which of two face parts (e.g. two noses) appeared in a previously shown face when they are tested in the context of the whole face than when they are tested in isolation, and the ‘composite effect’ (Young et al. 1987), in which subjects are slower to identify one-half of a chimeric face, if it is aligned with an inconsistent other half-face than if the two half-faces are misaligned. Consistent with the holistic hypothesis, Yovel et al. (2005a) have found that the probability of correctly identifying a whole face is greater than the sum of the probabilities of matching each of its component face halves. Taken together, these effects suggest that upright faces are processed in a distinctive ‘holistic’ manner (McKone et al. 2001; Tanaka & Farah 2003), i.e. that faces are processed as wholes rather than processing each of the parts of the face independently. All the holistic effects mentioned above are either absent or reduced for inverted faces and non-face objects (Tanaka & Farah 1993; Robbins 2005), indicating that this holistic style of processing is specific to upright faces. According to the expertise hypothesis, it is our extensive experience with faces that leads us to process them in this distinctive holistic and orientationsensitive fashion. The original impetus for this hypothesis came from Diamond & Carey’s (1986) classic report that dog experts show inversion effects for dog stimuli. However, there have been no published replications of this result since it was published 30 years ago, and one careful and extensive recent effort completely failed to replicate the original result (Robbins 2005). Another recent study also failed to find a significant inversion effect for objects of expertise (fingerprints in fingerprint experts), although this study argues for holistic processing of these stimuli by experts based on superadditive contributions to performance accuracy from the two halves of the stimulus (Busey & Vanderkolk 2005). Other studies have investigated much shorter term cases of visual expertise, claiming that a mere 10 h of laboratory training can produce ‘face-like’ processing of non-face stimuli (Gauthier et al. 1998). However, an examination of the actual data in those studies in fact reveals little or no evidence for disproportionate inversion effects, part–whole effects or composite effects for laboratory-trained stimuli (McKone & Kanwisher 2005; McKone et al. in press). Even 10 h of training on inverted faces does not lead to holistic processing of inverted faces Phil. Trans. R. Soc. B (2006)

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(Robbins & McKone 2003). Thus, despite widespread claims to the contrary, behavioural data from normal subjects do not support the expertise hypothesis. Instead, behavioural signatures of configural/holistic processing are either reduced (as in the inversion effect and the part–whole effect) or absent (in the composite effect) for non-face stimuli, including objects of expertise. These findings support the face-specificity hypothesis and argue against each of its domain-general alternatives. (c) Electrophysiology in humans Face-selective electrophysiological responses occurring 170 ms after stimulus onset have also been measured in humans using scalp electrodes (Bentin et al. 1996; Jeffreys 1996). Although it has been claimed that this face-selective N170 response is sensitive to visual expertise with non-face stimuli (Tanaka & Curran 2001; Rossion et al. 2002; Gauthier et al. 2003), no study has demonstrated the basic result that would support this finding: an event-related potential (ERP) response that is higher both for faces than non-faces (thus demonstrating face selectivity) and objects of expertise than control objects (thus demonstrating a role for expertise; McKone & Kanwisher 2005). Showing the selectivity of the N170 for faces in each experiment is important because the N170 is not face selective at all electrode locations (and not even necessarily at the canonical face-selective locations of T5 and T6), so this face selectivity must be demonstrated in each study. One study did show a delay of the N170 for inverted compared with upright fingerprints in fingerprint experts, resembling the similar delay seen in the N170 to inverted versus upright faces (Busey & Vanderkolk 2005). However, in the same study, the behavioural inversion effect for these stimuli was not significant, and as the authors of this study note, the delay of the N170 for inverted stimuli has been found for cars (in non-experts; Rossion et al. 2003b), and it is therefore not a specific marker of face-like processing. Finally, a magnetoencephalography (MEG) study investigating the similarly face-selective magnetic ‘M170’ response (Halgren et al. 2000; Liu et al. 2002) found no elevated response to cars in car experts and no trial-by-trial correlation between the amplitude of the M170 response and successful identification of cars by car experts (Xu et al. 2005). Thus, the N170 and M170 appear to be truly face selective and at least the M170 response is not consistent with any of the domain-general hypotheses discussed above. Although the spatial resolution of ERP and MEG are limited, subdural ERP measurements in epilepsy patients have shown strongly face-selective responses in discrete patches of the temporal lobe (Allison et al. 1994, 1999). A powerful demonstration of the causal role of these regions in face perception comes from two studies demonstrating that electrical stimulation of these ventral temporal sites can produce a transient inability to identify faces (Puce et al. 1999; Mundel et al. 2003). (d) Neurophysiology and fMRI in monkeys Data from monkeys show stunning face specificity at both the single-cell level and the level of cortical

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Figure 1. Tsao et al. recorded the response of single cells within an fMRI identified face-selective patch of cortex. The figure shows the average response across all 320 visually responsive neurons in the face-selective patches of two monkeys, to 96 different stimulus images, indicating very high selectivity for faces by the cells in this patch.

regions. Numerous studies dating back decades have reported face-selective responses from single neurons (‘face cells’) in the temporal lobes of macaques (Desimone et al. 1984; Tsao et al. 2003). More recently, face-selective regions have been reported in macaques using fMRI (Tsao et al. 2003; Pinsk et al. 2005) and in vervets using a novel dual-activity mapping technique based on induction of the immediate early gene zif268 (Zangenehpour & Chaudhuri 2005). Strong claims of face selectivity entail the prediction that no non-face stimulus will ever produce a response as strong as a face; since the set of non-face stimuli is infinite, there is always some possibility that a future study will show that a putative face-selective cell or region actually responds more to some previously untested stimulus (say, armadillos) than to faces. However, recent advances in neurophysiology have addressed this problem about as well as can practically be hoped for. Foldiak et al. (2004) used rapid serial visual presentation to test each cell on over 1000 natural images and found some cells that were truly face selective: for some cells, the 70 stimuli producing the strongest responses all contained faces, and the next ‘best’ stimuli produced less than one-fifth the maximal response. Although these data demonstrate individual cells that are strikingly face selective, they do not address the face selectivity of whole regions of cortex. However, a new study demonstrates a spectacular degree of selectivity of whole regions of cortex: Tsao et al. (2003) directed electrodes into the face-selective patches they had previously identified with fMRI and found that 97% of the visually responsive cells in this region responded selectively (indeed, for most cells, exclusively) to faces (figure 1). These stunning data suggest that the weak responses of the FFA to non-face stimuli may result from ‘partial voluming’, i.e. from the inevitable blurring of face-selective and non-faceselective regions that arise when voxel sizes are large relative to the size of the underlying functional unit. Thus, these data suggest an answer to the question of whether ‘non-preferred’ responses carry discriminative information about non-preferred stimuli (Haxby et al. 2001; see §3f ): at least in face-selective regions in macaques, non-preferred responses cannot carry much information because these responses are close to zero. Phil. Trans. R. Soc. B (2006)

(i) Section summary Taken together, these lines of research make a compelling case for the existence of specialized cognitive and neural machinery for face perception per se (the face-specificity hypothesis), and argue against the individuation and expertise hypotheses. First, neuropsychological double dissociations exist between face recognition and visual expertise for nonface stimuli, casting doubt on the claim that these two phenomena share processing mechanisms. Second, behavioural data from normal subjects show a number of ‘signatures’ of holistic face processing that are not observed for other stimulus classes, such as inverted faces and objects of expertise. Third, electrophysiological measurements indicate face-specific processing at or before 200 ms after stimulus onset (N170). Fourth, fMRI and physiological investigations in monkeys show strikingly selective (and often exclusive) responses to faces both within individual neurons and more recently also within cortical regions. Against this backdrop, one might have expected that fMRI studies demonstrating face-selective responses in the human temporal lobe (Kanwisher et al. 1997; McCarthy et al. 1997b) would be considered relatively uncontroversial. As we see next, this expectation would have been wrong (Gauthier et al. 2000a; Haxby et al. 2001).

3. EVIDENCE FROM fMRI: FUNCTIONAL SPECIFICITY OF THE FFA In the early 1990s, PET studies demonstrated activation of the ventral visual pathway, especially the fusiform gyrus, in a variety of face perception tasks (Haxby et al. 1991; Sergent et al. 1992). fMRI studies of the specificity of these cortical regions for faces per se began in the mid-1990s, with demonstrations of fusiform regions that responded more strongly to faces than to letter strings and textures (Puce et al. 1996), flowers (McCarthy et al. 1997a), and other stimuli, including mixed everyday objects, houses, and hands (Kanwisher et al. 1997). Although face-specific fMRI activations could also be seen in many subjects in the region of the superior temporal sulcus (fSTS) and in the occipital lobe in a region named the ‘occipital face area’ (OFA), the most consistent and robust faceselective activation was located on the lateral side of the mid-fusiform gyrus in a region we named the ‘fusiform face area’ or FFA (Kanwisher et al. 1997; figure 2).

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The fusiform face area With the methods currently used in our laboratory, we can functionally identify this region in almost every normal subject in a short ‘localizer’ fMRI scan contrasting the response to faces versus objects. In the ‘functional region of interest’ (fROI) approach, the FFA is first functionally localized in each individual, then its response magnitude is measured in a new set of experimental conditions. This method enables the FFA to be studied directly despite its anatomical variability across subjects, in a statistically powerful yet unbiased fashion (Saxe et al. 2006). Since the FFA is the most robust of the three face-selective regions (Kanwisher et al. 1997; Yovel & Kanwisher 2004), it has been investigated most completely and will be the focus of this review, although later in §5b we contrast the functional properties of the FFA with those of the other two face-selective regions. Here, we review evidence bearing on five of the most widely proposed alternatives to the face-specificity hypothesis for the FFA. (a) Is the FFA selective for simple visual features? Three lines of evidence indicate that the FFA responds specifically to faces, and not to lower level stimulus features usually present in faces (such as a pair of horizontally arranged dark regions). First, the FFA responds strongly and similarly to a wide variety of face stimuli that would appear to have few low-level features in common, including front and profile photographs of faces (Tong et al. 2000), line drawings of faces (Spiridon & Kanwisher 2002), cat faces (Tong et al. 2000) and two-tone stylized ‘Mooney faces’. Second, the FFA response to upright Mooney faces is almost twice as strong as the response to inverted Mooney stimuli in which the face is difficult to detect (Kanwisher et al. 1998; Rhodes et al. 2004), even though most low-level features (such as spatial frequency composition) are identical in the two stimulus types. Finally, for bistable stimuli such as the illusory face–vase (Hasson et al. 2001; Andrews et al. 2002), or for binocularly rivalrous stimuli in which a face is presented to one eye and a non-face is presented to the other eye (Tong et al. 1998; Pasley et al. 2004; Williams et al. 2004), the FFA responds more strongly when subjects perceive a face than when they do not see a face even though the retinal stimulation is unchanged. For all these reasons, it is difficult to account for the selectivity of the FFA in terms of lower level features that covary with faceness. Nonetheless, the facespecificity hypothesis of the FFA has been challenged with a number of other alternatives that we discuss next (Gauthier et al. 2000a; Haxby et al. 2001). (b) The individuation hypothesis applied to the FFA Is the FFA engaged not simply during face perception, but whenever subjects must discriminate between similar exemplars within a category (Gauthier et al. 1999a)? Early evidence against this hypothesis was presented in our first paper on the FFA (Kanwisher et al. 1997), in which the FFA responded much less strongly when subjects performed a 1-back (consecutive matching) task on blocks of house stimuli or hand stimuli (see also McCarthy et al. 1997b). Although this task was not matched for difficulty, a more recent Phil. Trans. R. Soc. B (2006)

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experiment from our laboratory carefully adjusted the difficulty of within-category discrimination for faces and houses (see figure 3) and still found about three times the FFA response during face discrimination as house discrimination (Yovel & Kanwisher 2004). Thus, the FFA does not simply respond strongly whenever subjects make a difficult discrimination between exemplars of any category. The individuation hypothesis is thus not a viable account of the operations conducted in FFA. (c) The expertise hypothesis applied to the FFA According to the expertise hypothesis, the FFA responds when subjects view stimuli for which they have gained substantial perceptual expertise. This hypothesis has been argued for vigorously by Gauthier, Tarr and colleagues (Gauthier & Tarr 1997) on the basis of fMRI studies in which subjects undergo extensive training in the laboratory on novel stimuli called ‘Greebles’, as well as other studies of real-world expertise for cars and birds (akin to the dog experts tested in the original Diamond & Carey study). We discuss these two kinds of studies in turn. Gauthier et al. (1999b) scanned subjects looking at faces and Greebles, and report that activation for upright minus inverted Greebles in the FFA region increased throughout Greeble training. While Gauthier et al. (1999b) interpreted their data as evidence for an expertise effect in the FFA, there are several problems with this conclusion. First, rather than measuring the per cent signal change from baseline for each stimulus type, they reported only the difference between upright and inverted orientations; this tells us nothing about the crucial question of the magnitude of response to upright Greebles and upright faces after training. Second, since Greebles resemble faces (and/or bodies), they are a poor choice of stimulus to distinguish between the face-specificity and expertise hypotheses. Third, the ‘FFA’ was defined as a large square ROI, over a centimetre on a side, a method that guarantees the inclusion of voxels neighbouring but not in the FFA. Thus, it is possible, for example, that any training effects on Greebles may arise from the body-selective ‘fusiform body area’ (FBA; Peelen & Downing 2005; Schwarzlose et al. 2005) which is adjacent to the FFA (see §3e) rather than from the FFA itself. Finally, ‘activation’ was defined as the sum across the 64 voxels in the ROI of t-values resulting from a comparison of upright to inverted responses within each voxel (after excluding all t-values less than 0.1). This truncated ‘sum-of-ts’ measure (see also Gauthier & Tarr 2002) confounds an increase in signal change for upright versus inverted stimuli after training with a reduction in variance of this measure after training. Further, the authors failed to separately report the per cent signal change values for the upright and inverted conditions, which is standard in both behavioural and neural investigations of inversion effects. These problems leave the results of this study difficult to interpret. In three recent studies that avoid these problems (Moore et al. 2006; Yue et al. in press; Op de Beeck et al. submitted), subjects were trained for many hours on fine-grained discrimination between exemplars of novel

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Figure 2. Face-selective activation (faces O objects, p!0.0001) on an inflated brain of one subject, shown from lateral and ventral views of the right and left hemispheres. Three face-selective regions are typically found: the FFA in the fusiform gyrus along the ventral part of the brain, the OFA in the lateral occipital area and the fSTS in the posterior region of the superior temporal sulcus.

stimuli that do not resemble faces or bodies. None of these studies found a significant increase in the response of the FFA for trained compared to untrained object classes after training, but all three found significant training-induced increases in response in a nearby region called the lateral occipital complex (LOC), which is responsive to object shape in general, not faces in particular. Thus, laboratory training studies to date provide no evidence for the expertise hypothesis, instead supporting the face-specificity hypothesis. Of course, 10 h of laboratory training is a far cry from the decades of expertise involved in face recognition or real-world expertise for dogs, cars or birds. Gauthier et al. (2000a) reported a greater increase in the right FFA response for cars and birds versus control objects in car and bird experts, respectively. This result has been replicated in one study (Xu 2005), but produced only a marginally significant trend in another study (Rhodes et al. 2004), and no effect at all in another (Grill-Spector et al. 2004). Note that even in the studies that do find expertise effects in the FFA, the effect size is very small and the response to faces (in per cent signal increase from fixation) remains at least twice as high as to any objects of expertise. Further, although Gauthier et al. emphasize as their strongest finding the correlation across subjects between behavioural expertise for cars/ birds and the FFA response to cars/birds (Gauthier et al. 2000a), this correlation was in fact not found in Phil. Trans. R. Soc. B (2006)

the very task where the expertise hypothesis would predict it, namely during a task requiring discrimination of objects of expertise, but only when subjects were performing a location discrimination task on the same objects. The observed pattern is hard to account for within the expertise hypothesis, but is accounted for naturally by the alternate hypothesis that ‘expertise effects’ merely reflect increased attentional engagement (Wojciulik et al. 1998) of an expert on their objects of expertise, an effect that would be expected to be larger in the context of an orthogonal location task than an object discrimination task which forces attention onto object shape anyway. Consistent with the idea that the elevated activation for objects of expertise is simply due to greater attentional engagement by these objects, the available evidence suggests that any increased responses with expertise are not restricted to the FFA. Indeed, Rhodes et al. (2004) found significantly larger expertise effects outside the FFA than inside, and although Gauthier et al. (2000a) emphasize expertise effects in the FFA, their fig. 6 shows what appears to be substantially larger effects of expertise in parahippocampal cortex. Thus, real-world expertise effects are not restricted to the FFA, and when they are found in the FFA they are small in magnitude and uncorrelated with behavioural performance on expert object individuation. Taken together, laboratory training studies and realworld expertise studies do not provide convincing evidence for the expertise hypotheses.

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Figure 3. Face and house stimuli designed to test the face-specificity hypothesis, from a study by Yovel & Kanwisher (Kanwisher et al. 1997; Yovel & Kanwisher 2004). House stimuli were constructed in exactly the same way as the face stimuli: the faces or houses differed in either their parts (eyes and mouth for faces, and windows and door for houses) or the spacing among these parts. Subjects performed a discrimination task on pairs of faces or houses that differed in either spacing or parts. Performance was matched across the stimuli and the spacing and part conditions. Thus, discrimination of the faces and of the houses are very similar in overall difficulty and in the nature of the perceptual discriminations required. Thus, the threefold higher FFA response for the face tasks than the house tasks (Kanwisher et al. 1997; Yovel & Kanwisher 2004) provides strong support to the facespecificity hypothesis and is inconsistent with the individuation hypothesis and with the hypothesis that the FFA conducts domain-general processing of configuration/spacing information.

(d) Domain-general processing of configuration/spacing in the FFA Although the individuation and expertise hypotheses have received the greatest attention in the literature, other domain-general accounts of the function of FFA are possible. Given the behavioural evidence that we are highly sensitive to the particular location of face parts (spacing) in upright faces (Haig 1984; Kemp et al. 1990), is it possible that this processing of configuration/spacing information could be applied to nonfaces, and if so, might it engage the FFA? We tested this hypothesis by attempting to force subjects to process houses in the same way they process faces (Yovel & Kanwisher 2004; see figure 3). To do this, we constructed house stimuli that varied in the relative positions of the windows and doors, and a parallel set of faces was constructed that varied in the positions of eyes and mouths. These stimuli were carefully adjusted until performance in same–different discrimination of successively presented stimulus pairs was exactly matched across pairs of faces and of houses. Subjects were further informed that when two faces, or two houses, differed, it would be in the relative position of the parts of the face/house. Thus, we did everything possible to induce the same kinds of processing on the faces and houses. Nonetheless, the FFA response to faces was about three times as strong as the FFA response to houses in this task. Evidently, it is not possible to engage the FFA on non-face stimuli by inducing subjects to process those stimuli like faces. However, note that it remains an open question whether there is any way to induce face-like holistic Phil. Trans. R. Soc. B (2006)

processing on non-face stimuli, and whether such processing would recruit the FFA (for review, see Tanaka & Farah 2003). (e) Is the FFA specific not only for faces but also for bodies? Several recent studies have reported strong FFA responses to stimuli depicting headless bodies or body parts (Cox et al. 2004; Peelen & Downing 2005; Spiridon et al. 2005), challenging the specificity of the FFA for faces. Does the FFA actually respond strongly to body parts or is this apparently high response instead due to spillover activation from the adjacent body and face-selective FBA described by Peelen & Downing (2006)? To find out, we scanned subjects with relatively high-resolution fMRI (1.4!1.4!2 mm voxels instead of the more standard 3!3!4 mm voxels; Schwarzlose et al. 2005). We found that at high resolution, two distinct regions can be identified, one exclusively selective for faces but not bodies (the FFA) and another exclusively selective for bodies but not faces (the FBA). Thus, the apparently strong FFA response to body stimuli seen at standard scanning resolution apparently reflects the pooling of responses from two distinct regions (‘partial voluming’), one truly face selective and the other truly body selective. Interestingly, regions selective for faces and bodies are also nearby or adjacent in the region of the STS in humans (Downing et al. 2001), and they are also adjacent in macaques (Tsao et al. 2003; Pinsk et al. 2005). Once again, these findings support the face-specificity hypothesis.

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(f ) Do ‘non-preferred’ responses in the FFA form part of the code for non-faces? In an important challenge to a more modular view of face and object processing, Haxby et al. (2001) argued that objects and faces are coded via the distributed profile of response across much of the ventral visual pathway. Central to this view is the suggestion that ‘non-preferred’ responses, for example to objects in the FFA, may form an important part of the neural code for those objects. While this ‘distributed coding’ hypothesis is still an active matter of debate, several considerations suggest that the FFA does not, in fact, play an important role in the representation of non-face objects. First, two studies have found that the profile of response across the voxels within face-selective patches in humans (Spiridon & Kanwisher 2002) and monkeys (Tsao et al. 2003) does not contain information enabling discrimination between different non-faces. Further, note that even if some discriminative information about non-face objects were present in the FFA (perhaps at higher resolution), it is not clear that this information would be used in perceptual performance. Indeed, the fact that some people with acquired prosopagnosia have apparently normal object recognition (Wada & Yamamoto 2001; Humphreys 2005) suggests that cortical regions that are necessary for face recognition are not necessary for object recognition. Finally, Tsao’s single-unit recordings from face-selective patches in monkeys (see §2d ) indicate that non-preferred responses in face-selective regions are virtually non-existent (Tsao et al. 2006), suggesting that the non-preferred responses observed in the FFA with fMRI may result from blurring of responses from an extremely faceselective FFA with neighbouring non-face-selective cortex (Schwarzlose et al. 2005). For all these reasons, we doubt that non-preferred responses in the FFA play an important role in coding for nonface objects. Indeed, more recently, Haxby and his colleagues have conceded that ‘preferred regions for faces.are not well suited to object classifications that do not involve faces.’ (O’Toole et al. 2005). (i) Section summary The evidence reviewed here argues against each of the six alternatives to the face-specificity hypothesis: the FFA does not appear to be selective for either lower level features or for the higher level category of bodies. Further, the evidence described here does not support a domain-general role for the FFA in individuation of exemplars of any category (including categories of expertise) or in extraction of the relative positions of parts within any stimulus type. Finally, we argue against the hypothesis that the FFA forms part of a distributed representation of non-face objects (Haxby et al. 2001), because damage to this region is devastating to face recognition but often leaves object recognition intact, and because physiological data from monkeys find almost no evidence for any response to non-face stimuli within face-selective patches in the first place. (In §4b, we describe evidence against another alternative hypothesis that the FFA is engaged in processing semantic information about people.) Phil. Trans. R. Soc. B (2006)

Instead, existing data support the hypothesis that the FFA is selectively engaged in the processing of faces per se. This conclusion brings us to the more interesting questions of what computations are performed on faces in the FFA, and what kinds of representations it extracts from faces.

4. WHAT IS THE NATURE OF THE FACE REPRESENTATIONS IN THE FFA? Many experiments implicate the FFA in determining face identity, i.e. in extracting the perceptual information used to distinguish between individual faces. For example, we showed a higher FFA response on trials in which subjects correctly identified a famous face than on trials in which they failed to recognize the same individual (Grill-Spector et al. 2004), implicating this region in the extraction of information about face identity. (No comparable correlation between the FFA response and performance was seen for identification of specific types of cars, guitars, buildings, etc.) Further evidence that the FFA is critical for distinguishing between individual faces comes from the fact that the critical lesion site for prosopagnosia is very close to the FFA (Barton et al. 2002; Bouvier & Engel 2005). However, these results tell us nothing about the nature of the representations extracted from faces in the FFA, which we turn to next. What aspects of a face does the FFA respond to? Three prominent features of face stimuli are the classic frontal face configuration (the arrangement of two horizontally and symmetrically placed parts above two vertically placed parts), the presence of specific face parts (eyes, nose and mouth) and the bounding contour of a roughly oval shape with hair on the top and sides. Which of these stimulus properties are important in driving the response of the FFA? Liu et al. (2003) created stimuli in which each of these three attributes was orthogonally varied. The face configuration was either canonical or scrambled (with face parts rearranged to occur in different positions), veridical face parts were either present or absent (i.e. replaced by black ovals) and external features were either present or absent (with a rectangular frame showing only internal features, omitting chin and hairline). This study found that the FFA responds to all three kinds of face properties. Another study from our laboratory leads to the consistent conclusion that the FFA is involved in processing both the parts and the spacing among the parts of faces. We (Yovel & Kanwisher 2004) scanned subjects while they performed a successive discrimination task on pairs of faces that differed in either the individual parts or the configuration (i.e. spacing) of those parts (figure 3). Subjects were informed in advance of each block which kind of discrimination they should perform. The FFA response was similar and strong in both conditions, again indicating a role of the FFA in the discrimination of both face parts and face configurations. Thus, the FFA does not appear to be sensitive to only a few specific face features, but instead seems to respond generally to a wide range of features spanning the whole face.

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The fusiform face area (a) Invariances of face representations in the FFA To understand the representations of faces extracted by the FFA, we need to determine their equivalence classes: which sets of stimuli are taken to be the same and which are taken to be different? If the FFA is involved in discriminating between individuals, then it must extract different representations for different individuals. But are these representations invariant across images of the same face that differ in size, position, view, etc? The best current method for approaching this problem with fMRI is fMR adaptation (Grill-Spector et al. 1999; Kourtzi & Kanwisher 2001; Koutstaal et al. 2001), in which the blood oxygenation level dependent (BOLD) response to two (or more) stimuli in a given region of the brain is lower when they are the same than when they are different, indicating a sensitivity of that brain region to that stimulus difference. This sensitivity to the sameness of two stimuli enables us to ask each brain region which stimulus pairs it takes to be the same and which it takes to be different. Thus, this method enables us to discover equivalence classes and invariances in neural representations of faces in the FFA (Grill-Spector et al. 1999).1 Several studies have found robust fMR adaptation for faces in the FFA, i.e. a lower response to an identically repeated face than to new faces (e.g. Gauthier & Nelson 2001; Yovel & Kanwisher 2004; Avidan & Behrmann 2005; Eger et al. 2005; Pourtois et al. 2005b; Rotshtein et al. 2005). Does this adaptation reflect a representation of face identity that is invariant across different images of the same person? Indeed, several studies have found adaptation across repeated images of the same face even when those images differ in position (Grill-Spector et al. 1999), image size (Grill-Spector et al. 1999; Andrews & Ewbank 2004) and spatial scale (Eger et al. 2004). Further, Rotshtein et al. (2004) used categorical perception of morphed faces to show adaptation across physically different images that were perceived to be the same (i.e. two faces that were on the same side of a perceptual category boundary), but not across physically different images that were perceived to be different (i.e. two faces that straddled the category boundary). Thus, representations in the FFA are not tied to very low-level image properties, but instead show at least partial invariance to simple image transformations. However, representations in the FFA do not appear to be invariant to non-affine changes in lighting direction (Bradshaw 1968), viewpoint (Warrington et al. 1971; Pourtois et al. 2005a; see also Fang & He 2005) and combinations thereof (Avidan & Behrmann 2005; Pourtois et al. 2005b). However, a recent study by Fang et al. (2006) reveals evidence for view-invariant representation of face identity in the FFA, in particular when the first stimulus (adaptor) is presented for a long duration (25 s). These findings suggest that long-term adaptation may reveal invariant properties of face representation in face-selective regions, which are not found in the typically used short-term adaptation. In sum, studies conducted to date converge on the conclusion that neural representations of faces in the FFA discriminate between faces of different individuals Phil. Trans. R. Soc. B (2006)

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and are partly invariant to simple image transformations including size, position and spatial scale. However, these representations are not invariant to changes in viewpoint, lighting and other non-affine image transformations. (b) Does the FFA discriminate between familiar and unfamiliar faces? A finding that the FFA responds differently to familiar and unfamiliar faces would support the role of this region in face recognition (though it is not required by this hypothesis as discussed shortly). Several fMRI studies have investigated this question (Sergent et al. 1992; Gorno-Tempini et al. 1998; George et al. 1999; Haxby et al. 2000; Leveroni et al. 2000; Wiser et al. 2000; Henson et al. 2002) using either famous faces or faces studied in the laboratory as familiar faces. For the purpose of this review, we will mainly focus on studies that report the response of the FFA to familiar and unfamiliar faces. Two studies that investigated faces learned in the laboratory found opposite results, one showing an increase in the response to familiar compared with unfamiliar faces in the FFA (Lehmann et al. 2004) and the other (using PET) finding a decrease in the response to familiar faces (Rossion et al. 2003c). Although this discrepancy may be due to the use of different tasks in the two experiments (Rossion et al. 2003c; see also Henson et al. 2002), studies of famous faces, which provide a stronger manipulation of familiarity, do not give a much clearer picture. One study found a small but significant increase in the response to famous compared with non-famous faces (Avidan & Behrmann 2005), but two other studies found no difference in the response to famous versus non-famous faces in the FFA (Eger et al. 2005; Pourtois et al. 2005b; see also Gorno-Tempini et al. 1998; Gorno-Tempini & Price 2001). Taken together, these studies do not show a consistently different FFA response for familiar versus unfamiliar faces. Although these studies do not strengthen the case that the FFA is important for face recognition, it is important to note that they do not provide evidence against this hypothesis either. These results may simply show that the FFA merely extracts a perceptual representation from faces in a bottom-up fashion, with actual recognition (i.e. matching to stored representations) occurring at a later stage of processing. It is also possible that information about face familiarity is represented in the FFA but not by an overall difference in the mean response. However, these studies do enable us to address a different question about the FFA, concerning its role in processing of non-visual semantic information about people. Since famous faces are associated with rich semantic information about the person, but nonfamous faces are not, the lack of a consistently and robustly higher response for famous than non-famous faces in the FFA casts doubt on the idea espoused by some (Martin & Chao 2001), that this region is engaged in processing not only perceptual but also semantic information about people (Turk et al. 2005).

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(c) The face-inversion effect and holistic processing in the FFA As described in §2b, behavioural studies have discovered distinctive ‘signatures’ of face-like processing, including the face-inversion effect (Yin 1969) and the ‘composite’ effect. Does the FFA mirror these behavioural signatures of face-specific processing? Early studies of the face-inversion effect in the FFA found little (Haxby et al. 1999; Kanwisher et al. 1999) or no (Aguirre et al. 1999; Leube et al. 2003) difference in the response to upright and inverted faces. However, we recently reported a substantially higher FFA response for upright compared with inverted faces (Yovel & Kanwisher 2004). Further, in a subsequent study, Yovel & Kanwisher (2005) reported that the FFA-face-inversion effect was correlated across subjects with the behavioural face-inversion effect. In other words, subjects who showed a large increment in performance for upright versus inverted faces also showed a large increment in the FFA response to upright versus inverted faces. Second, we found greater fMR adaptation for upright than inverted faces, indicating that the FFA is more sensitive to identity information in upright than inverted faces (Yovel & Kanwisher 2005; see also Mazard et al. 2005). Thus, consistent with the behavioural face-inversion effect, the FFA better discriminates faces when they are upright than inverted. In summary, in contrast to the previous findings that found only a weak relationship between the FFA and the face-inversion effect, our findings show a close link between these behavioural and neural markers of specialized face processing. The larger inversion effect for faces than objects has been taken as evidence for holistic processing of upright but not inverted faces (Farah et al. 1995). However, more direct evidence for holistic processing comes from the composite effect (Young et al. 1987) in which subjects are not able to process the upper or lower half of a composite face independently from the other half of the face even when instructed to do so, unless the two halves are misaligned. This effect is found for upright but not inverted faces. If the FFA is engaged in holistic processing of faces, then we might expect it to show an fMRI correlate of the composite effect. Indeed, a recent study used fMRI adaptation to show evidence for a composite face effect in the FFA. In particular, the FFA only showed adaptation across two identical top halves of a face (compared with two different top halves) when the bottom half of the face was also identical, consistent with the behavioural composite face effect. As with the behavioural composite effect, the fMRI composite effect was found only for upright faces and was absent for inverted faces or misaligned faces. Thus, fMRI measurements from the FFA show neural correlates of the classical behavioural signatures of face-like processing, including the face-inversion effect and the composite effect. These findings serve to link the behavioural evidence on face-specific processing with research on the FFA, as well as helping to characterize the operations and representations that occur in the FFA. Phil. Trans. R. Soc. B (2006)

(d) Norm-based coding of faces The power of caricatures to capture the likeness of a face suggests that face identity is coded in terms of deviation from the norm or average face, a hypothesis supported by behavioural studies (Rhodes et al. 1987; Leopold et al. 2001). A recent fMRI study found higher FFA responses to atypical compared with average faces, implicating the FFA in such norm-based coding of face identity (Loffler et al. 2005). However, efforts in this study to unconfound such face typicality effects from the greater adaptation effects expected between highly similar faces (in the average-face condition) versus very different faces (in the atypical face condition) were not entirely satisfactory. Therefore, the interesting hypothesis that the FFA codes faces in terms of deviation from the average face remains to be completely tested and explored. (e) Is the FFA involved in representing facial expression information? Functional MRI studies of face expression have primarily focused on the amygdala (e.g. Glascher et al. 2004; Williams et al. 2004). Studies that have investigated the response of the temporal cortex have found higher responses to emotional than neutral faces in the fusiform gyrus (Breiter et al. 1996; Dolan et al. 2001; Vuilleumier et al. 2001, 2003; Williams et al. 2004). It has been suggested that this effect is modulated by connections from the amygdala (Dolan et al. 2001). Consistent with this hypothesis, effects of facial expression (in contrast to face identity) are not specific to the FFA. Given the higher arousal generated by emotional faces, the higher response to expressive than neutral faces in the FFA may reflect a general arousal effect rather than specific representation of facial expression. Indeed, a recent fMRadaptation study (Winston et al. 2003), in which expression and identity were manipulated in a factorial manner, did not reveal significant fMR adaptation to expression information in the fusiform gyrus, but did find fMR adaptation to face expression in regions in the STS. These findings are consistent with the idea that the FFA is involved in identity, but not expression processing, whereas the STS shows the opposite pattern of response (Haxby et al. 2000). However, a recent study found a higher FFA response during expression judgements than during identity judgements on faces (Ganel et al. 2005), casting some doubt on the simple idea that the FFA is involved exclusively in processing face identity information. (i) Section summary The results reviewed in this section provide the beginnings of a characterization of the computations and the representations that occur in the FFA. The FFA is implicated in face detection and face recognition, but evidence on the role of the FFA in discriminating familiar from unfamiliar faces or in discriminating emotional expressions in faces is inconsistent. Representations of faces in the FFA are partly invariant to simple image transformations such as changes in size, position and spatial scale, but largely non-invariant to changes in most viewpoints and

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The fusiform face area lighting direction of the face image. The FFA shows both a face-inversion effect (i.e. a higher response for upright than inverted faces) and holistic processing of faces, as expected if this region plays a major role in face-processing phenomena established in previous behavioural work. 5. AREAL SPECIFICITY: DO REPRESENTATIONS IN THE FFA DIFFER FROM THOSE IN NEARBY CORTICAL REGIONS? Does the FFA show not only functional specificity, i.e. a different profile of response to faces versus other stimuli (see §3 above), but also areal specificity, i.e. a different profile of response from that seen in other nearby cortical regions? Here, we contrast the pattern of response in the FFA with that of: (i) the nearby (and sometimes slightly overlapping) object-selective LOC (Malach et al. 1995), and (ii) the two other most widely reported face-selective regions, the OFA and the faceselective region in the STS. (a) Contrasting the response of the FFA and the LOC Numerous behavioural experiments have suggested that our representations of faces differ in important respects from our representations of non-face objects (e.g. see §2b). If the FFA plays an important role in the generation of these ‘special’ face representations, we should see parallel differences in the pattern of the BOLD response in FFA versus response of other cortical regions involved in representing object shape, such as the LOC. Importantly, in the studies described below, object-selective regions were defined as cortical regions that respond more strongly to objects than to scrambled images of objects, rather than as regions that respond more strongly to objects than faces, a comparison that has been used in some studies (Aguirre et al. 1999; Haxby et al. 1999; Andrews & Schluppeck 2004), but that is likely to yield not the LOC but a functionally very different region called the parahippocampal place area (PPA; Epstein & Kanwisher 1998). The problem with using the region identified with a contrast of objects greater than faces is that the response to faces is very low to begin with in this region, so the absence of sensitivity to stimulus manipulations here might be merely due to floor effects. In contrast, the LOC shows a high response to faces, in particular in its lateral occipital region, and it is therefore a more valid region to compare to the FFA. Several studies have recently reported robust dissociations between the response of the LOC and the FFA. First, the FFA and LOC exhibit important and striking differences in the face-inversion effect. Whereas the FFA shows a significantly higher response to upright than inverted faces, the LOC shows an opposite effect of a higher response to inverted than upright faces (Yovel et al. 2005b; see also Aguirre et al. (1999) and Haxby et al. (1999) who found similar pattern in non-face-selective regions that responded higher to houses than faces). Furthermore, we measured the correlation across subjects between the magnitude of the fMR-face-inversion effect (i.e. the difference between fMRI response to upright and Phil. Trans. R. Soc. B (2006)

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inverted faces), and the behavioural face-inversion effect (i.e. the difference between performance level to upright and inverted faces in a face discrimination task that subjects performance in the scanner; Yovel et al. 2005b). Only in the FFA was the fMR-face-inversion effect correlated across subjects with the behavioural face-inversion effect. This correlation was absent with the (opposite direction) fMR-face-inversion effect in LOC. These findings suggest that the FFA, but not LOC, is a neural source of the behavioural faceinversion effect. Second, the sensitivity of the FFA to identity information in faces was recently assessed using an event-related fMR-adaptation technique (Yovel et al. 2005b). As explained in §4a, in fMRI adaptation, a higher response in a given brain region to two successively presented stimuli when they are different than when they are the same indicates sensitivity to that stimulus difference in that region of the brain. We created face stimuli with subtle differences between the faces (e.g. the faces shared the same hair but differed subtly in face identity information) and found robust adaptation for these faces in the FFA but no adaptation to faces in LOC. These data again suggest that only the FFA (not the LOC) is sensitive to subtle differences between different faces. Third, as mentioned above, Grill-Spector et al. (2004) found a higher FFA response on trials in which subjects correctly identified famous faces versus when they were incorrect on faces of the same individuals. Importantly, LOC did not show this trialby-trial correlation with successful discrimination of faces, showing once again a greater involvement of the FFA than the LOC in face identification. Finally, we reported that the right FFA response was similar when subjects discriminated faces that differed in their parts or in the spacing among these parts (Yovel & Kanwisher 2004). The FFA response to houses was much lower than to faces and also similar for the spacing and part tasks. In contrast, LOC showed a higher response on the part task than the spacing task for both faces and houses (see figure 4). These findings resonate with theories of object recognition, which emphasize the role of parts in representations of object shape (Hoffman & Richards 1984; Biederman 1987), and contrast sharply with theories of face processing, which emphasize holistic representations. Taken together, these findings indicate that the representations in the FFA differ in many respects from the representations in LOC. Thus, the FFA is not only selective for faces, but also generates a specialized representation of faces that is qualitatively different from the representations of faces in other regions. Next, we contrast the FFA with other face-selective regions. (b) Dissociation between face-selective regions (FFA, OFA and STS) Several studies have compared the response of the FFA to the response of the two other face-selective regions, the OFA in the lateral occipital cortex and what we will call the fSTS (a face-selective region in the posterior part of the superior temporal gyrus). Figure 2 shows these face-selective activations on an inflated brain from one subject. Overall, these studies suggest that the

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Figure 4. The response of the FFA and LOC to the face and house stimuli (see figure 3) when subjects discriminate the stimuli based on their parts (eyes and mouth for faces, and windows and doors for houses) or the spacing among the parts. Findings show a clear dissociation between the FFA, which responds more strongly to faces than houses but similarly on the spacing and part tasks versus the LOC, which shows a similar response to faces and houses and a higher response when subjects discriminate stimuli based on parts than based on the spacing among the parts.

FFA and OFA are primarily involved in distinguishing between individual faces, whereas the fSTS apparently extracts other dimensions of faces such as their emotional expression and gaze (Haxby et al. 2000). FFA versus OFA. Findings by Rotshtein et al. (2005) showed that the OFA is more sensitive to physical aspects of the face stimulus than the FFA. In their morphed face experiment, the OFA showed a similar response to two faces that differed physically regardless of whether the subject perceived the two stimuli as similar or different. This finding contrasts with the FFA, which was sensitive to the perceived similarity, but not the physical similarity in their study. Second, in a recent study that investigated the neural basis of the face-inversion effect, Yovel et al. (2005b) found that the OFA showed a similar response to upright and inverted faces, and there was no correlation across subjects between the magnitude of the behavioural faceinversion effect and the difference in the response of the OFA to upright and inverted faces (OFA-faceinversion effect). In contrast, the FFA showed higher response to upright than inverted faces and this difference was correlated across subjects with the behavioural face-inversion effect. Finally, whereas the FFA responds to first-order stimulus information about both face parts and face configurations, the Phil. Trans. R. Soc. B (2006)

OFA is sensitive only to face parts (Liu et al. 2003). Taken together, these findings suggest that the representation of faces in the FFA is closer to the perceived identity of the face, whereas the OFA representation reflects more closely the physical aspects of the face stimulus. Evidence that the OFA may be a critical stage in the face-recognition pathway comes from the case of an acquired prosopagnosic patient with no OFA in either hemisphere (Rossion et al. 2003a). Although this result by itself makes sense, a puzzle arises from the fact that the same patient shows an FFA in fMRI. One possible account of these findings is that this patient’s FFA is present but not functioning normally because normal input from the OFA is disrupted. Indeed, a recent paper has used fMRI adaptation to show that the FFA in this subject does not discriminate between individual faces (Schiltz & Rossion 2006). FFA versus fSTS. Studies that have examined the response of both the FFA and the fSTS show clear functional dissociations between the two regions. First, two studies have found that the FFA but not the fSTS is correlated with successful face detection. Andrews & Schluppeck (2004) presented ambiguous stimuli (Mooney faces) that were perceived as faces on some trials but as novel blobs on others. Whereas the FFA response was stronger for face than blob percepts (see also Kanwisher et al. 1998), the fSTS showed no difference between the two types of trials. These findings are consistent with Grill-Spector et al. (2004), who found that the response of the FFA was correlated with successful detection of faces in brief masked stimuli, but the response of the fSTS was not. The failure to find a correlation with successful face detection in the fSTS when stimuli are held constant (or are similar) is somewhat surprising, given that this region by definition responds more strongly when faces are present than when they are not. In any event, the correlation with successful face detection of the FFA but not fSTS, which was found in both studies, shows a dissociation between the two regions. Given the findings just described, it is not surprising that the fSTS shows no sensitivity to face identity information. The first study to report a dissociation between FFA and fSTS found a higher response in the FFA when subjects performed a 1-back task on face identity than gaze information, and vice versa in the face-selective fSTS (Hoffman & Haxby 2000). Consistent with these findings, Grill-Spector et al. (2004) found no correlation of the fSTS response with successful identification of faces. Similarly, studies that used fMR adaptation found sensitivity to face identity in the FFA but not in the fSTS (Andrews & Ewbank 2004; Yovel et al. 2005b). The face selective fSTS did show fMR adaptation for identical faces relative to faces that differed in expression, gaze and viewpoint (Andrews & Ewbank 2004). However, since the faces differed in all three dimensions, it is hard to know whether the fSTS was sensitive to only expression, gaze or head rotation or to any combination of the three. Several studies have found a robust face-inversion effect (higher response to upright than inverted faces) in the fSTS (Haxby et al. 1999; Leube et al. 2003; Yovel

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The fusiform face area et al. 2005b). However, in contrast to the FFA, this difference between upright and inverted faces was not correlated with the behavioural face-inversion effect measured in a face identity discrimination task (Yovel et al. 2005b). These findings are consistent with the idea that the fSTS is not involved in face identity processing. Its higher response to upright than inverted faces may suggest that the computations which are done in the fSTS to extract dynamic aspects of facial information are specific to upright faces. Taken together, these data indicate a robust dissociation between the face representations in the fSTS and the FFA, in which the FFA but not the rSTS represents identity information. (i) Section summary The evidence reviewed here indicates that the FFA differs functionally in a number of respects from both the shape-selective LOC and the two other best-known face-selective regions of cortex, the OFA and fSTS. Functional ROI analyses are sometimes criticized for focusing narrowly on one brain region, while ignoring the rest of the brain. Here, we show that a functional ROI investigation of the FFA which is accompanied by similar analyses of nearby regions allows us to assess the extent to which the FFA response is indeed ‘special’. The clear functional dissociations between these regions also demonstrate that the functional localizers used to define these regions indeed are picking out functionally distinct regions, reinforcing the importance of studying them independently. Many of the functional dissociations described in this section would probably not be apparent in a group analysis, because the necessarily imperfect registration of physically different brains would blur across nearby but functionally distinct regions such as the FFA and LOC.

6. OPEN QUESTIONS As our review of the literature shows, considerable progress has been made in understanding the FFA and its role in face perception. However, fundamental questions remain unanswered. In our final section, we speculate on two of these: the developmental origins of the FFA; and the question of whether the FFA is unique in the cortex or whether it is one of a large number of other cortical regions specialized for domain-specific cognitive functions. We end with a summary of the main conclusions from this review. (a) Origins of the FFA How does the FFA arise in development? Recent neuroimaging studies show that the FFA is still developing into the early teenage years (Passarotti et al. 2003; Aylward et al. 2005; Golarai et al. 2005). Intriguing as this finding is, it does not tell us about the mechanisms that give rise to the FFA. Is it constructed by a process of experience-dependent cortical selforganization ( Jacobs 1997) or is it partly innately specified? For the case of faces, this question is hard to answer because both experiential and evolutionary arguments are plausible, and we have very little data to constrain our speculation. Phil. Trans. R. Soc. B (2006)

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On the one hand, experience must surely play some instructive role in the development of face areas, given the ample evidence that neurons in the ventral visual pathway are tuned by experience (Baker et al. 2002; Op de Beeck et al. submitted). Evidence of such experiential tuning of face perception, in particular, is seen in the ‘other race effect’, in which behavioural performance (Malpass & Kravitz 1969; Meissner & Brigham 2001) and neural responses (Golby et al. 2001) are higher for faces of a familiar than an unfamiliar race, even if the relevant experience occurs after age 3 (Sangrigoli et al. 2005). On the other hand, at least some aspects of face perception appear to be innately specified, as infants less than 24 h old preferentially track schematic faces compared with visually similar scrambled or inverted faces ( Johnson et al. 1991; Cassia et al. 2004). However, these two observations leave open a vast space of possible scenarios in which genes and environment could interact in the construction of a selective region of cortex such as the FFA. What does seem pretty clear is that the development of normal adult face processing (and thus by hypothesis the development of the FFA) is constrained both anatomically and chronologically. First, the very fact that the FFA lands in roughly the same location across subjects, along with its predominant lateralization to the right hemisphere, suggests some constraints on its development. Second, neuropsychological patients who selectively lose face-recognition abilities as a result of focal brain damage are rarely, if ever, able to relearn this ability, suggesting that the remaining visual cortex (which is adequate for visual recognition of non-face objects) cannot be trained on face recognition in adulthood (but see DeGutis et al. (in press) for evidence of short-term improvement in face recognition in a case of developmental prosopagnosia following extensive perceptual training with faces). Third, this apparent inability to shift face processing to alternate neural structures may be set very early in development, as evidenced by a patient who sustained damage to the fusiform region when only 1 day old, and who as an adult still has severe difficulties in the recognition of faces (and some other object categories; Farah et al. 2000). Although it is not clear what is so special about this region of the fusiform gyrus that the FFA apparently has to live here, one intriguing clue comes from reports that face-selective cortex also responds more strongly to central than peripheral visual stimuli (even non-faces; Levy et al. 2001). This fact may suggest that face-selective regions reside in centre-biased cortex either because it has computational properties necessary for face processing, or because we tend to foveate faces during development (Kanwisher 2001). Other clues about the development of specialized mechanisms for face processing come from individuals with ’developmental prosopagnosia’, who have no brain damage discernible from MRI images or life histories, but who have severe and lifelong impairments of face recognition (Behrmann & Avidan 2005). For at least some of these individuals, the deficit is remarkably selective for face processing only (Duchaine et al. 2006), providing powerful converging support for the

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face-specificity hypothesis. Anecdotal reports suggest that developmental prosopagnosia may run in families (De Haan 1999; Duchaine & Nakayama 2005; Kennerknecht et al. 2006). The possible heritability of this syndrome, its strong specificity for faces and its developmental nature all suggest that genetic factors may contribute to the construction of face-processing mechanisms. One as yet unresolved mystery is why many developmental prosopagnosic subjects have FFAs (Hasson et al. 2003; see also Vuilleumier et al. 2003). This may indicate that either the deficit in these subjects arises at a later stage of processing or the FFAs in these subjects exist but do not function normally (Schiltz & Rossion 2006). Although Avidan et al. (2005) have argued that the FFAs of prosopagnosic subjects show normal fMR adaptation for face identity, these studies were conducted using a blocked design which is subject to attentional confounds.1 Evidence that very early experience is also crucial in the development of normal adult face recognition comes from studies of individuals born with dense bilateral cataracts (Maurer et al. 2005). These people have no pattern vision until their cataracts are surgically corrected between two and six months of age. After surgery, pattern vision is generally intact, though not quite normal. Surprisingly, these individuals never develop normal face perception. As adults, they are impaired (relative to normal subjects) at discriminating between upright faces. Although it has been claimed that the deficit in these patients is specific to discriminations between faces on the basis of the position of the features, not the shapes of individual features, the stimuli used in the study making this case (i.e. the Jane face) confound spacing/ part changes with overall difficulty. Importantly, studies that matched the task difficulty of the spacing and the part tasks found that prosopagnosic individuals showed deficits for both spacing and part discrimination tasks (Yovel & Duchaine 2006). Second, face parts used by Le Grand et al. (2004) differed not only in shape, but also in contrast/ brightness information (e.g. lipstick). A recent study showed that prosopagnosic individuals can normally discriminate between faces in which the parts differ in contrast/brightness in addition to shape information (Yovel & Duchaine 2006). Thus, to determine the role of spacing and part-based information in face recognition in these patients, it will be important to retest the early-cataract subjects with these more balanced stimuli in which face parts differ by shape and not by contrast/brightness information, which can be discriminated by non-face mechanisms. Studies that examined holistic processing showed that these patients do not show the composite effect (described in §1; Young et al. 1987) indicating a failure to process faces holistically (Le Grand et al. 2004). Thus, pattern vision in the first few months of life is necessary for the development of normal face processing as an adult; years of subsequent visual experience with faces is not sufficient. Most intriguingly, it is early deprivation of input specifically to the right hemisphere that leads to adult impairments in face processing in these individuals; early deprivation Phil. Trans. R. Soc. B (2006)

of visual input to the left hemisphere does not (Le Grand et al. 2003). Thus, although these investigations point to a critical role of experience in the construction or maintenance of face-processing mechanisms, this experience must be directed to a specific anatomical target (the right hemisphere) and must occur very early in development. Two important pieces of this puzzle have yet to be answered empirically. First, is the deficit in cataract patients specific to face perception? Here, it would be particularly useful to measure the performance of these people on closely matched face and non-face stimuli such as those shown in figure 3. Second, what happens to the FFA in individuals with early bilateral cataracts? We speculate that they may have FFAs (as developmental prosopagnosic subjects do), but their FFAs may not function normally. A brief comment about studies of the supposed lack of FFAs in individuals with autism spectrum disorder (ASD; Schultz et al. 2000; Critchley et al. 2001; Pierce et al. 2001). This finding has been cited as evidence for a role of experience in the construction of the FFA, based on the argument that ASD subjects tend not to look at faces during development as much as normal subjects do. However, this argument has multiple flaws. First, few would doubt the conclusion that experience with faces is important in the development of the FFA. The interesting question is whether experience plays an instructive rather than a permissive role (Crair 1999). (An instructive role for experience might predict that people—or more likely, monkeys—raised in an environment where faces had a very different structure would develop face-processing mechanisms that are selectively responsive to this alternate structure.) Studies of autism cannot answer this question. Second, even if individuals with ASD lacked FFAs as claimed, this would not demonstrate the importance of experience for the development of the FFA, because these disorders also have a genetic component which could itself be responsible for the lack of an FFA. Third, given the well-documented tendency of individuals with ASD to avoid looking at faces, any failure to find FFAs in subjects with ASD may result from the failure of the subjects to look at the stimuli during the scans (!). Indeed, studies that required subjects to fixate faces found normal face activation in the fusiform gyrus in subjects with ASD (Hadjikhani et al. 2004; Dalton et al. 2005). Thus, current investigations of FFAs in ASD subjects do not help us understand the developmental mechanisms by which FFAs are constructed. One way to unconfound genetic and experiential factors in the development of category-specific regions of cortex is to consider a category for which a specific role of genes is unlikely: visual word recognition. People have only been reading for a few thousand years, which is probably not long enough for natural selection to have produced specialized machinery for visual word recognition (Polk & Farah 1998). Thus, strong evidence for a region of cortex selectively involved in the visual recognition of letters or words would provide an existence proof that experience alone with a given category of stimulus, without a specific genetic predisposition, can play an instructive role in the construction of a region of cortex that is selectively

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The fusiform face area involved in the recognition of stimuli of that category. Some evidence has been reported for cortical specializations for visually presented letters (Polk et al. 2002) and words (Cohen et al. 2000). Ongoing work in our laboratory reinforces these conclusions, showing small letter string selective regions in most subjects tested individually, and further showing that these selectivities are shaped by experience. Of course, the fact that experience can apparently create cortical selectivities in the absence of a specific genetic blueprint for that cortical region does not imply that this is the origin of the FFA. In sum, substantial evidence indicates important roles for both genetic factors and specific early experience, in the construction of the FFA. Although a detailed account of this process remains elusive, the recent discovery of a possible homologue of the FFA in macaques (Tsao et al. 2003; see §2d ) opens up the exciting new possibility of investigating the effect of early experience on the development of face-selective regions of cortex. (b) Cortical specialization for other functions? Of course, the evidence for the face-specificity hypothesis reviewed here need not imply that all of cognition is conducted by domain-specific mechanisms. Are faces unique in this degree of functional specificity or do other similarly selective regions of cortex exist in the human brain? Within the occipitotemporal pathway, we have characterized two other category-selective regions, the PPA, which responds selectively to images of places (Epstein & Kanwisher 1998) and the extrastriate body area (EBA) that responds selectively to images of bodies and body parts (Downing et al. 2001). Like the FFA, these areas can be found in more or less the same anatomical location in almost every normal subject. These category-selective regions thus constitute part of the basic functional architecture of the human brain. Are these three category-selective regions just the tip of the iceberg, with dozens more in the occipitotemporal pathway waiting to be discovered? In a broad survey of 20 different stimulus categories, Downing et al. (2006) replicated the FFA, PPA and EBA in the vast majority of subjects, but failed to find other categories that produce the kind of strongly selective response in a focal region of cortex seen in the FFA, PPA and EBA. Of course, there are many ways to fail to detect a category-selective region that actually exists and new ones may be evident when we scan at higher resolution (Schwarzlose et al. 2005). Nonetheless, it appears that we do not have special regions of cortex on the spatial scale of the FFA, PPA and EBA for many common categories; faces, places and bodies may be ‘special’ in the cortex. Why these categories and (apparently) not others? In our efforts to answer this question, explorations of other domains of cognition may provide important clues. The recent discovery of a region in the temporoparietal junction which is very selectively involved in the representation of other people’s beliefs (Saxe & Kanwisher 2003; Saxe & Wexler 2005) shows that a high degree of cortical specificity is not restricted to the realm of high-level vision. Ongoing work is Phil. Trans. R. Soc. B (2006)

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investigating the possibility that the human brain also contains cortical regions selectively involved in other domains of cognition, such as number (Dehaene et al. 2004; Shuman & Kanwisher 2004), language (Caplan 2001) and music (Peretz & Zatorre 2005).

7. SUMMARY In this review, we began with the classic question of whether face processing recruits domain-specific mechanisms specialized for face perception per se (the face-specificity hypothesis). This question has remained at the heart of theoretical and experimental work on face perception for decades. The research reviewed here shows that the field is in fact making progress in resolving this longstanding debate, as the evidence supporting the face-specificity hypothesis is getting ever stronger. Studies of the FFA have contributed importantly, enabling us to rule out five of the most widely discussed domain-general accounts of the function of this cortical region and supporting the face-specificity hypothesis. We then turned to the question of what the FFA does with faces and what kinds of representations it extracts from them. Many studies implicate the FFA in extracting the perceptual representations of faces used in face recognition (and face detection), and several studies have further shown that the pattern of response in the FFA mirrors classic behavioural signatures of face processing such as the face-inversion effect. Further work using fMRI adaptation has enabled researchers to characterize the representations of faces in the FFA, which are partly invariant to simple image transformations (such as changes in size and position), but not to changes in viewpoint or lighting direction. In §5, we reviewed the evidence that the FFA shows not only functional specificity (for faces versus objects) but also area specificity: the response profile of the FFA differs in many respects from that of the nearby shapeselective LOC, as well as that of two other face-selective cortical regions (the OFA and the fSTS). We then speculated about the origins of the FFA in development, noting that experience with faces is likely to be crucial, but that evidence also suggests strong anatomical and chronological constraints on when and where this experience can be used in the construction of the FFA. Finally, we returned to the question of domain specificity of mind and brain, pointing out that despite the very strong evidence for domain-specific mechanisms for face perception, there is no reason to assume that all or even most of cognition will be implemented in similarly domain-specific mechanisms. Thus, the nature and specificity of the mechanisms underlying other domains of cognition can only be resolved by detailed investigation of each. In this enterprise, the cognitive neuroscience of face perception will serve as an informative case study. We would like to thank Chris Baker, Mike Mangini, Scott Murray and Rachel Robbins for their comments on the manuscript. We also thank Bettiann McKay for help with manuscript preparation. This research was supported by NIH grants 66696 and EY13455 to N.K.

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ENDNOTE 1

One caveat should be noted here, however. Several fMRI-adaptation studies (Tarr & Gauthier 2000) have used blocked designs, which is problematic because subjects are likely to pay less attention to a block in which the identical stimulus is presented many times in a row, than a block in which each stimulus is new. Thus, this design confounds adaptation with attention (which is well known to affect the FFA response (Wojciulik et al. 1998) leading to potential overestimation of adaptation effects. For this reason most current studies minimize this confound by using event-related methods to measure adaptation (Kourtzi & Kanwisher 2001).

REFERENCES Aguirre, G. K., Singh, R. & D’Esposito, M. 1999 Stimulus inversion and the responses of face and object-sensitive cortical areas. Neuroreport 10, 189–194. Allison, T., Ginter, H., McCarthy, G., Nobre, A. C., Puce, A., Luby, M. & Spencer, D. D. 1994 Face recognition in human extrastriate cortex. J. Neurophysiol. 71, 821–825. Allison, T., Puce, A., Spencer, D. D. & McCarthy, G. 1999 Electrophysiological studies of human face perception. I: potentials generated in occipitotemporal cortex by face and non-face stimuli. Cereb. Cortex 9, 415–430. (doi:10. 1093/cercor/9.5.415) Andrews, T. J. & Ewbank, M. P. 2004 Distinct representations for facial identity and changeable aspects of faces in the human temporal lobe. Neuroimage 23, 905–913. (doi:10.1016/j.neuroimage.2004.07.060) Andrews, T. J. & Schluppeck, D. 2004 Neural responses to Mooney images reveal a modular representation of faces in human visual cortex. Neuroimage 21, 91–98. (doi:10.1016/ j.neuroimage.2003.08.023) Andrews, T. J., Schluppeck, D., Homfray, D., Matthews, P. & Blakemore, C. 2002 Activity in the fusiform gyrus predicts conscious perception of Rubin’s vase-face illusion. Neuroimage 17, 890–901. (doi:10.1016/S10538119(02)91243-7) Avidan, G. & Behrmann, M. 2005 Cortical networks mediating face familiarity and identity in the human brain. Vision Sciences Society. Florida, FL: Sarasota. Avidan, G., Hasson, U., Malach, R. & Behrmann, M. 2005 Detailed exploration of face-related processing in congenital prosopagnosia: 2. functional neuroimaging findings. J. Cogn. Neurosci. 17, 1150–1167. (doi:10.1162/089 8929054475145) Aylward, E. H., Park, J. E., Field, K. M., Parsons, A. C., Richards, T. L., Cramer, S. C. & Meltzoff, A. N. 2005 Brain activation during face perception: evidence of a developmental change. J. Cogn. Neurosci. 17, 308–319. (doi:10.1162/0898929053124884) Baker, C. I., Behrmann, M. & Olson, C. R. 2002 Impact of learning on representation of parts and wholes in monkey inferotemporal cortex. Nat. Neurosci. 5, 1210–1216. (doi:10.1038/nn960) Barton, J. J., Press, D. Z., Keenan, J. P. & O’Connor, M. 2002 Lesions of the fusiform face area impair perception of facial configuration in prosopagnosia. Neurology 58, 71–78. Behrmann, M. & Avidan, G. 2005 Congenital prosopagnosia: face-blind from birth. Trends Cogn. Sci. 9, 180–187. (doi:10.1016/j.tics.2005.02.011) Bentin, S., Allison, T., Puce, A., Perez, E. & McCarthy, G. 1996 Electrophysiological studies of face perception in humans. J. Cogn. Neurosci. 8, 551–565. Biederman, I. 1987 Recognition-by-components—a theory of human image understanding. Psychol. Rev. 94, 115–147. (doi:10.1037/0033-295X.94.2.115) Phil. Trans. R. Soc. B (2006)

Bouvier, S. E. & Engel, S. A. 2005 Behavioral deficits and cortical damage loci in cerebral achromatopsia. Cereb. Cortex 16, 183–191. (doi:10.1093/cercor/bhi096) Bradshaw, J. L. 1968 Load and pupillary changes in continuous processing tasks. Br. J. Psychol. 59, 265–271. Breiter, H. C., Etcoff, N. L., Whalen, P. J., Kennedy, W. A., Rauch, S. L., Buckner, R. L., Strauss, M. M., Hyman, S. E. & Rosen, B. R. 1996 Response and habituation of the human amygdala during visual processing of facial expression. Neuron 17, 875–887. (doi:10.1016/S08966273(00)80219-6) Busey, T. A. & Vanderkolk, J. R. 2005 Behavioral and electrophysiological evidence for configural processing in fingerprint experts. Vis. Res. 45, 431–448. (doi:10.1016/ j.visres.2004.08.021) Caplan, D. 2001 Functional neuroimaging studies of syntactic processing. J. Psycholinguist. Res. 30, 297–320. (doi:10.1023/A:1010495018484) Cassia, V. M., Turati, C. & Simion, F. 2004 Can a nonspecific bias toward top-heavy patterns explain newborns’ face preference? Psychol. Sci. 15, 379–383. (doi:10.1111/ j.0956-7976.2004.00688.x) Cohen, L., Dehaene, S., Naccache, L., Lehericy, S., Dehaene-Lambertz, G., Henaff, M. A. & Michel, F. 2000 The visual word form area: spatial and temporal characterization of an initial stage of reading in normal subjects and posterior split-brain patients. Brain 123, 291–307. (doi:10.1093/brain/123.2.291) Cox, D., Meyers, E. & Sinha, P. 2004 Contextually evoked object-specific responses in human visual cortex. Science 304, 115–117. (doi:10.1126/science.1093110) Crair, M. C. 1999 Neuronal activity during development: permissive or instructive? Curr. Opin. Neurobiol. 9, 88–93. (doi:10.1016/S0959-4388(99)80011-7) Critchley, H. D., Melmed, R. N., Featherstone, E., Mathias, C. J. & Dolan, R. J. 2001 Brain activity during biofeedback relaxation: a functional neuroimaging investigation. Brain 124, 1003–1012. (doi:10.1093/brain/124.5.1003) Dalton, K. M., Nacewicz, B. M., Johnstone, T., Schaefer, H. S., Gernsbacher, M. A., Goldsmith, H. H., Alexander, A. L. & Davidson, R. J. 2005 Gaze fixation and the neural circuitry of face processing in autism. Nat. Neurosci. 8, 519–526. De Haan, E. H. 1999 A familial factor in the development of face recognition deficits. J. Clin. Exp. Neuropsychol. 21, 312–315. DeGutis, J., Bentin, S., Robertson, L. & D’Esposito, M. In press. Functional plasticity in ventral temporal cortex following configural training with faces in a congenital prosopagnosic. Neuron. Dehaene, S., Molko, N., Cohen, L. & Wilson, A. J. 2004 Arithmetic and the brain. Curr. Opin. Neurobiol. 14, 218–214. (doi:10.1016/j.conb.2004.03.008) Desimone, R., Albright, T. D., Gross, C. G. & Bruce, C. 1984 Stimulus-selective properties of inferior temporal neurons in the macaque. J. Neurosci. 4, 2051–2062. Diamond, R. & Carey, S. 1986 Why faces are and are not special: an effect of expertise. J. Exp. Psychol. Gen. 115, 107–117. (doi:10.1037/0096-3445.115.2.107) Dolan, R. J., Morris, J. S. & deGelder, B. 2001 Crossmodal binding of fear in voice and face. Proc. Natl Acad. Sci. USA 98, 10 006–10 010. (doi:10.1073/pnas.171288598) Downing, P. E., Jiang, Y., Shuman, M. & Kanwisher, N. 2001 A cortical area selective for visual processing of the human body. Science 293, 2470–2473. (doi:10.1126/science. 1063414) Downing, P. E., Chan, A. W., Peelen, M. V., Dodds, C. M. & Kanwisher, N. 2006 Domain specificity in visual cortex. Cereb. Cortex 16, 1453–1461. (doi:10.1093/cercor/bhj086)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

The fusiform face area Duchaine, B. & Nakayama, K. 2005 Dissociations of face and object recognition in developmental prosopagnosia. J. Cogn. Neurosci. 17, 249–246. (doi:10.1162/0898929053124857) Duchaine, B. C., Dingle, K., Butterworth, E. & Nakayama, K. 2004 Normal greeble learning in a severe case of developmental prosopagnosia. Neuron 43, 469–473. (doi:10.1016/j.neuron.2004.08.006) Duchaine, B., Yovel, G., Butterworth, E. & Nakayama, K. 2006 Elimination of all domain-general hypotheses of prosopagnosia in a single individual with developmental prosopagnosia. Cogn. Neuropsychol. 23, 714–747. Eger, E., Schyns, P. G. & Kleinschmidt, A. 2004 Scale invariant adaptation in fusiform face-responsive regions. Neuroimage 22, 232–242. (doi:10.1016/j.neuroimage. 2003.12.028) Eger, E., Schweinberger, S. R., Dolan, R. J. & Henson, R. N. 2005 Familiarity enhances invariance of face representations in human ventral visual cortex: fMRI evidence. Neuroimage 26, 1128–1139. (doi:10.1016/j.neuroimage. 2005.03.010) Epstein, R. & Kanwisher, N. 1998 A cortical representation of the local visual environment. Nature 392, 598–601. (doi:10.1038/33402) Fang, F. & He, S. 2005 Viewer-centered object representation in the human visual system revealed by viewpoint after effects. Neuron 45, 793–800. (doi:10.1016/j.neuron. 2005.01.037) Fang, F., Murray, S. O. & He, S. 2006 Duration-dependent fMRI adaptation and distributed viewer-centered face representation in human visual cortex. Cereb. Cortex. (doi:10.1093/cercor/bhl053). [Epub ahead of print 11 August 2006] Farah, M. J., Tanaka, J. W. & Drain, H. M. 1995 What causes the face inversion effect? J. Exp. Psychol.: Hum. Percept. Perform. 21, 628–634. (doi:10.1037/0096-1523.21.3.628) Farah, M. J., Rabinowitz, C., Quinn, G. E. & Liu, G. T. 2000 Early commitment of neural substrates for face recognition. Cogn. Neuropsychol. 17, 117–123. (doi:10.1080/ 026432900380526) Foldiak, P., Xiao, D., Keysers, C., Edwards, R. & Perrett, D. I. 2004 Rapid serial visual presentation for the determination of neural selectivity in area STSa. Prog. Brain Res. 144, 107–116. Ganel, T., Valyear, K. F., Goshen-Gottstein, Y. & Goodale, M. A. 2005 The involvement of the “fusiform face area” in processing facial expression. Neuropsychologia 43, 1645–1654. (doi:10.1016/j.neuropsychologia.2005.01. 012) Epub 2005 Feb 25 43, 1645–1654 Gauthier, I. & Nelson, C. A. 2001 The development of face expertise. Curr. Opin. Neurobiol. 11, 219–224. (doi:10. 1016/S0959-4388(00)00200-2) Gauthier, I. & Tarr, M. J. 1997 Orientation priming of novel shapes in the context of viewpoint-dependent recognition. Perception 26, 51–73. Gauthier, I. & Tarr, M. J. 2002 Unraveling mechanisms for expert object recognition: bridging brain activity and behavior. J. Exp. Psychol. Hum. Percept. Perform. 28, 431–446. (doi:10.1037/0096-1523.28.2.431) Gauthier, I., Williams, P., Tarr, M. J. & Tanaka, J. 1998 Training ’greeble’ experts: a framework for studying expert object recognition processes. Vis. Res. 38, 2401–2428. (doi:10.1016/S0042-6989(97)00442-2) Gauthier, I., Behrmann, M. & Tarr, M. J. 1999a Can face recognition really be dissociated from object recognition? J. Cogn. Neurosci. 11, 349–370. (doi:10.1162/089892999 563472) Gauthier, I., Tarr, M. J., Anderson, A. W., Skudlarski, P. & Gore, J. C. 1999b Activation of the middle fusiform ‘face area’ increases with expertise in recognizing novel objects. Nat. Neurosci. 2, 568–573. (doi:10.1038/9224) Phil. Trans. R. Soc. B (2006)

N. Kanwisher & G. Yovel 2125

Gauthier, I., Skudlarski, P., Gore, J. C. & Anderson, A. W. 2000a Expertise for cars and birds recruits brain areas involved in face recognition. Nat. Neurosci. 3, 191–197. (doi:10.1038/72140) Gauthier, I., Tarr, M. J., Moylan, J., Skudlarski, P., Gore, J. C. & Anderson, A. W. 2000b The fusiform “face area” is part of a network that processes faces at the individual level. J. Cogn. Neurosci. 12, 495–504. (doi:10.1162/ 089892900562165) Gauthier, I., Curran, T., Curby, K. M. & Collins, D. 2003 Perceptual interference supports a non-modular account of face processing. Nat. Neurosci. 6, 428–432. (doi:10. 1038/nn1029) George, N., Dolan, R. J., Fink, G. R., Baylis, G. C., Russell, C. & Driver, J. 1999 Contrast polarity and face recognition in the human fusiform gyrus. Nat. Neurosci. 2, 574–580. (doi:10.1038/9230) Glascher, J., Tuscher, O., Weiller, C. & Buchel, C. 2004 Elevated responses to constant facial emotions in different faces in the human amygdala: an fMRI study of facial identity and expression. BMC Neurosci. 5, 45. (doi:10. 1186/1471-2202-5-45) Golarai, G., Ghahremani, D. G., Grill-Spector, K. & Gabrielii, J. D. E. 2005 Evidence for maturation of the fusiform face area (FFA) in 7 to 16 yr old children. In Vision Sciences Society: Sarasota, FL. Golby, A. J., Gabrieli, J. D., Chiao, J. Y. & Eberhardt, J. L. 2001 Differential responses in the fusiform region to samerace and other-race faces. Nat. Neurosci. 4, 775–776. (doi:10.1038/90565) Gorno-Tempini, M. L. & Price, C. J. 2001 Identification of famous faces and buildings: a functional neuroimaging study of semantically unique items. Brain 124, 2087–2097. (doi:10.1093/brain/124.10.2087) Gorno-Tempini, M. L., Price, C. J., Josephs, O., Vandenberghe, R., Cappa, S. F., Kapur, N. & Frackowiak, R. S. 1998 The neural systems sustaining face and proper-name processing. Brain 121, 2103–2118. (doi:10.1093/brain/121.11.2103) Grill-Spector, K., Kushnir, T., Edelman, S., Avidan, G., Itzchak, Y. & Malach, R. 1999 Differential processing of objects under various viewing conditions in the human lateral occipital complex. Neuron 24, 187–203. (doi:10. 1016/S0896-6273(00)80832-6) Grill-Spector, K., Knouf, N. & Kanwisher, N. 2004 The fusiform face area subserves face perception, not generic within-category identification. Nat. Neurosci. 7, 555–562. (doi:10.1038/nn1224) Hadjikhani, N. et al. 2004 Activation of the fusiform gyrus when individuals with autism spectrum disorder view faces. Neuroimage 22, 1141–1150. (doi:10.1016/j.neuroimage.2004.03.025) Haig, N. D. 1984 The effect of feature displacement on face recognition. Perception 13, 505–512. Halgren, E., Raij, T., Marinkovic, K., Jousmaki, V. & Hari, R. 2000 Cognitive response profile of the human fusiform face area as determined by MEG. Cereb. Cortex 10, 69–81. (doi:10.1093/cercor/10.1.69) Hasson, U., Hendler, T., Ben Bashat, D. & Malach, R. 2001 Vase or face? A neural correlate of shape-selective grouping processes in the human brain. J. Cogn. Neurosci. 13, 744–753. (doi:10.1162/08989290152541412) Hasson, U., Avidan, G., Deouell, L. Y., Bentin, S. & Malach, R. 2003 Face-selective activation in a congenital prosopagnosic subject. J. Cogn. Neurosci. 15, 419–431. (doi:10. 1162/089892903321593135) Haxby, J. V., Grady, C. L., Horwitz, B., Ungerleider, L. G., Mishkin, M., Carson, R. E., Herscovitch, P., Schapiro, M. B. & Rapoport, S. I. 1991 Dissociation of object and

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2126

N. Kanwisher & G. Yovel

The fusiform face area

spatial visual processing pathways in human extrastriate cortex. Proc. Natl Acad. Sci. USA 88, 1621–1625. (doi:10. 1073/pnas.88.5.1621) Haxby, J. V., Ungerleider, L. G., Clark, V. P., Schouten, J. L., Hoffman, E. A. & Martin, A. 1999 The effect of face inversion on activity in human neural systems for face and object perception. Neuron 22, 189–199. (doi:10.1016/ S0896-6273(00)80690-X) Haxby, J. V., Hoffman, E. A. & Gobbini, M. I. 2000 The distributed human neural system for face perception. Trends Cogn. Sci. 4, 223–233. (doi:10.1016/S1364-6613 (00)01482-0) Haxby, J. V., Gobbini, M. I., Furey, M. L., Ishai, A., Schouten, J. L. & Pietrini, P. 2001 Distributed and overlapping representations of faces and objects in ventral temporal cortex. Science 293, 2425–2430. (doi:10.1126/ science.1063736) Henke, K., Schweinberger, S. R., Grigo, A., Klos, T. & Sommer, W. 1998 Specificity of face recognition: recognition of exemplars of non-face objects in prosopagnosia. Cortex 34, 289–296. Henson, R. N., Shallice, T., Gorno-Tempini, M. L. & Dolan, R. J. 2002 Face repetition effects in implicit and explicit memory tests as measured by fMRI. Cereb. Cortex 12, 175–186. (doi:10.1093/cercor/12.2.178) Hoffman, D. D. & Richards, W. A. 1984 Parts of recognition. Cognition 18, 65–96. (doi:10.1016/0010-0277(84)90022-2) Hoffman, E. A. & Haxby, J. V. 2000 Distinct representations of eye gaze and identity in the distributed human neural system for face perception. Nat. Neurosci. 3, 80–84. (doi:10.1038/71152) Huettel, S. A., Song, A. W. & McCarthy, G. 2004 Fuctional magnetic resonance imaging. Sunderland, MA: Sinauer Associates. Humphreys, G. 2005 Modularity in face processing-evidence from prosopagnosia. In Institute for Cognitive Neuroscience. London. Jacobs, R. A. 1997 Nature, nurture, and the developmnet of functional specializations: a computational approach. Psychol. Bull. Rev. 4, 2999–2309. Jeffreys, D. A. 1996 Evoked potential studies of face and object processing. Vis. Cogn. 3, 1–38. Johnson, M. H., Dziurawiec, S., Ellis, H. & Morton, J. 1991 Newborns’ preferential tracking of face-like stimuli and its subsequent decline. Cognition 40, 1–19. (doi:10.1016/ 0010-0277(91)90045-6) Kanwisher, N. 2001 Faces and places: of central (and peripheral) interest. Nat. Neurosci. 4, 455–456. Kanwisher, N. G., McDermott, J. & Chun, M. M. 1997 The fusiform face area: a module in human extrastriate cortex specialized for face perception. J. Neurosci. 17, 4302–4311. Kanwisher, N., Tong, F. & Nakayama, K. 1998 The effect of face inversion on the human fusiform face area. Cognition 68, B1–B11. (doi:10.1016/S0010-0277(98)00035-3) Kanwisher, N., Yin, C. & Wojciulik, E. 1999 Repetition blindness for pictures: evidence for the rapid computation of abstract visual descriptions. In Fleeting memories: cognition of brief visual stimuli (ed. V. Coltheart), pp. 119–150. Cambridge, MA: MIT Press. Kemp, R., McManus, C. & Pigott, T. 1990 Sensitivity to the displacement of facial features in negative and inverted images. Perception 19, 531–543. Kennerknecht, I., Grueter, T., Welling, B., Wentzek, S., Horst, J., Edwards, S. & Grueter, M. 2006 First report of prevalence of non-syndromic hereditary prosopagnosia (HPA). Am. J. Med. Genet. A 140, 1617–1622. (doi:10. 1002/ajmg.a.31343) Phil. Trans. R. Soc. B (2006)

Kourtzi, Z. & Kanwisher, N. 2001 Representation of perceived object shape by the human lateral occipital complex. Science 293, 1506–1509. (doi:10.1126/science. 1061133) Koutstaal, W., Wagner, A. D., Rotte, M., Maril, A., Buckner, R. L. & Schacter, D. L. 2001 Perceptual specificity in visual object priming: functional magnetic resonance imaging evidence for a laterality difference in fusiform cortex. Neuropsychologia 39, 184–199. (doi:10.1016/ S0028-3932(00)00087-7) Le Grand, R., Mondloch, C. J., Maurer, D. & Brent, H. P. 2003 Expert face processing requires visual input to the right hemisphere during infancy. Nat. Neurosci. 6, 1108–1112. (doi:10.1038/nn1121) Le Grand, R., Mondloch, C. J., Maurer, D. & Brent, H. P. 2004 Impairment in holistic face processing following early visual deprivation. Psychol. Sci. 15, 762–768. (doi:10. 1111/j.0956-7976.2004.00753.x) Lehmann, C., Mueller, T., Federspiel, A., Hubl, D., Schroth, G., Huber, O., Strik, W. & Dierks, T. 2004 Dissociation between overt and unconscious face processing in fusiform face area. Neuroimage 21, 75–83. (doi:10.1016/ j.neuroimage.2003.08.038) Leopold, D. A., O’Toole, A. J., Vetter, T. & Blanz, V. 2001 Prototype-referenced shape encoding revealed by high-level aftereffects. Nat. Neurosci. 4, 89–94. (doi:10.1038/82947) Leube, D. T., Yoon, H. W., Rapp, A., Erb, M., Grodd, W., Bartels, M. & Kircher, T. T. 2003 Brain regions sensitive to the face inversion effect: a functional magnetic resonance imaging study in humans. Neurosci. Lett. 342, 143–146. (doi:10.1016/S0304-3940(03)00232-5) Leveroni, C. L., Seidenberg, M., Mayer, A. R., Mead, L. A., Binder, J. R. & Rao, S. M. 2000 Neural systems underlying the recognition of familiar and newly learned faces. J. Neurosci. 20, 878–886. Levy, I., Hasson, U., Avidan, G., Hendler, T. & Malach, R. 2001 Center-periphery organization of human object areas. Nat. Neurosci. 4, 533–539. Liu, J., Harris, A. & Kanwisher, N. 2002 Stages of processing in face perception: an MEG study. Nat. Neurosci. 5, 910–916. (doi:10.1038/nn909) Liu, J., Harris, A., Mangini, M., Wald, L., Kwong, K., Kanwisher & K. 2003 Distinct representations of faces in the FFA and the OFA: an fMRI study. In Society for Neuroscience. New Orleans, LA. Loffler, G., Yourganov, G., Wilkinson, F. & Wilson, H. R. 2005 fMRI evidence for the neural representation of faces. Nat. Neurosci. 8, 1386–1390. (doi:10.1038/nn1538) Malach, R. et al. 1995 Object-related activity revealed by functional magnetic resonance imaging in human occipital cortex. Proc. Natl Acad. Sci. USA 92, 8135–8139. (doi:10. 1073/pnas.92.18.8135) Malpass, R. S. & Kravitz, J. 1969 Recognition for faces of own and other race. J. Pers. Soc. Psychol. 13, 330–334. (doi:10. 1037/h0028434) Martin, A. & Chao, L. L. 2001 Semantic memory and the brain: Structure and processes. Curr. Opin. Neurobiol. 11, 194–201. (doi:10.1016/S0959-4388(00)00196-3) Maurer, D., Lewis, T. L. & Mondloch, C. J. 2005 Missing sights: consequences for visual cognitive development. Trends Cogn. Sci. 9, 144–151. (doi:10.1016/j.tics.2005.01.006) Mazard, A., Schiltz, C. & Rossion, B. 2005 Recovery from adaptation to facial identity is larger for upright than inverted faces in the human occipito-temporal cortex. Neuropsychologia 44, 912–922. (doi:10.1016/j.neuropsychologia.2005.08.015) McCarthy, G., Luby, M., Gore, J. & Goldman-Rakic, P. 1997a Infrequent events transiently activate human prefrontal and parietal cortex as measured by functional MRI. J. Neurophysiol. 77, 1630–1634.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

The fusiform face area McCarthy, G., Puce, A., Gore, J. C. & Allison, T. 1997b Face-specific processing in the human fusiform gyrus. J. Cogn. Neurosci. 9, 605–610. McKone, E. & Kanwisher, N. 2005 Does the human brain process objects of expertise like faces? A review of the evidence. In From monkey brain to human brain (ed. S. Dehaene, J. R. Duhamel, M. Hauser & G. Rizzolatti). Cambridge, MA: MIT Press. McKone, E., Martini, P. & Nakayama, K. 2001 Categorical perception of face identity in noise isolates configural processing. J. Exp. Psychol. Hum. Percept. Perform. 27, 573–599. (doi:10.1037/0096-1523.27.3.573) McKone, E., Kanwisher, N. & Duchaine, B. In press. Can generic expertise explain special processing for faces? Trends Cogn. Sci. McMullen, P., Fisk, J., Phillips, S. & Maloney, W. 2000 Apperceptive agnosia and face recognition. Neurocase 6, 403–414. McNeil, J. E. & Warrington, E. K. 1993 A face-specific disorder. Q. J. Exp. Psychol. 46A, 1–10. Meissner, C. A. & Brigham, J. C. 2001 Thirty years of investigating the own-race bias in memory for faces: a meta-analytic review. Psychol. Publ. Policy Law 7, 3–35. (doi:10.1037/1076-8971.7.1.3) Moore, C., Cohen, M. X. & Ranganath, C. 2006 Neural mechanisms of expert skills in visual working memory. J. Neurosci. 26, 11187–11196. (doi:10.1523/jneurosci. 1873-06.2006) Moscovitch, M., Winocur, G. & Behrmann, M. 1997 What is special about face recognition? Nineteen experiments on a person with visual object agnosia and dyslexia but normal face recognition. J. Cogn. Neurosci. 9, 555–604. Mundel, T. et al. 2003 Transient inability to distinguish between faces: electrophysiologic studies. J. Clin. Neurophysiol. 20, 102–110. (doi:10.1097/00004691-20030400000003) Op de Beeck, H., Baker, C., DiCarlo, J. & Kanwisher, N. Submitted. Object discrimination training alters object representations in human extrastriate cortex. O’Toole, A. J., Jiang, F., Abdi, H. & Haxby, J. V. 2005 Partially distributed representations of objects and faces in ventral temporal cortex. J. Cogn. Neurosci. 17, 580–590. (doi:10.1162/0898929053467550) Pasley, B. N., Mayes, L. C. & Schultz, R. T. 2004 Subcortical discrimination of unperceived objects during binocular rivalry. Neuron 42, 163–172. (doi:10.1016/S0896-6273 (04)00155-2) Passarotti, A., Paul, B., Bussiere, J., Buxton, R., Wong, E. & Stiles, J. 2003 The development of face and location processing: an fMRI study. Dev. Sci. 6, 100–117. (doi:10. 1111/1467-7687.00259) Peelen, M. V. & Downing, P. E. 2005 Selectivity for the human body in the fusiform gyrus. J. Neurophysiol. 93, 603–608. (doi:10.1152/jn.00513.2004) Peretz, I. & Zatorre, R. J. 2005 Brain organization for music processing. Annu. Rev. Psychol. 56, 89–114. (doi:10.1146/ annurev.psych.56.091103.070225) Pierce, K., Muller, R. A., Ambrose, J., Allen, G. & Courchesne, E. 2001 Face processing occurs outside the fusiform ’face area’ in autism: evidence from functional MRI. Brain 124, 2059–2073. (doi:10.1093/brain/124.10. 2059) Pinsk, M. A., DeSimone, K., Moore, T., Gross, C. G. & Kastner, S. 2005 Representations of faces and body parts in macaque temporal cortex: a functional MRI study. Proc. Natl Acad. Sci. USA 102, 6996–7001. (doi:10.1073/pnas. 0502605102) Polk, T. A. & Farah, M. J. 1998 Letters. Proc. Natl Acad. Sci. USA 95, 847–852. (doi:10.1073/pnas.95.3.847) Phil. Trans. R. Soc. B (2006)

N. Kanwisher & G. Yovel 2127

Polk, T. A., Stallcup, M., Aguirre, G. K., Alsop, D. C., D’Esposito, M., Detre, J. A. & Farah, M. J. 2002 Neural specialization for letter recognition. J. Cogn. Neurosci. 14, 145–159. (doi:10.1162/089892902317236803) Pourtois, G., Schwartz, S., Seghier, M. L., Lazeyras, F. & Vuilleumier, P. 2005a Portraits or people? Distinct representations of face identity in the human visual cortex. J. Cogn. Neurosci. 17, 1043–1057. (doi:10.1162/08989290 54475181) Pourtois, G., Thut, G., Grave de Peralta, R., Michel, C. & Vuilleumier, P. 2005b Two electrophysiological stages of spatial orienting towards fearful faces: early temporoparietal activation preceding gain control in extrastriate visual cortex. Neuroimage 26, 149–163. (doi:10.1016/ j.neuroimage.2005.01.015) Puce, A., Allison, T., Asgari, M., Gore, J. C. & McCarthy, G. 1996 Differential sensitivity of human visual cortex to faces, letterstrings, and textures: a functional magnetic resonance imaging study. J. Neurosci. 16, 5205–5215. Puce, A., Allison, T. & McCarthy, G. 1999 Electrophysiological studies of human face perception. III: effects of top-down processing on face-specific potentials. Cereb. Cortex 9, 445–458. (doi:10.1093/cercor/9.5.445) Rhodes, G., Brennan, S. & Carey, S. 1987 Identification and ratings of caricatures: implications for mental representations of faces. Cogn. Psychol. 19, 473–497. (doi:10.1016/ 0010-0285(87)90016-8) Rhodes, G., Byatt, G., Michie, P. T. & Puce, A. 2004 Is the fusiform face area specialized for faces, individuation, or expert individuation? J. Cogn. Neurosci. 16, 189–203. (doi:10.1162/089892904322984508) Robbins, R. 2005 Face and object processing: what changes with experience? PhD thesis, Australian National University. Robbins, R. & McKone, E. 2003 Can holistic processing be learned for inverted faces? Cognition 88, 79–107. (doi:10. 1016/S0010-0277(03)00020-9) Rossion, B., Curran, T. & Gauthier, I. 2002 A defense of the subordinate-level expertise account for the N170 component. Cognition 85, 189–196. (doi:10.1016/S0010-0277 (02)00101-4) Rossion, B., Caldara, R., Seghier, M., Schuller, A. M., Lazeyras, F. & Mayer, E. 2003a A network of occipitotemporal face-sensitive areas besides the right middle fusiform gyrus is necessary for normal face processing. Brain 126, 2381–2395. (doi:10.1093/brain/awg241) Rossion, B., Joyce, C. A., Cottrell, G. W. & Tarr, M. J. 2003b Early lateralization and orientation tuning for face, word, and object processing in the visual cortex. Neuroimage 20, 1609–1624. (doi:10.1016/j.neuroimage.2003.07.010) Rossion, B., Schiltz, C. & Crommelinck, M. 2003c The functionally defined right occipital and fusiform “face areas” discriminate novel from visually familiar faces. Neuroimage 19, 877–883. (doi:10.1016/S1053-8119(03) 00105-8) Rotshtein, P., Henson, R. N., Treves, A., Driver, J. & Dolan, R. J. 2005 Morphing Marilyn into Maggie dissociates physical and identity face representations in the brain. Nat. Neurosci. 8, 107–113. (doi:10.1038/nn1370) Sangrigoli, S., Pallier, C., Argenti, A. M., Ventureyra, V. A. & de Schonen, S. 2005 Reversibility of the other-race effect in face recognition during childhood. Psychol. Sci. 16, 440–444. Saxe, R. & Kanwisher, N. 2003 People thinking about thinking people. The role of the temporo-parietal junction in “theory of mind”. Neuroimage 19, 1835–1842. (doi:10. 1016/S1053-8119(03)00230-1) Saxe, R. & Wexler, A. 2005 Making sense of another mind: the role of the right temporo-parietal junction. Neuropsychologia 43, 1391–1399. (doi:10.1016/j.neuropsychologia. 2005.02.013)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2128

N. Kanwisher & G. Yovel

The fusiform face area

Saxe, R., Brett, M. & Kanwisher, N. 2006 Divide and conquer: a defense of functional localizers. Neuroimage 30, 1088–1096; discussion 1097–1099 Schiltz, C. & Rossion, B. 2006 Faces are represented holistically in the human occipito-temporal cortex. Neuroimage 32, 1385–1394. (doi:10.1016/j.neuroimage.2006. 05.037) Schultz, R. T. et al. 2000 Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. Arch. Gen. Psychiatry 57, 331–340. (doi:10.1001/archpsyc.57.4.331) Schwarzlose, R. F., Baker, C. I. & Kanwisher, N. 2005 Separate face and body selectivity on the fusiform gyrus. J. Neurosci. 25, 11055–11059. (doi:10.1523/ JNEUROSCI.2621-05.2005) Sergent, J., Ohta, S. & MacDonald, B. 1992 Functional neuroanatomy of face and object processing. A positron emission tomography study. Brain 115, 15–36. Shuman, M. & Kanwisher, N. 2004 Numerical magnitude in the human parietal lobe; tests of representational generality and domain specificity. Neuron 44, 557–569. (doi:10. 1016/j.neuron.2004.10.008) Spiridon, M. & Kanwisher, N. 2002 How distributed is visual category information in human occipito-temporal cortex? An fMRI study. Neuron 35, 1157–1165. (doi:10.1016/ S0896-6273(02)00877-2) Spiridon, M., Fischl, B. & Kanwisher, N. 2006 Location and spatial profile of category-specific regions in human extrastriate cortex. Hum. Brain Mapp. 27, 77–89. (doi:10.1002/hbm.20169) Tanaka, J. W. & Curran, T. 2001 A neural basis for expert object recognition. Psychol. Sci. 12, 43–47. (doi:10.1111/ 1467-9280.00308) Tanaka, J. W. & Farah, M. J. 1993 Parts and wholes in face recognition. Q. J. Exp. Psychol. A, Hum. Exp. Psychol. 46A, 225–245. Tanaka, J. & Farah, M. 2003 Holistic face recognition. In Analytic and holistic processes in the perception of faces, objects and scenes, vol. 2 (ed. M. Peterson & G. Rhodes). Oxford, UK: Oxford University Press. Tarr, M. J. & Gauthier, I. 2000 FFA: a flexible fusiform area for subordinate-level visual processing automatized by expertise. Nat. Neurosci. 3, 764–769. (doi:10.1038/ 77666) Tong, F., Nakayama, K., Vaughan, J. T. & Kanwisher, N. 1998 Binocular rivalry and visual awareness in human extrastriate cortex. Neuron 21, 753–759. (doi:10.1016/ S0896-6273(00)80592-9) Tong, F., Nakayama, K., Moscovitch, M., Weinrib, O. & Kanwisher, N. 2000 Response properties of the human fusiform face area. Cogn. Neuropsychol. 17, 257–279. (doi:10.1080/026432900380607) Tsao, D. Y., Freiwald, W. A., Knutsen, T. A., Mandeville, J. B. & Tootell, R. B. 2003 Faces and objects in macaque cerebral cortex. Nat. Neurosci. 6, 989–995. (doi:10.1038/ nn1111) Tsao, D. Y., Freiwald, W. A., Tootell, R. B. H. & Livingstone, M. S. 2006 A cortical region consisting entirely of faceselective cells. Science 311, 670–674. Turk, D. J., Rosenblum, A. C., Gazzaniga, M. S. & Macrae, C. N. 2005 Seeing John Malkovich: the neural substrates of person categorization. Neuroimage 24, 1147–1153. (doi:10.1016/j.neuroimage.2004.10.032) Vuilleumier, P., Armony, J. L., Driver, J. & Dolan, R. J. 2001 Effects of attention and emotion on face processing in the human brain: an event-related fMRI study. Neuron 30, 829–841. (doi:10.1016/S0896-6273(01)00328-2)

Phil. Trans. R. Soc. B (2006)

Vuilleumier, P., Armony, J. L., Driver, J. & Dolan, R. J. 2003 Distinct spatial frequency sensitivities for processing faces and emotional expressions. Nat. Neurosci. 6, 624–631. (doi:10.1038/nn1057) Wada, Y. & Yamamoto, T. 2001 Selective impairment of facial recognition due to a haematoma restricted to the right fusiform and lateral occipital region. J. Neurol. Neurosurg. Psychiatry 71, 254–257. (doi:10.1136/jnnp.71. 2.254) Warrington, E. K., Logue, V. & Pratt, R. T. C. 1971 The anatomical localisation of selective impairment of auditory-verbal short-term memory. Neuropsychologia 9, 377–387. (doi:10.1016/0028-3932(71)90002-9) Williams, M. A., Morris, A. P., McGlone, F., Abbott, D. F. & Mattingley, J. B. 2004 Amygdala responses to fearful and happy facial expressions under conditions of binocular suppression. J. Neurosci. 24, 2898–2904. (doi:10.1523/ JNEUROSCI.4977-03.2004) Winston, J. S., Vuilleumier, P. & Dolan, R. J. 2003 Effects of low-spatial frequency components of fearful faces on fusiform cortex activity. Curr. Biol. 13, 1824–1829. (doi:10.1016/j.cub.2003.09.038) Wiser, A. K., Andreasen, N., O’Leary, D. S., CrespoFacorro, B., Boles-Ponto, L. L., Watkins, G. L. & Hichwa, R. D. 2000 Novel vs. well-learned memory for faces: a positron emission tomography study. J. Cogn. Neurosci. 12, 255–266. (doi:10.1162/089892900562084) Wojciulik, E., Kanwisher, N. & Driver, J. 1998 Covert visual attention modulates face-specific activity in the human fusiform gyrus: fMRI study. J. Neurophysiol. 79, 1574–1578. Xu, Y. 2005 Revisiting the role of the fusiform face area in visual expertise. Cereb. Cortex 15, 1234–1242. Xu, Y., Liu, J. & Kanwisher, N. 2005 The M170 is selective for faces, not for expertise. Neuropsychologia 43, 588–597. (doi:10.1016/j.neuropsychologia.2004.07.016) Yin, R. 1969 Looking at upside down faces. J. Exp. Psychol. 81, 141–145. (doi:10.1037/h0027474) Young, A. W., Hellawell, D. & Hay, D. C. 1987 Configurational information in face perception. Perception 16, 747–759. Yovel, G. & Duchaine, B. 2006 Specialized face perception mechanisms extract both part and spacing information: evidence from developmental prosopagnosia. J. Cogn. Neurosci. 18, 580–593. Yovel, G. & Kanwisher, N. 2004 Face perception: domain specific, not process specific. Neuron 44, 747–748. (doi:10. 1016/j.neuron.2004.11.020) Yovel, G. & Kanwisher, N. 2005 The neural basis of the behavioral face-inversion effect. Curr. Biol. 15, 2256–2262. (doi:10.1016/j.cub.2005.10.072) Yovel, G., Paller, K. A. & Levy, J. 2005a Does a whole face equal the sum of its halves? Interactive processing in face perception. Vis. Cogn. 12, 337–352. (doi:10.1080/1350 6280444000210) Yovel, G., Duchaine, B., Nakayama, K. & Kanwisher, N. 2005b Is the fusiform face area abnormal in individuals with developmental prosopagnosia? Paper presented at the Society for Neuroscience, San Diego, CA. Yue, X., Tjan, B. & Biederman, I. In press. What makes faces special? Vision Res. Zangenehpour, S. & Chaudhuri, A. 2005 Patchy organization and asymmetric distribution of the neural correlates of face processing in monkey inferotemporal cortex. Curr. Biol. 15, 993–1005. (doi:10.1016/j.cub.2005.04.031)

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Phil. Trans. R. Soc. B (2006) 361, 2129–2141 doi:10.1098/rstb.2006.1935 Published online 3 November 2006

Genetic influences on the neural basis of social cognition David Skuse* Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, 30 Guilford Street, London WCIN 1EH, UK The neural basis of social cognition has been the subject of intensive research in both human and non-human primates. Exciting, provocative and yet consistent findings are emerging. A major focus of interest is the role of efferent and afferent connectivity between the amygdala and the neocortical brain regions, now believed to be critical for the processing of social and emotional perceptions. One possible component is a subcortical neural pathway, which permits rapid and preconscious processing of potentially threatening stimuli, and it leads from the retina to the superior colliculus, to the pulvinar nucleus of the thalamus and then to the amygdala. This pathway is activated by direct eye contact, one of many classes of potential threat, and may be particularly responsive to the ‘whites of the eyes’. In humans, autonomic arousal evoked by this stimulus is associated with the activity in specific cortical regions concerned with processing visual information from faces. The integrated functioning of these pathways is modulated by one or more X-linked genes, yet to be identified. The emotional responsiveness of the amygdala, and its associated circuits, to social threat is also influenced by functional polymorphisms in the promoter of the serotonin transporter gene. We still do not have a clear account of how specific allelic variation, in candidate genes, increases susceptibility to developmental disorders, such as autism, or psychiatric conditions, such as anxiety or depressive illness. However, the regulation of emotional responsiveness to social cues lies at the heart of the problem, and recent research indicates that we may be nearing a deeper and more comprehensive understanding. Keywords: social cognition; amygdala; X-chromosome; emotion; candidate genes; serotonin transporter

1. INTRODUCTION Social interactions with other people are distinctively coloured by emotions, in ways that are both obvious and subtle. Neuroscientists are making rapid progress in understanding the interface between the neural processing of emotions, feelings and social cognition— that set of rules and responses which makes for a welladjusted individual. Research on emotion processing, by both cortical and subcortical mechanisms, is illuminating our understanding of how social competence develops and how it is maintained. Emotions represent ‘complex psychological and physiological states that, to a greater or lesser degree, index occurrences of value’ (Dolan 2002). Psychological and physiological states influence our behaviour by making some activities more desirable, and hence more likely to be rewarding. On the other hand, they may also render other activities less desirable and unlikely to be associated with reward, or alternatively associated with an adverse and unpleasant outcome. The range of emotions an organism experiences will reflect the complexity of its adaptive niche. Higher-order primates, in particular humans, live in a complex social world. For that reason, in them, emotional *[email protected] One contribution of 14 to a Theme Issue ‘The neurobiology of social recognition, attraction and bonding’.

regulation is closely linked to social behaviour, and any perturbation in the ability to regulate our emotions will have adverse consequences for our social adaptation. Unlike most psychological states, emotions are embodied and manifested in uniquely recognizable, and stereotyped, behavioural patterns of facial expression, comportment and autonomic arousal (Dolan 2002). Most of us can ‘read’ other people’s emotional states without effort. Our ability to respond appropriately to such states has a huge significance on our ability to successfully rear our young and to find a mate with whom to reproduce ourselves. When the ability to read another’s emotional states is significantly impaired, we appear at the very least socially gauche, with difficulty responding appropriately in any social situation, a characteristic feature of autistic conditions (Schultz 2005). From studies of fear and anxiety, there is considerable evidence that the amygdala is a central component in the processing of threatening stimuli in human and non-human primates, as well as other animals (Adolphs & Tranel 2000; LeDoux 2000). Stimuli with different objective levels of threat lead to variable activation of the amygdala. During interpersonal interactions, such threat may be posed by facial expression, by tone of voice or by body posture. Fearful facial expressions are particularly potent signals of danger (Thomas et al. 2001). Presentation

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of negative facial expressions in full consciousness activates, in particular, the amygdala and produces a neurophysiological arousal response (Phan et al. 2002; Wager et al. 2003). Selective responsiveness by the amygdala to negative facial expressions encompasses not only fearful, but also angry faces. Adams et al. (2003) followed up the idea that the amygdala’s response may not only be important for detecting threat, but also interpreting whether the threat is direct or indirect. On the other hand, meeting the direct gaze of someone looking angry is also potentially seriously threatening. Angry faces with direct gaze and fearful faces with averted gaze are recognized more quickly and accurately than either of the alternatives. Adams et al. (2003) hypothesized that the more ambiguous the stimulus, the greater the amygdala response would be. In other words, a longer period of ambiguity implies greater activation of the neural circuits recruited by the facial expression and gaze combination. They confirmed that angry faces with indirect gaze and fearful faces with direct gaze did indeed elicit greater activation in the left (but not the right) amygdala. Their observation is consistent with the evidence that the left amygdala is more consistently activated by facial stimuli that require cognitive processing (e.g. Singer et al. 2004; Das et al. 2005). This is an important dissociation, which will be discussed in greater detail. The left amygdala is involved not only in discerning facially communicated threat, but is also activated by the cortical and subcortical circuits that process that threat, especially when gaze perception is involved. On the other hand, the right amygdala arousal may be linked to the intensity of the affective response (measured by autonomic arousal; Anderson & Sobel 2003); the amygdala participates in autonomic activity, such as skin conductance responses (SCRs; Critchley et al. 2002; Sah et al. 2003). Efferent projections from the central nucleus include pathways to brainstem regions controlling motor and visceromotor responses, and hypothalamic areas that control hormonal release (Davis 1997). Co-activation of amygdala and arousal systems is thought to enable the cortex to distinguish fear signals from other arousal responses to novel stimuli (Damasio 2000).

2. FACE PROCESSING AND SOCIAL ADJUSTMENT Critically important information can be gained about how to respond appropriately in social encounters by monitoring the expression on another’s face. This provides information about the other person’s emotional state and disposition. In certain circumstances, someone else’s emotional expressions can evoke that same emotion in oneself—disgust, happiness and sadness are obvious examples. Haxby et al. (2000) proposed that there are dedicated systems for processing emotion expressions in other’s faces, in which the amygdala and the insula play a crucial role. The interpretation of the emotional content of a face takes into account a wide range of visual cues. These include, first, whether we know the individual or not (face recognition memory), the facial configuration Phil. Trans. R. Soc. B (2006)

(e.g. whether the mouth is wide open or shut, whether the eyes are wide open or narrowed) and, in particular, eye gaze (is this person looking at me or at something/someone else?). There are developmental trends in the ability to recognize emotions accurately, with some emotions being more readily recognized in early childhood, whereas others are not associated with adult levels of recognition until after puberty (Wade et al. 2005). There are also developmental trends in face recognition memory, and in the capacity to interpret direction of gaze as a social cue (is this person looking at me? Campbell et al. 2005, 2006). 3. FACE PROCESSING AND THE AMYGDALA Studies from humans with congenital or acquired damage to the amygdala (Calder et al. 2001), and from primates in which lesions have been induced (Amaral 2002), show that this subcortical structure influences our ability to gain and to maintain socially appropriate behaviour by affecting face recognition memory, facial expression interpretation and eye-gaze monitoring. Whether its functional integrity is critical for normal social cognitive development in humans is still an open question (Amaral et al. 2003). However, there is a growing evidence to indicate that functional deficits in the integrated system that links amygdala with other neural centres, in what has been termed the ‘social brain’ (Adolphs et al. 2000), may be associated with autistic symptomatology. Schultz (2005) has argued that an abnormality early in the development in the amygdala can give rise to later social perceptual deficits in face identity and facial expression perception. Because the visual cortices that are involved in face perception are also involved in representing semantic knowledge about people, aberrations in face perception may not only affect social perception, but also create deficits in the social knowledge system, with impaired social skills. Modulation of amygdala activity by reciprocal connections from anterior cingulate/medial prefrontal regions may affect our evaluation of fear-related signals (Davis & Whalen 2001). Das et al. (2005) argue that there is a dynamic interplay between the anterior cingulate cortex (ACC) and thalamo-amygdala pathways, and that a breakdown in their functional differentiation could lead to neuropsychiatric disorders, including paranoid schizophrenia and post-traumatic stress syndrome. 4. EYE CONTACT, AMYGDALA AROUSAL AND FEAR PERCEPTION Fearful faces are often considered to be processed automatically and independent of attention (Vuilleumier et al. 2001, 2002; Williams et al. 2005b) and awareness (Anderson & Sobel 2003; Pasley et al. 2004). Note, contrary evidence has been reported (e.g. Pessoa et al. 2002). Functional MRI studies that record the amygdala blood oxygen level dependent (BOLD) response to the presentation of facial expressions find a greater activation when we perceive fear compared with other emotional faces (Morris et al. 1998a). If the amygdala is bilaterally ablated, or degenerates, the perception of fear is selectively impaired (Adolphs et al. 1999). We do not

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Genetic influences on social cognition fully understand why this is so, but recent evidence suggests that the amygdala responds specifically to eye contact in adults, and that it is maximally activated by exaggerated wide-open eyes, such as are associated with a fearful expression (Morris et al. 2002). This response occurs because direct gaze can be threatening (Nahm 1997). A simple stare is often the most effective stimulus in evoking a fight or flight response in non-human primates (Emery 2000), and in humans too in certain social situations—especially between males. Which cortical circuits modulate, and are modulated by, amygdala activity that is evoked by eye contact? The amygdala is an essential and central component of a threat-detection system. It has extensive neocortical and subcortical connections that are crucial for the automatic non-conscious responses to a threatening stimulus (e.g. fight and flight). Appropriate social responses require complex cortical processing of potential threatening stimuli (Davidson et al. 2000; Hariri et al. 2000, 2003; Phan et al. 2002). How we respond to direct eye contact is critically dependent upon the social context in which it occurs. We must evaluate the stimulus, by means of complex neocortical connections. In humans, a crucial component of the modulating circuitry is the recruitment of language centres, and the conscious processing of a ‘feeling’ (or visceral) response, which is important especially in social interactions with strangers (Kim et al. 2004). As adults, we find it harder to maintain eye contact with a stranger than with a familiar individual. There is an additional level of complexity, depending on the relative sex of the people concerned. While there are limits to the modulating ability of these higher cortical circuits, humans are in general able to tolerate direct eye contact for longer than other primates (Kleinke 1986). Eye contact evokes amygdala activation, in tandem with conscious (explicit) and non-conscious (implicit) neural mechanisms. Processing of direct eye contact necessitates the appropriate functioning of these pathways, which is essential for the development and maintenance of social cognitive skills.

5. SUBCORTICAL PROCESSING OF THREATENING STIMULI Implicit processing of visual stimuli that could constitute a threat, including fearful expressions and other fear-evoking stimuli, is hypothesized to engage subcortical visual pathways that are routed directly to the amygdala, without passing through the visual cortex first (Morris 1998a,b, 2001). Consequently, threatening visual percepts can evoke a very rapid physiological response—before the neocortex has had time to consider the information and decide on an appropriate course of action (Morris et al. 2001). Normally, the main visual perception pathway to the amygdala brings information that has been processed by early visual cortical areas (e.g. V1, V4; Stefanacci & Amaral 2002), and it provides a hierarchically processed and detailed representation of objects. However, responses elicited by the activation of this pathway are at least 100–200 ms after stimulus presentation. If the object is threatening, it has been argued that this response time is too lengthy for an Phil. Trans. R. Soc. B (2006)

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appropriate adaptive reaction. Some amygdala neurons in non-human primates have response latencies to particular classes of visual threat (e.g. snakes) that are as short as 60 ms. Because these latencies are too rapid to be compatible with prior cortical processing, there must be an alternative visual route to the amygdala. This could convey crude, but critical, visual material to the ‘threat-detection system’ and evoke very rapid reactions (Nakamura et al. 2000). One proposed course of the subcortical visual pathway leads from the retina to the superior colliculus (a phylogenetically ancient visual processing module), to the pulvinar nuclei of the thalamus and then to the amygdala (Morris et al. 1999, 2001; figure 1). Evidence that this pathway does exist comes from a variety of sources. In non-human primates, there is anatomical evidence (Stepniewska et al. 2000). In humans, supporting evidence has come from the study of patients with ‘blindsight’, meaning that a lesion in primary visual (striate) cortex (V1), or in the connections between the lateral geniculate nucleus and V1, has prevented the conscious perception of visual material. Humans with blindsight claim that they can see nothing at all in their blind visual field or hemi-field, yet certain classes of stimulus do evoke neural responses. Blindsight implies the existence of alternative pathways, including the superior colliculus pathway that runs via the pulvinar (in thalamus) to V5 (the visual motion area at the temporal–parietal– occipital junction) with feedback to V4 (lingual and fusiform gyri of the inferior temporal cortex, a region activated by facial cues). Because blindsight patients may have amygdala activation to emotionally salient stimuli (e.g. fearful faces) that are presented to their ‘blind’ visual cortices, Morris et al. (2001) concluded that some processing must be going on subcortically by the alternative visual pathway. On the other hand, for a variety of reasons (summarized by Pasley et al. 2004), this inference was not indisputable, owing to the evidence that there are links between the superior colliculus and inferior temporal regions of the cortex. Pasley et al. (2004) decided to measure the ability of the amygdala to discriminate complex emotionally salient objects in isolation from the inferior temporal neural representation of those objects. They aimed to show that highly processed information from the inferior temporal region is not required to support visual discrimination of certain emotionally salient cues in the amygdala. Previous studies aimed at isolating subcortical visual processing have not managed to avoid getting some target-related neural activity in the inferior temporal region (Whalen et al. 1998; Morris et al. 2001). Pasley et al. (2004) used the ‘binocular rivalry’ technique in which each eye is presented with a different, incompatible image. The observer does not fuse such images, but suppresses one and experiences alternating perceptual dominance—the suppressed image is not consciously perceived. It appears from both monkey neurophysiology (Sheinberg & Logothetis 1997) and human MRI studies (Cohen & Tong 2001) that suppressed visual information does not reach inferior temporal cortex. They presented subjects with images that were either fearful faces (and hence potentially of

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Figure 1. A representation of the proposed neural systems outlined in the article, which respond to potentially threatening stimuli such as a fearful face. The ventral visual pathway is not shown. The subcortical pathway (e.g. Pasley et al. 2004) is shown, linking superior colliculus with amygdala bilaterally. Amygdala activation on left and right is linked with cognitive processing networks and autonomic responses, respectively. Feedback from the somatic response to threat enhances cognitive processing, possibly mediated by intra-amygdala connectivity (Adolphs et al. 2005). X-linked genes influence the functional integrity of pathways marked by asterisk symbols (Skuse et al. 2005). Pathways influenced by allelic variation in the serotonin transporter gene promoter are indicated by the hash symbol (Heinz et al. 2005; Pezawas et al. 2005). There is a positive functional coupling between the amygdala, the rostral anterior cingulate cortex (ACC) and the ventromedial prefontal cortex, and inhibitory feedback from the caudal ACC. The pathway marked in dashed line is a putative link, which could confound studies of nonconscious response to threat that focus on amygdala-mediated neural activity.

interest to the amygdala threat-detection system) or chairs (of no interest to the amygdala, being emotionally neutral), in conditions of complete perceptual suppression. If the subcortical circuit did detect threats, beyond conscious awareness, there should be differential neural activity in the suppressed image conditions, with increased neural activity—especially in the amygdala— to fearful faces rather than to chairs. This prediction was supported, with increased activity in the left amygdala to suppressed fearful faces, but no increased signal for images of chairs. There was no increase in inferior temporal lobe activation in response to suppressed faces or chairs, suggesting that this cortical site could not be influencing differential amygdala responsiveness. Pasley et al. (2004) confirmed earlier reports of significant correlations between the subcortical visual structures, which represent way stations in the pathway, including the left amygdala, the left superior colliculus and the left dorsal–posterior–lateral region of the thalamus. This set of activations is consistent with the ‘low-road’ to amygdala activation hypothesis of LeDoux (2000). Further evidence in support of the ‘subcortical threatdetection system’ is provided by Hamm et al. (2003), who discuss a patient with total cortical blindness. He could be conditioned to a visually presented stimulus (a line drawing of an aeroplane) in a fear-conditioning paradigm, in which the unconditioned stimulus was an Phil. Trans. R. Soc. B (2006)

aversive electric shock. The key finding was that startle responses (eyeblink) were enhanced when elicited in the presence of the conditioned visual stimulus. The presented stimulus was not biologically meaningful and the authors (Hamm et al. 2003) suggest that using more biologically relevant (threat) cues, like pictures of snakes or fearful faces, might increase the stimulus specificity of the subcortical threat detection system, although no such study has yet been published. The subcortical pathway linking superior colliculus, putamen and amygdala can only respond to lowresolution displays (Vuilleumier et al. 2003). High spatial frequencies are necessary to identify facial features and some facial emotions. On the other hand, low spatial frequencies are sufficient to get the gist (gestalt) of a facial perception (Schyns & Oliva 1999). The superior colliculus is thought to have a phylogenetically ancient ability to process simple forms within a narrow range of low spatial frequencies (Emery 2000; Lomber 2002). Nevertheless, if the amygdala can be activated by this visual circuit (as in the Pasley et al. (2004) experiment), what information about the ‘threatening’ face is passed to the amygdala from the superior colliculus? Morris et al. (2002) proposed that the key percept was ‘fearful eyes’ (figure 1). Using an ingenious fMRI-based investigation, they found that wide-open eyes alone are sufficient to evoke increased neural responses in this

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Genetic influences on social cognition non-conscious circuit (Morris et al. 1999). The existence of a subcortical circuit that supported a primitive representation of high-contrast elements, relating to the location of the eyes and the mouth, had been predicted by Morton & Johnson (1991). Therefore, there is accumulating evidence that the amygdala is not only generally responsive to certain facial expressions, but that the eye region of the face is a critical source of information about the potential threat posed by another person (Morris et al. 2002). In bilateral lesions of the amygdala, failure to address the information contributed by the eyes in a test of facial expression recognition renders it very difficult for a subject to identify accurately the associated facial expression of fear (Adolphs et al. 2005). It is worth remarking that the facial expression of surprise is also marked by wide-open eyes, and this is the very expression that is most commonly confused with fear in experiments in which subjects are presented with static facial expressions. The key difference between the two is in the mouth; this implies that making that emotion differentiation could require rather longer cortical processing time than, say, differentiating sadness from happiness. There are data to show that the amygdala is particularly responsive to the ‘wide-eyed’ expressions of both fear and surprise, and it seems a reasonable hypothesis that what the amygdala is responding to is the relative proportions of sclera to iris in the observed face. Whalen et al. (2004) tested this hypothesis by measuring whether the larger the size of ‘fearful’ sclera, the greater the response of the amygdala, irrespective of any other visual information. They modified standardized fearful and happy face stimuli by removing all the information from the face, with the exception of the whites of the eyes. Images were presented in a backward masking paradigm, in which the larger ‘wide’ eyes such as are found in association with fear and surprise alternated with the smaller eye whites that are associated with happy expressions. The signal intensity within the ventral amygdala was greater to fearful than to happy eye whites, even though all subjects reported being unaware of the presence of the masked stimuli. The authors conclude that responsiveness of the amygdala appears to be driven by the size of the white scleral field (not by the outline of the eyes), which is consistent with the hypothesis discussed previously that the amygdala is more responsive to low spatial frequency stimuli (Vuilleumier et al. 2003).

6. AMYGDALA–CORTICAL FUNCTIONAL CONNECTIVITY AND PARANOIA Threatening or traumatic stimuli are probably processed in parallel by two distinct neural systems (Bechara et al. 1995; LeDoux 2000). The subjective experience of fear relies upon amygdala–medial frontal activity (as well as autonomic arousal). Setting threats into context depends upon hippocampal–lateral frontal activity. In order to confirm this differentiation, Williams et al. (2001) studied healthy individuals by means of functional magnetic resonance imaging (fMRI) and simultaneous SCR measures of phasic arousal (disentangling overlapping SCRs in a short Phil. Trans. R. Soc. B (2006)

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interstimulus interval paradigm), while they viewed fearful and neutral faces. The fMRI activity was subaveraged according to whether or not there was an arousal SCR to each discrete face stimulus (fearful faces would evoke arousal). The fMRI responses to fearful faces associated with arousal were differentiated from those without associated arousal. This contrast differentiated left amygdala and hippocampal networks. Amygdala–medial frontal activity was observed only in association with stimuli that evoked SCRs, whereas right hippocampus–lateral frontal activity occurred only in the absence of SCRs. The authors concluded that amygdala and hippocampal networks differentiated visceral experience from declarative fact processing of fear-inducing stimuli. Both tonic and phasic autonomic arousal abnormalities have been observed in association with schizophrenia (Kring & Neale 1996; Salem et al. 1996). The salience of fearful faces to the symptoms experienced by paranoid schizophrenics has also been a subject of some interesting investigations (Phillips et al. 1999; Williams et al. 2004a–c). Normally, amygdala and correlated medial prefrontal activity is associated with the subjective appraisal of threat and autonomic arousal, as measured by SCR. In contrast, the system for setting emotionally significant events in context is normally linked to hippocampal–lateral prefrontal activity, not associated consistently with SCR. Williams et al. (2004a) studied paranoid schizophrenic patients. Using fearful faces as the arousing stimuli, they found emotion recognition accuracy was impaired, coupled with significantly greater SCR than comparisons to both fearful and neutral facial expressions. Patients lacked integrated activity in amygdala and prefrontal circuits. The authors speculate that a lack of feedback from the medial prefrontal region, which does not respond to threat in the usual way in paranoid schizophrenia, leads to a perseveration and exacerbation of arousal (SCR) responses. Cognitive theories of persecutory delusions in schizophrenia include increased attention to threat and impaired decisionmaking in the interpretation of potential threats. Phillips et al. (2000) studied visual scan paths in schizophrenic patients with persecutory delusions, using black-and-white photographs of social scenes rated as depicting either neutral, ambiguous or overtly threatening activity. As anticipated, the schizophrenic patients did perceive potential threats in inappropriate places. However, to date there has not been a specific study of perceived threat in paranoid individuals as manifested by their response to direct social gaze.

7. AMYGDALA AND GAZE MONITORING The ability to follow and respond to the direction of gaze of a conspecific is a crucial skill in humans, shared with some, but not all, primate species (Perrett et al. 1985; Jellema et al. 2000). Our ability to meet and to follow another’s gaze is present during early infancy and is associated with a growing appreciation of salient events in a socially structured world (Allison et al. 2000). The perception of direct gaze from a face that is neither threatening nor fearful also elicits an amygdala response in humans (Kawashima et al. 1999).

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In monkeys too, there are cells in the amygdala that respond selectively to eye gaze (Sato & Nakamura 2001). Neural interactions between the amygdala and the neocortical regions that are engaged by visual stimuli of faces are enhanced if those faces have direct gaze orientations (George et al. 2001). Kobayashi & Kohshima (2001) pointed out that human eyes have a widely exposed white sclera surrounding the darker coloured iris, making it easy to discern the direction in which they are looking. They compared the external morphology of primate eyes in nearly half of all primate species, and showed that this feature is uniquely human. Humans have the largest ratio of exposed sclera in the eye outline, which itself is elongated horizontally. They suggested that these are adaptations to extend the visual field by allowing greater eye movement, especially in the horizontal direction, and to enhance the ease of detecting the gaze direction of another individual. There are two components to the developed skill of eye-gaze monitoring, which we have termed ‘allocentric’ and ‘egocentric’ (Elgar et al. 2002). In allocentric gaze monitoring, the directional aspect of perceiving and processing gaze becomes recruited for the purpose of following the intentional gaze of another, and it is thus critical for the development of joint attention (Slaughter & McConnell 2003). Allocentric gaze means paying attention to the salience and significance of events extrinsic to the viewer; to things happening ‘out there’. It enables the viewer to engage effectively with external and potentially distant events, orienting the observer to the appropriate location, and it uses extrinsic spatial coordinates. Its development normally occurs during the first few years of post-natal life, and we become increasingly accurate at determining where someone else is looking with experience (Langton et al. 2000). Allocentric gaze skill can be contrasted with egocentric or direct engagement of gaze with the onlooker (Elgar et al. 2002). In contrast to the relatively slow development of allocentric gaze sensitivity, infants show egocentric gaze sensitivity from birth (Farroni et al. 2002). The young infant responds actively to being looked at, exhibiting a range of teasing and smiling behaviours of increasing complexity, suggesting an early developing ability to engage with conspecifics by facial acts involving direct gaze with the interactant. This interest in the gaze of others upon herself is accompanied by increasing precision in the child’s ability to detect when she is being looked at (Lee et al. 1998). The main function of egocentric gaze relates primarily to the viewpoint of the perceiver and the onlooker, rather than to the spatial relations of the extrinsic world. Its goal is to engage the viewer and to control interaction. Neural circuitry that involves the amygdala, the orbito-frontal cortices and the superior temporal sulcus constitutes a probable basis for the development of gaze monitoring, which is critically involved in the perceptual processing of a range of social behaviours (Brothers 1990). This network is preferentially activated when viewing faces and especially eye regions (Allison et al. 2000; Calder et al. 2002). Individuals with bilateral disruption to amygdala-related Phil. Trans. R. Soc. B (2006)

circuits typically have impairments of gaze monitoring (Adolphs et al. 2005). Failure of a social partner to make a direct eye contact, when in dyadic communication, has profound consequences for our interpretation of their mental health or trustworthiness. The importance that different cultures place on the appropriate role of eye contact in social interactions (Kleinke 1986) does not detract from that conclusion— rather, it emphasizes its validity. 8. AMYGDALA AND FEAR CONDITIONING The amygdala plays a critical role in fear conditioning, which is a variant of Pavlovian classical conditioning (LeDoux 2000). The conditioned stimulus in a fearconditioning experiment with humans might involve a loud noise (the unconditioned stimulus), a negative facial expression (the conditioned stimulus) and an autonomic response, such as an increased skin conductance (the conditioned response). Conditioned fear learning occurs very quickly in normal people, and it can result in persistent associations. On the other hand, repeated exposure to the conditioned stimulus in the absence of the unconditioned stimulus usually leads to ‘extinction’, and the conditioned response ‘habituates’ and diminishes in magnitude. Bechara et al. (1995) discuss a patient with ablation of the amygdala bilaterally, who had a complete blockage of conditioned SCRs, despite retaining conscious awareness of the stimulus contingencies. They contrast him with another with bilateral hippocampal damage, who had retained aversive skin conductance conditioning, but who had no such declarative memory for the contingencies. 9. FUNCTIONAL DISSOCIATION BETWEEN ROLES OF LEFT AND RIGHT AMYGDALA Left and right amygdala play distinct, but complementary, roles in the somatic and cognitive responses to facial expressions. Damage to the left amygdala leaves autonomic responses intact, but this is associated with a severe cognitive deficit (Glascher & Adolphs 2003; figure 1). Damage to the right amygdala can lead to autonomic arousal impairment, with a modest influence on cognitive evaluation. It is plausible that cognitive appraisal of negative facial expressions by the left amygdala is enhanced by concomitant somatic arousal, as measured by SCR (Glascher & Adolphs 2003; Williams et al. 2005a). The right amygdala serves to facilitate the cognitively mediated recognition of negative emotions by the left amygdala (Morris et al. 1997; Phillips et al. 1998; Dubois et al. 1999; Lane et al. 1999). All studies of the functional consequences for humans of bilateral or unilateral amygdala damage have inevitably involved damage to the associated temporal lobes as well as neural fibres that pass through the amygdala. Even in relatively circumscribed degeneration of the amygdala in the rare case of Urbach–Wiethe disease (Siebert et al. 2003), there is calcification of surrounding and more posterior temporal lobe. This contrasts with studies of induced and focussed lesions in primates, particularly the meticulous work of Amaral and colleagues (e.g. Amaral et al. 2003). Therefore, it is not possible to state with certainty the relative roles of

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Genetic influences on social cognition the amygdala and the overlying cortex in regulating social behaviour, in humans. Summarizing data from lesion studies, we are, however, led to the conclusion that the right amygdala is generally responsive to arousing stimuli (e.g. facial expressions) independent of their valence (Williams et al. 2004c). Left and right amygdala may work in concert, to produce an orchestrated behavioural response to threat, which guides cognition and behaviour (Hariri et al. 2003). An intact (right amygdala mediated) autonomic response enhances cognitive evaluation, but it is neither sufficient nor necessary for an accurate appraisal of a threatening stimulus. Preserved cognitive evaluation requires efferent and afferent connectivity between the left amygdala and the cortical regions associated with face processing, such as the fusiform gyrus (Kanwisher 2000; Kanwisher & Moscovitch 2000). While a dissociation between the cognitive and the autonomic processing of threatening stimuli by the amygdala has been hinted at in a previous literature, the interpretation of findings has been complicated by the fact that all subjects have had extensive damage to the amygdala, usually as a result of surgery for intractable epilepsy, which often impacts on other medial temporal structures such as the hippocampus. These regions are also reported as responsive to negative facial emotions (Surguladze et al. 2003). Until recently (Skuse et al. 2005), there were no reports of intact autonomic responses to facial expressions of fear, in the absence of accurate cognitive evaluation, other than in instances of physical damage to the amygdala.

10. X-LINKED GENES AND THE MODULATION OF AMYGDALA ACTIVATION The autonomic and cognitive functions of the amygdala have been shown to be dissociated in X-monosomic females, in whom brain structure is essentially normal. Specific deficits in the cognitive appraisal of threat can have functional origins, as well as being related to structural damage to the amygdala (Skuse et al. 2005). These functional mechanisms may reflect an abnormality of dosage regulation in genes that escape X-inactivation and are required in two copies for normal female neural development ( Jacobs et al. 1997; Clement-Jones et al. 2000; Carrel & Willard 2005). Gene dosage is haploinsufficient in females, who only have a single X-chromosome (Turner syndrome, 45, X). In X-monosomy, the form and severity of deficits in the cognitive appraisal of facial expressions and social emotions are virtually identical to those seen in patients who have had a bilateral amygdalectomy (Adolphs et al. 1994; Calder et al. 1996; Broks et al. 1998; Lawrence et al. 2003). Difficulties are found in the recognition of negative facial emotions, primarily in the recognition of fear (Sato et al. 2002; Hariri et al. 2003), but also in their recognition of anger (Adams et al. 2003). Turner syndrome females have difficulty in recognizing complex emotions and linking complex emotional expressions to emotional labels (Lawrence et al. 2003). This deficit implicates an abnormality of the functions of the left amygdala in particular; this circuit Phil. Trans. R. Soc. B (2006)

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is linked to the cognitive appraisal of potentially threatening stimuli as discussed earlier (Killgore et al. 2000; Williams et al. 2005a,b), although it cannot mediate entirely normal responses in the absence of the right amygdala, which enhances cognitive performance by inducing arousal signalled by the threatening stimulus (Glascher & Adolphs 2003). The subjective experience of fear must be linked to the functional integration of the arousal response with cognitive appraisal; therefore, it is very interesting to discover that in X-monosomy, the consciously perceived visceral response to threat is much reduced (Good et al. 2003). This implies that there is a functional dissociation in the syndrome between the correlates, at a cortical level, of left and right amygdala-related activities. Lateralization of amygdala activation could reflect verbal and non-verbal hemispheric asymmetries, typically ascribed to higher cortical functions in humans (Anderson & Phelps 2000). Left lateralized amygdala responses have been previously reported to explicit (i.e. unmasked) presentations of fearful faces (Breiter et al. 1996; Morris et al. 1996; Thomas et al. 2001; Wright et al. 2001; Vuilleumier et al. 2002). Others have found evidence, from lesion studies, that right amygdala ablation is associated with a deficit in the recognition of fearful faces (Adolphs et al. 2001), or with a more general deficit in attributing emotional intensity ratings accurately (Anderson et al. 2000). We examined the integrity of amygdala-related functions in Turner syndrome by means of a behavioural study of fear conditioning, in which angry faces were used as the conditioned stimulus. Patients with bilateral amygdala lesions have impaired autonomic responsiveness in a fear-conditioning paradigm (Bechara et al. 1995). We used an aversive loud sound as the unconditioned stimulus (Morris & Dolan 2004) and measured SCRs. Despite their very poor performance on the cognitive task requiring the accurate identification of negative facial expressions, females with Turner syndrome showed normal acquisition of fear conditioning, indicating that in this respect they had normal amygdala function (LeDoux 2000). There is evidence from this experiment that amygdala-related cognitive performance could be impaired, in the presence of intact autonomic responsiveness to a threatening stimulus. Previous work (Glascher & Adolphs 2003; Hariri et al. 2003) had shown the converse; cognitive performance can be intact, in the presence of an amygdala lesion, despite the absence of normal autonomic responsiveness to threat. We tested the dissociation hypothesis in a study of 12 X-monosomic (maternal origin) and 12 control females who participated in fMRI, during which simultaneous skin conductance recordings were acquired (Skuse et al. 2005). Faces depicting fear or neutral emotions were presented to both case and control subjects, in random order. Arousal to the contrast (fearful–neutral) faces was associated with transiently increased SCRs and bilateral amygdala activation in both groups. However, X-monosomic females had a proportionately greater and more persistent right amygdala activation than controls and arousal (SCR) was intact, in both Turner syndrome and normal 46,XX females. The fact that

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arousal-related functions of the right amygdala were intact was consistent with the preliminary behavioural studies we had conducted, using a fear-conditioning paradigm. In the comparison group, the greater the SCR, the better the performance on the cognitive task, supporting the hypothesis that in normal individuals there is functional integration between amygdalamediated autonomic responses and cognitive evaluation of a threatening stimulus. Neocortical sensory processing of emotionally salient stimuli (e.g. in left inferior temporal neocortex) seems to be enhanced by the autonomic feedback emanating ultimately from the activity of the right amygdala (Williams et al. 2004b). We found that there was a severe deficit in recognizing fearful facial expressions in about onethird of the X-monosomic sample. Evaluation of the aetiology of this deficit indicated that it originated in a lack of coordination between activity in the left amygdala and activation of the left fusiform cortex. Activation of the left (but not the right) fusiform gyrus was positively correlated with explicit cognitive performance on the task in both groups. This is consistent with the previous research indicating that cognitive appraisal of threat is left-biased. However, in X-monosomy, the magnitude of that left fusiform response was diminished, whereas left amygdala responsiveness to the stimulus, measured simply as a subtraction (BOLD response, fearful–neutral faces), did not differentiate the groups. A psychophysiological interaction analysis confirmed this lack of coordinated activity in the left amygdala/left fusiform gyrus of the 45,X females. This implied that the core deficit included a functional dissociation between activity in the left amygdala and the left fusiform gyrus (figure 1). In summary, the left fusiform cortex receives prominent feedback projections from the amygdala (Amaral 1992), and these are associated with cognitive processing of (negative) emotional stimuli (Morris et al. 1998a). Threatening visual stimuli co-activate the left amygdala and the fusiform gyrus; therefore, it is activated more by fearful than by neutral faces (Lane et al. 1999; Vuilleumier & Schwartz 2001; Hadjikhani & de Gelder 2003). In broader terms, there is a suggestion that failure of integrated functional connectivity between these regions is associated with failure to recognize accurately the broader classes of negative/ aversive emotional stimuli, such as emotionally salient oddball words (Strange et al. 2000; Anderson & Phelps 2001). Taken together, these findings show that in the condition of X-monosomy, there are several deficits associated with the impaired cognitive response to the presentation of a fearful face (i.e. the inability to classify accurately the emotion). First, there is an absence of a significant correlation between cognitive performance and activation of either amygdala. Second, activation of the left amygdala is functionally dissociated from that of the left fusiform activation. Third, autonomic arousal (reflecting right amygdala activation) is present, but it is dissociated from left fusiform responsiveness. Specific deficits in the cognitive appraisal of threat can have functional origins, as well as being related to structural damage. In this investigation, we showed that those functional origins appear to be related to Phil. Trans. R. Soc. B (2006)

dosage–regulation problems in a certain class of X-linked genes that escape X-inactivation and are required in two copies for normal female neural development (Skuse 2005). There may be additional modifying effects of insufficient sex steroid exposure, but these are currently speculative. Accordingly, we provide the first evidence that the binding of somatic (bodily arousal) responses to cognitive appraisal of emotional stimuli (Damasio 2000) has a genetic substrate. Our earlier research (Good et al. 2003) indicates that the genetic mechanism responsible is associated with one or more X-linked genes lying in a 5 Mb region on the short arm of the X-chromosome at Xp11.3-4. The candidate gene that is responsible for the normal association between left amygdala and cortical responsiveness to fearful faces has yet to be identified. There are likely to be several genetic mechanisms regulating these pathways, and recent evidence suggests that emotional responsiveness to fearful faces could also be influenced by the serotonin transporter gene on chromosome17q11-12 and allelic variants in the promoter region of that gene. These, in turn, may influence susceptibility disorders of emotion, such as depression and anxiety.

11. GENETIC INFLUENCES ON AMYGDALA FUNCTION AND SUSCEPTIBILITY TO PSYCHIATRIC DISORDER Affective disorders, such as generalized anxiety and depression, exhibit considerable variability between individuals (Davidson 2002). The genetic substrates underlying these individual differences are for the large part unknown, but in the past few years attention has been drawn to the serotonin transporter gene (5-HTT). Common variants in the promoter region of the gene have been associated with susceptibility to pathological anxiety and depression, and influence the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in treating these conditions (Nemeroff & Owens 2003). Two alleles have attracted particular attention: the short (s) and the long (l) versions of a particular variable repeat sequence in the promoter of the gene. In general, possession of at least one copy of the short variant is associated with increased risk of depression and poorer response to SSRI treatment; the short allele is associated with reduced serotonin availability compared with the long allele (Hamann 2005). The physiological influence of these variants is likely to be in the prefrontal cortex and amygdala. Hariri et al. (2002) showed that normal individuals with one or two copies of the short allele of the 5-HTT promoter polymorphism had greater right amygdala neuronal activity, measured by the BOLD response, to faces showing threatening expressions (anger/fear) than those who were homozygous for the long version of the allele. Right posterior fusiform gyrus also showed a greater activity when presented with the threatening stimuli, in individuals with an ‘s’ than individuals who were homozygous for an ‘l’ allele. The findings of this investigation were subsequently replicated (Heinz et al. 2005) and are consistent with the hypothesis that feedback from the amygdala to the fusiform gyrus improves recognition, and refines behavioural responses, to aversive/threatening cues

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Genetic influences on social cognition such as faces showing negative emotions (Armony et al. 1998; figure 1). Individuals with an ‘s’ allele in the promoter of the 5-HTT gene therefore appear to have a hyperresponsive amygdala to threat. This observation was followed up in a subsequent study by the same group (Pezawas et al. 2005). This latter investigation studied healthy individuals again, this time with a view to studying potential mechanisms by which carriers of an ‘s’ allele of the 5-HTT promoter region (5-HTTLPR) polymorphism could be more prone to depression. There is considerable evidence to show that serotonin is an important modulator of emotion, and that depressed patients have abnormalities in their regulation of serotonin-related neural circuitry. Their subjects were free from any significant psychiatric history (both a strength and a weakness of the study, which sought clinical relevance). Those who were ‘s’ carriers had substantially reduced grey matter in the perigenual cingulate (pACC)—maximally in the rostral region, to a lesser extent in the caudal region—and in the amygdala (maximal on right). It is notable that reduced activity of the rostral ACC has been reported in both depression and induced sadness, and that this reduction can be reversed by SSRIs. The pACC has the greatest density of 5-HTT terminals within the human cortex, and it is a major target for projections from the amygdala with an excitatory circuit leading to the rostral ACC, which is in turn linked to the caudal region of the ACC, and weakly to the ventromedial prefrontal cortex. From the caudal ACC, inhibitory projections return to the amygdala (figure 1). In fMRI studies, homozygotes for the ‘l’ allele showed strong functional interactions between ventromedial prefrontal cortex, perigenual anterior cingulate and amygdala. This circuit was involved in extinguishing negative affect evoked by threat stimuli. However, the coupling was much diminished in people with at least one ‘s’ allele, implying that they were likely to become disproportionately aroused in response to threats. Scores on a self-rated scale of temperamental anxiety correlated well with the magnitude of cingulate– amygdala interaction; nearly 30% of the variance in harm avoidance scores on a standardized personality questionnaire were predicted by the measure of amygdala–p(rostral)ACC functional connectivity. Pezawas et al. (2005) speculate that there may be a compensatory overactivity in the ventromedial prefrontal cortex in ‘s’ carriers. This is an ingenious proposal, which links developmental differences in 5-HTdependent neuronal pathways to impaired interactions in a regulatory network mediating emotional reactivity. Genetically driven variability in 5-HT signalling therefore shapes the connectivity of the amygdala with the rostral anterior cingulate cortex, and in ‘s’ carriers, it is associated with persistent and inappropriate overactivity in response to threat, which in turn leads to the symptoms of anxiety and depression. The circuit could be responsive, in this way, to life events. Inadequate regulation of amygdala arousal, aggregated over lifetime experiences, will eventually result in different susceptibilities to depression/anxiety depending on the intensity and negative quality of those experiences (Hariri et al. 2005). Phil. Trans. R. Soc. B (2006)

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12. CONCLUSIONS The amygdala lies at the confluence of widely distributed neural circuits that constitute components of the network known as the ‘social brain’ (Adolphs 2001). Deficits in the development of this network during childhood can lead to conditions, such as autistic spectrum disorders, in which social–cognitive competence is seriously compromised. Anomalies in the functioning of these circuits in adulthood can lead, on the one hand, to anxiety or depressive disorders and, on the other hand, to paranoid symptoms. It is probable that the functional integrity of the networks that constitute the social brain is critically linked to interindividual genetic variation, but that the relationship is likely to be complex. Individual genetic influences on the functioning of the social brain, in the sense of the impact on susceptibility due to any single gene, are likely to be small. To date, it has not been shown conclusively that the genes which influence normal variation in responsiveness of the neural circuits to socially salient stimuli (e.g. fearful faces) are also responsible for dysregulation and a susceptibility to psychiatric disorder. Progress is nevertheless being made. Recent work has implicated vulnerability due to allelic variants in the promoter of the serotonin transporter gene in environmentally induced anxiety and depression, although this finding requires replication in different samples, both clinical and non-clinical. There is growing evidence that X-linked genetic mechanisms may also have a role to play in the functional integrity of the social brain, although no candidate genes have yet been identified. Nevertheless, the mechanisms by which X-linked genes could influence the development of social and emotional responsiveness are increasingly well understood (Carrel & Willard 2005; Skuse 2005) and rapid progress is likely to be made. The regulation of emotional reactivity to social cues may occur by means of both cortical and subcortical pathways. Subcortical, non-conscious pathways are thought to have evolved as a rapid response system, sensitive to low-resolution representations of threatening stimuli. Afferent tracts leading to the amygdala via this route pass through the superior colliculus and the putamen, carrying poorly specified but rapidly conveyed visual information. Interestingly, such threats include—in a social context—direct eye contact. Recent evidence implies that the circuit is susceptible to alerting when the eyes are wide open and showing a high scleral–iris ratio. Such eye displays are likely to be clearly differentiated even by a crude system that cannot process detailed information on context. Complementary efferent connectivity passing from the amygdala to primary striate visual processing centres (e.g. V4) may alert the visual system to any potential threat, and facilitate the extraction of more detailed information from high-resolution perceptions. When this further information is available, the potential social threat can be set in into context, in light of previous experience (e.g. do I know this person? Are they liable to attack me? Do they find me attractive?). Because a critical ‘threat stimulus’ is direct eye contact with a conspecific, this is handled in a unique way by the human neocortex. The arousal that is associated with face-to-face contact of this type, in

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which the eyes clearly show we are the centre of another’s attention, appears to be harnessed in human species for a variety of purposes. Although, phylogenetically, it appears that the appropriate course of action faced with such attention was ‘fight or flight’, and this is still the case with primate species, humans have adapted the system for purposes that are arguably, in the appropriate context, critical to the survival of our species for other reasons. These include the attachment between parent and infant, and pairbonding between adults. In order to achieve this relatively recent (in evolutionary terms) adaptation of a phylogenetically ancient neural system, we have developed systems of reciprocal control over amygdala activity—exercised, in particular, by fronto-cortical circuits involving the ventromedial prefrontal cortex, the anterior cingulate cortex and the insular cortex (Critchley et al. 2004). Uniquely among all other species, we are able to control this complex ‘survival system’—and we do so by means of a variety of inhibitory pathways, linked with memory and language centres of considerable complexity. Possibly owing to their relatively recent evolutionary origins, the inhibitory systems are liable to dysfunction—and when they are dysfunctional, one possible outcome is a negative impact on quintessentially human traits of social cognition.

REFERENCES Adams Jr, R. B., Gordon, H. L., Baird, A. A., Ambady, N. & Kleck, R. E. 2003 Effects of gaze on amygdala sensitivity to anger and fear faces. Science 300, 1536. (doi:10.1126/ science.1082244) Adolphs, R. 2001 The neurobiology of social cognition. Curr. Opin. Neurobiol. 11, 231–239. (doi:10.1016/S09594388(00)00202-6) Adolphs, R. & Tranel, D. 2000 Emotion recognition and the human amygdala. In The amygdala. A functional analysis (ed. J. P. Aggleton), pp. 587–630. New York, NY: Oxford University Press. Adolphs, R., Tranel, D., Damasio, H. & Damasio, A. 1994 Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 372, 669–672. (doi:10.1038/372669a0) Adolphs, R., Tranel, D., Hamann, S., Young, A. W., Calder, A. J., Phelps, E. A., Anderson, A., Lee, G. P. & Damasio, A. R. 1999 Recognition of facial emotion in nine individuals with bilateral amygdala damage. Neuropsychologia 37, 1111–1117. (doi:10.1016/S0028-3932(99)00039-1) Adolphs, R., Tranel, D. & Denburg, N. 2000 Impaired emotional declarative memory following unilateral amygdala damage. Learn. Mem. 7, 180–186. (doi:10.1101/lm. 7.3.180) Adolphs, R., Tranel, D. & Damasio, H. 2001 Emotion recognition from faces and prosody following temporal lobectomy. Neuropsychology 15, 396–404. Adolphs, R., Gosselin, F., Buchanan, T. W., Tranel, D., Schyns, P. & Damasio, A. R. 2005 A mechanism for impaired fear recognition after amygdala damage. Nature 433, 68–72. (doi:10.1038/nature03086) Allison, T., Puce, A. & McCarthy, G. 2000 Social perception from visual cues: role of the STS region. Trends Cogn. Sci. 4, 267–278. (doi:10.1016/S13646613(00)01501-1) Phil. Trans. R. Soc. B (2006)

Amaral, D. G. 1992 Anatomical organization of the primate amygdaloid complex. In The amygdala: neurobiological aspects of emotion, memory and mental dysfunction (ed. J. P. Aggleton), pp. 1–66. New York, NY: Wiley-Liss. Amaral, D. G. 2002 The primate amygdala and the neurobiology of social behavior: implications for understanding social anxiety. Biol. Psychiatry 51, 11–17. (doi:10. 1016/S0006-3223(01)01307-5) Amaral, D. G., Capitanio, J. P., Jourdain, M., Mason, W. A., Mendoza, S. P. & Prather, M. 2003 The amygdala: is it an essential component of the neural network for social cognition? Neuropsychologia 41, 235–240. (doi:10.1016/ S0028-3932(02)00154-9) Anderson, A. K. & Phelps, E. A. 2000 Perceiving emotion: there’s more than meets the eye. Curr. Biol. 10, R551–R554. (doi:10.1016/S0960-9822(00)00612-6) Anderson, A. K. & Phelps, E. A. 2001 Lesions of the human amygdala impair enhanced perception of emotionally salient events. Nature 411, 305–309. (doi:10.1038/ 35077083) Anderson, A. K. & Sobel, N. 2003 Dissociating intensity from valence as sensory inputs to emotion. Neuron 39, 581–583. (doi:10.1016/S0896-6273(03)00504-X) Anderson, A. K., Spencer, D. D., Fulbright, R. K. & Phelps, E. A. 2000 Contribution of the anteromedial temporal lobes to the evaluation of facial emotion. Neuropsychology 14, 526–536. (doi:10.1037/0894-4105.14.4.526) Armony, J. L., Quirk, G. J. & LeDoux, J. E. 1998 Differential effects of amygdala lesions on early and late plastic components of auditory cortex spike trains during fear conditioning. J. Neurosci. 18, 2592–2601. Bechara, A., Tranel, D., Damasio, H., Adolphs, R., Rockland, C. & Damasio, A. R. 1995 Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 269, 1115–1118. Breiter, H. C., Etcoff, N. L., Whalen, P. J., Kennedy, W. A., Rauch, S. L., Buckner, R. L., Strauss, M. M., Hyman, S. E. & Rosen, B. R. 1996 Response and habituation of the human amygdala during visual processing of facial expression. Neuron 17, 875–887. (doi:10.1016/S08966273(00)80219-6) Broks, P. et al. 1998 Face processing impairments after encephalitis: amygdala damage and recognition of fear. Neuropsychologia 36, 59–70. (doi:10.1016/S0028-3932 (97)00105-X) Brothers, L. 1990 The social brain: a project for integrating primate behaviour and neurophysiology in a new domain. Concept. Neurosci. 1, 27–51. Calder, A. J., Young, A. W., Rowland, D., Perrett, D. I., Hodges, J. R. & Etcoff, N. L. 1996 Facial emotion recognition after bilateral amygdala damage: differentially severe impairment of fear. Cogn. Neuropsychol. 13, 699–745. (doi:10.1080/026432996381890) Calder, A. J., Lawrence, A. D. & Young, A. W. 2001 Neuropsychology of fear and loathing. Nat. Rev. Neurosci. 2, 352–363. (doi:10.1038/35072584) Calder, A. J., Lawrence, A. D., Keane, J., Scott, S. K., Owen, A. M., Christoffels, I. & Young, A. W. 2002 Reading the mind from eye gaze. Neuropsychologia 40, 1129–1138. (doi:10.1016/S0028-3932(02)00008-8) Campbell, R., Lawrence, K., Mandy, W., Mitra, C., Jeyakuma, L. & Skuse, D. 2005 Meanings in motion and faces: developmental associations between the processing of intention from geometrical animations and gaze detection accuracy. Dev. Psychopathol. 18, 99–118. (doi:10.1017/S0954579406060068) Campbell, R., Lawrence, K., Mandy, W., Mitra, C., Jeyakuma, L. & Skuse, D. 2006 Meanings in motion and

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Genetic influences on social cognition faces: developmental associations between the processing of intention from geometrical animations and gaze detection accuracy. Dev. Psychopathol. 18, 99–118. Carrel, L. & Willard, H. F. 2005 X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434, 400–404. (doi:10.1038/nature 03479) Clement-Jones, M. et al. 2000 The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum. Mol. Genet. 9, 695–702. (doi:10.1093/ hmg/9.5.695) Cohen, J. D. & Tong, F. 2001 Neuroscience. The face of controversy. Science 293, 2405–2407. (doi:10.1126/ science.1066018) Critchley, H. D., Mathias, C. J. & Dolan, R. J. 2002 Fear conditioning in humans: the influence of awareness and autonomic arousal on functional neuroanatomy. Neuron 33, 653–663. (doi:10.1016/S0896-6273(02)00588-3) Critchley, H. D., Wiens, S., Rotshtein, P., Ohman, A. & Dolan, R. J. 2004 Neural systems supporting interoceptive awareness. Nat. Neurosci. 7, 189–195. (doi:10.1038/ nn1176) Damasio, A. R. 2000 The feeling of what happens: body and emotion in the making of consciousness. London, UK: Heinemann. Das, P., Kemp, A. H., Liddell, B. J., Brown, K. J., Olivieri, G., Peduto, A., Gordon, E. & Williams, L. M. 2005 Pathways for fear perception: modulation of amygdala activity by thalamo-cortical systems. Neuroimage 26, 141–148. (doi:10.1016/j.neuroimage.2005.01.049) Davidson, R. J. 2002 Anxiety and affective style: role of prefrontal cortex and amygdala. Biol. Psychiatry 51, 68–80. (doi:10.1016/S0006-3223(01)01328-2) Davidson, R. J., Putnam, K. M. & Larson, C. L. 2000 Dysfunction in the neural circuitry of emotion regulation—a possible prelude to violence. Science 289, 591–594. (doi:10.1126/science.289.5479.591) Davis, M. 1997 Neurobiology of fear responses: the role of the amygdala. J. Neuropsychiatry Clin. Neurosci. 9, 382–402. Davis, M. & Whalen, P. J. 2001 The amygdala: vigilance and emotion. Mol. Psychiatry 6, 13–34. (doi:10.1038/sj.mp. 4000812) Dolan, R. J. 2002 Emotion, cognition, and behavior. Science 298, 1191–1194. (doi:10.1126/science.1076358) Dubois, S., Rossoin, B., Schiltz, C., Bodart, J. M., Michel, C., Bruyer, R. & Crommelinck, M. 1999 Effect of familiarity on the processing of human faces. Neuroimage 9, 278–289. (doi:10.1006/nimg.1998.0409) Elgar, K., Campbell, R. & Skuse, D. 2002 Are you looking at me? Accuracy in processing line-of-sight in Turner syndrome. Proc. R. Soc. B 269, 2415–2422. (doi:10. 1098/rspb.2002.2173) Emery, N. J. 2000 The eyes have it: the neuroethology, function and evolution of social gaze. Neurosci. Behav. Rev. 24, 581–604. Farroni, T., Csibra, G., Simion, F. & Johnson, M. H. 2002 Eye contact detection in humans from birth. Proc. Natl Acad. Sci. USA 99, 9602–9605. (doi:10.1073/pnas. 152159999) George, N., Driver, J. & Dolan, R. J. 2001 Seen gazedirection modulates fusiform activity and its coupling with other brain areas during face processing. Neuroimage 13, 1102–1112. (doi:10.1006/nimg.2001.0769) Glascher, J. & Adolphs, R. 2003 Processing of the arousal of subliminal and supraliminal emotional stimuli by the human amygdala. J. Neurosci. 23, 10 274–10 282. Good, C. D., Lawrence, K., Thomas, N. S., Price, C. J., Ashburner, J., Friston, K. J., Frackowiak, S. J., Oreland, L. & Skuse, D. H. 2003 Dosage sensitive X-linked locus Phil. Trans. R. Soc. B (2006)

D. Skuse

2139

influences the development of amygdala and orbito-frontal cortex, and fear recognition in humans. Brain 126, 2431–2446. (doi:10.1093/brain/awg242) Hadjikhani, N. & de Gelder, B. 2003 Seeing fearful body expressions activates the fusiform cortex and amygdala. Curr. Biol. 13, 2201–2205. (doi:10.1016/j.cub.2003. 11.049) Hamm, A. O., Weike, A. I., Schupp, H. T., Treig, T., Dressel, A. & Kessler, C. 2003 Affective blindsight: intact fear conditioning to a visual cue in a cortically blind patient. Brain 126, 267–275. (doi:10.1093/brain/awg037) Hamann, S. 2005 Blue genes: wiring the brain for depression. Nat. Neurosci. 8, 701–702. (doi:10.1038/ nn0605-701) Hariri, A. R., Bookheimer, S. Y. & Mazziotta, J. C. 2000 Modulating emotional responses: effects of a neocortical network on the limbic system. Neuroreport 11, 43–48. Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., Egan, M. F. & Weinberger, D. R. 2002 Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400–403. (doi:10.1126/science.1071829) Hariri, A. R., Mattay, V. S., Tessitore, A., Fera, F. & Weinberger, D. R. 2003 Neocortical modulation of the amygdala response to fearful stimuli. Biol. Psychiatry 53, 494–501. (doi:10.1016/S0006-3223(02)01786-9) Hariri, A. R., Drabant, E. M., Munoz, K. E., Kolachana, B. S., Mattay, V. S., Egan, M. F. & Weinberger, D. R. 2005 A susceptibility gene for affective disorders and the response of the human amygdala. Arch. Gen. Psychiatry 62, 146–152. (doi:10.1001/archpsyc.62.2.146) Haxby, J. V., Hoffman, E. A. & Gobbini, M. I. 2000 The distributed human neural system for face perception. Trends Cogn. Sci. 4, 223–233. (doi:10.1016/S13646613(00)01482-0) Heinz, A. et al. 2005 Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat. Neurosci. 8, 20–21. (doi:10.1038/nn1366) Jacobs, P., Dalton, P., James, R., Mosse, K., Power, M., Robinson, D. & Skuse, D. 1997 Turner syndrome: a cytogenetic and molecular study. Ann. Hum. Genet. 61, 471–483. (doi:10.1017/S0003480097006507) Jellema, T., Baker, C. I., Wicker, B. & Perrett, D. I. 2000 Neural representation for the perception of the intentionality of actions. Brain Cogn. 44, 280–302. (doi:10.1006/ brcg.2000.1231) Kanwisher, N. 2000 Domain specificity in face perception. Nat. Neurosci. 3, 759–763. (doi:10.1038/77664) Kanwisher, N. & Moscovitch, M. 2000 The cognitive neuroscience of face processing: an introduction. Cogn. Neuropsychol. 17, 1–11. (doi:10.1080/026432900380454) Kawashima, R., Sugiura, M., Takashi, K., Nakamura, A., Hatano, K., Ito, K., Fukuda, H., Kojima, S. & Nakamura, K. 1999 The human amygdala plays an important role in gaze monitoring: a PET study. Brain 122, 779–783. (doi:10.1093/brain/122.4.779) Killgore, W. D., Casasanto, D. J., Yurgelun-Todd, D. A., Maldjian, J. A. & Detre, J. A. 2000 Functional activation of the left amygdala and hippocampus during associative encoding. Neuroreport 11, 2259–2263. Kim, H., Somerville, L. H., Johnstone, T., Polis, S., Alexander, A. L., Shin, L. M. & Whalen, P. J. 2004 Contextual modulation of amygdala responsivity to surprised faces. J. Cogn. Neurosci. 16, 1730–1745. (doi:10.1162/0898929042947865) Kleinke, C. L. 1986 Gaze and eye contact: a research review. Psychol. Bull. 100, 78–100. (doi:10.1037/0033-2909.100. 1.78)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2140

D. Skuse

Genetic influences on social cognition

Kobayashi, H. & Kohshima, S. 2001 Unique morphology of the human eye and its adaptive meaning: comparative studies on external morphology of the primate eye. J. Hum. Evol. 40, 419–435. (doi:10.1006/jhev.2001.0468) Kring, A. M. & Neale, J. M. 1996 Do schizophrenic patients show a disjunctive relationship among expressive, experiential, and psychophysiological components of emotion? J. Abnorm. Psychol. 105, 249–257. (doi:10.1037/0021843X.105.2.249) Lane, R. D., Chua, P. M. & Dolan, R. J. 1999 Common effects of emotional valence, arousal and attention on neural activation during visual processing of pictures. Neuropsychologia 37, 989–997. (doi:10.1016/S00283932(99)00017-2) Langton, S. R., Watt, R. J. & Bruce, I. I. 2000 Do the eyes have it? Cues to the direction of social attention. Trends Cogn. Sci. 4, 50–59. (doi:10.1016/S1364-6613(99)01436-9) Lawrence, K., Campbell, R., Swettenham, J., Terstegge, J., Akers, R., Coleman, M. & Skuse, D. 2003 Interpreting gaze in Turner syndrome: impaired sensitivity to intention and emotion, but preservation of social cueing. Neuropsychologia 41, 894–905. (doi:10.1016/S0028-3932(03) 00002-2) LeDoux, J. E. 2000 Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184. (doi:10.1146/annurev.neuro. 23.1.155) Lee, K., Eskritt, M., Symons, L. A. & Muir, D. 1998 Children’s use of triadic eye gaze information for “mind reading”. Dev. Psychol. 34, 525–539. (doi:10.1037/00121649.34.3.525) Lomber, S. G. 2002 Learning to see the trees before the forest: reversible deactivation of the superior colliculus during learning of local and global visual features. Proc. Natl Acad. Sci. USA 99, 4049–4054. (doi:10.1073/pnas. 062551899) Morris, J. S. & Dolan, R. J. 2004 Dissociable amygdala and orbitofrontal responses during reversal fear conditioning. Neuroimage 22, 372–380. (doi:10.1016/j.neuroimage. 2004.01.012) Morris, J. S., Frith, C. D., Perrett, D. I., Rowland, D., Young, A. W., Calder, A. J. & Dolan, R. J. 1996 A differential neural response in the human amygdala to fearful and happy facial expressions. Nature 383, 812–815. (doi:10. 1038/383812a0) Morris, J. S., Friston, K. J. & Dolan, R. J. 1997 Neural responses to salient visual stimuli. Proc. R. Soc. B 264, 769–775. (doi:10.1098/rspb.1997.0109) Morris, J. S., Friston, K. J., Buchel, C., Frith, C. D., Young, A. W., Calder, A. J. & Dolan, R. 1998a A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain 121, 47–57. (doi:10. 1093/brain/121.1.47) Morris, J. S., Ohman, A. & Dolan, R. J. 1998b Conscious and unconscious emotional learning in the human amygdala. Nature 393, 467–470. (doi:10.1038/30976) Morris, J. S., Ohman, A. & Dolan, R. J. 1999 A subcortical pathway to the right amygdala mediating “unseen” fear. Proc. Natl Acad. Sci. USA 96, 1680–1685. (doi:10.1073/ pnas.96.4.1680) Morris, J. S., Buchel, C. & Dolan, R. J. 2001 Parallel neural responses in amygdala subregions and sensory cortex during implicit fear conditioning. Neuroimage 13, 1044–1052. (doi:10.1006/nimg.2000.0721) Morris, J. S., deBonis, M. & Dolan, R. J. 2002 Human amygdala responses to fearful eyes. Neuroimage 17, 214–222. (doi:10.1006/nimg.2002.1220) Morton, J. & Johnson, M. H. 1991 CONSPEC and CONLERN: a two-process theory of infant face recognition. Psychol. Rev. 98, 164–181. (doi:10.1037/0033295X.98.2.164) Phil. Trans. R. Soc. B (2006)

Nahm, F. K. 1997 Heinrich Kluver and the temporal lobe syndrome. J. Hist. Neurosci. 6, 193–208. Nakamura, K. et al. 2000 Functional delineation of the human occipito-temporal areas related to face and scene processing. A PET study. Brain 123, 1903–1912. (doi:10. 1093/brain/123.9.1903) Nemeroff, C. B. & Owens, M. J. 2003 Neuropharmacology of paroxetine. Psychopharmacol. Bull. 37(Suppl. 1), 8–18. Pasley, B. N., Mayes, L. C. & Schultz, R. T. 2004 Subcortical discrimination of unperceived objects during binocular rivalry. Neuron 42, 163–172. (doi:10.1016/S0896-6273 (04)00155-2) Perrett, D. I., Smith, P. A., Potter, D. D., Mistlin, A. J., Head, A. S., Milner, A. D. & Jeeves, M. A. 1985 Visual cells in the temporal cortex sensitive to face view and gaze direction. Proc. R. Soc. B 223, 293–317. Pessoa, L., McKenna, M., Gutierrez, E. & Ungerleider, L. G. 2002 Neural processing of emotional faces requires attention. Proc. Natl Acad. Sci. USA 99, 11 458–11 463. (doi:10.1073/pnas.172403899) Pezawas, L. et al. 2005 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat. Neurosci. 8, 828–834. (doi:10.1038/nn1463) Phan, K. L., Wager, T., Taylor, S. F. & Liberzon, I. 2002 Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 16, 331–348. (doi:10.1006/nimg.2002.1087) Phillips, M. L. et al. 1998 Neural responses to facial and vocal expressions of fear and disgust. Proc. R. Soc. B 265, 1809–1817. (doi:10.1098/rspb.1998.0506) Phillips, M. L., Williams, L., Senior, C., Bullmore, E. T., Brammer, M. J., Andrew, C., Williams, S. C. & David, A. S. 1999 A differential neural response to threatening and non-threatening negative facial expressions in paranoid and non-paranoid schizophrenics. Psychiatry Res. 92, 11–31. Phillips, M. L., Senior, C. & David, A. S. 2000 Perception of threat in schizophrenics with persecutory delusions: an investigation using visual scan paths. Psychol. Med. 30, 157–167. (doi:10.1017/S0033291799001397) Sah, P., Faber, E. S., Lopez, D. A. & Power, J. 2003 The amygdaloid complex: anatomy and physiology. Physiol. Rev. 83, 803–834. Salem, J. E., Kring, A. M. & Kerr, S. L. 1996 More evidence for generalized poor performance in facial emotion perception in schizophrenia. J. Abnorm. Psychol. 105, 480–483. (doi:10.1037/0021-843X.105.3.480) Sato, N. & Nakamura, K. 2001 Detection of directed gaze in rhesus monkeys (Macaca mulatta). J. Comp. Psychol. 115, 115–121. (doi:10.1037/0735-7036.115.2.115) Sato, W., Kubota, Y., Okada, T., Murai, T., Yoshikawa, S. & Sengoku, A. 2002 Seeing happy emotion in fearful and angry faces: qualitative analysis of facial expression recognition in a bilateral amygdala-damaged patient. Cortex 38, 727–742. Schultz, R. T. 2005 Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area. Int. J. Dev. Neurosci. 23, 125–141. (doi:10.1016/j.ijdevneu.2004.12.012) Schyns, P. G. & Oliva, A. 1999 Dr. Angry and Mr. Smile: when categorization flexibly modifies the perception of faces in rapid visual presentations. Cognition 69, 243–265. (doi:10.1016/S0010-0277(98)00069-9) Sheinberg, D. L. & Logothetis, N. K. 1997 The role of temporal cortical areas in perceptual organization. Proc. Natl Acad. Sci. USA 94, 3408–3413. (doi:10.1073/pnas. 94.7.3408)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Genetic influences on social cognition Siebert, M., Markowitsch, H. J. & Bartel, P. 2003 Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease. Brain 126, 2627–2637. (doi:10. 1093/brain/awg271) Singer, T., Kiebel, S. J., Winston, J. S., Dolan, R. J. & Frith, C. D. 2004 Brain responses to the acquired moral status of faces. Neuron 41, 653–662. (doi:10.1016/S0896-6273(04) 00014-5) Skuse, D. H. 2005 X-linked genes and mental functioning. Hum. Mol. Genet. 14(Spec No. 1), R27–R32. (doi:10. 1093/hmg/ddi112) Skuse, D. H., Morris, J. S. & Dolan, R. J. 2005 Functional dissociation of amygdala-modulated arousal and cognitive appraisal, in Turner syndrome. Brain 128, 2084–2096. (doi:10.1093/brain/awh562) Slaughter, V. & McConnell, D. 2003 Emergence of joint attention: relationships between gaze following, social referencing, imitation, and naming in infancy. J. Genet. Psychol. 164, 54–71. Stefanacci, L. & Amaral, D. G. 2002 Some observations on cortical inputs to the macaque monkey amygdala: an anterograde tracing study. J. Comp. Neurol. 451, 301–323. (doi:10.1002/cne.10339) Stepniewska, I., Ql, H. X. & Kaas, J. H. 2000 Projections of the superior colliculus to subdivisions of the inferior pulvinar in New World and Old World monkeys. Vis. Neurosci. 17, 529–549. (doi:10.1017/S0952523800174048) Strange, B. A., Henson, R. N., Friston, K. J. & Dolan, R. J. 2000 Brain mechanisms for detecting perceptual, semantic, and emotional deviance. Neuroimage 12, 425–433. (doi:10.1006/nimg.2000.0637) Surguladze, S. A., Brammer, M. J., Young, A. W., Andrew, C., Travis, M. J., Williams, S. C. & Phillips, M. L. 2003 A preferential increase in the extrastriate response to signals of danger. Neuroimage 19, 1317–1328. (doi:10.1016/ S1053-8119(03)00085-5) Thomas, K. M., Drevets, W. C., Whalen, P. J., Eccard, C. H., Dahl, R. E., Ryan, N. D. & Casey, B. J. 2001 Amygdala response to facial expressions in children and adults. Biol. Psychol. 49, 309–316. (doi:10.1016/S0006-3223(00) 01066-0) Vuilleumier, P. & Schwartz, S. 2001 Emotional facial expressions capture attention. Neurology 56, 153–158. Vuilleumier, P., Armony, J. L., Driver, J. & Dolan, R. J. 2001 Effects of attention and emotion on face processing in the human brain: an event-related fMRI study. Neuron 30, 829–841. (doi:10.1016/S0896-6273(01)00328-2) Vuilleumier, P., Armony, J. L., Clarke, K., Husain, M., Driver, J. & Dolan, R. J. 2002 Neural response to emotional faces with and without awareness: event-related fMRI in a parietal patient with visual extinction and spatial neglect. Neuropsychologia 40, 2156–2166. (doi:10.1016/ S0028-3932(02)00045-3)

Phil. Trans. R. Soc. B (2006)

D. Skuse

2141

Vuilleumier, P., Armony, J. L., Driver, J. & Dolan, R. J. 2003 Distinct spatial frequency sensitivities for processing faces and emotional expressions. Nat. Neurosci. 6, 624–631. (doi:10.1038/nn1057) Wade, A. M., Lawrence, K., Mandy, W. & Skuse, D. 2005 Charting the development of emotion recognition from 6 years of age. J. Appl. Stat. 33, 297–315. (doi:10.1080/ 02664760500445756) Wager, T. D., Phan, K. L., Liberzon, I. & Taylor, S. F. 2003 Valence, gender, and lateralization of functional brain anatomy in emotion: a meta-analysis of findings from neuroimaging. Neuroimage 19, 513–531. (doi:10.1016/ S1053-8119(03)00078-8) Whalen, P. J., Rauch, S. L., Etcoff, N. L., McInerney, S. C., Lee, M. B. & Jenike, M. A. 1998 Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. J. Neurosci. 18, 411–418. Whalen, P. J. et al. 2004 Human amygdala responsivity to masked fearful eye whites. Science 306, 2061. (doi:10. 1126/science.1103617) Williams, L. M. et al. 2001 Arousal dissociates amygdala and hippocampal fear responses: evidence from simultaneous fMRI and skin conductance recording. Neuroimage 14, 1070–1079. (doi:10.1006/nimg.2001.0904) Williams, L. M. et al. 2004a Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia. Am. J. Psychiatry 161, 480–489. (doi:10.1176/appi.ajp. 161.3.480) Williams, L. M., Liddell, B. J., Rathjen, J., Brown, K. J., Gray, J., Phillips, M., Young, A. & Gordon, E. 2004b Mapping the time course of nonconscious and conscious perception of fear: an integration of central and peripheral measures. Hum. Brain Mapp. 21, 64–74. (doi:10.1002/ hbm.10154) Williams, M. A., Morris, A. P., McGlone, F., Abbott, D. F. & Mattingley, J. B. 2004c Amygdala responses to fearful and happy facial expressions under conditions of binocular suppression. J. Neurosci. 24, 2898–2904. (doi:10.1523/ JNEUROSCI.4977-03.2004) Williams, L. M., Das, P., Liddell, B., Olivieri, G., Peduto, A., Brammer, M. J. & Gordon, E. 2005a BOLD, sweat and fears: fMRI and skin conductance distinguish facial fear signals. Neuroreport 16, 49–52. (doi:10.1097/00001756200501190-00012) Williams, M. A., McGlone, F., Abbott, D. F. & Mattingley, J. B. 2005b Differential amygdala responses to happy and fearful facial expressions depend on selective attention. Neuroimage 24, 417–425. (doi:10.1016/j.neuroimage. 2004.08.017) Wright, C. I., Fischer, H., Whalen, P. J., McInerney, S. C., Shin, L. M. & Rauch, S. L. 2001 Differential prefrontal cortex and amygdala habituation to repeatedly presented emotional stimuli. Neuroreport 12, 379–383. (doi:10.1097/ 00001756-200102120-00039)

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Phil. Trans. R. Soc. B (2006) 361, 2143–2154 doi:10.1098/rstb.2006.1936 Published online 3 November 2006

Reproductive strategy, sexual development and attraction to facial characteristics R. Elisabeth Cornwell1,2,*, Miriam J. Law Smith1, Lynda G. Boothroyd1, Fhionna R. Moore1, Hasker P. Davis2, Michael Stirrat1, Bernard Tiddeman3 and David I. Perrett1,* 1

School of Psychology, University of St Andrews, South Street, St Andrews, Fife KY16 9JP, UK 2 Department of Psychology, University of Colorado at Colorado Springs, Colorado Springs, CO 80918, USA 3 School of Computer Science, University of St Andrews, North Haugh, St Andrews, Fife KY16 9SX, UK Sexual reproduction strategies vary both between and within species in the level of investment in offspring. Life-history theories suggest that the rate of sexual maturation is critically linked to reproductive strategy, with high investment being associated with few offspring and delayed maturation. For humans, age of puberty and age of first sex are two developmental milestones that have been associated with reproductive strategies. Stress during early development can retard or accelerate sexual maturation and reproduction. Early age of menarche is associated with absence of younger siblings, absence of a father figure during early life and increased weight. Father absence during early life is also associated with early marriage, pregnancy and divorce. Choice of partner characteristics is critical to successful implementation of sexual strategies. It has been suggested that sexually dimorphic traits (including those evident in the face) signal high-quality immune function and reproductive status. Masculinity in males has also been associated with low investment in mate and offspring. Thus, women’s reproductive strategy should be matched to the probability of male investment, hence to male masculinity. Our review leads us to predict associations between the rate of sexual maturation and adult preferences for facial characteristics (enhanced sexual dimorphism and attractiveness). We find for men, engaging in sex at an early age is related to an increased preference for feminized female faces. Similarly, for women, the earlier the age of first sex the greater the preference for masculinity in opposite-sex faces. When we controlled sexual dimorphism in male faces, the speed of sexual development in women was not associated with differences in preference for male facial attractiveness. These developmental influences on partner choice were not mediated by self-rated attractiveness or parental relationships. We conclude that individuals assort in preferences based on the rapidity of their sexual development. Fast developing individuals prefer opposite-sex partners with an increased level of sexually dimorphic facial characteristics. Keywords: face; attraction; development; masculinity; mate value; assortative mating

1. INTRODUCTION Sexual maturation is a key milestone in human development, and much research has focused on multiple factors influencing its timing. These include psychosocial factors (Belsky & Draper 1987; Belsky et al. 1991; MacDonald 1999; Ellis & Garber 2000; Ellis et al. 2003), hormones (Nottlemann et al. 1987; Tremblay et al. 1998) and genetics (Comings et al. 2002). Timing of puberty, independent of the factors mediating it, influences the social environment of adolescence. Whether one matures early, late or ‘ontime’ will shape individual experiences in interactions

* Authors for correspondence ([email protected] and rcornwel@ uccs.edu). One contribution of 14 to a theme issue ‘The neurobiology of social recognition, attraction and bonding’.

with peers as well as adults. The outcome of these interactions contributes to the overall psychosocial well-being of the individual during adolescence. Our interest is to go beyond the immediate influences of pubertal timing and sexual maturation on adolescent behaviour and question the outcome of sexual maturational timing on adult mate choice and strategies. We speculate that adults who were early sexual maturers, e.g. in terms of both puberty and initiation of sexual intercourse, will differ from late maturers when making judgements of opposite-sex facial attractiveness. This over-arching hypothesis is framed by alternative reproductive strategies that are responses to the developmental environment. These strategy differences are reflected in individual preference judgements for particular facial characteristics. We consider three issues: (i) early maturation as a negative outcome owing to stress; (ii) early maturation as a

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positive influence on social status; and (iii) mate choice preferences as a product of learning through peer social interactions. (a) Alternative reproductive strategies Alternative tactics to maximize reproductive fitness are found across a wide variety of species, including humans (Gross 1985, 1996; Henson & Warner 1997). The theoretical framework offered by both game theory (Maynard Smith 1982) and evolutionarily stable strategy (Maynard Smith & Price 1973) offers a platform from which investigations into humans’ use of alternative reproductive strategies can be launched. Beginning with the most basic assumptions of human female/male differences: females invest heavily in offspring, through pregnancy and lactation, males by contrast need only to contribute sperm for successful reproduction. To maximize reproductive success (by producing as many offspring as possible), males are thought to take the approach of capitalizing on as many mating opportunities as possible, but are constrained by female choice and demands for investment (Trivers 1972). Females, on the other hand, should seek out mates who are willing to provide, but they are forced to make trade-offs between good paternal investment and genetic fitness of the male (immunocompetence; Møller & Thornhill 1998; Perrett et al. 1999; Scheib et al. 1999; Scheib 2001). In a competitive market, high-quality males (with a healthy immune system) may find that they are in high demand and can potentially contribute less paternal investment, especially when considering partnership with a lowquality female. If a low-quality female wishes to secure a more genetically fit male’s genes for her offspring, she could opt to settle for a short-term sexual relationship with him and sacrifice other benefits such as long-term financial support and paternal care for her offspring (Little & Hancock 2002; Penton-Voak et al. 2003). Research on attraction has successfully used this theoretical framework to explain individual differences in female preferences for symmetric and sexually dimorphic facial characteristics in opposite-sex faces. High-quality individuals have a greater ability to attract high-quality mates and thus procure higher reproductive advantages. A more attractive male can adopt a mating strategy of multiple mating partners, investing less in each partner (Thornhill & Gangestad 1994) with less risk to his offspring (Burley 1986; Gowaty 1996; Sheldon 2000; Badyael & Hill 2002). Females of highquality can not only attract high-quality mates, but can also enforce demands for paternal investment and thereby circumvent the trade-off between good genes (for immunity) and high investment. Individuals of lesser quality cannot successfully employ these strategies, despite their desire to do so, and this gives rise to variation in mate choice strategies. Humans offer us a unique opportunity to investigate the influence of self-assessed quality on mate choice and strategies. (b) r and K strategies Robert MacArthur (1962) incorporated aspects of R. A. Fisher and J. B. S. Haldane’s theorems to account for varying degrees of inbreeding and effects of population density in terms of fitness. From this, as well Phil. Trans. R. Soc. B (2006)

as later work (MacArthur & Wilson 1967), arose r and K selection theories. The names come from two parameters of standard population dynamic theory. K-strategists are said to live close to K, the carrying capacity of the environment; and r-strategists are said to maximize r, the intrinsic rate of increase of the population. The general premise is that organisms must adapt to their environment to maximize their fitness, and environments vary in stability. In unstable environments, the best strategy would be to produce large numbers of offspring, many of which will die but a few are likely to survive. In stable environments, the better strategy is to have fewer offspring, but invest more in each so that offspring survival chances are increased. Thus, r-selected species are short-lived, reproduce rapidly, take advantage of open niches, and are prone to boom or bust populations depending on the vagaries of the environment. K-selection refers to species that are longer-lived, reproduce slower, and are more immune to environmental swings. Compared with r-strategists, K-strategists are larger, the energy to produce one offspring is high, few offspring are produced, life expectancy is long, individuals can reproduce multiple times, sexual maturity is slow to arrive, and survival of offspring should be fairly high—with most offspring living a full-maximum lifespan. Humans lie near the K end of the continuum if we go by our long lives, slow maturation, few offspring and good offspring survival rates (Mace 2000). But, some scientists have suggested that even within a species there is variation of strategy, and have employed the ideas of r and K strategies to characterize human mating strategies, reproduction and parental investment (Draper & Harpending 1982; Belsky et al. 1991; MacDonald 1997; Bereczkei & Csanaky 2001). The idea is that in unstable environments, humans may opt to increase their rate of reproduction, investing less in each individual offspring, and that offspring will reach sexual maturity earlier and begin their own reproduction earlier than humans raised in stable environments. Unstable environments during development could affect reproductive strategies, including mate choice. Indeed, girls who experienced longer duration of father absence (e.g. fathers left the family earlier) were more likely to engage in sexual intercourse earlier than girls whose fathers left later or remained ‘faithful’ (Ellis et al. 2003). Quinlan (2003) looked at retrospective data for 10 847 US women to examine the effects of divorce and separation of parents, including any effects related to the age of the child when divorce or separation took place. He found that when women’s parents divorced or separated early during her childhood (before birth up to 5 years of age), the women were more likely to reach menarche earlier, engage in sexual intercourse earlier, become pregnant earlier and their marriages were shorter in duration when compared with women whose parents’ separation occurred later or not at all. Additionally, Quinlan found that if parents divorced or separated during the women’s adolescence, these women were likely to have more sexual partners than women whose parents did not separate or divorce. The original work by MacArthur & Wilson (1967) was not intended to explain mating strategies, but to account for varying degrees of inbreeding and effects of

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Sexual development and facial attraction R. E. Cornwell and others population density in terms of fitness. Certainly, it was not developed to explain the individual differences of mate choice within a species. Consideration of the home environment during human development is important, as many factors can affect adult behaviour. These include attachment to parents, parenting styles, presence of siblings, size of extended family, moving house, illness, and home and community (e.g. level of neighbourhood violence). Whether these factors can be fitted into r and K selection is perhaps debatable. (c) Life-history theory Life-history theory has been particularly useful for exploring pubertal timing from an evolutionarydevelopmental perspective (for review see Geary 2002; Ellis 2004). Unlike r and K strategies, lifehistory theory specifically relates to within-species differences and explores environmental (e.g. stress, nutrition and father absence) and genetic influences that could influence maturation rates and sexual strategies. Phenotypic plasticity and ability to adapt to environmental factors contribute to the decision process in individual organisms in terms of trade-offs. This is not to imply that decision processes affecting choice of strategies are conscious. For example, by ‘choosing’ to delay maturation and reproduction, individuals may reduce their overall number of offspring compared with individuals with accelerated maturation and onset of reproduction, but slow maturers gain by producing healthier, higher quality offspring (Black & DeBlassie 1985; Overpeck et al. 1998; Elfenbein & Felice 2003). Thus, increased fitness is measured through multiple generations rather than the number of immediate offspring. Ellis (2004) argues that selection for adaptive responses, i.e. plasticity, of the individual was favoured during our evolutionary history. While there are several competing and complementary hypotheses within lifehistory theory, the central questions are: when is it optimal for an individual to cease expending energy in growth and redirect it towards reproductive efforts and what are the critical determinants of timing (Ellis 2004)? Contributing factors influencing maturation include: (i) poor nutrition which is associated with late maturation and decreased fertility (Miller 1994; MacDonald 1999); (ii) negative physical or social conditions delaying reproductive maturation (stresssuppression theory, e.g. Miller 1994; MacDonald 1999), or accelerating reproductive maturation (Draper & Harpending 1982; Belsky et al. 1991; Chisholm 1993, 1996; Wilson & Daly 1997); and (iii) father absence which can speed up development in females (Ellis & Garber 2000). In essence, all lifehistory theories suggest that early environmental factors affect the developmental profile of the individual. This in turn will also have effects on later adult behaviours, including reproductive strategies and mate choice. (d) Timing of puberty and reproductive strategies The possible environmental factors mediating pubertal timing have been studied since the 1930s, and family, economic, physical and nutritional stressors have been indicated as having effects on sexual maturation. Phil. Trans. R. Soc. B (2006)

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Despite the amount of research expended, there remains a great deal of controversy as to which particular stressors accelerate and which decelerate puberty timing (Hoier 2003; Romans et al. 2003). Some psychologists have examined the role of environmental stressors and their possible influence on reproductive strategies, including the timing of sexual maturation and mate choice. Humans, it is argued, have been selected to respond to environmental cues by adopting a reproductive tactic most suited to enhance fitness; furthermore, the choice of tactic is sensitive to the environmental cues experienced during development ( Jones et al. 1972; Belsky & Draper 1987; Surbey 1990; Belsky et al. 1991; Moffitt et al. 1992; MacDonald 1999; Ellis & Garber 2000; Ellis et al. 2003). It has been asserted that more precocious sexual behaviours indicate a strategy of early reproduction, more offspring, but less investment; whereas later sexual maturity and conservative sexual activity may reflect an investment-biased reproductive strategy with fewer offspring, but heavier investment. Adopting either of these strategies may reflect the environment to which the individual was exposed at specific times during development or throughout development. (e) Parental influences Puberty is the key developmental milestone towards achieving adult sexual status, and its timing has been linked to strong hormonal and genetic influences. There remains debate concerning the contribution of genetic (Pickles et al. 1998) and hormonal influences on development (Dorn et al. 2003a,b). One factor, mother’s age of menarche, has been found to be the best predictor of daughter’s age of menarche (Kirk et al. 2001). Environmental factors also mediate age of menarche, with stressful family situations such as father absence accelerating menarche (Jones et al. 1972; Belsky & Draper 1987; Surbey 1990; Belsky et al. 1991; Moffitt et al. 1992), while having younger siblings decelerates it (Jones et al. 1972; Hoier 2003). Less work has been done on the effect of father absence on puberty in males, but father absence for 1 year or longer during childhood is significantly associated with earlier spermarche (Kim et al. 1997; Kim & Smith 1998). Early spermarche and puberty have been associated with increased number of romantic partners, sexual partners, earlier onset of sexual interest (dating) and earlier first intercourse (Kim & Smith 1998; Edgardh 2002). In contrast, good relationships with parents, especially between girls and their mothers, can decrease the likelihood of early sexual intercourse (McNeely et al. 2002). Since poor relations between parent and offspring are thought to accelerate sexual maturation and negatively affect mate quality (Boothroyd & Perrett 2006), they must be taken into account when investigating the association between sexual development and mate choice preferences. Parental relationships may affect mate choice preferences in a way that is independent of maturation effects, such as through an effect on selfesteem and psychological well-being (McNeely et al. 2002; Spencer et al. 2002; Berg 2003). We therefore investigate the effect of maturation and relationship with parents on adult partner preference.

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(f ) Peer interactions Adolescence is a time for individuals to explore and come to terms with peer group social hierarchy and their rank within it (Harris 1995; Hawley 1999, 2003; Hawley & Vaughn 2003). If adolescence is a particularly sensitive time for determining reproductive strategies, then social status and adolescent sexual behaviour should be of particular importance. While there is evidence that early puberty can have negative psychological, social and behavioural effects both during and after adolescence, there is also evidence for its positive effects (Dorn et al. 2003a,b; Weichold et al. 2003; Weisfeld & Woodward 2004). Reaching puberty slightly ahead of peers may give distinct advantages in terms of social status, and these advantages may in fact continue on into adulthood. Higher levels of testosterone during early puberty in boys have also been associated with social success (Schaal et al. 1996). Boys who mature earlier are often looked up to by their same sex peers (Peterson & Crockett 1985), and have greater opportunity to affiliate romantically with females (Susman et al. 1987; Halpern et al. 1998). Such affiliations increase the potential for earlier initiation of sexual activity compared with their slower developing peers (Stattin & Magnusson 1990). Girls who mature earlier are more likely to procure the attention of older, more physically mature boys (Magnusson et al. 1985; Stattin & Magnusson 1990; Weichold & Silbereisen 2001; Gowen et al. 2004), and such girls find older boys to be more attractive than boys of peer age (Kracke 1993). Associating with older boys may give early maturing girls access to social activities and the trappings of higher social status not afforded to slower developing peers, as well as increase the likelihood of engaging in romantic and/or sexual activity (Silbereisen & Kracke 1997; Prokope`a´kova´ 1998). These early affiliations with earlier like-developing opposite-sex peers may enhance preferences for more sexually mature characteristics. Faster developing girls, for example, may learn positive associations with more masculine-looking boys (also faster developers) and in turn, boys may relate more feminine characteristics in female faces with early sexual rewards. These preferences could continue on into adulthood, and thus associations between early maturation and preferences for exaggerated sexually dimorphic features would be expected in mate choice for those with early maturation. Another possible influence of sexual development on mate choice is that both early maturing girls and boys may gain social status within their peer groups, and thus enhance selfperceived attractiveness and mate value. If selfperceptions established during development continue into adulthood, early maturers are likely to perceive themselves as high-status and high-quality adults. Effects of self-perceived quality have been found to influence adult partner choice. For example, highquality individuals prefer partners of similar quality. This is reflected in their increased preferences for quality markers such as symmetry and exaggerated sexually dimorphic facial characteristics (Little et al. 2001; Penton-Voak et al. 2003). For these reasons, we examine the influence of self-rated attractiveness Phil. Trans. R. Soc. B (2006)

on preferences for sexual dimorphism in oppositesex faces. (g) Mate quality signals (i) Sexually dimorphic facial traits Symmetry is considered a positive characteristic for both sexes, as it indicates good immunocompetence during the difficulties of the developmental process (Perrett et al. 1999; Jones et al. 2001). By contrast, the particular growth patterns mediated by sex hormones resulting in epigamic traits are thought to signal both positive and negative mate characteristics (Perrett et al. 1998). Characteristics more typical of the female face include full lips, large eyes, small nose and delicate features, which are thought to be associated with higher levels of oestrogen. Feminine facial characteristics may signal fecundity in women (Enlow 1990) and immunocompetence (Seli & Arici 2002). Faces of women with higher levels of oestrogen are rated as more feminine looking than faces of women with lower levels (Law Smith et al. 2006). A feminine female face shape is found attractive by both sexes, and confers personality merits such as warmth and nurturing (Perrett et al. 1998). Thus, enhanced sexually dimorphic features are attractive in female faces. The more classic male facial features include square jaw, heavier brow and thinner lips, which are related to testosterone levels during development. Faces of males with higher levels of testosterone were rated as looking more masculine than faces of males with lower levels (Penton-Voak & Chen 2004). Testosterone is known to depress the immune system (Ahmed & Talal 1990), and Folstad & Karter (1992) argue that only the healthiest males with the best genes for immunocompetence are capable of displaying such epigamic traits. Testosterone is also related to male–male competition, and it is reasoned that male characteristics may enhance signals related to male dominance (Mazur & Booth 1998). Masculine features simultaneously suggest both positive and negative signals, including personality attributes such as dominance, high risk taking, aggression, sexual impulsivity, spousal abuse, inability to commit to a relationship and anti-social behaviour (Olweus et al. 1988; Mazur & Booth 1998; Perrett et al. 1998). Therefore, masculine features are of contrary desirability, and women must resolve tradeoffs between (masculine) males with genes signalling high immunocompetence and (feminine) males signalling affable personality traits and high paternal investment. As we review above, such trade-offs will depend on sexual strategies: high-quality women will seek and retain high-quality sexually dimorphic males. In essence, this claim points towards assortment in mate quality; (high-quality) feminine women and (high-quality) masculine men are most likely to form partnerships. Moreover, women following high investment reproductive strategies and who desire high paternal investment might seek out less masculine male partners. (ii) Attractiveness beyond sexual dimorphism What is ‘attractiveness’? In the context of mate preferences, it should mean that one individual is ‘attracted to’ or ‘drawn-in’ by another individual as a

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Sexual development and facial attraction R. E. Cornwell and others potential sexual partner. It is also used in more general terms, as a sort of rating system. For example, compared to asymmetrical faces, symmetrical faces are generally preferred; thus, symmetrical faces are described as being more ‘attractive’. Researchers studying mating strategies need to understand whether attractiveness means the same thing across a variety of individuals. In the last section, we noted that partnership and even attraction to sexually dimorphic males could vary with female reproductive strategy. Thus, it may be that attraction to particular individuals is not universal but can be strategic. In a meta-analysis, Langlois et al. (2000) found strong agreement between raters on judgements of facial attractiveness, both within and across cultures. Still, while individuals may agree in general who is or is not attractive, there still might be disagreement on what faces individuals prefer. We see variation of this sort when examining the influence of hormonal markers on facial preferences. Women’s preferences for masculine facial characteristics have been far from consistent across a range of studies. Women have been found to prefer more masculinized male faces in some studies (Grammer & Thornhill 1994; Scheib et al. 1999; Penton-Voak & Perrett 2001), and to prefer more feminized male faces in others (Perrett et al. 1998; Penton-Voak et al. 1999, 2003). Women are not the only ones who appear fickle, as male preferences for feminine facial characteristics also vary among individuals (Cunningham et al. 1995; Swaddle & Reierson 2002; Cornwell et al. 2004). So, if women and men concur on facial attractiveness but differ on preferences of sexual dimorphism, is there an aesthetic quality in the human face that we do not yet fully understand? And if so, what is its role in mate choice? Masculine and feminine facial characteristics are signals of mate quality, but strong indicators of sexual dimorphism do not automatically confer attractiveness. For example, Arnold Schwarzenegger’s ‘Terminator’ would certainly be judged as a ‘highly masculinized’ male, but not all women would judge him as facially attractive. On the other hand, the character Everett, as played by the actor George Clooney in the film ‘O Brother, Where Art Thou?’, is both masculine and to many women very attractive. Likewise, feminine facial characteristics are not the only feature contributing to a woman’s attractiveness. Both Sigourney Weaver and Meg Ryan are highly attractive, and yet Ms Ryan would likely be judged as being much more feminine looking than Ms Weaver. The point we are making is that there are aesthetic qualities that alter our judgements of attractiveness outside of or in addition to feminine or masculine facial characteristics. We assert that these ‘attractiveness’ characteristics are a signal to mate value, but whether these signals suggest the same meanings as epigamic facial characteristics is unknown. To investigate whether there is an ‘attractiveness’ component to the face, we have attempted to isolate it from variations of facial masculinity or femininity by creating a new range of facial images. These images attempt to keep constant sexually dimorphic characteristics and vary in a characteristic we shall at this time refer to as Phil. Trans. R. Soc. B (2006)

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‘attractiveness’. Reciprocally, we created images that vary in masculinity and femininity, while attempting to keep attractiveness characteristics constant. If epigamic traits and the attractiveness component convey distinct information to the receiver, then there should be independent variation in preferences for these characteristics. While we are attempting to understand the variation found in the literature regarding female preferences for male facial appearance and how these variations relate to mate qualities, for the sake of parity we created comparable female face images attempting to manipulate attractiveness and femininity independently and conducted parallel research on male preferences. (iii) Timing of puberty and predictions for facial preferences Based on our review of prior research, and theories relating to reproductive strategies and assortative mating, we offer three predictions for the effects of sexual maturation on preferences for facial epigamic traits. (i) If early timing of sexual maturity is associated with high stress and therefore producing lowquality individuals, then early maturing men should prefer low-quality female faces, i.e. less feminine and less attractive faces, while later maturing men should indicate preferences for high-quality female faces. Early developing women should indicate preference for lowquality males by choosing less masculine and less attractive male faces. However, it should be noted that owing to the use of short-term strategies, low-quality women may indicate a preference for high-quality males if they are considering short-term relationships. (ii) If learning occurs, that is to say early developing adolescents have learned to associate increased sexually dimorphic characteristics with potential mates, then we would expect to see early maturers preferring increased sexual dimorphism but not necessarily indicating a preference for higher facial attractiveness. (iii) If early maturers have higher social status and consider themselves to be higher quality mates owing to social success through puberty, then early maturing men and women should choose high-quality mates on both facial dimensions, i.e. more sexually dimorphic and more attractive opposite-sex faces.

2. MATERIAL AND METHODS (a) Rating original images We began with a collection of 701 original face images (more than 90% Caucasian; 456 female: age meanZ20.21, s.d.Z3.18 years; 245 male: age mean 21.21, s.d.Z3.58 years). Seventeen participants (11 females) rated attractiveness and 14 participants (7 females) rated facial femininity of female faces and masculinity of male faces. Images were masked (to exclude hair and clothing) and presented in random order. Participants were Caucasian and aged 18–29 years. Each image was assessed on scales of 1–7 for (i) attractiveness for both female and male faces; (ii) masculinity

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on male faces; and (iii) femininity on female faces. Initial correlation analyses revealed that the female rating of male facial attractiveness and facial masculinity were significantly correlated (r196Z0.202, pZ0.005), and correlations between the male ratings of female facial attractiveness and facial femininity were even stronger (r345Z0.592, p!0.001). To create our new images, we first matched the facial images on one dimension, and then from within the matched group we selected the high and low faces on the second dimension. For the attractiveness images, we averaged shape, colour and texture of those male Caucasian faces (nZ26–30) that had been rated either high or low on the dimension of attractiveness, while rated similarly on the second dimension of male masculinity (Tiddeman et al. 2001). This effectively created high and low attractiveness male face prototypes that were matched on the dimension of masculinity (scale: 1–7; mean attractiveness ratings 3.42 versus 2.43; mean masculinity ratings 4.38 versus 3.93). The same process was then used to create two male prototypes of high and low masculinity matched on attractiveness (mean masculinity ratings 5.18 versus 2.88; mean attractiveness ratings 2.85 versus 2.75), two female prototypes of high and low femininity while controlling for attractiveness (mean femininity ratings 4.98 versus 2.92; mean attractiveness 3.10 versus 2.97), and two female prototypes of high and low attractiveness while controlling for femininity (mean attractiveness ratings 4.22 versus 2.26; mean attractiveness 4.26 versus 4.44). (b) Composite image calibration The male face prototype images were rated on both attractiveness and masculinity, and the female faces were rated for attractiveness and femininity. The raters were recruited through an introductory psychology class at the University of Colorado at Colorado Springs for course credit. For our analyses, we included only female raters under 25 years of age (NZ38, mean ageZ18.7G1.2, range 17–23 years) and not taking hormonal contraceptives or pregnant. Male raters were under 25 years of age (NZ39, mean ageZ19.6G1.4, range 17–23 years). Analyses are based on opposite-sex ratings. Images were presented individually and in random order among filler items, and rated on a 7-point scale. Paired t-test analyses revealed that the high masculine male face prototype was judged more masculine than the low masculine male face prototype, t(37)Z7.3, p!0.001, h2Z0.59. When judged on attractiveness, the high and low masculinity face prototypes were found not to be significantly different, t(33)ZK0.114, pZ0.91. For the high and low attractive male images, we found that the high attractive male face was rated significantly more attractive than the low attractive face, t(33)Z4.112, p!0.001, h2Z0.34. When rated on masculinity, the two were not significantly different t(37)Z1.02, pZ0.31. These data show that the intended manipulation of male face prototypes along one dimension while controlling a second dimension was successful. However, for the female images, the calibration results indicate that segregating attractiveness and femininity in female faces was not successful. The high and low feminine face pairs were rated differently on femininity, t(28)Z3.92, pZ0.001, h2Z0.354, but the same images were also judged differently on attractiveness, t(20)Z3.25, pZ0.004, h2Z0.346. The high and low attractiveness female faces were rated differently on attractiveness, t(20)Z3.301, pZ0.004, h2Z0.353, but also differed on rated femininity, t(28)Z 3.111, pZ0.004, h2Z0.257. These results, though disappointing, are not surprising owing to the strong positive Phil. Trans. R. Soc. B (2006)

relationship found between men’s attractiveness ratings and female facial femininity in previous research (Perrett et al. 1998; Cornwell et al. 2004). Given the ambiguity of female facial stimuli, we restricted further analysis to the female composites based on sexual dimorphism which are unambiguous for this trait, since this was the dimension we set out to investigate. (c) Experimental images Three composite ‘base’ male faces were made by averaging eight randomly chosen Caucasian male face images, aged between 18 and 24 years. Three ‘base’ female faces were similarly created. These base faces differing in apparent identity, were then transformed by G115% of the difference in face shape, colour and texture between the high and low sexually dimorphic and high/low attractive prototypes (Tiddeman et al. 2001). Finally, a sequence of 25 images was created by interpolating between the C115 and K115% end-point images. This effectively created three face continua (of 25 images) for each sex that differed along one dimension but were matched in other respects (i.e. different in apparent masculinity but matched in identity and attractiveness). For illustration see figures 1 and 2. For analysis, the mean value for each of the three examples for each participant was correlated with questionnaire responses. These continua were used to create three interactive sequences, with 25 individual images in each sequence. Participants were asked to choose the image that they considered to be the most attractive from the range available (Perrett et al. 1998; Little et al. 2001). (d) Participants Heterosexual undergraduate students were recruited from the University of St Andrews: 46 women not taking hormonal contraceptives or reporting pregnancy (age range 18–23 years, mean 19.50G1.36) and 52 men (age range 18–24 years, mean 20.62G1.60).

3. MATERIALS To assess preferences for facial masculinity and attractiveness, interactive face-sequence trials were used, consisting of three male and three female Caucasian faces. Participants were also asked to complete a questionnaire, which included life-history questions relating to age of menarche/puberty and age of first sex. For individuals reporting not having had sex or sexual partners (9 males and 16 females), current age was used as age of first sex. Additionally, family relationship questions included warmth towards father and mother, quality of parents’ relationship with one another which used a 9-point Likert-type scale and current age of parents. Also relevant to this study was self-rated attractiveness, which used a 7-point Likert-type scale. Father absence was assessed with questions relating to the participant’s age at the time of parents’ separation. (a) Procedures After reading and signing a consent form, participants were asked to complete an on-line questionnaire. Participants were presented with two conditions of interactive face-sequence trials, sexual dimorphism and attractiveness for opposite-sex faces. Both the conditions and the example faces within each condition

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Sexual development and facial attraction R. E. Cornwell and others (a) (i) 50% less masculine

(ii) 50% more masculine

(b) (i) 50% less attractive

(ii) 50% more attractive

Figure 1. Example stimuli used in the studies. (a) Masculinity lowered (i) and raised (ii) while attempting to keep attractiveness constant. (b) Attractiveness lowered (i) and raised (ii) while attempting to keep masculinity constant.

(a)

(b)

(i) 50% less feminine

(ii) 50% more feminine

(i) 50% less attractive

(ii) 50% more attractive

Figure 2. Example stimuli used in the studies. (a) Femininity lowered (i) and raised (ii) while attempting to keep attractiveness constant. (b) Attractiveness lowered (i) and raised (ii) while attempting to keep femininity constant.

were randomized. For each face, the participants were asked to select the face they found most attractive by moving the cursor over the image to scroll through the continua of sequenced faces. By clicking on the computer mouse, the participant chose the face he or she found most attractive as well as moving them on to the next trial. 4. RESULTS (a) Women We performed initial Spearman’s rank correlations and found that age of first sex significantly correlated with preference for masculine facial characteristics Phil. Trans. R. Soc. B (2006)

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(r39ZK0.427, pZ0.007) and showed a trend to correlate with male facial attractiveness (r39Z0.292, pZ0.071). Women with early sexual experience preferred more masculine-looking males, yet showed a reduced tendency to prefer attractive male faces. Interestingly, we did not find a significant correlation between age of menarche and any facial characteristic preferences (all r42, pO0.314). In our sample, we did not find a relationship between our two developmental markers, age of first sex and age of menarche (r42Z 0.047, pZ0.768). Additionally, face preferences for attractiveness and masculinity were not significantly correlated (r42ZK0.047, pZ0.769). (b) Control variables and partial correlations Our Spearman’s rank correlations revealed that both warmth towards father (r44Z0.297, pZ0.050) and warmth towards mother (r44Z0.313, pZ0.036) significantly correlated with parents’ relationship, as well as with one another (r44Z0.585, p!0.001). Thus, we chose quality of parents’ relationship as a control variable. Our analysis also revealed that self-rated attractiveness was positively correlated with preferences for more attractive male faces (r42Z0.307, pZ0.048), indicating that as self-perceived attractiveness increased, so did a preference for more attractive male faces. None of our other control variables were found to significantly relate to preferences for facial characteristics (all pO0.180). To assess our hypothesis that timing of developmental milestones influenced women’s preferences for male facial characteristics, partial correlations were used to control the possibility of other factors known to influence mate choice preferences. We found that the relationship between age of first sex and preferences for male facial masculinity remained significant after controlling for current age, self-rated attractiveness, dad’s age, and quality of parents’ relationship (r31ZK0.423, pZ0.014). The other correlations between sexual developmental markers (age of first sex and age of menarche) and face preferences remained non-significant (all pO0.18). The relationship between age of menarche and male face masculinity was non-significant (r29Z0.173, pZ0.35). We did not find any other significant correlations with masculinity preferences among our control variables (all pO0.22). To investigate further the relationship of self-rated attractiveness and our dependent variable male facial attractiveness, we ran a partial correlation with age of first sex, age of menarche, current age, dad’s age and quality of parents’ relationship as control variables. The relationship between self-rated attractiveness and preference for male facial attractiveness remained significant (r29Z0.431, pZ0.016), while the relationship between self-rated attractiveness and masculinity remained non-significant (r29Z0.185, pZ0.320). (c) Men We hypothesized that timing of developmental markers would influence adult mate choice preferences. Correlations indicate that both age of puberty (Spearman’s r 49ZK0.331, pZ0.020) and age of first sex (r51ZK0.286, pZ0.042) related to preferences for facial femininity. Thus, early male sexual development

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was associated with increased preference for feminized characteristics in women’s faces. Despite findings in previous research linking age of puberty with age of first sex, we found only a positive but non-significant correlation (r50Z0.204, pZ0.156), perhaps owing to the small sample size. (d) Control variables and partial correlations We used partial correlations to determine whether other known effects (i.e. family background, own age and attractiveness) contributed to the current finding of a relationship between male sexual maturation and preference for female facial femininity. Spearman’s rank correlations revealed that both warmth towards mother (r52Z0.419, pZ0.002) and warmth towards father (r52Z0.465, pZ0.001) were positively correlated with quality of parents’ relationship, and with one another (r52Z0.587, p!0.001). We therefore opted to use quality of parents’ relationship as a control variable. Our partial correlations indicated that the relationship between male sexual maturation and femininity preference in women’s faces remained significant (after controlling quality of parents’ relationship, current age, mother’s age and self-rated attractiveness) with age of puberty (r43 ZK0.302, pZ0.044), although the relationship with age of first sex was only marginally significant (r44ZK0.285, pZ0.055). Additionally, none of the control variables (quality of parents’ relationship, current age, mother’s age and self-rated attractiveness) related to face preferences in zero-order Spearman’s correlation (all pO0.23). 5. DISCUSSION (a) Stimuli For this experiment, we used novel stimuli in an attempt to differentiate between sexual dimorphism and another factor we labelled ‘attractiveness’. We made explicit predictions concerning preferences for these new stimulus dimensions. Our calibration study indicated that the male attractive faces were judged to vary in attractiveness but not masculinity, and the male masculine faces were judged to vary in masculinity but not in attractiveness. This suggests, as Langlois et al. (2000) implied, that there is a general agreement about attractiveness. Moreover, there is also an agreement as to what constitutes facial masculinity in males, and that these two dimensions for the male face are not necessarily the same. For the female face, we were unsuccessful at separating facial attractiveness from feminine facial characteristics; thus, we looked only at the high and low feminine faces and found that the timing of men’s sexual development was associated with preferences for more feminine female faces. (b) Facial preferences and timing of sexual maturation As predicted, the timing of sexual developmental markers was found to influence both women and men’s mate preferences, and earlier maturers preferred increased sexual dimorphism in opposite-sex faces. Men who had experienced earlier puberty and earlier initial sexual intercourse were found to prefer more Phil. Trans. R. Soc. B (2006)

feminized female faces compared with those males who matured later. Women who experienced earlier first sex preferred more masculine male faces while those who experienced initial sex later, or remained virgins, preferred less masculinized faces. We did not find, as predicted, that age of menarche was associated with facial preferences. Other factors known to influence preferences for mate facial characteristics, self-rated attractiveness, parental relationships, age of oppositesex parent or own age, could not explain the developmental differences in preferences for facial sexual dimorphism. In addition to our general prediction that timing of puberty and age of first sex would be associated with facial preferences, we considered three specific explanations regarding how mating strategies may have been influenced by sexual development. The third explanation that early maturing adolescents would view themselves as having higher social status than their peers was not supported by the data. High status individuals should show increased preference for high-quality individuals, and therefore should prefer both sexual dimorphism and attractiveness. We found support for the former but not the latter. Our first prediction had mixed results. We suggested that if early developers are low-quality individuals, then as per an assortative mating strategy these individuals should seek low-quality mates. Based on this inference, our data suggest that early maturers are high- and not low-quality individuals. We did not ask participants to choose the most attractive face based on either long- or short-term relationships, so we cannot exclude the possibility that low-quality women were selecting for short- and not long-term mates. It has been suggested that low-quality women will seek out high-quality males for a short-term opportunistic mating in order to obtain better genes for immunocompetence. To use this explanation to interpret our data, we do need to make unsubstantiated assumptions that (i) the early maturing women were employing a short-term mating strategy and (ii) a ‘condition-dependent’ preference (Little et al. 2001) is exclusive to sexually dimorphic traits. Our findings suggest that early sexually maturing men select high-quality females because they themselves are high-quality. Thus, the results indicate then the early sexual maturation of both sexes is associated with ‘high’ quality. We note that it is best to consider early and late maturers as having different types of characteristics of mate quality rather than categorizing them as high and low levels of condition. We therefore suggest that individuals varying in rates of maturation emphasize different qualities and seek self-similar qualities in others. The observation that earlier sexual development was associated with preferences for sexual dimorphism but not for attractiveness characteristics in the face supports our second explanation that learning plays a role in adult mate choice. We reasoned that early maturing adolescents were more likely to receive positive feedback from early maturing opposite-sex adolescents in their early forays into sexual behaviour. Adolescents who matured later would more likely be spurned by early maturing opposite-sex adolescents

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Sexual development and facial attraction R. E. Cornwell and others and could possibly associate negative feedback with these interactions. The signals of early maturation would be associated with exaggerated sexually dimorphic characteristics in the face, and these characteristics would be associated with either positive or negative experiences during adolescence. These preferences for epigamic traits would continue on into adulthood. The facial characteristics we have labelled as attractive would not be associated with pubertal timing, and therefore we would not expect to see a strong preference for these characteristics associated with sexual maturation rate. (c) Self-rated attractiveness and condition dependence Among women, we found that as ratings of selfperceived attractiveness increased, so too did preferences for our ‘attractive’ male faces but not preferences for the masculine male faces. Previous work examining condition dependence found that women rated by others as more attractive preferred more masculinelooking males (Penton-Voak et al. 2003). We attribute these contrary findings to the differences between stimuli. Penton-Voak and his colleagues varied their images along a continuum of masculinity in face shape. Our stimuli varied in three ways, in colour and texture as well as shape. We also went a step further to refine facial dimensions by separating epigamic traits from other facial characteristics signalling mate quality. What we have found is an answer to the question if there is something other than facial masculinity which contributes to mate choice preferences. The answer is positive. However, questions remain as to what information our masculine and attractive male faces stimuli suggest to women, and why women who rate themselves as attractive prefer one and not the other. The results may be a manifestation of assortative mating or matching on self-similar qualities (Berscheid et al. 1971; Feingold 1988, 1990). In other words, early maturing individuals prefer early maturing (sexually dimorphic) partners, while attractive individuals prefer attractive partners. Prior research has not separated maturation and attractiveness in stimuli or observers. 6. CLOSING CONSIDERATIONS Accelerated sexual maturation is associated with preferences for exaggerated sexually dimorphic features in opposite-sex faces in both men and women. We suggest that these preferences are due to learning influences during adolescence. It is possible that early maturers are higher quality; however, this conclusion is speculative and requires further investigation. A more parsimonious explanation is that early maturing men and women are seeking out similar individuals in much the same way as more attractive individuals seek out partners with similar attractiveness. Signs of early maturation are most likely to be enhanced sexually dimorphic characteristics in the face and body shape, and seeking out self-similar oppositesex partners would fit in with the ‘matching-hypothesis’ (Berscheid et al. 1971; Feingold 1988). We asked individuals to select those faces they found most Phil. Trans. R. Soc. B (2006)

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attractive, without any type of interpersonal or social feedback; this method is perhaps akin to how we might decide whom to approach in social situation. Our research suggests that people initially seek out individuals who are more like themselves on the dimension of sexual dimorphism. Feingold (1988) found that men and women do initially seek out partners who are selfsimilarly attractive, and there is a mild correlation in terms of attractiveness between partners in long-term relationships; however, other components such as socio-economic status, within-group desirability, and interpersonal similarity become much more important in long-term partnerships. Initial attraction is only a small part of the picture, and it is not surprising that we use facial appearance to sort out initial likes and dislikes. Special thanks to Lesley Ferrier, Robert Pitman, Susie Whiten, Bill Calderhead, Carolyn Cheetham, Fiona Elder, Jen Hardingham, Laura Johnson, Anne Marie Morgan, Anne Perrett and Lisa DeBruine.

REFERENCES Ahmed, S. A. & Talal, N. 1990 Sex-hormones and the immune-system. Part 2. Animal data. Baillieres Best Pract. Res. Clin. Rheumatol. 4, 13–31. Badyael, A. V. & Hill, G. E. 2002 Paternal care as a conditional strategy: distinct reproductive tactics associated with elaboration of plumage ornamentation in the house finch. Behav. Ecol. 13, 591–597. (doi:10.1093/ beheco/13.5.591) Belsky, J. & Draper, P. 1987 Reproductive strategies and radical solutions. Society 24, 20–24. Belsky, J., Steinberg, L. & Draper, P. 1991 Childhood experience, interpersonal development, and reproductive strategy—an evolutionary theory of socialization. Child Dev. 62, 647–670. (doi:10.2307/1131166) Bereczkei, T. & Csanaky, A. 2001 Stressful family environment, mortality, and child socialisation: life history strategies among adolescents and adults from unfavourable social circumstances. Int. J. Behav. Dev. 25, 501–508. (doi:10.1080/01650250042000573) Berg, E. C. 2003 The effects of perceived closeness to custodial parents, stepparents and non-resident parents on adolescent self-esteem. J. Divorce Remarriage 40, 69–86. (doi:10.1300/J087v40n01_05) Berscheid, E., Dion, K., Walster, E. & Walster, G. W. 1971 Physical attractiveness and dating choice: a test of the matching hypothesis. J. Exp. Social Psychol. 7, 173–189. (doi:10.1016/0022-1031(71)90065-5) Black, C. & DeBlassie, R. R. 1985 Adolescent pregnancy: contributing factors, consequences, treatment, and plausible solutions. Adolescence 20, 281–290. Boothroyd, L. G. & Perrett, D. I. 2006 Facial and bodily correlates of father absence. Proc. R. Soc. B 273, 2375–2380. (doi:10.1098/rspb.2006.3579) Burley, N. T. 1986 Sexual selection for aesthetic traits in species with biparental care. Am. Nat. 127, 415–445. (doi:10.1086/284493) Chisholm, J. S. 1993 Death, hope, and sex: life-history theory and the development of reproductive strategies. Curr. Anthropol. 34, 1–24. (doi:10.1086/204131) Chisholm, J. S. 1996 The evolutionary ecology of attachment organization. Hum. Nat. 7, 1–37. Comings, D. E., Muhleman, D., Johnson, J. P. & MacMurray, J. P. 2002 Parent–daughter transmission of the androgen receptor gene as an explanation of the effect of father absence on age of menarche. Child Dev. 73, 1046–1051. (doi:10.1111/1467-8624.00456)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2152

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Cornwell, R. E., Boothroyd, L., Burt, D. M., Feinberg, D. R., Jones, B. C., Little, A. C., Pitman, R., Whiten, S. & Perrett, D. I. 2004 Concordant preferences for opposite-sex signals? Human pheromones and facial characteristics. Proc. R. Soc. B 271, 635–640. (doi:10.1098/rspb.2003.2649) Cunningham, M. R., Roberts, A. R., Barbee, A. P., Druen, R. B. & Wu, C.-H. 1995 “Their ideas of beauty are, on the whole, the same as ours”: consistency and variability in the cross-cultural perception of female physical attractiveness. J. Pers. Soc. Psychol. 68, 261–279. (doi:10.1037/00223514.68.2.261) Dorn, L. D., Dahl, R. E., Williamson, D. E., Birmaher, B., Axelson, D., Perel, J., Stull, S. D. & Ryan, N. D. 2003a Developmental markers in adolescence: implications for studies of pubertal processes. J. Youth Adolesc. 32, 315–324. (doi:10.1023/A:1024945113763) Dorn, L. D., Susman, E. J. & Ponirakis, A. 2003b Pubertal timing and adolescent adjustment and behavior: conclusions vary by rater. J. Youth Adolesc. 32, 157–167. (doi:10.1023/A:1022590818839) Draper, P. & Harpending, H. 1982 Father absence and reproductive strategy: an evolutionary perspective. J. Anthropol. Res. 38, 255–273. Edgardh, K. 2002 Sexual behaviour and early coitarche in a national sample of 17-year old Swedish boys. Acta Paediatr. 91, 985–991. (doi:10.1080/080352502760272704) Elfenbein, D. S. & Felice, M. E. 2003 Adolescent pregnancy. Pediatr. Clin. North Am. 50, 781. (doi:10.1016/S00313955(03)00069-5) Ellis, B. J. 2004 Timing of pubertal maturation in girls: an integrated life history approach. Psychol. Bull. 130, 920–958. (doi:10.1037/0033-2909.130.6.920) Ellis, B. J. & Garber, J. 2000 Psychosocial antecedents of variation in girls’ pubertal timing: maternal depression, stepfather presence, and marital and family stress. Child Dev. 71, 4585–4501. Ellis, B. J., Bates, J. E., Dodge, K. A., Fergusson, D. M., Horwood, L. J., Pettit, G. S. & Woodward, L. J. 2003 Does father absence place daughters at special risk for early sexual activity and teenage pregnancy? Child Dev. 74, 801–821. (doi:10.1111/1467-8624.00569) Enlow, D. H. 1990 Facial growth. Philadelphia, PA: Harcourt Brace Javanovich. Feingold, A. 1988 Matching for attractiveness in romantic partners and same-sex friends: a meta-analysis and theoretical critique. Psychol. Bull. 104, 226–235. (doi:10. 1037/0033-2909.104.2.226) Feingold, A. 1990 Gender differences in effects of physical attractiveness on romantic attraction: a comparison across five research paradigms. J. Pers. Soc. Psychol. 59, 981–993. (doi:10.1037/0022-3514.59.5.981) Folstad, I. & Karter, A. J. 1992 Parasites, bright males and the immunocompetence handicap. Am. Nat. 139, 603–622. (doi:10.1086/285346) Geary, D. C. 2002 Sexual selection and human life history. Adv. Child Dev. Behav. 30, 41–101. Gowaty, P. A. 1996 Field studies of parental care in birds. Adv. Study Behav. 25, 477–531. Gowen, L. K., Feldman, S. S., Diaz, R. & Somera Yisrael, D. 2004 A comparison of the sexual behaviors and attitudes of adolescent girls with older vs. similar-aged boyfriends. J. Youth Adolesc. 33, 167–176. (doi:10.1023/B:JOYO. 0000013428.41781.a0) Grammer, K. & Thornhill, R. 1994 Human (Homo sapiens) facial attractiveness and sexual selection: the role of symmetry and averagness. J. Comp. Psychol. 108, 233–242. (doi:10.1037/0735-7036.108.3.233) Gross, M. R. 1985 Disruptive selection for alternative life histories in salmon. Nature 313, 47–48. (doi:10.1038/ 313047a0) Phil. Trans. R. Soc. B (2006)

Gross, M. R. 1996 Alternative reproductive strategies and tactics: diversity within the sexes. Trends Ecol. Evol. 11, 92–98. (doi:10.1016/0169-5347(96)81050-0) Halpern, C. T., Udry, J. R. & Suchindran, C. 1998 Monthly measures of salivary testosterone predict sexual activity in adolescent males. Arch. Sex. Behav. 27, 445–465. (doi:10. 1023/A:1018700529128) Harris, J. R. 1995 Where is the child’s environment? A group socialization theory of development. Psychol. Rev. 102, 458–489. (doi:10.1037/0033-295X.102.3.458) Hawley, P. H. 1999 The ontogenesis of social dominance: a strategy based evolutionary perspective. Dev. Rev. 19, 97–132. (doi:10.1006/drev.1998.0470) Hawley, P. H. 2003 Prosocial and coercive configurations of resource control in early adolescence: a case for the welladapted Machiavellian. Merrill-Palmer Q. J. Dev. Psychol. 49, 279–309. Hawley, P. H. & Vaughn, B. E. 2003 Aggression and adaptive functioning: the bright side to bad behavior. Merrill-Palmer Q. J. Dev. Psychol. 49, 239–242. Henson, S. A. & Warner, R. R. 1997 Male and female alternative reproductive behaviors in fishes: a new approach using intersexual dynamics. Annu. Rev. Ecol. Syst. 28, 571–592. (doi:10.1146/annurev.ecolsys.28.1.571) Hoier, S. 2003 Father absence and age at menarche—a test of four evolutionary models. Hum. Nat. Interdisciplinary Biosoc. Perspect. 14, 209–233. Jones, B. C., Leeton, J., McLeod, I. & Wood, C. 1972 Factors influencing the age of menarche in a lower socieconomic group in Melbourne. Med. J. Aust. 21, 533–535. Jones, B. C., Little, A. C., Penton-Voak, I. S., Tiddeman, B. P., Burt, D. M. & Perrett, D. I. 2001 Facial symmetry and judgements of apparent health. Support for a “good genes” explanation of the attractiveness—symmetry relationship. Evol. Hum. Behav. 22, 417–429. (doi:10. 1016/S1090-5138(01)00083-6) Kim, K. & Smith, P. K. 1998 Retrospective survey of parental marital relations and child reproductive development. Int. J. Behav. Dev. 22, 729–751. (doi:10.1080/ 016502598384144) Kim, K., Smith, P. K. & Palermiti, A.-L. 1997 Conflict in childhood and reproductive development. Evol. Hum. Behav. 18, 109–142. (doi:10.1016/S1090-5138(96) 00114-6) Kirk, K. M., Blomberg, S. P., Duffy, D. L., Heath, A. C., Owens, I. P. F. & Martin, N. G. 2001 Natural selection and quantitative genetics of life-history traits in western women: a twin study. Evolution 55, 423–435. (doi:10. 1554/0014-3820(2001)055[0423:NSAQGO]2.0.CO;2) Kracke, B. 1993 Pubertaet und Problemverhalten bei Jungen [Puberty and behavior problems of male adolescents]. Weinheim, Germany: Beltz PVU. Langlois, J. H., Kalakanis, L., Rubenstein, A. J., Larson, A., Hallam, M. & Smoot, M. 2000 Maxims or myths of beauty? A meta-analytic and theoretical review. Psychol. Bull. 126, 390–423. (doi:10.1037/0033-2909.126.3.390) Law Smith, M. J. et al. 2006 Facial appearance is a cue to oestrogen levels in women. Proc. R. Soc. B 273, 135–140. (doi:10.1098/rspb.2005.3296) Little, A. C. & Hancock, P. J. 2002 The role of masculinity and distinctiveness in judgments of human male facial attractiveness. Br. J. Psychol. 93, 451–464. (doi:10.1348/ 000712602761381349) Little, A. C., Burt, D. C., Penton-Voak, I. & Perrett, D. I. 2001 Self-perceived attractiveness influences human female preferences for sexual dimorphism and symmetry in male faces. Proc. R. Soc. B 268, 39–44. (doi:10.1098/ rspb.2000.1327) MacArthur, R. H. 1962 Some generalized theorems of natural selection. Genetics 48, 1893–1897.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Sexual development and facial attraction R. E. Cornwell and others MacArthur, R. H. & Wilson, E. O. 1967 The theory of island biogeography. Princeton, NJ: Princeton University Press. MacDonald, K. 1997 Life history theory and human reproductive behavior—environmental/contextual influences and heritable variation. Hum. Nat. Interdisciplinary Biosoc. Perspec. 8, 327–359. MacDonald, K. 1999 An evolutionary perspective on human fertility. Popul. Environ. 21, 223–246. Mace, R. 2000 Evolutionary ecology of human life history. Anim. Behav. 59, 1–10. (doi:10.1006/anbe.1999.1287) Magnusson, D., Stattin, H. & Allen, V. L. 1985 Biological maturation and social development: a longitudinal study of some adjustment processes from midadolescence to adulthood. J. Youth Adolesc. 14, 267–283. (doi:10.1007/ BF02089234) Maynard Smith, J. 1982 Evolution and the theory of games. Cambridge, UK: Cambridge University Press. Maynard Smith, J. & Price, G. R. 1973 The logic of animal conflict. Nature 246, 15–18. (doi:10.1038/246015a0) Mazur, A. & Booth, A. 1998 Testosterone and dominance in men. Behav. Brain Sci. 21, 353–397. (doi:10.1017/ S0140525X98001228) McNeely, C., Shew, M. L., Beuhrink, T., Sieving, R., Miller, B. C. & Blum, R. W. M. 2002 Mothers’ influence on the timing of first sex among 14- and 15-year olds. J. Adolesc. Health 31, 256–265. (doi:10.1016/S1054-139X(02) 00350-6) Miller, E. M. 1994 Optimal adjustment of mating effort to environmental-conditions—a critique of Chisholms application of life-history theory with comments on race differences in male paternal investment strategies. Mankind Q. 34, 297–316. Moffitt, T. E., Caspi, A., Belsky, J. & Silva, P. A. 1992 Childhood experience and the onset of menarche—a test of a sociobiological model. Child Dev. 63, 47–58. (doi:10. 2307/1130900) Møller, A. P. & Thornhill, R. 1998 Male parental care, differential parental investment by females and sexual selection. Anim. Behav. 55, 1507–1515. (doi:10.1006/ anbe.1998.0731) Nottlemann, E. D., Susman, E. J., Dorn, L. D., InoffGermain, G., Loriaux, D. L., Cutler Jr, G. B. & Chrousos, G. P. 1987 Developmental processes in early adolescence. J. Adolesc. Health Care 8, 246–260. (doi:10.1016/01970070(87)90428-1) Olweus, D., Mattsson, D., Schalling, D. & Lo¨w, H. 1988 Circulating teststerone levels and aggression in adolescent males: a causal analysis. Psychosom. Med. 50, 261–272. Overpeck, M. D., Brenner, R. A., Trumble, A. C., Trifiletti, L. B. & Berendes, H. W. 1998 Risk factors for infant homicide in the United States. New Engl. J. Med. 339, 1211–1216. (doi:10.1056/NEJM199810223391706) Penton-Voak, I. S. & Chen, J. Y. 2004 High salivary testosterone is linked to masculine male facial appearance in humans. Evol. Hum. Behav. 25, 229–241. (doi:10.1016/ j.evolhumbehav.2004.04.003) Penton-Voak, I. S. & Perrett, D. I. 2001 Male facial attractiveness: perceived personality and shifting female preferences for male traits across the menstrual cycle. Adv. Study Behav. 30, 219–259. (doi:10.1016/S0065-3454(01) 80008-5) Penton-Voak, I. S., Perrett, D. I., Castles, D. L., Burt, D. M., Kobayashi, T., Murray, L. K. & Minamisawa, R. 1999 Menstrual cycle alters face preferences. Nature 399, 714–742. (doi:10.1038/21557) Penton-Voak, I. S., Little, A. C., Jones, B. C., Burt, D. M., Tiddeman, B. P. & Perrett, D. I. 2003 Female condition influences preferences for sexual dimorphism in faces of male Homo sapiens. Comp. Psychol. 117, 264–271. (doi:10. 1037/0735-7036.117.3.264) Phil. Trans. R. Soc. B (2006)

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Perrett, D. I., Lee, K. J., Penton-Voak, I. S., Rowland, D. R., Yoshikawa, S., Burt, D. M., Henzi, S. P., Castles, D. L. & Akamatsu, S. 1998 Effects of sexual dimorphism on facial attractiveness. Nature 394, 884–887. (doi:10.1038/29772) Perrett, D. I., Burt, D. M., Penton-Voak, I. S., Lee, K. J., Rowland, D. A. & Edwards, R. 1999 Symmetry and human facial attractiveness. Evol. Hum. Behav. 20, 295–307. (doi:10.1016/S1090-5138(99)00014-8) Peterson, J. C. & Crockett, L. J. 1985 Pubertal timing and grade effects on adjustment. J. Youth Adolesc. 14, 191–206. (doi:10.1007/BF02090318) Pickles, A., Pickering, K., Simonoff, E., Silberg, J., Meyer, J. & Maes, H. 1998 Genetic ‘clocks’ and ‘soft’ events: a twin model for pubertal development and other recalled sequences of developmental milestones, transitions, or ages at onset. Behav. Genet. 28, 243–253. (doi:10.1023/ A:1021615228995) Prokope`a´kova´, A. 1998 Drug experimenting and pubertal maturation in girls. Studia Psychol. 40, 287–290. Quinlan, R. J. 2003 Father absence, parental care, and female reproductive development. Evol. Hum. Behav. 24, 376–390. (doi:10.1016/S1090-5138(03)00039-4) Romans, S. E., Martin, J. M., Gendall, K. & Herbison, G. P. 2003 Age of menarche: the role of some psychosocial factors. Psychol. Med. 33, 933–939. (doi:10.1017/ S0033291703007530) Schaal, B., Tremblay, R. E., Soussignan, R. & Susman, E. J. 1996 Male testosterone linked to high social dominance but low physical aggression in early adolescence. J. Acad. Child Adolesc. Psychiatry 35, 1322–1331. (doi:10.1097/ 00004583-199610000-00018) Scheib, J. E. 2001 Context-specific mate choice criteria: women’s trade-offs in the contexts of long-term and extrapair mateships. Pers. Relat. 8, 371–389. (doi:10.1111/ j.1475-6811.2001.tb00046.x) Scheib, J. E., Gangestad, S. W. & Thornhill, R. 1999 Facial attractiveness, symmetry and cues of good genes. Proc. R. Soc. B 266, 1913–1917. (doi:10.1098/rspb.1999.0866) Seli, E. & Arici, A. 2002 Sex steroids and the immune system. Immunol. Allergy Clin. North Am. 22, 407. (doi:10.1016/ S0889-8561(02)00017-6) Sheldon, B. C. 2000 Differential allocation: tests, mechanisms and implications. Trends Ecol. Evol. 15, 397–402. (doi:10. 1016/S0169-5347(00)01953-4) Silbereisen, R. K. & Kracke, B. 1997 Self-reported maturational timing and adaptation in adolescence. In Health risks and developmental transitions during adolescence (ed. J. Schulenberg, J. L. Maggs & K. Hurrelmann), pp. 85–109. Cambridge, UK: Cambridge University Press. Spencer, J. M., Zimet, G. D., Aalsma, M. C. & Orr, D. P. 2002 Self-esteem as a predictor of initiation of coitus in early adolescents. Pediatrics 109, 581–584. (doi:10.1542/ peds.109.4.581) Stattin, H. & Magnusson, D. 1990 Pubertal maturation in female development. Paths through life, vol. 2. Hillsdale, NJ; Oxford, UK: Lawrence Erlbaum Associates. Surbey, M. K. 1990 Family composition, stress, and the timing of human menarche. In Sociendocrinology of primate reproduction, vol. XIII (ed. F. B. Bercovitch), pp. 11–32 Monographs in primatology. New York, NY: Wiley. Susman, E. J., Inoff-Germain, G., Nottlemann, E. D., Loriaux, D. L., Cutler Jr, G. B. & Chousos, G. P. 1987 Hormones, emotional dispositions, and aggressive attributes in young adolescents. Child Dev. 58, 1114–1134. (doi:10.2307/1130551) Swaddle, J. P. & Reierson, G. W. 2002 Testosterone increases perceived dominance but not attractiveness in human males. Proc. R. Soc. B 269, 2285–2289. (doi:10.1098/rspb. 2002.2165)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

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Thornhill, R. & Gangestad, S. W. 1994 Human fluctuating asymmetry and sexual behavior. Psychol. Sci. 5, 297–302. (doi:10.1111/j.1467-9280.1994.tb00629.x) Tiddeman, B. P., Burt, D. M. & Perrett, D. I. 2001 Prototyping and transforming facial texture for perception research. IEEE Comput. Graph. Appl. 21, 42–50. (doi:10. 1109/38.946630) Tremblay, R. E., Schaal, B., Boulerice, B., Arseneault, L., Soussignan, R. G., Paquette, D. & Laurent, D. 1998 Testosterone, physical aggression, dominance, and physical development in early adolescence. Int. J. Behav. Dev. 22, 753–777. (doi:10.1080/016502598 384153) Trivers, R. 1972 Parental investment and sexual selection. In Sexual selection and the descent of man: 1871–1971 (ed. B. Campbell), pp. 136–179. Chicago, IL: Aldine.

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Weichold, K. & Silbereisen, R. K. 2001 Pubertal timing and substance use: the role of peers and leisure context. In Seventh European Congress of Psychology, London. Weichold, K., Sibereisen, R. K. & Schmitt-Rodermund, E. 2003 Short-term and long-term consequences of early versus late maturation in adolescents. In Gender differences at puberty (International studies on child & adolescent health) (ed. C. Hayward). Cambridge, UK: Cambridge University Press. Weisfeld, G. E. & Woodward, L. 2004 Current evolutionary perspectives on adolescent romantic relations and sexuality. J. Am. Acad. Child Adolesc. Psychiatry 41, 11–19. (doi:10.1097/00004583-200401000-00010) Wilson, M. & Daly, M. 1997 Life expectancy, economic inequality, homicide, and reproductive timing in Chicago neighbourhoods. Br. Med. J. 314, 1271–1274.

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Phil. Trans. R. Soc. B (2006) 361, 2155–2172 doi:10.1098/rstb.2006.1937 Published online 6 November 2006

Behavioural and neurophysiological evidence for face identity and face emotion processing in animals Andrew J. Tate, Hanno Fischer, Andrea E. Leigh and Keith M. Kendrick* Cognitive and Behavioural Neuroscience, Babraham Institute, Babraham, Cambridge CB2 4AT, UK Visual cues from faces provide important social information relating to individual identity, sexual attraction and emotional state. Behavioural and neurophysiological studies on both monkeys and sheep have shown that specialized skills and neural systems for processing these complex cues to guide behaviour have evolved in a number of mammals and are not present exclusively in humans. Indeed, there are remarkable similarities in the ways that faces are processed by the brain in humans and other mammalian species. While human studies with brain imaging and gross neurophysiological recording approaches have revealed global aspects of the face-processing network, they cannot investigate how information is encoded by specific neural networks. Single neuron electrophysiological recording approaches in both monkeys and sheep have, however, provided some insights into the neural encoding principles involved and, particularly, the presence of a remarkable degree of high-level encoding even at the level of a specific face. Recent developments that allow simultaneous recordings to be made from many hundreds of individual neurons are also beginning to reveal evidence for global aspects of a population-based code. This review will summarize what we have learned so far from these animalbased studies about the way the mammalian brain processes the faces and the emotions they can communicate, as well as associated capacities such as how identity and emotion cues are dissociated and how face imagery might be generated. It will also try to highlight what questions and advances in knowledge still challenge us in order to provide a complete understanding of just how brain networks perform this complex and important social recognition task. Keywords: face recognition; face emotion; face imagery; neural encoding; temporal cortex

1. INTRODUCTION The use of visual cues for recognition of individuals and their emotional state is of key importance for humans and has clear advantages over olfactory cues which may need to be highly proximal and auditory ones that are totally dependent upon whether an individual vocalizes or not. Therefore, it is not surprising that social recognition using visual cues is widely used by diurnal social mammals. However, there has been some debate as to the extent that the use of specialized visual cues from the face, and consequent development of associated specializations within the brain, is a unique feature of primate social evolution. This is also particularly suggested for face emotion with the extensive evolution of facial expressions in primates, notably in the great apes and humans. However, studies performed on ungulate species such as sheep and goats, particularly those in our own group, yield compelling evidence for the use of facial cues in both identification and recognition of emotional state and associated brain specializations in subprimate mammals. This has offered further opportunities to investigate general principles of how the brain may be organized to carry out the highly complex task * Author for correspondence ([email protected]). One contribution of 14 to a theme issue ‘The neurobiology of social recognition, attraction and bonding’.

of distinguishing between large subsets of highly homogeneous faces. It also provides further opportunities to develop a better understanding of how identity and emotion cues are integrated by these specialized systems as well as offering potential insights into the extent to which other species may be able to form mental images of the faces of individuals who are missing from the social environment. In this review, we focus on what we have learned about the abilities of different mammalian species to use visual cues from the face to identify individuals. We also consider the extent to which faces provide an important source of potential information for social attraction and interpretation of emotional state. It will then consider what has been learned from neurophysiological experiments on non-human species about the way the brain encodes faces during perception and imagery. Finally, we suggest where future research may advance our understanding further of how brain networks process these important social signals.

2. BEHAVIOURAL EVIDENCE Compared with the large amount of behavioural work carried out on human face recognition, there is considerably less concerning other animal species. Of course, faces are just exemplars of complex visual patterns, so it should be possible to demonstrate facerecognition abilities in many different species. However,

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it is important in this context to show firstly whether individuals of a particular species normally use the facial cues to identify others. Secondly, if we are to compare other species with humans, do the same advantages and limitations exist in a particular species for recognizing faces that have been demonstrated in humans? Such evidence would indicate the presence in the brain of similar mechanisms specific to processing faces and distinct from those for processing other visual objects. 3. FACE IDENTITY RECOGNITION AND MEMORY FOR FACES (a) Face recognition in non-human primates The human face processing system has been found to be configurally sensitive and exhibits a profound inversion effect (Yin 1969) and shows evidence for hemispheric asymmetry (see review by Kanwisher & Yovel 2006). Given that most non-human primates have excellent binocular vision and are social animals living in large cohorts, it may be expected that there will exist a system for the visual recognition of conspecifics. Indeed, many studies (Rosenfeld & Van Hoesen 1979; Bruce 1982; Phelps & Roberts 1994; Pascalis et al. 1998; Weiss et al. 2001) have found evidence for face-recognition abilities in different non-human primate species. Researchers have also examined whether nonhuman primates make use of features corresponding to those used by humans for individual recognition. Dittrich (1990) found that the configuration of facial features was important to macaques and concluded that the facial outline was important to the recognition, as well as both the eyes and the mouth, suggesting an emotional component to their recognition system. Study of schematic face preferences in infant macaques ascertained that before one month of age, the configuration of the features of the face was more important in recognition than the features themselves (Kuwahata et al. 2004). Investigations into an inversion effect in non-human primates have shown mixed and contrasting results. Perrett et al. (1988) showed that monkeys were significantly slower to respond to faces presented upside-down compared with upright faces, although others (Rosenfeld & Van Hoesen 1979; Bruce 1982) found that macaques were able to distinguish faces regardless of their orientation. It is likely that nonhuman primates show an inversion effect to some degree, but this may simply degrade rather than abolish recognition ability (Perrett et al. 1995). In humans, some adjustments to face stimuli, such as changes in colour and lighting, have no effect on the recognition abilities. A similar effect is found in non-human primates with alterations in colour, lighting or size having no effect on the animal’s ability to recognize a face (Dittrich 1990; Hietanen et al. 1992). (b) Face recognition in sheep Sheep, like other ungulates such as goats, cattle and horses, are a social species that live in large groups and possess a highly developed visual sense. The importance of visual cues from the face for individual recognition in natural social contexts was first suggested by Shillito-Walser (1978) who noted that mother ewes had difficulty in recognizing their lambs at Phil. Trans. R. Soc. B (2006)

a distance when the appearance of the head region was altered using coloured dyes. Behavioural studies in our laboratory using choice mazes and operant discrimination tasks have revealed quite remarkable face-recognition abilities in sheep, similar to those found in humans. The first of these simply showed preferences for particular types of faces independent of learning and which therefore indicated that the animals were using face-recognition cues as part of their normal lives. Here, the reward for choosing a particular face was gaining access to the individual to whom the face belonged. These experiments showed that sheep could discriminate between sheep and human faces, between different breeds of sheep and between sexes in the same breed (Kendrick et al. 1995). The eyes appeared to play the most important single feature in recognition similar to humans. Interestingly, while sheep had greater difficulty in discriminating between the same individuals using vocal cues, mismatching face and vocal cues for the same individuals impaired performance, suggesting some degree of integration between face and vocal processing. By employing test paradigms which use face pairs of either socially familiar or unfamiliar faces and by providing food rewards for correct choices, we have found that sheep have very good acuity for discriminating between faces. They can still recognize face pictures reduced to one-third of normal size, and using facemorphing programmes, we have shown that they can discriminate between pairs of faces which differ only 10% from one another (figure 1). To date, we have not investigated the developmental time courses for face recognition in detail. However, initial studies attempted to determine how long it took for lambs to learn to recognize their mother’s face; it was clear that this took at least one to two months (Kendrick 1998). Therefore, it seems likely that this reflects a slow time course, as in humans, and a lengthy phase of developing the necessary expertise through learning. But do sheep recognize faces in the same expert way as humans? Sheep also show classical inversion effects with faces but not objects and can use configural cues from the internal features of faces in the same way as we do (Kendrick et al. 1996; Peirce et al. 2000). They learn to discriminate between the faces of socially familiar individuals to obtain a reward more quickly than with unfamiliar ones (Kendrick et al. 1996) and can remember faces of conspecifics for a period of up to 2 years (Kendrick et al. 2001c). They can also recognize different human faces and show inversion effects, although they take longer to learn to discriminate between them (Kendrick et al. 1996). Under freeviewing conditions, Peirce et al. (2000) found evidence for a left visual-field bias (right-hemisphere advantage) for familiar, but not unfamiliar, sheep faces using a series of experiments using chimeric face composites, an effect also found in human face processing. Interestingly, sheep did not show this visual-field bias for human faces (Peirce et al. 2001) suggesting that there is an expertise and familiarity requirement for developing a right brain hemisphere advantage. Therefore, sheep seem to have a specialized ability for identifying faces comparable with non-human

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Face identity and face emotion processing primates and, as such, provide an important additional animal model for studying the neural basis of face processing.

4. FACE ATTRACTION Both monkeys and sheep exhibit preferences for faces of familiar conspecifics, but this does not necessarily address the question as to whether they find faces attractive per se or if some faces are more attractive than others. However, we have shown that female sheep exhibit specific preferences for the faces of individual males independent of social familiarity with them (Kendrick et al. 1995). In addition, simple exposure to face pictures of sheep of the same breed (but unfamiliar individuals) reduces behavioural, autonomic and endocrine indices of stress caused by social isolation (da Costa et al. 2004). Cross-fostering studies between sheep and goats have also shown that general preferences for sheep and goat faces are determined by the species providing maternal care even when individuals are exposed to extensive social interactions with both the species during development (Kendrick et al. 1998, 2001b). There is a small amount of evidence suggesting that this may also be the case in monkeys (Fujita 1993). 5. FACE-BASED EMOTION RECOGNITION (FaBER) The expression of emotions in action and physiology is mainly determined by brain structures and neuronal networks, such as the limbic system (overview, Morgane et al. 2005). These networks have been conserved and are, at least to a certain extent, shared between the higher vertebrate phyla. In any social animal species, emotion displays are sources of information, have evocative functions and provide incentives for desired social behaviour. The expression of emotional signals therefore represents both an emotional response and a social communication. Initially, the ability to extract emotional information from facial expression was attributed exclusively to species with sophisticated orofacial motor systems (primates and humans, Chevalier-Skolnikoff 1973; Sherwood et al. 2005). However, our own research on sheep which, as we have described above, have excellent acuity in using visual cues for recognizing the identity of individuals from facial cues, also reveals a capacity for responding to emotion cues in faces. Therefore, it seems likely that facebased emotion recognition (FaBER) might be quite widespread in mammals with good visual acuity. Obviously, carrying out formal behavioural assessments of face-emotion recognition in animals can be quite difficult in terms of determining the optimal stimulus face pictures for conveying a particular emotion expression. This is important not only for the face appearance, but also in terms of the role of dynamic aspects of the making of expression. Another very important consideration is to control face stimuli such that neither identity cues nor subtle differences in the images used can be used to make a discrimination independent of the emotion cues. Phil. Trans. R. Soc. B (2006)

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(a) Face emotion recognition in non-human primates Species with highly developed orofacial motor systems, such as apes and monkeys (e.g. Huber 1931) possess a large repertoire of emotional facial displays. Like humans, facial expressions in non-human primates are not limited to ‘discrete’ displays of a given emotion, allowing the expressed emotion to be ‘graded’ (Marler 1976). Thus, facial expression of emotion is partly a dynamic process involving eye, eyelid and mouth movements as well as changes in the shape of a facial feature or the appearance of additional features (e.g. displaying teeth; Van Hooff 1962). This means that FaBER requires the perception and processing of both static and transient facial features, including different face views (e.g. full versus profile) and head positions. This explains why, in general, the performance of animals during any kind of FaBER tests depends strongly on the design of the behavioural tests, e.g. whether static face images or dynamic video presentations are presented (e.g. Bauer & Phillip 1983; Parr 2003). Apes and monkeys looking at face pictures show a predominant interest in the eyes and the region surrounding eyes and mouth, i.e. the primary components of facial expressions (Keating & Keating 1982; Nahm 1997). Behavioural studies in apes suggest that, for certain emotions, FaBER depends on the number of specific facial features that differs between two expression types, such as eye shape, mouth position or the presence of teeth (Parr et al. 1998). However, other expressions are reliably recognized despite the absence of such distinctive visual features (Parr 2003). Like humans, but unlike other monkey species (Kanazawa 1996), apes seem to process conspecific face expressions categorically (Parr 2003). Experiments using face chimeras have also shown that they exhibit a left visual-field advantage for face emotion recognition (Fernandez-Carriba et al. 2002a,b). (b) Face emotion recognition in sheep In combination with general body language, sheep, like other ungulates, use facial features to display emotional information. These displays are limited to negatively valenced emotions, such as stress or anxiety. However, it seems reasonable to assume that the absence of a facial display of negative emotion plays an equally important role during social communication. Stress-related facial cues include enlarged protruding eyes, pupils showing the whites, flared nostrils and flattened ears. Are sheep able to recognize (and use) face emotion cues to interact socially? An initial approach to address this question used face pictures of the same sheep when it was calm or stressed/anxious (following a period of social isolation and where heart rate, as an autonomic indicator of stress, was significantly increased; da Costa et al. 2004). We also used human face pictures with the same individual either smiling or showing an expression of anger. When the sheep (nZ8) were given a free choice of the two pictures (they received a food reward whichever one they chose), they showed more than 80% preference for the calm sheep face or the smiling human one over the first 40 trials. Similar results were

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obtained for face sets using familiar or unfamiliar individual sheep or humans. We have also trained sheep to discriminate between pairs of frontal view face pictures of familiar conspecifics, with each pair consisting of a calm versus a stressed facial display (figure 2a) and where choice of the calm face was rewarded but not the stressed one. When presented subsequently with pairs of unfamiliar conspecific faces, sheep significantly preferred the picture displaying a neutral facial expression to the picture displaying signs of stress or anxiety (figure 2b). When the calm face in pairs of familiar conspecifics was replaced by one of the unfamiliar conspecific, the sheep showed a preference for this even though the stressed face was from a familiar animal (figure 2b). As sheep normally prefer the faces of familiar individuals to those of unfamiliar ones, this shows that they find the sight of a stressed face of a familiar individual more aversive than the calm face of an unfamiliar one. From a solely behavioural point of view, this suggests a greater bias towards face emotion cues than for those of identity. Other experiments have started to reveal the key facial features used for face emotion recognition in sheep. These have shown that ear position and appearance of the eyes are of particular importance. With the latter, the most prominent change in a stressed and anxious state is an increase in the amount of sclera (whites of eyes) visible and pupil dilation. The Phil. Trans. R. Soc. B (2006)

importance of the amount of white visible in the eyes for fear/stress detection has also been reported in cattle (Sandem et al. 2004). Recent experiments using a two choice maze and chimeric face images have also revealed that sheep, like humans and chimpanzees, use left visual-field cues more than right visual-field ones for detecting negative emotion cues on faces, suggesting a right brain hemisphere bias in detecting negative emotions (Elliker 2006; Kendrick 2006). However, at this stage, we do not know whether the cues from the right visual field are more important for discriminating accurately between face emotions as has been shown in recent human experiments (Indersmitten & Gurr 2003). 6. FACE IMAGERY Although the memory for faces is robust in both monkeys and sheep, this does not mean in itself that they can voluntarily ‘think’ about absent individuals. A key and difficult question to address in animal species other than humans is the capacity to form and use mental imagery. This can allow individuals potentially to ‘think’ of individuals or other objects in their absence and is a key element of consciousness. However, while it is easy with humans to ask individuals to imagine faces, this is not something which can be done with other species. Thus, it is necessary to develop tasks where solution would appear

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Face identity and face emotion processing

7. NEURAL ENCODING OF FACE IDENTITY, FACE EMOTION AND FACE IMAGERY Research on humans based primarily on functional imaging and evoked potential experiments, and neuropsychological observations on patients with brain damage has provided a reasonably detailed picture of the neural substrates involved in face identity and face emotion recognition as well as in face imagery (see Kanwisher & Yovel 2006; Skuse 2006). However, electrophysiological work with both monkeys and sheep has been able to investigate in more detail how faces are processed by the neural networks within the different substrates. Most of this work has relied on single-unit recordings which are somewhat limited in terms of their ability to sample reliably large-scale neural networks and where it is difficult to assess the extent to which population/global encoding principles may be operating. However, recent developments have allowed simultaneous recordings to be made from more than 200 neurons simultaneously and some of this work we have carried out in sheep is indeed suggesting Phil. Trans. R. Soc. B (2006)

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to depend upon the ability of an individual to form and hold some kind of mental image. In general, such tasks involve objects which disappear for varying lengths of time and whose identity is required to be remembered in order to complete subsequent choice decisions. The classic one of these is delayed matching or nonmatching to sample where a learning stimulus is first presented and then disappears followed by a variable delay and then the presentation of two test stimuli, one of which is the same as the original leaning stimulus. The correct decision is then to identify which stimulus is the same (matching) or different (non-matching) from the original. There are a number of variations on the paradigm which can make it simpler since many animal species, including monkeys, find it quite difficult to learn. However, monkeys, like humans, are generally capable of performing such tasks (Sereno & Amador 2006). Sheep and goats can also perform matching to sample tasks with simple visual symbols (Soltysik & Baldwin 1972) and although they may have some ability to do this with faces, we have had difficulty in getting them to perform consistently (Kendrick et al. 2001c). They are nevertheless capable of dealing with delays in remembering the identity and location of disappearing faces at delays of up to 10 s (Man et al. 2003). Another potential example where mental imagery might be employed is in the context of mental rotation. Many spatial memory tasks require a subject to imagine how an object would appear from another viewpoint, and to solve such problems, it is necessary to rotate the test object in some way mentally (e.g. Gaylord & Marsh 1975). The same can be true for faces where a subject is presented only with a frontal or profile view of a face and then required to match another view to it. In sheep, we have found that they can do this with either human or sheep faces without relearning the task (Kendrick et al. 2001c). However, it is always difficult to overcome the potential criticism that there is some element of stimulus generalization being used, even though frontal and profile views of faces appear very different.

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Figure 2. (a) Pair of sheep faces presented during operant discrimination tasks. An example of (i) neutral/calm sheep face and the same individual displaying (ii) stress/anxiety is shown. During face identity recognition tasks, pairs of neutral/calm faces of two different conspecifics were presented. (b) Performance during face identity and face emotion recognition tasks. Sheep are able to recognize individual conspecifics by their faces ((i) N, neutral/calm face of a familiar conspecific; N, neutral/calm face of an unfamiliar individual). Furthermore, sheep are able to discriminate between calm and stressed/anxious facial displays of familiar conspecific (N versus S). When presented with the same choice, however, using pictures of unfamiliar conspecifics (N versus S), sheep prefer the neutral display. When eventually presented with a choice between unfamiliar neutral faces and familiar stressed/anxious faces ((ii) N versus S), sheep prefer the unfamiliar neutral faces.

the presence of such population encoding within faceprocessing networks.

8. FACE IDENTITY RECOGNITION (a) Non-human primates Studies in non-human face recognition have concentrated primarily on single-unit electrophysiological recordings of the macaque visual system, in particular, the temporal cortex. The temporal cortex receives afferents from the striate cortex via the prestriate area, and these visual inputs, plus the fact that removal of the area led to specific visual defects, led early researchers to surmise that it must have some additional part to play in visual processing beyond that of the simple processing in the visual cortex (Gross et al. 1972). Initial work on anaesthetized macaques established that the majority of cells in the temporal cortex were sensitive to many separate parameters (size, shape, orientation and direction of movement). However, some cells had very unique trigger features, such as hands and faces (Gross et al. 1972). Further studies involving conscious behaving macaques found specific cells in one particular area of the temporal lobe, the

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inferior temporal cortex (IT), had complex trigger features and seemed to be modulated by the situation and how much the attention the animal was paying (Gross et al. 1979). This led researchers to suggest that the area had a function in the recognition of complex visual stimuli, such as objects, and was likely influenced by top-down feedback from higher cognitive areas. Additional work on the IT studied the ability of neurons in the area to distinguish and retain behaviourally relevant visual features, suggesting that it was susceptible to the significance of the stimuli (Fuster & Jervey 1981). Many cells in the IT were found to respond non-specifically to all visual stimuli, but a small population was found that responded preferentially to faces. The IT cells were also established to be sensitive not only to the face, but also to the particular configuration of features of the face, with neuronal responses dependent on configuration of facial features but independent of size and position (Desimone et al. 1984; Yamane et al. 1988). Elaboration on configural coding found that cells in the IT were more sensitive to intact faces, with the total number of cells activated by an intact face greater than that of the separate elements of the face (Rolls et al. 1994). More recently, IT neurons have been found to be fine-tuned for specific facial features (Sigala 2004). In another specific area of the temporal cortex, the superior temporal sulcus (STS), 30% of cells recorded in this area of the cortex exhibited specific trigger features, with some exhibiting selectivity purely for face stimuli (Bruce et al. 1981). Recordings from cells in the STS found that they were sensitive to different views of the head and most cells that responded were viewspecific, i.e. only responded to one particular view of the head. They also found more cells that responded to frontal full face and side-profile views than intermediate views (Perrett et al. 1991). It is evident from the early studies that the IT and the STS are involved in different components of the face-recognition process. Hasselmo and co-workers were the first to study the dissociate identity from emotion on face processing, finding that although neurons in both the IT and the STS responded to faces, cells in the IT responded more strongly to the identity of the face, while the STS cells responded more to expression (Hasselmo et al. 1989). It has been suggested that the IT and STS have different roles to play in face processing, with the IT related to face identity and the STS related to other perceptual information (facial views, eye gaze and expression) and that the two areas work together to process the face (Eifuku et al. 2004). In hierarchical societies, such as those seen in monkeys, a key component of facial expressions is the eye-gaze direction, which is involved in the expression of dominant or submissive social signalling (e.g. maintained stare versus eyes averted; Van Hooff 1962). In this connection, eye-gaze direction and head position are often compatible (e.g. profile view of the head also means that the eyes are averted from the viewer). The upper bank of the STS contains a population of face-specific neurons that are sensitive to head position, with different views of the head activating different subpopulations of face-specific neurons (Perrett et al. 1984, 1985). In addition, and Phil. Trans. R. Soc. B (2006)

depending on the view of the head, these neurons respond specifically to different eye-gaze direction: populations functionally tuned to full view of the face show high sensitivity to eye contact, whereas populations tuned to profiles respond to averted eyes (Perrett et al. 1985). However, a certain proportion of neurons responding to gaze direction lacks any apparent sensitivity to head view, suggesting that gaze direction and head position are, at least partly, processed independently of each other. Furthermore, most of the neurons are sensitive to the dynamics of facial expressions, i.e. the movement of facial features, such as mouth opening, eyebrow raising, etc. Sensitivity to the expression of static faces is frequently related to mouth configuration, such as open mouth threads and yawning (Perrett et al. 1984, 1985). The most intriguing question relating to the processing of faces is how a population of neurons encodes a face. Two separate hypotheses have been put forward: firstly that the face could be encoded by distributed patterns of activity in a population of cells, or secondly that a single cell is activated by a specific face—the ‘grandmother cell’ hypothesis. Young and co-workers were the first to look at the how the population of face-sensitive neurons that had been found worked together to encode a face. They reported a high level of redundancy in the cells, suggesting that only a few cells would be sufficient to encode a face. These sparse population responses were statistically significant in relation to the dimensions of the face (Young & Yamane 1992). This hypothesis falls between the two extremes and suggests that a few individual cells which are highly selective to behaviourally relevant stimuli encode object properties. Sugase & Yamane (1999) found evidence that single neurons could convey information about specific faces in terms of response latency, without the need of a population code. They found that global (category) information was communicated in the earliest part of the response (approx. 117 ms after presentation) followed by the fine information (identity and expression) in the later stage on the response profile (approx. 165 ms after presentation; Sugase et al. 1999). The prevailing view is that of Young’s sparse population code, with a small network of cells communicating via a temporal code to produce recognition of a face. Examinations of inhibitory neurons in the macaque IT suggest that they may exert a stimulus-specific inhibition on adjacent neurons, which contributes to the shaping of this stimulus selectivity and code in the IT (Eifuku et al. 2004). Work on human face processing has suggested a hemispheric asymmetry in the processing, with the right hemisphere more responsive to faces than the left. However, work on macaques has found no such lateralization, or in fact the opposite, with cells more responsive in the left STS (Perrett et al. 1988). How higher cognitive areas, such as those involved in memory and behaviour, influence face processing is also an area of present study. Early work found that the IT is modulated by attentional variables (Fuster 1990) and neurons in the prefrontal cortex selectively process information related to identity in faces and that the neurons responding to faces were localized to a very

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Face identity and face emotion processing restricted area, suggesting a specialized system for aiding face processing in higher cognitive areas (O’Scalaidhe et al. 1997). Suggestion has been made that the IT is involved in the analysis of currently viewed shapes, with the prefrontal cortex (PFC) involved in decisions involving category, memory and behavioural meaning (Freedman et al. 2003). The hippocampus may also play a role and extracts the behaviourally relevant stimuli for encoding into memory and the unique combinations of features (Hampson et al. 2004). Taken together, mnemonic activity in the IT may be supported by top-down influences of the PFC, middle temporal cortex structures and the hippocampus (Ranganath & D’Esposito 2005). The visual field has also been found to be biased towards certain stimuli. Objects in the visual field compete for representation and the system is biased in favour of behaviourally relevant stimuli, decided by top-down influences (Chelazzi et al. 1998). How the face-processing system develops is another interesting question in the field and may illuminate how it is organized. Both humans and monkey infants are capable of fixating a face from birth; therefore, it has been suggested that there must be at least a partially innate ability to recognize faces, and studies of infant monkeys have been carried out to look at how the face system of non-human animals might develop. Study of schematic face preferences in infant macaques ascertained that before one month of age, the configuration of the features of the face was more important in recognition than the features themselves (Kuwahata et al. 2004), and although neurons in the infant monkeys have lower responses than those of adults to faces, these responses are similar to adult monkey neurons (Rodman et al. 1993). Similarly, training has an effect on the activity of neurons responding to faces, with visual expertise being acquired through development and the proportion of cells responding to faces becoming greater in trained monkeys (Kobatake et al. 1998; Crair 1999). This suggests that although neuronal activity is not needed for the development of the gross morphology of the cortex, it is essential for the final connections of neurons. Thus, early exposure to faces is necessary for a completely developed face-processing system (Crair 1999). A small amount of work has been performed on the ability of other primates apart from macaques to recognize faces. Cotton-top tamarins (a species of New World monkey) seem to have the ability to recognize faces although their face-processing system seems to be simpler than that of macaques. They seem to use only the external features to recognize faces and do not show an inversion effect, suggesting a lack of configural encoding (Weiss et al. 2001). Research on the ability of animals to recognize their own faces in a self-recognition test has been inconclusive. Chimpanzees marked with a red spot were able to use a mirror to assess and touch the spot on themselves (Gallup 1977). This capability has also been shown in other animals that are seen to have superior cognitive abilities, such as other higher primates (Keenan et al. 2001), dolphins (Marten & Psarakos 1994, 1995; Reiss & Marino 2001), whales and sea lions (Delfour & Marten 2001). In Phil. Trans. R. Soc. B (2006)

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chimpanzees, one study showed approximately 50% of animals tested displayed some ability to recognize themselves (de Veer et al. 2003), but also suggested that this ability may decline with age. In macaques, electrophysiological studies have demonstrated a possible right hemisphere advantage for self-recognition (Keenan et al. 2001). This ability is lacking in lower primates and other animals. The methodology of some of these studies has been criticized and this research leads into a more vague field of whether an animal has a sense of itself and can discriminate between ‘own’ and ‘other’, and the ethical implications surrounding such findings (Griffin 2001; Bekoff 2002). (b) Sheep The existence of similar neuronal populations in the temporal cortex of a non-primate species, the sheep, responding preferentially to faces was first reported by Kendrick & Baldwin (1987). These initial single-unit studies deliberately focused on trying to ascertain whether faces of specific behavioural and emotional significance were encoded differentially. They did indeed reveal that separate populations of cells tuned to faces with horns were sensitive to horn size (an important visual feature for determining relative social dominance and also gender) and faces of individuals of the same breed, and in particular, socially familiar individuals (sheep prefer to stay with members of their own breed and form consortships with specific individuals) and faces of potentially threatening species (humans and dogs). As with cells in primate temporal cortex, response latencies were relatively short (ca 100–150 ms) and indicated that the networks were organized for rapid identification of different classes of individual, or facial attributes such as horn size, which evoked discrete behavioural or emotional responses. The response latencies are proportional to the level of identity specificity. Cells responding to simple facial features, such as horns, or generically to faces, have shorter response latencies than those responding only to categories of face or even to one or two specific individuals (Kendrick 1991; Peirce & Kendrick 2002). This suggests a degree of hierarchical encoding within the network (see Kendrick 1994). Studies revealed that face-sensitive cells often responded poorly to inverted views of faces (Kendrick & Baldwin 1987; Kendrick 1991). Detailed analysis of response profiles to different face views has also confirmed the presence of separate face-sensitive populations which are either view-dependent or viewindependent. The majority of view-dependent cells are tuned to a frontal view of the face, although some are also tuned to a profile view. The view-independent cells are in the greatest proportion and particularly in the frontal cortex where this reaches 69% (see figure 4a). The view-independent cells have significantly longer response latencies than view-dependent ones (figure 4b) and in terms of their response magnitude are relatively insensitive to manipulations of different facial features or inversion or presentation of hemifaces (figure 3). By contrast, the view-dependent cells tend to show a reduced magnitude of response not only to inversion and view, but also to whether the eyes are visible, or the external or internal face features are

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Figure 3. (a) Picture set used to investigate response specificities of cells responding to a sheep face. (b) Histograms show overall meanGs.e.m. firing rate changes (per cent change from period with fixation spot displayed immediately before face stimulus is displayed) for 14 view-dependent (frontal view only) and 21 view-independent (equivalent responses to front and profile views) neurons recorded from the right temporal cotex of four sheep. (c) Same as (b) but for eight view-dependent and 11 viewindependent neurons from the left temporal cortex. Phil. Trans. R. Soc. B (2006)

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removed, or which half of the face is viewed (figure 3). It is these latter types of manipulations which impair behavioural discrimination of faces (Kendrick et al. 1995, 1996; Peirce et al. 2000) and so a reasonable hypothesis is that it is the cells in the network which show view-dependent tuning that are used primarily for accurate and rapid identification of faces, at least in the first instance. The view-independent ones may be of more importance for maintaining recognition as the individual being viewed moves and, as we will discuss in a moment, possibly for the formation of face imagery. (c) Learning and memory for face identity Relatively little work has been carried out on how learning influences face-processing networks. Studies using molecular markers of neural plasticity changes in sheep (brain-derived nerve growth factor and its receptor trk-B) have found increased mRNA levels in face-processing regions of the temporal and frontal cortices and basal amygdala after successful social recognition memory formation in sheep (Broad et al. 2002). At the single neuron level, electrophysiological recordings provide clear evidence of learning, with cells showing varying degrees of specific tuning to the faces of particular familiar sheep or human faces in both the temporal and the frontal cortices (Kendrick et al. 2001a). We have also found evidence that categorization of humans as distinct from sheep can be modified; cells responding to socially familiar Phil. Trans. R. Soc. B (2006)

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Figure 5. Activity maps: pseudo-colour grids showing activity changes across the recording array during face discrimination tasks. (a) Example of different activation profiles in response to either a novel, non-familiar face or a learnt, familiar face. Overall, the number of units responding to the face decreases as the face becomes more familiar to the subject. Individually, some units no longer react to the stimulus while others show increases/decreases in their firing rates. (b) Activity map across grid in response to familiar face showing higher levels of inhibition as opposed to excitation across the population.

sheep respond equivalently to a highly familiar human but not to other humans (Kendrick et al. 2001a). In terms of neural correlates of the behavioural evidence for long-term memory for faces, we found clear evidence for maintained responses to the faces of familiar individual sheep and humans that had not been seen for a year or more (Kendrick et al. 2001a). Interestingly though, while the overall proportion of cells responding to these faces was not significantly influenced, there was a reduction in the number responding to each selectively (Kendrick et al. 2001a). This suggests that becoming familiar with the faces of members in a social group results in a progressive increase in the proportion of cells which selectively encode them. When such individuals leave, the process of forgetting their faces is associated with their faces gradually becoming more generically encoded. (d) Population encoding As described earlier, for many years researchers have been recording electrical activity of individual neurons in the IT while animals perform behavioural tasks related to face perception and memory. This technique allows for extensive study of the response properties of single cells while an animal is presented

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with face stimuli. However, it does not allow one to study the coordinated activity of many neurons simultaneously. Recently, a number of research groups (e.g. Dave et al. 1999; Wiest et al. 2005), including ours (Tate et al. 2005), have started using multielectrode array (MEA) techniques to study large numbers of neurons together to elucidate how a population of neurons might cooperate and compete to encode stimuli. The development of MEA techniques to record neural activity not only allows researchers to continue the study of individual neuronal responses to stimuli, but also allows for investigation into simultaneous activation/deactivation of subpopulations within a neural ensemble. Therefore, an investigator can study both the local response of neurons as well as more global activity changes across a population. This approach combines the high temporal resolution of single-cell recordings with the study of large spatial arrangements of cells. In our laboratory, large-scale MEA recordings have enabled us to acquire extensive datasets in response to face stimuli which, in turn, has also led to the development of novel techniques for their analysis and interpretation (Horton et al. 2005, submitted). Using these data, it is possible to plot basic activity maps showing differential activation and deactivation across the recording area (figure 5) in response to familiar faces. Preliminary results suggested that the learning of identity is associated with a reduction in the number of cells in an ensemble responding to the face pairs (figure 5b) and this reduction may also be primarily in excitatory neurons, suggesting a large role for inhibition during learning. As described later in this article, reduction due to learning— sparsening—may be computationally beneficial for the brain. (e) Face attraction In humans, faces are an important source of sexual attraction (see Cornwell et al. 2006; Fisher et al. 2006) with differential potential for altering activity in brain regions controlling emotional and sexual responses and reward. This also seems to be the case in sheep. Initial studies using a molecular marker of altered brain activation (c-fos mRNA expression) showed that exposure to visual cues from males only activated brain regions beyond the temporal cortex mediating sexual, emotional and reward responses in females when the male was sexually attractive (Ohkura et al. 1997). A further study found that when females were presented with the faces of two males to which they were differentially attracted, only the preferred male elicited release of dopamine, noradrenaline and serotonin in the hypothalamus during the period of their cycle when they found a male sexually attractive (Fabre-Nys et al. 1997). (f ) Lateralization of face-identity processing The behavioural bias towards using visual cues from the half of the face appearing in the left visual field does indeed seem to have some basis in a right brain hemisphere bias. Several studies using molecular markers of altered brain activation (c-fos and zif/268 mRNA expression) have shown significant changes Phil. Trans. R. Soc. B (2006)

only in the right inferior and superior temporal cortices, frontal cortex and basolateral amygdala (Broad et al. 2000; da Costa et al. 2004). However, as with observations from work on rhesus monkey, temporal cortex single-unit recordings do not reveal differences in the numbers or tuning specificities of face-sensitive cells in the right and the left hemispheres (Peirce & Kendrick 2002). The only exception to this is that view-dependent cells in the right hemisphere show a more pronounced reduction in response to faces where the half of the face appearing in the left visual field is obscured (figure 3). However, there are pronounced response latency differences in cells tuned to categories of faces or specific individuals as distinct from those with generic responses to all visual objects or faces. Cell responses can be up to 400 ms faster in the right than in the left temporal cortex (Peirce & Kendrick 2002). Indeed, the response latencies of many of the cells in the left hemisphere are longer than the time the animals need to make an accurate identification of faces. This has led us to speculate that the right hemisphere may indeed be involved primarily in face identification with the left dealing more with the behavioural, emotional and mnemonic consequences of recognition. Present work in this laboratory using MEA electrophysiological recordings has confirmed these latency differences between the two hemispheres and aims to try to elucidate potential encoding differences that may exist. (g) Comparisons with human face identity recognition As has already been discussed, human studies have primarily relied on non-invasive neuroimaging studies which cannot, unlike the above electrophysiological studies on monkeys and sheep, reveal detailed neural network encoding principles. However, in general, similar brain substrates seem to be involved in the different species, although in humans a highly delineated area in the temporal lobe, the fusiform face area, has been identified (Kanwisher et al. 1997). Two recent studies have crossed this threshold, using functional magnetic resonance imaging (fMRI) scanning on macaque monkeys. ‘Face patches’ have been established in the areas from V4 to IT using fMRI, whereas previous studies had always suggested that face-responsive neurons were scattered throughout the temporal cortex, with limited concentration in one area (Tsao et al. 2003). Specific face selective areas have also been found in the posterior and the anterior STS of the macaque using fMRI (Pinsk et al. 2005); this study also found a hemispheric asymmetry, with the posterior STS more active in the right hemisphere. Kanwisher & Yovel (2006) argue for the merits of a face-specific system over domain-general alternatives in humans, so is the system found in animals also facespecific? The evidence from studies involving animal face processing supports this view. Animals are able to recognize conspecific faces with a degree of accuracy comparative with humans and also exhibit similar patterns of recognition, such as configural coding, inversion effects and view invariance. It seems logical that conserved mechanisms for face processing will exist alongside increasing complexities of the visual system.

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Face identity and face emotion processing Although the lack of orofacial musculature of lower primates and mammals reduces the complexity of their faces, it is still evident that animals using vision as their primary sense could, and in fact do, use the face for both identity recognition and expression recognition. 9. FACE-BASED EMOTION RECOGNITION The functional model of face processing by Bruce & Young (1986) still offers the best fit to present findings and is applied to humans and animals alike. It proposes separate parallel routes for processing facial identity and facial expression cues. However, by extensively reviewing the existing experimental evidence in humans and animals, the actual degree of separation between both pathways has recently been questioned (Calder & Young 2005). One major reason for this challenge is the experimental design of the studies involved: relatively few functional imaging (George et al. 1993; Sergent et al. 1994; Winston et al. 2004) and electrophysiological (Hasselmo et al. 1989; Sugase et al. 1999) approaches have investigated the processing of facial identity and expression in a single experiment, and their results are inconsistent. Furthermore, in animals, face-emotion processing has been almost exclusively addressed postperceptually, despite the presentation of faces with different expressions often forming ‘routine’ parts of experimental paradigms, e.g. to assess changes in general cognitive abilities as part of aetiological studies (e.g. Lacreuse & Herndon 2003) or in the context of more general brain-functional investigations (e.g. O’Scalaidhe et al. 1999). This means, despite a considerable amount of behavioural evidence showing that a variety of animal species are capable of recognizing faces, still very little is known about the cellular mechanism underlying face identity and face expression recognition and their mutual interaction. In animal studies in particular, and from an experimental point of view, one of the greatest challenges is still the design of test paradigms that allow for an experimental distinction between the neural mechanisms encoding face identity, as opposed to face expression/emotion. (a) Non-human primates In general, the primate brain contains over 30 regions dedicated to visual processing, including areas with neurons responding to visual social signals such as facial expressions. In apes and monkeys, neurons responsive to facial expression are predominantly (but not exclusively) located in the upper and lower bank of the STS, whereas neurons responding to identity are primarily (but not exclusively) found in the IT region. Furthermore, within the population of face-specific neurons responding to expression, responses of individual neurons are related to particular expressions, such as threat or fear (Perrett et al. 1984; Hasselmo et al. 1989). Neurons particularly responsive to ‘facial feature arrangement’ and ‘overall configuration of many features’ had been previously identified in the macaque IT region (Desimone et al. 1984; Baylis et al. 1985). Based on the stimulus paradigms used (i.e. monkey face with neutral expression versus same Phil. Trans. R. Soc. B (2006)

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picture with scrambled features, Desimone et al. 1984; faces with different expression in different individuals, Rolls 1984; Baylis et al. 1985), no direct conclusion as to whether these neurons encode identity and/or expression can be drawn. However, taken together with investigations correlating quantified facial features, such as intereye and eye-to-mouth distances, with response characteristics of face-specific neurons in the macaque IT region (Yamane et al. 1988) and together with recordings from infant monkeys (Rodman et al. 1991), this supports the hypothesis that at least some of the IT neurons might also be involved in FaBER. A recent detailed analysis of the response of individual face-specific neurons in the macaque IT cortex, including the STS region, revealed that the response encodes two different scales of information subsequently: (i) global information, thereby initially categorizing a visual stimulus as either face or object, followed by (ii) fine information, and depending on type/location of the cell, encoding either identity or expression (Sugase et al. 1999). (b) Sheep Face emotion research in monkeys has almost exclusively focused upon the response characteristics of single neurons to face emotion cues. By using bilateral MEAs, and thereby recording from a large number of neurons simultaneously, our work now extends this scope and focuses on principles of how face emotion information is represented across subpopulations of neurons in the temporal cortex during FaBER tasks and on how this representation interacts with the representation of other facial non-emotional cues, such as identity. Our results show that the total number of recorded cells responding either with an increase (i.e. ‘excitatory’-type, E-type) or a decrease (‘inhibitory’type, I-type response) in spike frequency to face emotion stimuli did not change significantly over the four month time period during which the recordings were made. In addition, the level of population sparseness, i.e. the proportion of cells responsive to face emotion stimuli, was observed to be constant. Overall, approximately 90% of the responsive cells exhibited exclusively either E- or I-type responses to a face emotion stimulus. For the remaining cells, both E- and I- responses were found. None of the units examined exhibited high selectivity for a particular identity (familiar, unfamiliar) or emotional (stressed/ anxious, calm) cue. Differential activity maps (figure 6a) comparing the population response with face emotion stimuli displayed by familiar versus unfamiliar conspecifics (figure 2) were used for an analysis of the spatiotemporal activity patterns. In each hemisphere, the total number of responsive neurons did not change significantly depending on whether the individuals presented were familiar or unfamiliar (figure 6b). However, during trials using familiar conspecifics, the number of I-type responses was significantly higher and the number of E-type responses significantly lower than in trials using novel faces (figure 6b). The difference between given activity maps (so-called array difference, i.e. the numeric difference as an

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Figure 6. (a) Differential activity map of temporal cortical neurons during a face-based emotion recognition (FaBER) task. The map highlights the activity differences across the population observed in response to an emotional (stressed/ anxious) face stimulus of a familiar sheep face as opposed to an unfamiliar sheep face. (b) In both hemispheres, the total number of neurons (T) responding to the face does not change irrespective of whether a familiar (N) or an unfamiliar (N) neutral/calm sheep face is presented during the discrimination task. However, the proportion of E-type neurons (i.e. neurons with an increased firing rate, E) is higher whereas the number of I-type responses (decreased firing rate, I) is lower across the population if the neutral/calm face is unfamiliar (N). (c) Bihemispherical comparison of the response latencies (DtLKR) of the neurons reveals right hemisphere dominance during sole face identity recognition tasks where animals discriminated between a familiar neutral/calm (N) and an unfamiliar neutral/calm (N) face. Right hemisphere dominance is less pronounced during the face emotion recognition tasks (N versus S, N versus S).

estimate of the reliability of the representation of a particular face stimulus across a defined population of neurons) was approximately 16% when a given face emotion stimulus was presented repeatedly. Furthermore, the array difference between average activity maps representing faces of different familiar conspecifics was significantly higher (29%), whereas the average array difference reached its highest values for familiar versus unfamiliar faces (approx. 33%). For both E- and I-type neurons, our present results do not show a significant difference between the average response latencies to a face emotion stimulus displayed by a familiar or by an unfamiliar conspecific. Our data suggest that in sheep, the representation of face identity and face emotion relies to a certain extent on population encoding by cortical visual networks. What are the advantages of a distributed representation of face information using population encoding Phil. Trans. R. Soc. B (2006)

in cortical networks, as opposed to more ‘local’ encoding schemes? Algorithms applied to samples of single-cell data obtained from the primate temporal visual cortex revealed that the representational capacity (i.e. the number of stimuli that can be encoded) of a population of neurons using a distributed representation scheme increases exponentially as the number of cells in the population increases (Rolls et al. 1997). Since visual information is highly complex, the representational capacity using a population encoding scheme is therefore much higher than using local encoding schemes, such as ‘grandmother’ cells, in which the number of stimuli encoded increases only linearly with population size. Furthermore, extremely sparse codes, such as ‘grandmother’ schemes where the coding of relatively large amounts of information (e.g. a whole face plus different views), confer high sensitivity to damage and low capacity. Nevertheless, using sparse codes in combination with distributed representations offers certain theoretical advantages (Perez-Orive et al. 2002). These include a reduction in the amount of overlap between individual representations, thereby limiting interference between memories, much simpler (hence involving fewer elements) comparisons between stimulus-evoked activity patterns and stored memories, e.g. in terms of any amygdala–cortical emotional assessment (Aggleton & Young 2000; Sato et al. 2004) and, in general, more synthetic representations. Finally, given a large total population size of the temporal cortex visual neurons and levels of sparseness that are not extreme, the memory capacity of the system can still be very high. Our present findings also suggest that the process of recognition, i.e. ‘getting familiar’ with a conspecific, might be represented by an increased number of inhibited neurons across the recorded population. Interestingly, research on olfactory networks in vertebrates and, particularly in invertebrates, suggests a similar principle, showing increased numbers of inhibited neurons during olfactory memory formation (Sachse & Galizia 2002). Increased levels of inhibition might therefore be a common principle whereby neural networks encode complex multi-component stimuli such as odours or faces. This can enable a globally modulated, contrast-enhanced and predictable representation of information across subpopulations of neurons. (c) Lateralization of face-emotion processing Like humans, apes (Parr & Hopkins 2000; FernandezCarriba et al. 2002a,b) and monkeys (Hauser 1993; Hook-Costigan & Rogers 1998) express emotions more intensively in the left hemi-face. In this context, cerebral asymmetries (lateralization and laterality) in emotional processing have received a great deal of attention. Presently, there are two major theories: (i) the righthemisphere theory (e.g. Suberi & McKeever 1977; Ley & Bryden 1979; Borod et al. 1997) suggests that the right hemisphere is predominantly processing all emotional information regardless of its valence; on the contrary, (ii) the valence theory (e.g. Davidson 1992) suggests that the two cerebral hemispheres are differentially involved in emotion processing, with the left hemisphere dominating positive emotions, whereas

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negative emotions are associated with higher righthemisphere activity. In animals, evidence on lateralization during face emotion recognition comes predominantly from behavioural studies. Furthermore, the evidence regarding the nature of lateralization is still conflicting. For example, when using human chimeric faces as stimuli, findings in chimpanzees suggest a right hemisphere advantage perceiving positive emotional (smile) facial displays (Morris & Hopkins 1993). For the same species, a more recent study has shown a left-hemisphere bias during neutral and positive (play) visual emotional stimuli, whereas a right-hemisphere bias was found during negative (aggression) stimuli (Parr & Hopkins 2000). However, studies in adult split-brain monkeys by using a paradigm separating facial identity from (positive and negative) expression cues suggest righthemisphere superiority (Vermeire et al. 1998), more pronounced in females than in males (Vermeire & Hamilton 1998). Similar to humans, apes and monkeys, our data in sheep indicate right hemisphere dominance (figure 6c). However, our present data suggest that these hemispherical differences might be less pronounced during face emotion recognition, implicating a greater involvement of the left hemisphere in face emotion tasks. Interestingly, this is in agreement with the valence hypothesis in humans, suggesting a left-biased processing of positive (in our case, neutral) facial information, as opposed to negative emotions, biased to towards the right (e.g. Demaree et al. 2005).

10. NEURAL ENCODING OF FACE IMAGERY In humans, brain-imaging studies have revealed a remarkable concordance in patterns of activation changes in face-processing regions during actual perception of faces and imagining them (Kanwisher & Yovel 2006), suggesting that common networks are involved in face perception and face imagery. Is this also the case in other species? If so, can electrophysiological studies reveal potential differences in the neural representation of perceived and imagined faces? (a) Neural activity during face imagery in non-human primates Only one study has investigated electrophysiological responses of IT neurons in conditions where object permanence is being tested in the context of individual recognition and therefore face/body imagery might be anticipated to occur. This used a simple approach of individuals/objects disappearing and reappearing from behind a screen, and found cells in STS which showed activity changes for periods of up to 11 s when objects were completely obscured behind the screen (Baker et al. 2001). Many studies have shown cell activity changes being maintained during the delay period in a matching or non-matching to sample experiment in a variety of brain regions (O’Scalaidhe et al. 1997, 1999), but we are not aware of any using faces during recordings in the temporal cortex. Phil. Trans. R. Soc. B (2006)

per cent of change in firing rate

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200 150 100 50 0 front view

profile view

odour

Figure 7. MeanGs.e.m. per cent change in firing rate in frontal cortex neurons in five maternal sheep responding to the sight of their lamb’s face and to its odour. Viewdependent neurons (nZ12) only respond to a frontal view and not to the lamb’s odour. However, view-independent neurons (nZ25) respond equivalently to frontal and profile views and also to just the lamb’s odour. For 8 of these cells when the lamb’s face and odour were presented in combination there was no evidence for any additive response.

(b) Neural activity during face imagery in sheep We have used various approaches to attempt to cue face imagery in sheep. The first of these was to use the high level of motivation that maternal ewes have to find their lambs when they are temporarily absent. Under these circumstances, showing a picture of the lamb’s face or hearing its bleat (but not a scrambled sequence of the bleat) activated (c-fos mRNA expression), the region of the temporal cortex that responds to faces. Since cells have not normally been found in this region that respond specifically to vocalizations as opposed to simple auditory stimuli, one possibility is that the vocal cue has evoked a mental image of the missing lamb’s face (Kendrick et al. 2001c). Single unit recording approaches have also been used in varying contexts where face imagery might be evoked. In the first of these, video sequences revealing a highly familiar sheep in its home pen were used, while recordings were made from cells in the temporal cortex that responded preferentially to the individual’s face. It was found that the cells showed activity changes both in anticipation of the appearance of the sheep in the film as well as when it actually appeared. They also responded to the point in a film where the sheep should have appeared, but did not because it had been edited out (Kendrick et al. 2001c). This certainly shows that these face-sensitive cells can respond in the absence of a face and may reflect the generation of face imagery, although there is obviously no way of proving this. Finally, in a recent preliminary experiment, we have made recordings from cells in the frontal cortex of maternal sheep that respond significantly to the sight of their lamb’s face. The view-independent population of these cells also showed highly selective responses to the odour of the lamb as well. However, when face and odour were combined, there was no alteration in the magnitude of the response (figure 7) and very few other cells were responsive to odours. Again, this might suggest that the odour stimuli were evoking face imagery. If so, it is interesting that it is only the viewindependent cells which are involved and not the

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view-dependent ones. This again suggests that the networks of view-dependent cells are particularly involved in identification of faces which are actually perceived. It is clearly necessary for more experimental approaches to be carried out to investigate the capacity for these face-recognition networks in non-human species to generate imagery and to establish how this differs from actual perception of faces. However, at this stage, there is at least some supportive evidence for the idea that, like the human brain, there may also be considerable overlap between imagery and perceptual mechanisms in these species.

11. CONCLUSIONS AND FUTURE DIRECTIONS In this paper, we have reviewed experimental evidence for specialized face processing systems in animals, available from behavioural, electrophysiological and neuroimaging studies. Behavioural studies of the capacities for different animal species to use visual cues for face identity and face emotion are still relatively sparse compared with humans. Yet the obvious prediction from studies showing that mammals other than primates do appear to have sophisticated recognition abilities in this respect suggests that the use of face cues may be quite widespread in species with reasonable visual acuity. However, we still know relatively little about how extensively emotion cues are transmitted via changes in facial appearance in these species, or indeed, how able they are at distinguishing the many different expressions they may see on our faces when they interact closely with us. Similarly, faces appear to play an important role for individual social and sexual attraction in other species besides humans, although we still know relatively little about what makes one face more attractive than another and whether some of the same general rules of attraction, such as symmetry and configuration, are important. As in humans, many animal studies have revealed face-responsive areas in the temporal cortex, with individual neurons responding preferentially to faces as opposed to other visual objects. Where the tuning of these cells has been tested, they show high specificity for different categories of face information, including different faces and various face views, features and expressions. Whereas recording from single cells allows a controlled and detailed analysis of individual cell response properties, this also means focusing on the local mechanisms of face representations in the brain. However, evidence from a variety of studies using different approaches, including recent developments in animal neuroimaging studies, suggests that face recognition relies on a distributed network of subpopulations of neurons located in various brain areas. In sheep, our approach to bridge the gap between the single-cell recording and neuroimaging is the use of MEA electrophysiology. This enables us not only to study the individual cell responses to a face, but also to investigate an entire (though limited by array size) subpopulation of neurons involved in the processing of face information. Our data suggest that the Phil. Trans. R. Soc. B (2006)

representation of face identity and face emotion relies to a certain extent on sparse population encoding by cortical visual networks. However, major questions of what neural mechanisms underlie this encoding process still remain unanswered. What core principles might neuronal populations employ to represent information? How does the neural activity of a given population of neurons correspond to a particular visual stimulus? How might previous experience affect this activity? How does a population differentially encode face emotion as opposed to face identity? How does encoding in the temporal cortex influence patterns of activity in regions important for emotional control and expression, such as the frontal cortex and the amygdala? How does representation of mental images of faces differ from actual perception of them? Present investigations in our laboratory are focused on spatio-temporal distributions of neural activity and their changes in relation to identity, emotion and imagery cues. This also includes analysing the formation and repetition of certain activity patterns across the population using specific pattern-detecting software and identifying correlational strength between pairs of neurons of a given population. These are already beginning to reveal the presence of altered patterning and correlation shifts across distributed networks of neurons independent of firing frequency changes (Tate et al. 2005). The ability to recognize faces and their emotional content is a key feature underlying successful social interactions and bonding. However, it is clear that social cognition is a highly complex task which relies strongly on additional features such as the ability to direct attention towards conspecifics, interpreting the emotional context of visual cues presented and relating present experience to memory of previously encountered situations. Only by combining behavioural, neuroimaging, single-cell and MEA studies on all these systems working together, and by employing computational approaches, will we be able to move closer to understanding the organizational and functional principles that operate within the social brain. This work was partly supported by a BBSRC Grant (BBS/B/07961). Dr Jon Peirce contributed to some of the single cell recording studies described and we are grateful to Mr Michael Hinton for his help with preparing the figures.

REFERENCES Aggleton, J. P. & Young, A. W. 2000 The enigma of the amygdala: on its contribution to human emotion. In Cognitive neuroscience of emotion (ed. R. D. Lane & L. Nadel), pp. 106–128. New York, NY: Oxford University Press. Baker, C. I., Keysers, C., Jellema, T., Wicker, B. & Perrett, D. I. 2001 Neuronal representation of disappearing and hidden objects in temporal cortex of the macaque. Exp. Brain. Res. 140, 375–381. (doi:10.1007/s002210100828) Bauer, H. R. & Philip, M. 1983 Facial and vocal individual recognition in the common chimpanzee. Psychol. Rec. 33, 161–170. Baylis, G. C., Rolls, E. T. & Leonard, C. M. 1985 Selectivity between faces in the responses of a population of neurons in the cortex in the superior temporal sulcus of the monkey. Brain. Res. 342, 91–102. (doi:10.1016/00068993(85)91356-3)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Face identity and face emotion processing Bekoff, M. 2002 Animal reflections. Nature 419, 255. (doi:10. 1038/419255a) Borod, J. C., Haywood, C. S. & Koff, E. 1997 Neuropsychological aspects of facial asymmetry during emotional expression: a review of the normal adult literature. Neuropsychol. Rev. 7, 41–60. Broad, K. D., Mimmack, M. L. & Kendrick, K. M. 2000 Is right hemisphere specialization for face discrimination specific to humans? Eur. J. Neurosci. 12, 731–741. (doi:10. 1046/j.1460-9568.2000.00934.x) Broad, K. D., Mimmack, M. L., Keverne, E. B. & Kendrick, K. M. 2002 Increased BDNF and trk-B mRNA expression in cortical and limbic regions following formation of a social recognition memory. Eur. J. Neurosci. 16, 2166–2174. (doi:10.1046/j.1460-9568.2002.02311.x) Bruce, C. 1982 Face recognition by monkeys: absence of an inversion effect. Neuropsychologia 20, 515–521. (doi:10. 1016/0028-3932(82)90025-2) Bruce, V. & Young, A. 1986 Understanding face recognition. Br. J. Psychol. 77, 305–327. Bruce, C., Desimone, R. & Gross, C. G. 1981 Visual properties of neurons in a polysensory area in the superior temporal sulcus of the macaque. J. Neurophysiol. 46(2), 369–384. Calder, A. J. & Young, A. W. 2005 Understanding the recognition of facial identity and facial expression. Nat. Rev. Neurosci. 6, 641–651. (doi:10.1038/nrn1724) Chelazzi, L., Duncan, J., Miller, E. K. & Desimone, R. 1998 Responses of neurons in inferior temporal cortex during memory-guided visual search. J. Neurophysiol. 80, 2918–2940. Chevalier-Skolnikoff, S. 1973 Visual and tactile communication in Macaca arctoides and its ontogenetic development. Am. J. Phys. Anthropol. 38, 515–518. (doi:10.1002/ ajpa.1330380258) Cornwell, R. E., Law Smith, M. J., Boothroyd, L. G., Moore, F. R., Davis,, H. P., Stirrat, M., Tiddeman, B. & Perrett, D. I. 2006 Reproductive strategy, sexual development and attraction to facial characteristics. Phil. Trans. R. Soc. B 361, 2143–2154. (doi:10.1098/rstb.2006.1936) Crair, M. C. 1999 Neuronal activity during development: permissive or instructive? Curr. Opin. Neurobiol. 9, 88–93. (doi:10.1016/S0959-4388(99)80011-7) Da Costa, A. P. C., Leigh, A. E., Man, M.-S. & Kendrick, K. M. 2004 Face pictures reduce behavioural, autonomic, endocrine and neural indices of stress and fear in sheep. Proc. R. Soc. B 271, 2077–2084. (doi:10.1098/rspb.2004. 2831) Dave, A. S., Yu, A. C., Gilpin, J. J. & Margoliash, D. 1999 Methods for chronic neuronal ensemble recordings in singing birds. In Methods for neural ensemble recordings (ed. M. A. L. Nicolelis), pp. 101–120. Boca Raton, FL: CRC Press. Davidson, R. J. 1992 Anterior cerebral asymmetry and the nature of emotion. Brain Cogn. 20, 125–151. (doi:10. 1016/0278-2626(92)90065-T) Delfour, F. & Marten, K. 2001 Mirror image processing in three marine mammal species: killer whales (Orcinus orca), false killer whales (Pseudorca crassidens) and California sea lions (Zalophus californianus). Behav. Process. 53, 181–190. (doi:10.1016/S0376-6357(01)00134-6) Demaree, H. A., Everhart, D. E., Youngstrom, E. A. & Harrison, D. W. 2005 Brain lateralization of emotional processing: historical roots and a future incorporating “dominance”. Behav. Cogn. Neurosci. Rev. 4, 3–20. (doi:10.1177/1534582305276837) Desimone, R., Albright, T. D., Gross, C. G. & Bruce, C. 1984 Stimulus-selective properties of inferior temporal neurons in the macaque. J. Neurosci. 4, 2051–2062. Phil. Trans. R. Soc. B (2006)

A. J. Tate and others 2169

de Veer, M. W., Gallup, G. G., Theall, L. A., van den Bos, R. & Povinelli, D. J. 2003 An 8-year longitudinal study of mirror self-recognition in chimpanzees (Pan troglodytes). Neuropsychologia 41, 229–234. (doi:10.1016/S00283932(02)00153-7) Dittrich, W. H. 1990 Representation of faces in longtailed macaques (Macaca fascicularis). Ethology 85, 265–278. Eifuku, S., De Souza, W. C., Tamura, R., Nishijo, H. & Ono, T. 2004 Neuronal correlates of face identification in the monkey anterior temporal cortical areas. J. Neurophysiol. 91, 358–371. (doi:10.1152/jn.00198.2003) Elliker, K. 2006 Recognition of emotion in sheep. Ph.D. thesis, University of Cambridge. Fabre-Nys, C., Ohkura, S. & Kendrick, K. M. 1997 Male faces and odours evoke differential patterns of neurochemical release in the mediobasal hypothalamus of the ewe during oestrus: an insight into sexual motivation? Eur. J. Neurosci. 9, 1666–1677. (doi:10.1111/j.1460-9568. 1997.tb01524.x) Fernandez-Carriba, S., Loeches, A., Morcillo, A. & Hopkins, W. D. 2002a Functional asymmetry of emotions in primates: new findings in chimpanzees. Brain Res. Bull. 57, 561–564. (doi:10.1016/S0361-9230(01)00685-2) Fernandez-Carriba, S., Loeches, A., Morcillo, A. & Hopkins, W. D. 2002b Asymmetry in facial expression of emotions by chimpanzees. Neuropsychologia 40, 1523–1533. (doi:10.1016/S0028-3932(02)00028-3) Fisher, H. E., Aron, A. & Brown, L. L. 2006 Romantic love: a mammalian brain system for mate choice. Phil. Trans. R. Soc. B 361, 2173–2186. (doi:10.1098/rstb.2006.1938) Freedman, D. J., Riesenhuber, M., Poggio, T. & Miller, E. K. 2003 A comparison of primate prefrontal and inferior temporal cortices during visual categorization. J. Neurosci. 23, 5235–5246. Fujita, K. 1993 Development of visual preference for closely related species by infant and juvenile macaques with restricted social experience. Primates 34, 141–150. (doi:10.1007/BF02381385) Fuster, J. M. 1990 Inferotemporal units in selective visual attention and short-term memory. J. Neurophysiol. 64, 681–697. Fuster, J. M. & Jervey, J. P. 1981 Inferotemporal neurons distinguish and retain behaviorally relevant features of visual stimuli. Science 212, 952–955. (doi:10.1126/science. 7233192) Gallup, G. G. 1977 Absence of self-recognition in a monkey following prolonged exposure to a mirror. Dev. Psychobiol. 91, 642–648. Gaylord, S. A. & Marsh, G. R. 1975 Age differences in the speed of a spatial cognitive process. J. Gerontol. 30, 674–678. George, M. S., Ketter, T. A., Gill, D. S., Haxby, J. V., Ungerleider, L. G., Herscovitch, P. & Post, R. M. 1993 Brain regions involved in recognizing facial emotion or identity: an oxygen-15 PET study. J. Neuropsych. Clin. Neurosci. 5, 384–394. Griffin, D. R. 2001 Animals know more than we used to think. Proc. Natl Acad. Sci. USA 98, 4833–4834. (doi:10. 1073/pnas.091088198) Gross, C. G., Rocha-Miranda, C. E. & Bender, D. B. 1972 Visual properties of neurons in inferotemporal cortex of the macaque. J. Neurophysiol. 35, 96–111. Gross, C. G., Bender, D. B. & Gerstein, G. L. 1979 Activity of inferior temporal neurons in behaving monkeys. Neuropsychologia 17, 215–229. (doi:10.1016/0028-3932 (79)90012-5) Hampson, R. E., Pons, T. P., Stanford, T. R. & Deadwyler, S. A. 2004 Categorization in the monkey hippocampus: a

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2170

A. J. Tate and others Face identity and face emotion processing

possible mechanism for encoding information into memory. Proc. Natl Acad. Sci. USA 101, 3184–3189. (doi:10.1073/pnas.0400162101) Hasselmo, M. E., Rolls, E. T. & Baylis, G. C. 1989 The role of expression and identity in the face-selective responses of neurons in the temporal visual cortex of the monkey. Behav. Brain Res. 32, 203–218. Hauser, M. D. 1993 Right hemisphere dominance for the production of facial expression in monkeys. Science 261, 475–477. (doi:10.1126/science.8332914) Hietanen, J. K., Perrett, D. I., Oram, M. W., Benson, P. J. & Dittrich, W. H. 1992 The effects of lighting conditions on responses of cells selective for face views in the macaque temporal cortex. Exp. Brain Res. 89, 157–171. (doi:10. 1007/BF00229013) Hook-Costigan, M. A. & Rogers, L. J. 1998 Lateralized use of the mouth in production of vocalizations by marmosets. Neuropsychologia 36, 1265–1273. (doi:10.1016/S00283932(98)00037-2) Horton, P., Bonny, L., Nicol, A. U., Kendrick, K. M. & Feng, J. F. 2005 Applications of multi variate analysis of variance (MANOVA) to multi electrode array electrophysiology data. J. Neurosci. Methods 46, 22–41. (doi:10.1016/ j.jneumeth.2005.01.008) Horton, P., Nicol, A. U., Kendrick, K. M. & Feng, J. F. In press. Spike sorting based upon machine learning algorithms (SOMA). J. Neurosci. Methods. Huber, E. 1931 The evolution of facial musculature and facial expression. Baltimore, MD: John Hopkins Press. Indersmitten, T. & Gur, R. C. 2003 Emotion processing in chimeric faces: hemispheric asymmetries in expression and recognition of emotions. J. Neurosci. 23, 3820–3825. Kanazawa, S. 1996 Recognition of facial expressions in a Japanese monkey. Primates 37, 25–38. (doi:10.1007/ BF02382917) Kanwisher, N. & Yovel, G. 2006 The fusiform face area: a cortical region specialized for the perception of faces. Phil. Trans. R. Soc. B 361, 2109–2128. (doi:10.1098/rstb. 2006.1934) Kanwisher, N., McDermott, J. & Chun, M. M. 1997 The fusiform face area: a module in human extrastriate cortex specialized for face perception. J. Neurosci. 17, 4302–4311. Keating, C. F. & Keating, E. G. 1982 Visual scan patterns of rhesus monkeys viewing faces. Perception 11, 211–219. Keenan, J. P., Nelson, A., O’Connor, M. & Pascual-Leone, A. 2001 Self-recognition and the right hemisphere. Nature 409, 305. (doi:10.1038/35053167) Kendrick, K. M. 1991 How the sheep’s brain controls the visual recognition of animals and humans. J. Anim. Sci. 69, 5008–5016. Kendrick, K. M. 1994 Neurobiological correlates of visual and olfactory recognition in sheep. Behav. Process. 33, 89–112. (doi:10.1016/0376-6357(94)90061-2) Kendrick, K. M. 1998 Intelligent perception. Appl. Anim. Behav. Sci. 57, 213–231. Kendrick, K. M. 2006 Brain asymmetries for face recognition and emotion control in sheep. Cortex 42, 96–98. Kendrick, K. M. & Baldwin, B. A. 1987 Cells in temporal cortex of conscious sheep can respond to the sight of faces. Science 236, 448–450. (doi:10.1126/science.3563521) Kendrick, K. M., Atkins, K., Hinton, M. R., Broad, K. D., Fabre-Nys, C. & Keverne, B. 1995 Facial and vocal discrimination in sheep. Anim. Behav. 49, 1665–1676. (doi:10.1016/0003-3472(95)90088-8) Kendrick, K. M., Atkins, K., Hinton, M. R., Heavens, P. & Keverne, B. 1996 Are faces special for sheep? Evidence from facial and object discrimination learning tests showing effects of inversion and social familiarity. Behav. Process. 38, 19–35. (doi:10.1016/0376-6357(96)00006-X) Phil. Trans. R. Soc. B (2006)

Kendrick, K. M., Hinton, M. R., Atkins, K., Haupt, M. A. & Skinner, J. D. 1998 Mothers determine sexual preferences. Nature 395, 229–230. (doi:10.1038/26129) Kendrick, K. M., da Costa, A. P., Leigh, A. E., Hinton, M. R. & Peirce, J. W. 2001a Sheep don’t forget a face. Nature 414, 165–166. (doi:10.1038/35102669) Kendrick, K. M., Haupt, M. A., Hinton, M. R., Broad, K. D. & Skinner, J. D. 2001b Sex differences in the influence of mothers on the sociosexual preferences of their offspring. Horm. Behav. 40, 322–338. (doi:10.1006/hbeh.2001. 1672) Kendrick, K. M., Leigh, A. E. & Peirce, J. 2001c Behavioural and neural correlates of mental imagery in sheep using face recognition paradigms. Anim. Welf. 10, S89–101. Kobatake, E., Wang, G. & Tanaka, K. 1998 Effects of shapediscrimination training on the selectivity of inferotemporal cells in adult monkeys. J. Neurophysiol. 80, 324–330. Kuwahata, H., Adachi, I., Fujita, K., Tomonaga, M. & Matsuzawa, T. 2004 Development of schematic face preference in macaque monkeys. Behav. Process. 66, 17–21. (doi:10.1016/j.beproc.2003.11.002) Lacreuse, A. & Herndon, J. G. 2003 Estradiol selectively affects processing of conspecifics’ faces in female rhesus monkeys. Psychoneuroendocrinology 28, 885–905. (doi:10. 1016/S0306-4530(02)00104-X) Ley, R. G. & Bryden, M. P. 1979 Hemispheric differences in processing emotions and faces. Brain Lang. 7, 127–138. (doi:10.1016/0093-934X(79)90010-5) Man, M.-S., Leigh, A. E. & Kendrick K. M. 2003 Can sheep form mental images of faces? Society for neuroscience program no. 362.1, Abstract viewer/itinerary planner. Society for Neuroscience, San Diego. Marler, P. 1976 Social organization, communication, and graded signals: the chimpanzee and the gorilla. In Growing points in ethology (ed. P. P. G. Bateson & R. A. Hinde), pp. 238–270. London, UK: Cambridge University Press. Marten, K. & Psarakos, S. 1994 Evidence of self-awareness in the bottlenose dolphin (Tursiops truncatus). In Selfawareness in animals and humans (ed. S. T. Parker, R. W. Mitchell & M. L. Boccia), pp. 361–379. New York, NY: Cambridge University Press. Marten, K. & Psarakos, S. 1995 Using self-view television to distinguish between self-examination and social behavior in the bottlenose dolphin (Tursiops truncatus). Conscious. Cogn. 4, 205–224. (doi:10.1006/ccog.1995.1026) Morgane, P. J., Galler, J. R. & Mokler, D. J. 2005 A review of systems and networks of the limbic forebrain/limbic midbrain. Prog. Neurobiol. 75, 143–160. (doi:10.1016/ j.pneurobio.2005.01.001) Morris, R. D. & Hopkins, W. D. 1993 Perception of human chimeric faces by chimpanzees: evidence for a right hemisphere advantage. Brain Cogn. 21, 111–122. (doi:10.1006/brcg.1993.1008) Nahm, F. K. 1997 Heinrich Kluver and the temporal lobe syndrome. J. Hist. Neurosci. 6, 193–208. Ohkura, S., Fabre-Nys, C., Broad, K. D. & Kendrick, K. M. 1997 Sex hormones enhance the impact of male sensory cues on both primary and association cortical components of visual and olfactory processing pathways as well as in limbic and hypothalamic regions in female sheep. Neuroscience 80, 285–297. (doi:10.1016/S0306-4522(97) 00103-6) O’Scalaidhe, S. P., Wilson, F. A. & Goldman-Rakic, P. S. 1997 A real segregation of face-processing neurons in prefrontal cortex. Science 278, 1135–1138. (doi:10.1126/ science.278.5340.1135) O’Scalaidhe, S. P., Wilson, F. A. & Goldman-Rakic, P. S. 1999 Face-selective neurons during passive viewing and

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Face identity and face emotion processing working memory performance of rhesus monkeys: evidence for intrinsic specialization of neuronal coding. Cereb. Cortex 9, 459–475. (doi:10.1093/cercor/9.5.459) Parr, L. A. 2003 The discrimination of faces and their emotional content by chimpanzees (Pan troglodytes). Ann. NY Acad. Sci. 1000, 56–78. (doi:10.1196/annals.1280. 005) Parr, L. A. & Hopkins, W. D. 2000 Brain temperature asymmetries and emotional perception in chimpanzees, Pan troglodytes. Physiol. Behav. 71, 363–371. (doi:10.1016/ S0031-9384(00)00349-8) Parr, L. A., Hopkins, W. D. & de Waal, F. B. M. 1998 The perception of facial expressions in chimpanzees (Pan troglodytes). Evol. Commun. 2, 1–23. Pascalis, O., de Haan, M., Nelson, C. A. & de Schonen, S. 1998 Long-term recognition memory for faces assessed by visual paired comparison in 3- and 6-month-old infants. J. Exp. Psychol. Learn. Mem. Cogn. 24, 249–260. (doi:10. 1037/0278-7393.24.1.249) Peirce, J. W. & Kendrick, K. M. 2002 Functional asymmetry in sheep temporal cortex. Neuroreport 13, 2395–2399. (doi:10.1097/00001756-200212200-00004) Peirce, J. W., Leigh, A. E. & Kendrick, K. M. 2000 Configurational coding, familiarity and the right hemisphere advantage for face recognition in sheep. Neuropsychologia 38, 475–483. (doi:10.1016/S0028-3932(99) 00088-3) Peirce, J. W., Leigh, A. E., da Costa, A. P. C. & Kendrick, K. M. 2001 Human face recognition in sheep: lack of configurational coding and right hemisphere advantage. Behav. Process. 55, 13–26. (doi:10.1016/S0376-6357(01) 00158-9) Perez-Orive, J., Mazor, O., Turner, G. C., Cassenaer, S., Wilson, R. I. & Laurent, G. 2002 Oscillations and sparsening of odor representations in the mushroom body. Science 297, 359–365. (doi:10.1126/science.1070502) Perrett, D. I., Smith, P. A., Potter, D. D., Mistlin, A. J., Head, A. S., Milner, A. D. & Jeeves, M. A. 1984 Neurones responsive to faces in the temporal cortex: studies of functional organization, sensitivity to identity and relation to perception. Hum. Neurobiol. 3, 197–208. Perret, D. I., Smith, P. A., Mistlin, A. J., Chitty, A. J., Head, A. S., Potter, D. D., Broennimann, R., Milner, A. D. & Jeeves, M. A. 1985 Visual analysis of body movement by neurons in the temporal cortex of the macaque monkey: a preliminary report. Behav. Brain Res 16, 153–170. Perrett, D. I., Mistlin, A. J., Chitty, A. J., Smith, P. A., Potter, D. D., Broennimann, R. & Harries, M. 1988 Specialized face processing and hemispheric asymmetry in man and monkey: evidence from single unit and reaction time studies. Behav. Brain. Res. 29, 245–258. (doi:10.1016/ 0166-4328(88)90029-0) Perrett, D. I., Oram, M. W., Harries, M. H., Bevan, R., Hietanen, J. K., Benson, P. J. & Thomas, S. 1991 Viewercentred and object-centred coding of heads in the macaque temporal cortex. Exp. Brain Res. 86, 159–173. (doi:10.1007/BF00231050) Perrett, D. I., Benson, P. J., Hietanen, J. K., Oram, M. W. & Dittrich, W. H. 1995 When is a face not a face? In The artful eye (ed. R. Gregory, J. Harris, P. Heard & D. Rose), pp. 95–124. New York, NY: Oxford University Press. Phelps, M. T. & Roberts, W. A. 1994 Memory for pictures of upright and inverted primate faces in humans (Homo sapiens), squirrel monkeys (Saimiri sciureus), and pigeons (Columba livia). J. Comp. Psychol. 108, 114–125. (doi:10. 1037/0735-7036.108.2.114) Pinsk, M. A., DeSimone, K., Moore, T., Gross, C. G. & Kastner, S. 2005 Representations of faces and body Phil. Trans. R. Soc. B (2006)

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parts in macaque temporal cortex: a functional MRI study. Proc. Natl Acad. Sci. USA 102, 6996–7001. (doi:10. 1073/pnas.0502605102) Ranganath, C. & D’Esposito, M. 2005 Directing the mind’s eye: prefrontal, inferior and medial temporal mechanisms for visual working memory. Curr. Opin. Neurobiol. 15, 175–182. (doi:10.1016/j.conb.2005.03.017) Reiss, D. & Marino, L. 2001 Mirror self-recognition in bottlenose dolphins: a case of cognitive convergence. Proc. Natl Acad. Sci. USA 98, 5937–5942. (doi:10.1073/pnas. 101086398) Rodman, H. R., Skelly, J. P. & Gross, C. G. 1991 Stimulus selectivity and state dependence of activity in inferior temporal cortex of infant monkeys. Proc. Natl Acad. Sci. USA 88, 7572–7575. (doi:10.1073/pnas.88.17.7572) Rodman, H. R., Scalaidhe, S. P. & Gross, C. G. 1993 Response properties of neurons in temporal cortical visual areas of infant monkeys. J. Neurophysiol. 70, 1115–1136. Rolls, E. T. 1984 Neurons in the cortex of the temporal lobe and in the amygdala of the monkey with responses selective for faces. Hum. Neurobiol. 3, 209–222. Rolls, E. T., Tovee, M. J., Purcell, D. G., Stewart, A. L. & Azzopardi, P. 1994 The responses of neurons in the temporal cortex of primates, and face identification and detection. Exp. Brain Res. 101, 473–484. (doi:10.1007/ BF00227340) Rolls, E. T., Treves, A. & Tovee, M. J. 1997 The representational capacity of the distributed encoding of information provided by populations of neurons in primate temporal visual cortex. Exp. Brain Res. 114, 149–162. (doi:10.1007/PL00005615) Rosenfeld, S. A. & Van Hoesen, G. W. 1979 Face recognition in the rhesus monkey. Neuropsychologia 17, 503–509. (doi:10.1016/0028-3932(79)90057-5) Sachse, S. & Galizia, C. G. 2002 Role of inhibition for temporal and spatial odor representation in olfactory output neurons: a calcium imaging study. J. Neurophysiol. 87, 1106–1117. Sandem, A. I., Janczak, A. M. & Braastad, B. O. 2004 A short note on effects of exposure to a novel stimulus (umbrella) on behaviour and percentage of eye-white in cows. Appl. Anim. Behav. Sci. 89, 309–314. (doi:10.1016/j.applanim. 2004.06.011) Sato, W., Yoshikawa, S., Kochiyama, T. & Matsumura, M. 2004 The amygdala processes the emotional significance of facial expressions: an fMRI investigation using the interaction between expression and face direction. Neuroimage 22, 1006–1013. (doi:10.1016/j.neuroimage.2004. 02.030) Sereno, A. B. & Amador, S. C. 2006 Attention and memoryrelated responses of neurons in the lateral intraparietal area during spatial and shape-delayed match-to-sample tasks. J. Neurophysiol. 95, 1078–1098. (doi:10.1152/ jn.00431.2005) Sergent, J., Ohta, S., MacDonald, B. & Zuck, E. 1994 Segregated processing of identity and emotion in the human brain: a PET study. Vis. Cogn. 1, 349–369. Sherwood, C. C., Hof, P. R., Holloway, R. L., Semendeferi, K., Gannon, P. J., Frahm, H. D. & Zilles, K. 2005 Evolution of the brainstem orofacial motor system in primates: a comparative study of trigeminal, facial, and hypoglossal nuclei. J. Hum. Evol. 48, 45–84. (doi:10.1016/ j.jhevol.2004.10.003) Shillito-Walser, E. R. 1978 A comparison of the role of vision and hearing in ewes finding their own lambs. Appl. Anim. Ethol. 4, 71–79. (doi:10.1016/0304-3762(78)90095-0) Sigala, N. 2004 Visual categorization and the inferior temporal cortex. Behav. Brain. Res. 149, 1–7. (doi:10. 1016/S0166-4328(03)00224-9)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

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Skuse, D. 2006 Genetic influences on the neural basis of social cognition. Phil. Trans. R. Soc. B 361, 2129–2141. (doi:10.1098/rstb.2006.1935) Soltysik, S. S. & Baldwin, B. A. 1972 The performance of goats in triple choice delayed response tasks. Acta Neurobiol. Exp. 32, 73–86. Suberi, M. & McKeever, W. C. 1977 Differential right hemispheric memory storage of emotional and nonemotional faces. Neuropsychologia 15, 757–768. (doi:10. 1016/0028-3932(77)90006-9) Sugase, Y., Yamane, S., Ueno, S. & Kawano, K. 1999 Global and fine information coded by single neurons in the temporal visual cortex. Nature 400, 869–873. (doi:10. 1038/23703) Tate, A. J., Nicol, A. U., Fischer, H., Segonds-Pichon, A., Feng, J., Magnussen M. S. & Kendrick, K. M. 2005 Lateralized local and global encoding of face stimuli by neural networks in the temporal cortex. Program no. 362.1 Abstract viewer/itinerary planner. Washington, DC: Society for Neuroscience. Tsao, D. Y., Freiwald, W. A., Knutsen, T. A., Mandeville, J. B. & Tootell, R. B. 2003 Faces and objects in macaque cerebral cortex. Nat. Neurosci. 6, 989–995. (doi:10.1038/ nn1111) Van Hooff, J. A. R. A. M. 1962 Facial expressions in higher primates. Symp. Zool. Soc. Lond. 8, 97–125. Vermeire, B. A. & Hamilton, C. R. 1998 Effects of facial identity, facial expression, and subject’s sex on laterality in

Phil. Trans. R. Soc. B (2006)

monkeys. Laterality 3, 1–19. (doi:10.1080/135765098 397377) Vermeire, B. A., Hamilton, C. R. & Erdmann, A. L. 1998 Right-hemispheric superiority in split-brain monkeys for learning and remembering facial discriminations. Behav. Neurosci. 112, 1048–1061. (doi:10.1037/0735-7044.112. 5.1048) Weiss, D. J., Kralik, J. D., Garibaldi, B. T. & Hauser, M. D. 2001 Face processing in cotton-top tamarins (Saguinus oedipus). Anim. Cogn. 4, 191–205. (doi:10.1007/s100710000076) Wiest, M. C., Bentley, N. & Nicolelis, M. A. L. 2005 Heterogeneous integration of bilateral whisker signals by neurons in primary somatosensory cortex of awake rats. J. Neurophysiol. 93, 2966–2973. (doi:10.1152/jn.00556. 2004) Winston, J. S., Henson, R. N., Fine-Goulden, M. R. & Dolan, R. 2004 fMRI-adaptation reveals dissociable neural representations of identity and expression in face perception. J. Neurophysiol. 92, 1830–1839. (doi:10.1152/ jn.00155.2004) Yamane, S., Kaji, S. & Kawano, K. 1988 What facial features activate face neurons in the inferotemporal cortex of the monkey? Exp. Brain Res. 73, 209–214. (doi:10.1007/ BF00279674) Yin, R. K. 1969 Looking at upside-down faces. J. Exp. Psychol. 81, 141–145. (doi:10.1037/h0027474) Young, M. P. & Yamane, S. 1992 Sparse population coding of faces in the inferotemporal cortex. Science 256, 1327–1331. (doi:10.1126/science.1598577)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Phil. Trans. R. Soc. B (2006) 361, 2173–2186 doi:10.1098/rstb.2006.1938 Published online 13 November 2006

Romantic love: a mammalian brain system for mate choice Helen E. Fisher1,*, Arthur Aron2 and Lucy L. Brown3 1

Department of Anthropology, Rutgers University, 131 George Street, New Brunswick, NJ 08901-1414, USA 2 Department of Psychology, State University of New York, Stony Brook, NY 11794, USA 3 Department of Neuroscience, Department of Neurology, Albert Einstein College of Medicine, New Haven, CT 06519-130, USA Mammals and birds regularly express mate preferences and make mate choices. Data on mate choice among mammals suggest that this behavioural ‘attraction system’ is associated with dopaminergic reward pathways in the brain. It has been proposed that intense romantic love, a human crosscultural universal, is a developed form of this attraction system. To begin to determine the neural mechanisms associated with romantic attraction in humans, we used functional magnetic resonance imaging (fMRI) to study 17 people who were intensely ‘in love’. Activation specific to the beloved occurred in the brainstem right ventral tegmental area and right postero-dorsal body of the caudate nucleus. These and other results suggest that dopaminergic reward and motivation pathways contribute to aspects of romantic love. We also used fMRI to study 15 men and women who had just been rejected in love. Preliminary analysis showed activity specific to the beloved in related regions of the reward system associated with monetary gambling for uncertain large gains and losses, and in regions of the lateral orbitofrontal cortex associated with theory of mind, obsessive/compulsive behaviours and controlling anger. These data contribute to our view that romantic love is one of the three primary brain systems that evolved in avian and mammalian species to direct reproduction. The sex drive evolved to motivate individuals to seek a range of mating partners; attraction evolved to motivate individuals to prefer and pursue specific partners; and attachment evolved to motivate individuals to remain together long enough to complete species-specific parenting duties. These three behavioural repertoires appear to be based on brain systems that are largely distinct yet interrelated, and they interact in specific ways to orchestrate reproduction, using both hormones and monoamines. Romantic attraction in humans and its antecedent in other mammalian species play a primary role: this neural mechanism motivates individuals to focus their courtship energy on specific others, thereby conserving valuable time and metabolic energy, and facilitating mate choice. Keywords: mate choice; romantic love; dopamine; oxytocin; vasopressin; evolution

1. ROMANTIC LOVE: A MAMMALIAN BRAIN SYSTEM FOR MATE CHOICE Individuals of many species exhibit mate preferences and focus their courtship energy on these favoured conspecifics. The phenomenon of ‘courtship attraction’ is so common in nature that the ethological literature regularly uses several terms to describe it, including ‘female choice’, ‘mate preference’, ‘individual preference’, ‘favouritism’, ‘sexual choice’ and ‘selective proceptivity’ (Andersson 1994). Charles Darwin regarded this phenomenon, what has become known as ‘mate choice’, as a central aspect of intersexual selection, the type of sexual selection by which individuals of one sex evolve traits that attract members of the opposite sex (Darwin 1871/n.d). Mammalian and avian species (as well as other species) have evolved many physical and behavioural characteristics by means of mate choice. The peacock’s * Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘The neurobiology of social recognition, attraction and bonding’.

tail feathers are the standard example. But investigations have focused on the traits that ‘display producers’ have evolved to attract mates. The corresponding neural mechanism by which ‘display choosers’ become attracted to these traits and focus their mating energy on particular preferred individuals, thereby making a mate choice, has not been defined. Therefore, it has been proposed (Miller 2000; Fisher et al. 2002a,b) that two aspects of intersexual selection evolved in tandem: (i) traits that evolved in the ‘display producer’ to attract mates, and (ii) corresponding neural mechanisms in the ‘display chooser’, the viewer of the display, that evolved to enable him/her to discriminate between various displays, become attracted to some and pursue these specific preferred individuals. Several brain systems most probably operate in tandem to orchestrate mate choice, including the neural systems for sensory perception, memory, and cognitive and emotional responses. But the specific brain mechanism discussed in this review is the neural mechanism that motivates the display chooser to pursue a preferred mating partner, the courtship attraction

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system. Courtship attraction is characterized in mammals by increased energy, focused attention, obsessive following, affiliative gestures, possessive mate guarding and motivation to win a preferred mating partner (Fisher 2004). A number of groups have reported that the basic human motivations and emotions arise from distinct systems of neural activity and that these brain systems derive from mammalian precursors (Davidson 1994; Panksepp 1998). Thus, it is parsimonious to suggest that a mammalian brain mechanism for courtship attraction is also active in Homo sapiens. Moreover, because human romantic love (also known as passionate love, obsessive love and ‘being in love’) is a universal human phenomenon ( Jankowiak & Fischer 1992), because romantic love’s central characteristic is mate preference and because ‘being in love’ exhibits many of the other traits associated with mammalian courtship attraction, it has been hypothesized that human romantic love is a developed form of this mammalian neural mechanism for mate choice (Fisher 1998). In most species, courtship attraction is brief, lasting only for minutes, hours, days or weeks; in humans, intense early stage romantic love can last 12–18 months (Marazziti et al. 1999) or more. This review discusses the present evidence for this brain system in mammals and humans, focusing on recent neuroimaging studies of romantic love in humans (Bartels & Zeki 2000, 2004; Aron et al. 2005; Fisher et al. 2005a,b). It examines how this brain system varies from the sex drive and how it changes across time (Aron et al. 2005). It also discusses preliminary data on neural mechanisms associated with romantic rejection (Fisher et al. 2005a,b). Finally, it proposes that this brain system is one of the three primary mating drives which interact in many ways and which have evolved in mammalian and avian species to direct various aspects of reproduction. (i) The sex drive evolved to motivate individuals to seek copulation with a range of partners, (ii) courtship attraction/romantic love evolved to enable ‘display choosers’ to focus their mating energy on specific mates, thereby conserving courtship time and metabolic energy, and (iii) partner attachment evolved to motivate mating individuals to remain together long enough to perform speciesspecific parental duties (Fisher 1998).

2. MAMMALIAN COURTSHIP ATTRACTION ‘It was evidently a case of love at first sight, for she swam about the new-comer caressingly...with overtures of affection’ (Darwin 1871/n.d.). Darwin was describing a female Mallard duck. Blackbirds, thrush, black grouse, pheasants, these and many other birds, were reported as ‘fell in love with one another’ (Darwin 1871/n.d.). A myriad of other descriptions of courtship attraction have been reported by ethologists (Andersson 1994). Gladikas (1995) reports of a free-ranging orangutan living in the Tanjung Putting Reserve, Borneo, ‘The object of TP’s adoration was Priscilla . I thought that TP would have chosen a more comely female. But . TP was smitten with her . He couldn’t take his eyes off her. He didn’t even bother to eat, so enthralled was he by her balding charms’. Housing Phil. Trans. R. Soc. B (2006)

conditions are likely to alter the display of mate preferences among laboratory animals when not presented with a choice, but free-ranging individuals regularly exhibit sexual favouritism. Yet despite hundreds of ethological descriptions of courtship attraction in a wide array of mammalian and avian species, ethologists have traditionally lumped this motivation/emotion system together with the sex drive. However, there are exceptions. Beach (1976) made a distinction between the sex drive and the courtship attraction, writing that the occurrence of copulation depended as much on individual affinities and aversions as upon the presence or absence of sex hormones and that proceptive and receptive behaviour in the female may depend upon different anatomical and neurochemical systems in the brain. Hutchison & Hutchison (1983) proposed that courtship entailed a sequence of choices, each requiring different mechanisms, and they questioned whether the sex hormones had any specific role in the establishment and expression of mating preferences. Pfaff (2002) distinguishes between the hormone-dependent facilitation of sexual arousal and the expression of approach and other courtship behaviours, regarding these as distinct aspects of mating behaviour and physiology. Kendrick & Dixson (1986) have shown that anteromedial hypothalamic lesions block proceptivity but not receptivity in the female common marmoset. Finally, Goodall (1986) reported that males of many primate species ‘show clear-cut preferences for particular females, which may be independent of cycle stage’. Various neurochemical mechanisms have also been associated with courtship attraction. Darwin hypothesized that female mate preferences arose from their innate sense of beauty. But he (understandably) offered no hypothesis regarding which specific neural mechanisms might be involved (Darwin 1871/n.d.). Miller (2000) noted that several faculties must have evolved to discern and respond to the courtship traits of display producers, referring to this constellation of neural mechanisms as ‘mental machinery’ and ‘sexual choice equipment’. Miller (2000) also distinguished between ‘cold choosers’, such as insects that become attracted to ornamental displays without any sensation of pleasure, and ‘hot choosers’, animals whose choice of mates is directed by subjective feelings of pleasure; and he proposed that the endorphins may be involved in the mate choices of hot choosers. Beach (1976) suggested that the monoamines were involved in mate preference, saying, ‘The mating behaviour of female rats treated with monoamine receptor blocking agents indicates that lordotic behaviour and soliciting behaviour may be mediated by anatomically and possibly neurochemically distinct systems’. Present research supports Beach’s hypothesis. When a female laboratory-maintained prairie vole (Microtus ochrogaster) is mated with a male, she forms a distinct preference for him associated with a 50% increase in dopamine in the nucleus accumbens (Gingrich et al. 2000). When a dopamine antagonist is injected into the accumbens, the female no longer prefers this partner and when a female is injected with a dopamine agonist, she begins to prefer the conspecific that is present at the time of infusion, even if she has not mated with this

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Romantic love male (Wang et al. 1999; Gingrich et al. 2000). An increase in central dopamine is also associated with courtship attraction in female sheep (Fabre-Nys 1997, 1998). In male rats, too, increased striatal dopamine release has been shown in response to the presence of a receptive female rat (Robinson et al. 2002; Montague et al. 2004). Recent data on several peptides also suggest that central dopamine plays a role in regulating mate preference. Kendrick & Dixson (1985) showed that in marmosets, luteinizing hormone-releasing hormone specifically facilitated female proceptive behaviours, and oxytocin and vasopressin have been shown to facilitate social recognition in mammalian species. All of these peptides facilitate monoamine release (Kendrick 2000). Therefore, it has been suggested that mate preference may be influenced as these peptides rewire brain circuits so that sensory and other stimuli from specific individuals have more potent effects on monoamine release, particularly release of dopamine in brain reward centres (Lim et al. 2004). The extensive ethological literature on sexually dimorphic traits that evolved to attract mates, in conjunction with the above physiological data on mate preference in several species, suggests that intersexual selection involves interactions between the display traits of display producers and a brain system for mate preference in display choosers, courtship attraction. Moreover, the data suggest that the brain system for courtship attraction is distinct from, yet operates in tandem with, the sex drive to orchestrate proceptivity in birds and mammals. Finally, the dopaminergic reward pathways may be involved.

3. HUMAN ROMANTIC LOVE It was appropriate to investigate this brain system in Homo sapiens for several reasons. Foremost, intense romantic love is a cross-cultural universal. In a survey of 166 societies, Jankowiak & Fischer (1992) found evidence of romantic love in 147 of them. No negative data were found; in the 19 remaining cultures, anthropologists had failed to ask the appropriate questions; all were cases of ethnographic oversight. Jankowiak & Fischer (1992) concluded that romantic love constitutes a ‘human universal . or near universal’. Moreover, romantic love is associated with a specific set of physiological, psychological and behavioural traits (Tennov 1979; Hatfield & Sprecher 1986; Shaver et al. 1987; Hatfield et al. 1988; Harris & Christenfeld 1996; Fisher 1998; Gonzaga et al. 2001); and most of these traits are also characteristic of mammalian courtship attraction, including increased energy, focused attention, obsessive following, affiliative gestures, possessive mate guarding, goal-oriented behaviours and motivation to win a preferred mating partner (Fisher et al. 2002a,b; Fisher 2004). Romantic love begins as an individual starts to regard another individual as special and unique. The lover then focuses his/her attention on the beloved, aggrandizing the beloved’s worthy traits and overlooking or minimizing his/her flaws. The lover expresses increased energy, ecstasy when the love affair Phil. Trans. R. Soc. B (2006)

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is going well and mood swings into despair during times of adversity. Adversity and barriers heighten romantic passion, what has been referred to as ‘frustration attraction’ (Fisher 2004). The lover suffers ‘separation anxiety’ when apart from the beloved and a host of sympathetic nervous system reactions when with the beloved, including sweating and a pounding heart. Lovers are emotionally dependent; they change their priorities and daily habits to remain in contact with and/or impress the beloved. Smitten humans also exhibit empathy for the beloved; many are willing to sacrifice, even die for this ‘special’ other. The lover expresses sexual desire for the beloved, as well as intense sexual possessiveness, mate guarding. Yet the lover’s craving for emotional union supersedes his/her craving for sexual union with the beloved. Most characteristic, the lover thinks obsessively about the beloved, ‘intrusive thinking’. Rejected lovers first experience a phase of protest, during which they try to win back the beloved and often feel abandonment rage; then they move into the second stage of rejection, associated with resignation and despair. Romantic love is also involuntary, difficult to control and generally impermanent. Since romantic love shares many characteristics with mammalian courtship attraction, it has been hypothesized that this human preference system would also be associated with the monoamines, specifically elevated activity of central dopamine and/or central norepinephrine (Liebowitz 1983; Fisher 1998).

4. ROMANTIC LOVE: FUNCTIONAL MAGNETIC RESONANCE IMAGING RESEARCH To investigate the constellation of neural correlates associated with romantic love, Fisher, Aron, Brown and colleagues recruited 10 women and 7 men who were intensely in love. The age range was 18–26 years (MZ20.6; medianZ21); the reported duration of ‘being in love’ was 1–17 months (MZ7.4; medianZ7). Each participant was orally interviewed in a semi-structured format to establish the duration, intensity and range of his/her feelings of romantic love. Each also completed the Passionate Love Scale (PLS), a 9-point Likert scale self-report questionnaire which measures traits commonly associated with romantic love (Hatfield & Sprecher 1986; Cronbach’s alpha for questionnaire reliability in this studyZ0.81; Cronbach 1951). A preliminary investigation had identified a photograph of the beloved as an effective stimulus for eliciting feelings of intense romantic love (Mashek et al. 2000). Thus, the protocol employed photographs and consisted of four tasks presented in an alternating block design: for 30 s, each participant viewed a photo of his/ her beloved (positive stimulus); for the following 40 s, each performed a countback distraction task; for the following 30 s, each viewed a photograph of an emotionally neutral acquaintance (neutral stimulus); and for the following 20 s, each performed a similar countback task. The countback task involved viewing a large number, such as 8421, and mentally counting backwards (beginning with this number) in increments of seven. We included the countback task to decrease

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the carry-over effect after the participant viewed the positive stimulus because it is difficult to quell intense feelings of romantic love. This four-part sequence (or a counterbalanced version beginning with the neutral stimulus) was repeated six times; the total stimulus protocol was 720 s (12 min). Pre-scanning instructions were to think about a non-sexual euphoric experience with the beloved; post-scanning interviews established that the participants had engaged in romantic thinking and feeling. Group activation specific to the beloved occurred in several regions, including the right ventral tegmental area (VTA) localized in the region of A10 dopamine cells (Aron et al. 2005). The VTA is a central region of the brain’s reward system (Wise 1996; Schultz 2000; Martin-Soelch et al. 2001), associated with pleasure, general arousal, focused attention and motivation to pursue and acquire rewards (Schultz 2000; Delgado et al. 2000; Elliot et al. 2003). The VTA sends projections to several brain regions (Gerfen et al. 1987; Oades & Halliday 1987; Williams & Goldman-Rakic 1998), including the caudate nucleus where we also found group activations, specifically in the right medial and postero-dorsal body (Aron et al. 2005). The caudate plays a role in reward detection and expectation, the representation of goals and the integration of sensory inputs to prepare for action (e.g. Schultz 2000; Martin-Soelch et al. 2001; Lauwereyns et al. 2002; O’Doherty et al. 2002). Zald et al. (2004) found that predictable monetary reward presentation caused dopamine release in the medial caudate body where we found activation. Using functional magnetic resonance imaging (fMRI), Bartels & Zeki (2000) also investigated brain activity in 17 men and women who reported being ‘truly, deeply and madly in love’. Eleven were women; all looked at a photograph of his/her beloved, as well as photographs of three friends of similar age, sex and length of friendship. But the participants in that study had been in love substantially longer than those in our study (28.8 months versus 7.4 months t[32]Z4.28, p!0.001). They were also less intensely in love. This was established because both study groups were (serendipitously) administered the same questionnaire on romantic love, the PLS (respective scores were 7.55 versus 8.54, t[31]Z3.91, p!0.001). In spite of these differences in protocol, Bartels & Zeki (2000, 2004) found activity in regions of the ventral tegmental area and caudate nucleus, as we did. These data are consistent with the above animal literature, suggesting that mesolimbic dopamine pathways in the reward system of the brain play a role in the pleasurable feelings, focused attention, motivation and goal-oriented behaviours associated with romantic love. However, activation of subcortical dopaminergic pathways of the VTA and caudate nucleus may comprise only the ‘general arousal’ component (Pfaff 1999) of this brain system for mate preference and mate pursuit (Fisher 2004). Other neurotransmitters are likely to be involved, including glutamate in the mesocortical system, owing to their role in the release of dopamine in the VTA (Legault & Wise 1999) and/or their fast signals in the prefrontal cortex regarding reward (Lavin et al. 2005). Phil. Trans. R. Soc. B (2006)

Central norepinephrine may also be associated with courtship attraction (Fisher 1998). This was hypothesized because increased activity of norepinephrine generally produces alertness, energy, sleeplessness and loss of appetite (Coull 1998; Robbins et al. 1998), increased attention (Posner & Peterson 1990) and increased memory for new stimuli (Griffin & Taylor 1995), some of the primary characteristics of human romantic love (Tennov 1979; Hatfield & Sprecher 1986; Fisher 2004). As norepinephrine is also associated with peripheral sympathetic nervous system responses, including increased heart rate, sweating and trembling, central norepinephrine may contribute to these aspects of romantic love/courtship attraction as well (Fisher 1998). The above data suggest that mammalian courtship attraction and human romantic love are associated with dopaminergic reward pathways in the brain. These data also support the hypothesis that romantic love is distinct from the sex drive (Aron & Aron 1991; Fisher 1998).

5. THE SEX DRIVE The sex drive is characterized by the urge for sexual gratification. It is associated with the androgens and oestrogens in non-primate mammalian species and primarily with the androgens in many primates, especially humans (Edwards & Booth 1994; Sherwin 1994; Van Goozen et al. 1997). Humans with higher circulating levels of testosterone tend to engage in more sexual activity (Edwards & Booth 1994; Sherwin 1994). Women tend to feel more sexual desire during and around ovulation, when testosterone activity increases (Van Goozen et al. 1997). Both sexes have fewer sexual fantasies, masturbate less regularly and engage in less intercourse as levels of the androgens decline with age (Edwards & Booth 1994). The balance between the androgens, oestrogens and other bodily systems, as well as childhood and adult experiences and a host of other biological and environmental factors play a role in when, where and how often individuals express the sex drive (Nyborg 1994). Nevertheless, the androgens are central to the sex drive and these gonadal and adrenal hormones have not been associated with human romantic love. Moreover, when humans self-administer androgens to boost sex drive, they do not report that they fall in love. These two neural systems do not always act in tandem in Homo sapiens. Several fMRI studies support the hypothesis that the sex drive is associated with specific networks of brain activation and that these networks are largely distinct from those associated with human romantic love/ mammalian courtship attraction. Arnow et al. (2002) reports that when young male heterosexual subjects look at erotic video material while wearing a custombuilt pneumatic pressure cuff around the penis, their sexual arousal is associated with strong activations in the right subinsular region, including the claustrum, left caudate and putamen, right middle occipital/ middle temporal gyri, bilateral cingulate gyrus, right sensorimotor and pre-motor regions, and right hypothalamus.

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Romantic love Using fMRI, Beauregard et al. (2001) measured brain activation in men as they viewed erotic film excerpts. Activations occurred in limbic and paralimbic structures, including the right amygdala, right anterior temporal pole and hypothalamus. Using fMRI, Karama et al. (2002) also recorded brain activity while men and women viewed erotic film excerpts. Activity increased in the anterior cingulate, medial prefrontal cortex, orbitofrontal cortex, insula and occipitotemporal cortices, as well as in the amygdala and ventral striatum. Men showed activation in the thalamus and significantly greater activation than women in the hypothalamus, specifically in a sexually dimorphic area associated with sexual arousal and behaviour. Animal studies also indicate that several brain structures are associated with the sex drive and sexual expression, including the medial amygdala, medial preoptic area, paraventricular nucleus and periaqueductal gray (PAG; Heaton 2000), as well as the septum and the ventromedial hypothalamus (Dixson 1998). Although the neural regions associated with the sex drive overlap those associated with courtship attraction, these two neural systems show many differences, suggesting that the primary brain system for the sex drive is distinct from the brain system associated with human romantic love (Aron & Aron 1991; Fisher 1998). Anecdotal behavioural data in humans support this hypothesis. (i) The sex drive is focused on a specific goal, sexual union with another, and romantic love is focused on a different goal, emotional union with another. (ii) The sex drive is often expressed towards a range of individuals and romantic love is focused on one particular individual. (iii) The sex drive is often temporarily quelled when satisfied and romantic love does not decrease with coitus and often persists unabated for months, even years. (iv) Most liberated adults have engaged in coitus with individuals for whom they felt no romantic love and many have also been ‘in love’ with someone with whom they have had no physical contact. Several lines of investigation indicate that the sex drive and the courtship attraction/romantic love are distinct neural systems, designed to orchestrate different aspects of the reproductive process. The sex drive enables individuals to initiate courtship and mating with a range of partners; courtship attraction/ romantic love motivates them to focus their mating energy on specific individuals, thereby conserving time and metabolic energy. Nevertheless, the brain systems for the sex drive and the courtship attraction regularly interact to coordinate mammalian mate choice.

6. THE SEX DRIVE AND MATE PREFERENCE: INTERACTIONS The biological relationships between the sex drive and the courtship attraction are most likely dose dependent and variable, depending on which brain regions are involved and many other biological and environmental factors. However, data suggest that these brain systems have a positive correlation. Phil. Trans. R. Soc. B (2006)

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Animal studies indicate that elevated activity of dopaminergic pathways can stimulate a cascade of reactions, including the release of testosterone and oestrogen (Wenkstern et al. 1993; Kawashima &Takagi 1994; Ferrari & Giuliana 1995; Hull et al. 1995, 1997, 2002; Szezypka et al. 1998; Wersinger & Rissman 2000). Likewise, increasing levels of testosterone and oestrogen promote dopamine release (Hull et al. 1999; Auger et al. 2001; Becker et al. 2001; Appararundaram et al. 2002; Creutz & Kritzer 2002; Pfaff 2005). When a male rat is placed in an adjacent cage, where he can see or smell an oestrous female, activity of central dopamine increases and contributes to sexual arousal and pursuit of the female (West et al. 1992; Wenkstern et al. 1993; Hull et al. 1995, 1997, 2002). When the barrier is removed and the male is allowed to copulate, activity of dopamine continues to rise in the medial preoptic area (Hull et al. 1995). When dopamine is injected into specific brain regions of the male rat, the infusion stimulates copulatory behaviour (Ferrari & Giuliana 1995). Blocking the activities of central dopamine in rats diminishes several proceptive sexual behaviours, including hopping and darting (Herbert 1996). Finally, electrochemical studies in male rats show increased dopamine release in the dorsal and the ventral striatum in response to the presence of a receptive female rat (Robinson et al. 2002; Montague et al. 2004). Pfaff (2005) reports that in male rats, dopamine increases male sexual behaviour in at least three ways: it increases sexual arousal and courtship behaviour; it potentiates the motor acts of mounting; and it facilitates genital responses to stimulation. This positive relationship between elevated activity of central dopamine, elevated sex steroids and elevated sexual arousal and sexual performance (Herbert 1996; Fiorino et al. 1997; Liu et al. 1998; Pfaff 2005) also occurs in humans (Walker et al. 1993; Clayton et al. 2000; Heaton 2000). When individuals exhibiting hypoactive sexual desire disorder are treated with dopamine-enhancing medications, libido improves (Segraves et al. 2001). When patients suffering from depression take drugs that elevate central dopamine activity, their sex drive often improves (Walker et al. 1993; Ascher et al. 1995; Coleman et al. 1999). In fact, since elevated activity of central serotonin is inhibitory to the sex drive (Rosen et al. 1999; Montejo et al. 2001), some patients taking serotonin-enhancing antidepressants supplement this therapy with medications that elevate the activity of dopamine (and norepinephrine) solely to maintain or elevate sexual appetite and arousal (Walker et al. 1993; Ascher et al. 1995; Coleman et al. 1999; Rosen et al. 1999). Animal studies indicate that norepinephrine is also positively linked with sexual motivation and sexual arousal (Van Bockstaele et al. 1989; Clayton et al. 2002; Fraley 2002; Pfaff 2005). When a female prairie vole is exposed to a drop of male urine on the upper lip, norepinephrine in the olfactory bulb contributes to the release of oestrogen and concomitant proceptive behaviour (Dluzen et al. 1981). The reverse also occurs; oestradiol and progesterone contribute to the release of norepinephrine in the hypothalamus to produce lordosis in rats (Etgen et al. 1999). Moreover, when ovariectomized, sexually receptive female rats

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receive injections of oestrogen and are then permitted to mate, copulation produces the release of norepinephrine in the lateral ventromedial hypothalamus (Etgen & Morales 2002). Drug users attest to this positive chemical relationship between norepinephrine and the sex drive. In the right oral dose, amphetamines (norepinephrine and dopamine agonists) enhance sexual desire (Buffum et al. 1988). The complex interaction between these catecholamines and gonadal hormones suggests why the sex drive and the courtship attraction have traditionally been lumped into a single behavioural category, proceptivity. Instead, these distinct neural systems appear to work in tandem to enable display choosers to explore an array of mating partners, focus their courtship attention on preferred individuals and then sustain attraction and sexual arousal long enough to complete species-specific mating behaviours.

7. PARTNER ATTACHMENT The full array of brain systems associated with courtship, mating and parenting and the interactions between these brain systems need further investigation (Fisher & Thomson in press). Nevertheless, the available literature suggests that at least three distinct, yet interrelated neural systems play a role in reproduction: the sex drive, courtship attraction and partner attachment. Each of these motivation/emotion systems is associated with a different behavioural repertoire, each is associated with a different and dynamic constellation of neural correlates and each evolved to direct a different aspect of reproduction (Fisher 1998). The relationship between courtship attraction/romantic love and the sex drive has been discussed above, and partner attachment is considered next. Partner attachment, or pairbonding, in birds and mammals is characterized by mutual territory defence and/or nest building, mutual feeding and grooming, maintenance of close proximity, separation anxiety, shared parental chores and affiliative behaviours. The ethological literature commonly infers that this constellation of attachment behaviours associated with pairbonding evolved primarily to motivate mating partners to sustain an affiliative connection long enough to complete species-specific parental duties. This parental attachment system has been associated with the activity of the neuropeptides, oxytocin (OT) in the nucleus accumbens and arginine vasopressin (AVP) in the ventral pallidum (Carter 1992; Winslow et al. 1993; Wang et al. 1994; Carter et al. 1997; Young et al. 1998; Lim & Young 2004; Lim et al. 2004), although the brain’s opioid system (Moles et al. 2004) and other neural systems are involved as well (Kendrick 2000). Bowlby (1969, 1973) and Ainsworth et al. (1978) proposed that, to promote survival of the young, primates have evolved an innate attachment system designed to motivate infants to seek comfort and safety from their primary caregiver, generally their mother. More recently, researchers have emphasized that this attachment system remains active throughout their life and serves as a foundation for attachment between spouses as they raise children (Hazan & Shaver 1987; Hazan & Diamond 2000). Data from the Demographic Phil. Trans. R. Soc. B (2006)

Yearbooks of the United Nations on 97 societies suggest the prevalence of this attachment system in humans. Approximately 93.1% of women and 91.8% of men marry by age 49 (Fisher 1992). Pairbonding and attachment behaviours are central aspects of the multi-part human reproductive strategy (Fisher 1992). Hatfield (1988) refers to feelings of attachment as companionate love, which she defines as ‘a feeling of happy togetherness with someone whose life has become deeply entwined with yours’. Extensive research has been done on this attachment system in adults (Fraley & Shaver 2000), but this literature does not regularly distinguish between feelings of attachment and feelings of romantic love (Aron et al. 2006). However, cross-cultural and historical data indicate that people in other societies and centuries do distinguish between feelings of romantic love and attachment. Nisa, a !Kung Bushman woman of the Kalahari Desert, Botswana, reported, ‘When two people are first together, their hearts are on fire and their passion is very great. After a while, the fire cools and that’s how it stays. They continue to love each other, but it’s in a different way–-warm and dependable’ (Shostak 1981). The Taita of Kenya say that love comes in two forms, an irresistible longing, a ‘kind of sickness’, and a deep enduring affection for another (Bell 1995). In Korea, ‘sarang’ is a word close to the western concept of romantic love, while ‘chong’ is more like feelings of long-term attachment; Abigail Adams, wife of America’s second president, distinguished these feelings when writing to John Adams in 1793, ‘Years subdue the ardor of passion, but in lieu thereof friendship and affection deep-rooted subsists, which defies the ravages of time’ (McCullough 2001). Current brain imaging investigations in humans and animal studies indicate some of the neural correlates of this attachment mechanism. These data also suggest that the neural correlates for attachment are distinct from those for early-stage intense romantic love in humans and courtship attraction in other mammalian species, yet these two brain systems interact.

8. NEUROIMAGING AND ANIMAL STUDIES OF ATTACHMENT As discussed earlier, using fMRI, Bartels & Zeki (2000) studied 17 men and women who were in love. However, their subjects were in love for an average of 28.8 months, a considerably longer period of time compared with our participants who were in love for an average of 7.4 months (Aron et al. 2005); their subjects were less passionately in love (Aron et al. 2005). Their participants also exhibited activity in several brain regions where our subjects showed none, including the anterior cingulate cortex and midinsular cortex. These varying results stimulated us to examine the subset of our subjects in longer relationships, specifically those who were in love between 8 and 17 months. In our subset of individuals in longer relationships, several regions showed activations, including the right anterior and posterior cingulate cortex, and right mid-insular cortex (Aron et al. 2005).

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Romantic love Thus, we confirmed Bartels & Zeki’s (2000) findings that the anterior cingulate and insular cortex are involved in longer term love relationships. More relevant to this discussion, we also found activation in the ventral putamen/pallidum (Aron et al. 2005). Activity in this region, associated with a specific distribution pattern of vasopressin (V1a) receptors, has been linked with pairbonding and attachment behaviours in monogamous prairie voles (Lim & Young 2004; Lim et al. 2004), monogamous California mice and monogamous marmosets, whereas promiscuous white-footed mice and promiscuous rhesus monkeys do not express pairbonding/attachment behaviours or this distribution of V1a receptors in the ventral pallidum (Wang et al. 1997; Young et al. 1997; Bester-Meredith et al. 1999; Young 1999). Hence, activity in the ventral pallidum is greater in longer term human relationships than in shorter ones and activity in the ventral pallidum, specifically associated with vasopressin, is evident in other pairbonding/attaching mammals. But vasopressin activity in the ventral pallidum also affects partner preference, a central characteristic of mammalian courtship attraction and human romantic love. Lim & Young (2004) report that arginine vasopressin antagonists infused into the ventral pallidum prevented partner preference formation among male prairie voles. Yet they also report that V1aR activation in this region is necessary for pairbond formation (Lim & Young 2004). Activity of central oxytocin in the nucleus accumbens also contributes to both pairbonding and partner preference (Lim et al. 2004). Williams et al. (1994) report that when oxytocin was administered intracerebroventricularly, ovariectomized female prairie voles preferred the partner who was present at the time of infusion; and Lim, Murphy and Young report that when an oxytocin receptor (OTR) antagonist is infused directly into the nucleus accumbens of a female prairie vole, this antagonist blocks partner preference formation (Young et al. 2001; Lim et al. 2004). Yet they also conclude that among monogamous prairie voles, OTRs and vasopressin V1a receptors (V1aR) in the ventral forebrain play critical roles in the formation of pairbonds. Research on the genetic basis of pairbonding also lumps partner preference and attachment behaviours. Pitkow et al (2001) reported that structural differences in the V1 receptor gene of socially monogamous male voles (as opposed to asocial promiscuous voles) increased levels of the expression of this receptor in the ventral pallidum; moreover, these males also exhibited heightened levels of social affiliation. They formed a preference for a specific female and began to cohabit with her, even though they had not mated with this female. Lim, Young and colleagues report that when they transfected this genetic variant (the monogamous version) into the pallidum of meadow voles, an asocial promiscuous species, vasopressin receptors were upregulated; each male also began to fixate on a particular female and mate exclusively with her, even though other females were available (Lim et al. 2004). The activities of central oxytocin and vasopressin have been associated with both partner preference and Phil. Trans. R. Soc. B (2006)

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attachment behaviours, while dopaminergic pathways have been associated more specifically with partner preference. So Lim et al. (2004) integrate these data, proposing that when monogamous prairie voles and other pairbonding creatures engage in sex, copulation triggers the activity of vasopressin in the ventral pallidum and oxytocin in the nucleus accumbens and facilitates dopamine release in these reward regions, which motivates males and females to prefer a current mating partner and initiates attachment/pairbonding behaviours. Moreover, males of promiscuous species (who lack one link in this chain for encoding the V1a receptor for vasopressin in the ventral pallidum) most probably feel attraction, but do not associate this pleasurable feeling with their specific mating partner so they do not initiate a longer term attachment. In species that do not form these bonds, this relationship with dopamine reward centres is much weaker (Kendrick 2000). Like the brain systems for the sex drive and the courtship attraction, the neural mechanism for attachment is complex, flexible, varies in its threshold and intensity and is most likely integrated with many other brain systems (Kendrick 2000), probably including the opioids (Moles et al. 2004). Nevertheless, the above data suggest that the neural systems for courtship attraction and partner attachment work in tandem in a pairbonding species, motivating individuals to prefer a specific mating partner and also motivating them to form an attachment to this mate. These data also suggest that courtship attraction and partner attachment can operate independently in non-monogamous species, enabling individuals to prefer specific mating partners yet avoid long-term attachments. Data on the neural correlates of maternal love support the proposition that feelings of attachment and feelings of romantic love are distinct yet interrelated neural systems. Bartels & Zeki (2004) used fMRI to measure brain activity in mothers while each looked at a photo of her own infant, an infant with whom she was acquainted, an adult best friend and an adult acquaintance. They then compared these data on the neural mechanisms associated with maternal attachment with their data on the neural correlates of (later stage) romantic love (Bartels & Zeki 2000). Maternal love activated several specific brain regions that differed from those associated with romantic love, including the lateral orbitofrontal cortex and the PAG. Maternal love also activated some brain regions that were the same as those activated by romantic love, including regions of the medial insula, anterior cingulate gyrus and caudate nucleus. Finally, activity associated with maternal love and romantic love overlapped in brain areas rich in oxytocin and vasopressin receptors, including the substantia nigra (Bartels & Zeki 2004). The neural flexibility of these brain systems for reproduction and their interactions with one another and other brain systems are complex (Kendrick 2000). For example, central dopamine (and norepinephrine) can stimulate the release of oxytocin and vasopressin in neurohypophyseal tissues (Kendrick et al. 1992; Ginsberg et al. 1994; Galfi et al. 2001); but increasing

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activity of central dopamine can also inhibit release of central oxytocin (Seybold et al. 1978; Vizi & Volbekas 1980). Increasing activity of central oxytocin can stimulate release of norepinephrine and dopamine (Kendrick 2000) or interfere with dopamine and norepinephrine pathways (Schwarzberg et al. 1981; Kovacs & Telegdy 1983; Kovacs et al. 1990; Van de Kar et al. 1998). Finally, a small microsatellite repeat sequence in the gene coding for V1aR controls its density of expression in the ventral pallidum and this gene region is subject to a number of polymorphisms that contribute to variability in the strength of monogamous bonding in male prairie voles (Hammock & Young 2005). The Homo sapiens version of this gene has similar polymorphisms, which might contribute to individual differences in human monogamous pairbonding as well. The above data suggest that the mammalian attachment system is distinct from, yet interacts with, the neural mechanisms for courtship attraction and the sex drive. This flexible, combinatorial system would provide individuals of myriad species with the range of motivations, emotions and behaviours necessary to pursue their species-specific reproductive strategy. These data on attachment and romantic love also lend perspective to another aspect of reproduction, rejection in love.

9. REJECTION IN LOVE Romantic love is expressed in many graded forms, but it has two extremes: love that is returned and love that is rejected. To understand the range of neural mechanisms associated with mate choice, Fisher, Aron, Brown and colleagues used fMRI to study 10 women and 5 men who were still very much in love but had recently been rejected by their romantic partner (Fisher et al. 2005a,b). We used the same protocol as with our happily in-love subjects (Aron et al. 2005). Rejected participants alternately viewed a photograph of their abandoning beloved (positive stimulus) and a photograph of a familiar, emotionally neutral individual (neutral stimulus), interspersed with a distraction– attention task. Preliminary analysis of the positive–neutral contrast showed significant group effects in the right nucleus accumbens/ventral putamen/pallidum, lateral orbitofrontal cortex and anterior insular/operculum cortex (Fisher et al. 2005a,b). We then compared these data on rejected lovers with the results from our study of 17 happily in-love individuals (Aron et al. 2005). Rejected lovers expressed significantly greater activity in the ventral striatum/putamen/pallidum than did those who were happily in love (figure 1). Other studies have shown that the nucleus accumbens/ventral pallidum/putamen region where we found activity becomes more active as an individual chooses a high-risk investment associated with big gains or big losses, making it an uncertain gain (Kuhnen & Knutson 2005), or anticipates a money reward (Zald et al. 2004); data from rat studies are consistent with the idea that the nucleus accumbens core is important for choices for uncertain rewards and delayed reinforcement (e.g. Cardinal & Howes 2005); activity Phil. Trans. R. Soc. B (2006)

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Figure 1. Three axial sections through the human brain at 2 mm intervals show a consistent activation difference between a group happily in love and a group in love but recently rejected (yellow colour, p!0.01). Those who were recently rejected show greater activation in the right ventral putamen–pallidum and accumbens core (side definition is radiological convention) than those who were happily in love. These regions have been associated with reward, especially uncertain large gains and losses in gambling, and uncertain reinforcement in rats. (Figure data from Aron et al. 2005 and a preliminary report, Fisher et al. 2005a,b).

in the nucleus accumbens has also been associated with pairbond formation and maintenance in prairie voles (Lim et al. 2004). The region of the anterior insula/ operculum cortex where we found activity has been associated with skin and muscle pain and with anxiety (Schreckenberger et al. 2005). The region of the lateral orbitofrontal cortex where we found activity has been associated with theory of mind (Vollm et al. 2006), evaluating punishers (Kringelbach & Rolls 2004), implementing appropriate adjustments in behaviour (Ridderinkhof et al. 2004), obsessive/compulsive behaviours (Evans et al. 2004) and with controlling anger in recently abstinent cocaine-dependent individuals (Goldstein et al. 2005). These results suggest that brain systems associated with reward and motivation remain active in recently romantically rejected men and women, but differ in their precise location. These preliminary results also suggest that neural regions associated with risk-taking for big gains or losses, physical pain, obsessive/compulsive behaviours, ruminating on the intentions and actions of the rejecter, evaluating options, and emotion regulation increase in their activity when someone is rejected by a beloved. Our study is the second investigation of romantic rejection. Najib et al. (2004) studied nine women who were ‘actively grieving’ over a recent romantic breakup. Our preliminary comparisons uncovered no commonalities; in fact, in several regions where we found activations, they found deactivations. Since our subjects regularly reported anger and hope for reconciliation, while subjects in the Najib et al. (2004) study more regularly reported acceptance, we suspect that our subjects were in the initial stage of romantic rejection, the protest phase, while their participants were largely in the subsequent resignation/despair phase. The combined aforementioned data may contribute understanding to the high cross-cultural rates of stalking, homicide, suicide and clinical depression associated with rejection in love (Meloy & Fisher 2005).

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Romantic love 10. THE DRIVE TO LOVE The psychological literature distinguishes between emotions (affective states of feeling) and motivations (brain systems oriented around the planning and pursuit of a specific want or need). Aron has proposed that romantic love is not primarily an emotion, but a motivation system designed to enable suitors to build and maintain an intimate relationship with a preferred mating partner (Aron & Aron 1991; Aron et al. 1995). The fMRI and animal experiments we have reviewed above support Aron’s hypothesis. The VTA is directly associated with motivation- and goal-oriented behaviours, as is the caudate nucleus. Moreover, the caudate nucleus has widespread afferents from all of the cortex except primary visual areas (Kemp & Powell 1970; Selemon & Goldman-Rakic 1985; Saint-Cyr et al. 1990; Eblen & Graybiel 1995; Flaherty & Graybiel 1995) and is organized to integrate diverse sensory, motor and limbic functions (Brown 1992; Parthasarathy et al. 1992; Eblen & Graybiel 1995; Parent & Hazrati 1995; Parent et al. 1995; Brown et al. 1998; Haber 2003). Thus, regions of the caudate nucleus could effectively integrate the behavioural and biological actions associated with a complex state, such as romantic love. In fact, these findings suggest that romantic love is a primary motivation system, a fundamental human mating drive (Fisher 2004). Pfaff (1999) defines a drive as a neural state that energizes and directs behaviour to acquire a particular biological need to survive or reproduce and he reports that all drives are associated with the activity of dopaminergic pathways and a few other specific neural systems (as well as other neural systems specific to each individual drive state). Romantic love has many characteristics in common with drives (Fisher 2004). (i) Like drives, romantic love is tenacious and emotions ebb and flow, (ii) romantic love is focused on a specific reward and emotions are associated with a range of phenomena instead, (iii) romantic love is not associated with a distinct facial expression and the primary emotions are all associated with specific facial expressions, (iv) romantic love is difficult to control and all of the basic drives are difficult to control, and (v) human romantic love and mammalian courtship attraction are associated with dopamine-rich neural regions and all the basic drives are also associated with dopaminergic pathways. Drives lie along a continuum. Thirst is almost impossible to control, while the sex drive can be redirected, even quelled. Romantic love is evidently stronger than the sex drive because when one’s sexual overtures are rejected, people do not kill themselves or someone else. Instead, abandoned lovers sometimes stalk, commit suicide or homicide or fall into a clinical depression. More investigations need to be made to understand the flexibility, variability and durability of this neural mechanism for mate choice, romantic love. Data could be collected on how the neural mechanisms for romantic love vary in conjunction with specific traumatic childhood experiences; how specific personality profiles affect the biological expression of romantic love; how specific diseases, such as schizophrenia and Parkinson’s disease, and addictions, such as cocaine, Phil. Trans. R. Soc. B (2006)

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amphetamine and alcohol addiction, facilitate or inhibit the biological expression of romantic love; how the constellation of neural correlates associated with romantic love varies during the course of a longterm relationship; how the biology of romantic love varies according to sexual orientation; and how this brain system varies in cultures with different marital patterns and in different mammalian species with diverse reproductive strategies. More research into the brain mechanisms associated with romantic love may also help to explain some of the basic principles of brain lateralization and lend further understanding of the reward system and its interactions with cognitive and emotional processes that together produce complex behaviours. It might also be valuable to investigate gender differences in the constellation of neural correlates associated with early stage (and later stage) romantic love. In a preliminary study of gender differences, we did a between-subject analysis of our 10 women and 7 men who were happily in love. Although men and women were similar in many ways, we did find gender differences. Men tended to show more activity than women in a region of the right posterior dorsal insula that has been correlated with penile turgidity (Arnow et al. 2002) and male viewing of beautiful faces (Aharon et al. 2001). Men also showed more activity in regions associated with the integration of visual stimuli (Narumoto et al. 2001). Women tended to show more activity than men in regions associated with attention, memory and emotion (Gray et al. 2002; Maddock et al. 2003; Velanova et al. 2003). Extensive cross-cultural data indicate that courting men respond more strongly than women to visual signals of youth and beauty (Buss et al. 1990); hence, we speculate that the above male activation pattern evolved, in part, to enable ancestral men to respond to the visual signals of women who could bear them viable young (Fisher 2004). Cross-cultural data indicate that women are more attracted than men to potential mates who offer status and resources (Buss et al. 1990). To calculate the reproductive value of a man, a woman must remember the promises and provisioning record of her potential partner. Thus, we speculate that the above female activation pattern evolved, in part, to enable ancestral women to remember male behaviour patterns and thus make adaptive long-term mate choices (Fisher 2004). But more research is necessary to confirm this hypothesis, to establish the cultural variables that contribute to gender differences and to find more gender differences in the brain associated with romantic love. We expect that human romantic love will be found to engage a wide range of varying, overlapping and dynamic brain systems, as would be appropriate of a multi-faceted phenomenon that has significant social, reproductive and genetic consequences. Nevertheless, the primary neural correlates associated with intense, early-stage romantic love are likely to remain similar across individuals and cultures, even among species, because this neural mechanism evolved to direct a crucial aspect of mammalian reproduction, mate choice.

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REFERENCES Aharon, I., Etcoff, N., Ariely, D., Chabris, C. F., O’Connor, E. & Breiter, H. C. 2001 Beautiful faces have variable reward value: fMRI and behavioral evidence. Neuron 32, 537–551. Ainsworth, M. D. S., Blehar, M. C., Waters, E. & Wall, S. 1978 Patterns of attachment: a psychological study of the strange situation. Hillsdale, NJ: Erlbaum. Andersson, M. 1994 Sexual selection. Princeton, NJ: Princeton University Press. Appararundaram, S., Huller, J., Lakhlani, S & Jennes L. 2002 Ovariectomy-induced alterations of choline and dopamine transporter activity in the rat brain. Society for Neuroscience Abstract Viewer/Itinerary Planner: p.368.20. Arnow, B. A., Desmond, J. E., Banner, L. L., Glover, G. H., Solomon, A., Polan, M. L., Lue, T. F. & Atlas, S. W. 2002 Brain activation and sexual arousal in healthy, heterosexual males. Brain 125, 1014–1023. Aron, A. & Aron, E. N. 1991 Love and sexuality. In Sexuality in close relationships (ed. K. McKinney & S. Sprecher), pp. 25–48. Hillsdale, NJ: Lawrence Erlbaum. Aron, A., Paris, M. & Aron, E. N. 1995 Falling in love: prospective studies of self-concept change. J. Pers. Social Psychol. 69, 1102–1112. Aron, A., Fisher, H. E., Mashek, D. J., Strong, G., Li, H. F. & Brown, L. L. 2005 Reward, motivation and emotion systems associated with early-stage intense romantic love: an fMRI study. J. Neurophysiol. 94, 327–337. Aron, A., Fisher, H. E. & Strong, G. 2006 Romantic love. In The Cambridge handbook of personal relationships (ed. D. Perlman & A. Vangelisti). Cambridge, MA: Cambridge University Press. Ascher, J. A. et al. 1995 Bupropion: a review of its mechanism of antidepressant activity. J. Clin. Psychiatry 56, 396–402. Auger, A. P., Meredith, J. M., Snyder, G. L. & Blaustein, J. D. 2001 Oestradiol increases phosphorylation of a dopamineand cyclic AMP-regulated phosphoprotein (DARPP-32) in female rat brain. J. Neuroendocrinol. 13, 761–768. Bartels, A. & Zeki, S. 2000 The neural basis of romantic love. Neuroreport 11, 3829–3834. Bartels, A. & Zeki, S. 2004 The neural correlates of maternal and romantic love. NeuroImage 21, 1155–1166. Beach, F. A. 1976 Sexual attractivity, proceptivity, and receptivity in female mammals. Horm. Behav. 7, 105–138. Beauregard, M., Levesque, J. & Bourgouin, P. 2001 Neural correlates of conscious self-regulation of emotion. J. Neurosci. 21, RC165. Becker, J. B., Rudick, C. N. & Jenkins, W. J. 2001 The role of dopamine in the nucleus accumbens and striatum during sexual behavior in the female rat. J. Neurosci. 21, 3236–3241. Bell, J. 1995 Notions of love and romance among the Taita of Kenya. In Romantic passion: a universal experience? (ed. W. Jankowiak). New York, NY: Columbia University Press. Bester-Meredith, J. K., Young, L. J. & Marler, C. A. 1999 Species differences in paternal behavior and aggression in Peromyscus and their associations with vasopressin immunoreactivity and receptors. Horm. Behav. 36, 25–38. Bowlby, J. 1969. Attachment and loss: attachment, vol. 1. New York, NY: Basic Books. Bowlby, J. 1973. Attachment and loss: separation, vol. 2. New York, NY: Basic Books. Brown, L. L. 1992 Somatotopic organization in rat striatum: evidence for a combinational map. Proc. Natl Acad. Sci. USA 89, 7403–7407. Brown, L. L., Smith, D. M. & Goldbloom, L. M. 1998 Organizing principles of cortical integration in the rat Phil. Trans. R. Soc. B (2006)

neostriatum: corticostriate map of the body surface is an ordered lattice of curved laminae and radial points. J. Comp. Neurol. 392, 468–488. Buffum, J., Moser, C. & Smith, D. 1988 Street drugs and sexual function. In Handbook of sexology, vol. 6 (ed. J. M. A. Sitsen) The pharmacology and endocrinology of sexual function. New York, NY: Elsevier Science Publishers. Buss, D. M. et al. 1990 International preferences in selecting mates: a study of 37 societies. J. Cross Cult. Psychol. 21, 5–47. Cardinal, R. N. & Howes, N. J. 2005 Effects of lesions of the accumbens core on choice between small uncertain rewards in rats. BMC Neurosci. 6, 37–56. Carter, C. S. 1992 Oxytocin and sexual behavior. Neurosci. Biobehav. Rev. 1, 131–144. Carter, C. S., DeVries, A., Taymans, S. E., Roberts, R. L., Williams, J. R. & Getz, L. L. 1997 Peptides steroids, and pair bonding. In The integrative neurobiology of affiliation, vol. 807 (ed. C. S. Carter, I. I. Lederhendler & B. Kirkpatrick), pp. 260–272. Annals of the New York Academy of Sciences, New York, NY: The New York Academy of Sciences. Clayton, A. H. et al. 2000 Bupropion as an antidote to SSRIinduced sexual dysfunction. Poster presented at the New Clinical Drug Evaluation Unit Program (NCDEU), Boca Raton, FL. Clayton, A. H., Pradko, J. F., Croft, H. A., Montano, C. B., Leadbetter, R. A., Bolden-Watson, C., Bass, K. I., Donahue, R. M., Jamerson, B. D. & Metz, A. 2002 Prevalence of sexual dysfunction among newer antidepressants. J. Clin. Psychiatry 63, 357–366. Coleman, C. C., Cunningham, L. A., Foster, V. J., Batey, S. R., Donahue, R. M. J., Houser, T. L. & Ascher, J. A. 1999 Sexual dysfunction associated with the treatment of depression: a placebo-controlled comparison of buproprion sustained release and sertraline treatment. Ann. Clin. Psychiatry 11, 205–215. Coull, J. 1998 Neural correlates of attention and arousal Insights from electrophysiology, functional neuroimaging and psychopharmacology. Prog. Neurobiol. 55, 343–361. Creutz, L. M. & Kritzer, M. F. 2002 Estrogen receptorbeta immunoreactivity in the midbrain of adult rats: regional, subregional, and cellular localization in the A10, A9, and A8 dopamine cell groups. J. Comp. Neurol. 446, 288–300. Cronbach, L. J. 1951 Coefficient alpha and the internal structure of tests. Psychometrika 16, 297–334. Darwin, C. 1871/n.d. The descent of man and selection in relation to sex. New York, NY: The Modern Library/ Random House. Davidson, R. J. 1994 Complexities in the search for emotionspecific physiology. In The nature of emotion: fundamental questions (ed. P. Ekman & R. J. Davidson). New York, NY: Oxford University Press. Delgado, M. R., Nystrom, L. E., Fissell, C., Noll, D. C. & Fiez, J. A. 2000 Tracking the hemodynamic responses to reward and punishment in the striatum. J. Neurophysiol. 84, 3072–3077. Dixson, A. F. 1998 Primate sexuality. Oxford, UK: Oxford University Press. Dluzen, D. E., Ramirez, V. D., Carter, C. S. & Getz, L. L. 1981 Male vole urine changes luteinizing hormonereleasing hormone and norepinephrine in female olfactory bulb. Science 212, 573–575. Eblen, F. & Graybiel, A. M. 1995 Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey. J. Neurosci. 15, 5999–6013.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Romantic love Edwards, J. N. & Booth, A. 1994 Sexuality, marriage, and well-being: the middle years. In Sexuality across the life course (ed. A. S. Rossi). Chicago, IL: University of Chicago Press. Elliott, R., Newman, J. L., Longe, O. A. & Deakin, J. W. F. 2003 Differential response patterns in the striatum and orbitofrontal cortex to financial reward in humans: a parametric functional magnetic resonance imaging study. J. Neurosci. 23, 303–307. Etgen, A. & Morales, J. C. 2002 Somatosensory stimuli evoke norepinephrine release in the anterior ventromedial hypothalamus of sexually receptive female rats. J. Neuroendocrinol. 14, 213–218. Etgen, A. M., Chu, H. P., Fiber, J. M., Karkanias, G. B. & Morales, J. M. 1999 Hormonal integration of neurochemical and sensory signals governing female reproductive behavior. Behav. Brain Res. 105, 93–103. Evans, D. W., Lewis, M. D. & Iobst, E. 2004 The role of the orbitofrontal cortex in normally developing compulsivelike behaviors and obsessive–compulsive disorder. Brain Cogn. 55, 220–234. Fabre-Nys, C. 1997 Male faces and odors evoke differential patterns of neurochemical release in the mediobasal hypothalamus of the ewe during estrus: an insight into sexual motivation. Eur. J. Neurosci. 9, 1666–1677. Fabre-Nys, C. 1998 Steroid control of monoamines in relation to sexual behaviour. Rev. Reprod. 3, 31–41. Ferrari, F. & Giuliani, D. 1995 Sexual attraction and copulation in male rats: effects of the dopamine agonist SND 919. Pharmacol. Biochem. Behav. 50, 29–34. Fiorino, D. F., Coury, A. & Phillips, A. G. 1997 Dynamic changes in nucleus accumbens dopamine efflux during the Coolidge effect in male rats. J. Neurosci. 17, 4849–4855. Fisher, H. E. 1992 Anatomy of love: the natural history of monogamy, adultery and divorce. New York, NY: WW Norton. Fisher, H. 1998 Lust, attraction, and attachment in mammalian reproduction. Human Nature 9, 23–52. Fisher, H. 2004 Why we love: the nature and chemistry of romantic love. New York, NY: Henry Holt. Fisher, H., Aron, A., Mashek, D., Strong, G., Li, H. & Brown, L. L. 2002a The neural mechanisms of mate choice: a hypothesis. Neuroendocrinol. Lett. 23(Suppl. 4), 92–97. Fisher, H., Aron, A., Mashek, D., Strong, G., Li, H. & Brown, L. L. 2002b Defining the brain systems of lust, romantic attraction and attachment. Arch. Sexual Behav. 31, 413–419. Fisher, H., Aron, A., Mashek, D., Strong, G., Li, H. & Brown, L. L. 2005a Motivation and emotion systems associaed with romantic love following rejection: an fMRI study. Program no. 660.7. Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, Online. Fisher, H., Aron, A. & Brown, L. L. 2005b Romantic love: an fMRI study of a neural mechanism for mate choice. J. Comp. Neurol. 493, 58–62. Fisher, H. E. & Thomson, J. A. In press. Lust, attraction, attachment: the neural mechanisms of mate choice and how antidepressants jeopardize romantic love, attachment and one’s genetic future. In Evolutionary cognitive neuroscience. Steven Platek (ed.). Cambridge, MA: MIT Press. Flaherty, A. W. & Graybiel, A. M. 1995 Motor and somatosensory corticostriatal projection magnifications in the squirrel monkey. J. Neurophysiol. 74, 2638–2648. Fraley, G. S. 2002 Immunolesion of hindbrain catecholaminergic projections to the medial hypothalamus attenuates penile reflexive erections and alters hypothalamic peptide mRNA. J. Neuroendocrinol. 14, 345–348. Phil. Trans. R. Soc. B (2006)

H. E. Fisher and others

2183

Fraley, R. C. & Shaver, P. R. 2000 Adult romantic attachment: theoretical developments, emerging controversies and unanswered questions. Rev. Gen. Psychol. 4, 132–154. Galfi, M., Janaky, T., Toth, R., Prohaszka, G., Juhasz, A., Varga, C. & Laszlo, F. A. 2001 Effects of dopamine and dopamine-active compounds on oxytocin and vasopressin production in rat neurohypophyseal tissue cultures. Regul. Pept. 98, 49–54. Gerfen, C. R., Herkenham, M. & Thibault, J. 1987 The neostriatal mosaic: II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems. J. Neurosci. 7, 3915–3934. Gingrich, B., Liu, Y., Cascio, C. Z. & Insel, T. R. 2000 Dopamine D2 receptors in the nucleus accumbens are important for social attachment in female prairie voles (Microtus ochrogaster). Behav. Neurosci. 114, 173–183. Ginsberg, S. D., Hof, P. R., Young, W. G. & Morrison, J. H. 1994 Noradrenergic innervation of vasopressin- and oxytocin-containing neurons in the hypothalamic paraventricular nucleus of the macaque monkey: quantitative analysis using double-label immunohistochemistry and confocal laser microscopy. J. Comp. Neurol. 341, 476–491. Gladikas, B. M. 1995 Reflections of Eden: my years with the Orangutans of Borneo. New York, NY: Little Brown and Company. Goldstein, R. Z., Alai-Klein, N., Leskovjan, A. C., Fowler, J. S., Wang, G. J., Gur, R. C., Hitzemann, R. & Volkow, N. D. 2005 Anger and depression in cocaine addiction: association with the orbitofrontal cortex. Psychiatry Res. 138, 13–22. Gonzaga, G. C., Keltner, D., Londahl, E. A. & Smith, M. D. 2001 Love and the commitment problem in romantic relations and friendship. J. Pers. Soc. Psychol. 81, 247–262. Goodall, J. 1986 The Chimpanzees of Gombe: patterns of behavior. Cambridge, MA: The Belknap Press of Harvard University Press. Gray, J. R., Braver, T. S. & Raichle, M. E. 2002 Integration of emotion and cognition in the lateral prefrontal cortex. Proc. Natl Acad. Sci. USA 99, 4115–4120. Griffin, M. G. & Taylor, G. T. 1995 Norepinephrine modulation of social memory: evidence for a timedependent functional recovery of behavior. Behav. Neurosci. 109, 466–473. Haber, S. N. 2003 The primate basal ganglia: parallel and integrative networks. J. Chem. Neuroanat. 26, 317–330. Hammock, E. A. D. & Young, L. J. 2005 Microsatellite instability generates diversity in brain and sociobehavioral traits. Science 308, 1630–1634. Harris, C. R. & Christenfeld, N. 1996 Gender, jealousy, and reason. Psychol. Sci. 7, 364–366. Hatfield, E. 1988 Passionate and companionate love. In The psychology of love (ed. R. J. Sternberg & M. S. L. Barnes). New Haven, CT: Yale University Press. Hatfield, E. & Sprecher, S. 1986 Measuring passionate love in intimate relations. J. Adolesc. 9, 383–410. Hatfield, E., Schmitz, E., Cornelius, J. & Rapson, R. L. 1988 Passionate love: how early does it begin? J. Psychol. Hum. Sex. 1, 35–51. Hazan, C. & Diamond, L. M. 2000 The place of attachment in human mating. Rev. Gen. Psychol. 4, 186–204. Hazan, C. & Shaver, P. R. 1987 Romantic love conceptualized as an attachment process. J. Pers. Social Psychol. 52, 511–524. Heaton, J. P. 2000 Central neuropharmacological agents and mechanisms in erectile dysfunction: the role of dopamine. Neurosci. Biobehav. Rev. 24, 561–569. Herbert, J. 1996 Sexuality, stress and the chemical architecture of the brain. Annu. Rev. Sex Res. 7, 1–44.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2184

H. E. Fisher and others

Romantic love

Hull, E. M., Du, J., Lorrain, D. S. & Matuszewich, L. 1995 Extracelular dopamine in the medial preoptic area: implicatons for sexual motivation and hormonal control of copulation. J. Neurosci. 15, 7465–7471. Hull, E. M., Du, J., Lorrain, D. S. & Matuszewick, L. 1997 Testosterone, preoptic dopamine, and copulation in male rats. Brain Res. Bull. 44, 327–333. Hull, E. M., Lorrain, D. S., Du, J., Matuszewick, L., Lumley, L. A., Putnam, S. K. & Moses, J. 1999 Hormone– neurotransmitter interactions in the control of sexual behavior. Behav. Brain Res. 105, 105–116. Hull, E., Meisel, R. & Sachs, B. D. 2002 Male sexual behavior. In Hormones, brain, and behavior (ed. D. W. Pfaff, A. P. Arnold, A. M. Etgen, S. E. Fahrbach & R. T. Rubin), pp. 1–139. Boston, MA: Academic Press. Hutchison, J. B. & Hutchison, R. E. 1983 Hormonal mechanisms of mate choice in birds. In Mate choice (ed. P. Bateson), pp. 389–405. Cambridge: Cambridge University Press. Jankowiak, W. R. & Fischer, E. F. 1992 A cross-cultural perspective on romantic love. Ethnology 31, 149. Karama, S., Lecours, A. R., Leroux, J. M., Bourgouin, P., Beaudoin, G., Joubert, S. & Beauregard, M. 2002 Areas of brain activation in males and females during viewing of erotic film excerpts. Hum. Brain Mapp. 16, 1–13. Kawashima, S. & Takagi, K. 1994 Role of sex steroids on the survival, neuritic outgrowth of neurons, and dopamine neurons in cultured preoptic area and hypothalamus. Horm. Behav. 28, 305–312. Kemp, J. M. & Powell, T. P. 1970 The cortico-striate projection in the monkey. Brain 93, 525–546. Kendrick, K. M. 2000 Oxytocin, motherhood and bonding. Exp. Physiol. 85S, 111S–124S. Kendrick, K. M. & Dixson, A. F. 1985 Luteinizing hormone releasing hormone enhances proceptivity in a primate. Neuroendocrinology 41, 449–453. Kendrick, K. M. & Dixson, A. F. 1986 Anteromedial hypothalamic lesions block proceptivity but not receptivity in the female common marmoset (Callithrix jacchus). Brain Res. 375, 221–229. Kendrick, K. M., Keverne, E. B., Hinton, M. R. & Goode, J. A. 1992 Oxytocin, amino acid and monoamine release in the region of the medial preoptic area and bed nucleus of the stria terminalis of the sheep during parturition and suckling. Brain Res. 569, 199–209. Kovacs, G. & Telegdy, G. 1983 Effects of oxytocin, desglycinamide-oxytocin and anti-oxytocin serum on the alpha-MPT-induced disappearance of catecholamines in the rat brain. Brain Res. 268, 307–314. Kovacs, G. L., Sarnyai, Z., Barbarczi, E., Szabo, G. & Telegdy, G. 1990 The role of oxytocin-dopamine interactions in cocaine-induced locomotor hyperactivity. Neuropharmacology 29, 365–368. Kringelbach, M. L. & Rolls, E. T. 2004 The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology. Prog. Neurobiol. 72, 341–372. Kuhnen, C. M. & Knutson, B. 2005 The neural basis of financial risk taking. Neuron 47, 763–770. Lauwereyns, J., Takikawa, Y., Kawagoe, R., Kobayashi, S., Koizumi, M., Coe, B., Sakagami, M. & Hikosaka, O. 2002 Feature-based anticipation of cues that predict reward in monkey caudate nucleus. Neuron 33, 463–473. Lavin, A., Nogueira, L., Lapish, C. C., Wightman, R. M., Phillips, P. E. M. & Seamans, J. K. 2005 Mesocortical dopamine neurons operate in distinct temporal domains using multimodal signaling. J. Neurosci. 25, 5013–5023. Phil. Trans. R. Soc. B (2006)

Legault, M. & Wise, R. A. 1999 Injections of N-methylD-asparate into the ventral hippocampus increase extraceullular dopamine in the ventral tegmental area and nucleus accumbens. Synapse 31, 241–249. Liebowitz, M. R. 1983 The chemistry of love. Boston, MA: Little Brown. Lim, M. M. & Young, L. J. 2004 Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole. Neuroscience 128, 35–45. Lim, M. M., Murphy, A. Z. & Young, A. J. 2004 Ventral striatopallidal oxytocin and vasopressin V1a receptors in the monogamous prairie vole (Microtus ochrogaster). J. Comp. Neurol. 468, 555–570. Liu, Y.-C, Sachs, B. D. & Salamone, J. D. 1998 Sexual behavior in male rats after radiofrequency or dopaminedepleting lesions in nucleus accumbens. Pharmacol. Biochem. Behav. 60, 585–592. Maddock, R. J., Garrett, A. S. & Buonocore, M. H. 2003 Posterior cingulate cortex activation by emotional words: fMRI evidence from a valence decision task. Hum. Brain Mapp. 18, 30–41. Marazziti, D., Akiskal, H. S., Rossi, A. & Cassano, G. B. 1999 Alteration of the platelet serotonin transporter in romantic love. Psychol. Med. 29, 741–745. Martin-Soelch, C., Leenders, K. L., Chevalley, A. F., Missimer, J., Kunig, G., Magyar, S., Mino, A. & Schultz, W. 2001 Reward mechanisms in the brain and their role in dependence: evidence from neurophysiological and neuroimaging studies. Brain Res. Rev. 36, 139–149. Mashek, D., Aron, A. & Fisher, H. E. 2000 Identifying, evoking, and measuring intense feelings of romantic love. Rep. Res. Social Psychol. 24, 48–55. McCullough, D. 2001 John Adams. New York, NY: Simon and Schuster. Meloy, J. R. & Fisher, H. 2005 Some thoughts on the neurobiology of stalking. Forensic Sci. 50, 1472–1480. Miller, G. 2000 The mating mind: how sexual choice shaped the evolution of human nature. New York, NY: Doubleday. Moles, A., Kieffer, B. L. & D’Amato, F. R. 2004 Deficit in attachment behavior in mice lacking the u-opioid receptor gene. Science 304, 1983–1985. Montague, P. R., McClure, S. M., Baldwin, R. P., Phillips, P. E., Budygin, E. A., Stuber, G. D., Kilpatrick, M. R. & Wightman, R. M. 2004 Dynamic gain control of dopamine delivery in freely moving animals. J. Neurosci. 24, 1754–1759. Montejo, A. L., Llorca, G., Izquierdo, J. A. & RicoVallademoros, F. 2001 Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. J. Clin. Psychiatry 62, 1020. Najib, A., Lorberbaum, J. P., Kose, S., Bohning, D. E. & George, M. S. 2004 Regional brain activity in women grieving a romantic relationship breakup. Am. J. Psychiatry 161, 2245–2256. Narumoto, J., Okada, T., Sadato, N., Fukui, K. & Yonekura, Y. 2001 Attention to emotion modulates fMRI activity in human right superior temporal sulcus. Brain Res. Cogn. 12, 225–231. Nyborg, H. 1994 Hormones, sex and society. Westport, CT: Praeger. Oades, R. D. & Halliday, G. M. 1987 Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res. 434, 117–165. O’Doherty, J. P., Deichmann, R., Critchley, H. D. & Dolan, R. J. 2002 Neural responses during anticipation of a primary taste reward. Neuron 33, 815–826.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Romantic love Panksepp, J. 1998 Affective neuroscience: the foundations of human and animal emotions. New York, NY: Oxford University Press. Parent, A. & Hazrati, L. N. 1995 Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamocortical loop. Brain Res. Brain Res. Rev. 20, 91–127. Parent, A., Cote, Y. & Lavoie, B. 1995 Anatomy of primate basal ganglia. Prog. Neurobiol. 46, 131–197. Parthasarathy, H. B., Schall, J. D. & Graybiel, A. M. 1992 Distributed but convergent ordering of corticostriatal projections: analysis of the frontal eye field and the supplementary eye field in the macaque monkey. J. Neurosci. 12, 4468–4488. Pfaff, D. W. 1999 DRIVE: neurobiological and molecular mechanisms of sexual motivation. Cambridge, MA: The MIT Press. Pfaff, D. W. 2005 Brain arousal and information theory. Cambridge, MA: Harvard University Press. Pfaff, D., Frohlich, J. & Morgan, M. 2002 Hormonal and genetic influences on arousal – sexual and otherwise. Trends Neurosci. 25, 45–50. Pitkow, L. J., Sharer, C. A., Ren, X., Insel, T. R., Terwilliger, E. F. & Young, L. J. 2001 Facilitation of affiliation and pair-bond formation by vasopressin receptor gene transfer into the ventral forebrain of a monogamous vole. J. Neurosci. 21, 7392–7396. Posner, M. & Petersen, S. 1990 The attention system of the human brain. Annu. Rev. Neurosci. 13, 25–42. Ridderinkhof, K. R., van den Wildenberg, W. P., Segalowitz, S. J. & Carter, C. S. 2004 Neurocognitive mechanisms of cognitive control: the role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning. Brain Cogn. 56, 129–140. Robbins, T., Granon, S., Muir, J., Durantou, P., Harrison, A. & Everitt, B. 1998 Neural systems underlying arousal and attention: implications for drug abuse. Ann. NY Acad. Sci. 846, 222–237. Robinson, D. L., Heien, M. L. & Wightman, R. M. 2002 Frequency of dopamine concentration transients increases in dorsal and ventral striatum of male rats during introduction of conspecifics. J. Neurosci. 22, 10 477–10 486. Rosen, R. C., Lane, R. M. & Menza, M. 1999 Effects of SSRIs on sexual function: a critical review. J. Clin. Psycopharmacol. 19, 67–85. Saint-Cyr, J. A., Ungerleider, L. G. & Desimone, R. 1990 Organization of visual cortical inputs to the striatum and subsequent outputs to the pallido-nigral complex in the monkey. J. Comp. Neurol. 298, 129–156. Schreckenberger, M., Siessmeier, T., Viertmann, A., Landvogt, C., Buchholz, H. G., Rolke, R., Treede, R. D. & Bartenstein, F. 2005 The unpleasantness of tonic pain is encoded by the insular cortex. Neurology 64, 1175–1183. Schultz, W. 2000 Multiple reward signals in the brain. Nat. Rev. Neurosci. 1, 199–207. Schwarzberg, H., Kovacs, G. L., Szabo, G. & Telegdy, G. 1981 Intraventricular administration of vasopressin and oxytocin affects the steady-state levels of serotonin, dopamine and norepinephrine in rat brain. Endocrinol. Exp. 15, 75–80. Segraves, R. T., Croft, H., Kavoussi, R., Ascher, J. A., Batey, S. R., Foster, V. J., Bolden-Watson, C. & Metz, A. 2001 Bupropion sustained release (SR) for treatment of hypoactive sexual desire disorder (HSDD) in nondepressed women. J. Sex Marital Ther. 27, 303–316. Selemon, L. D. & Goldman-Rakic, P. S. 1985 Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. J. Neurosci. 5, 776–794. Phil. Trans. R. Soc. B (2006)

H. E. Fisher and others

2185

Seybold, V. S., Miller, J. W. & Lewis, P. R. 1978 Investigation of a dopaminergic mechanism for regulating oxytocin release. J. Pharmacol. Exp. Ther. 207, 605–610. Shaver, P., Schwartz, J., Kirson, D. & O’Connor, C. 1987 Emotion knowledge: further exploration of a prototype approach. J. Pers. Soc. Psychol. 52, 1061–1086. Sherwin, B. B. 1994 Sex hormones and psychological functioning in postmenopausal women. Exp. Gerontol. 29, 423–430. Shostak, M. 1981 Nisa: the life and words of a !Kung woman. Cambridge, MA: Harvard University Press. Szezypka, M. S., Zhou, Q. Y. & Palmiter, R. D. 1998 Dopamine-stimulated sexual behavior is testosterone dependent in mice. Behav. Neurosci. 112, 1229–1235. Tennov, D. 1979 Love and limerence: the experience of being in love. New York, NY: Stein and Day. Van Bockstaele, E. J., Pieribone, V. A. & Aston-Jones, G. 1989 Diverse afferents converge on the nucleus paragigantocellularis in the rat ventrolateral medulla: retrograde and anterograde tracing studies. J. Comp. Neurol. 290, 561–584. Van de Kar, L. D., Levy, A. D., Li, Q. & Brownfield, M. S. 1998 A comparison of the oxytocin and vasopressin responses to the 5-HT1A agonist and potential anxiolytic drug alnespirone (S-20499). Pharmacol. Biochem. Behav. 60, 677–683. Van Goozen, S., Wiegant, V. M., Endert, E., Helmond, F. A. & Van de Poll, N. E. 1997 Psychoendocrinological assessment of the menstrual cycle: the relationship between hormones, sexuality, and mood. Arch. Sex. Behav. 26, 359–382. Velanova, K., Jacoby, L. L., Wheeler, M. E., McAvoy, M. P., Petersen, S. E. & Buckner, R. L. 2003 Functionalanatomic correlates of sustained and transient processing components engaged during controlled retrieval. J. Neurosci. 23, 8460–8470. Vizi, E. S. & Volbekas, V. 1980 Inhibition by dopamine of oxytocin release from isolated posterior lobe of the hypophysis of the rat: disinhibitory effect of betaendorphin/enkephalin. Neuroendocrinology 31, 46–52. Vollm, B. A., Taylor, A. N., Richardson, P., Corcoran, R., Stirling, J., McKie, S., Deakin, J. F. & Elliott, R. 2006 Neuronal correlates of theory of mind and empathy: a functional magnetic resonance imaging study in a nonverbal task. Neuroimage 29, 90–98. Walker, P. W., Cole, J. O. & Gardner, E. A. 1993 Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion. J. Clin. Psychiatry 54, 459–465. Wang, Z. X., Ferris, C. F. & De Vries, G. J. 1994 The role of septal vasopressin innervation in paternal behavior in prairie voles (Microtus ochrogaster). Proc. Natl Acad. Sci. USA 91, 400–404. Wang, Z., Toloczko, D., Young, L. J., Moody, K., Newman, J. D. & Insel, T. R. 1997 Vasopressin in the forebrain of common marmosets (Calithrix jacchus): studies with in situ hybridization, immunocytochemistry and receptor autoradiography. Brain Res. 768, 147–156. Wang, Z., Yu, G., Cascio, C., Liu, Y., Gingrich, B. & Insel, T. R. 1999 Dopamine D2 receptor-mediated regulation of partner preferences in female prairie voles (Microtus ochrogaster): a mechanism for pair bonding? Behav. Neurosci. 113, 602–611. Wenkstern, D., Pfaus, J. G. & Fibiger, H. C. 1993 Dopamine transmission increases in the nucleus accumbens of male rats during their first exposure to sexually receptive female rats. Brain Res. 618, 41–46. Wersinger, S. R. & Rissman, E. F. 2000 Dopamine activates masculine sexual behavior independent of the estrogen receptor alpha. J. Neurosci. 20, 4248–4254.

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West, C. H. K., Clancy, A. N. & Michael, R. P. 1992 Enhanced responses of nucleus accumbens neurons in male rats to novel odors associated with sexually receptive females. Brain Res. 585, 49–55. Williams, S. M. & Goldman-Rakic, P. S. 1998 Widespread origin of the primate mesofrontal dopamine system. Cereb. Cortex 8, 321–345. Williams, J. R., Insel, T. R., Harbaugh, C. R. & Carter, C. S. 1994 Oxytocin administered centrally facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster). J. Neuroendocrinol. 6, 247–250. Winslow, J. T., Hastings, N., Carter, C. S., Harbaugh, C. R. & Insel, T. R. 1993 A role for central vasopressin in pair bonding in monogamous prairie voles. Nature 365, 545–548. Wise, R. A. 1996 Neurobiology of addiction. Curr. Opin. Neurobiol. 6, 243–251.

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Young, L. J. 1999 Oxytocin and vasopressin receptors and species-typical social behaviors. Horm. Behav. 36, 212–221. Young, L. J., Winslow, J. T., Nilsen, R. & Insel, T. R. 1997 Species differences in V1a receptor gene expression in monogamous and nonmonogamous voles: behavioral consequences. Behav. Neurosci. 111, 599–605. Young, L. J., Wang, Z. & Insel, T. R. 1998 Neuroendocrine bases of monogamy. Trends Neurosci. 21, 71–75. Young, L. J., Lim, M. M., Gingrich, B. & Insel, T. R. 2001 Cellular mechanisms of social attachment. Horm. Behav. 40, 133–138. Zald, D. H., Boileau, I., El-Dearedy, W., Gunn, R., McGlone, F., Dichter, G. S. & Dagher, A. 2004 Dopamine transmission in the human striatum during monetary reward tasks. J. Neurosci. 24, 4105–4112.

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Phil. Trans. R. Soc. B (2006) 361, 2187–2198 doi:10.1098/rstb.2006.1939 Published online 6 November 2006

Oxytocin, vasopressin and pair bonding: implications for autism Elizabeth A. D. Hammock and Larry J. Young* Department of Psychiatry and Behavioural Sciences, Centre for Behavioural Neuroscience, Yerkes National Primate Research Centre, Emory University, Atlanta, GA 30329, USA Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species. High levels of oxytocin receptor (OTR) in the nucleus accumbens and high levels of vasopressin 1a receptor (V1aR) in the ventral pallidum contribute to monogamous social structure in the prairie vole. While little is known about the genetic factors contributing to species-differences in OTR distribution, the species-specific distribution pattern of the V1aR is determined in part by a speciesspecific repetitive element, or ‘microsatellite’, in the 5 0 regulatory region of the gene encoding V1aR (avpr1a). This microsatellite is highly expanded in the prairie vole (as well as the monogamous pine vole) compared to a very short version in the promiscuous montane and meadow voles. These species differences in microsatellite sequence are sufficient to change gene expression in cell culture. Within the prairie vole species, intraspecific variation in the microsatellite also modulates gene expression in vitro as well as receptor distribution patterns in vivo and influences the probability of social approach and bonding behaviour. Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders. In sum, comparative studies in pair-bonding rodents have revealed neural and genetic mechanisms contributing to social-bonding behaviour. These studies have generated testable hypotheses regarding the motivational systems and underlying molecular neurobiology involved in social engagement and social bond formation that may have important implications for the core social deficits characterizing autism spectrum disorders. Keywords: individual differences; regulatory microsatellite; prairie vole; autism; vasopressin; oxytocin

1. INTRODUCTION When Leo Kanner first described autism in 1943, he indicated that the main deficits were social withdrawal and lack of empathy, or in his words, an ‘innate inability to form the usual.affective contact with people’ (Kanner 1943). This can have devastating consequences for the emotional well-being of families with affected individuals, the rate of which is ca 1 per thousand individuals (Gillberg & Wing 1999). It is now clear that autism spectrum disorders are complex neurodevelopmental disorders likely involving many * Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘The neurobiology of social recognition, attraction and bonding’.

genetic and environmental interactions. Furthermore, these disorders are typically characterized by phenotypes beyond the disruptions in social engagement, including impairment in communication skills, and restricted, repetitive and stereotyped patterns of behaviour. While there are currently no animal models reflecting the broad range of the autism behavioural and neurological phenotypes, studies into the neurobiology of normal social cognition, engagement and bonding in animals may provide important clues useful for understanding the neurobiological mechanisms underlying the devastating social deficits in autism. While it is true that the ‘typical’ social behavioural phenotype of humans includes not only social engagement, but also empathy and attachment to varying degrees, social bonding outside of the mother–infant

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bond is not typical in the vast majority of mammals. Social behavioural traits vary widely across and within species. This diversity in social behaviour can actually be harnessed as a tool to investigate the neural and the genetic components regulating normal social engagement and bonding that may be relevant to autism. One example illustrating the power of the comparative approach for understanding the neurobiology of social behaviour is the study of pair bonding in voles. Voles are hamster-sized rodents that vary widely in their social organization across species (Carter et al. 1995). Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form bonds with a mate and only the females take part in rearing the young. These data were first obtained from extensive field studies and then brought into the laboratory in the 1980s (Getz et al. 1981). Based on earlier studies in rats, which demonstrated a role for the neuropeptide oxytocin in mother–infant bonding (Pedersen & Prange 1979; Kendrick et al. 1987), and vasopressin in social recognition (Dantzer et al. 1987; Le Moal et al. 1987), oxytocin and vasopressin systems were the initial candidate targets for exploration in these two species. Since then, both oxytocin and vasopressin systems have proved to be essential players in the regulation of social bonding in voles (Young & Wang 2004). Newer genetic techniques, such as viral vector gene transfer technology in combination with pharmacological manipulations have allowed for the testing of hypotheses about the regulation of social behaviour in voles as well as more conventional laboratory models such as mice and rats. This review focuses on genetic and neural studies demonstrating the role of oxytocin and vasopressin in pair bonding in prairie voles. We also discuss relevant findings in more conventional laboratory models where appropriate. We emphasize the value of ‘comparative neuroethological’ and ‘individual differences’ approaches in understanding the neural bases of complex social behaviours. Additionally, we review the findings in humans which implicate oxytocin and vasopressin systems in human social behaviour, and the data suggesting their potential dysregulation in autism.

2. OXYTOCIN AND ARGININE VASOPRESSIN IN SOCIAL BOND FORMATION Species with high levels of social-bonding behaviour must have in place neural mechanisms to reinforce or motivate its members to socially engage and bond. In the vole model, social bonding is part of a suite of behaviours associated with the monogamous social structure. As described previously, monogamy includes a long-term selective association with a partner throughout the breeding and non-breeding seasons and paternal contribution to care for the young (Carter et al. 1995). It is important to note that this definition of monogamy does not preclude sexual promiscuity. Additionally, prairie voles show selective aggression towards novel conspecifics after becoming sexually experienced (Winslow et al. 1993). Furthermore, pups of monogamous prairie voles, but not nonmonogamous montane voles, show a robust stress Phil. Trans. R. Soc. B (2006)

response to maternal separation with increased vocalization and increased serum corticosterone levels (Shapiro & Insel 1990). In the field, monogamy can be observed when male and female pairs are routinely trapped together and share nest sites (Getz et al. 1981). In the laboratory, monogamy can be quantitatively assessed by measuring several social behaviours such as: preference for a familiar partner, biparental care of offspring and selective aggression towards unfamiliar intruders. Most of the laboratory investigations of the neural basis of social bonding have used the partner preference assay to test for the presence of a pair bond ( Williams et al. 1992a). It is important to note that the partner preference assay gives us a window into the development and maintenance of the pair bond, but it should not be confused with the pair bond itself. In the laboratory, ‘pair bonds’ are created by the experimenter. While there is mate choice in the wild, in the laboratory, pairs are randomly assigned by the experimenter. Sexually naive males and females are paired for a cohabitation period. The longer the pair are together, the greater the likelihood of pair bond formation as measured by partner preference ( Williams et al. 1992a). Mating during this period of cohabitation greatly facilitates the formation of partner preferences, although partner preferences can occur in the absence of mating. After a period of cohabitation, the animals are tested in a 3-h ‘partner preference test’, in which the preference of only one of the pair is tested. The testing chamber consists of three cages connected by Plexiglas tubes. The test subject is allowed access to all three cages. The test subject’s ‘partner’ (from the cohabitation period) is tethered in one of the cages, a ‘stranger’ animal is tethered in a second cage and a middle connecting cage is considered ‘neutral’ and does not contain an animal. Both males and females can be tested in this apparatus. A ‘partner preference’ is operationally defined by the amount of time the test animal spends with the partner compared with the stranger. In most studies, the animals are considered to have a ‘partner preference’ when the test animal spends twice as much time in side-by-side social contact with the partner than with a stranger. Monogamous prairie voles show a preference for their partner in this behavioural paradigm ( Williams et al. 1992a; Winslow et al. 1993). In contrast, non-monogamous meadow and montane voles do not show a preference for either animal (Insel & Hulihan 1995; Lim et al. 2004b). Instead, these non-monogamous animals often actually spend more time alone in the neutral cage compared to monogamous voles, although meadow voles have been observed to form pair bonds under certain circumstances (Parker et al. 2001). As mentioned above, prolonged cohabitation and mating both facilitate the development of partner preferences. These parameters can be altered to increase or decrease the frequency of partner preference behaviour in a given sample of prairie voles. For example, decreasing the length of the cohabitation period or preventing mating allows one to test the ability of pharmacological agents to facilitate the development of partner preferences. Likewise, extensions of the cohabitation period as well as confirming mating allow

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Neuropeptides and autism one to test agents that can decrease the frequency of partner preference formation. Oxytocin plays a very important role in several social behaviours such as social recognition, maternal behaviour and maternal–infant bonding (Pedersen & Prange 1979; Kendrick et al. 1997; Ferguson et al. 2001). Additionally, oxytocin infusions into the brain increased side-by-side contact and decreased aggressive behaviour in female prairie voles ( Witt et al. 1990), and increased social contact in male rats (Witt et al. 1992) and squirrel monkeys ( Winslow & Insel 1991). Using the partner preference test as described above with truncated cohabitation periods and no mating, chronic central infusion of oxytocin facilitated partner preference formation in female prairie voles ( Williams et al. 1994). In the complementary experiment, a selective oxytocin receptor (OTR) antagonist chronically infused into the lateral ventricles inhibited partner preference formation in females that experienced prolonged cohabitation and mating with the male ( Williams et al. 1994; Insel & Hulihan 1995). In both cases, the manipulation of oxytocin systems did not affect sexual behaviour; it selectively modulated partner preference behaviour. These data demonstrate that central oxytocin and its receptor are involved in facilitating partner preference formation in female prairie voles; however, since these pharmacological manipulations were performed intracerebroventricularly, they do not indicate where in the brain oxytocin may be acting. Additionally, the data do not explain why some species display bonding behaviour and others do not, since it is believed that all mammals have genes encoding oxytocin and the OTR, as both are necessary for lactation (Nishimori et al. 1996). Oxytocin is produced in the hypothalamus, including the supraoptic and paraventricular nucleus (Gainer & Wray 1994). Magnocellular neurons in these nuclei send projections to the posterior pituitary, where oxytocin is released into the bloodstream and has effects on parturition and milk ejection during lactation. Other cells in the paraventricular nucleus project to several forebrain limbic structures, the brainstem and spinal cord (Swanson & McKellar 1979; Swanson & Kuypers 1980). These sites of oxytocin synthesis and their projections are very highly conserved throughout mammalian species. In contrast, there are significant species differences in OTR distribution patterns among monogamous and non-monogamous vole species (figure 1a,b; Insel & Shapiro 1992). Some regions of the brain, including the caudate putamen and the nucleus accumbens (NAcc), have high densities of receptors in monogamous species compared with nonmonogamous species. Oxytocin receptor antagonists applied directly to the NAcc or prefrontal cortex of female prairie voles inhibit mating-induced partner preference formation (Young et al. 2001), indicating that activation of OTRs in these areas of the brain is necessary for the development of partner preferences in prairie voles. The molecular mechanisms that lead to the species differences in OTR expression have not been elucidated, although several differences in putative transcription factor binding sites have been found between the OTR genes of prairie and montane voles (Young et al. 1996). Phil. Trans. R. Soc. B (2006)

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While oxytocin may also play a role in pair bond formation in males (Cho et al. 1999; Liu et al. 2001), the majority of studies on male, pair bond formation have focused on vasopressin. Vasopressin is involved in many social behaviours in males, including flank marking and aggression in hamsters (Albers & Bamshad 1998) and social recognition in rats and mice (Dantzer et al. 1988; Englemann & Landgraf 1994; Bielsky et al. 2004, 2005). Partner preference in voles requires prolonged cohabitation with a partner and is facilitated by mating. In vivo microdialysis studies suggest that vasopressin is released within the brain during mating (Morales et al. 2004). Indeed, infusions of vasopressin directly into the brain facilitate partner preference formation (without mating) and receptor antagonists block partner preference formation in male prairie voles ( Winslow et al. 1993). As with oxytocin, all mammals studied to date have genes encoding the neuropeptide vasopressin and its primary brain receptor, the vasopressin 1a receptor (V1aR). Vasopressin cell and fibre distribution patterns are highly conserved across species (Wang et al. 1996b). Several brain areas contain either vasopressinergic cells (cells expressing vasopressin mRNA and vasopressin immunoreactivity) and/or vasopressin immunoreactive fibres. Vasopressin production occurs in immunoreactive and mRNA-containing cells in the hypothalamus (suprachiasmatic nucleus, SCN; paraventricular nucleus, PVN; supraoptic nucleus, SON), the bed nucleus of the stria terminalis (BST) and the medial amygdala (MeA). Those sites of production send projections to brain areas where vasopressin immunoreactive fibres appear including the lateral septum (LS), ventral pallidum (VP), lateral habenular nucleus (LH), medial preoptic area (MPOA), BST, PVN and MeA (De Vries & Buijs 1983). Therefore, like oxytocin, vasopressin production, while localized to just a few brain areas, has the potential to affect receptors throughout the brain. Vasopressin expression levels in brain areas outside the hypothalamus are sexually dimorphic: males have higher numbers of vasopressin expressing cells in the BST and more fibres in the LS and lateral habenula (De Vries & Buijs 1983; De Vries et al. 1983; De Vries 1990). Sexual dimorphism in these brain areas is regulated by gonadal steroids (De Vries et al. 1983), and the steroids have both organizational and activational effects (Wang et al. 1993). In rats, when neonatal males are castrated, they mature into adult males with female-like numbers of cells and fibres in the BST, amygdala and septum. In contrast, when castrated as adults, only the intensity of the immunoreactivity falls while cell numbers are maintained. In the prairie vole, when sexually naive adult males are castrated, levels of vasopressin immunoreactivity are reduced in cells and fibres of brain areas thought to be involved in paternal care in this species: cells of the BST and MeA and their projections to the LS (Wang & De Vries 1993). In contrast, vasopressin levels in hypothalamic regions of the brain (PVN, SCN, SON) are not altered by castration (Wang & De Vries 1993). Infusion of vasopressin into the LS of castrated males increases pup-directed behaviours and antagonist treatment decreases the same (Wang et al. 1994). Vasopressin

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(a)

(b) PFC CP NAcc

(c)

(d)

LS

VP

Figure 1. Autoradiograms illustrating the distribution of oxytocin receptors (a,b) and vasopressin receptors (c,d ) in the monogamous prairie vole (a,c) and non-monogamous meadow vole (b,d ). Note the species differences in oxytocin receptors in the NAcc and the vasopressin receptors in the VP. PFC, prefrontal cortex; CP, caudate putamen; NAcc, nucleus accumbens; LS, lateral septum; VP, ventral pallidum.

immunoreactivity is altered in male prairie voles after cohabitation with mating and pup exposure (Bamshad et al. 1993, 1994). Vasopressin immunoreactivity decreases in the LS with sexual experience and onset of parental care, while vasopressin mRNA levels rise in the BST (Bamshad et al. 1994). Since the vasopressin immunoreactive fibres in the LS originate from the BST, the coincidental decrease in LS vasopressin immunoreactivity and increased vasopressin mRNA in the BST are consistent with increased vasopressin release in the LS and a compensatory increase in vasopressin synthesis. In contrast to the findings presented above, castrated sexually naive prairie voles, with no vasopressin immunoreactivity in the LS, show only very mild deficits in spontaneous paternal behaviour (Lonstein & De Vries 1999). This indicates that vasopressin may not be required for the expression of paternal care, although it does not preclude a role for its modulatory influence. Considering that vasopressin distribution is so highly conserved across species, it is interesting that it has such dramatic differences in behavioural effects when injected into the brain (Young et al. 1997, 1999). The brain distribution pattern for V1aR is not conserved even across closely related species like prairie and montane voles (figure 1c,d ). Like the OTR, species differences in V1aR distribution have been hypothesized to contribute to the species differences in social structure (Insel et al. 1994; Young et al. 1997, 1999). In particular, the V1aR levels are higher in the VP, central nucleus of the amygdala, cingulate cortex and laterodorsal thalamus in monogamous prairie voles compared with promiscuous montane voles. In contrast to the sexually dimorphic levels of vasopressin peptide production outside of the hypothalamus, Phil. Trans. R. Soc. B (2006)

within the prairie vole species there do not appear to be any sex differences in the distribution patterns of V1aR (Insel et al. 1994; Phelps & Young 2003; Lim et al. 2004a). Interestingly, comparisons of other monogamous and non-monogamous species of rodents and primates revealed that high densities of V1aR in the ventral pallidal area are associated with monogamy (Young 1999). To test the idea that species-specific V1aR distribution patterns have important behavioural consequences, site-specific modulation of V1aR has been used. For example, a V1aR antagonist prevents partner preference formation when applied directly to the VP at low doses that are ineffective when delivered into the lateral ventricles (Lim & Young 2004). A viral vector containing the prairie vole avpr1a with a neuronspecific enolase promoter has been used to alter V1aR levels in specific brain regions. Increasing V1aR density in the VP of male prairie voles using this V1aRexpressing virus facilitates partner preference formation in the absence of mating (Pitkow et al. 2001). If the species differences in V1aR levels in the VP are sufficient to alter species-typical behaviour, then experimentally increasing V1aR levels in the VP of promiscuous meadow voles should facilitate the development of partner preferences in this species. Lim and colleagues performed this experiment by injecting promiscuous meadow voles with a V1aR-expressing viral vector directly into the VP (Lim et al. 2004b). After injection and recovery, the animals were tested for their ability to form pair bonds in the partner preference test. All of the meadow voles that displayed increased levels of V1aR binding in the VP displayed partner preferences. Therefore, even though these two species diverged long ago, this simple change in the expression of a single gene replicated a hypothetical evolutionary event

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Neuropeptides and autism that may have ultimately led to the development of monogamy. Since both the NAcc and VP are key relay nuclei in the brain circuits involved in motivation and reward, it has been hypothesized that both oxytocin and vasopressin may be facilitating affiliation and social attachment in monogamous species by modulating these reward pathways (Insel & Young 2001; Young et al. 2001; Insel 2003; Young & Wang 2004). Dopamine in the NAcc plays a major role in the regulation of pair bond formation in prairie voles. After mating, dopamine turnover increases in the NAcc in both females (Gingrich et al. 2000) and males (Aragona et al. 2003). Dopamine D2 receptor antagonists in the NAcc block partner preference formation and agonists facilitate partner preference formation (Gingrich et al. 2000; Aragona et al. 2003). Concurrent activation of D2 dopamine and OTRs in the NAcc are necessary for partner preference formation in female prairie voles (Liu & Wang 2003). Additionally, the effect of increasing the V1aR levels in the VP on partner preference behaviour in the meadow vole depends on intact dopamine signalling, although this signalling has not yet been localized to the NAcc (Lim et al. 2004b). The VP and the NAcc are heavily interconnected (Zahm & Heimer 1990). Perhaps the activation of OTR in the NAcc of females and V1aR in the VP of males, along with concurrent activation of dopamine D2 receptors in ‘reward circuitry’ in both males and females provide sex-specific, but parallel mechanisms for pair bond formation in this species (Lim et al. 2004a). Historically, dopamine innervation of the NAcc was thought to mediate the pleasurable sensations accompanying reinforcing stimuli. In contrast, newer theories of the role of dopamine along these pathways involve detection of cue saliency and perhaps calculation of costs and benefits, and more generally as a modulator of behavioural drive (Salamone et al. 2005). Regardless of the actual correlates of dopamine signalling, both theories of dopamine signalling are compatible with the idea that species-specific modulation of this pathway by oxytocin or vasopressin can influence the probability of partner preference formation. Therefore, if oxytocin and vasopressin, released during prolonged cohabitation and mating, modulate dopamine signalling in the NAcc in the prairie vole (but not in the montane or meadow vole) then both neuropeptides can alter the reinforcing properties of the mate and thereby influence the future behavioural interactions with the mate. Clearly, the species differences in V1aR-binding patterns in the brain have important consequences for behaviour. These differences could be due to differences in receptor pharmacology across the two species or gene regulation. It appears that the latter is the case. The two species are highly homologous in the coding region for the avpr1a gene (Young et al. 1999) and consequently, there are no differences in the receptor pharmacology across the two species (Insel et al. 1994). Additionally, the species differences in receptor-binding levels are apparent at the perinatal period, indicating that environmental effects on regulation are less likely than genetic effects (Wang et al. 1996a). Furthermore, the species differences in distribution are not only apparent at the level of Phil. Trans. R. Soc. B (2006)

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receptor binding, but also at the mRNA level, suggesting species differences in gene regulation rather than in post-translational processing (Young et al. 1997). In the regulatory region of the avpr1a gene, there is a striking species difference at ca 660 bp upstream of transcription start site. In monogamous prairie and pine voles, there is a 500 bp highly repetitive expansion, referred to as a microsatellite, at this locus which is only ca 50 bp long in the promiscuous meadow and montane voles (Young et al. 1999). It is possible that this microsatellite modifies gene expression patterns by changing the promoter structure of the avpr1a gene across monogamous and promiscuous species (Young et al. 1999; Hammock & Young 2002). A transgenic mouse for the prairie vole avpr1a gene, including this microsatellite, has a receptor distribution pattern which is more like that of a prairie vole than like a wild-type mouse, suggesting that sequences in the prairie vole avpr1a gene contribute to species-specific distribution patterns. In cell culture, this prairiespecific microsatellite modulates gene expression. Specifically, deleting the microsatellite results in an increase in the activity of a reporter gene in some, but not all, of the cell lines that were tested (Hammock & Young 2004). This indicates that the microsatellite acts in a cell-type-dependent manner to regulate gene expression. We would expect that such a regulatory mechanism is also functioning in the brain because not all brain areas show species differences in receptorbinding levels. In addition, when the prairie vole microsatellite is replaced with the montane vole microsatellite, the short montane vole microsatellite also increased reporter gene activity relative to the long prairie microsatellite, demonstrating that species differences in microsatellite length affect gene regulation (Hammock & Young 2004). It is plausible that the species differences in gene structure lead to changes in gene expression patterns, which ultimately have behavioural consequences. Therefore, it does seem likely that the addition of the V1aR in the VP, by expansion or lack of contraction of this unstable repetitive element in the 5 0 regulatory region of the avpr1a gene, was permissive for the natural selection of monogamous behaviour in the evolutionary history of prairie voles. If the instability of microsatellite sequences can serve as some sort of evolutionary tuning knob (King 1994), then there may still exist a genotype–phenotype relationship within the prairie vole species. Within the prairie vole species, there is significant variability in the length of this microsatellite. There is also variability within-species in receptor distribution patterns and social behaviour (Hammock & Young 2002; Phelps & Young 2003). To test the hypothesis that the microsatellite serves as an evolutionary tuning knob, prairie voles were selectively bred for the length of their microsatellite and the parents and offspring were tested for their social behaviour and their distribution of V1aR in the brain determined (Hammock & Young 2005). First, it should be noted that subtle intraspecific variation in microsatellite length was able to modify gene expression in transcription reporter assays in cell culture, indicating that it might also function to regulate gene expression in some cell types in the brain. Second,

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the paternal care of the breeder males, but not the breeder females, was associated with genotype. Specifically, breeder males with longer microsatellites spent more time in licking and grooming the pups, which is an important rodent parental behaviour that is known to be modulated by manipulating V1aR signalling (Wang et al. 1994). We tested the male offspring of the breeder pairs for their social behaviour and found that offspring with long microsatellites, as a group, were quicker to approach strangers and had higher rates of partner preference formation. The microsatellite appeared to have an effect on V1aR distribution patterns, as well. The effect of the microsatellite was region specific. A long allele appeared to increase V1aR levels in the olfactory bulb and LS and decrease in the hypothalamus, BST and several other brain regions. Interestingly, there were no differences in the VP and MeA, which are two brain regions that have been shown pharmacologically to play important roles in prairie vole typical social behaviour. Therefore, it seems as though unstable microsatellites may indeed play a critical role in the evolution of social behaviour by the generation of individual differences in brain and consequent behavioural traits. Interestingly, a similar mutational event in the primate AVPR1A may have contributed to the evolution of primate social behaviour. Humans and bonobos, both known for high levels of social reciprocity, empathy and sociosexual bonding, have a repetitive microsatellite locus 3625 bp upstream of the transcription start site. In contrast, this microsatellite locus is absent in the common chimpanzee, reminiscent of the genetic differences between highly social and asocial voles at this locus (Hammock & Young 2005).

3. OXYTOCIN AND ARGININE VASOPRESSIN IN SOCIAL RECOGNITION For social bonding to occur, individuals must have a capacity for social recognition, which includes the ability to detect as well as discriminate familiar individuals. In rodents, the main and accessory olfactory bulbs and their projections contribute significantly to this process. Oxytocin and vasopressin facilitate social recognition through these pathways. To facilitate social learning, these neuropeptides may act as more direct carriers of social information or may serve to modulate the activity of other neurotransmitter systems to increase the salience of social olfactory cues. Social recognition requires a complex set of processes: social approach and investigation, sensory processing and learning and memory. Social recognition in rats and mice can be assessed experimentally owing to their high levels of novelty preference. Rats and mice will investigate a novel individual more than the one they have investigated recently. In tests for social recognition, the test animal is exposed to animal A and allowed to investigate for a brief period of time. This trial is followed by re-exposure to the same stimulus animal A or a novel stimulus animal B. With each exposure, the investigator records the duration of anogenital and perioral sniffing by the test animal. With repeated presentations of the same stimulus animal A, the test animal will spend less and less time Phil. Trans. R. Soc. B (2006)

investigating animal A. This decrease in the amount of investigation by the test animal is interpreted as social recognition, because now the familiar animal does not have novel properties. If the experimenter adds novel stimulus animal B to the test arena, then the test animal reverts to a thorough anogenital/perioral investigation behaviour. In this assay, social recognition memory has been determined to be ca 2 h or less for rats and mice (Dantzer et al. 1987), but can be prolonged or truncated with various behavioural and pharmacological manipulations. Behaviourally, grouphoused mice display drastic improvements (days) in the duration of social memory (Kogan et al. 2000). Oxytocin plays a role in social recognition. In rats, when infused into the olfactory bulb minutes prior to behavioural testing, oxytocin prolongs the duration of social recognition responses (Dluzen et al. 1998a). Oxytocin seems to modulate norepinephrine signalling in the olfactory bulb to enhance social recognition. Lesions of norepinephrine containing cells by intrabulb infusions of 6-hydroxydopamine prevent the prolonged social recognition response to oxytocin (Dluzen et al. 1998b). Norepinephrine seems to play a critical role in olfactory-mediated social recognition. Even without oxytocin coadministration, pharmacological induction of norepinephrine signalling in the olfactory bulb, by blockade of norepinephrine reuptake with nisoxetine or stimulation of alpha-2 noradrenergic receptors with clonidine, increases social recognition (Dluzen et al. 2000; Shang & Dluzen 2001). The emerging model is that oxytocin potentiates the release of norepinephrine in the olfactory bulb, since oxytocin treatment results in increased norepinephrine release as measured by microdialysis of the bulb (Dluzen et al. 2000). Oxytocin induced enhancement of norepinephrine stimulates alpha-2 noradrenergic receptors, which inhibit local inhibitory granule cells. In addition to its role in the olfactory bulb, oxytocin appears to act in other brain areas to regulate social recognition behaviour. Infusions of oxytocin in both the LS and MPOA of male rats can prolong social recognition (Popik & Van Ree 1991, 1992). Male and female oxytocin knockout mice have an impaired ability to remember a mouse they have just met (Ferguson et al. 2000; Choleris et al. 2003). This deficit is rescued by infusion of oxytocin into the MeA before the learning trial, and in wild-type animals, the deficit can be reproduced with the application of an OTR antagonist into the MeA (Ferguson et al. 2001). The timing of treatment with oxytocin and its receptor antagonist indicate that oxytocin plays a role in the early stages of social-recognition memory formation rather than in the subsequent expression of social-recognition behaviour. Furthermore, mice with disruptions in the genes encoding oestrogen receptor alpha and beta, which are known to regulate the expression of OTR and oxytocin, also show social-recognition deficits (Choleris et al. 2003). Like oxytocin, vasopressin is also involved in social recognition. Infusion of vasopressin into the brain can prolong the duration of social-recognition memory in rats (Le Moal et al. 1987). Vasopressin appears to act in the LS to mediate this affect, since vasopressin applied directly to the LS also prolongs the social-recognition

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Neuropeptides and autism response, while a V1aR antagonist into the LS of rats inhibits social recognition (Dantzer et al. 1988). The Brattleboro rat, which cannot produce vasopressin, displays a social-recognition deficit, while application of vasopressin directly into the LS of these rats restores social recognition behaviour (Englemann & Landgraf 1994). Manipulating the numbers of receptors in the LS also influences social recognition behaviour in the predicted manner. For example, using V1aR selective antisense oligonucleotides to downregulate V1aR in the dorsal LS of normal rats inhibits social-recognition behaviour (Landgraf et al. 1995). Additionally, utilizing viral vector gene transfer of V1aR to increase V1aR density in the LS of normal rats enhances the apparent durability of social-recognition memories (Landgraf et al. 2003). Mice lacking the V1aR also have a socialrecognition deficit (Bielsky et al. 2004) and this deficit is corrected with replacement of the receptor by viral vector gene transfer into the LS (Bielsky et al. 2005). Another brain receptor for vasopressin, the vasopressin 1b receptor (V1bR) also appears to be capable of influencing social recognition. The V1bR knockout also has a modest impairment in social recognition, although the primary phenotype is a reduction in aggression (Wersinger et al. 2002). In addition to its role in the LS, vasopressin also facilitates social recognition by acting in the olfactory bulb. Direct application of vasopressin to the olfactory bulbs prolongs the expression of the social-recognition response (Dluzen et al. 1998a), and as with oxytocin, the treatment effect may depend on intact noradrenergic signalling in the olfactory bulb (Dluzen et al. 1998b). Like most mammals, rat pups are born helpless and evolution has developed mechanisms to ensure that the young receive the care they need. Rodent pups learn very quickly to associate received maternal care with sensory stimuli of the mother, most notably her odour. Rodent dams spend a lot of time licking and grooming the pup. This aspect of maternal care can be experimentally simulated using a paintbrush. When ‘licked’ with a paintbrush during exposure to a novel odour such as peppermint, rat pups will show a learned preference for peppermint odour that persists for some time after training (Sullivan et al. 1989). Therefore, maternal licking enhances olfactory learning in the pup. There appears to be a critical period for this kind of learning and it is associated with increased activity of the developing locus coeruleus, the major site of norepinephrine production. Rat pups have increased noradrenergic neurotransmission from the locus coeruleus into the olfactory bulb relative to adults (Sullivan et al. 2000; Sullivan 2003). In fact, this learning of and subsequent preference for an odour can be reproduced with exogenous application of norepinephrine into the bulb or stimulation of the locus coeruleus (Sullivan et al. 2000). Perhaps in rat pups, oxytocin and/or vasopressin potentiates the release of norepinephrine to modulate social memory as oxytocin does in adult rats (Dluzen et al. 2000). Normal rat pups learn to associate a nonsocial odour (such as lemon scent) with the odour of their mom and will subsequently show a preference for the lemon-scent even in the absence of their mother. In contrast, pre-weanling vasopressin-deficient Phil. Trans. R. Soc. B (2006)

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Brattleboro rats do not make the association of mother odour cues with a non-social odour, or at least fail to show a preference for the lemon odour after repeated mom-odour pairings (Nelson & Panksepp 1998). Likewise, in normal pre-weanling rats, intracerebroventricular OTR antagonist administration prior to the learning trial inhibits the association of mother odour with a non-social odour (Nelson & Panksepp 1996). Therefore, an emerging model of social olfactory learning in the rodent pup includes increased noradrenergic drive to the olfactory bulb which is potentiated by oxytocin and or vasopressin released with social stimuli. This increased noradrenergic drive probably reduces the inhibitory tone on the olfactory bulb, allowing increased activity of the main output cells of the bulb. This increased excitation in the output cells of the bulb probably results in plasticity in both the bulb and its downstream projections. Individual differences in developmental plasticity of the olfactory bulb may impact adult sociobehavioural phenotypes by differential tuning of the system to attend differently to social odours. In rats and mice, it is very clear that appropriate social behaviour requires an intact sensory modality (olfaction) for social recognition, a way to assess the valency of the olfactory input (as in the amygdala) and regulation of motivation and reward circuitry (ventral forebrain). This circuitry is influenced by steroid hormones, neuropeptides and classical neurotransmitters like norepinephrine and dopamine. This is clearly a very simplified model as there are many other brain regions containing many hormones and gene products that contribute to the regulation of the many aspects of complex affiliative behaviour. Interestingly, while there are clear data that suggest a role for vasopressin and oxytocin in social-recognition memory in rats and mice, the role of these neurohormones in the requisite social-recognition component of pair bonding behaviour in voles is not known. What little we do know about general vole social recognition does fit into the theoretical framework generated by rat and mouse studies. Lesion studies in female prairie voles have demonstrated that the main and accessory olfactory bulbs are critical for partner preference formation (Williams et al. 1992b; Curtis et al. 2001). In male prairie voles, lesions of the olfactory bulb result in decreased social behaviour (Kirkpatrick et al. 1994).

4. OXYTOCIN AND ARGININE VASOPRESSIN IN HUMAN SOCIAL BEHAVIOUR As stated at the outset, we propose that understanding the neurobiological mechanisms regulating normal social behaviour in animal models will provide valuable clues to the regulation of human social behaviour, and perhaps suggest how dysregulation of these systems might contribute to developmental disorders such as autism. We are only at the very earliest stages of understanding the genetics and neural circuitry of complex social behaviours. However, ultimately it is hoped that these approaches will lead to novel pharmacological therapies that may ameliorate at least the social behavioural deficits in autism and Asperger’s syndrome. The studies outlined above, as well as the

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examples discussed below, make a very strong case in support of the hypothesis that oxytocin and vasopressin may modulate human social behaviour. However, at this point, a strong argument for a role of oxytocin and vasopressin in autism cannot be made, and that is not our intent here. With that disclaimer, we will discuss some intriguing data consistent with the hypothesis that disruptions in oxytocin and vasopressin systems may contribute to the behavioural phenotype of autism. One important caveat when trying to link the animal literature on oxytocin and vasopressin discussed above to human behaviour is that the majority of the social behaviours modulated by these peptides in animals rely on olfactory projections to subcortical areas. In contrast, social cognition in humans involves visual and auditory sensory processing as well as attentional and executive areas of the cortex. However, it is possible that these neuropeptides modulate limbic areas in humans which receive multimodal sensory and cortical, rather than primarily olfactory, input. This is particularly plausible given the evolutionary plasticity in the neuroanatomical distribution of oxytocin and vasopressin receptors (figure 1) across mammalian species. Studies examining the effects of oxytocin and vasopressin on visual social cognition in humans would be useful for examining this possibility. The distribution of the human OTR is consistent with an interaction with the dopamine system (Loup et al. 1991), with receptors concentrated in the substantia nigra, globus pallidus and nucleus of Meynert. Interestingly, a functional magnetic resonance imaging study suggests a high degree of overlap between OTR distribution and brain activation while viewing romantic partners or in mothers viewing images of their infant (Bartels & Zeki 2004). Plasma oxytocin levels have been reported to increase both during sexual intercourse and during breastfeeding in humans (Carmichael et al. 1987; Unvas-Moberg 1998). More recent studies have directly tested the influence of oxytocin on social behaviour by using intranasal infusions. First, intranasal infusion of oxytocin appears to enhance the buffering of social support in humans, as indicated by decreased stress response during a socially stressful situation (Heinrichs et al. 2003). A more recent study found that intranasal infusion of oxytocin increased trust among humans (Kosfeld et al. 2005). There is modest, yet intriguing evidence linking oxytocin to autism. Oxytocin levels in blood plasma of boys with autism was found to be lower than in a group of age-matched controls (Modahl et al. 1998). Within the control group, oxytocin levels were positively associated with measures of social behaviour such as socialization, social coping and interpersonal relationships as well as some non-social measures like personal care and daily living skills. In contrast, oxytocin levels within the autistic group were negatively correlated with interpersonal relationships, socialization, community skills, personal care and daily living skills in addition to other behaviours. The oxytocin levels did show some overlap between the autistic group and the control group. The opposite directions of the correlations of oxytocin and behaviour mean that autistic kids with the most normal oxytocin levels had the worst social Phil. Trans. R. Soc. B (2006)

phenotype. This makes the data difficult to interpret and the potential role of oxytocin in the aetiology of autism very unclear. It is possible that the differences in oxytocin levels could reflect differences in medication between the groups. Additionally, the entire study is based on serum measures of oxytocin rather than measures from cerebrospinal fluid, which adds a layer of complexity as well. A follow-up study on these same samples revealed that the differences in plasma oxytocin levels were associated with an increase in incompletely processed oxytocin fragments, suggesting that peptide processing may be dysregulated in the autistic patients (Green et al. 2001). A second study has replicated these initial findings in a separate population of subjects (Al-Ayadhi 2005). This study also found lower levels of vasopressin in the plasma of autistic children. No studies have yet examined the pharmacological influences of oxytocin on the social deficits in autism; however, infusions of synthetic oxytocin and pitocin significantly reduced repetitive behaviours in patients with autistic and Asperger’s disorders (Hollander et al. 2003). While the plasma oxytocin data are consistent with the hypothesis that disruptions in the oxytocin system contribute to the social behavioural phenotype in autism, it is also equally plausible that these differences in oxytocin levels may be the consequence of altered cognitive processing in autistic patients. Autism is also characterized by general cognitive impairments, altered sensory processing and also cortical and cerebellar development, each of which are likely independent of the oxytocin and vasopressin systems. The altered processing of social stimuli resulting from altered brain wiring may actually prevent the normal activation of the oxytocin and vasopressin systems resulting in decreased plasma concentrations. However, there is some modest evidence suggesting a possible association of the OTR gene with autism. A combined analysis of the primary genome scan data of the autism genetic resource exchange Finnish autism samples identified chromosome locus 3p24–26 as a candidate autism locus (Ylisaukko-Oja et al. 2005). This region contains 40 genes, including the OTR gene. However, this study failed to identify an association between specific polymorphisms and autism, although a limited number of polymorphisms were analysed. However, a separate study did report a significant positive association of the OTR gene with autism in a Chinese Han population (Wu et al. 2005). For vasopressin, the most intriguing data suggesting a potential role for autism comes from genetic studies of the AVPR1A gene. There are three polymorphic microsatellites in the 5 0 flanking region of the human AVPR1A (Thibonnier et al. 2000). Using a sample of 115 trio families, Kim et al. (2001) reported a nominally significant transmission disequilibrium between a microsatellite in the 5 0 flanking region of the human AVPR1A and autism. This microsatellite is located 3625 bp upstream of the transcription start site and consists of a complex repeat of (CT)4-TT-(CT)8(GT)n where n ranges from 9 to 25, resulting in 16 different alleles in the population. It should be noted that the transmission disequilibrium in this study fails to be significant if Bonferroni corrected for all of the

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– 660 bp prairie vole

(a)

montane vole –3625 bp human bonobo common chimp (b)

OB short

HYP

LS long

Figure 2. (a) Schematic of the structure of the vasopressin receptor gene avpr1a in voles and AVPR1A in primates. The black bars represent the transcribed region of the gene. The hatched bars represent the microsatellite sequences in the 5 0 flanking region of the gene as discussed in the text. Numbers above the microsatellites indicate the relative position upstream of the transcription start site. (b) Autoradiograms illustrating the differences in vasopressin receptor binding in prairie voles with either short (top row) or long (bottom row) versions of the microsatellite in the avpr1a gene. Note the strain differences in the olfactory bulb (OB), lateral septum (LS) and the hypothalamus (HYP).

genes examined in this set of trios; therefore these data must be viewed with caution. However, it should also be noted that given the estimation that several dozen genes may be involved in the aetiology of autism, stronger associations may not be expected. The association between this microsatellite and autism was recently replicated by a second independent study (Wassink et al. 2004). Interestingly, this study found the strongest transmission disequilibrium in the subset of autistic children without language impairment. While the chromosomal locus of AVPR1A has not been identified in genome scans as a candidate locus in autism, one study in which only autistic subjects with normal language function were analysed, a chromosomal locus containing AVPR1A was identified as a candidate site. Therefore, while variation at this locus alone is not likely to cause autism and may not be associated at all with some forms of autism, variation may contribute to the severity of disease phenotype in some individuals, or potentially interact with other genetic or environmental factors that more directly cause autism. Interestingly, this same polymorphic microsatellite in the human AVPR1A that has been associated with autism is absent in the common chimpanzee, but present in the bonobo (Hammock & Young 2005). Bonobos are known for their high levels of sociosexual reciprocity and they appear to use sexuality to promote social reconciliation as well as social bonding within their group (De Waal & Lanting 1997). Therefore, it is intriguing to consider that as in voles, variations in unstable microsatellite sequences in the promoters of the primate vasopressin receptor gene (figure 2) may Phil. Trans. R. Soc. B (2006)

contribute to species differences in expression and social behaviour, as well as to individual differences in social behaviour. 5. CONCLUSION Basic research into ethologically relevant behaviour of the prairie vole has allowed us to gain insight into some of the underlying neural and genetic mechanisms of social-bonding behaviour in mammals. Humans may share some of these mechanisms and when these mechanisms are disrupted, either by genetic, environmental or interactive causes, extreme phenotypes such as autism may be revealed. These studies illustrate the power of the comparative neuroethological approach for understanding human neurobiology and suggest that examining the neurobiological bases of complex social behaviour in divergent species is a valuable approach to gaining insights into human pathologies. REFERENCES Al-Ayadhi, L. Y. 2005 Altered oxytocin and vasopressin levels in autistic children in Central Saudi Arabia. Neurosciences 10, 47–50. Albers, H. E. & Bamshad, M. 1998 Role of vasopressin and oxytocin in the control of social behavior in Syrian hamsters (Mesocricetus auratus). Prog. Brain Res. 119, 395–408. Aragona, B. J., Liu, Y., Curtis, T. J., Stephan, F. K. & Wang, Z. X. 2003 A critical role for nucleus accumbens dopamine in partner preference formation of male prairie voles. J. Neurosci. 23, 3483–3490. Bamshad, M., Novak, M. A. & DeVries, G. J. 1993 Sex and species differences in the vasopressin innervation

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

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of sexually naive and parental prairie voles, Microtus ochrogaster and meadow voles, M. pennsylvanicus. J. Neuroendocrinol. 5, 247–255. Bamshad, M., Novak, M. & de Vries, G. 1994 Cohabitation alters vasopressin innervation and paternal behavior in prairie voles (Microtus ochrogaster). Physiol. Behav. 56, 751–758. Bartels, A. & Zeki, S. 2004 The neural correlates of maternal and romantic love. Neuroimage 21, 1155–1166. Bielsky, I. F., Hu, S.-B., Szegda, K. L., Westphal, H. & Young, L. J. 2004 Profound impairment in social recognition and reduction in anxiety in vasopressin V1a receptor knockout mice. Neuropsychopharmacology 29, 483–493. Bielsky, I. F., Hu, S. B., Ren, X., Terwilliger, E. F. & Young, L. J. 2005 The V1a vasopressin receptor is necessary and sufficient for normal social recognition: a gene replacement study. Neuron 47, 503–513. Carmichael, M. S., Humbert, R., Dixen, J., Palmisano, G., Greenleaf, W. & Davidson, J. M. 1987 Plasma oxytocin increases in the human sexual response. J. Clin. Endocrinol. Metab. 64, 27–31. Carter, C. S., DeVries, A. C. & Getz, L. L. 1995 Physiological substrates of mammalian monogamy: the prairie vole model. Neurosci. Biobehav. Rev. 19, 303–314. Cho, M. M., DeVries, A. C., Williams, J. R. & Carter, C. S. 1999 The effects of oxytocin and vasopressin on partner preferences in male and female prairie voles (Microtus ochrogaster). Behav. Neurosci. 113, 1071–1079. Choleris, E., Gustafsson, J. A., Korach, K. S., Muglia, L. J., Pfaff, D. W. & Ogawa, S. 2003 An estrogen-dependent fourgene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice. Proc. Natl Acad. Sci. USA 100, 6192–6197. Curtis, J. T., Liu, Y. & Wang, Z. 2001 Lesions of the vomeronasal organ disrupt mating-induced pair bonding in female prairie voles (Microtus ochrogaster). Brain Res. 901, 167–174. Dantzer, R., Bluthe, R. M., Koob, G. F. & Moal, M. L. 1987 Modulation of social memory in male rats by neurohypophyseal peptides. Psychopharmacology 91, 363–368. Dantzer, R., Koob, G., Bluthe, R. & Moal, M. L. 1988 Septal vasopressin modulates social memory in male rats. Brain Res. 457, 143–147. De Vries, G. J. 1990 Sex differences in the brain. J. Neuroendocrinol. 2, 1–13. De Vries, G. & Buijs, R. 1983 The origin of vasopressinergic and oxytocinergic innervation of the rat brain with special reference to the lateral septum. Brain Res. 273, 307–317. De Vries, G. J., Best, W. & Sluiter, A. A. 1983 The influence of androgens on the development of a sex difference in the vasopressinergic innervation of the rat lateral septum. Brain Res. 284, 377–380. De Waal, F. & Lanting, F. 1997 Bonobo: the forgotten ape. Berkeley and Los Angeles, CA: University of California Press. Dluzen, D. E., Muraoka, S., Engelmann, M. & Landgraf, R. 1998a The effects of infusion of arginine vasopressin, oxytocin, or their antagonists into the olfactory bulb upon social recognition responses in male rats. Peptides 19, 999–1005. Dluzen, D. E., Muraoka, S. & Landgraf, R. 1998b Olfactory bulb norepinephrine depletion abolishes vasopressin and oxytocin preservation of social recognition responses in rats. Neurosci. Lett. 254, 161–164. Dluzen, D. E., Muraoka, S., Engelmann, M., Ebner, K. & Landgraf, R. 2000 Oxytocin induces preservation of social recognition in male rats by activating alpha-adrenoceptors of the olfactory bulb. Eur. J. Neurosci. 12, 760–766. Phil. Trans. R. Soc. B (2006)

Englemann, M. & Landgraf, R. 1994 Microdialysis administration of vasopressin into the septum improves social recognition in Brattleboro rats. Physiol. Behav. 55, 145–149. Ferguson, J. N., Young, L. J., Hearn, E. F., Insel, T. R. & Winslow, J. T. 2000 Social amnesia in mice lacking the oxytocin gene. Nat. Genet. 25, 284–288. Ferguson, J. N., Aldag, J. M., Insel, T. R. & Young, L. J. 2001 Oxytocin in the medial amygdala is essential for social recognition in the mouse. J. Neurosci. 21, 8278–8285. Gainer, H. & Wray, W. 1994 Cellular and molecular biology of oxytocin and vasopressin. In The physiology of reproduction (ed. E. Knobil & J. D. Neill), pp. 1099–1129. New York, NY: Raven Press. Getz, L. L., Carter, C. S. & Gavish, L. 1981 The mating system of the prairie vole Microtus ochrogaster: field and laboratory evidence for pair bonding. Behav. Ecol. Sociobiol. 8, 189–194. Gillberg, C. & Wing, L. 1999 Autism: not an extremely rare disorder. Acta Psychiatr. Scand. 99, 399–406. Gingrich, B., Liu, Y., Cascio, C., Wang, Z. & Insel, T. R. 2000 Dopamine D2 receptors in the nucleus accumbens are important for social attachment in female prairie voles (Microtus ochrogaster). Behav. Neurosci. 114, 173–183. Green, L. A., Fein, D., Mohahl, C., Feinstein, C., Waterhouse, L. & Morris, M. 2001 Oxytocin and autistic disorder: alterations in peptide forms. Biol. Psychiatry 50, 609–613. Hammock, E. A. D. & Young, L. J. 2002 Variation in vasopressin V1a receptor promoter and expression: implications for inter- and intraspecific variation in social behavior. Eur. J. Neurosci. 16, 399–402. Hammock, E. A. D. & Young, L. J. 2004 Functional microsatellite polymorphisms associated with divergent social structure in vole species. Mol. Biol. Evol. 21, 1057–1063. Hammock, E. A. D. & Young, L. J. 2005 Microsatellite instability generates diversity in brain and sociobehavioral traits. Science 308, 1630–1634. Heinrichs, M., Baumgartner, T., Kirschbaum, C. & Ehlert, U. 2003 Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol. Psychiatry 54, 1389–1398. Hollander, E., Novotny, S., Hanratty, M., Yaffe, R., DeCaria, C. M., Aronowitz, B. R. & Mosovich, S. 2003 Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 28, 193–198. Insel, T. R. 2003 Is social attachment an addictive disorder. Physiol. Behav. 79, 351–357. Insel, T. R. & Hulihan, T. 1995 A gender-specific mechanism for pair bonding: oxytocin and partner preference formation in monogamous voles. Behav. Neurosci. 109, 782–789. Insel, T. R. & Shapiro, L. E. 1992 Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proc. Natl Acad. Sci. USA 89, 5981–5985. Insel, T. R. & Young, L. J. 2001 Neurobiology of social attachment. Nat. Neurosci. 2, 129–136. Insel, T. R., Wang, Z. & Ferris, C. F. 1994 Patterns of brain vasopressin receptor distribution associated with social organization in microtine rodents. J. Neurosci. 14, 5381–5392. Kanner, L. 1943 Autistic disturbances of affective contact. Nervous Child 2, 217–250. Kendrick, K. M., Keverne, E. B. & Baldwin, B. A. 1987 Intracerebroventricular oxytocin stimulates maternal behaviour in the sheep. Neuroendocrinology 46, 56–61.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Neuropeptides and autism Kendrick, K. M., Costa, A. P. C. D., Broad, K. D., Ohkura, S., Guevara, R., Levy, F. & Keverne, E. B. 1997 Neural control of maternal behavior and olfactory recognition of offspring. Brain Res. Bull. 44, 383–395. Kim, S. et al. 2001 Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism. Mol. Psychiatry 7, 503–507. King, D. G. 1994 Triple repeat DNA as a highly mutable regulatory mechanism. Science 263, 595–596. Kirkpatrick, B., Williams, J. R., Slotnick, B. M. & Carter, C. S. 1994 Olfactory bulbectomy decreases social behavior in male prairie voles (M. ochrogaster). Physiol. Behav. 55, 885–889. Kogan, J. H., Frankland, P. W. & Silva, A. J. 2000 Long-term memory underlying hippocampus-dependent social recognition in mice. Hippocampus 10, 47–56. Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U. & Fehr, E. 2005 Oxytocin increases trust in humans. Nature 435, 673–676. Landgraf, R., Gerstberger, R., Montkowski, A., Probst, J. C., Wotjak, C. T., Holsboer, F. & Engelmann, M. 1995 V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities and anxiety-related behavior in rats. J. Neurosci. 15, 4250–4258. Landgraf, R., Frank, E., Aldag, J. M., Neumann, I. D., Ren, X., Terwilliger, E. F., Wigger, A. & Young, L. J. 2003 Viral vector mediated gene transfer of the vole V1a vasopressin receptor in the rat septum: improved social discrimination and affiliative behavior. Eur. J. Neurosci. 18, 403–411. Le Moal, M., Dantzer, R., Michaud, B. & Koob, G. F. 1987 Centrally injected arginine vasopressin (AVP) facilitates social memory in rats. Neurosci. Lett. 77, 353–359. Lim, M. M. & Young, L. J. 2004 Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole. Neuroscience 125, 35–45. Lim, M. M., Murphy, A. Z. & Young, L. J. 2004a Ventral striato-pallidal oxytocin and vasopressin V1a receptors in the monogamous prairie vole (Microtus ochrogaster). J. Comp. Neurol. 468, 555–570. Lim, M. M., Wang, Z., Olaza´bal, D. E., Ren, X., Terwilliger, E. F. & Young, L. J. 2004b Enhanced partner preference in promiscuous species by manipulating the expression of a single gene. Nature 429, 754–757. Liu, Y. & Wang, Z. X. 2003 Nucleus accumbens dopamine and oxytocin interact to regulate pair bond formation in female prairie voles. Neuroscience 121, 537–544. Liu, Y., Curtis, J. T. & Wang, Z. X. 2001 Vasopressin in the lateral septum regulates pair bond formation in male prairie voles (Microtus ochrogaster). Behav. Neurosci. 115, 910–919. Lonstein, J. S. & De Vries, G. J. 1999 Sex differences in the parental behaviour of adult virgin prairie voles: independence from gonadal hormones and vasopressin. J. Neuroendocrinol. 11, 441–449. Loup, F., Tribollet, E., Dubois-Dauphin, M. & Dreifuss, J. J. 1991 Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. An autoradiographic study. Brain Res. 555, 220–232. Modahl, C., Green, L. A., Fein, D., Morris, M., Waterhouse, L., Feinstein, C. & Levin, H. 1998 Plasma oxytocin levels in autistic children. Biol. Psychiatry 43, 270–277. Morales, J. C., Cole, C., Neumann, I. D., Langraf, R. & Young, L. J. 2004 Vasopressin release in the ventral pallidum during mating in the monogamous male prairie vole. Soc. Neurosci. Abs. 214.1. Nelson, E. & Panksepp, J. 1996 Oxytocin mediates acquisition of maternally associated odor preferences in preweanling rat pups. Behav. Neurosci. 110, 583–592. Phil. Trans. R. Soc. B (2006)

E. A. D. Hammock & L. J. Young

2197

Nelson, E. E. & Panksepp, J. 1998 Brain substrates of infantmother attachment: contributions of opioids, oxytocin, and norepinephrine. Neurosci. Biobehav. Rev. 22, 437–452. Nishimori, K., Young, L. J., Guo, Q., Wang, Z., Insel, T. R. & Matzuk, M. M. 1996 Oxytocin is required for nursing but is not essential for partuition or reproductive behavior. Proc. Natl Acad. Sci. USA 93, 11 699–11 704. Parker, K. J., Phillips, K. M. & Lee, T. M. 2001 Development of selective partner preferences in captive male and female meadow voles, Microtus pennsylvanicus. Anim. Behav. 61, 1217–1226. Pedersen, C. A. & Prange Jr, A. J. 1979 Induction of maternal behavior in virgin rats after intracerebroventricular administration of oxytocin. Proc. Natl Acad. Sci. USA 76, 6661–6665. Phelps, S. M. & Young, L. J. 2003 Extraordinary diversity in vasopressin (V1a) receptor distributions among wild prairie voles (Microtus ochrogaster): patterns of variation and covariation. J. Comp. Neurol. 466, 564–576. Pitkow, L. J., Sharer, C. A., Ren, X., Insel, T. R., Terwilliger, E. F. & Young, L. J. 2001 Facilitation of affiliation and pair-bond formation by vasopressin receptor gene transfer into the ventral forebrain of a monogamous vole. J. Neurosci. 21, 7392–7396. Popik, P. & Van Ree, J. M. 1991 Oxytocin but not vasopressin facilitates social recognition following injection into the medial preoptic area of the rat. Eur. Neuropsychopharmacol. 1, 555–560. Popik, P. & Van Ree, J. M. 1992 Long-term facilitation of social recognition in rats by vasopressin related peptides: a structure-activity study. Life Sci. 50, 567–572. Salamone, J. D., Correa, M., Mingote, S. M. & Weber, S. M. 2005 Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine. Curr. Opin. Pharmacol. 5, 34–41. Shang, Y. & Dluzen, D. E. 2001 Nisoxetine infusion into the olfactory bulb enhances the capacity for male rats to identify conspecifics. Neuroscience 104, 957–964. Shapiro, L. E. & Insel, T. R. 1990 Infant’s response to social separation reflects adult differences in affiliative behavior: a comparative developmental study in prairie and montane voles. Dev. Psychobiol. 23, 375–394. Sullivan, R. M. 2003 Developing a sense of safety: the neurobiology of neonatal attachment. Ann. NY Acad. Sci. 1008, 122–131. Sullivan, R. M., Wilson, D. A. & Leon, M. 1989 Norepinephrine and learning-induced plasticity in infant rat olfactory system. J. Neurosci. 9, 3998–4006. Sullivan, R. M., Stackenwalt, G., Nasr, F., Lemon, C. & Wilson, D. A. 2000 Association of an odor with activation of olfactory bulb noradrenergic beta-receptors or locus coeruleus stimulation is sufficient to produce learned approach responses to that odor in neonatal rats. Behav. Neurosci. 114, 957–962. Swanson, L. W. & Kuypers, H. G. J. M. 1980 The paraventricular nucleus of the hypothalamus: cytoarchitectonic subdivisions and organization of projections to the pituitary, dorsal vagal complex, and spinal cord as demonstrated by retrograde fluorescence double-labeling methods. J. Comp. Neurol. 194, 555–570. Swanson, L. W. & McKellar, S. 1979 The distribution of oxytocin- and neurophysin-stained fibers in the spinal cord of the rat and monkey. J. Comp. Neurol. 188, 87–106. Thibonnier, M., Graves, M. K., Wagner, M. S., Chatelain, N., Soubrier, F., Corvol, P., Willard, H. F. & Jeunemaitre, X. 2000 Study of V1-vascular vasopressin receptor gene microsatellite polymorphisms in human essential hypertension. J. Mol. Cell. Cardiol. 32, 557–564.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2198

E. A. D. Hammock & L. J. Young

Neuropeptides and autism

Unvas-Moberg, K. 1998 Oxytocin may mediate the benefits of positive social interaction and emotions. Psychoneuroendocrinology 23, 819–835. Wang, Z. & De Vries, G. J. 1993 Testosterone effects on paternal behavior and vasopressin immunoreactive projections in prairie voles (Microtus ochrogaster). Brain Res. 631, 156–160. Wang, Z., Bullock, N. A. & De Vries, G. J. 1993 Sexual differentiation of vasopressin projections of the bed nucleus of the stria terminalis and medial amygdaloid nucleus in rats. Endocrinology 132, 2299–2306. Wang, Z., Ferris, C. F. & De Vries, G. J. 1994 Role of septal vasopressin innervation in paternal behavior in prairie voles (Microtus ochrogaster). Proc. Natl Acad. Sci. USA 91, 400–404. Wang, Z., Young, L. J., Liu, Y. & Insel, T. R. 1996a Species differences in vasopressin receptor binding are evident early in development: comparative anatomic studies in prairie and montane voles. J. Comp. Neurol. 378, 535–546. Wang, Z. X., Zhou, L., Hulihan, T. J. & Insel, T. R. 1996b Immunoreactivity of central vasopressin and oxytocin pathways in microtine rodents: a quantitative comparative study. J. Comp. Neurol. 366, 726–737. Wassink, T. H., Piven, J., Vieland, V. J., Pietila, J., Goedken, R. J., Folstein, S. E. & Sheffield, V. 2004 Examination of AVPR1a as an autism susceptibility gene. Mol. Psychiatry 9, 968–972 ePub Wersinger, S. R., Ginns, E. I., O’Carroll, A. M., Lolait, S. J. & Young 3rd, W. S. 2002 Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol. Psychiatry 7, 975–984. Williams, J., Catania, K. & Carter, C. 1992a Development of partner preferences in female prairie voles (Microtus ochrogaster): the role of social and sexual experience. Horm. Behav. 26, 339–349. Williams, J. R., Slotnick, B. M., Kirkpatrick, B. W. & Carter, C. S. 1992b Olfactory bulb removal affects partner preference development and estrus induction in female prairie voles. Physiol. Behav. 52, 635–639. Williams, J. R., Insel, T. R., Harbaugh, C. R. & Carter, C. S. 1994 Oxytocin administered centrally facilitates formation of a partner preference in prairie voles (Microtus ochrogaster). J. Neuroendocrinol. 6, 247–250.

Phil. Trans. R. Soc. B (2006)

Winslow, J. T. & Insel, T. R. 1991 Social status in pairs of squirrel monkeys determines the behavioral response to central oxytocin administration. J. Neurosci. 11, 2032–2038. Winslow, J., Hastings, N., Carter, C. S., Harbaugh, C. & Insel, T. 1993 A role for central vasopressin in pair bonding in monogamous prairie voles. Nature 365, 545–548. Witt, D. W., Carter, C. S. & Walton, D. M. 1990 Central and peripheral effects of oxytocin administration in prairie voles (Microtus ochrogaster). Pharmacol. Biochem. Behav. 37, 63–69. Witt, D. M., Winslow, J. T. & Insel, T. R. 1992 Enhanced social interactions in rats following chronic, centrally infused oxytocin. Pharmacol. Biochem. Behav. 43, 855–861. Wu, S. et al. 2005 Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol. Psychiatry 58, 74–77. Ylisaukko-Oja, T. et al. 2005 Search for autism loci by combined analysis of Autism Genetic Resource Exchange and Finnish families. Ann. Neurol. 59, 145–155. Young, L. J. 1999 Frank A. Beach Award. Oxytocin and vasopressin receptors and species-typical social behaviors. Horm. Behav. 36, 212–221. Young, L. J. & Wang, Z. 2004 The neurobiology of pair bonding. Nat. Neurosci. 7, 1048–1054. Young, L. J., Huot, B., Nilsen, R., Wang, Z. & Insel, T. R. 1996 Species differences in central oxytocin receptor gene expression: comparative analysis of promoter sequences. J. Neuroendocrinol. 8, 777–783. Young, L. J., Winslow, J. T., Nilsen, R. & Insel, T. R. 1997 Species differences in V1a receptor gene expression in monogamous and non-monogamous voles: behavioral consequences. Behav. Neurosci. 111, 599–605. Young, L. J., Nilsen, R., Waymire, K. G., MacGregor, G. R. & Insel, T. R. 1999 Increased affiliative response to vasopressin in mice expressing the vasopressin receptor from a monogamous vole. Nature 400, 766–768. Young, L. J., Lim, M., Gingrich, B. & Insel, T. R. 2001 Cellular mechanisms of social attachment. Horm. Behav. 40, 133–148. Zahm, D. S. & Heimer, L. 1990 Two transpallidal pathways originating in the rat nucleus accumbens. J. Comp. Neurol. 302, 437–446.

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Phil. Trans. R. Soc. B (2006) 361, 2199–2214 doi:10.1098/rstb.2006.1940 Published online 6 November 2006

Mother–infant bonding and the evolution of mammalian social relationships K. D. Broad, J. P. Curley and E. B. Keverne* Sub-Department of Animal Behaviour, University of Cambridge, Madingley, Cambridge CB3 8AA, UK A wide variety of maternal, social and sexual bonding strategies have been described across mammalian species, including humans. Many of the neural and hormonal mechanisms that underpin the formation and maintenance of these bonds demonstrate a considerable degree of evolutionary conservation across a representative range of these species. However, there is also a considerable degree of diversity in both the way these mechanisms are activated and in the behavioural responses that result. In the majority of small-brained mammals (including rodents), the formation of a maternal or partner preference bond requires individual recognition by olfactory cues, activation of neural mechanisms concerned with social reward by these cues and gender-specific hormonal priming for behavioural output. With the evolutionary increase of neocortex seen in monkeys and apes, there has been a corresponding increase in the complexity of social relationships and bonding strategies together with a significant redundancy in hormonal priming for motivated behaviour. Olfactory recognition and olfactory inputs to areas of the brain concerned with social reward are downregulated and recognition is based on integration of multimodal sensory cues requiring an expanded neocortex, particularly the association cortex. This emancipation from olfactory and hormonal determinants of bonding has been succeeded by the increased importance of social learning that is necessitated by living in a complex social world and, especially in humans, a world that is dominated by cultural inheritance. Keywords: maternal behaviour; pair bonding; oxytocin; endorphin; opioids; olfactory memory; prefrontal cortex; social learning

1. INTRODUCTION A major development in the evolution of mammals was placentation, internal development of the foetus and protracted care after birth to ensure infant survival to reproductive age. The only parent guaranteed to be present at birth, that directly invests time and energy resources for in utero development and equipped to provide initial post-natal feeding through lactation, is the mother. Therefore, it is hardly surprising that females form their strongest social bonds with their own offspring. However, in most mammalian species, females do not show spontaneous maternal care, as the brain first requires priming with the hormones of pregnancy that are produced or regulated by the foetal placenta (Keverne 2005). The pivotal cells of the placenta are trophoblast cells, a tissue unique to mammals and intimately linked to the evolution of viviparity. The cells of this lineage are responsible for the production of steroids and hormonal peptides which not only regulate growth and development of the placenta, but also enter the maternal circulation to adapt maternal physiology, metabolism and behaviour (Heap 1994). Hence, the conceptus, via the hormones of the extraembryonic trophectoderm, capitalizes on the maternal neuroendocrine response system to ensure the synchronization of birth with maternal care and milk availability. * Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘The neurobiology of social recognition, attraction and bonding’.

The social behaviour of male and female mammals also reflects these different lifestyle strategies. Reproductive success in males is generally determined by competing with other males to mate with as many females as possible. Hence, males rarely form strong social bonds and male coalitions are typically hierarchical with an emphasis on aggressive rather than affiliative behaviour. The female reproductive strategy is one of investing in the production of a relatively few offspring compared with egg-laying vertebrates, and success is determined by the quality of care and the ability to enable infant survival beyond the weaning age. Females therefore form strong social bonds with their infants and female–female relationships are also strongly affiliative, especially among matrilineal kin which often assist with infant care (Hrdy 1999). In a minority of mammals (less than 5%) ecological conditions are such that promiscuous male strategies are disadvantageous, and here males form a partner preference (bond) with females, defend them from intruders, and participate in parental care (Kleiman 1977). The majority of mammals are small-brained (i.e. they have a high ratio of limbic to cortical structures), with the regulation of social relationships requiring individual recognition by olfactory cues. This occurs during those biologically significant life events, such as mating and parturition, which precede bond formation. The hormonal changes which accompany these events induce changes in the expression of a range of neuropeptides (e.g. b-endorphin, corticotrophin-releasing factor (CRF), oxytocin (OT) and arginine vasopressin (AVP))

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that are thought to be critically important in the mediation of maternal and other social behaviours (Keverne & Curley 2004; Curley & Keverne 2005). Gender-specific aspects of mammalian social behaviour are regulated by the steroid hormones, notably oestrogens and progestogens, which determine the expression and distribution of these receptors for neuropeptides such as endorphins, OT and AVP (Dantzer 1998; Kalamatianos et al. 2004). In monogamous voles, a genus which has been investigated in some detail, male monogamy is little more than a variation on this theme, with AVP and CRF receptor expression in males evolving to mirror that of OT receptor expression in females. Moreover, this activation of vasopressin receptors is triggered by the unusual combination of female–male aggression which precedes oestrus, and oestrus is in turn induced by the male’s pheromones (de Kloet et al. 1986; Insel & Shapiro 1992; Lim et al. 2001, 2004; Bielsky & Young 2004; Lim & Young 2004). Thus, a common biology linked to olfaction underpins many aspects of social behaviour in small-brained mammals. With the cortical brain expansion seen in monkeys and apes, there has been an increase in the complexity of social relationships and a decreased dependency on olfactory communication (Curley & Keverne 2005). There has also been a degree of emancipation from hormonal determinants of behaviour; maternal care occurs even in the absence of priming by pregnancy hormones, and much of Old World primate sexual activity is non-reproductive occurring outside the periods of fertility. The olfactory link to areas of the brain concerned with social reward is replaced by neocortical inputs, particularly those concerned with multimodal sensory cues, forward planning and emotional regulation (Schultz et al. 2000; Chiba et al. 2001). Moreover, the development of temporary alliances and deployment of intelligent behavioural strategies seen in primates with large brains has had a significant impact on the way social organization has evolved away from the exclusivity of contexts determined by hormones. This in turn has accelerated the importance of social learning and consequent development of cultural inheritance. The aims of this review paper are to draw together the underlying neural and hormonal mechanisms that are common to many aspects of maternal and social bonding and explore how these events have been influenced by the evolution of the mammalian brain.

2. PARENTAL BONDS IN SMALL-BRAINED MAMMALS The majority of small-brained mammals such as rodents are altricial and produce relatively large numbers of offspring in each litter that are deaf, blind and helpless at birth, and severely deficient in motor control and temperature regulation. These offspring require considerable care by the mother, not only in nursing and suckling, but also by providing a warm nest and retrieving the offspring back into the nest when they first become mobile. In such species, maternal care may be considered as an extension of physiological homeostasis. The hormones of pregnancy, under the control of the foetal placenta, inhibit sexual behaviour, Phil. Trans. R. Soc. B (2006)

feeding brain

sex maternal behaviour (primed OT synthesis and OT receptors)

high progesterone low oestrogen milk production periphery

vaginal cornification uterus (primed OT receptors)

Figure 1. The importance of hormones for signalling context across and synchronizing biologically relevant events in the brain and somatic compartments.

promote feeding behaviour, develop the mammary glands and prime the brain for maternal care (figure 1), which is then triggered by parturition (Keverne 2005). Although maternal care is a function of the brain, its onset is dependent on events originating in the placenta which, in turn, are regulated by the foetal genome. Likewise, maintenance of maternal care is dependent on the presence of neonates and is synchronized with their post-natal development. Nest building stops on the day when pups can regulate their body temperature and milk production terminates when the pups decrease their suckling times, events that are related to the mother leaving the nest more frequently to prevent overheating (Leon et al. 1990). Hence, the onset, maintenance and termination of maternal behaviour are controlled by hormones which, in turn, are released in response to stimuli from the foetus. OT is a neuropeptide that plays a fundamental role in maternalism, acting centrally to promote maternal care and peripherally to promote parturition and milk let-down (Keverne & Kendrick 1992; Kendrick 2000). During late pregnancy, receptors for OT are upregulated in both the brain and the uterus in response to elevated oestrogen levels. OT, synthesized in the hypothalamic neurons, is released into the brain at birth, facilitating olfactory recognition of offspring (Keverne et al. 1993), aiding parturition (Neumann et al. 1996) and stimulating the onset of maternal care (Keverne et al. 1993). The maintenance of maternal behaviour during lactation may also require the coordinated involvement of the OT, cholecystokinin, prolactin and dopamine (DA) systems (Mann et al. 1995; Grattan 2001; Champagne et al. 2004; Ferris et al. 2005). OT release during other key life events similarly facilitates social interactions and is required for the formation of the olfactory memory that enables the social recognition of conspecifics (Dluzen et al. 2000; Ferguson et al. 2000, 2001; Winslow & Insel 2002). The formation of these relationships requires familiarity, which for kin is brought about by prolonged contact involving licking and grooming. For completely novel stimuli, such as strange males or newly born offspring, overcoming neophobia is also a necessary prelude to forming new relationships. OT release is significant in this context too, since it is noteworthy

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Parental and social bonds in mammals that OT knockout mice exhibit altered levels of anxiety (Mantella et al. 2003; Amico et al. 2004) and intracerebroventricular (icv) administration of oxytocin receptor antagonists increases anxiety in female rats (Neumann et al. 2000). In the context of mate recognition by the female, the formation of this familiar relationship requires sexual activity, which can only occur when the female is in oestrus. Offspring recognition immediately follows parturition, the female having completed pregnancy. Both pregnancy and oestrus provide the endocrine context for the synthesis of OT and the OT receptors (Thomas et al. 1996; Bale & Dorsa 1997; Young et al. 1997). Oestrogen acts through the oestrogen receptors ERa and ERb; ERb is expressed in the hypothalamic neurons that synthesize OT, whereas ERa is required for synthesis of OT receptors in the amygdala (Patisaul et al. 2003). Interestingly, both the ERa and the ERb knockout mice are impaired in social recognition tests similar to mice targeted for the OT gene deletion (Choleris et al. 2003, 2004). Hence, in the context of oestrus and pregnancy, the female’s brain undergoes radical reorganization with respect to the synthesis and activation of OT and its receptor. In particular, it is those areas of the brain associated with the social recognition that are required for olfactory preferences which underlie bond formation that are primarily affected, i.e. the olfactory bulb (OB), the amygdala (AMY ) and the nucleus accumbens (NAcc; Broad et al. 1999; Ogawa et al. 1999; Choleris et al. 2004; Kavaliers et al. 2004; Young & Wang 2004). Although the OB has no oxytocinergic terminals there is an abundance of OT receptors. This mismatch of terminals with receptors in the OB is functionally addressed by the neurohumoral release of OT into cerebrospinal fluid at parturition and mating (Yu et al. 1996a). Thus, pregnancy and parturition produce changes in sensitivity, synaptic efficacy and neural firing in the OB, changes that are part of the olfactory learning process for social familiarity (Yu et al. 1996b). Hence, OT infusions into the cerebral ventricles enhance olfactory memory for conspecifics in rats. OT infusion directly into the OB enhances maternal care and increases both the frequency and the amplitude of spontaneous excitatory post-synaptic currents of granule cells (Yu et al. 1996b) by both pre- and postsynaptic mechanisms, a process integral to olfactory recognition memory (Dluzen et al. 1998, 2000; Engelmann et al. 1998; Osako et al. 2001). The amygdala has reciprocal connections with the NAcc, and both structures show enhanced levels of neural activation in rodents following exposure to biologically significant odours (Moncho-Bogani et al. 2005). Olfactory activation during social encounters between mother and pups induces neural activation of the amygdala (Fleming & Korsmit 1996), lesions to the amygdala eliminate aversion of pup odours in virgin rats (Fleming et al. 1980), and both OTand vasopressin release in the central amygdala regulates the autonomic expression of fearful or neophobic responses (Huber et al. 2005). The medial amygdala is also important for social recognition in mice, and infusions of OT into the medial amygdala of mice with a targeted deletion of the OT gene restores olfactory social recognition Phil. Trans. R. Soc. B (2006)

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(Ferguson et al. 2000, 2001). OT receptors are particularly notable in both the shell and the core of the NAcc, and lesions to these areas have shown that maternal retrieval is impaired and the rewarding experience of maternal care is not carried forward to subsequent mother–pup interactions (Lee et al. 1999; Numan et al. 2005). Moreover, if the socially relevant behaviour is experienced in the same context as biologically neutral odours, mimicking other social sensory cues in the animal’s real world, a conditioned association of these second-order cues as attractive takes place and they subsequently develop behaviourally rewarding properties (Kippin et al. 2003) Thus, small-brained female rodents do form bonded social relationships with their offspring and with mates, both of which are regulated by odour cues and both of which are short-lived. Male partners generally do not stay attached after mating, and owing to the close dependence of mother–offspring interaction on the maternal hormones, the mother–infant bond is restricted until weaning. Although pregnancy is a life event of considerable significance for the female (enduring for weeks as opposed to the few hours for mating), maternal care, nevertheless, gives way to other motivational priorities as hormonal secretions change. Most altricial mammals produce large litters and fail to distinguish between individual offspring. Indeed, the removal of individuals produces no obvious signs of behavioural loss, and even removing the whole litter results in the female returning to oestrus within a few days, following which mating and a further pregnancy rapidly ensue. Hence, in these rodent species, reproductive success does not require strong, enduring parental or social bonds. These relationships are transient and secondary to maximizing high ‘throughput’ offspring production to sustain reproductive success.

3. PRECOCIAL MAMMALS: MATERNAL BONDING Grazing mammals, such as ungulates, live in relatively large social groups that are constantly on the move in search of food. These mammals have an alternative life history to small-brained mammals such as rodents, as it is important that their offspring should be relatively well advanced at birth in order to maintain contact with the herd. The young are born precocial, capable of maintaining their own body temperature and able to stand and walk soon after birth. Most ungulate mothers are seasonal breeders, producing synchronized births with only one or two offspring in any one year. Mothers invest heavily in producing large quantities of high quality milk to ensure the rapid maturation of their young. Because offspring are precocial and mobile, there is ample opportunity for them to extract milk from other mothers in the flock. To select against this, maternal care becomes exclusive within 1–2 h of parturition, and any strange non-related young that try to suckle are violently rejected. Initially, this selective recognition memory and selective bond is also based exclusively on olfactory cues. Sheep provide a good example of precocial mammals and have been studied extensively in the context of maternal bonding. It is relatively easy to determine the establishment of selective bonding in sheep from the

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proactive response of the mother to her own lamb (low pitch bleats, approach, suckle) which contrasts with rejection behaviour shown to strange lambs (high pitch bleats, head-butts and withdrawal from suckling approach). Moreover, any separation of the lamb from its mother following the initial bonding process produces distress calls and hyperactivity in the mother that lasts for several days (Kendrick & Keverne 1991). The neural mechanisms that serve this selective bonding require a maternal motivational state, which is dependent on the hormones of pregnancy, and a recognition memory, which is primarily dependent on olfactory cues. The temporal profiles of oestrogen and progesterone secretion during pregnancy (Poindron & Levy 1990) and their effects on neuropeptide gene expression have much in common at the cellular and molecular level with those occurring in small-brained mammals (Broad et al. 1993a). Indeed, there are also many similarities across these species with regard to the neural mechanisms subserving olfactory recognition and its importance. However, there are also crucial differences, particularly in the selectivity of the recognition process and how this, in the presence of strange lambs, is able to activate rejection behaviour. In a female ewe that is highly maternal, being able to suppress maternal behaviour and then initiate a violent response to a lamb that provides many of the cues that invoke maternal care, requires a precise recognition mechanism. Although the olfactory recognition process is complex, its function serves to reject strange lambs, since anosmic ewes are fully maternal both to their own and to strange lambs (Baldwin & Shillito 1974; Levy et al. 1995a,b). Olfactory recognition is complex because the odour of their own lamb has more components in common with the odour of strange lambs than it has differences, but it is these differences which activate rejection in a maternally motivated mother. As for all mammals, production of the steroid hormones during pregnancy is under the control of the foetal placenta. High levels of both progesterone and oestrogen promote synthesis of OT in both magnocellular and parvocellular neurons found in many parts of the brain that play a part in maternal behaviour (e.g. paraventricular nucleus, PVN; supraoptic nucleus, SON; bed nucleus of the stria terminalis, BNST; medial preoptic area, MPOA), with levels of OT mRNA expression in these neurons peaking at the time of birth (Broad et al. 1993a). Towards the end of pregnancy, oestrogen levels increase and promote the production of OT receptors in a number of brain regions that process olfactory information, in parts of the hypothalamus that mediate maternal behaviour and in the diagonal band of Broca, a region responsible for the cholinergic innervation of the OB and frontal cortex. Maternal experience further enhances increases in OT receptor expression in the paraventricular nucleus (Broad et al. 1993a,b, 1999). Because the paraventricular nucleus is the main source of OT release into the brain, upgrading autoreceptors on OT-containing neurons serves to promote further OT release throughout the brain. Certainly, during parturition, levels of OT in cerebrospinal fluid (CSF) increase to 400 pg mlK1 and reach all areas of the brain including the OB, where receptors are upregulated during pregnancy (da Costa et al. 1996). Since there are no OT terminals in Phil. Trans. R. Soc. B (2006)

the OB, this humoral transport serves an important function in the context of receptor terminal mismatch (Yu et al. 1996a,b). The importance of parturition for the induction of maternal behaviour cannot be emphasized enough, since delivery of lambs under peridural anaesthesia blocks central OT release and inhibits maternal behaviour, while subsequent intracerebral infusions of OTrestore this behaviour (Krehbiel et al. 1987; Levy et al. 1992). Moreover, induction of maternal behaviour in non-pregnant ewes can be established by hormonal priming with oestrogen and progesterone followed by vaginal stimulation, which also induces central OT release. (Keverne et al. 1983; Kendrick et al. 1988) Precocial mammals rapidly learn to selectively recognize their own offspring within the first few hours post-partum. In sheep, this selective recognition is dependent on odour cues from the lamb mediated by the main olfactory system. Lesioning of this main olfactory system at the level of receptor neurons or at the first neural relay prevents selective recognition but notably does not impair the proactive behaviour associated with maternal care (Baldwin & Shillito 1974; Levy et al. 1995a,b). Electrophysiological studies of the OB have shown changes to occur in the response of mitral cells to lamb odours, while in vivo microdialysis studies have reported altered neurotransmitter release that is causally linked to the olfactory memory formation underlying selective recognition. These studies have further demonstrated that there are extensive plastic changes that occur in the OB as a consequence of parturition, and further changes are consequent on lamb exposure and memory formation (Kendrick et al. 1992, 1997; Keverne et al. 1993; Levy et al. 1995a,b). The medial nucleus of the amygdala, in particular, is a key structure for olfactory social recognition. In sheep, OT receptors in the medial amygdala increase at parturition (Broad et al. 1999) and icv infusions of OT induce full maternal behaviour and bonding in nongestant ewes (Kendrick et al. 1987). In the sheep, reversibly inactivating various nuclei in the amygdala at the time of post-partum olfactory memory formation, by lidocaine infusions, reveals the medial nucleus to be the one required for memory formation to occur (Keller et al. 2004a,b). However, the medial nucleus is not required for olfactory perception per se or for the process of olfactory memory retrieval for lambs. Disruption of the medial amygdala by lidocaine infusions does not impair bonding and proactive behaviour to the ewe’s own lamb, but it does impair the expression of rejection behaviour to strange lambs (Keller et al. 2004a,b). Moreover, mapping studies using the induction of immediate early gene expression (c-fos, zif268) or the neurotrophic growth factors (brain-derived nerve growth factor (BDNF) and trk-B) have shown that a distributed network of neuroanatomical substrates, including the anterior cingulate and medial frontal cortices, amygdala and ventral striatum are active and undergoing neurotrophicmediated plasticity changes following lamb exposure post-partum or after artificial vagino-cervical stimulation (da Costa et al. 1997; Broad et al. 2002a,b). All of these brain regions also undergo upregulation of OT receptors towards the end of pregnancy (Broad et al. 1999). The medial prefrontal cortex (mPFC) is

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Parental and social bonds in mammals particularly important since, in contrast to small-brained rodents, this heterogeneous region is unusually large in the sheep and is recognized from primate studies to play an important role in modulating integrative, attentional and emotional responses which allow the emancipation of behaviours from stimulus response modes and hormonal control.

4. SOCIAL AND MATERNAL BONDING IN PRIMATES The evolutionary conserved biology which underpins mother–infant bonding in mammals raises the question as to what neural changes have occurred in the maternal behaviour of humans and certain non-human primates that enable mother–infant bonding to occur outside the context of pregnancy and parturition and in the absence of lactation. In Old World monkeys, apes and humans, the hormones of pregnancy, parturition and lactation are not necessary for maternal or alloparental care, as females of these species can be motherly towards infants even without ever being pregnant. Nevertheless, of major significance in primate and human maternal care is the endogenous opioid system. Indeed, it has been suggested that the activation of this system at parturition and during suckling promotes the positive affect arising from maternal behaviour (Franceschini et al. 1989; Broad et al. 1993a,b; Martel et al. 1993, 1995). Studies on naloxone treatment of post-partum rhesus monkey mothers living in social groups have addressed the importance of opioids in maternal bonding. During the early post-partum period, a mother’s social interactions are almost exclusively with her infant, and opiate receptor blockade in the mother has marked effects on the mother–infant relationship. Naloxone treatment reduces the mother’s caregiving and protective behaviour shown towards her infants. During the first weeks of life when infant retrieval is normally very high, naloxone-treated mothers neglect their infants and show little retrieval even when the infant moves a distance away. As the infants approach eight weeks of age, when a bonded grooming relationship normally develops between the mother and the infant, mothers treated with naloxone fail to groom their infant. Moreover, they permit other females to groom their infants, while saline-treated control females are very possessive and protective of their infants from contact with others at this stage. The infant is not rejected from suckling, but a mother’s usual possessive preoccupation with the infant declines with opioid receptor blockade. The mother is not the normal attentive caregiver, and mother–infant interactions are invariably infant-initiated (Martel et al. 1993, 1995; Keverne et al. 1997). Primates and other mammals have in common opioid involvement in maternal care, but the consequences of opioid blockade in small-brained mammals are much greater for the biological aspects of maternal behaviour. In sheep, interference with the endogenous opioid system severely impairs maternal behaviour, including suckling, whereas monkeys neglect to show a focused preoccupation with infant care but still permit suckling (Kendrick & Keverne 1989; Martel et al. 1993). These differences may Phil. Trans. R. Soc. B (2006)

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reflect the degree of emancipation from endocrine determinants that maternal behaviour has undergone in primates, and the increased importance of ‘emotional reward’ for the bonding mechanism. If the endogenous opioid system in the monkey is positively linked to mother–infant bonding, heroin addiction, which acts at the same opioid receptor, would be predicted to have severe consequences for human maternal bonding. Women who are heroin addicted have many aspects of their social and economic life disrupted, making the data difficult to disentangle. Nevertheless, the facts are that by 1 year of age nearly 50% of children are living away from their biological mothers, and by school age only 12% remain with their biological mothers (Mayes 1995). These infants have been abandoned for adoption or are taken into the care of their grandparents and other female kin. Moreover, in a follow-up of 57 methadone-maintained mothers compared with controls matched for ethnicity, socioeconomic status, infant birth weight and gestational age, opiate-addicted mothers were found to be less likely to have remained the child’s primary parent. Their children were significantly more likely to have been referred to child protective care or special service agencies for neglect, abandonment or abuse (Lejeune et al. 1997). It is also the case that human mothers develop an attachment with their unborn foetus, but women with a history of drug abuse who were using methadone had diminished maternal–foetal attachment score when compared with normal women (Mikhail et al. 1995). Integral to the bonding process in large-brained primates is the action of the endogenous opioid system on receptors which have been localized to the ventral striatum (Koob & Le Moal 1997). This area of the brain is involved in ‘reward’ and also requires the mesolimbic DA projection which detects rewarding stimuli and the ways in which they occur differently from prediction to enable ‘updating’ of the stimulus (Schultz & Dickinson 2000). In primates, the OT system may also be important in bonding, and in humans peripheral OT release is increased at birth, following female orgasm and exposure to neonatal images or sounds (McNeilly et al. 1983; Carmichael et al. 1987). The mother–infant bonding process entails obsessive grooming, especially to hands, face and genitalia, by mothers, and these are the morphological traits of infant monkeys that show the greatest changes during development. Because primates show extended post-partum care, offspring recognition requires the continual updating of any changes in these morphological features and in behavioural development. This updating of infant recognition involves visual cues and prefrontal–ventral striatal pathways which are also intimately linked to the emotional brain via the amygdala. The positive emotional responses which infants generate in females enable parental care to occur without the continual priming by pregnancy and parturition. Human mothers also experience preoccupations and rituals in the context of maternal care, and even before the birth of their baby they are obsessive with cleaning and creating a safe environment. After birth, safety is the major concern and mothers frequently check on their baby even at times when they know the baby is fine

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(Leckman et al. 1999). The evolution of these obsessive psychological and behavioural states can be seen as a developmental extension of the preoccupations which all primates show for their infants. Thus, it is notable that areas of the human brain which, using magnetic resonance imaging, have been shown to be responsive to babies crying include the brain’s reward structures (mesolimbic DA from the ventral tegmental area (VTA), ventral striatum and amygdala). These same regions of the brain are also active in the context of romantic love (Bartels & Zeki 2004). The evolutionary progression away from hormonalcentric determinants of maternal behaviour to emotional, reward-fulfilling activation probably involves dopaminergic and opioidergic activity in the ventral striatum. The enhanced role of this circuitry for regulating behaviour in humans may also provide vulnerability to various forms of psychopathology such as obsessive compulsive disorder (OCD) and substance abuse. Mild forms of addictive behaviour (gambling, video games, internet use, and consumption of caffeine and chocolate) are such indicators of this neurological predisposition for obsessive behaviour seen in humans (Greenberg et al. 1999). In vivo neuro-imaging studies identify the orbital frontal cortex, head of the caudate, and closely associated ventral striatum and anterior cingulate as being involved in OCD (Rauch 2000), while acquired OCD occurs later in life in patients with striatal lesions (Chacko et al. 2000). There is also evidence that CSF levels of the neuropeptide, OT are elevated in OCD, and this peptide also plays a fundamental role in many obsessive aspects of maternalism (Leckman et al. 1994). Therefore, not surprisingly, OCD is more common in women. The influence of gonadal hormones on periodicity of OCD (Weiss et al. 1995) and the post-partum exacerbation of OCD symptoms in women suggest that the course of this disorder may be influenced by the hormones of pregnancy (Williams & Koran 1997; Labad et al. 2005). Hence, there are components of human behaviour that occur in the post-partum maternal period which are influenced by hormones, but interestingly they relate to areas of the brain concerned with reward and not with the direct execution of maternal behaviour per se.

5. A DECLINING ROLE FOR OLFACTORY SYSTEMS IN SOCIAL REWARD FOR PARENTING Olfaction is the most important sensory modality coordinating social behaviour of small-brained mammals, with this information being processed via both the main and the accessory olfactory systems. The accessory system contains the vomeronasal organ (VNO) enclosed in a cartilaginous capsule on the medial surface of the nasal septum, from which neurons convey non-volatile odour (pheromones) signals directly to the brain’s hypothalamic and limbic systems (Keverne 1999). Through this chemosensory system, pheromone signals are able to change endocrine states (e.g. advance the onset of oestrus) and regulate parental and sexual behaviour (Brennan & Keverne 2004). The chemosensory receptors of this system are divided into two distinct families (V1r, V2r) and are coded for by approximately 300 genes, while Phil. Trans. R. Soc. B (2006)

the functional importance of this chemosensory system in regulating the social behaviour of rodents can be observed from transgenic mice studies. Male mice that have one subfamily cluster (12% of the 137 gene V1r gene family) selectively excised have motivational behavioural defects, including reduced sexual interest (Del Punta et al. 2002). Transgenic male mice that have a mutation in the Trp2c cation channel gene, the selective pheromone transduction channel in mice, also exhibit motivational behaviour impairments, including a failure of nursing mothers to engage maternal aggression to intruders when they are suckling their young (Leypold et al. 2002). Males with this mutation fail to show sexual preferences for females and readily mate with other males (Stowers et al. 2002). Moreover, mice selectively lacking heterotrimeric G-proteins of the Gq family (transduction proteins) in vomeronasal receptors do not display any maternal behaviour despite having normal levels of OT and prolactin, and exhibiting normal lactation. Using c-fos immunohistochemistry to investigate pup-induced neuronal activation in post-partum females reveals a significant reduction in activity in those areas of the brain concerned with motivated behaviour, including MPOA, BNST and lateral septum, in post-partum females (Wettschureck et al. 2004). The pheromone to which the mother rat’s VNO responds is dodecyl propionate, which originates in the pup’s preputial gland and stimulates licking of the anogenital region (Brouette-Lahlou et al. 1999). This licking is an important component of rat maternal behaviours and is thought to be involved in maternal bonding and promotes pup survival. The main olfactory system has the capacity to respond to a vast array of odours, many of which have no intrinsic social significance, but can acquire this social significance through association when activated in contexts that are rewarding and biologically significant (Kippin et al. 2003). Thus, in the context of parturition, odours that convey individual or group identity become important recognition signatures which give added social value to these individuals. The main olfactory system of small-brained mammals (rodents) has over 1200 olfactory receptor genes, the largest mammalian gene family (Zhang & Firestein 2002), and incredible sensitivity brought about by a 1000 : 1 convergence of each receptor neuron at the first relay (Hellman & Chess 2002). Biological odours are rarely simple and the spatial and temporal patterns that can be generated at this first relay have the coding capacity to distinguish individuals in the social group. This is a very significant function for odour in species like rodents which are nocturnal, live underground and have poorly developed vision. A question of some importance is how does the brain confer significance to non-significant odours? One way is to associate this odour with other sensory cues that signify biologically significant contexts, usually contexts associated with motivational reward (feeding, sexual activity, birth and aggression; Kippin et al. 2003). For visually impaired nocturnal rodent species, it is the two olfactory sensory systems that work in harmony to sustain this association (figure 2). The limited repertoire of vomeronasal receptors that

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main olfactory system

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potentiation Figure 2. Convergence of main and accessory olfactory systems for distinguishing and appropriately engaging behaviour through the NAcc/ventral striatal ‘reward’ system. The hormones of pregnancy upregulate oxytocin receptors (filled circle) and opioid (open circle) receptors which provide the ‘maternal’ context. AMY (BL), basolateral amygdala; AMY (Me), medial amygdala; 5HT, 5-hydroxytryptamine; VMN, ventromedial nucleus.

respond to social pheromones (sex, aggression, feeding and parenting) have a direct projection to those parts of the brain that promote and are integral to primary motivated behaviour. This projection is via the medial amygdala to the various hypothalamic nuclei that regulate these behaviours. These same neural pathways that transduce pheromone signals also access the brain’s ‘reward’ circuitry via the amygdala to the shell of the NAcc (Moncho-Bogani et al. 2005). The main olfactory projections also relay in the amygdala via the main OB and pyriform cortex, the pyriform cortex also making connections with the frontal cortex via the medial–dorsal nucleus of the thalamus (figure 2). Major outputs from the rodent frontal cortex then project to the NAcc. Hence, these dual chemosensory pathways converge at the amygdala and NAcc, a part of the brain concerned with reward and capable of providing the incentive salience of reward related cues which access the NAcc via the frontal cortex. Interestingly, unlike lesions to the main olfactory system, lesions of the vomeronasal system do not prevent rodents from distinguishing biologically salient differences in odour; however, they do prevent them from employing the salience of these cues to demonstrate a preference (Pankevich et al. 2004). What might be the function of this olfactory relay via the frontal cortex in small brained rodents? Generally speaking, biological odours, including those of amniotic fluid and pups, are complex and composed of a multitude of components. Oscillations across cortical structures (usually in the low frequency range of 7–11 Hz) are known to be important for the synchronization of populations of neurons that simultaneously process these components. In this context, the frontal cortex electroencephalogram has been recorded in rats in various reproductive states. During periods of lactation, nest bedding odours from pups invoke Phil. Trans. R. Soc. B (2006)

increased electric activity at 8–11 Hz frequency in the mPFC when compared with virgin females (12–21 Hz) provided with the same odour (Hernandez-Gonsalez et al. 2005). This lower frequency activity is common to other regions of the brain processing olfactory information and may provide the synchronized frequency for ‘binding’ of neurons that respond to odour (Keverne 1995a,b). This synchronizing of activity across a population of olfactory neurons along the pathway to reward processing nuclei and motor generating regions of the brain provides the gestalt for recognition-to-action, the context of which is provided by the hormones of pregnancy and parturition. Evolutionary changes in olfactory processing across mammals are clearly illustrated from comparative genetic analysis of the Trp2c gene; a gene which is central to regulating pheromone-induced motivational behaviour in rodents (Liman & Innan 2003; Zhang & Webb 2003). This gene encodes a cation channel that enables vomeronasal neurons to generate action potentials, but has become a non-functional pseudogene in primates, as indeed have genes that code for vomeronasal receptors (Grus et al. 2005; Young et al. 2005). Furthermore, while it appears that ancestral primates were able to process olfactory information via the vomeronasal system, this ability became vestigial ca 23 Myr ago in the ancestor of modern day New World and Old World monkeys and apes (Zhang & Webb 2003). Hence, Old World primates, including the rhesus monkey (Macaca mullata), gorilla (Gorilla gorilla), chimpanzee (Pan troglodytes) and orang-utan (Pongo pygmaeus), exhibit a decreased reliance on olfactory information, particularly via the vomeronasal pheromonal system, for the regulation of social behaviour. Good evidence for degenerate function of the main olfactory system comes from comparative phylogenetic analysis of the genes that encode olfactory

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Figure 3. (a) A substantial number of olfactory receptors are coded for by non-functional pseudogenes which increase in number with the enhanced development of the neocortex. (b) Congruent with this reduction in olfactory receptors, there is a reduction in the proportion of cortex given over to processing olfactory information. This decreases from insectivores through primates.

receptors (Gilad et al. 2003, 2004; Whinnett & Mundy 2003; figure 3a). These studies estimate from sequence disruptions that more than 30% of olfactory receptor genes are non-functional pseudogenes in non-human primates, rising to more than 60% in the human genome. Coupled with these genetic changes, there has also been a dramatic reduction in the size of the olfactory cortex, from 65% of total cortex in insectivorous mammals to less than 5% in Old World primates (figure 3b; Frahm et al. 1982; Stephan et al. 1982). This decline in olfactory processing has clearly been driven by the need of large-brained mammals to gather their social information from visual cues, as they evolved from nocturnal to a diurnal lifestyle. Arguably, the most significant visual change in Old World primates was the evolution of trichromacy (Surridge et al. 2003), which occurred at approximately the same time as the pseudogenization of the Old World primate chemosensory genome (Gilad et al. 2004; Webb et al. 2004), allowing individuals to interpret social information such Phil. Trans. R. Soc. B (2006)

as colourful sexual adornments. In primates, postpartum maternal care also extended mother–infant bonding beyond the period of suckling, thereby increasing selection for visual recognition of offspring when infant mobility required facial recognition at a distance. Congruent with these selective pressures, the primate visual cortex has also become especially enlarged, comprising up to 50% of the total neocortex (Barton 1998). Visual association areas have, likewise, become increasingly complex, with several regions devoted to the differential processing of specialist visual information such as facial expression (Perrett et al. 1992). Indicative of this shift in the regulation of social behaviours from reliance on olfactory information in small-brained rodents, to dependence on visual information in primates, is the negative correlation found between the size of an area of the brain central to relaying visual information (the lateral geniculate nucleus) and the size of the OB, which relays chemosensory information (Barton 1998).

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Parental and social bonds in mammals 6. FRONTAL CORTEX ENHANCED ROLE IN SOCIAL REWARD FOR PARENTING The frontal cortex is a part of the brain which has shown progressive enlargement throughout mammalian evolution. In small-brained rodents, the mPFC matures around day 13–15 post-partum (Diergaarde et al. 2005) while in the human, this development continues late into adolescence (years 17–21; Sowell et al. 2001). In the rat, this area of the cortex mainly receives a strong olfactory input via the mediodorsal thalamic nucleus, and lesions to this system decrease the frequency with which the mother protects her pups by attacking intruders who threaten to cannibalize her infants (Ferreira et al. 1987). Unlike males, females rarely initiate aggression to others unless they are nursing offspring. The mPFC synchronizes this response to odour cues via the release of CRF from the BNST and PVN where the majority of CRF neurons are found (Spencer et al. 2005). A second major output from mPFC is to the ventral striatum (NAcc), an area of the brain concerned with reward. Hence, in the context of emotionally rewarding behaviours associated with maternal care, olfactory signals relayed in the mPFC are endowed with incentive salience. The reward value provided by the NAcc requires a biological context signalled by the hormonal state of the female and activated by the release of opioids and DA in the NAcc. It is well established that oestrogen increases synthesis of preproenkephalin (PPE) in the NAcc (LeSaux & Di Paolo 2005), while the dopaminergic projections from the mesolimbic neurons of the midbrain are also immunoreactive for oestrogen receptors (Creutz & Kritzer 2004). In sheep that have already given birth, exposure to lamb odours provokes intense c-fos activity in the mPFC as well as in the pyriform and cortical amygdala, all relays for main olfactory inputs known to be important in lamb recognition and selective bonding. However, in sheep, reversible inactivation of the medial frontal cortex (medial limbic area) using tetracaine infusions is not required for the performance of proactive maternal behaviour or for own lamb recognition. However, it is required to enable the ewe to execute an aggressive motor action in response to the odours of strange lambs. This reversible inactivation does not interfere with other forms of motor activity related to maternal care including emotionally generated rejection vocalizations, walking, approaching, licking and suckling lambs and or feeding (Broad et al. 2002a,b). Rejection behaviour directed at strange lambs is associated with increases in c-fos mRNA expression in the large output cells of layer V of the mPFC (which project to the ventral striatum). This suggests that in order to execute the aggressive motor response underlying rejection, novel and anxiety provoking olfactory information needs to be routed by the projections from the cells in this layer to the striatum (Lidow et al. 1998). Aggressive responses to the odours of strange lambs are also associated with increased levels of DA, 5-hydroxytryptamine (5-HT), glutamate and g-aminobutyric acid (GABA) in this cortical region, increases that did not occur in the absence of rejection behaviour (Broad et al. 2002a). It Phil. Trans. R. Soc. B (2006)

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seems likely that the primary action of the local anaesthetic under these circumstances is to cause a shutdown of neuronal activity in the mPFC which promotes local large increases in inhibitory transmitter concentrations (notably GABA and 5-HT). Tetracaine has effects similar to localized cooling on inhibiting membrane conductance (Luzzati et al. 1999) and therefore it is probable that behavioural and neurochemical actions observed with tetracaine infusions result from inhibition of these mPFC neurons disabling their communication with the ventral striatum. Medial frontal cortex infusions of tetracaine, which prevent overt motor rejection of strange lambs, resemble the type of behaviour seen in ewes failing to form an olfactory recognition memory. However, following the withdrawal of tetracaine, maternal selectivity returns, showing the olfactory recognition memory to be intact. Inactivating this discrete part of the mPFC during the critical period for lamb recognition memory did not, therefore, interfere with memory formation of the lamb. Moreover, inactivating the mPFC does not prevent memory retrieval for generating emotional vocal responses, but prevents the ewe downloading the information necessary for initiating an aggressive motor response via the striatum (Broad et al. 2002a,b). Olfactory recognition in multiparous sheep is usually established by 2 h post-partum (Kendrick et al. 1992). The data demonstrating the effects of inactivating the frontal cortex for 4 h are consistent with some of the human and rat data which demonstrate that some medial areas of the frontal cortex have little or no influence on mnemonic encoding, but have a greater influence on the suppression of learned strategies in response to changes in behavioural contingencies. This executive function is believed to facilitate the matching of an appropriate behavioural strategy to rapid changes in task requirements (Bechara et al. 1994, 1996, 2000; Ragozzino et al. 1999a,b). All female mammals in immediate post-partum period are extremely maternal, and preoccupied with their offspring to the extent that they show no interest in food or sexual activity. What is unusual in sheep is that lambs which have many physical features in common, apart from their odour, can be selectively rejected by aggressive head butts by a highly maternal ewe. This one sensory feature, odour cues, is sufficient to switch a maternal ewe from proactive acceptance behaviour to aggressive rejection. Such a response has much in common with the post-partum aggression of rodents initiated by the odour of strange intruders. These studies interestingly reveal how different parts of the brain, in the biological context of parturition, respond to odour cues that confer recognition integral to selective bonding. The recognition component in this bonding process requires the medial amygdala for bonding to occur (Keller et al. 2004b), but is not necessary for retrieval of the recognition memory required to reject strange lambs, while the mPFC is necessary for selective rejection but not required for recognition memory of own lamb (Broad et al. 2002a,b; Keller et al. 2004a,b). Neither of these areas, when inactivated, impairs maternal behaviour, but they do impair the selective nature of the bond. The question

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potentiation

Figure 4. Redundancy in the olfactory systems together with increases in the volume of the prefrontal cortex provide for complex polymodal cues to address the ventral striatal ‘reward’ system. Emotionally arousing cues (infant distress cries, infant faces and infant suckling) signal release of DA in the ventral striatum both within and beyond the context signalled by the hormones of pregnancy.

arises, therefore, as to which regions of the brain are required to sustain proactive maternal care and the positive aspects of the bond. In addition to increasing OT synthesis and OT receptor synthesis in the brain, the hormones of pregnancy also induce pro-opiomelanocortin (POMC) and PPE synthesis in the hypothalamus of sheep (Broad et al. 1993a,b) and the release of opioids into CSF at parturition (Wardlaw & Frantz 1983). Moreover, an opioid agonist or CRF given icv is effective in enhancing proactive maternal care (low pitch bleats, licking) towards lambs as well as reducing rejection behaviour (head butts, high pitch bleats) in the context of vaginal–cervical stimulation (Keverne & Kendrick 1991), while the opiate receptor blocker, naltrexone, blocks the induction of proactive behaviour that signifies positive bonding (Kendrick & Keverne 1989). These potentiating effects of exogenous opiates together with OT on acceptance behaviour and bonding in ewes are probably subserved by opioid receptors in the ventral striatum, an area of the brain that increases c-fos mRNA expression in ewes on exposure to own lambs (da Costa et al. 1997). Infant primates, both human and non-human, are highly susceptible to social perturbations in maternal care. While the mother’s brain has been ‘maternalized’ by the hormones of pregnancy generated by the foetal extra-embryonic placenta, the infant’s developing brain requires social stimulation from a mother committed to providing the emotional rewards of suckling, huddling and grooming. It is clear that the process of infant socialization benefits from this close relationship and, because this occurs during early brain development, mother–infant separations are likely to have long-term consequences (Hinde et al. 1978). Indeed, extreme consequences for social relationships and maternal bonding when adult occur if infants are separated from Phil. Trans. R. Soc. B (2006)

mother and reared with peers (Suomi & Harlow 1975; Kraemer et al. 1991). Nursery reared rhesus monkeys deprived of a maternal upbringing demonstrate reduced OT secretion and social behaviours, but show increased aggressive and stereotypical behaviours. Increased stereotypical behaviours are often classically associated with the disruption of frontal cortical function and often result from an inability to suppress inappropriate behavioural responses (Winslow et al. 2003). Squirrel monkeys, 4 years after experiencing separations from their mother early during development, generate differences in emotional behaviour, stress physiology and development of the brain, notably in the mPFC. Behaviour tests have subsequently shown these monkeys to be impaired in reward-related memory tasks (Lyons & Schatzberg 2003). Electrophysiological recordings from normal adult monkeys have shown that the mPFC mediates the achievement of goals (Matsumoto & Tanaka 2004). The precise involvement of the prefrontal cortex in reward-related behaviour has also been examined in humans using imaging techniques (figure 4). Interestingly, the detection of unfavourable outcomes, response conflict and decision uncertainty elicit overlapping clusters of activation foci in the mPFC (Ridderinkhof et al. 2004). Choosing between actions associated with uncertain rewards and punishments in humans is mediated by neural circuitry involving frontal cortex, anterior cingulate and striatum (Rogers et al. 2004). Showing alternating videos of the own child versus that of a stranger to mothers provoked the greatest signal contrasts in the mPFC and orbitofrontal cortex. These distinctions required face recognition and emotional processing which correlated with activation in the visual cortex, temporal pole and amygdala (Ranote et al. 2004). The extent to which social cognition, the ability to perceive inferences about psychological aspects of

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Parental and social bonds in mammals other people, relies on distinct frontal cortical areas is supported by recent human neuro-imaging research. Medial regions of the frontal cortex appear to contribute to the recognition of different emotions (Hornak et al. 1996; Shamay-Tsoory et al. 2005) and to the task of forming a ‘person impression’. This area is activated specifically when subjects are asked to form an impression of a person but not when they are asked to form an impression of an inanimate object, suggesting that this region specifically indexes social cognition (Mitchell et al. 2005).

7. DISCUSSION The word bonding is a loosely used descriptive term to signify an especially meaningful relationship between two or more individuals. In all mammalian species, this relationship primarily involves mother and infant. The evolution of viviparity and the birth of live offspring as opposed to egg production have required consolidation of the mother’s in utero investment, resulting in extended post-natal care. This in turn has required offspring recognition. Common to all bonding relationships are hormonal mechanisms, brain reward mechanisms and sensory recognition (Curley & Keverne 2005). However, the way in which these mechanisms are deployed and their relative importance are dependent on the species and in particular on the evolution of the brain. The precise nature of bonding needs to be examined in the context of its biology. Hence, in monogamous species, this terminology embraces father–infant, mother–father as well as mother–infant, while in large-brained primates it extends beyond the mother– infant to include social cohort, usually of kin related through the matriline. In looking for common mechanisms that sustain bonding and cross-species boundaries, it is important to take into account the evolutionary expansion of the brain. Thus, although recognition is common to all bonded relationships, in nocturnal small-brained altricial mammals this is primarily dependent on olfaction. This recognition is not for individual pups, but for the litter as a whole since the pups are immobile and unlikely to crossfoster. The interbirth interval is relatively short and the elements of the olfactory recognition memory are carried forward to subsequent births and result in reduced cannibalism. In precocial ungulates that are seasonal breeders and produce a single offspring at yearly intervals, recognition is unique to each offspring. Here offspring are mobile within hours of birth and are likely to attempt cross-fostering; therefore mothers need to be selective in their bonding to ensure only their own offspring receives milk. Within weeks of birth, multiple sensory cues, including auditory and visual are used for offspring recognition, which in comparison with nocturnal rodents involves increased deployment of PFC. With enhanced brain evolution, trichromatic vision in primates has been the dominant sensory system for infant recognition. The olfactory system is deconstructed at the genetic level with total redundancy of the vomeronasal genome and substantial silencing of main olfactory receptor genes. In the context of Phil. Trans. R. Soc. B (2006)

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mother–infant bonding, the steroid hormones of pregnancy are virtually redundant in that maternal care can and does occur without pregnancy and parturition, and in humans infant-bonded relationships extend to sister, fathers, aunts and grandparents. The hormones of pregnancy do, however, prime the mesolimbic DA projection to the NAcc as well as upregulation of receptors for OT and opioids in the ventral striatum/NAcc. This undoubtedly predisposes the brain reward system to forming mother–infant bonds at birth. However, adoption of infants and alloparenting by related kin is clearly successful outside the context of neuroendocrine priming. At the cellular level, it is well established that steroid (progesterone and oestrogen) signalling converges with DA transmission through recruitment and phosphorylation of co-regulators (steroid receptor coactivator 1; Mani 2003). Hence, in the mouse with a genetically modified non-functional progesterone receptor, DA agonists are still able to facilitate hormone-dependent behaviour. Such redundancy and hence emancipation from hormonal determinants of bonding enables extended parental and alloparental care to continue long after weaning. Indeed, they are lifetime occupations for many primate species, a development that has, in turn, impacted significantly on brain evolution. Brain growth is energetically costly, and postponing the greater part of this to the post-partum period has not only conserved the energetic demands on mother, but also has enabled brain growth to expand the cranial capacity way beyond the dimensions of the pelvic floor and birth canal. Moreover, postponing most of cortical brain growth to the post-partum period has also ensured that the brain develops in a social environment which promotes social skills as well as provides experience in alloparenting. Even more significant is the provision of an attachment figure, usually that of the mother, which provides the secure base from which to explore and develop other social relationships. K.D.B. and E.B.K. are supported by the BBSRC. J.P.C. and E.B.K. are supported by the Leverhulme Trust.

REFERENCES Amico, J. A., Mantella, R. C., Vollmer, R. R. & Li, X. 2004 Anxiety and stress responses in female oxytocin deficient mice. J. Neuroendocrinol. 16, 319–324. (doi:10.1111/ j.0953-8194.2004.01161.x) Baldwin, B. A. & Shillito, E. 1974 The effects of ablation of the olfactory bulbs on parturition and maternal behaviour in Soay sheep. Anim. Behav. 22, 220–223. (doi:10.1016/ S0003-3472(74)80072-2) Bale, T. L. & Dorsa, D. M. 1997 Cloning, novel promoter sequence, and estrogen regulation of a rat oxytocin receptor gene. Endocrinology 138, 1151–1158. (doi:10. 1210/en.138.3.1151) Bartels, A. & Zeki, S. 2004 The neural correlates of maternal and romantic love. Neuroimage 21, 1155–1166. (doi:10. 1016/j.neuroimage.2003.11.003) Barton, R. 1998 Visual specialization and brain evolution in primates. Proc. R. Soc. B 265, 1933–1937. (doi:10.1098/ rspb.1998.0523) Bechara, A., Damasio, A. R., Damasio, H. & Anderson, S. W. 1994 Insensitivity to future consequences following damage to human prefrontal cortex. Cognition 50, 7–15. (doi:10.1016/0010-0277(94)90018-3)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2210

K. D. Broad and others Parental and social bonds in mammals

Bechara, A., Tranel, D., Damasio, H. & Damasio, A. R. 1996 Failure to respond autonomically to anticipated future outcomes following damage to prefrontal cortex. Cereb. Cortex 6, 215–225. Bechara, A., Tranel, D. & Damasio, H. 2000 Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions. Brain 123, 2189–2202. (doi:10.1093/brain/123.11.2189) Bielsky, I. F. & Young, L. J. 2004 Oxytocin, vasopressin, and social recognition in mammals. Peptides 25, 1565–1574. (doi:10.1016/j.peptides.2004.05.019) Brennan, P. A. & Keverne, E. B. 2004 Something in the air? New insights into mammalian pheromones. Curr. Biol. 14, R81–R89. (doi:10.1016/j.cub.2003.12.052) Broad, K. D., Kendrick, K. M., Sirinathsinghji, D. J. S. & Keverne, E. B. 1993a Changes in oxytocin immunoreactivity and mRNA levels in the ovine brain during pregnancy, parturition and lactation and in response to oestrogen and progesterone. J. Neuroendocrinol. 5, 435–444. (doi:10.1111/j.1365-2826.1993.tb00505.x) Broad, K. D., Kendrick, K. M., Sirinathsinghji, D. J. S. & Keverne, E. B. 1993b Changes in pro-opiomelanocortin and pre-proenkephalin and mRNA levels in the ovine brain during pregnancy, parturition and lactation and in response to oestrogen and progesterone. J. Neuroendocrinol. 5, 711–719. (doi:10.1111/j.1365-2826.1993.tb00544.x) Broad, K. D., Levy, F., Evans, G., Kimura, T., Keverne, E. B. & Kendrick, K. M. 1999 Previous maternal experience potentiates the effects of parturition on oxytocin receptor mRNA expression in the paraventricular nucleus. Eur. J. Neurosci. 11, 3725–3737. (doi:10.1046/j.1460-9568. 1999.00782.x) Broad, K. D., Hinton, M. R., Keverne, E. B. & Kendrick, K. M. 2002a Involvement of the medial prefrontal cortex in mediating behavioural responses to odour cues rather than olfactory recognition memory. Neuroscience 114, 715–729. (doi:10.1016/S0306-4522(02)00231-2) Broad, K. D., Mimmack, M. L., Keverne, E. B. & Kendrick, K. M. 2002b Increased BDNF and trk-B mRNA in cortical and limbic regions following formation of a social recognition memory. Eur. J. Neurosci. 16, 1–11. (doi:10. 1046/j.1460-9568.2002.02311.x) Brouette-Lahlou, I., Godinot, F. & Vernet-Maury, E. 1999 The mother rat’s vomeronasal organ is involved in detection of dodecyl proprionate, the pup’s preputial gland pheromone. Physiol. Behav. 66, 427–436. (doi:10. 1016/S0031-9384(98)00334-5) Carmichael, M. S., Humbert, R., Dixen, J., Parmisano, G., Greenleaf, W. & Davidson, J. 1987 Plasma oxytocin increases in the human sexual response. J. Clin. Endocrinol. Metab. 64, 27–31. Chacko, R. C., Corbin, M. A. & Harper, R. B. 2000 Acquired obsessive–compulsive disorder associated with basal ganglia lesions. J. Neuropsychiatry Clin. Neurosci. 12, 269–272. Champagne, F. A., Chretien, P., Stevenson, C. W., Zhang, T. Y., Gratton, A. & Meaney, M. J. 2004 Variations in nucleus accumbens dopamine associated with individual differences in maternal behaviour in the rat. J. Neurosci. 24, 4113–4123. (doi:10.1523/JNEUROSCI.5322-03.2004) Chiba, T., Kayahara, T. & Nakano, K. 2001 Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata. Brain Res. 888, 83–101. (doi:10.1016/S00068993(00)03013-4) Choleris, E., Gustafsson, J. A., Korach, K. S., Muglia, L. J., Pfaff, D. W. & Ogawa, S. 2003 An estrogen-dependent four-gene micronet regulating social recognition: a study Phil. Trans. R. Soc. B (2006)

with oxytocin and estrogen receptor-alpha and -beta knockout mice. Proc. Natl Acad. Sci. USA 100, 6192–6197. (doi:10.1073/pnas.0631699100) Choleris, E., Kavaliers, M. & Pfaff, D. W. 2004 Functional genomics of social recognition. J. Neuroendocrinol. 16, 383–389. (doi:10.1111/j.0953-8194.2004.01178.x) Creutz, L. M. & Kritzer, M. F. 2004 Mesostriatal and mesolimbic projections of midbrain neurons immunoreactive for estrogen receptor beta or androgen receptors in rats. J. Comp. Neurol. 476, 348–362. (doi:10.1002/cne. 20229) Curley, J. P. & Keverne, E. B. 2005 Genes, brains and mammalian social bonds. Trends Ecol. Evol. 20, 561–567. (doi:10.1016/j.tree.2005.05.018) da Costa, A. P. C., Guevara-Guzman, R., Ohkura, S., Goode, J. A. & Kendrick, K. M. 1996 The role of oxytocin release in the paraventricular nucleus in the control of maternal behaviour in sheep.. J. Neuroendocrinol. 8, 163–177. (doi:10.1046/j.1365-2826.1996.04411.x) da Costa, A. P. C., Broad, K. D. & Kendrick, K. M. 1997 Olfactory memory and maternal behaviour-induced changes in c-fos and zif-268 mRNA expression in the sheep brain. Mol. Brain Res. 46, 63–76. (doi:10.1016/ S0169-328X(96)00272-0) Dantzer, R. 1998 Vasopressin, gonadal steroids and social recognition. Prog. Brain Res. 119, 409–414. de Kloet, E. R., Voorhuis, D. A., Boschma, Y. & Elands, J. 1986 Estradiol modulates density of putative “oxytocin receptors” in discrete rat brain regions. Neuroendocrinology 44, 415–421. Del Punta, K., Leinders-Zufall, T., Rodriguez, I., Jukam, D., Wysocki, C. J., Ogawa, S., Zufall, F. & Mombaerts, P. 2002 Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes. Nature 419, 70–74. (doi:10.1038/nature00955) Diergaarde, L., Gerrits, M. A., Brouwers, J. P. & van Ree, J. M. 2005 Early amygdala damage disrupts performance on medial prefrontal cortex-related tasks but spares spatial learning and memory in the rat. Neuroscience 130, 581–590. (doi:10.1016/j.neuroscience.2004.09.022) Dluzen, D. E., Muroaka, S., Engelmann, M. & Landgraf, R. 1998 The effects of infusion of arginine vasopressin, oxytocin, or their antagonists into the olfactory bulb upon social recognition responses in male rats. Peptides 19, 999–1005. (doi:10.1016/S0196-9781(98)00047-3) Dluzen, D. E., Muroaka, S., Engelmann, M., Ebner, K. & Landgraf, R. 2000 Oxytocin induces preservation of social recognition in male rats by activating alpha-adrenoreceptors of the olfactory bulb. Eur. J. Neurosci. 12, 760–766. (doi:10.1046/j.1460-9568.2000.00952.x) Engelmann, M., Ebner, K., Wotjak, C. T. & Landgraf, R. 1998 Endogenous oxytocin is involved in short-term olfactory memory in female rats. Behav. Brain Res. 90, 89–94. (doi:10.1016/S0166-4328(97)00084-3) Ferguson, J. N., Young, L. J., Hearn, E. F., Matzuk, M. M., Insel, T. R. & Winslow, J. T. 2000 Social amnesia in mice lacking the oxytocin gene. Nat. Genet. 25, 284–288. (doi:10.1038/77040) Ferguson, J. N., Aldag, J. M., Young, L. J. & Insel, T. R. 2001 Oxytocin in the medial amygdala is essential for social recognition in the mouse. J. Neurosci. 21, 8278–8285. Ferreira, A., Dahlof, L. G. & Hansen, S. 1987 Olfactory mechanisms in the control of maternal aggression, appetite, and fearfulness: effects of lesions to olfactory receptors, mediodorsal thalamic nucleus, and insular prefrontal cortex. Behav. Neurosci. 101, 709–717. (doi:10.1037/0735-7044.101.5.709) Ferris, C. F., Kulkani, P., Sullivan, J. M., Harder, J. A., Messenger, T. L. & Febo, M. 2005 Pup suckling is more rewarding than cocaine: evidence from functional

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Parental and social bonds in mammals magnetic resonance imaging and three dimensional computational analysis. J. Neurosci. 25, 149–156. (doi:10.1523/JNEUROSCI.3156-04.2005) Fleming, A. S. & Korsmit, M. 1996 Plasticity in the maternal circuit: effects of maternal experience on Fos-Lir in hypothalamic, limbic, and cortical structures in the postpartum rat. Behav. Neurosci. 110, 567–582. (doi:10. 1037/0735-7044.110.3.567) Fleming, A. S., Vaccarino, F. & Luebke, C. 1980 Amygdaloid inhibition of maternal behavior in the nulliparous female rat. Physiol. Behav. 25, 731–743. (doi:10.1016/00319384(80)90377-7) Frahm, H. D., Stephan, H. & Stephan, M. 1982 Comparison of brain structure volumes in Insectivora and Primates. I. Neocortex. J. Hirnforsch. 23, 375–389. Franceschini, R., Venturini, P. L., Cataldi, A., Barreca, T., Ragni, N. & Rolandi, E. 1989 Plasma beta-endorphin concemtrations during suckling in lactating women. Br. J. Obstet. Gynaecol. 96, 711–713. Gilad, Y., Bustamante, C. D., Lancet, D. & Paabo, S. 2003 Natural selection on the olfactory receptor gene family in humans and chimpanzees. Am. J. Hum. Genet. 73, 489–501. (doi:10.1086/378132) Gilad, Y., Wiebe, V., Przeworski, M., Lancet, D. & Paabo, S. 2004 Loss of olfactory receptor genes coincides with the acquisition of full trichromatic vision in primates. PLoS Biol. 2, 120–125. (doi:10.1371/journal.pbio.0020005) Grattan, D. R. 2001 The actions of prolactin in the brain during pregnancy and lactation. Prog. Brain Res. 133, 153–171. Greenberg, J. L., Lewis, S. E. & Dodd, D. K. 1999 Overlapping addictions and self-esteem among college men and women. Addict. Behav. 24, 562–571. (doi:10. 1016/S0306-4603(98)00080-X) Grus, W. E., Shi, P., Zhang, Y. P. & Zhang, J. 2005 Dramatic variation of the vomeronasal pheromone receptor gene repertoire among five orders of placental and marsupial mammals. Proc. Natl Acad. Sci. USA 102, 5767–5772. (doi:10.1073/pnas.0501589102) Heap, R. B. 1994 Paracrine and autocrine functions of the placenta: a key to the success of viviparity? Exp. Clin. Endocrinol. 102, 262–268. Hellman, A. & Chess, A. 2002 Olfactory axons: a remarkable convergence. Curr. Biol. 12, 849–851. (doi:10.1016/ S0960-9822(02)01351-9) Hernandez-Gonsalez, M., Prieto-Beracoechea, C., NavarroMeza, M., Ramos-Guevara, J. P., Reyes-Cortes, R. & Guevara, M. A. 2005 Prefrontal and tegmental electrical activity during olfactory stimulation in virgin and lactating rats. Physiol. Behav. 83, 749–758. (doi:10.1016/j.physbeh. 2004.09.013) Hinde, R. A., Leighton-Shapiro, M. E. & McGinnis, L. 1978 Effects of various types of separation experience on rhesus monkeys 5 months later. J. Child Psychol. Psychiatry 19, 199–211. Hornak, J., Rolls, E. T. & Wade, D. 1996 Face and voice expression identification in patients with emotional and behavioural changes following ventral frontal lobe damage. Neuropsychologia 34, 247–261. (doi:10.1016/ 0028-3932(95)00106-9) Hrdy, S. 1999 Mother nature: a history of mothers, infants, and natural selection. New York, NY: Pantheon Books. Huber, D., Veinante, P. & Stoop, R. 2005 Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 308, 245–248. (doi:10.1126/science. 1105636) Insel, T. R. & Shapiro, L. E. 1992 Oxytocin receptor distribution reflects social organisation in monogamous and polygamous voles. Proc. Natl Acad. Sci. USA 89, 5981–5985. (doi:10.1073/pnas.89.13.5981) Phil. Trans. R. Soc. B (2006)

K. D. Broad and others

2211

Kalamatianos, T., Kallo, I., Goubillon, M. L. & Coen, C. W. 2004 Cellular expression of V1a vasopressin receptor mRNA in the female rat preoptic area: effects of oestrogen. J. Neuroendocrinol. 16, 525–533. (doi:10.1111/j.13652826.2004.01199.x) Kavaliers, M., Agmo, A., Choleris, E., Gustafsson, J. A., Korach, K. S., Muglia, L. J., Pfaff, D. W. & Ogawa, S. 2004 Oxytocin and estrogen receptor alpha and beta knockout mice provide discriminably different odor cues in behavioural assays. Genes Brain Behav. 3, 189–195. (doi:10.1111/j.1601-183x.2004.00068.x) Keller, M., Meurisse, M. & Levy, F. 2004a Mapping the neural substrates involved in maternal responsiveness and lamb olfactory memory in parturient ewes using Fos imaging. Behav. Neurosci. 118, 1274–1284. (doi:10.1037/ 0735-7044.118.6.1274) Keller, M., Perrin, G., Meurisse, M., Ferreira, G. & Levy, F. 2004b Cortical and medial amygdala are both involved in the formation of olfactory offspring memory in sheep. Eur. J. Neurosci. 20, 3433–3441. (doi:10.1111/j.1460-9568. 2004.03812.x) Kendrick, K. M. 2000 Oxytocin, motherhood and bonding. Exp. Physiol. 85, 112–124. (doi:10.1111/j.1469-445X. 2000.tb00014.x) Kendrick, K. M. & Keverne, E. B. 1989 Effects of intracerebroventricular infusions of naltrexone and phentolamine on central and peripheral oxytocin release and on maternal behaviour induced by vaginocervical stimulation in the ewe. Brain Res. 505, 329–332. (doi:10.1016/00068993(89)91462-5) Kendrick, K. M. & Keverne, E. B. 1991 Importance of progesterone and estogen priming for the induction of maternal behavior by vaginocervical stimulation in sheep: effects of maternal experience. Physiol. Behav. 49, 745–750. (doi:10.1016/0031-9384(91)90313-D) Kendrick, K. M., Keverne, E. B., Chapman, C. & Baldwin, B. A. 1988 Microdialysis measurement of oxytocin, aspartate, GABA and glutamate release from the olfactory bulb of the sheep during vaginocervical stimulation. Brain Res. 442, 171–174. (doi:10.1016/0006-8993(88)91447-3) Kendrick, K. M., Levy, F. & Keverne, E. B. 1992 Changes in the sensory processing of olfactory signals induced by birth in sheep. Science 256, 833–836. (doi:10.1126/ science.1589766) Kendrick, K. M., Guevara-Guzman, R., Zorrilla, J., Hinton, M. R., Broad, K. D., Mimmack, M. & Ohkura, S. 1997 Formation of olfactory memories mediated by nitric oxide. Nature 388, 670–674. (doi:10.1038/41765) Keverne, E. B. 1995a Olfactory learning. Curr. Opin. Neurobiol. 5, 482–488. (doi:10.1016/0959-4388(95)80009-3) Keverne, E. B. 1995b Neurochemical changes accompanying the reproductive process: their significance for maternal care in primates and other mammals. In Motherhood in human and nonhuman primates (ed. C. R. Pryce, R. D. Martin & D. Skuse), pp. 69–71. Basel: Karger. Keverne, E. B. 1999 The vomeronasal organ. Science 286, 716–720. (doi:10.1126/science.286.5440.716) Keverne, E. B. 2005 Trophoblast regulation of maternal endocrine function and behaviour. In Biology and pathology of trophoblast (ed. A. Moffat), pp. 368–411. Cambridge, UK: Cambridge University Press. Keverne, E. B. & Curley, J. P. 2004 Vasopressin, oxytocin and social behaviour. Curr. Opin. Neurobiol. 14, 777–783. (doi:10.1016/j.conb.2004.10.006) Keverne, E. B. & Kendrick, K. M. 1991 Morphine and corticotrophin-releasing factor potentiate maternal acceptance in multiparous ewes after vaginocervical stimulation. Brain Res. 540, 55–62. (doi:10.1016/0006-8993 (91)90492-E)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

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Keverne, E. B. & Kendrick, K. M. 1992 Oxytocin facilitation of maternal behaviour in sheep. Ann. NY Acad. Sci. 652, 83–101. Keverne, E. B., Levy, F., Poindron, P. & Lindsay, D. R. 1983 Vaginal stimulation: an important determinant of maternal behaviour in sheep. Science 19, 81–83. (doi:10. 1126/science.6849123) Keverne, E. B., Levy, F., Guevara-Guzman, R. & Kendrick, K. M. 1993 Influence of birth and maternal experience on olfactory bulb neurotransmitter release. Neuroscience 56, 557–565. (doi:10.1016/0306-4522(93)90356-K) Keverne, E. B., Nevison, C. M. & Martel, F. L. 1997 Early learning and the social bond. Ann. NY Acad. Sci. 807, 329–339. Kippin, T. E., Cain, S. W. & Pfaus, J. G. 2003 Estrous odors and sexually conditioned neutral odors activate separate neural pathways in the male rat. Neuroscience 117, 971–979. (doi:10.1016/S0306-4522(02)00972-7) Kleiman, D. G. 1977 Monogamy and mammals. Q. Rev. Biol. 52, 39–69. (doi:10.1086/409721) Koob, G. F. & Le Moal, M. 1997 Drug abuse: hedonic homeostatic dysregulation. Science 278, 52–58. (doi:10. 1126/science.278.5335.52) Kraemer, G. W., Ebert, M. H., Schmidt, D. E. & McKinney, W. T. 1991 Strangers in a strange land: a psychobiological study of infant monkeys before and after separation from real or inanimate mothers. Child Dev. 62, 548–566. (doi:10.2307/1131130) Krehbiel, D., Poindron, P., Levy, F. & Prud’homme, M. J. 1987 Effects of peridural anaesthesia on maternal behaviour in primiparous and multiparous parturient ewes. Physiol. Behav. 40, 463–472. (doi:10.1016/00319384(87)90031-X) Labad, J., Menchon, J. M., Alonso, P., Segalas, C., Jimenez, S. & Vallejo, J. 2005 Female reproductive cycle and obsessive–compulsive disorder. J. Clin. Psychiatry 66, 428–435. Leckman, J. F. et al. 1994 The role of central oxytocin in obsessive compulsive disorder and related normal behavior. Psychoneuroendocrinology 19, 723–749. (doi:10. 1016/0306-4530(94)90021-3) Leckman, J. F., Mayes, L. C., Feldman, R., Evans, D. W., King, R. A. & Cohen, D. J. 1999 Early parental preoccupations and behaviors and the possible relationship to the symptoms of obsessive–compulsive disorder. Acta Psychiatr. Scand. 396, 1–26. Lee, A., Li, M., Watchus, J. & Fleming, A. S. 1999 Neuroanatomical basis of maternal memory in postpartum rats: selective role for the nucleus accumbens. Behav. Neurosci. 113, 523–538. (doi:10.1037/0735-7044. 113.3.523) Lejeune, C., Ropert, J. C., Montamat, S., Floch-Tudal, C., Mazy, F., Wijkhuisen, N. & Froment, H. 1997 Medicalsocial outcome of 59 infants born to addicted mothers. J. Gynecol. Obstet. Biol. Reprod. (Paris) 26, 395–404. Leon, M., Coopersmith, R., Beasley, L. J. & Sullivan, R. M. 1990 Thermal aspects of parenting. In Mammalian parenting. Biochemical, neurobiological and behavioural determinants (ed. N. A. Krasnegor & R. S. Bridges), pp. 400–416. Oxford, UK: Oxford University Press. LeSaux, M. & Di Paolo, T. 2005 Chronic estrogenic drug treatment increases preproenkephalin mRNA levels in the rat striatum and nucleus accumbens. Psychoneuroendocrinology 30, 251–260. (doi:10.1016/j.psyneuen. 2004.08.002) Levy, F., Kendrick, K. M., Keverne, E. B., Piketty, Y. & Poindron, P. 1992 Intracerebral oxytocin is important for the onset of maternal behaviour in experienced ewes delivered under peridural anaesthesia. Behav. Neurosci. 106, 427–432. (doi:10.1037/0735-7044.106.2.427) Phil. Trans. R. Soc. B (2006)

Levy, F., Locatelli, A., Piketty, V., Tillet, Y. & Poindron, P. 1995a Involvement of the main but not the accessory olfactory system in maternal behaviour of primiparous and multiparous ewes. Physiol. Behav. 57, 97–104. (doi:10. 1016/0031-9384(94)00200-O) Levy, F., Kendrick, K. M., Goode, J. A., Guevara-Guzman, R. & Keverne, E. B. 1995b Oxytocin and vasopressin release in the olfactory bulb of parturient ewes: changes with maternal experience and effects on acetylcholine, gamma-aminobutyric acid, glutamate and noradrenaline release. Brain Res. 669, 197–206. (doi:10.1016/00068993(94)01236-B) Leypold, B. G., Yu, C. R., Leinders-Zufall, T., Kim, M. M., Zufall, F. & Axel, R. 2002 Altered sexual and social behaviours in trp2 mutant mice. Proc. Natl Acad. Sci. USA 99, 6376–6381. (doi:10.1073/pnas.082127599) Lidow, M. S., Wang, F., Cao, Y. & Goldman-Rakic, P. S. 1998 Layer V neurons bear the majority of mRNAs encoding the five distinct dopamine receptor subtypes in the primate prefrontal cortex. Synapse 28, 10–20. (doi:10. 1002/(SICI)1098-2396(199801)28:1!10::AID-SYN2O 3.0.CO;2-F) Lim, M. M. & Young, L. J. 2004 Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole. Neuroscience 125, 35–45. (doi:10.1016/j.neuroscience.2003.12.008) Lim, M. M., Murphy, A. Z. & Young, L. J. 2001 Ventral striatopallidal oxytocin and vasopressin V1a receptors in the monogamous prairie vole (Microtus ochrogaster). J. Comp. Neurol. 468, 555–570. (doi:10.1002/cne.10973) Lim, M. M., Wang, Z., Olazabal, D. E., Ren, X., Terwilliger, E. F. & Young, L. J. 2004 Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene. Nature 429, 754–757. (doi:10.1038/nature 02539) Liman, E. & Innan, H. 2003 Relaxed selective pressure on an essential component of pheromone transduction in primate evolution. Proc. Natl Acad. Sci. USA 100, 3328–3332. (doi:10.1073/pnas.0636123100) Luzzati, V., Mateu, L., Marquez, G. & Borgo, M. 1999 Structural and electrophysiological effects of local anesthetics and of low temperature on myelinated nerves: implication of the lipid chains in nerve excitability. J. Mol. Biol. 286, 1389–1402. (doi:10.1006/jmbi.1998.2587) Lyons, D. M. & Schatzberg, A. F. 2003 Early maternal availability and prefrontal correlates of reward-related memory. Neurobiol. Learn. Mem. 80, 97–104. (doi:10. 1016/S1074-7427(03)00044-3) Mani, S. 2003 Signalling mechanisms in progesterone– neurotransmitter interactions. J. Mol. Endocrinol. 30, 127–137. (doi:10.1677/jme.0.0300127) Mann, P. E., Felicio, L. F. & Bridges, R. S. 1995 Investigation into the role of cholecystokinin (CCK) in the induction and maintenance of maternal behaviour in rats. Horm. Behav. 29, 392–406. (doi:10.1006/hbeh.1995.1027) Mantella, R. C., Vollmer, R. R., Li, X. & Amico, J. A. 2003 Female oxytocin-deficient mice display enhanced anxietyrelated behavior. Endocrinology 144, 2291–2296. (doi:10. 1210/en.2002-0197) Martel, F. L., Nevison, C. M., Rayment, F. D., Simpson, M. J. & Keverne, E. B. 1993 Opioid receptor reduces affect and social grooming in rhesus monkeys. Psychoneuroendocrinology 18, 307–321. (doi:10.1016/0306-4530(93) 90027-I) Martel, F. L., Nevison, C. M., Simpson, M. J. & Keverne, E. B. 1995 Effects of opioid receptor blockade on the social behaviour of rhesus monkeys living in large family groups. Dev. Psychobiol. 28, 71–84. (doi:10.1002/dev. 420280202)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Parental and social bonds in mammals Matsumoto, K. & Tanaka, K. 2004 The role of the medial prefrontal cortex in achieving goals. Curr. Opin. Neurobiol. 14, 178–185. (doi:10.1016/j.conb.2004.03.005) Mayes, L. C. 1995 In Substance abuse and parenting, vol. 4 (ed. M. H. Bornstein), pp. 101–126. Handbook of parenting: applied and practical parenting. New Jersey, NJ: Lawrence Erlbaum Associates. McNeilly, A. S., Robinson, I. C. A. F., Houston, M. J. & Howie, P. W. 1983 Release of oxytocin and prolactin in response to suckling. Br. Med. J. 286, 207–209. Mikhail, M. S., Youchah, J., DeVore, N., Ho, G. Y. & Anyaegbunam, A. 1995 Decreased maternal–fetal attachment in methadone-maintained pregnant women: a preliminary study. J. Assoc. Acad. Minor Phys. 6, 112–114. Mitchell, J. P., Neil Macrae, C. & Banaji, M. R. 2005 Forming impressions of people versus inanimate objects: social-cognitive processing in the medial prefrontal cortex. Neuroimage 26, 251–257. (doi:10.1016/j.neuroimage. 2005.01.031) Moncho-Bogani, J., Martinez-Garcis, F., Novejarque, A. & Lanuza, E. 2005 Attraction to sexual pheromones and associated odorants in female mice involves activation of the reward and basolateral amygdala. Eur. J. Neurosci. 21, 2186–2198. (doi:10.1111/j.1460-9568.2005.04036.x) Neumann, I., Douglas, A. J., Pittman, Q. J., Russel, J. A. & Landgraf, R. 1996 Oxytocin released within the supraoptic nucleus of the rat brain by positive feedback action is involved in parturition related events. J. Neuroendocrinol. 8, 227–233. (doi:10.1046/j.1365-2826.1996.04557.x) Neumann, I. D., Torner, L. & Wigger, A. 2000 Brain oxytocin: differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats. Neuroscience 95, 567–575. (doi:10. 1016/S0306-4522(99)00433-9) Numan, M., Numan, M. J., Scharz, J. M., Neuner, C. M., Flood, T. F. & Smith, C. D. 2005 Medial preoptic area interactions with the nucleus accumbens–ventral pallidum circuit and maternal behaviour in rats. Behav. Brain Res. 158, 53–68. (doi:10.1016/j.bbr.2004.08.008) Ogawa, S., Chan, J., Chester, A. E., Gustafsson, J. A., Korach, K. S. & Pfaff, D. W. 1999 Survival of reproductive behaviours in estrogen receptor beta gene-deficient (betaERKO) male and female mice. Proc. Natl Acad. Sci. USA 96, 12 887–12 892. (doi:10.1073/pnas.96.22. 12887) Osako, Y., Otsuka, T., Taniguchi, M., Oka, T. & Kaba, H. 2001 Oxytocin enhances presynaptic and postsynaptic glutamatergic transmission between rat olfactory bulb neurones in culture. Neurosci. Lett. 299, 65–68. (doi:10. 1016/S0304-3940(00)01779-1) Pankevich, D. E., Barum, M. J. & Cherry, J. A. 2004 Olfactory sex discrimination persists, whereas the preference for urinary odorants from estrous females disappears in male mice after vomeronasal organ removal. J. Neurosci. 24, 9451–9457. (doi:10.1523/JNEUROSCI. 2376-04.2004) Patisaul, H. B., Scordalakes, E. M., Young, L. J. & Rissman, E. F. 2003 Oxytocin, but not oxytocin receptor, is regulated by oestrogen receptor beta in the female mouse hypothalamus. J. Neuroendocrinol. 15, 787–793. Perrett, D. I., Hietanen, J. K., Oram, M. W. & Benson, P. J. 1992 Organization and function of cells responsive to faces in temporal cortex. Phil. Trans. R. Soc. B 335, 23–30. Poindron, P. & Levy, F. 1990 Physiological, sensory, and experimental determinants of maternal behaviour in sheep. In Mammalian parenting. Biochemical, neurobiological and behavioural determinants (ed. N. A. Krasnegor & R. S. Bridges), pp. 133–157. Oxford, UK: Oxford University Press. Phil. Trans. R. Soc. B (2006)

K. D. Broad and others

2213

Ragozzino, M. E., Detrick, S. & Kesner, R. P. 1999a Involvement of the prelimbic–infralimbic areas of the rodent pre-frontal cortex in behavioural flexibility for place and response learning. J. Neurosci. 19, 4585–4594. Ragozzino, M. E., Wilcox, C., Raso, M. & Kesner, R. P. 1999b Involvement of rodent prefrontal cortex subregions in strategy switching. Behav. Neurosci. 113, 32–41. Ranote, S., Elliott, R., Abel, K. M., Mitchell, R., Deakin, J. F. & Appleby, L. 2004 The neural basis of maternal responsiveness to infants: an fMRI study. Neuroreport 15, 1825–1929. (doi:10.1097/01.wnr.0000137078.64128.6a) Rauch, S. L. 2000 Neuroimaging research and the neurobiology of obsessive–compulsive disorder: where do we go from here? Biol. Psychiatry 47, 168–170. (doi:10.1016/ S0006-3223(99)00297-8) Ridderinkhof, K. R., van den Wildenberg, W. P., Segalowitz, S. J. & Carter, C. S. 2004 Neurocognitive mechanisms of cognitive control: the role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning. Brain Cogn. 56, 129–140. (doi:10.1016/j.bandc.2004.09.016) Rogers, R. D., Ramnani, N., Mackay, C., Wilson, J. L., Jezzard, P., Carter, C. S. & Smith, S. M. 2004 Distinct portions of anterior cingulate cortex and medial prefrontal cortex are activated by reward processing in separable phases of decision-making cognition. Biol. Psychiatry 55, 594–602. (doi:10.1016/j.biopsych.2003.11.012) Schultz, W. & Dickinson, A. 2000 Neuronal coding of prediction errors. Annu. Rev. Neurosci. 23, 473–500. (doi:10.1146/annurev.neuro.23.1.473) Schultz, W., Tremblay, L. & Hollerman, J. R. 2000 Reward processing in primate orbitofrontal cortex and basal ganglia. Cereb. Cortex 10, 272–284. (doi:10.1093/cercor/ 10.3.272) Shamay-Tsoory, S. G., Tomer, R. & Aharon-Peretz, J. 2005 The neuroanatomical basis of understanding sarcasm and its relationship to social cognition. Neuropsychology 19, 288–300. (doi:10.1037/0894-4105.19.3.288) Sowell, E. R., Thompson, P. M., Tessner, K. D. & Toga, A. W. 2001 Mapping continued brain growth and gray matter density reduction in dorsal frontal cortex: inverse relationships during postadolescent brain maturation. J. Neurosci. 21, 8819–8829. Spencer, S. J., Buller, K. M. & Day, T. A. 2005 Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: possible role of the bed nucleus of the stria terminalis. J. Comp. Neurol. 481, 363–376. (doi:10.1002/cne.20376) Stephan, H., Baron, G. & Frahm, H. D. 1982 Comparison of brain structure volumes in Insectivora and Primates. II. Accessory olfactory bulb (AOB). J. Hirnforsch. 23, 575–591. Stowers, L., Holy, T. E., Meister, M., Dulac, C. & Koentges, G. 2002 Loss of sex discrimination and male–male aggression in mice deficient for Trp2. Science 295, 1493–1500. (doi:10.1126/science.1069259) Suomi, S. J. & Harlow, H. F. 1975 Effects of differential removal from group on social development of rhesus monkeys. J. Child Psychol. Psychiatry 16, 149–164. Surridge, A. K., Osorio, D. & Mundy, N. I. 2003 Evolution and selection of trichromatic vision in primates. Trends Ecol. Evol. 18, 198–205. (doi:10.1016/S0169-5347(03) 00012-0) Thomas, A., Kim, N. B. & Amico, J. A. 1996 Differential regulation of oxytocin and vasopressin messenger ribonucleic acid levels by gonadial steroids in post partum rats. Brain Res. 738, 48–52. (doi:10.1016/0006-8993(96) 00760-3)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2214

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Wardlaw, S. L. & Frantz, A. G. 1983 Brain beta-endorphin during pregnancy, parturition, and the postpartum period. Endocrinology 113, 1664–1668. Webb, D. M., Cortes-Ortiz, L. & Zhang, J. 2004 Genetic evidence for the coexistence of pheromone perception and full trichromatic vision in howler monkeys. Mol. Biol. Evol. 21, 697–704. (doi:10.1093/molbev/msh068) Weiss, M., Baerge, E., Wiseboard, S. & Temple, J. 1995 The influence of gonadal hormones on periodicity of obsessive– compulsive disorder. Can. J. Psychiatry 40, 205–207. Wettschureck, N., Moers, A., Hamalainen, T., Lemberger, T., Schutz, G. & Offermanns, S. 2004 Heterotrimeric G proteins of the Gq/11 family are crucial for the induction of maternal behavior in mice. Mol. Cell Biol. 24, 8048–8054. (doi:10.1128/MCB.24.18.8048-8054.2004) Whinnett, A. & Mundy, N. 2003 Isolation of novel olfactory receptor genes in marmosets (Callithrix): insights into pseudogene formation and evidence for functional degeneracy in non-human primates. Gene 304, 87–96. (doi:10. 1016/S0378-1119(02)01182-4) Williams, K. E. & Koran, L. M. 1997 Obsessive–compulsive disorder in pregnancy, the puerperium, and the premenstruum. J. Clin. Psychiatry 58, 330–334. Winslow, J. T. & Insel, T. R. 2002 The social deficits of the oxytocin receptor mouse. Neuropeptides 36, 221–229. (doi:10.1054/npep.2002.0909) Winslow, J. T., Noble, P. L., Lyons, C. K., Sterk, S. M. & Insel, T. R. 2003 Rearing effects of cerebrospinal fluid oxytocin concentration and social buffering in rhesus monkeys. Neuropsychopharmacolgy 28, 910–918.

Phil. Trans. R. Soc. B (2006)

Young, L. J. & Wang, Z. 2004 The neurobiology of pair bonding. Nat. Neurosci. 7, 1048–1054. (doi:10.1038/ nn1327) Young, L. J., Muns, S., Wang, Z. & Insel, T. R. 1997 Changes in oxytocin receptor mRNA in rat brain during pregnancy and the effects of estrogen and interleukin-6. J. Neuroendocrinol. 9, 859–865. (doi:10.1046/j.1365-2826. 1997.00654.x) Young, J. M., Kambere, M., Trask, B. J. & Lane, R. P. 2005 Divergent V1R repertoires in five species: amplification in rodents, decimation in primates, and a surprisingly small repertoire in dogs. Genome Res. 15, 231–240. (doi:10. 1101/gr.3339905) Yu, G. Z., Kaba, H., Okuani, F., Takahashi, S., Higuchi, T. & Seto, K. 1996a The action of oxytocin originating in the hypothalamic paraventricular nucleus on mitral and granule cells in the rat main olfactory bulb. Neuroscience 72, 1073–1082. (doi:10.1016/0306-4522(95)00599-4) Yu, G. Z., Kaba, H., Okutani, F., Takahashi, S. & Tiguchi, T. 1996b The olfactory bulb: a critical site of action for oxytocin in the induction of maternal behaviour in the rat. Neuroscience 72, 1083–1088. (doi:10.1016/0306-4522(95) 00600-1) Zhang, X. & Firestein, S. 2002 The olfactory receptor gene superfamily of the mouse. Nat. Neurosci. 5, 124–133. Zhang, J. & Webb, D. 2003 Evolutionary deterioration of the vomeronasal pheromone transduction pathway in catarrhine primates. Proc. Natl Acad. Sci. USA 100, 8337–8341. (doi:10.1073/pnas.1331721100)

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Phil. Trans. R. Soc. B (2006) 361, 2215–2228 doi:10.1098/rstb.2006.1941 Published online 6 November 2006

Social buffering: relief from stress and anxiety Takefumi Kikusui1,*, James T. Winslow2 and Yuji Mori1 1

Laboratory of Veterinary Ethology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan 2 Non-Human Primate Core, The Division of Intramural Research Programs, National Institute of Mental Health, 9000 Rockville Pike, Bethesda, MD 20892, USA Communication is essential to members of a society not only for the expression of personal information, but also for the protection from environmental threats. Highly social mammals have a distinct characteristic: when conspecific animals are together, they show a better recovery from experiences of distress. This phenomenon, termed ‘social buffering’, has been found in rodents, birds, non-human primates and also in humans. This paper reviews classical findings on social buffering and focuses, in particular, on social buffering effects in relation to neuroendocrine stress responses. The social cues that transmit social buffering signals, the neural mechanisms of social buffering and a partner’s efficacy with respect to social buffering are also detailed. Social contact appears to have a very positive influence on the psychological and the physiological aspects of social animals, including human beings. Research leading towards further understanding of the mechanisms of social buffering could provide alternative medical treatments based on the natural, individual characteristics of social animals, which could improve the quality of life. Keywords: social buffering; stress responses; social affiliation; glucocorticoids; oxytocin

1. INTRODUCTION Social animals live in groups and communicate with each other in order to cooperate and manage the group in such a way that is beneficial to each individual member. To date, most empirical studies of social influences on stress have focused on the negative, stress-inducing aspects of social interaction (Levine 2001; Buwalda et al. 2005). Social interaction and communication are essential not only for cooperation within a group, but also for protection from environmental threats; this is one of the most beneficial aspects of establishing a society. For example, social mammals communicate with other group members to inform them of danger using vocal (Seyfarth & Cheney 2003), visual (Liddell et al. 2005) and pheromonal cues (Regnier & Law 1968; Rottman & Snowdon 1972; Wheeler 1976; Kikusui et al. 2001). It is conceivable that social subjects feel safe when they are with other colony members, because companionship provides protection for the subject from environmental threats. Therefore, solitude itself can be a stressor to social mammals (Hatch et al. 1965; Valzelli 1973; Clancy & McBride 1975; Noble et al. 1976), and they may show a high stress response when socially isolated. Highly social mammals have a distinct characteristic: when conspecific animals are together, they show a better recovery from aversive experiences. This phenomenon, termed ‘social buffering’, has been found in rats (Davitz & Mason 1955), guinea pigs (Hennessy et al. 2000), non-human primates (Coe et al. 1978; Levine et al. 1978; Mendoza et al. 1978) * Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘The neurobiology of social recognition, attraction and bonding’.

and humans (Thorsteinsson et al. 1998). Social species can also display an ‘isolation syndrome’, in which isolated animals show high levels of stress responses to a variety of stimuli, including endocrine, behavioural and autonomic stimuli (Hatch et al. 1965; Valzelli 1973; Clancy & McBride 1975; Noble et al. 1976), when they are housed individually over a long period. In humans, social isolation has been related to a risk of physiological and mental pathogenesis (Rabkin & Struening 1976; West et al. 1986); on the other hand, social support can have a positive influence on human health (Cobb 1976; Ell 1996). Therefore, understanding the mechanisms of social buffering could certainly be beneficial for human health as well as animal welfare. Several types of studies have been conducted using social mammals as models, and this paper will discuss mechanisms of social buffering that allow animals to find relief from stressful experiences. 2. ORIGINAL FINDINGS OF RESEARCH INTO SOCIAL BUFFERING (a) Behavioural findings Researchers have found that when conspecific animals are together in a semi-natural environment, there is a reduction in their stress level. For example, a cat’s fear of eating was reduced by observing a non-fearful cat eating (Measserman 1943) and a goat kid demonstrated a greater ability to tolerate a novel environment when it was accompanied by its mother (Liddell 1950). Davitz & Mason (1955) found that the fearful withdrawal of rats in an open field diminished when other rats accompanied them. In this experiment, fearconditioned rats displayed decreased locomotor activity when they were exposed to the conditioned

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stimuli in a novel open field, but the presence of another non-fearful rat increased their locomotor activity, and the fear-conditioned rats showed higher affiliation behaviour towards other rats. It appears that when conspecific animals are together, fear is allayed, and fear reduction may contribute to the social attraction of individuals. Researchers such as Ewer have found that social mammals are highly attracted to conspecifics, and that this affiliation behaviour is both powerful and persistent (Ewer 1968; Latane´ 1975; Taylor 1976, 1981). It has also been suggested that for rats, the opportunity to interact with an unrestrained conspecific animal is a powerful reinforcer. Latane´ (1969) demonstrated that social affiliation behaviour in rats increased with repeated encounters, supporting the hypothesis that social affiliation activates reward mechanisms in the brain. In addition, Taylor (1981) found that stressed rats were more highly attracted to other animals than were non-stressed rats, indicating that stressed animals sought to encounter conspecific animals on their own, potentially to ameliorate negative emotions (Davitz & Mason 1955) or to obtain positive neurochemical rewards (Nelson & Panksepp 1998). Human subjects are also more likely to affiliate when under stress (Zucker et al. 1968; Teichman 1974; Morris et al. 1976; Friedman 1981), and a shared stress experience can lead to an increased attraction between partners (Latane´ et al. 1966). Therefore, it is possible that a human affiliation behaviour also activates a neural reward system (Aron et al. 2005). (b) Endocrine findings The first reported evidence of social buffering in nonhuman primates was demonstrated with mother– infant bonding in squirrel monkeys (Coe et al. 1978; Mendoza et al. 1978; Wiener et al. 1987). In those studies, infant monkeys showed an increase in cortisol when separated from their mothers, but if infants were placed in a familiar social environment containing colony members, the plasma cortisol responses were lower after the separation from their mothers. This evidence suggests that a familiar environment, which includes companions, has an ameliorating effect on stress response in infant monkeys. When the researchers conducted different procedures in which adult monkeys were exposed to fear-conditioned stimuli or snakes, they found that multiple companions, rather than a single familiar partner, were effective in stress amelioration after the stress exposure (Coe et al. 1982; Stanton et al. 1985). Based on these findings, research into the effects of social buffering has focused on neuroendocrine responses to a variety of stress episodes and in a variety of social contexts; presently, the neural mechanisms of social buffering are the target of study. 3. SOCIAL BUFFERING/ENDOCRINE EFFECTS (a) Stress–endocrine response An organism’s response to an aversive situation depends not only on the severity and type of stressor, but also on how past experiences and available coping options style its perception of the stressful event. Selye Phil. Trans. R. Soc. B (2006)

is the most recognized name associated with stress response and coping style. He was the first to bring attention to the major role played by adrenocortical hormones in physiological responses to stress (Selye 1956). So far, the observed increase in adrenocortical hormones after stress episodes has been the most widely studied phenomenon and the most dependable index of endocrine response to stress. There is an increase in adrenocortical hormones during psychological challenges (Mason 1968) and as a response to deleterious physical stimuli. The most essential regulating system of adrenocortical hormone secretion is a stress–neuroendocrine axis, called the hypothalamic– pituitary–adrenal (HPA) axis. Three primary hormones are involved in the HPA axis endocrine regulation. One is the corticotrophin-releasing factor (CRF), which is synthesized in the paraventricular nucleus (PVN) of the hypothalamus (Vale et al. 1981), and released into a portal blood vessel. CRF acts on the pituitary and stimulates the adrenocorticotropic hormone (ACTH); it is the major physiological regulator if the increased HPA activity occurs as a response to stress. This has been demonstrated with data showing that the administration of CRF antisera almost completely blocked the pituitary–adrenal responses to a variety of stressors (Rivier & Vale 1983). ACTH travels through the peripheral circulation and stimulates synthesis and secretion of corticosteroids at the adrenal cortex. While ACTH is the major modulator of corticosteroid release, adrenocortical output can be modulated by neuronal inputs that adjust responsiveness to ACTH. The end effects of glucocorticoids’ action include energy mobilization (glycogenolysis) in the liver, suppression of innate immunity in immune organs, inhibition of bone and muscle growth, potentiation of sympathetic nervous system-mediated vasoconstriction, proteolysis and lipolysis, suppression of reproductive function along the HPA axis and behavioural depression (Lombardi et al. 1991; Christensen & Kessing 2001). The wide variety of these effects suggests that glucocorticoids act to restore homeostasis following disruption (Munck et al. 1984). (b) Social buffering on HPA axis Studies investigating the social buffering effects on stress–endocrine activity have focused on the HPA axis. As described above, the first evidence of social buffering in non-human primates was demonstrated in squirrel monkey mother–infant bonding (Coe et al. 1978; Mendoza et al. 1978; Wiener et al. 1987), and Levine later reviewed details of these findings (Levine et al. 1997; Levine 2000, 2001). One simple example of the above phenomenon was that mother monkeys who lived separately from a group showed an increase in cortisol after their infants were removed, but mothers who lived in groups did not (Mendoza et al. 1978). In the paradigm of mother–infant separation, the cortisol response was also observed in infant dyads. However, if the infant monkeys were accompanied by familiar group members in a familiar environment, the cortisol response to separation decreased significantly, indicating that a familiar environment including group members produced social buffering effects in infant monkeys (Levine 2000). Being accompanied by a

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Figure 1. Behavioural and cortisol responses to separation stress of mother- or nursery-reared rhesus monkeys. Data represent behavioural and endocrine responses of nursery-reared (NR, open symbol and bars) and mother-reared monkeys (MR, closed symbol and bars) to a 30 min novel cage test with (pair) and without (single) a familiar social companion. (a) The mean (Gs.e.m.) frequencies of abnormal/repetitive behaviour. (b) The mean (Gs.e.m.) time engaged in social contact behaviour. The plasma levels of cortisol depicted in (c) represent samples collected within 5 min of capture (basal) or after 30 min in a novel cage with and without a social companion. Asterisk represents p!0.05 determined by Mann–Whitney U comparisons. For cortisol, asterisk represents cortisol differences ( p!0.05) between single and paired conditions measured by paired t-test, whereas plus symbol represents differences ( p!0.05) between NR and MR monkeys within condition measured by an independent t-test.

familiar group member has social buffering effects not only with regard to social separation stress, but also to natural threats. For example, exposing group-housed adult monkeys to a live snake, one of the most agitating stimulations for monkeys, induced avoidance behaviour, but did not produce an increase in cortisol response (Coe et al. 1982). Systematic aversive stimulation also increased cortisol levels in squirrel monkeys, and the presence of a familiar partner also decreased the neuroendocrine response to stimuli, as demonstrated by the classical fear-conditioning paradigm (Stanton et al. 1985). In this paradigm, the monkeys were first conditioned with the associations of cue stimuli (lighting) and aversive stimuli (shock). Thereafter, the monkeys were exposed to the cues and demonstrated an increase in cortisol levels. However, if a monkey was with a familiar partner, there was a lesser increase in cortisol production. These data indicate that the presence of social partners ameliorates the neuroendocrine response to various types of stressors. It is worth noting that the size of a social group also modulates the efficacy of social buffering. When the monkeys were exposed to a live snake, they exhibited an increase in cortisol levels, even when accompanied by a partner, suggesting that in this species, a certain amount of social stimuli from group members is required for social buffering. Gust et al. (1993, 1994, 1996) demonstrated social buffering in rhesus monkeys, in which existence of companion ameliorated separation or novelty induced cortisol levels. Contrary to the squirrel monkeys, pair housing was enough to cause a social buffering effect on neuroendocrine responses to novelty stress in rhesus monkeys, as demonstrated by the fact that mother-reared monkeys had a lower cortisol response to a novel environment when accompanied by a partner (Winslow et al. 2003). Phil. Trans. R. Soc. B (2006)

Therefore, there might be differences between species with regard to the effects of group size on social buffering. Winslow et al. (2003) demonstrated that the efficacy of neuroendocrine response with regard to social buffering in a novel environment is modulated by the conditions in which the subject animals were reared (figure 1). In their experiment, mother-reared or human nursery-reared monkeys were subjected to a novel environment with or without a cage mate. The monkeys reared by their mothers exhibited a reduction in cortisol response when a social partner was available, while nursery-reared monkeys did not. Moreover, social contact, such as allogrooming and intermale mounting, was drastically reduced in nursery-reared monkeys. These data suggest that nursery-reared monkeys have lower levels of social communication in a novel environment, which resulted in reduced efficacy with respect to social buffering involving cortisol responses. Rodent models showed similar social buffering results in neuroendocrine responses to stress. If rats were exposed to a novel environment with partner rats, they showed a lower corticosterone response than solitary animals did, which were also exposed to the novel environment (Armario et al. 1983a,b). Studies on monogamous species such as the prairie vole and titi monkey demonstrated that these species showed an increase in corticosterone after the individuals were separated from their bonding partner in a novel environment; when pairs were reunited, corticosterone levels dropped (DeVries 2002). When the rats were exposed in a novel open field, their secretion not only of corticosterone, but also of prolactin, which is released from the pituitary under conditions of stress, decreased (Wilson 2000).

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(c) Social buffering on PVN Stress–endocrine responses are mainly mediated by PVN, which contains CRF neurons. The social buffering effects have been observed as neural activity in PVN, assessed by immediate early gene product c-Fos immunoreactivity (Kiyokawa et al. 2004c). In that experiment, rats were first fear-conditioned to a shock box, then re-exposed to the box with or without a partner. The rats re-exposed to the box showed an increase in freezing and a decrease in activity, as well as an increase in PVN c-Fos immunoreactivity; however, if the rats were accompanied by a partner, c-Fos immunoreactivity decreased in comparison with solitary animals that were also exposed to the box. Similar results were obtained from another study, in which sheep were introduced to a novel environment and researchers measured their mRNA expression level of c-fos and zif268, another immediate early gene, assessed in the PVN (da Costa et al. 2004). Interestingly, visual presentation of pictures of sheep faces was sufficient to induce social buffering in terms of behavioural, endocrine and autonomic responses to stress. These visual stimulations also ameliorated expression levels of c-fos and zif268 mRNA in the PVN, indicating that social buffering effects were mediated at the level of PVN and, as a result, corticosterone decreased. 4. CUES RESPONSIBLE FOR SOCIAL BUFFERING Cues that contain information leading to social buffering are released from partner animals and perceived by receivers. Social cues creating the effect of social buffering are varied among species and experimental contexts. The reason for this is that the tools used to inform animals of another animal’s social or emotional state vary widely; a single species may use several cues to communicate social information to conspecific animals, depending on the circumstances. Therefore, an ethological viewpoint is important when trying to understand the cues responsible for social buffering. (a) Tactile cues In rats, tactile direct contact is an important cue for inducing social buffering. Latane´ (1969) demonstrated that social interaction between a free-moving dyad reduced the novelty-induced fear response, but this was not effective in a caged rat. In juvenile rats, the prolactin response to novelty stress was negatively related to the number of play bouts with a free-moving rat, and this ameliorating effect diminished if the partner was introduced in a cage (Wilson 2001). As described below, oxytocin may be a key mediator of social buffering; release of oxytocin was observed in animals that were subjected to non-noxious tactile stimulations, warm temperature and vibration, all of which are likely to activate somatosensory afferents caused by social contact and grooming (Uvnas-Moberg et al. 1993; Nelson & Panksepp 1998). However, studies have also reported that the amount of social interaction is not correlated with the HPA axis reduction in rats (Cirulli et al. 1996) and guinea pigs (Graves & Hennessy 2000; Hennessy et al. 1995b), implying that not only quantitative, but also qualitative Phil. Trans. R. Soc. B (2006)

social interaction is important in the transmission of social buffering. Social contact/behaviour is also important for transmitting social buffering in rhesus monkeys. As described above, Winslow et al. (2003) conducted an experiment in which mother- and peer-reared monkeys were subjected to a novel environment with or without cage mates. In nursery-reared monkeys, social contact, such as allogrooming and intermale mounting, was drastically reduced, accompanied with a lack of social buffering efficacy. These data suggest that because nursery-reared monkeys have less social contact in a novel environment, social buffering of cortisol reactivity is impaired. This impairment may have profound consequences for the impact of repeated stresses in the life history of these animals. (b) Olfactory cues Recently, studies have examined a comparative spec˚ gren et al. trum of effects induced by olfactory cues. A demonstrated that injecting oxytocin into a rat’s cage mate induced reduction in ACTH and corticosterone, and prolonged withdrawal latency to heat stimuli in the ˚ gren et al. 1997; A ˚ gren & Lundeberg non-treated rat (A 2002). When olfactory cues were removed by nasal lesion in subject rats, this effect disappeared, indicating that social buffering is mediated by chemical cues. In rodents and other species, chemical communication is important for transmitting certain kinds of information, such as information about sex, age, dominant hierarchy, health, kin relationship and emotion. Exposing rats to a pheromone of alarm increases behavioural vigilance, stress-induced hyperthermia and Fos immunoreactivity in the PVN, suggesting that chemical cues can transmit emotional status to conspecific animals (Kikusui et al. 2001; Kiyokawa et al. 2004a,b, 2005b). Moreover, odours from the neck region have ameliorating effects on stress-induced tachycardia in rats, implying that an appeasing pheromone exists (figure 2; Kiyokawa et al. 2005a). In applied animal sciences, there is a commercially available appeasing pheromone, which may have an anti-stress property, for dogs, cats, pigs and horses (Guiraudie et al. 2003; Sheppard & Mills 2003). In pigs, this appeasing pheromone is found on the peripheral region of lactating nipples, and it attracts piglets to the nipples (Morrow-Tesch & McGlone 1990). When used within a group of unfamiliar piglets, it can reduce agonistic behaviour among them (McGlone et al. 1986). Pig appeasing pheromones can also have a positive effect on adult female pigs (Yonezawa et al. in preparation). Studies on humans have shown that maternal breast odour has an attractive property to infants, and it has been shown to elicit positive responses in babies (Porter & Winberg 1999). Therefore, chemical cues may modulate social buffering in some species, including human. (c) Vocal cues Some species use vocal communication to transmit their emotionality and familiarity. South American New World monkey marmosets exhibit a variety of vocal communication. They form heterosexual bonding units for cooperative infant care and, in this situation, they use a ‘voice signature’ for individual

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identification (Sonwdon & Cleveland 1980; Jones et al. 1993). Rukstalis & French (2005) demonstrated that the separation of bonded partners increased urinary cortisol levels, and that hearing a bonding partner’s voice, as compared to an unfamiliar marmoset voice, or to no auditory stimulation, attenuated cortisol levels. Therefore, in species that use voices, vocal buffering may be effective for the communication of emotions and attachment identification. (d) Visual cues When sheep were exposed to a novel pen, the presence of a peer from the same flock reduced corticosteroid secretion. In this species, visible cues are enough to induce social buffering effects. Da Costa et al. (2004) conducted an experiment in which socially isolated sheep were exposed to pictures of faces of familiar sheep, goats or to an artificially reversed triangle. They measured behavioural, autonomic, endocrine and neural responses to the stress of isolation. Sheep exposed to familiar sheep faces showed a decrease in these responses, as compared with other groups of sheep. Visible cues may contain enough information to transmit social buffering signals in sheep, because they use visual information to understand emotionality and familiarity in other sheep (Peirce et al. 2000; Kendrick et al. 2001; Broad et al. 2002). Humans also depend on visual information to communicate emotional status and familiarity (Morton & Johnson 1991; Morris et al. 1996). It is very possible that visual information transmits social buffering signals and stimulates its effects; recent imaging studies have indicated that pictures of the face of a loved one or of one’s own children deactivate the amygdaloid nucleus, which controls fear-related responses (Bartels & Zeki 2000, 2004). Generally, it is a common practice to place pictures of one’s family or a loved one on a desk or shelf, and it is possible that individuals may feel relieved when looking at the pictures after an experience involving stress; this offers some indication that visual information has a social buffering effect in humans. Understanding what kinds of cues are important for social buffering in specific species might be related to Phil. Trans. R. Soc. B (2006)

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understanding how a particular species communicates emotional states and familiarity. If a species uses a number of sensory cues to communicate among themselves, each cue may contribute to the creation of social buffering effects, and when the recipient integrates such information, social buffering effects, therefore, appear. For example, human beings use many sensory cues for communication and, consequently, they need higher cognitive functions to integrate information about individual recognition, familiarity, kin relationship and emotional status. Thus, each type of sensory cue may contribute, in different degrees, to the creation of social buffering effects, but the actual presence of a partner in this communication constitutes the most effective sensory cue.

5. PARTNER’S EFFICACY IN SOCIAL BUFFERING (a) Familiarity of the partner The presence of a conspecific animal is sometimes a stressor and sometimes a stress ameliorating stimulation. The outcome in this situation may depend on the context in which there is a dyad encounter. For example, if a male rat encounters another male rat in his territory, the presence of the other party becomes a stressor for both sides (Miczek 1974, 1979), but if a male rat is accompanied by another male in an anxious and novel situation, the existence of the other party may become a stress ameliorating stimulation. It is important to note that the familiarity of a partner is another factor which can influence what the presence of another party means to a subject. Monogamous male prairie voles show aggressive behaviour when they encounter unrelated subjects, even females (Williams et al. 1992; Winslow et al. 1993a,b). On the other hand, the presence of a bonding partner induces social buffering effects, such as a decline in corticosterone levels (DeVries 2002). Similar results have been obtained in monogamous species, such as the titi monkey (Hennessy et al. 1995a) and the Siberian hamster (Castro & Matt 1997a,b). It may be that efficacy with respect to social buffering depends on the degree of affiliation/attachment between subject and partner. Social attachment can be distinguished from social affiliation; when a social attachment is broken, animals show separation anxiety as well as activation in the HPA axis response, but this is not the case with social affiliation (DeVries 2002). As described previously, the presence of the mother in a squirrel monkey mother–infant dyad was enough to induce social buffering effects in infant monkeys separated from their group. Multiple familiar (not mother) adult monkeys were needed to create the same effect. This implies that a bonded partner is more effective in inducing social buffering (Coe et al. 1982; Stanton et al. 1985). Partner familiarity has also been observed to influence social buffering effects in rodents. In rats and guinea pigs, a familiar partner was more effective with respect to social buffering as far as behavioural and endocrine responses to stress were concerned (Terranova et al. 1999; Graves & Hennessy 2000; Hennessy et al. 2000, 2002); however, a number of controversial studies have reported that an unfamiliar partner is more effective (Armario et al. 1983a,b), or

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that familiarity had no effect (Cirulli et al. 1996). Since the presence of a conspecific animal can induce aggression, dominant–subordinate relationships, sexual interaction, play behaviour, and so on, it is important to understand the kinds of subject involved, i.e. their sex, age, species, social history, and how familiar animals have been housed, as well as the kind of context the dyad is exposed to during the stress experience. In guinea pigs, the presence of a mother reduces HPA activation during either pre- or post-weaning, not only in the period of infancy, but also in the periadolescent period (Graves & Hennessy 2000). A reduction in HPA activity was also observed when young guinea pigs were accompanied by another female guinea pig, but not by males (Graves & Hennessy 2000). In terms of persistence of the ability, it is also important to note that the biological mother was more effective than an unrelated female guinea pig (Hennessy et al. 2002), indicating that kin relationships also influence the efficacy of social buffering. The persistent ability of biological mothers to reduce HPA activity in their offspring has also been found in squirrel and titi monkeys (Hennessy et al. 1995a). When these species are observed in the wild, weaned infant monkeys continue to follow their mothers; therefore, in these species, a weak bond may continue to exist between mother and infant after weaning. (b) Emotional status of the partner Recent studies have demonstrated that emotional status is also important to the efficacy of social buffering (Kiyokawa et al. 2004c). We used the classical fearconditioning paradigm; subject rats were conditioned by an association of contextual cues (exposure to a shock box) and aversive stimuli (foot-shocks). One day after the conditioning day, the subjects were re-exposed to the shock box with either a previously shocked partner that had also been fear-conditioned or a nonshocked partner. We examined behavioural, autonomic and c-Fos expression in the PVN in response to exposure to the shock box. As expected, being accompanied by a partner decreased the stress-related response, but if the subjects were re-exposed with a non-shocked partner, stress responses of behavioural, autonomic and Fos expression decreased even more, suggesting that the emotional status of a partner affects the efficacy of social buffering. Davitz & Mason (1955) demonstrated similar results in rats; fearful withdrawal in an open field diminished when rats were accompanied by another rat. In their experiments, fearconditioned rats displayed less locomotor activity when they were exposed to the conditioned stimuli in a novel open field, but the presence of another non-fearful rat increased their locomotor activity, and fear-conditioned rats showed higher affiliation behaviour towards other rats. It is worth noting that if a subject was accompanied by a fearful rat which had been fearconditioned in the same way, social buffering efficacy was diminished, suggesting that the emotional status of a partner is also important for efficacy in social buffering. As mentioned previously, tactile stimulation during social interaction seems to be the most important cue for transmitting social buffering in rats Phil. Trans. R. Soc. B (2006)

(Latane´ 1969), hence we measured social interaction behaviour between the subject and the non-shocked or shocked partner. However, there was no obvious difference in terms of amicable social behaviour between a non-shocked and a shocked partner. There may be other cues that are responsible for transmitting a partner’s emotional status. 6. NEURAL MECHANISMS OF SOCIAL BUFFERING Several studies have focused on how information is processed in a receiver’s central nervous system. As described above, tools for transmitting the effects of social buffering vary widely, meaning that various sensory systems receiving the information are involved in processing social buffering, and that sensory processing differs between species and experimental contexts. A number of studies suggest that social buffering has positive effects on health and stress responses, but little is known about the physiological and the neurochemical mechanisms through which positive social interactions suppress corticosteroids (Cohen 1988; Uchino et al. 1996; DeVries et al. 2003). (a) Oxytocin Neuropeptide oxytocin has been a candidate molecule for transmission of social buffering information (figure 3). Oxytocin plays a major neuroendocrine role, modulating diverse physiological functions, such as parturition and lactation in mammals (for a review, see Ludwig 1998; Russell & Leng 1998). During physiological and psychological stress responses, oxytocinergic neurons are activated, particularly in the paraventricular nucleus of the hypothalamus and secreted into the circulating blood (Ludwig 1998; Neumann 2002; Onaka 2004). Increase in oxytocin release from the hypothalamus inhibits HPA axis activation (Neumann et al. 2000; Neumann 2002; DeVries et al. 2003). Most natural observation about HPA axis suppression due to oxytocin has been conducted in lactating animals (Walker et al. 1995; Windle et al. 1997b; Neumann et al. 1998); nipple stimulation increases oxytocin levels peripherally and centrally, and it is accompanied by a decrease in cortisol levels (Chiodera et al. 1991; Amico et al. 1994). In humans, one study showed that breastfeeding after physical exercise attenuated an increase in cortisol as well as ACTH in the blood (Altemus et al. 1995). In rats, lactation blunted HPA activity in response to several stressors, including noise (Windle et al. 1997b), forced swim (Walker et al. 1995), exposure to cold (Adels et al. 1986) and lipopolysaccharide injection (Shanks et al. 1999). Oxytocin’s ability to inhibit HPA axis can be mediated through three different levels. First, peripheral oxytocin acts on the adrenal gland to inhibit corticosteroid secretion. Legros et al. (1987, 1988) demonstrated that human males treated with exogenous oxytocin followed by synthetic ACTH showed a blunted response in cortisol secretion, suggesting that exogenous oxytocin inhibits corticosteroid synthesis in the adrenal gland. Second, Neumann et al. (1998) demonstrated that peripheral oxytocin inhibits ACHT release from the pituitary

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CORT endocrine responses Figure 3. Schematic putative mechanisms of social buffering. Sensory cues, such as tactile, visual, olfactory and auditory ones, are transmitted from the senders to the receivers, which contains individual and emotional information. These information are integrated and transmitted to the amygdala. Oxytocin (OXY) release in the amygdala increases by social buffering cues, and they modulate behavioural responses to the stressors. Amygdaloid OXY has a positive effect on dopamine (DA) transmission in the nucleus acumens, which is essential for social bonding. In addition, increase of OXY occurs in the hypothalamus, which is responsible for amelioration of stress neuroendocrine responses. Opioids (OPD) also have a modulating role in social buffering, reducing CRF activity in the PVN, and analgesia was found in socially stimulated animals.

gland. They injected exogenous CRF into lactating rats and measured ACTH responses, finding a reduction in ACTH response. Third, central oxytocin has inhibitory effects on the hypothalamic CRF activation. For example, intracerebroventricular injection of synthetic oxytocin decreased CRF mRNA responses to physical stress (Windle et al. 1997a, 2004; Carter 1998), and lactating female rats showed a similar decrease in CRF mRNA expression in response to stressors (da Costa et al. 2001). Studies have documented that in humans, the inhibitory property of exogenous oxytocin is mediated through the pituitary and adrenal glands (Legros et al. 1988; Chiodera et al. 1991), but recent articles have shown that intranasal administration of oxytocin, which passed directly into the brain (Born et al. 2002), suppressed cortisol response to psychological stress, as well as attenuated emotional functions after stress episodes (Heinrichs et al. 2003). Therefore, in humans, the inhibitory effect of oxytocin on HPA activity is also mediated in the central nervous system. Oxytocin also causes a behavioural modification to stress response. In rodent models, it has been demonstrated that oxytocin has anxiolytic properties, as well as a significant role in the style of stress coping (Neumann 2002; Ebner et al. 2005), especially through modulating the central nucleus of the amygdala. Along with its stress-ameliorating effects, oxytocin seems to be involved in the social bond/affiliation behaviour of some mammalian species (Insel 1992, 1997; Winslow et al. 1993b; Young 2002; Young et al. 2002). Genetically manipulated mice lacking oxytocin exhibited the defect of social amnesia, whereas other reproductive behaviours were normal in both males and females (Ferguson et al. 2000, 2002; Winslow & Insel 2002, 2004). Oxytocin concentration in cerebrospinal fluid is positively correlated with social behaviour in rats (Haller et al. 1996). Moreover, recent findings suggest that central oxytocin is released in Phil. Trans. R. Soc. B (2006)

response to physical contact (Uvnas-Moberg 1997) and induces excessive grooming when injected into the brain (Pedersen et al. 1988). In an experiment on rhesus monkeys, sociality was one of the main ways that information about social buffering was transmitted ( Winslow et al. 2003). In that study, researchers assessed neuropeptide levels in cerebrospinal fluid and found that central oxytocin levels were lower in nursery-reared monkeys. Heinrichs et al. (2003) demonstrated that in humans, intranasal administration of oxytocin reduced anxiety levels, measured with the Trier Social Stress Test. Taken together, these results indicate that oxytocin attenuates not only the HPA axis response to stress, but also reduces negative emotions by increasing social affiliation behaviour. A recent study from Rilling et al. (2001) suggests that activation of the left dorsolateral portion of the prefrontal cortex may contribute to social buffering of stress-induced cortisol release in non-human primates. These findings are consistent with present models of the contributions of frontocortical structures to the processing of emotional stimuli by the amygdala (Davidson 2002). (b) Opioids The opioid system plays an essential role in the neural mechanisms of social attachment. Symptoms of opioid addiction may share similar properties with social attachment; both involve high levels of dependence, and withdrawal of stimuli induces agitation and anxiety behaviours (Panksepp et al. 1978, 1980). Several lines of investigation have been conducted, and it appears that opioids have ameliorating effects on separationinduced anxiety behaviour (Panksepp et al. 1978, 1980; Billington et al. 1990), and that social contact and interaction stimulate the release of opioids (Panksepp & Bishop 1981; Nelson & Panksepp 1998). Specifically, rat pups exhibited an increase in opioids when they were in

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physical contact with their mothers (Carden & Hofer 1990a,b; for an opposing view, see Winslow & Insel 1991), and b-endorphin levels in monkeys increased after social grooming (Keverne et al. 1989). Recently, it was demonstrated that m-opioid receptor knockout mouse pups did not show attachment behaviour to their mothers, as assessed by ultrasonic vocalization (Moles et al. 2004). In adult mice, social contact induced analgesia, while this effect was blocked by administration of an opioid antagonist (D’Amato & Castellano 1989; D’Amato & Pavone 1996). Interestingly, the analgesia induced in mice by social contact was modulated by the familiarity of the partner; sib-pair mice showed higher analgesic symptoms than unrelated mice pairs (D’Amato 1997, 1998). These results indicate that greater social recognition is involved in analgesia induced by social contact, which is very similar to the transmission of social buffering effects. The neural opioid system has a strong rewarding effect, and this would explain why social animals are very attracted to conspecific animals (Ewer 1968; Latane´ 1975; Taylor 1976, 1981) and seek affiliation behaviour, resulting in the reduction of stress-related outputs. (c) Interactions of oxytocin and opioids As described above, social affiliation behaviour has a rewarding effect; that is, social animals seek affiliation behaviour, and experience of this behaviour enhances the motivation for seeking it. These results indicate that social affiliation and attachment have a natural rewarding property; indeed, as Insel (1997) has claimed, ‘Love is addiction’. Social bonding/attachment is the key factor in social buffering; when a social dyad establishes attachment, as in a mother–infant and pair bonding, they show an increase in HPA activity when separated. However, the partner’s presence ameliorates stress neuroendocrine responses (DeVries 2002). Therefore, it is very possible that the neural mechanisms in social attachment are also involved in modulating social buffering. The neurobiology of social attachment has been reviewed extensively elsewhere, especially with regard to prairie voles (Insel et al. 1997; Young et al. 2001; Wang & Aragona 2004) and sheep (Kendrick et al. 1997; Kendrick 2004), hence only the main findings are mentioned here. Researchers have reported that establishing social attachment is involved in a neural reward system, such as dopamine and opioid systems (Nelson & Panksepp 1998; Young & Wang 2004). These two systems and the oxytocin system communicate with each other. Specifically, social stimulations such as mating and nipple suckling are key stimuli for establishing social attachments (Insel 1997; Insel et al. 1997; Carter 1998; Young et al. 2001; Kendrick 2004). These stimulations increase oxytocin release in mesocorticolimbic pathways; blocking the oxytocin neurotransmission abolished social attachment, indicating that an oxytocin pathway is indispensable for attachment (Insel et al. 1997; Kendrick 2004; Wang & Aragona 2004; Young & Wang 2004). Oxytocin neurotransmission amplified the mesolimbic dopamine system ( Wang & Aragona 2004; Young & Wang 2004), suggesting that the reunion with a bonded partner after separation Phil. Trans. R. Soc. B (2006)

increases dopamine transmission and reinforces social affiliation behaviours. The release of opiate peptides is stimulated by oxytocin neurotransmission. Classical studies have demonstrated that chronic oxytocin treatment induced not only anti-stress effects, but also analgesia (Uvnas-Moberg et al. 1993); this analgesia effect was blocked by the opioid antagonist naloxone (UvnasMoberg 1997; Uvnas-Moberg et al. 1993), but not by an oxytocin antagonist, indicating that oxytocin increases endogenous opioid transmission. In both rats and humans, it was observed that lactating females showed analgesic symptoms in response to mechanical stimuli (Uvnas-Moberg 1996; Uvnas-Moberg & Eriksson 1996). Lim et al. (2004) also demonstrated that in prairie voles, local infusion of oxytocin increased preproenkephalin in the nucleus accumbens, suggesting that increase in oxytocin transmission activates neural rewarding systems and, as a result, established pair bonding. This increase of the endogenous opioid system via oxytocin may be the key mediator by which virgin females showed maternal ‘sensitizing’ behaviour with repeated exposure of neonate to the nipples. A lesion in the PVN, in which a large number of oxytocin neurons are present, results in diminished analgesia (Truesdell & Bodnar 1987), and descending oxytocin-containing fibres are projected to the spinal cord’s dorsal horn (Robinson et al. 2002), an area important for processing nociceptive inputs. Other reports showed that effects of oxytocin on the HPA axis might be mediated via an opioid-dependent pathway, because pretreatment with an opioid antagonist abolished oxytocin effects on corticosteroid concentration (Douglas et al. 1998; Douglas & Russell 2001). Therefore, there may be complex communication between the oxytocin and the opioid systems, which is in turn involved in the neural mechanisms of social buffering.

7. CLINICAL ASPECTS Studies on human subjects have demonstrated that social support significantly affects cortisol secretion (Kirschbaum et al. 1995) and cardiovascular and blood pressure responses to stress in laboratory settings (Gerin et al. 1992; Lepore et al. 1993; Uchino et al. 1996), and that it decreases the risk of cardiovascular diseases in clinical situations (Spitzer et al. 1992; Uchino et al. 1996; Gallo et al. 2000; Steptoe 2000; Uno et al. 2002). A positive social interaction/support has profound physical effects not only in human subjects, but also in laboratory animals. In many species, stress-induced hyperthermia and tachycardia are symptoms known to be associated with psychological stress. If the subject animals such as rats and sheep under stressful conditions are accompanied by a partner or social cues, these autonomic responses are ameliorated (da Costa et al. 2004; Kiyokawa et al. 2004c). In addition, social support can have positive effects on the risk of depression (Hays et al. 2001; Sayal et al. 2002), suicide (Rubenstein et al. 1998; Greening & Stoppelbein 2002), schizophrenia (Buchanan 1995; Erickson et al. 1998) and even stroke (Wyller et al. 1998). Several clinical studies have shown that periischaemic concentrations of corticosteroids can

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Social buffering augment brain injury (Koide et al. 1986; House et al. 1990; DeVries et al. 2001); a high concentration of corticosteroids may inhibit neuron ability to recover from damage. Positive social interaction can partially ameliorate cognitive and histological damage induced by experimental stroke in rodents (Hattori et al. 2000), and exogenous manipulations of corticosteroids levels have modulated social buffering effects on stroke symptoms (Sapolsky & Pulsinelli 1985). Decline in the HPA axis response to stress due to social support has other effects on physical functions. Wounds of socially supported patients healed faster than did wounds in non-supported patients (Rojas et al. 2002); this is mediated by adrenocortical hormones, and similar results have been obtained in experiments on animals (Detillion et al. 2004). In humans, the absolute number of T-cell subsets recovered more quickly with social support than when a solitary patient was exposed to a novel environment (Mohr & Genain 2004). It has been reported that diseases that respond to peripheral cortisol levels, such as cancer (Turner-Cobb et al. 2000; Spiegel & Sephton 2001; Miller et al. 2002), asthma (Buske-Kirschbaum et al. 2003) and infections (Cohen et al. 1997; Leserman et al. 2000; van Reenen et al. 2000) heal better in socially supported patients. Positive social relationships also increase oxytocin levels in humans (Heinrichs et al. 2003), and a high level of oxytocin induces long-term reduction in blood pressure and heart rate, as well as somatic growth (Uvnas-Moberg 1998). On the other hand, social stress and isolation are important factors in the aetiology of these diseases. Socially supported human subjects might consider the anticipated acute stressor as less threatening and more controllable than would an unsupported subject (Kirschbaum et al. 1995). Social support also affects foetuses. Morris et al. (1973) demonstrated that babies born from socially supported women had greater body weight than did babies from unsupported women. Social environments and relationships have opposite effects, mentally and physiologically: they sometimes cause negative symptoms, and are sometimes positive influences. It cannot be said that social union is always a good influence on human health, so an understanding of what kinds of relationships are positive or negative is critically important. Investigating the entire social buffering mechanisms, using animal models, could allow us to find a new approach to improving the quality of life.

REFERENCES Adels, L. E., Leon, M., Wiener, S. G. & Smith, M. S. 1986 Endocrine response to acute cold exposure by lactating and non-lactating Norway rats. Physiol. Behav. 36, 179–181. (doi:10.1016/0031-9384(86)90093-4) ˚ gren, G. & Lundeberg, T. 2002 Social stress blocks energy A conservation in rats exposed to an oxytocin-injected cagemate. Neuroreport 13, 1415–1419. ˚ gren, G., Uvnas-Moberg, K. & Lundeberg, T. 1997 A Olfactory cues from an oxytocin-injected male rat can induce anti-nociception in its cagemates. Neuroreport 8, 3073–3076. Altemus, M., Deuster, P. A., Galliven, E., Carter, C. S. & Gold, P. W. 1995 Suppression of hypothalmic–pituitary– Phil. Trans. R. Soc. B (2006)

T. Kikusui and others 2223

adrenal axis responses to stress in lactating women. J. Clin. Endocrinol. Metab. 80, 2954–2959. (doi:10.1210/jc.80.10. 2954) Amico, J. A., Johnston, J. M. & Vagnucci, A. H. 1994 Suckling-induced attenuation of plasma cortisol concentrations in postpartum lactating women. Endocr. Res. 20, 79–87. Armario, A., Luna, G. & Balasch, J. 1983a The effect of conspecifics on corticoadrenal response of rats to a novel environment. Behav. Neural Biol. 37, 332–337. (doi:10.1016/S0163-1047(83)91425-5) Armario, A., Ortiz, R. & Balasch, J. 1983b Corticoadrenal and behavioral-response to open-field in pairs of male rats either familiar or non-familiar to each other. Experientia 39, 1316–1317. (doi:10.1007/BF01990391) Aron, A., Fisher, H., Mashek, D. J., Strong, G., Li, H. & Brown, L. L. 2005 Reward, motivation, and emotion systems associated with early-stage intense romantic love. J. Neurophysiol. 94, 327–337. (doi:10.1152/jn.00838.2004) Bartels, A. & Zeki, S. 2000 The neural basis of romantic love. Neuroreport 11, 3829–3834. Bartels, A. & Zeki, S. 2004 The neural correlates of maternal and romantic love. Neuroimage 21, 1155–1166. (doi:10. 1016/j.neuroimage.2003.11.003) Billington, C. J., Herman, B. H., Bartness, T. J., Levine, A. S. & Morley, J. E. 1990 Effects of the opiate antagonists diprenorphine and naloxone and of selected opiate agonists on feeding behavior in guinea pigs. Life Sci. 46, 147–154. (doi:10.1016/00243205(90)90047-U) Born, J., Lange, T., Kern, W., McGregor, G. P., Bickel, U. & Fehm, H. L. 2002 Sniffing neuropeptides: a transnasal approach to the human brain. Nat. Neurosci. 5, 514–516. (doi:10.1038/nn849) Broad, K. D., Mimmack, M. L., Keverne, E. B. & Kendrick, K. M. 2002 Increased BDNF and trk-B mRNA expression in cortical and limbic regions following formation of a social recognition memory. Eur. J. Neurosci. 16, 2166–2174. (doi:10.1046/j.1460-9568.2002.02311.x) Buchanan, J. 1995 Social support and schizophrenia: a review of the literature. Arch. Psychiatry Nurs. 9, 68–76. (doi:10. 1016/S0883-9417(95)80003-4) Buske-Kirschbaum, A., von Auer, K., Krieger, S., Weis, S., Rauh, W. & Hellhammer, D. 2003 Blunted cortisol responses to psychosocial stress in asthmatic children: a general feature of atopic disease? Psychosom. Med. 65, 806–810. (doi:10.1097/01.PSY.0000095916.25975.4F) Buwalda, B., Kole, M. H., Veenema, A. H., Huininga, M., de Boer, S. F., Korte, S. M. & Koolhaas, J. M. 2005 Longterm effects of social stress on brain and behavior: a focus on hippocampal functioning. Neurosci. Biobehav. Rev. 29, 83–97. (doi:10.1016/j.neubiorev.2004.05.005) Carden, S. E. & Hofer, M. A. 1990a The effects of opioid and benzodiazepine antagonists on dam-induced reductions in rat pup isolation distress. Dev. Psychobiol. 23, 797–808. (doi:10.1002/dev.420230804) Carden, S. E. & Hofer, M. A. 1990b Independence of benzodiazepine and opiate action in the suppression of isolation distress in rat pups. Behav. Neurosci. 104, 160–166. (doi:10.1037/0735-7044.104.1.160) Carter, C. S. 1998 Neuroendocrine perspectives on social attachment and love. Psychoneuroendocrinology 23, 779–818. (doi:10.1016/S0306-4530(98)00055-9) Castro, W. L. & Matt, K. S. 1997a The importance of social condition in the hormonal and behavioral responses to an acute social stressor in the male Siberian dwarf hamster (Phodopus sungorus). Horm. Behav. 32, 209–216. (doi:10. 1006/hbeh.1997.1423)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2224

T. Kikusui and others Social buffering

Castro, W. L. & Matt, K. S. 1997b Neuroendocrine correlates of separation stress in the Siberian dwarf hamster (Phodopus sungorus). Physiol. Behav. 61, 477–484. (doi:10.1016/S0031-9384(96)00456-8) Chiodera, P., Salvarani, C., Bacchi-Modena, A., Spallanzani, R., Cigarini, C., Alboni, A., Gardini, E. & Coiro, V. 1991 Relationship between plasma profiles of oxytocin and adrenocorticotropic hormone during suckling or breast stimulation in women. Horm. Res. 35, 119–123. Christensen, M. V. & Kessing, L. V. 2001 The hypothalamo– pituitary–adrenal axis in major affective disorder: a review. Nord. J. Psychiatry 55, 359–363. (doi:10.1080/ 080394801317080873) Cirulli, F., Terranova, M. L. & Laviola, G. 1996 Affiliation in periadolescent rats: behavioral and corticosterone response to social reunion with familiar or unfamiliar partners. Pharmacol. Biochem. Behav. 54, 99–105. (doi:10. 1016/0091-3057(95)02169-8) Clancy, H. & McBride, G. 1975 The isolation syndrome in childhood. Dev. Med. Child Neurol. 17, 198–219. Cobb, S. 1976 Presidential address-1976. Social support as a moderator of life stress. Psychosom. Med. 38, 300–314. Coe, C. L., Mendoza, S. P., Smotherman, W. P. & Levine, S. 1978 Mother–infant attachment in the squirrel monkey: adrenal response to separation. Behav. Biol. 22, 256–263. (doi:10.1016/S0091-6773(78)92305-2) Coe, C. L., Franklin, D., Smith, E. R. & Levine, S. 1982 Hormonal responses accompanying fear and agitation in the squirrel monkey. Physiol. Behav. 29, 1051–1057. (doi:10.1016/0031-9384(82)90297-9) Cohen, S. 1988 Psychosocial models of the role of social support in the etiology of physical disease. Health Psychol. 7, 269–297. (doi:10.1037/0278-6133.7.3.269) Cohen, S., Line, S., Manuck, S. B., Rabin, B. S., Heise, E. R. & Kaplan, J. R. 1997 Chronic social stress, social status, and susceptibility to upper respiratory infections in nonhuman primates. Psychosom. Med. 59, 213–221. da Costa, A. P., Leigh, A. E., Man, M. S. & Kendrick, K. M. 2004 Face pictures reduce behavioural, autonomic, endocrine and neural indices of stress and fear in sheep. Proc. R. Soc. B 271, 2077–2084. (doi:10.1098/rspb.2004.2831) da Costa, A. P., Ma, X., Ingram, C. D., Lightman, S. L. & Aguilera, G. 2001 Hypothalamic and amygdaloid corticotropin-releasing hormone (CRH) and CRH receptor-1 mRNA expression in the stress-hyporesponsive late pregnant and early lactating rat. Brain Res. Mol. Brain Res. 91, 119–130. (doi:10.1016/S0169-328X(01)00137-1) D’Amato, F. R. 1997 Neurobiological and behavioral aspects of recognition in female mice. Physiol. Behav. 62, 1311–1317. (doi:10.1016/S0031-9384(97)00343-0) D’Amato, F. R. 1998 Kin interaction enhances morphine analgesia in male mice. Behav. Pharmacol. 9, 369–373. D’Amato, F. R. & Castellano, C. 1989 Behavioral effects of morphine in mice: role of experimental housing. Pharmacol. Biochem. Behav. 34, 361–365. (doi:10.1016/00913057(89)90327-4) D’Amato, F. R. & Pavone, F. 1996 Reunion of separated sibling mice: neurobiological and behavioral aspects. Neurobiol. Learn. Mem. 65, 9–16. (doi:10.1006/nlme. 1996.0002) Davidson, R. J. 2002 Anxiety and affective style: role of prefrontal cortex and amygdala. Biol. Psychiatry 51, 68–80. (doi:10.1016/S0006-3223(01)01328-2) Davitz, J. & Mason, D. J. 1955 Socially facilitated reduction of fear response in rats. J. Comp. Physiol. Psychol. 47, 941–947. Detillion, C. E., Craft, T. K., Glasper, E. R., Prendergast, B. J. & DeVries, A. C. 2004 Social facilitation of wound healing. Psychoneuroendocrinology 29, 1004–1011. (doi:10. 1016/j.psyneuen.2003.10.003) Phil. Trans. R. Soc. B (2006)

DeVries, A. C. 2002 Interaction among social environment, the hypothalamic–pituitary–adrenal axis, and behavior. Horm. Behav. 41, 405–413. (doi:10.1006/hbeh.2002.1780) DeVries, A. C., Joh, H. D., Bernard, O., Hattori, K., Hurn, P. D., Traystman, R. J. & Alkayed, N. J. 2001 Social stress exacerbates stroke outcome by suppressing Bcl-2 expression. Proc. Natl Acad. Sci. USA 98, 11 824–11 828. (doi:10.1073/pnas.201215298) DeVries, A. C., Glasper, E. R. & Detillion, C. E. 2003 Social modulation of stress responses. Physiol. Behav. 79, 399–407. (doi:10.1016/S0031-9384(03)00152-5) Douglas, A. J. & Russell, J. A. 2001 Endogenous opioid regulation of oxytocin and ACTH secretion during pregnancy and parturition. Prog. Brain Res. 133, 67–82. Douglas, A. J., Johnstone, H. A., Wigger, A., Landgraf, R., Russell, J. A. & Neumann, I. D. 1998 The role of endogenous opioids in neurohypophysial and hypothalamo–pituitary–adrenal axis hormone secretory responses to stress in pregnant rats. J. Endocrinol. 158, 285–293. (doi:10.1677/joe.0.1580285) Ebner, K., Bosch, O. J., Kromer, S. A., Singewald, N. & Neumann, I. D. 2005 Release of oxytocin in the rat central amygdala modulates stress-coping behavior and the release of excitatory amino acids. Neuropsychopharmacology 30, 223–230. (doi:10.1038/sj.npp.1300607) Ell, K. 1996 Social networks, social support and coping with serious illness: the family connection. Soc. Sci. Med. 42, 173–183. (doi:10.1016/0277-9536(95)00100-X) Erickson, D. H., Beiser, M. & Iacono, W. G. 1998 Social support predicts 5-year outcome in first-episode schizophrenia. J. Abnorm. Psychol. 107, 681–685. (doi:10.1037/ 0021-843X.107.4.681) Ewer, R. F. 1968 Ethology of mammals. New York, NY: Plenum Press. Ferguson, J. N., Young, L. J., Hearn, E. F., Matzuk, M. M., Insel, T. R. & Winslow, J. T. 2000 Social amnesia in mice lacking the oxytocin gene. Nat. Genet. 25, 284–288. (doi:10.1038/77040) Ferguson, J. N., Young, L. J. & Insel, T. R. 2002 The neuroendocrine basis of social recognition. Front. Neuroendocrinol. 23, 200–224. (doi:10.1006/frne.2002. 0229) Friedman, L. 1981 How affiliation affects stress in fear and anxiety situations. J. Pers. Soc. Psychol. 40, 1102–1117. (doi:10.1037/0022-3514.40.6.1102) Gallo, L. C., Smith, T. W. & Kircher, J. C. 2000 Cardiovascular and electrodermal responses to support and provocation: interpersonal methods in the study of psychophysiological reactivity. Psychophysiology 37, 289–301. (doi:10.1017/S0048577200982222) Gerin, W., Pieper, C., Levy, R. & Pickering, T. G. 1992 Social support in social interaction: a moderator of cardiovascular reactivity. Psychosom. Med. 54, 324–336. Graves, F. C. & Hennessy, M. B. 2000 Comparison of the effects of the mother and an unfamiliar adult female on cortisol and behavioral responses of pre- and postweaning guinea pigs. Dev. Psychobiol. 36, 91–100. (doi:10.1002/(SICI)10982302(200003)36:2!91::AID-DEV1O3.0.CO;2-1) Greening, L. & Stoppelbein, L. 2002 Religiosity, attributional style, and social support as psychosocial buffers for African American and white adolescents’ perceived risk for suicide. Suicide Life Threat Behav. 32, 404–417. (doi:10. 1521/suli.32.4.404.22333) Guiraudie, G., Pageat, P., Cain, A. H., Madec, I. & Meillour, P. N. 2003 Functional characterization of olfactory binding proteins for appeasing compounds and molecular cloning in the vomeronasal organ of pre-pubertal pigs. Chem. Senses 28, 609–619. (doi:10.1093/chemse/bjg052) Gust, D. A., Gordon, T. P., Hambright, M. K. & Wilson, M. E. 1993 Relationship between social factors and

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Social buffering pituitary–adrenocortical activity in female rhesus monkeys (Macaca mulatta). Horm. Behav. 27, 318–331. (doi:10. 1006/hbeh.1993.1024) Gust, D. A., Gordon, T. P., Brodie, A. R. & McClure, H. M. 1994 Effect of a preferred companion in modulating stress in adult female rhesus monkeys. Physiol. Behav. 55, 681–684. (doi:10.1016/0031-9384(94)90044-2) Gust, D. A., Gordon, T. P., Brodie, A. R. & McClure, H. M. 1996 Effect of companions in modulating stress associated with new group formation in juvenile rhesus macaques. Physiol. Behav. 59, 941–945. (doi:10.1016/0031-9384(95) 02164-7) Haller, J., Makara, G. B., Barna, I., Kovacs, K., Nagy, J. & Vecsernyes, M. 1996 Compression of the pituitary stalk elicits chronic increases in CSF vasopressin, oxytocin as well as in social investigation and aggressiveness. J. Neuroendocrinol. 8, 361–365. (doi:10.1046/j.13652826.1996.04654.x) Hatch, A. M., Wiberg, G. S., Zawidzka, Z., Cann, M., Airth, J. M. & Grice, H. C. 1965 Isolation syndrome in the rat. Toxicol. Appl. Pharmacol. 7, 737–745. (doi:10.1016/0041008X(65)90132-8) Hattori, K., Lee, H., Hurn, P. D., Crain, B. J., Traystman, R. J. & DeVries, A. C. 2000 Cognitive deficits after focal cerebral ischemia in mice. Stroke 31, 1939–1944. Hays, J. C., Steffens, D. C., Flint, E. P., Bosworth, H. B. & George, L. K. 2001 Does social support buffer functional decline in elderly patients with unipolar depression? Am. J. Psychiatry 158, 1850–1855. (doi:10.1176/appi.ajp.158. 11.1850) Heinrichs, M., Baumgartner, T., Kirschbaum, C. & Ehlert, U. 2003 Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol. Psychiatry 54, 1389–1398. (doi:10.1016/S00063223(03)00465-7) Hennessy, M. B., Mendoza, S. P., Mason, W. A. & Moberg, G. P. 1995a Endocrine sensitivity to novelty in squirrel monkeys and titi monkeys: species differences in characteristic modes of responding to the environment. Physiol. Behav. 57, 331–338. (doi:10.1016/0031-9384(94)00250-9) Hennessy, M. B., Nigh, C. K., Sims, M. L. & Long, S. J. 1995b Plasma cortisol and vocalization responses of postweaning age guinea pigs to maternal and sibling separation: evidence for filial attachment after weaning. Dev. Psychobiol. 28, 103–115. (doi:10.1002/dev.420280204) Hennessy, M. B., Maken, D. S. & Graves, F. C. 2000 Consequences of the presence of the mother or unfamiliar adult female on cortisol, ACTH, testosterone and behavioral responses of periadolescent guinea pigs during exposure to novelty. Psychoneuroendocrinology 25, 619–632. (doi:10.1016/S0306-4530(00)00014-7) Hennessy, M. B., O’Leary, S. K., Hawke, J. L. & Wilson, S. E. 2002 Social influences on cortisol and behavioral responses of preweaning, periadolescent, and adult guinea pigs. Physiol. Behav. 76, 305–314. (doi:10.1016/S00319384(02)00712-6) House, A., Dennis, M., Mogridge, L., Hawton, K. & Warlow, C. 1990 Life events and difficulties preceding stroke. J. Neurol. Neurosurg. Psychiatry 53, 1024–1028. Insel, T. R. 1992 Oxytocin—a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies. Psychoneuroendocrinology 17, 3–35. (doi:10.1016/0306-4530(92)90073-G) Insel, T. R. 1997 A neurobiological basis of social attachment. Am. J. Psychiatry 154, 726–735. Insel, T. R., Young, L. & Wang, Z. 1997 Molecular aspects of monogamy. Ann. NY Acad. Sci. 807, 302–316. Phil. Trans. R. Soc. B (2006)

T. Kikusui and others 2225

Jones, B., Harris, D. & Catchpole, C. 1993 The stability of the vocal signature in phee calls of the common marmoset Callithrix jacchus. Am. J. Primatol. 31, 67–75. (doi:10. 1002/ajp.1350310107) Kendrick, K. M. 2004 The neurobiology of social bonds. J. Neuroendocrinol. 16, 1007–1008. (doi:10.1111/j.13652826.2004.01262.x) Kendrick, K. M., Da Costa, A. P., Broad, K. D., Ohkura, S., Guevara, R., Levy, F. & Keverne, E. B. 1997 Neural control of maternal behaviour and olfactory recognition of offspring. Brain Res. Bull. 44, 383–395. (doi:10.1016/ S0361-9230(97)00218-9) Kendrick, K. M., da Costa, A. P., Leigh, A. E., Hinton, M. R. & Peirce, J. W. 2001 Sheep don’t forget a face. Nature 414, 165–166. (doi:10.1038/35102669) Keverne, E. B., Martensz, N. D. & Tuite, B. 1989 Betaendorphin concentrations in cerebrospinal fluid of monkeys are influenced by grooming relationships. Psychoneuroendocrinology 14, 155–161. (doi:10.1016/0306-4530(89) 90065-6) Kikusui, T., Takigami, S., Takeuchi, Y. & Mori, Y. 2001 Alarm pheromone enhances stress-induced hyperthermia in rats. Physiol. Behav. 72, 45–50. (doi:10.1016/S00319384(00)00370-X) Kirschbaum, C., Klauer, T., Filipp, S. H. & Hellhammer, D. H. 1995 Sex-specific effects of social support on cortisol and subjective responses to acute psychological stress. Psychosom Med. 57, 23–31. Kiyokawa, Y., Kikusui, T., Takeuchi, Y. & Mori, Y. 2004a Alarm pheromones with different functions are released from different regions of the body surface of male rats. Chem. Senses 29, 35–40. (doi:10.1093/chemse/bjh004) Kiyokawa, Y., Kikusui, T., Takeuchi, Y. & Mori, Y. 2004b Modulatory role of testosterone in alarm pheromone release by male rats. Horm. Behav. 45, 122–127. (doi:10. 1016/j.yhbeh.2003.09.007) Kiyokawa, Y., Kikusui, T., Takeuchi, Y. & Mori, Y. 2004c Partner’s stress status influences social buffering effects in rats. Behav. Neurosci. 118, 798–804. (doi:10.1037/07357044.118.4.798) Kiyokawa, Y., Kikusui, T., Takeuchi, Y. & Mori, Y. 2005a Alarm pheromone that aggrevated stress-induced hyperthermia is soluble in water. Chem. Senses 30, 513–519. (doi:10.1093/chemse/bji044) Kiyokawa, Y., Kikusui, T., Takeuchi, Y. & Mori, Y. 2005b Mapping the neural circuit activated by alarm pheromone perception by c-Fos immunohistochemistry. Brain Res. 1043, 145–154. (doi:10.1016/j.brainres.2005.02.061) Koide, T., Wieloch, T. W. & Siesjo, B. K. 1986 Chronic dexamethasone pretreatment aggravates ischemic neuronal necrosis. J. Cereb. Blood Flow Metab. 6, 395–404. Latane´, B. 1969 Gregariousness and fear in laboratory rats. J. Exp. Soc. Psychol. 5, 61–69. (doi:10.1016/0022-1031 (69)90006-7) Latane´, B. 1975 The persistence of social attraction in socially deprived and satiated rats. Anim. Learn. Behav. 3, 131–134. Latane´, B., Eckman, J. & Joy, V. 1966 Shared stress and interpersonal attraction. J. Exp. Soc. Psychol. 1(Suppl. 1), 142–146. Legros, J. J., Chiodera, P., Geenen, V. & von Frenckell, R. 1987 Confirmation of the inhibitory influence of exogenous oxytocin on cortisol and ACTH in man: evidence of reproducibility. Acta Endocrinol. 114, 345–349. Legros, J. J., Chiodera, P. & Geenen, V. 1988 Inhibitory action of exogenous oxytocin on plasma cortisol in normal human subjects: evidence of action at the adrenal level. Neuroendocrinology 48, 204–206.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2226

T. Kikusui and others Social buffering

Lepore, S. J., Allen, K. A. & Evans, G. W. 1993 Social support lowers cardiovascular reactivity to an acute stressor. Psychosom. Med. 55, 518–524. Leserman, J., Petitto, J. M., Golden, R. N., Gaynes, B. N., Gu, H., Perkins, D. O., Silva, S. G., Folds, J. D. & Evans, D. L. 2000 Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS. Am. J. Psychiatry 157, 1221–1228. (doi:10.1176/ appi.ajp.157.8.1221) Levine, S. 2000 Influence of psychological variables on the activity of the hypothalamic–pituitary–adrenal axis. Eur. J. Pharmacol. 405, 149–160. (doi:10.1016/S0014-2999 (00)00548-3) Levine, S. 2001 Primary social relationships influence the development of the hypothalamic–pituitary–adrenal axis in the rat. Physiol. Behav. 73, 255–260. (doi:10.1016/ S0031-9384(01)00496-6) Levine, S., Coe, C. L. & Smotherman, W. P. 1978 Prolonged cortisol elevation in the infant squirrel monkey after reunion with mother. Physiol. Behav. 20, 7–10. (doi:10. 1016/0031-9384(78)90194-4) Levine, S., Lyons, D. M. & Schatzberg, A. F. 1997 Psychobiological consequences of social relationships. Ann. NY Acad. Sci. 807, 210–218. Liddell, H. 1950 Some specific factors that modify tolerance for environmental stress. Res. Publ. Assoc. Res. Nerv. Mental Dis. 29, 155–171. Liddell, B. J., Brown, K. J., Kemp, A. H., Barton, M. J., Das, P., Peduto, A., Gordon, E. & Williams, L. M. 2005 A direct brainstem–amygdala–cortical ‘alarm’ system for subliminal signals of fear. Neuroimage 24, 235–243. (doi:10.1016/ j.neuroimage.2004.08.016) Lim, M. M., Murphy, A. Z. & Young, L. J. 2004 Ventral striatopallidal oxytocin and vasopressin V1a receptors in the monogamous prairie vole (Microtus ochrogaster). J. Comp. Neurol. 468, 555–570. (doi:10.1002/cne.10973) Lombardi, G., Merola, B., Savastano, S., Tommaselli, A. P., Valentino, R., Rossi, R., Ghiggi, M. R. & Cataldi, M. 1991 Hypothalamus–pituitary–adrenal (HPA) axis in physiological and pathological aging brain. Acta Neurol. (Napoli) 13, 368–373. Ludwig, M. 1998 Dendritic release of vasopressin and oxytocin. J. Neuroendocrinol. 10, 881–895. (doi:10.1046/ j.1365-2826.1998.00279.x) Mason, J. W. 1968 A review of psychoendocrine research on the pituitary–adrenal cortical system. Psychosom. Med. 30, 576–607. McGlone, J. J., Stansbury, W. F. & Tribble, L. F. 1986 Aerosolized 5 alpha-androst-16-en-3-one reduced agonistic behavior and temporarily improved performance of growing pigs. J. Anim. Sci. 63, 679–684. Measserman, J. H. 1943 Behavior and neurosis. Chicago, IL: University of Chicago Press. Mendoza, S. P., Coe, C. L., Lowe, E. L. & Levine, S. 1978 The physiological response to group formation in adult male squirrel monkeys. Psychoneuroendocrinology 3, 221–229. (doi:10.1016/0306-4530(78)90012-4) Miczek, K. A. 1974 Intraspecies aggression in rats: effects of d-amphetamine and chlordiazepoxide. Psychopharmacologia 39, 275–301. (doi:10.1007/BF00422968) Miczek, K. A. 1979 A new test for aggression in rats without aversive stimulation: differential effects of d-amphetamine and cocaine. Psychopharmacology 60, 253–259. (doi:10. 1007/BF00426664) Miller, G. E., Cohen, S. & Ritchey, A. K. 2002 Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol. 21, 531–541. (doi:10.1037/0278-6133.21.6.531) Mohr, D. C. & Genain, C. 2004 Social support as a buffer in the relationship between treatment for depression and Phil. Trans. R. Soc. B (2006)

T-cell production of interferon gamma in patients with multiple sclerosis. J. Psychosom. Res. 57, 155–158. (doi:10. 1016/S0022-3999(03)00601-9) Moles, A., Kieffer, B. L. & D’Amato, F. R. 2004 Deficit in attachment behavior in mice lacking the mu-opioid receptor gene. Science 304, 1983–1986. (doi:10.1126/ science.1095943) Morris, N., Udry, J. & Chase, C. L. 1973 Reduction of low birth weight rates by prevention of unwanted pregnancies. Am. J. Public Health 63, 935–938. Morris, W. N., Worchel, S., Bios, J. L., Pearson, J. A., Rountree, C. A., Samaha, G. M., Wachtler, J. & Wright, S. L. 1976 Collective coping with stress: group reactions to fear, anxiety, and ambiguity. J. Pers. Soc. Psychol. 33, 674–679. (doi:10.1037/0022-3514.33.6.674) Morris, J. S., Frith, C. D., Perrett, D. I., Rowland, D., Young, A. W., Calder, A. J. & Dolan, R. J. 1996 A differential neural response in the human amygdala to fearful and happy facial expressions. Nature 383, 812–815. (doi:10. 1038/383812a0) Morrow-Tesch, J. & McGlone, J. J. 1990 Sources of maternal odors and the development of odor preferences in baby pigs. J. Anim. Sci. 68, 3563–3571. Morton, J. & Johnson, M. H. 1991 CONSPEC and CONLERN: a two-process theory of infant face recognition. Psychol. Rev. 98, 164–181. (doi:10.1037/0033295X.98.2.164) Munck, A., Guyre, P. M. & Holbrook, N. J. 1984 Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr. Rev. 5, 25–44. Nelson, E. E. & Panksepp, J. 1998 Brain substrates of infant– mother attachment: contributions of opioids, oxytocin, and norepinephrine. Neurosci. Biobehav. Rev. 22, 437–452. Neumann, I. D. 2002 Involvement of the brain oxytocin system in stress coping: interactions with the hypothalamo–pituitary–adrenal axis. Prog. Brain Res. 139, 147–162. Neumann, I. D., Johnstone, H. A., Hatzinger, M., Liebsch, G., Shipston, M., Russell, J. A., Landgraf, R. & Douglas, A. J. 1998 Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes. J. Physiol. 508 (Pt 1), 289–300. Neumann, I. D., Kromer, S. A., Toschi, N. & Ebner, K. 2000 Brain oxytocin inhibits the (re)activity of the hypothalamo–pituitary–adrenal axis in male rats: involvement of hypothalamic and limbic brain regions. Regul. Pept. 96, 31–38. Noble, A. B., McKinney Jr, W. T., Mohr, C. & Moran, E. 1976 Diazepam treatment of socially isolated monkeys. Am. J. Psychiatry 133, 1165–1170. Onaka, T. 2004 Neural pathways controlling central and peripheral oxytocin release during stress. J. Neuroendocrinol. 16, 308–312. (doi:10.1111/j.0953-8194.2004.01186.x) Panksepp, J. & Bishop, P. 1981 An autoradiographic map of (3H)diprenorphine binding in rat brain: effects of social interaction. Brain Res. Bull. 7, 405–410. Panksepp, J., Herman, B., Conner, R., Bishop, P. & Scott, J. P. 1978 The biology of social attachments: opiates alleviate separation distress. Biol. Psychiatry 13, 607–618. Panksepp, J., Herman, B. H., Vilberg, T., Bishop, P. & DeEskinazi, F. G. 1980 Endogenous opioids and social behavior. Neurosci. Biobehav. Rev. 4, 473–487. (doi:10. 1016/0149-7634(80)90036-6) Pedersen, C. A., Caldwell, J. D., Drago, F., Noonan, L. R., Peterson, G., Hood, L. E. & Prange Jr, A. J. 1988 Grooming behavioral effects of oxytocin: pharmacology, ontogeny, and comparisons with other nonapeptides. Ann. NY Acad. Sci. 525, 245–256.

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Social buffering Peirce, J. W., Leigh, A. E. & Kendrick, K. M. 2000 Configurational coding, familiarity and the right hemisphere advantage for face recognition in sheep. Neuropsychologia 38, 475–483. (doi:10.1016/S0028-3932(99) 00088-3) Porter, R. H. & Winberg, J. 1999 Unique salience of maternal breast odors for newborn infants. Neurosci. Biobehav. Rev. 23, 439–449. (doi:10.1016/S0149-7634(98)00044-X) Rabkin, J. G. & Struening, E. L. 1976 Life events, stress, and illness. Science 194, 1013–1020. Regnier, F. E. & Law, J. H. 1968 Insect pheromones. J. Lipid Res. 9, 541–551. Rilling, J. K., Winslow, J. T., O’Brien, D., Gutman, D. A., Hoffman, J. M. & Kilts, C. D. 2001 Neural correlates of maternal separation in rhesus monkeys. Biol. Psychiatry 49, 146–157. (doi:10.1016/S0006-3223(00)00977-X) Rivier, C. & Vale, W. 1983 Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature 305, 325–327. Robinson, D. A., Wei, F., Wang, G. D., Li, P., Kim, S. J., Vogt, S. K., Muglia, L. J. & Zhuo, M. 2002 Oxytocin mediates stress-induced analgesia in adult mice. J. Physiol. 540, 593–606. (doi:10.1113/jphysiol.2001.013492) Rojas, I. G., Padgett, D. A., Sheridan, J. F. & Marucha, P. T. 2002 Stress-induced susceptibility to bacterial infection during cutaneous wound healing. Brain Behav. Immun. 16, 74–84. (doi:10.1006/brbi.2000.0619) Rottman, S. J. & Snowdon, C. T. 1972 Demonstration and analysis of an alarm pheromone in mice. J. Comp. Physiol. Psychol. 81, 483–490. Rubenstein, J. L., Halton, A., Kasten, L., Rubin, C. & Stechler, G. 1998 Suicidal behavior in adolescents: stress and protection in different family contexts. Am. J. Orthopsychiatry 68, 274–284. Rukstalis, M. & French, J. A. 2005 Vocal buffering of the stress response: exposure to conspecific vocalizations moderates urinary cortisol excretion in isolated marmosets. Horm. Behav. 47, 1–7. (doi:10.1016/j.yhbeh.2004. 09.004) Russell, J. A. & Leng, G. 1998 Sex, parturition and motherhood without oxytocin? J. Endocrinol. 157, 343–359. Sapolsky, R. M. & Pulsinelli, W. A. 1985 Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 229, 1397–1400. (doi:10.1126/science. 4035356) Sayal, K., Checkley, S., Rees, M., Jacobs, C., Harris, T., Papadopoulos, A. & Poon, L. 2002 Effects of social support during weekend leave on cortisol and depression ratings: a pilot study. J. Affect Disord. 71, 153–157. (doi:10. 1016/S0165-0327(01)00414-1) Selye, H. 1956 The stress of life. New York, NY: McGraw-Hill. Seyfarth, R. M. & Cheney, D. L. 2003 Meaning and emotion in animal vocalizations. Ann. NY Acad. Sci. 1000, 32–55. Shanks, N., Windle, R. J., Perks, P., Wood, S., Ingram, C. D. & Lightman, S. L. 1999 The hypothalamic–pituitary– adrenal axis response to endotoxin is attenuated during lactation. J. Neuroendocrinol. 11, 857–865. (doi:10.1046/ j.1365-2826.1999.00400.x) Sheppard, G. & Mills, D. S. 2003 Evaluation of dogappeasing pheromone as a potential treatment for dogs fearful of fireworks. Vet. Rec. 152, 432–436. Sonwdon, C. T. & Cleveland, J. 1980 Individual recognition of contact calls by pygmy marmosets. Anim. Behav. 28, 717–727. Spiegel, D. & Sephton, S. E. 2001 Psychoneuroimmune and endocrine pathways in cancer: effects of stress and support. Semin. Clin. Neuropsychiatry 6, 252–265. (doi:10.1053/scnp.2001.26995) Phil. Trans. R. Soc. B (2006)

T. Kikusui and others 2227

Spitzer, S. B., Llabre, M. M., Ironson, G. H., Gellman, M. D. & Schneiderman, N. 1992 The influence of social situations on ambulatory blood pressure. Psychosom. Med. 54, 79–86. Stanton, M. E., Patterson, J. M. & Levine, S. 1985 Social influences on conditioned cortisol secretion in the squirrel monkey. Psychoneuroendocrinology 10, 125–134. Steptoe, A. 2000 Stress, social support and cardiovascular activity over the working day. Int. J. Psychophysiol. 37, 299–308. (doi:10.1016/S0167-8760(00)00109-4) Taylor, G. T. 1976 Affiliation and aggression in rats. Anim. Learn. Behav. 4, 139–144. Taylor, G. T. 1981 Fear and affiliation in domesticated male rats. J. Comp. Physiol. Psychol. 95, 685–693. Teichman, Y. 1974 Predisposition for anxiety and affiliation. J. Pers. Soc. Psychol. 29, 405–410. (doi:10.1037/h0035920) Terranova, M. L., Cirulli, F. & Laviola, G. 1999 Behavioral and hormonal effects of partner familiarity in periadolescent rat pairs upon novelty exposure. Psychoneuroendocrinology 24, 639–656. (doi:10.1016/S0306-4530(99)00019-0) Thorsteinsson, E. B., James, J. E. & Gregg, M. E. 1998 Effects of video-relayed social support on hemodynamic reactivity and salivary cortisol during laboratory-based behavioral challenge. Health Psychol. 17, 436–444. Truesdell, L. S. & Bodnar, R. J. 1987 Reduction in coldwater swim analgesia following hypothalamic paraventricular nucleus lesions. Physiol. Behav. 39, 727–731. (doi:10. 1016/0031-9384(87)90257-5) Turner-Cobb, J. M., Sephton, S. E., Koopman, C., BlakeMortimer, J. & Spiegel, D. 2000 Social support and salivary cortisol in women with metastatic breast cancer. Psyc. Med. 62, 337–345. Uchino, B. N., Cacioppo, J. T. & Kiecolt-Glaser, J. K. 1996 The relationship between social support and physiological processes: a review with emphasis on underlying mechanisms and implications for health. Psychol. Bull. 119, 488–531. Uno, D., Uchino, B. N. & Smith, T. W. 2002 Relationship quality moderates the effect of social support given by close friends on cardiovascular reactivity in women. Int. J. Behav. Med. 9, 243–262. (doi:10.1207/S15327558IJBM0903_06) Uvnas-Moberg, K. 1996 Neuroendocrinology of the mother–child interaction. Trends Endocrinol. Metab. 7, 126–131. (doi:10.1016/1043-2760(96)00036-7) Uvnas-Moberg, K. 1997 Physiological and endocrine effects of social contact. Ann. NY Acad. Sci. 807, 146–163. Uvnas-Moberg, K. 1998 Oxytocin may mediate the benefits of positive social interaction and emotions. Psychoneuroendocrinology 23, 819–835. (doi:10.1016/S0306-4530 (98)00056-0) Uvnas-Moberg, K. & Eriksson, M. 1996 Breastfeeding: physiological, endocrine and behavioural adaptations caused by oxytocin and local neurogenic activity in the nipple and mammary gland. Acta Paediatr. 85, 525–530. Uvnas-Moberg, K., Bruzelius, G., Alster, P. & Lundeberg, T. 1993 The antinociceptive effect of non-noxious sensory stimulation is mediated partly through oxytocinergic mechanisms. Acta Physiol. Scand. 149, 199–204. Vale, W., Spiess, J., Rivier, C. & Rivier, J. 1981 Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213, 1394–1397. (doi:10.1126/science.6267699) Valzelli, L. 1973 The “isolation syndrome” in mice. Psychopharmacologia 31, 305–320. (doi:10.1007/BF00421275) van Reenen, C. G., Mars, M. H., Leushuis, I. E., Rijsewijk, F. A., van Oirschot, J. T. & Blokhuis, H. J. 2000 Social isolation may influence responsiveness to infection with bovine herpesvirus 1 in veal calves. Vet. Microbiol. 75, 135–143. (doi:10.1016/S0378-1135(00)00211-X)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2228

T. Kikusui and others Social buffering

Walker, C. D., Trottier, G., Rochford, J. & Lavallee, D. 1995 Dissociation between behavioral and hormonal responses to the forced swim stress in lactating rats. J. Neuroendocrinol. 7, 615–622. (doi:10.1111/j.13652826.1995.tb00799.x) Wang, Z. & Aragona, B. J. 2004 Neurochemical regulation of pair bonding in male prairie voles. Physiol. Behav. 83, 319–328. (doi:10.1016/j.physbeh.2004.08.024) West, D. A., Kellner, R. & Moore-West, M. 1986 The effects of loneliness: a review of the literature. Comp. Psychiatry 27, 351–363. (doi:10.1016/0010-440X(86)90011-8) Wheeler, J. W. 1976 Insect and mammalian pheromones. Lloydia 39, 53–59. Wiener, S. G., Johnson, D. F. & Levine, S. 1987 Influence of postnatal rearing conditions on the response of squirrel monkey infants to brief perturbations in mother–infant relationships. Physiol. Behav. 39, 21–26. (doi:10.1016/ 0031-9384(87)90339-8) Williams, J. R., Catania, K. C. & Carter, C. S. 1992 Development of partner preferences in female prairie voles (Microtus ochrogaster): the role of social and sexual experience. Horm. Behav. 26, 339–349. (doi:10.1016/ 0018-506X(92)90004-F) Wilson, J. H. 2000 A conspecific attenuates prolactin responses to open-field exposure in rats. Horm. Behav. 38, 39–43. (doi:10.1006/hbeh.2000.1600) Wilson, J. H. 2001 Prolactin in rats is attenuated by conspecific touch in a novel environment. Cogn. Affect Behav. Neurosci. 1, 199–205. Winslow, J. T. & Insel, T. R. 1991 Endogenous opioids: do they modulate the rat pup’s response to social isolation? Behav. Neurosci. 105, 253–263. (doi:10.1037/0735-7044. 105.2.253) Windle, R. J., Shanks, N., Lightman, S. L. & Ingram, C. D. 1997a Central oxytocin administration reduces stressinduced corticosterone release and anxiety behavior in rats. Endocrinology 138, 2829–2834. (doi:10.1210/en.138. 7.2829) Windle, R. J., Wood, S., Shanks, N., Perks, P., Conde, G. L., da Costa, A. P., Ingram, C. D. & Lightman, S. L. 1997b Endocrine and behavioural responses to noise stress: comparison of virgin and lactating female rats during non-disrupted maternal activity. J. Neuroendocrinol. 9, 407–414. (doi:10.1046/j.1365-2826.1997.00587.x)

Phil. Trans. R. Soc. B (2006)

Windle, R. J., Kershaw, Y. M., Shanks, N., Wood, S. A., Lightman, S. L. & Ingram, C. D. 2004 Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary–adrenal activity. J. Neurosci. 24, 2974–2982. (doi:10.1523/JNEUROSCI.3432-03.2004) Winslow, J. T. & Insel, T. R. 2002 The social deficits of the oxytocin knockout mouse. Neuropeptides 36, 221–229. (doi:10.1054/npep.2002.0909) Winslow, J. T. & Insel, T. R. 2004 Neuroendocrine basis of social recognition. Curr. Opin. Neurobiol. 14, 248–253. (doi:10.1016/j.conb.2004.03.009) Winslow, J. T., Hastings, N., Carter, C. S., Harbaugh, C. R. & Insel, T. R. 1993a A role for central vasopressin in pair bonding in monogamous prairie voles. Nature 365, 545–548. (doi:10.1038/365545a0) Winslow, J. T., Shapiro, L., Carter, C. S. & Insel, T. R. 1993b Oxytocin and complex social behavior: species comparisons. Psychopharmacol. Bull. 29, 409–414. Winslow, J. T., Noble, P. L., Lyons, C. K., Sterk, S. M. & Insel, T. R. 2003 Rearing effects on cerebrospinal fluid oxytocin concentration and social buffering in rhesus monkeys. Neuropsychopharmacology 28, 910–918. Wyller, T. B., Holmen, J., Laake, P. & Laake, K. 1998 Correlates of subjective well-being in stroke patients. Stroke 29, 363–367. Yonezawa, T., Koori, M., Kikusui, T. & Mori, Y. In preparation. Synthetic pig appeasing pheromone relieves stress in adult female pigs. Young, L. J. 2002 The neurobiology of social recognition, approach, and avoidance. Biol. Psychiatry 51, 18–26. (doi:10.1016/S0006-3223(01)01268-9) Young, L. J. & Wang, Z. 2004 The neurobiology of pair bonding. Nat. Neurosci. 7, 1048–1054. (doi:10.1038/ nn1327) Young, L. J., Lim, M. M., Gingrich, B. & Insel, T. R. 2001 Cellular mechanisms of social attachment. Horm. Behav. 40, 133–138. (doi:10.1006/hbeh.2001.1691) Young, L. J., Pitkow, L. J. & Ferguson, J. N. 2002 Neuropeptides and social behavior: animal models relevant to autism. Mol. Psychiatry 2(Suppl. 7), S38–S39. (doi:10.1038/sj.mp.4001175) Zucker, R. A., Manosevitz, M. & Lanyon, R. I. 1968 Birth order, anxiety, and affiliation during a crisis. J. Pers. Soc. Psychol. 8, 354–359. (doi:10.1037/h0025574)

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Phil. Trans. R. Soc. B (2006) 361, 2229–2237 doi:10.1098/rstb.2006.1942 Published online 3 November 2006

Genomic imprinting and the social brain Anthony R. Isles1,2,*, William Davies1 and Lawrence S. Wilkinson1 1

Laboratory of Cognitive and Behavioural Neuroscience, The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB2 4AT, UK 2 Developmental Psychiatry Section, University of Cambridge, Douglas House, 18a Trumpington Street, Cambridge CB2 4AH, UK Genomic imprinting refers to the parent-of-origin-specific epigenetic marking of a number of genes. This epigenetic mark leads to a bias in expression between maternally and paternally inherited imprinted genes, that in some cases results in monoallelic expression from one parental allele. Genomic imprinting is often thought to have evolved as a consequence of the intragenomic conflict between the parental alleles that occurs whenever there is an asymmetry of relatedness. The two main examples of asymmetry of relatedness are when there is partiality of parental investment in offspring (as is the case for placental mammals, where there is also the possibility of extended postnatal care by one parent), and in social groups where there is a sex-biased dispersal. From this evolutionary starting point, it is predicted that, at the behavioural level, imprinted genes will influence what can broadly be termed bonding and social behaviour. We examine the animal and human literature for examples of imprinted genes mediating these behaviours, and divide them into two general classes. Firstly, mother–offspring interactions (suckling, attachment and maternal behaviours) that are predicted to occur when partiality in parental investment in early postnatal offspring occurs; and secondly, adult social interactions, when there is an asymmetry of relatedness in social groups. Finally, we return to the evolutionary theory and examine whether there is a pattern of behavioural functions mediated by imprinted genes emerging from the limited data, and also whether any tangible predictions can be made with regards to the direction of action of genes of maternal or paternal origin. Keywords: imprinted genes; evolution; behaviour; cognition; X-chromosome

1. INTRODUCTION As our knowledge of genes and genomes has grown, it has become increasingly clear that in some cases the epigenetic status of genes is as important as the information encoded by DNA sequence itself. One class of genes that falls under the ‘epigenetics’ umbrella is imprinted genes. Here, the epigenetic marking, which consists of DNA methylation and chromatin modification, occurs in a parent-of-origin-specific manner (Delaval & Feil 2004). This epigenetic mark is established in the developing embryo by early postimplantation and distinguishes the maternal and paternal genomes, leading to a bias in expression between maternally and paternally inherited imprinted genes that in some cases results in expression solely from one parental allele. This is in contrast to normal (non-imprinted) autosomal gene expression which is generally biallelic, or indifferent to the parental origin of the allele being expressed. Although the number of known imprinted genes is relatively small (at present approximately 80 coding genes and 37 non-coding RNAs), their very existence contravenes Mendel’s third law of inheritance (that maternal and paternal genomes are functionally equivalent). Furthermore, despite their relatively small number, the first studies suggesting the existence * Author for correspondence ([email protected]). One contribution of 14 to a Theme Issue ‘The neurobiology of social recognition, attraction and bonding’.

of imprinted genes, in which androgenetic (diploid for paternally derived chromosomes only) and parthenogenetic (diploid for maternally derived chromosomes only) mouse embryos failed to survive beyond midgestation (Barton et al. 1984; McGrath & Solter 1984; Surani et al. 1984), demonstrated that they have important developmental functions. Since these discoveries, the genomic imprinting field has expanded rapidly, with many efforts focused on understanding the underpinning epigenetic control mechanisms and the physiological role of imprinted genes. (a) Kinship and evolution of imprinted genes Imprinted genes often show monoallelic expression, meaning an individual is effectively haploid at this locus, thus negating any benefits of diploidy and sexual reproduction (Orr 1995). This has led to an extensive debate as to why genomic imprinting has evolved (Hurst 1997). Although many theories have been put forward, the most resilient, in terms of predictions and explaining the existing data, is the kinship (or conflict) theory (Haig & Westoby 1989; Moore & Haig 1991). This theory is an extension of the parent–offspring conflict theory developed by Trivers (1974) which suggested that, with regard to resource provisioning, the interests of the offspring do not necessarily equate to the interests of the parents (or mother) who have to take into account their lifetime reproductive output. The conflict theory in relation to imprinted genes takes this thinking to the genomic level, and suggests that,

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owing to relatedness asymmetries, maternally and paternally derived genomes may be selected to favour differential outcomes in the offspring. There are a number of presumptions that underlie this thinking; critically, a male would not anticipate fathering all a given female’s offspring; either within her lifetime and/ or within a given brood. This would lead to an asymmetry of relatedness between the maternal and the paternal genomes in the offspring: maternal genomes in a given female’s offspring would be shared with the mother and among all her other offspring; however, paternal genomes are not shared with the mother, and are possibly shared with some, but not all her other offspring (figure 1a). It is this asymmetry of relatedness that gives rise to the differential interests of the maternal and paternal genomes of an individual. The possibility of intragenomic conflict is particularly obvious during the development of mammalian offspring in utero, where the system is possibly easiest to manipulate (Moore & Haig 1991). In this situation, paternally derived genes in the offspring would be expected to maximize nutrient resource acquisition from the mother via the placenta, given that the paternal genome is not shared with the mother and may not be shared with any of her subsequent offspring. However, this strategy may compromise the mother’s overall lifetime fitness. The maternal genome is shared with the mother, and will be shared with all the offspring she has throughout her reproductive lifetime. Consequently, it is in the maternal genome’s interest to redress the balance so that the mother can provide equal resources for all of her offspring, thus maximizing the overall lifetime fitness of the maternally derived genes. This prediction received strong support as the first few imprinted genes to be identified consisted of growth factors and their antagonistic counterparts acting mainly in utero, with paternally derived genes increasing, and maternally derived genes limiting, foetal growth (Dechiara et al. 1990; Barlow et al. 1991; Leighton et al. 1995). The conflict between parental genomes with regards to in utero resource allocation has often been used as an evolutionary framework in which to place observed functions of many imprinted genes (Haig & Graham 1991; Itier et al. 1998; Lefebvre et al. 1998; Li et al. 1999). However, the original synthesis of the conflict hypothesis merely suggested that in utero may be one of the potential battlegrounds. Certainly, it is easy to see that the critical period between birth and weaning may provide an additional area where intragenomic conflict, with regard to resources allocation between the mother and the offspring, can arise. However, a number of researchers have also shown in theoretical models that imprinting is unlikely to be confined to resource allocation between parents and offspring, and may evolve whenever there are asymmetries of relatedness (Haig 1997; Trivers & Burt 1999; Haig 2000); the two classic scenarios when this occurs are multiple paternity of a female’s offspring (either within-brood or over a reproductive lifetime), and when there is sexbiased dispersal from a social group. The latter scenario, although common in mammals (Greenwood 1980; Pusey 1987), has rarely been invoked when discussing the evolution of imprinted genes, and yet it Phil. Trans. R. Soc. B (2006)

provides an excellent starting point for discussion of those imprinted genes/parent-of-origin effects that influence postnatal functions extending into the adult. The main group of postnatal functions for which there is a growing body of evidence of imprinted gene/parentof-origin effects from both mouse work and studies of human mental disease is brain and behavioural functioning (Isles & Wilkinson 2000; Davies et al. 2001). A large number of imprinted genes are expressed in the brain (Davies et al. 2005b), and yet very few have questioned why imprinting should persist in the adult brain or why imprinted genes have evolved to affect brain functioning at all. In this article, we argue that, from the evolutionary standpoint, it is predicted that imprinted genes will influence what can broadly be termed social behaviours. We expand on the reasons for this, and examine the animal and human literature for examples of imprinted genes mediating social behaviour, and divide these into two general classes. Firstly, mother– offspring interactions that are predicted to occur when partiality in parental investment of offspring occurs; and secondly, adult social interactions, where there is an asymmetry of relatedness in social groups. 2. THE PRE-WEANING PERIOD AND MOTHER–OFFSPRING BONDING There is ample evidence from a number of mouse studies regarding imprinted genes and resource allocation in utero that appears to support the predictions made by the kinship theory (Reik et al. 2003). However, as discussed previously, there is also predicted to be selective pressure for the involvement of imprinted genes in the pre-weaning period, when the offspring are still dependent on their mother for resources (Constancia et al. 2004; Isles & Holland 2005). Support for this general idea is increasing, and there are a number of examples of imprinted genes affecting growth in the pre-weaning period (Itier et al. 1998; Curley et al. 2004; Plagge et al. 2004). (a) Suckling Within the context of nutrient supply during the preweaning period, evidence from animal models (Curley et al. 2004; Plagge et al. 2004), and clinical conditions (Holm et al. 1993; Haig & Wharton 2003), suggests that imprinted genes may impact on suckling behaviour, with paternally expressed genes enhancing resource acquisition as they do in utero. A case in point is the paternally expressed gene Gnasxl, which encodes an isoform of the stimulatory G-protein subunit Gsa (XLas). Gnasxl is expressed (among other places) in the facial, hypoglossal and trigeminal motor nuclei (Plagge et al. 2004), the key areas of the brain that provide innervation of the orofacial muscles controlling the jaw and the tongue (Lund et al. 1998; Sawczuk & Mosier 2001). Mice carrying a targeted deletion of this gene show a postnatal phenotype that includes deficits in suckling behaviour; they have substantially reduced milk content in their stomachs and postnatal weight gain is much less when compared with wild-type littermates (Plagge et al. 2004). Although not demonstrated directly, these suckling deficits in the targeted

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Genomic imprinting and the social brain A. R. Isles and others (a)

(b)

Figure 1. A diagram showing how asymmetries of relatedness can occur through multiple paternity of a female’s offspring, and in a simple matrilineal society with sex-biased dispersal. (a) With multiple paternity either within a brood or, as is more likely, across a female’s reproductive lifetime, offspring from the same mother differ in their relatedness owing to the presence of different paternal genomes. (b) Schematic of a simple matrilineal society as described in the text. Males, coming in from outside the group, hold short breeding tenure (matings with females are indicated by thin arrows). Male offspring (not shown) leave the group when sexually mature. What can be seen is that all females share, to differing degrees, maternally derived genes (in red)—this would of course also be true for male offspring. However, paternally derived genes are only present in the strata of the social group and are not shared as widely.

mutant mice are presumably owing to impaired activity in the orofacial motor neurons and the muscles they innervate. (b) Emotional cues and positive affect signals However, in many animals, mother–offspring interactions are not just about the supply and demand of food. Intragenomic conflict over resource allocation may also include aspects of care (licking and grooming) and emotional cues. A good example of where imprinted genes impact on this kind of function is provided by the neurogenetic disorder Angelman syndrome (AS). AS, which is characterized by abnormalities in neurological, motor and intellectual functioning, is caused by genetic anomalies involving a cluster of imprinted genes on chromosome 15. These causal anomalies include paternal chromosome 15 uniparental disomy, maternal deletion of the critical region (15q11–13) and mutations in the maternally expressed/paternally imprinted gene UBE3A (Clayton-Smith & Laan 2003). A key characteristic of individuals with AS is their unusually sociable Phil. Trans. R. Soc. B (2006)

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disposition and frequent laughter and smiling, with reduced displays of negative affect signals such as crying and tantrums (Summers et al. 1995; Brown & Consedine 2004). These positive affect behaviours, although originally considered to occur inappropriately (Clayton-Smith & Laan 2003), are increasingly thought to occur specifically in a social context (Yamada & Volpe 1990; Oliver et al. 2002). This suggests that one or both of the two known maternally expressed genes in the critical region (UBE3A and ATP10C) normally act as brake-limiting positive affect signals, and that this function is lost in AS when these gene products are absent. This idea is further supported by evidence from the clinical condition caused by the reciprocal mutation at 15q11–13, Prader–Willi syndrome (PWS). The main PWS characteristics are caused by an absence of paternally expressed gene product from this critical region (Goldstone 2004). However, two genetic subtypes, maternal chromosome 15 uniparental disomy and PWS-imprinting centre mutations, also have an overdosage of the maternally expressed UBE3A and ATP10C gene products owing to the presence of two maternal copies and a relaxation of the silencing of the paternal copy, respectively. In addition to the classic PWS symptoms, these individuals show increased negative affect signals (stubbornness and temper tantrums) and a much increased propensity to develop an affective psychosis (Boer et al. 2002; Vogels et al. 2003). In these cases of PWS, the overdosage of maternal gene products presumably leads to a greater than normal application on the brake that acts to limit positive affect signals. Taken together, these clinical data have led to the proposal that one or both of these maternally expressed genes influence attachment between offspring and mother, in that they limit the display of positive affect signalling (Isles & Holland 2005). This idea is predicted by the kinship theory (Brown & Consedine 2004), the suggestion being that these positive affect signals manipulate the sensory systems of receivers with respect to the allocation of social ‘resources’. In the same manner as manipulating nutrient resources, it is in the ‘interest’ of the paternal genome to maximize the amount of social resources received from the mother; whereas it is in the ‘interest’ of the maternal genome to equalize the amount of these resources across all maternally related kin. (c) Maternal behaviour So far, the focus has been on situations where imprinted genes impact on the ability of the offspring to extract ‘resources’ from the mother in the preweaning period. However, two classic studies examining mice with targeted mutations demonstrate that imprinted genes also influence maternal behaviours (Lefebvre et al. 1998; Li et al. 1999). Peg1 and Peg3 are both paternally expressed imprinted genes that were identified in a screen for novel imprinted genes (Kanekoishino et al. 1995; Kuroiwa et al. 1996). Both have enhancing effects on foetal growth and are highly expressed in the adult brain (Lefebvre et al. 1998; Li et al. 1999). Females who carry a targeted (null) copy of Peg1 or Peg3 inherited from their fathers show similar

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gross deficits in maternal care that are independent of any possible effects in the pups (Lefebvre et al. 1998; Li et al. 1999; Curley et al. 2004). Peg1 mutant females were deficit in normal aspects of maternal behaviour such as placentophagia, retrieval of pups, nest building and crouching (suckling). Needless to say, the consequence of these behavioural deficits is a reduced survivability of the offspring. Similarly, Peg3 mutant females also displayed deficits in aspects of normal maternal care (retrieval, nest building and crouching). Like the Peg1 mutant females (Lefebvre et al. 1998), this maternal care deficit was not due to olfactory dysfunction, and furthermore the Peg3 mutant females showed normal reaction to newly introduced pups (Li et al. 1999). Additionally, Peg3 mutant females showed reduced milk letdown, despite having histologically normal mammary glands. This suggested a deficit in the neurobiological control of lactation, and investigations demonstrated a reduced number of oxytocin-positive neurons in the hypothalamus of Peg3 mutant females (Li et al. 1999). Given the central role played by oxytocin in both maternal behaviour and milk letdown, the indication is that this is the neurobiological pathway via which Peg3 is exerting an effect (Keverne 2001), an idea that sits nicely with its involvement in the tumour necrosis factor signalling pathway affecting NFkB phosphorylation, apoptosis and cell survival (Relaix et al. 1998, 2000). At first glance, the effect of imprinted genes on maternal behaviour seems to fit quite nicely with the idea of intragenomic conflict over food resources, care and emotional bonds in the pre-weaning period (Constancia et al. 2004). However, this aspect of Peg1 and Peg3 functions is inconsistent with a kinship/ intragenomic conflict explanation, as relatedness asymmetries between parent and offspring do not carry over between generations (Hurst et al. 2000). Nevertheless, the gross physiological effects of mutant Peg1 and Peg3 on foetal growth (lack of paternally expressed product produces smaller offspring) are consistent with intragenomic conflict, leading to the suggestion that this is the main selective force behind the evolution of imprinting at these loci (Wilkins & Haig 2003). Additionally, Peg3 has recently been shown to have a role regulating suckling behaviour in pups in a similar manner to Gnasxl (Curley et al. 2004). This mutant phenotype also fits with intragenomic conflict as it relates to resource acquisition during the pre-weaning period, and may be due to disruption of similar hypothalamic processes that underlie maternal behaviour (Curley et al. 2004). Whether or not the effect of these two imprinted genes on maternal behaviour can be reconciled within the kinship hypothesis, or whether this function of these genes is subservient to their effects on in utero and pre-weaning resource acquisition remains to be seen.

3. SEX-BIASED DISPERSAL, INTRAGENOMIC CONFLICT AND SOCIAL BEHAVIOUR Asymmetries of relatedness can also be established in animal societies in which individuals of one or other of the sexes move away from the natal group (sex-biased dispersal). Take an animal social group that consists Phil. Trans. R. Soc. B (2006)

of maternally related females: sisters, maternal half-sisters, maternal cousins, maternal aunties, etc. Male offspring leave the group on becoming sexually mature, and the dominant/reproductive males come from outside of the group, holding tenure for only a few breeding cycles before being replaced by others. When a given female gives birth to an offspring, owing to the asymmetric relatedness of the group, this individual, regardless of gender, will share a large proportion of its maternally derived alleles with the other members of the group (figure 1b). Consequently, owing to this asymmetry of relatedness, the overall fitness benefit to these maternally derived alleles may, for example, be increased if this individual delays its own reproduction for a period in order to help the other members of the group raise their offspring. However, as a breeding male only holds tenure for a certain period, paternally derived alleles are less likely to be shared between individuals within the group. As a result, delaying reproduction to help the other female members of the group raise their offspring will be of no benefit and will in fact incur a cost to paternally derived alleles (unless the benefit can be tailored towards paternal relatives only—see later). Obviously, we can see that this scenario leads to conflict between the paternally and the maternally derived genomes within the offspring, and yet equally it does not necessarily involve growth or food allocation between mother and offspring. What is clear is that such an internal conflict would be manifest at the behavioural level, impacting on how individuals interact socially within the group. In social/family groups, as in our example, where relatedness asymmetries occur owing to sex-biased dispersal, imprinted genes are predicted to influence those behaviours that relate to how an individual interacts with the other members of a social group to which they belong (Trivers & Burt 1999). Unlike the asymmetry of relatedness situation in utero, where the predicted mode of action of imprinted genes is limited to the supply and demand for nutrient resources (Moore & Haig 1991), the potential functions of imprinted genes in social behaviours are far more expansive and complex. For instance, these could include one or many functions such as kin recognition, alarm calls, risk taking, grooming, communal nursing and aggressive behaviour (Hurst 1997; Trivers & Burt 1999; Isles et al. 2002; Roulin & Hager 2003). There are tentative suggestions from mouse studies that some of these functions are indeed subject to the action of imprinted genes. (a) Kin recognition Kin recognition is obviously a key factor in the cohesion of social groups, and in mice, like in many mammals, this is olfactory system based (Brennan 2004). Using reciprocal crosses between inbred strains of mice, Isles et al. (2001) demonstrated that there is a parentof-origin effect on olfactory-based kin-recognition mechanisms. Specifically, reciprocal F1 mice were more sensitive to, and avoided, female urinary odour from their genetic maternal strain (Isles et al. 2002). As the F1 mice had never been exposed to these maternal odours previously (all the animals were embryo transferred to foster mothers of a separate strain), the most parsimonious explanation for this behavioural

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Genomic imprinting and the social brain A. R. Isles and others parent-of-origin effect was that it was genetic in basis, and is therefore probably due to imprinted genes. Further investigations into the neurobiological basis of this behaviour suggested that this was not due to selfreferent phenotype matching (Mateo & Johnston 2000), as the urinary odours produced by the reciprocal F1 mice themselves were indistinguishable (Isles et al. 2001, 2002). Therefore, the action of this imprinted gene effect is most probably exerted via the neural systems controlling olfactory cue perception and/or information processing. (b) Exploratory behaviour and risk taking Another behavioural output that comes under the umbrella of social behaviour is risk taking, either in terms of alarm calling, looking for food or defending the group. Although caution needs to be used when discussing a behavioural construct as complex as ‘risktaking’, a recent study by us suggests that imprinted genes may impact on one aspect of this behaviour, namely exploration of a novel environment (Plagge et al. 2005). Mice carrying a maternally derived targeted allele of the gene Nesp showed a reduced propensity to explore a novel environment. Nesp is expressed only maternally, and is found in discrete locations in the brain including the noradrenergic locus coeruleus (Plagge et al. 2005), a key brain area in the control of reactivity to novel stimuli (Sara et al. 1995; Cole et al. 1988). In mice at least, it appears that the paternal interest may be to limit risk-taking (by silencing the paternal copy of Nesp), while it is in the maternal interest to promote these behaviours. (c) Imprinted genes and adult cognition Nevertheless, despite these examples, direct evidence for imprinted gene effects on adult social behaviours is limited. However, the fact that there are many examples of genes that are still subject to genomic imprinting in the adult brain (Davies et al. 2005b) suggests that not only is there a role for these genes in the brain, but that their imprinted status is also important. Consequently, further progress may be made by examining the role of imprinted genes in adult brain functions such as discrete aspects of cognition. This has been reviewed elsewhere (Isles & Wilkinson 2000), but in summary animal studies have so far demonstrated that imprinted genes impact on behavioural flexibility (Davies et al. 2005a) and several different aspects of memory functioning, including emotional (Brambilla et al. 1997), context dependent (Jiang et al. 1998) and spatial (Muscatelli et al. 2000). Studies on human mental dysfunction indicate a similar array of possible roles for imprinted genes in cognitive functioning (reviewed in Davies et al. 2001), including behavioural flexibility (Skuse et al. 1997), spatial memory (Curfs et al. 1991) and mental rotation (Bishop et al. 2000), and what can be broadly described as ‘social cognition’ (Cook et al. 1997; Skuse et al. 1997; Boer et al. 2002). Such ‘cold’ cognitive functions may seem remote from social behaviours such as grooming and alarm calls, but there is an accumulating body of evidence elucidating the neural basis of social interactions that suggests behaviours even as complex as deception, result as a consequence of the concerted Phil. Trans. R. Soc. B (2006)

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action of a number of basic psychological functions (Blakemore & Frith 2004). Consequently, knockout experiments in mice and studies on human mental dysfunction may shed light on the function of imprinted genes in distinct aspects of cognition and psychology that underpin how individuals interact socially. A good example of this is the case of E6-AP ubiquitin ligase encoded by the gene Ube3a. Imprinting of this gene is maintained in discrete regions of the adult brain (Albrecht et al. 1997; Rougeulle et al. 1997; Vu & Hoffman 1997), and as we have seen previously, this gene is involved in aspects of social functioning in the young (Oliver et al. 2002), so may well have a similar function in the adult. This idea is supported by the fact that UBE3A has been implicated in autismspectrum disorders (Cook et al. 1997; Samaco et al. 2005). A study of mice carrying a maternally derived null Ube3a allele demonstrated the importance of E6AP ubiquitin ligase in the degradation of certain effector proteins such as p53 in neurons, long-term potentiation in the hippocampus, and consequently context-dependent learning (Jiang et al. 1998). Clearly, it may be these neural and cognitive functions of E6-AP ubiquitin ligase underlying its role in social behaviour, particularly given the importance of contextual learning in social groups (Kamil 2004). The challenge is to make similar such links for those imprinted genes that are known to have a function in cognitive processes. (d) The special case of the X-chromosome Although limited, there is evidence for the existence of a number of X-linked imprinted genes in mice and humans (Skuse et al. 1997; Davies et al. 2005a; Raefski & O’Neill 2005). Interestingly, so far the vast majority of this evidence is brain based: brain-expressed imprinted genes (Davies et al. 2005a; Raefski & O’Neill 2005); parent-of-origin effects on structural changes and cognition in Turner syndrome (TS; Skuse et al. 1997; Bishop et al. 2000; Kesler et al. 2003); and cognitive functioning in mice (Davies et al. 2005a). These X-linked imprinted genes pose interesting questions in terms of the consequences of their expression and, interwoven with this, their evolution. What effect would an X-linked imprinted gene have on the hypothetical matrilineal society described above? An important factor to consider here is that recombination of genetic material between the sex chromosomes during meiosis in males is limited to the small pseudo-autosomal region, which constitutes less than 1% of the genes on the X. As a dominant male sires all the offspring during his tenure, it means that there will be strata of females in the group who are all effectively clonal for their paternally derived X-chromosomes (see figure 1b). In this case, the kinship theory would predict that X-linked paternally derived genes may lead to increased social interaction—restricted, however, to paternal female relatives. There is evidence from a number of social animals that individuals can recognize paternal sibs (Holmes 1986; Alberts 1999; Wahaj et al. 2004), suggesting that the mechanisms are in place for specific discrimination between maternal and paternal relatives. Furthermore,

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two separate primate studies have shown that this kin recognition can lead to altered behaviour, in that within groups females do bias their social behaviour towards their female paternal sisters (Widdig et al. 2001; Smith et al. 2003). These studies, one of rhesus macaques (Widdig et al. 2001) and the other of baboons (Smith et al. 2003), both showed that females demonstrated more approach, cohesion and grooming-related behaviours to paternal kin than non-kin. In both cases (although to varying degrees), this was present against a backdrop of strong maternal-kin bias as is found among matrilineal primate groupings such as these. Clearly, imprinted genes expressed from the paternally derived X could be a genetic mechanism that contributes to this bias in social behaviour, possibly via kin-recognition mechanisms alone or by influencing the behavioural output upon encountering paternal kin (i.e. increasing social behaviour). Conversely, genes expressed from the maternally derived X, which are shared much more widely within the group, would be expected to limit such a bias in behaviour towards paternal kin specifically. (e) Genetic sexual dimorphism Nevertheless, although it is clear that there are X-linked imprinted genes, some researchers have expressed dissatisfaction with a kinship explanation for their evolution. Instead, they argue that X-linked imprinting has evolved as a genetic mechanism to generate sexual dimorphisms, as male mammals (XY) always inherit their sole X from their mother, and therefore lack any paternally derived X-linked genes (provided there are no Y-linked homologues), and only females (XX) inherit a paternally derived X (Iwasa & Pomiankowski 1999; Iwasa & Pomiankowski 2001). Although gonadal hormones are a strong factor in generating sexually dimorphic traits, there is increasing evidence that genetic factors may also have an independent role (Arnold & Burgoyne 2004). A number of recognized sex differences, particularly in the brain, are observed before the advent of sex differences in gonadal hormones (Sibug et al. 1996; Dewing et al. 2003), and indeed occur independently of gonadal steroids (Carruth et al. 2002). These differences in brain development/function could be explained, for instance, by the action of X-linked imprinted genes. Indeed, this theory for the existence of X-linked imprinted genes has been used to explain the TS data in terms of generating the sexual dimorphism in social cognition (Skuse 1999), and possibly the differential vulnerability of males to mental diseases such as autism (Skuse 2000). 4. CONCLUDING REMARKS In this review, we have attempted to give an overview of the role played by imprinted genes in social behaviour. In line with the predictions from the most robust evolutionary hypothesis for genomic imprinting, the kinship theory, we have been able to classify imprinted gene effects on the social brain into mother–offspring bonding and adult interactions in social groups. The main idea behind the kinship theory is that there is an asymmetry of relatedness which leads to intragenomic Phil. Trans. R. Soc. B (2006)

conflict owing to the differential interests of the paternal and maternal genome. With regard to mother–offspring interactions, this asymmetry is generated by a father’s uncertain paternity of all of the mother’s offspring; while in social groups, an asymmetry of relatedness can become established when there is sex-biased dispersal from the group leading to matrilineal or patrilineal social groupings. With regards to the former (mother–offspring interactions), the predictive actions of maternally and paternally imprinted genes are relatively straightforward, being an extension of previously established effects in utero (Reik et al. 2003). However, whereas in utero where the differential interest regards the distribution of nutrient resources across the placenta, in the early postnatal period the definition of resources can be extended to include aspects of maternal care and mother–infant bonding. Classically, it would be in the paternal genome’s interest to increase resource acquisition from the mother by influencing suckling and consequently nutrient transfer; but acquisition of other resources such as care and emotional cues via affective signalling may also be affected (Brown & Consedine 2004). Conversely, it is in the maternal genome’s interest to reduce these effects, equalizing resource distribution across all the offspring in her lifetime. The second situation in which asymmetries of relatedness occur, and therefore imprinted genes are expected to evolve, is in social groups with sex-biased dispersal. Sex-biased dispersal of this kind is certainly not a theoretical convenience, and in fact is widespread among vertebrates (Pusey 1987). Indeed, although there are examples of female dispersal, it is mainly males that disperse in mammalian societies (Dobson 1982; Pusey 1987), particularly in primates (Wrangham 1980), mirroring the structure of the hypothetical society described above. This fact has led to the suggestion that the expansion of the forebrain regions in primates is related to increased sociality and that developmentally this brain evolution may have been mediated in part by imprinted genes (Keverne et al. 1996). Therefore, it is possible to make a tentative suggestion that in adults autosomal genes predominantly expressed from the maternally derived allele will generally promote social, cooperative behaviour among all group members, whereas those genes predominantly expressed from the paternally derived allele may suppress or inhibit such behaviour. However, these predictions may not hold up universally, and are very much dependent on the exact relatedness dynamics of the social group in question. Generally, there is increasing evidence, from both animal and human studies, that imprinted genes impact on social functioning, both in terms of affecting the mother–infant bond, and by influencing adult social behaviour and cognition. Overall, these data appear to support the theoretical standpoint, particularly with regards to mother–infant bonding. However, there are notable exceptions (for instance, the affect of Peg1 and Peg3 on maternal behaviour), and it is important to bear in mind that as there is an inherent flexibility in conflict-based theories to explain data (Hurst 1997), caution is needed when using the theory to explain data post hoc. Nevertheless, regardless of

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Genomic imprinting and the social brain A. R. Isles and others the evolutionary arguments, what is clear is that imprinted genes do have a role in brain functioning, and their effects are often felt via actions on social behaviour, both in early life and in the adult. A.R.I. is supported by the Beebe Trust and the Health Foundation. A.R.I., W.D. and L.S.W. are supported by the Biotechnology and Biological Sciences Research Council (Babraham Institute Synergy award to L.S.W.). L.S.W. is a member of the Medical Research Council (UK) Co-Operative on Imprinting in Health and Disease.

REFERENCES Alberts, S. C. 1999 Paternal kin discrimination in wild baboons. Proc. R. Soc. B 266, 1501–1506. (doi:10.1098/ rspb.1999.0807) Albrecht, U., Sutcliffe, J. S., Cattanach, B. M., Beechey, C. V., Armstrong, D., Eichele, G. & Beaudet, A. L. 1997 Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat. Genet. 17, 75–78. (doi:10.1038/ng0997-75) Arnold, A. P. & Burgoyne, P. S. 2004 Are XX and XY brain cells intrinsically different? Trends Endocrinol. Metab. 15, 6–11. (doi:10.1016/j.tem.2003.11.001) Barlow, D. P., Stoger, R., Herrmann, B. G., Saito, K. & Schweifer, N. 1991 The mouse insulin-like growth-factor type 2 receptor is imprinted and closely linked to the Tme locus. Nature 349, 84–87. (doi:10.1038/349084a0) Barton, S. C., Surani, M. A. & Norris, M. L. 1984 Role of paternal and maternal genomes in mouse development. Nature 311, 374–376. (doi:10.1038/311374a0) Bishop, D., Canning, E., Elgar, K., Morris, E., Jacobs, P. & Skuse, D. 2000 Distinctive patterns of memory function in subgroups of females with Turner syndrome: evidence for imprinted loci on the X-chromosome affecting neurodevelopment. Neuropsychologica 38, 712–721. (doi:10. 1016/S0028-3932(99)00118-9) Blakemore, S. J. & Frith, U. 2004 How does the brain deal with the social world? Neuroreport 15, 119–128. (doi:10. 1097/00001756-200401190-00024) Boer, H., Holland, A., Whittington, J., Butler, J., Webb, T. & Clarke, D. 2002 Psychotic illness in people with Prader–Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet 359, 135–136. (doi:10.1016/ S0140-6736(02)07340-3) Brambilla, R. et al. 1997 A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390, 281–286. (doi:10.1038/36849) Brennan, P. A. 2004 The nose knows who’s who: chemosensory individuality and mate recognition in mice. Horm. Behav. 46, 231–240. (doi:10.1016/j.yhbeh.2004.01.010) Brown, W. M. & Consedine, N. S. 2004 Just how happy is the happy puppet? An emotion signaling and kinship theory perspective on the behavioral phenotype of children with Angelman syndrome. Med. Hypotheses 63, 377–385. (doi:10.1016/j.mehy.2004.05.010) Carruth, L. L., Reisert, I. & Arnold, A. P. 2002 Sex chromosome genes directly affect brain sexual differentiation. Nat. Neurosci. 5, 933–934. (doi:10.1038/nn922) Clayton-Smith, J. & Laan, L. 2003 Angelman syndrome: a review of the clinical and genetic aspects. J. Med. Genet. 40, 87–95. (doi:10.1136/jmg.40.2.87) Cole, B. J., Robbins, T. W. & Everitt, B. J. 1988 Lesions of the dorsal noradrenergic bundle simultaneously enhance and reduce responsivity to novelty in a food preference test. Brain Res. 472, 325–349. (doi:10.1016/0006-8993(88) 91225-5) Constancia, M., Kelsey, G. & Reik, W. 2004 Resourceful imprinting. Nature 432, 53–57. (doi:10.1038/432053a) Phil. Trans. R. Soc. B (2006)

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Cook, E. H., Lindgren, V., Leventhal, B. L., Courchesne, R., Lincoln, A., Shulman, C., Lord, C. & Courchesne, E. 1997 Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am. J. Hum. Genet. 60, 928–934. Curfs, L. M., Wiegers, A. M., Sommers, J. R., Borghgraef, M. & Fryns, J. P. 1991 Strengths and weaknesses in the cognitive profile of youngsters with Prader–Willi syndrome. Clin. Genet. 40, 430–434. Curley, J. P., Barton, S., Surani, A. & Keverne, E. B. 2004 Coadaptation in mother and infant regulated by a paternally expressed imprinted gene. Proc. R. Soc. B 271, 1303–1309. (doi:10.1098/rspb.2004.2725) Davies, W., Isles, A. R. & Wilkinson, L. S. 2001 Imprinted genes and mental dysfunction. Ann. Med. 33, 428–436. Davies, W. et al. 2005a Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice. Nat. Genet. 37, 625–629. (doi:10.1038/ng1577) Davies, W., Isles, A. R. & Wilkinson, L. S. 2005b Imprinted gene expression in the brain. Neurosci. Biobehav. Rev. 29, 421–430. (doi:10.1016/j.neubiorev.2004.11.007) Dechiara, T. M., Efstratiadis, A. & Robertson, E. J. 1990 A growth-deficiency phenotype in heterozygous mice carry an insulin-like growth factor-II gene disrupted by targeting. Nature 345, 78–80. (doi:10.1038/345078a0) Delaval, K. & Feil, R. 2004 Epigenetic regulation of mammalian genomic imprinting. Curr. Opin. Genet. Dev. 14, 188–195. (doi:10.1016/j.gde.2004.01.005) Dewing, P., Shi, T., Horvath, S. & Vilain, E. 2003 Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation. Brain Res. Mol. Brain Res. 118, 82–90. (doi:10.1016/S0169-328X(03)00339-5) Dobson, F. S. 1982 Competition for mates and predominant juvenile male dispersal in mammals. Anim. Behav. 30, 1183–1192. (doi:10.1016/S0003-3472(82)80209-1) Goldstone, A. P. 2004 Prader–Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol. Metab. 15, 12–20. (doi:10.1016/j.tem.2003.11.003) Greenwood, P. J. 1980 Mating systems, philopatry and dispersal in birds and mammals. Anim. Behav. 28, 1140–1162. (doi:10.1016/S0003-3472(80)80103-5) Haig, D. 1997 Parental antagonism, relatedness asymmetries, and genomic imprinting. Proc. R. Soc. B 264, 1657–1662. (doi:10.1098/rspb.1997.0230) Haig, D. 2000 Genomic imprinting, sex-biased dispersal, and social behavior. Ann NY Acad. Sci. 907, 149–163. Haig, D. & Graham, C. 1991 Genomic imprinting and the strange case of the insulin-like growth-factor II receptor. Cell 64, 1045–1046. (doi:10.1016/0092-8674(91)90256-X) Haig, D. & Westoby, M. 1989 Parent-specific geneexpression and the triploid endosperm. Am. Nat. 134, 147–155. (doi:10.1086/284971) Haig, D. & Wharton, R. 2003 Prader–Willi syndrome and the evolution of human childhood. Am. J. Hum. Biol. 15, 320–329. (doi:10.1002/ajhb.10150) Holm, V. A., Cassidy, S. B., Butler, M. G., Hanchett, J. M., Greenswag, L. R., Whitman, B. Y. & Greenberg, F. 1993 Prader–Willi syndrome: consensus diagnostic criteria. Pediatrics 91, 398–402. Holmes, W. G. 1986 Identification of paternal half-siblings by captive belding ground-squirrels. Anim. Behav. 34, 321–327. (doi:10.1016/S0003-3472(86)80099-9) Hurst, L. 1997 Evolutionary theories of genomic imprinting. In Genomic imprinting, vol. 18 (ed. M. Surani & W. Reik), pp. 211–237. Oxford, UK: Oxford University Press. Hurst, L. D. et al. 2000 Peg3 and the conflict hypothesis. Science 287, 1167. (doi:10.1126/science.287.5456.1167a) Isles, A. R. & Holland, A. J. 2005 Imprinted genes and mother–offspring interactions. Early Hum. Dev. 81, 73–77. (doi:10.1016/j.earlhumdev.2004.10.006)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2236

A. R. Isles and others

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Isles, A. R. & Wilkinson, L. S. 2000 Imprinted genes, cognition and behaviour. Trends Cogn. Sci. 4, 309–318. (doi:10.1016/S1364-6613(00)01504-7) Isles, A. R., Baum, M. J., Ma, D., Keverne, E. B. & Allen, N. D. 2001 Urinary odour preferences in mice. Nature 409, 783–784. (doi:10.1038/35057323) Isles, A. R., Baum, M. J., Ma, D., Szeto, A., Keverne, E. B. & Allen, N. D. 2002 A possible role for imprinted genes in inbreeding avoidance and dispersal from the natal area in mice. Proc. R. Soc. B 269, 665–670. (doi:10.1098/rspb. 2001.1911) Itier, J. M. et al. 1998 Imprinted gene in postnatal growth role. Nature 393, 125–126. (doi:10.1038/30120) Iwasa, Y. & Pomiankowski, A. 1999 Sex specific X chromosome expression caused by genomic imprinting. J. Theor. Biol. 197, 487–495. (doi:10.1006/jtbi.1998.0888) Iwasa, Y. & Pomiankowski, A. 2001 The evolution of X-linked genomic imprinting. Genetics 158, 1801–1809. Jiang, Y. H., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D. & Beaudet, A. L. 1998 Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21, 799–811. (doi:10.1016/S0896-6273(00)80596-6) Kamil, A. C. 2004 Sociality and the evolution of intelligence. Trends Cogn. Sci. 8, 195–197. (doi:10.1016/j.tics.2004.03. 002) Kanekoishino, T. et al. 1995 Peg1/Mest imprinted gene on chromsome-6 identified by cDNA subtactive-hybridisation. Nat. Genet. 11, 52–59. (doi:10.1038/ng0995-52) Kesler, S. R., Blasey, C. M., Brown, W. E., Yankowitz, J., Zeng, S. M., Bender, B. G. & Reiss, A. L. 2003 Effects of X-monosomy and X-linked imprinting on superior temporal gyrus morphology in Turner syndrome. Biol. Psychiatry 54, 636–646. (doi:10.1016/S0006-3223(03)00289-0) Keverne, E. B. 2001 Genomic imprinting, maternal care, and brain evolution. Horm. Behav. 40, 146–155. (doi:10.1006/ hbeh.2001.1685) Keverne, E. B., Martel, F. L. & Nevison, C. M. 1996 Primate brain evolution: genetic and functional considerations. Proc. R. Soc. B 263, 689–696. Kuroiwa, Y. et al. 1996 Peg3 imprinted gene on proximal chromosome 7 encodes for a zinc finger protein. Nat. Genet. 12, 186–190. (doi:10.1038/ng0296-186) Lefebvre, L., Viville, S., Barton, S. C., Ishino, F., Keverne, E. B. & Surani, M. A. 1998 Abnormal maternal behaviour and growth retardation associated with loss of the imprinted gene Mest. Nat. Genet. 20, 163–169. (doi:10. 1038/2464) Leighton, P. A., Ingram, R. S., Eggenschwiler, J., Efstratiadis, A. & Tilghman, S. M. 1995 Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature 375, 34–39. (doi:10.1038/375034a0) Li, L. L., Keverne, E. B., Aparicio, S. A., Ishino, F., Barton, S. C. & Surani, M. A. 1999 Regulation of maternal behavior and offspring growth by paternally expressed Peg3. Science 284, 330–333. (doi:10.1126/science.284. 5412.330) Lund, J. P., Kolta, A., Westberg, K. G. & Scott, G. 1998 Brainstem mechanisms underlying feeding behaviors. Curr. Opin. Neurobiol. 8, 718–724. (doi:10.1016/S09594388(98)80113-X) Mateo, J. M. & Johnston, R. E. 2000 Kin recognition and the ‘armpit effect’: evidence of self-referent phenotype matching. Proc. R. Soc. B 267, 695–700. (doi:10.1098/rspb. 2000.1058) McGrath, J. & Solter, D. 1984 Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37, 179–183. (doi:10.1016/00928674(84)90313-1) Phil. Trans. R. Soc. B (2006)

Moore, T. & Haig, D. 1991 Genomic imprinting in mammalian development—a parental tug-of-war. Trends Genet. 7, 45–49. Muscatelli, F., Abrous, D. N., Massacrier, A., Boccaccio, I., Le Moal, M., Cau, P. & Cremer, H. 2000 Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader– Willi syndrome. Hum. Mol. Genet. 9, 3101–3110. (doi:10. 1093/hmg/9.20.3101) Oliver, C., Demetriades, L. & Hall, S. 2002 Effects of environmental events on smiling and laughing behavior in Angelman syndrome. Am. J. Ment. Retard. 107, 194–200. (doi:10.1352/0895-8017(2002)107!0194:EOEEOSO2.0. CO;2) Orr, H. A. 1995 Somatic mutation favors the evolution of diploidy. Genetics 139, 1441–1447. Plagge, A., Gordon, E., Dean, W., Boiani, R., Cinti, S., Peters, J. & Kelsey, G. 2004 The imprinted signaling protein XLalphas is required for postnatal adaptation to feeding. Nat. Genet. 36, 818–826. (doi:10.1038/ng1397) Plagge, A., Isles, A. R., Gordon, E., Humby, T., Dean, W., Gritsch, S., Fischer-Colbrie, R., Wilkinson, L. S. & Kelsey, G. 2005 Imprinted nesp55 influences behavioral reactivity to novel environments. Mol. Cell. Biol. 25, 3019–3026. (doi:10.1128/MCB.25.8.3019-3026.2005) Pusey, A. E. 1987 Sex-biased dispersal and inbreeding avoidance in birds and mammals. Trends Ecol. Evol. 2, 295–299. (doi:10.1016/0169-5347(87)90081-4) Raefski, A. S. & O’Neill, M. J. 2005 Identification of a cluster of X-linked imprinted genes in mice. Nat. Genet. 37, 620–624. (doi:10.1038/ng1567) Reik, W., Constancia, M., Fowden, A., Anderson, N., Dean, W., Ferguson-Smith, A., Tycko, B. & Sibley, C. 2003 Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J. Physiol. 547, 35–44. (doi:10.1113/jphysiol.2002.033274) Relaix, F., Wei, X. J., Wu, X. W. & Sassoon, D. A. 1998 Peg3/Pw1 is an imprinted gene involved in the TNF-NF kappa B signal transduction pathway. Nat. Genet. 18, 287–291. (doi:10.1038/ng0398-287) Relaix, F., Wei, X., Li, W., Pan, J., Lin, Y., Bowtell, D. D., Sassoon, D. A. & Wu, X. 2000 Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53mediated apoptosis. Proc. Natl Acad. Sci. USA 97, 2105–2110. (doi:10.1073/pnas.040378897) Rougeulle, C., Glatt, H. & Lalande, M. 1997 The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat. Genet. 17, 14–15. (doi:10.1038/ng0997-14) Roulin, A. & Hager, R. 2003 Indiscriminate nursing in communal breeders: a role for genomic imprinting. Ecol. Lett. 6, 165–166. (doi:10.1046/j.1461-0248.2003.00421.x) Samaco, R. C., Hogart, A. & Lasalle, J. M. 2005 Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum. Mol. Genet. 14, 483–492. (doi:10.1093/hmg/ddi045) Sara, S. J., Dyon-Laurent, C. & Herve, A. 1995 Novelty seeking behavior in the rat is dependent upon the integrity of the noradrenergic system. Brain Res. Cogn. Brain Res. 2, 181–187. (doi:10.1016/0926-6410(95)90007-1) Sawczuk, A. & Mosier, K. M. 2001 Neural control of tongue movement with respect to respiration and swallowing. Crit. Rev. Oral Biol. Med. 12, 18–37. Sibug, R., Kuppers, E., Beyer, C., Maxson, S. C., Pilgrim, C. & Reisert, I. 1996 Genotype-dependent sex differentiation of dopaminergic neurons in primary cultures of embryonic mouse brain. Brain Res. Dev. Brain Res. 93, 136–142. (doi:10.1016/0165-3806(96)00024-7)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Genomic imprinting and the social brain A. R. Isles and others Skuse, D. H. 1999 Genomic imprinting of the X chromosome: a novel mechanism for the evolution of sexual dimorphism. J. Lab. Clin. Med. 133, 23–32. (doi:10.1053/ lc.1999.v133.a94575) Skuse, D. 2000 Imprinting, the X-chromsome, and the male brain: explaining sex differences in the liability to autism. Pediatr. Res. 47, 9–16. Skuse, D. H. et al. 1997 Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature 387, 705–708. (doi:10.1038/42706) Smith, K., Alberts, S. C. & Altmann, J. 2003 Wild female baboons bias their social behaviour towards paternal halfsisters. Proc. R. Soc. B 270, 503–510. (doi:10.1098/rspb. 2002.2277) Summers, J. A., Allison, D. B., Lynch, P. S. & Sandler, L. 1995 Behaviour problems in Angelman syndrome. J. Intellect. Disabil. Res. 39(Pt 2), 97–106. Surani, M. A., Barton, S. C. & Norris, M. L. 1984 Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308, 548–550. (doi:10.1038/308548a0) Trivers, R. L. 1974 Parent–offspring conflict. Am. Zool. 14, 249–264. Trivers, R. & Burt, A. 1999 Kinship and genomic imprinting. In Genomic imprinting (ed. R. Ohlsson), pp. 1–21. Berlin, Heidelberg, Germany; New York, NY: Springer.

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Vogels, A., Matthijs, G., Legius, E., Devriendt, K. & Fryns, J. P. 2003 Chromosome 15 maternal uniparental disomy and psychosis in Prader–Willi syndrome. J. Med. Genet. 40, 72–73. (doi:10.1136/jmg.40.1.72) Vu, T. H. & Hoffman, A. R. 1997 Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat. Genet. 17, 12–13. (doi:10.1038/ng0997-12) Wahaj, S. A., Van Horn, R. C., Van Horn, T. L., Dreyer, R., Hilgris, R., Schwarz, J. & Holekamp, K. E. 2004 Kin discrimination in the spotted hyena (Crocuta crocuta): nepotism among siblings. Behav. Ecol. Sociobiol. 56, 237–247. (doi:10.1007/s00265-004-0783-8) Widdig, A., Nurnberg, P., Krawczak, M., Streich, W. J. & Bercovitch, F. B. 2001 Paternal relatedness and age proximity regulate social relationships among adult female rhesus macaques. Proc. Natl Acad. Sci. USA 98, 13 769–13 773. (doi:10.1073/pnas.241210198) Wilkins, J. F. & Haig, D. 2003 What good is genomic imprinting: the function of parent-specific gene expression. Nat. Rev. Genet. 4, 359–368. (doi:10.1038/ nrg1062) Wrangham, R. W. 1980 An ecological model of femalebonded primate groups. Behaviour 75, 262–300. Yamada, K. A. & Volpe, J. J. 1990 Angelman’s syndrome in infancy. Dev. Med. Child Neurol. 32, 1005–1011.

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Phil. Trans. R. Soc. B (2006) 361, 2239–2259 doi:10.1098/rstb.2006.1832 Published online 25 April 2006

The Ferrier Lecture 1998 The molecular biology of consciousness investigated with genetically modified mice Jean-Pierre Changeux* Institut Pasteur & Colle`ge de France, 25 rue du Dr Roux, 75724 Cedex 15, Paris, France The question is raised of the relevance of experimental work with the mouse and some of its genetically modified individuals in the study of consciousness. Even if this species does not go far beyond the level of ‘minimal consciousness’, it may be a useful animal model to examine the elementary building blocks of consciousness using the methods of molecular biology jointly with investigations at the physiological and behavioural levels. These building blocks which are anticipated to be universally shared by higher organisms (from birds to humans) may include: (i) the access to multiple states of vigilance, like wakefulness, sleep, general anaesthesia, etc.; (ii) the capacity for global integration of several sensory and cognitive functions, together with behavioural flexibility resulting in what is referred to as exploratory behaviour, and possibly a minimal form of intentionality. In addition, the contribution of defined neuronal nicotinic receptors species to some of these processes is demonstrated and the data discussed within the framework of recent neurocomputational models for access to consciousness. Keywords: consciousness; exploratory behaviour; nicotinic receptors; genetically modified mice

David Ferrier (1878) in his book on ‘The localization of cerebral diseases’ gives a brief report of the experiments he carried out on the ablation of the prefrontal lobes in the monkey. He mentions notable alterations in the ‘character and manners of the animals’ and notes that ‘instead of examining with interest and curiosity all what was happening in their field of observation, they remained apathic and weak, they were sleepy, responding only to sensations and impressions at the time’. ‘They had lost the capacity of intelligent observation and attention’. In the same book, Ferrier also reports the first observation of a frontal lobe lesion in humans, the famous case of Phineas Gage (see Damasio 1995). He notes that following his accident, changes in his emotional reactions and intellectual faculties took place: ‘he became nervous, irreverent. impatient. with an excessive obstination.capricious and undecided’. Ferrier further states that ‘what is true for the monkey is true for man’, thus introducing the important issue of the possible validity of animal models of human brain diseases. In the following years, the Italian neurologist, Luigi Bianchi (1921), went a step further. In his book ‘The mechanics of the brain: the function of the frontal lobes’, he states that ‘among the phenomenal factors of the activities of living organisms’ arises a ‘bond of coherence’, which ‘progresses with the development and complexity of living organisms and of their nervous system’. He refers to it as consciousness and further specifies that ‘the dawn of higher consciousness coincides with the apparition of the frontal lobes in the evolution of the

*[email protected] Lecture delivered 15 October 1998 Typescript received 17 January 2006

brain ’, also noting their ‘inhibitory power’ and their capacity for ‘intellectual syntheses’. Since these early times, the notion that nonhumans may possess consciousness gave rise to contrasting attitudes. Following Thomas Huxley’s (1874) provocative statement of his Belfast lecture that ‘we are conscious automata’, that ‘brutes’ share consciousness with humans and that ‘all states of consciousness in us, as in them, are immediately caused by molecular changes of brain substance’, non-human species have served as convenient experimental models for the scientific investigation of consciousness (Thorndike 1898; Yerkes 1916; Clark & Squire 1998; Jasper 1998; Hauser 2000; Dehaene & Changeux 2004; Koch 2004; Denton 2005). In particular, mice are easily accessible to pharmacological or genetic manipulations and carry out tasks that in humans involve awareness of the stimuli (e.g. Picciotto et al. 1995, 1998; Maskos et al. 2005). Yet, it may be argued that mice lack the most characteristic features of consciousness and ‘what it is like to be a mouse’ may wildly differ from ‘what it is like to be a human being’ (see Nagel 1974). Accordingly, only humans would feel and introspect. Subjective—first person—experience would be the ‘hard problem’ to explain, which requires the invention of far-fetched bridging principles (Chalmers 1998). The issue then becomes to what extent studying mice may help to understand consciousness in humans? Can the laboratory mouse become a relevant animal model to investigate the molecular biology of consciousness or at least some of its aspects? A first point to make is that looking at the broad spectrum of living species, including humans and the developing infants, ‘we must question the monitoring

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of this mental activity’. As already stated by Preyer (1894) in his book ‘Mental development in the child’, there is not the least reason for assuming in advance that every human being comes into the world endowed with complete consciousness of self’ and ‘that at the moment of birth an immortal soul is in waiting, as it were, for the new and as yet unconscious citizen of the world in order to take possession of him forever’. Preyer also noted that in the newborn the different senses gradually develop, in a non-concomitant manner, the feeling of selfhood that he refers to as ‘cortical ego’ developing later. He further states that, as the last step, ‘out of knowledge (science) (he) has developed his conscience’. Unambiguously, ‘there are several grades of consciousness’. The development of these grades, or levels of consciousness, has been reinvestigated recently, in humans from the newborn to the adult (Lagercrantz et al. 2002; Johnson 2005; Lagercrantz 2005; Lee et al. 2005; Bartocci et al. 2006), as in the course of biological evolution (see Boakes 1984; Changeux 2002; Zeki 2003; Zhou et al. 2005). Regrouping the evolutionary analysis of Barresi & Moore (1996), primarily based on social interactions (see also Trivers 1985), and the developmental data of Zelazo (1996, 2004), Lagercrantz (Lagercrantz et al. 2002; Bartocci et al. 2006) and others ( Johnson 2005; Lee et al. 2005) on the human newborn, one may propose a breakdown of ‘consciousness’ into multiplenested hierarchical levels. Beyond Edelman’s (1989) cleavage between what he refers to as ‘primary’ and ‘higher-order’ consciousness primarily on the basis of language use, one may suggest the following distinctions: (i) A lowest level of ‘minimal consciousness’ for simple organisms, like rats or mice, is characterized by the capacity to display spontaneous motor activity and to create representations, for instance, from visual and auditory experience, to store them in long-term memory and use them, for instance, for approach and avoidance behaviour and for what is referred to as exploratory behaviour. The comparability between the action of self and others is reduced. The 25–30-week preterm fetus, according to Lagercrantz (2005), would have reached a stage of brain maturation analogous (though not identical) to a newborn rat/mouse; he/she may process tactile and painful stimuli in the sensory cortex (Bartocci et al. 2006), would perceive pain and thus would show signs of minimal consciousness; (ii) ‘recursive consciousness’, which is present, for instance, in vervet monkeys (possibly also in some birds), manifests itself by functional use of objects and by proto-declarative pointing; organisms at this level may display elaborate social interactions, imitation, social referencing and joint attention; they possess the capacity to hold several mental representations in memory simultaneously, and are able to evaluate relations of self; they display elementary forms of recursivity in the handling Phil. Trans. R. Soc. B (2006)

of representations, yet without mutual understanding; along these lines, the newborn infant exhibits sensory awareness, ability to express emotions and processes mental representations (i.e. of a pacifier); he/she would already differentiate between self- and non-self touch (Rochat 2003) and imitate the tongue protrusion of an adult (Meltzoff 1990); and thus would have reached the stage of what Zelazo (2004) refers to as recursive consciousness; (iii) explicit ‘self-consciousness’ develops in infants at the end of the second year, together with working and episodic memory and some basic aspects of language; it is characterized by selfrecognition in mirror tests and by the use of single arbitrary rules with self–other distinction; to some extent chimpanzees might reach this level (see Boakes 1984); (iv) ‘reflective consciousness’, theory of mind and full conscious experience, with first person ontology and reportability, reaches full development in humans and develops following 3–5 years in children. The case of mice and rats is simple and unambiguous. These species do not go far beyond the level of minimal consciousness. The issue of selfor reflective consciousness is irrelevant. Nevertheless, the mouse may be useful in providing some elementary ‘building blocks’ (Searle 2000) of consciousness. As mentioned, it offers also the possibility of joint investigations at the behavioural, physiological and molecular levels, together with an easy access to a large spectrum of techniques (from molecular genetics to brain imaging), making possible the investigation of what I may refer to as the fundamentals of minimal consciousness. These fundamentals which are anticipated to be universally shared by higher organisms (from birds to humans, but also possibly some invertebrates; see Baars 2001) may include: (i) the access to multiple states of vigilance, like wakefulness, sleep, general anaesthesia, etc.; (ii) the capacity for global integration of several sensory and cognitive functions in goal-directed behaviour (see Hobson 1999), Bianchi’s ‘bond of coherence’, together with behavioural flexibility, and thus what may be referred to as a minimal form of ‘intentionality’ (see §8b). In his recent book, the ‘Quest for consciousness’, Christof Koch (2004) has reduced the issue of consciousness in animals to what he refers to as a ‘Turing test’ for consciousness. ‘Take your sensor–motor routine in some species and enforce a waiting period of a few seconds between the sensory input and the execution of an action. If the organism’s performance is only marginally affected by the delay, then the input must have been stored in some sort of intermediate buffer, implying some measures of consciousness’ (Koch 2004, p. 227). This definition, by its simplicity, is of significant interest; yet, as we shall see, it might not be sufficient, even in the case of the mouse, to specify the fundamentals of consciousness.

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Review 1. MODELLING CONSCIOUSNESS: THE NEURONAL WORKSPACE HYPOTHESIS In an attempt to implement in neural terms the ‘intermediate buffer’ (Koch 2004) or ‘global integration’ (Changeux 1983; Hobson 1999) aspects of consciousness, neurocomputational models referred to under the generic name of neuronal workspace hypothesis (Dehaene et al. 1998, 2003; Dehaene & Changeux 2004, 2005) were proposed (figure 1). These models which extend earlier formal models of delayed-response and card-sorting tasks and of the Tower of London test (Dehaene & Changeux 1989, 1991, 1997) offer, in particular, neuronal implementations of Baars (1998) psychological global workspace. The proposed architectures separate, in a first minimal description (see also Norman & Shallice 1980), two distinct computational spaces, each characterized by particular patterns of connections. Subcortical networks and most of the cortex would be viewed as a mosaic of specialized processors, each attuned to a particular type of information processing, such as sensory ( present), motor ( future), longterm memory ( past), evaluation (value, emotions), or attention focusing (selective amplification or inhibition). In spite of their diversity, processors share specialization, automaticity and fast feedforward and feedback processing (Dehaene et al. 2003) via a limited number of local and medium range connections. On top of this automatic non-conscious level, a distinct set of cortical ‘workspace’ neurons was postulated and characterized by their ability to send and receive projections to many distant areas through long-range excitatory axons. These neurons, mainly pyramidal neurons from cortical layers II and III, particularly dense in prefrontal, cingulate and parietal regions, would break the modularity of the cortex through the recruitment of sets of neurons in the underlying processors; they would allow the broadcasting of information, in a spontaneous and sudden manner— or ‘ignition’—to multiple neural targets, thus creating a global availability (or integration) that would be experienced in consciousness and would give rise to reportability. Other computational theories on consciousness, several of them consistent with the present proposal, have been recently reviewed (Dehaene & Changeux 2005; Maia & Cleeremans 2005). An important feature of these neuronal models of cognitive functions (Dehaene & Changeux 1989, 1991; Dehaene et al. 1998) has been the deliberate incorporation into their architecture of systems of evaluation through reward neurons (Dehaene & Changeux 1989) and even of auto-evaluation (Dehaene & Changeux 1997; see also the algorithms of Barto et al. (1983) and Friston et al. (1994)) implemented in terms of limbic/ mesencephalic aminergic neurons, with which the prefrontal cortex is densely interconnected, and to which dopaminergic (DA) and cholinergic, nicotinic systems may directly, or indirectly, contribute. More elaborate reward learning algorithms based on predictive Hebbian learning were also proposed (Montague et al. 1995, 1996), and their implementation studied both in silico and in vivo in the macaque (Schultz et al. 1997). In contrast with other views (Shallice 1988; Crick & Koch 2003; Koch 2004), Phil. Trans. R. Soc. B (2006)

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a close link was thus proposed between the neural basis of ‘making a conscious mental effort’ and the modelling of reward neurons (Dehaene et al. 1998; Dehaene & Changeux 2000). Simulations performed with the proposed neural architectures account for cognitive tasks which tax the prefrontal cortex, such as delayed-response tasks, the Stroop task, the attentional blink (Dehaene et al. 2003) or inattentional blindness, taking into account the ongoing spontaneous activity of the network (Dehaene & Changeux 2005). Yet, at this stage, many features which characterize the higher levels of consciousness, such as the recursive and reflective aspects of consciousness, have not been dealt with. On the other hand, a simple connectionist circuit initially proposed for self-evaluation (Dehaene & Changeux 1991, 1995) may serve as a basic ingredient to begin modellizing features of explicit self-consciousness. The mouse lies at a low level of the evolutionary scale with a rather reduced prefrontal cortex. Yet, in this species, long-range frontal and callosal connections are abundant, though with the distinctive feature (at variance with primate and cat) of large-scale maintenance of simultaneous projection by frontal cortical and callosal projection neurons in the adult (Mitchell & Macklis 2005). Also, in mice and rats, strong evidence exists for a relationship between working memory and prefrontal function and interaction ( Thinus-Blanc 1996; Jones 2002). Moreover, in mice and rats, all the neuronal modulatory systems (cholinergic, DA, serotoninergic, adrenergic, etc.) are present and functional in the regulation of states of wakefulness, attention but also in reward processes. The mouse may thus possess a sufficient number of building blocks ( Thinus-Blanc 1996) to make the scientific investigation of the fundamentals of minimal consciousness of relevant interest.

2. THE NEURONAL NICOTINIC RECEPTORS: ALLOSTERIC MEMBRANE PROTEINS THAT MODULATE HIGHER BRAIN FUNCTIONS Physiological, psychopharmacological and pathological evidence supports the concept of an implication of cholinergic systems in cognitive functions and conscious awareness (Woolf 1997; Perry et al. 1999; Perry & Perry 2004) to the extent that Koch (2004) states that ‘if a single neurotransmitter is critical for consciousness, then it must be acetylcholine’ (p. 90). Of particular interest in the context of consciousness, cholinergic neurons form discrete nuclei that provide widely divergent projections throughout the brain (rev. Semba 2004): (i) the basal forebrain neurons (including the nucleus basalis and medial septal nucleus) constitute the main afferent system to the cerebral cortex and thalamus, and its functions include arousal, selective attention and rapid eye movement (REM) sleep; (ii) the pedunculopontine neurons and lateral dorsal tegmental nucleus widely project to the forebrain regions, such as the thalamus but also to the brainstem reticular formation; this system also

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Figure 2. The nicotinic acetylcholine receptor: a typical allosteric membrane protein. Reconstituted atomic model of the a7 receptor (a) and in the resting closed (b(i)) and open-channel (b(ii)) states (from Taly et al. 2005).

contributes to the control of sleep and wakefulness in mammals (Semba 1999); moreover, both nuclei provide the cholinergic innervation of the DA cells of the ventral tegmental area (VTA) and subtantia nigra and play a role in the acquisition of drug-rewarded behaviour and drug addiction, in particular nicotine self-administration (DiChiara 2000; Robbins 2000; Balfour 2002; rev. Gutkin et al. 2006), together with rewarded cognitive tasks performance (Kobayashi & Isa 2002). Last, intrinsic cholinergic neurons are also distributed in the cerebral cortex and striatum, together with a variety of cholinergic cells dispersed in several brain regions (Semba 2004). Acetylcholine in the brain interacts with two distinct categories of pharmacological receptors: muscarinic receptors that belong to the broad family of G-proteincoupled receptors with seven transmembrane helices, and nicotinic acetylcholine receptors (nAChR), which are pentameric, transmembrane ligand-gated ion channels (figure 2). Muscarinic receptors control working memory, declarative memories, sustained visual attention and psychomotor speed (see Ellis et al. 2005), Phil. Trans. R. Soc. B (2006)

and drugs that antagonize muscarinic receptors cause hallucinations and reduce the level of consciousness (Perry et al. 1999; Perry & Perry 2004). On the other hand, nicotine acting on brain nAChRs enhances arousal, attention and working memory, causes EEG desynchronization and higher amounts of REM sleep (rev. Levin 2002). Moreover, nAChRs have been implicated in the mechanisms of general anaesthesia. Volatile anaesthetics and ketamine have been reported to inhibit nicotinic receptors (a4b2 and a3b4) at clinically relevant doses (Franks & Lieb 1994; Tassonyi et al. 2002; see §8a). The nAChRs are among the best-characterized pharmacological receptors and their contribution to brain functions actively investigated (rev. Changeux & Edelstein 2005). Their potential role in the control of consciousness will thus exclusively be considered in the subsequent sections of this review. Muscle nAChR was initially identified from fish electric organ (rev. Changeux 1981, 1990; Changeux & Edelstein 2005) as a protein of about 300 000 MW made up of five subunits of several different types. Extensive biochemical studies, including reconstitution experiments and expression studies from cloned subunit genes, have shown that

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this transmembrane oligomer carries several categories of binding sites: two distinct acetylcholine (nicotine and snake venom a-toxins) sites located at the interface between subunits, a unique ion channel located in the axis of pseudosymmetry perpendicular to the membrane plane and all the structural elements that mediate the signal transduction process elicited by the neurotransmitter acetylcholine: the activation and desensitization of the ion channel (Changeux & Edelstein 1998, 2005). Biochemical equilibrium studies, in vitro rapid kinetics and in vivo electrophysiological recordings in situ or from functional receptors reconstituted in frog oocytes from genetically engineered subunits (rev. Changeux & Edelstein 2005) support the extension to the nAChR of the scheme proposed by Monod, Wyman & Changeux (1965) (MWC) for regulatory enzymes (rev. Changeux 1981; Changeux & Edelstein 1998, 2005). In short, the signal transduction processes of activation and desensitization are viewed as resulting from: (i) the spontaneous occurrence of the receptor protein under discrete conformations in reversible equilibrium; (ii) the differential stabilization of one of these few conformations by the ligand for which it exhibits the highest affinity; (iii) the conservation of the molecular symmetry of the receptor oligomer in the course of these transitions; (iv) the differences in the states of activity of the discrete conformations involved: the active state is the only conformation where the channel is open, the desensitized state exhibits the highest affinity for agonists (and some antagonists); (v) the presence of multiple allosteric sites for physiological and/or pharmacological ligands (e.g. for local and general anaesthetics) through which ligand binding may differentially stabilize the conformations of the protein. Determination of the X-ray crystal structure of the snail acetylcholine-binding protein (a homologue of the extracellular domain of the nAChR; Brejc et al. 2001; Celie et al. 2004), together with the cryo-electron microscopy data of the membrane domain collected on Torpedo marmorata muscle type nAChR (Unwin 2000, 2005), has recently led to refined three-dimensional models of the receptor molecule (Paas et al. 2005; Taly et al. 2005; Unwin 2005). These studies demonstrate that: (i) the ACh-binding sites are far distant from each other ˚ ) and (ii) the signal transduction mechanism (ca 30 A that links the neurotransmitter sites and the ion channel involves a global structural change of the quaternary and tertiary structure of the protein that unites the two distinct domains of each subunit. In the absence of X-ray structural data, the conformational transitions were explored in silico by a computer method referred to as normal mode analysis. The first mode (over the first 10) was found to produce a structural reorganization of the model molecule compatible with channel gating. A wide opening of the channel pore resulted from the concerted symmetrical quaternary twist motion of the protein (Paas et al. 2005; Taly et al. 2005; Cheng et al. 2006). The data were found consistent, in first approximation, with the MWC two-state model of allosteric transition. Phil. Trans. R. Soc. B (2006)

Among the 17 genes encoding nAChR subunits that have been identified and cloned in mammals, nine (a2–a7 and b2–b4) are expressed in the brain. These subunits may co-assemble to form a wide variety of functional pentamers that are distributed throughout the brain with different pharmacological and electrophysiological properties. The most abundant combinations of subunits are: a4b2 containing nAChRs (a4b2
), which exhibit high affinity for acetylcholine and nicotine, do not bind a-bungarotoxin and are abundant in cerebral cortex and thalamus; a3b4, which is primarily present in the peripheral nervous system; and a7 homopentamers, which display a low affinity for acetylcholine, tightly bind a-bungarotoxin, desensitize very quickly and are abundant in the limbic systems and cerebral cortex (rev. Le Novere et al. 2002). The existence of overlapping patterns of expression of these subunits has thus hampered the elucidation of the role of a particular subunit (or subunits) in brain functions until mice deleted for specific nAChR genes became available (Picciotto et al. 1995, rev. Champtiaux & Changeux 2004). In parallel, gene targeting and homologous recombination experiments were carried out to create mice carrying mutations in nAChR genes associated with different diseases in humans. Several of them are relevant to this review, since they cause idiopathic epilepsies (Steinlein et al. 1995) and, as we shall see, may affect states of consciousness (Champtiaux & Changeux 2004; Steinlein 2004).

3. THE INTEGRATION OF NEURONAL NICOTINIC RECEPTORS TO THE NEURONAL WORKSPACE ARCHITECTURE The prefrontal areas of the neocortex are known to play a key role in higher cognitive functions (see Levin 1992, 2002; Sacco et al. 2004), and were postulated to be essential components of the conscious neuronal workspace architecture (Dehaene et al. 1998; Changeux 2004; Dehaene & Changeux 2004; see Bianchi 1921). An eventual contribution of nAChRs to this network was investigated at the cellular and synaptic levels (figure 3). Early work on synaptosomal preparations identified presynaptic nAChRs in vitro (rev. Wonnacott et al. 1995). Yet their cellular distribution and function in neuronal networks had not been established. In a first electrophysiological approach (Vidal & Changeux 1989), extracellular recordings of field potentials and unit discharges were taken from the superficial layers of slice preparations of the prelimbic area of the prefrontal cortex. They revealed excitatory effects of nicotine that were blocked by neuronal bungarotoxin, and thus possibly involved a3b2 or most likely a4b2 nAChRs. In subsequent experiments, still on in vitro slices (Vidal & Changeux 1993), intracellular recordings were made from pyramidal neurons located predominantly in layers II–III (where nicotine-binding sites were found concentrated; Clarke 1993), which belong to the longaxon neurons, subsequently postulated by the neuronal workspace hypothesis (Dehaene et al. 1998; Dehaene & Changeux 2004). Iontophoretic application of nicotine near the recording site increased the amplitude of

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Figure 3. Presence of functional nicotinic receptors in prefrontal cortex slices. Opposite effects of nicotine and muscarine on post-synaptic potentials in layers II/III neurons (from Vidal & Changeux 1993).

channel blocker tetradotoxin (TTX) was found to block these effects. The specificity of TTX is strictly limited to voltage sensitive NaC channels. These channels are thus mobilized in the coupling between nAChR and the terminal GABAsites release. The nAChRs involved, thus, are not located on the nerve ending. The term ‘preterminal’ was coined to qualify the occurrence of these nAChRs along the axon and the observation confirmed by other groups (McMahon et al. 1994; McGehee & Role 1996). The only plausible localizations of these axonal nAChRs are the ‘nœud de Ranvier’. Their precise role at this level is still not understood. As previously noted, the expansion of the neocortex and, in particular, of the prefrontal cortex in high mammals is accompanied by a massive increase of the white matter. A possible—but still highly speculative function—would be that they are the target of as yet unidentified cholinergic terminals that would exert global control of the state of activity of the long axons that compose the white matter and regulate, in a ‘paracrine’ or ‘volume’ manner, the states of consciousness mediated by the global workspace!

the postsynaptic potentials evoked by electrical stimulation of the superficial cortical layers. In contrast, muscarinic agonists decreased the amplitude of the postsynaptic response. In all instances, the early postsynaptic potentials were blocked by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptor antagonists (CNQX; 6-cyano-7-nitroquinolaxine-2,3-dione disodium), but not by NMDA (N-methyl-D-aspartic acid) glutamate receptor blockers (APV; D-2-amino-phosphonopentanoic acid). The facilitation of glutamatergic excitatory synapses by presynaptic nAChR has since then been confirmed in several laboratories (see McGehee & Role 1996). Many neurons in the brain have also been found to generate fast inward currents upon application of nicotine to the somatodendritic compartment, in particular cells from the locus ceruleus (Lena et al. 1999), VTA (Klink et al. 2001; Champtiaux & Changeux 2004), medial habenula and interpeduncular nucleus (IPN; Mulle & Changeux 1990; Mulle et al. 1991). Last, inhibitory GABAergic neurons have also been found to express nAChR, in particular at the postsynaptic level, where they enhance synaptic inhibition (rev. Klink et al. 2001; Maggi et al. 2003, 2004). In conclusion, nAChRs are abundant throughout the brain, in the prefrontal cortex and DA neurons in particular, where they differentially enhance both excitatory and inhibitory transmission. nAChRs are thus present at the level of workspace neurons and reward neurons where they may possibly control the access to the workspace and the processing of conscious information. In relation with this hypothesis, another unexpected target of nAChR was found on myelinated axons of the white matter. The discovery was casually made through whole-cell recordings of acutely isolated neurons from the IPN that had retained synaptic contacts from myelinated fibres still attached to their cell body. As anticipated, nicotine dramatically increased the frequency of GABAergic postsynaptic currents on the IPN neurons. Yet, rather unexpectedly, the NaC

4. NICOTINIC RECEPTORS AND STATES OF VIGILANCE IN THE MOUSE In mammals, including mice and men, two cholinergic systems exert activating effects on thalamocortical and cortical neurons: first, the pedunculopontine and laterodorsal tegmental nuclei that project to all thalamic nuclei, but have no direct projection to the cortex and second, the nucleus basalis that projects to the cortex and thalamic reticular nucleus. Acetylcholine release from both systems brings thalamic and cortical neurons closer to their firing threshold, ensuring fast responses to external stimuli during waking or to inner ones during REM sleep (rev. Steriade 2004). Acetylcholine excites pyramidal neurons through a prolonged depolarization mediated by muscarinic receptors, but also produces fast depolarization of interneurons through both muscarinic and nicotinic receptors (ref. Jones 2004). Moreover, nicotine intake has long been known to cause EEG desynchronization (Yamamoto & Domino 1965) and to increase arousal and attention (Lawrence et al. 2002; Levin 2002). Also, the nicotinic antagonist mecamylamine causes drowsiness and decreases the performance in attention-demanding tasks (Pickworth et al. 1997). Last, acetylcholine release increases in the rat prefrontal cortex during the performance of a visual attentional task (Passetti et al. 2000). In order to evaluate the specific contribution of nAChRs to the regulation of sleep and wakefulness, mice lacking the b2 subunit (b2K/K; Picciotto et al. 1995, 1998) were investigated. The b2K/K mice are devoided of high-affinity nicotinic-binding sites in the brain (Picciotto et al. 1995; Zoli et al. 1998), and exhibit a loss or reduction of nicotine-elicited currents in neurons from various brain regions (rev. Klink et al. 2001). Yet, they survive and reproduce without difficulties. Their respiration was monitored by plethysmography (Cohen et al. 2002, 2005) and their cerebral electrical activity recorded as polygraphic EEG or EMG (Lena et al. 2004).

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In a first series of experiments, the respiration of adult b2K/K individuals was followed by plethysmography (Cohen et al. 2002). During sleep, the episodes of quiet sleep manifest themselves by regular large-amplitude respiratory movements, which contrast with the irregular transient movements of wakefulness. Hypoxic challenge caused in b2K/K mice (compared to wild-type (WT)) an increased ventilatory response with a reduction of transient movements, revealing a contribution of b2
-nAChR to awakening under these conditions (Cohen et al. 2002). The plethysmography method was adapted to newborn mice and their breathing and arousal responses challenged, following exposure to controlled doses of nicotine during pregnancy. Newborn WT pups exposed to nicotine exhibited unstable breathing and impaired arousal, deficits remarkably similar to those detected in pups lacking b2
-nAChR. Chronic nicotine exposure thus, like the lack of b2
-nAChR, impairs the arousal response to distress of newborn mice (Cohen et al. 2005). The newborn mice maternally exposed to nicotine thus offer a plausible model of sudden infant death syndrome (SIDS), which prevalence is increased several folds with smoking mothers. The organization of sleep was monitored by polygraphic recordings (EEG, EMG) in adult b2K/K versus WT (Lena et al. 2004) (figure 4). First nicotine (1–2 mg kgK1, i.p.) produced an increase in the time spent in the awake state in WT mice and correlatively caused a rebound increase in sleep during the second hour after the injection. These two effects of nicotine were not observed in b2K/K mice. In contrast, under normal conditions, the b2K/K mice displayed the same amounts of waking, non-rapid eye movement (NREM) sleep and REM sleep as their WT counterparts. The endogenous physiological activation of b2
nAChR thus does not contribute critically to overall sleep regulation, but plays a discrete role in shaping sleep episodes. In particular, the b2K/K mice exhibited longer REM sleep episodes and a reduced fragmentation of NREM sleep by events referred to as ‘microarousals’ characterized notably by a transient increase in EEG power and an EMG activation. The lower frequency of microarousals during NREM sleep observed in b2K/K mice resembles the deficit in putative arousals reported above after a hypoxic challenge (Cohen et al. 2002). These results indicate that nAChRs are involved in the phasic expression of arousal promoting mechanisms (Halasz 1998; Terzano & Parrino 2000) observed in NREM sleep. They thus control transitions of brain circuits from the sleeping conscious state.

5. NICOTINIC RECEPTORS AND NOCTURNAL FRONTAL LOBE EPILEPSIES Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was the first congenital epilepsy found in humans to segregate as a single gene disorder (Schaeffer et al. 1994) and to be caused by point mutations within the genes coding for the a4 and b2 subunits of the neuronal nAChR (Steinlein et al. 1995; Phil. Trans. R. Soc. B (2006)

De Fusco et al. 2000; Phillips et al. 2001). ADNFLE is characterized by nocturnal motor seizures, which tend to cluster, and often occur several times at night. Seizures are mainly occurring during non-REM sleep, either shortly after falling asleep, or in the early morning hours. The main age of onset is within the first or second decade of age and the frequency of nocturnal attacks tends to decrease with advanced age and even to disappear. The first ADNFLE mutation identified a4 Ser248Phe (Steinlein et al. 1995) hits precisely the particular amino acid which was first identified by chlorpromazine in Torpedo ion channel transmembrane segment MII (Giraudat et al. 1986; Hucho et al. 1986). Several other ADNFLE mutations have been identified in a4 and b2 genes (Steinlein 2004). Even though their physiological phenotype may vary from one mutation to the other, there seems to be a general agreement on their ‘gain of function’ character (Revah et al. 1991; Bertrand et al. 1992; Devillers-Thie´ry et al. 1992; Itier & Bertrand 2002), a phenotype that is simply, but not exclusively, accounted for by the MWC model (Changeux & Edelstein 2005, see §8a). Interestingly, the seizures tend to occur in a stage of light sleep, where intense cydic microarousals activity takes place (Terzano & Parrino 2000), and in some ADNFLE cases, a direct temporal correlation was found between microarousals and epileptic manifestations (Zucconi & Ferini-Strambi 2000). Mouse models of several of the ADNFLE mutations have been created for a4 (but also for another a7) subunits (Labarca et al. 2001; Broide et al. 2002; Gil et al. 2002) by knockin technology. Mice homozygous for the a7-L270 T mutation die shortly after birth, while heterozygous animals are viable, but more sensitive to the convulsant effects of nicotine (Broide et al. 2002; Gil et al. 2002). The a4 homologues of known human ADNFLE mutations have been produced and display enhanced susceptibility to epileptic seizures (Tapper et al. 2004; Rodrigues-Pinguet et al. 2005). In conclusion, alteration of the allosteric transitions of the nAChR may cause the production of epileptic seizures. Discrete molecular properties of a receptor molecule thus ‘gate’, in a bottom-up manner, and the transitions between distinct brain states are known to affect the subject’s states of consciousness.

6. NICOTINIC RECEPTORS AND THE CONTENT OF CONSCIOUSNESS Already in the early 1990s, a rich body of pharmacological and behavioural observations underlined the importance of cholinergic pathways and their nicotinic component in working memory and attentional processes that rely on the contribution of the prefrontal cortex (figure 5; Nordberg & Winblad 1986; Levin 1992). To evaluate the role of nAChRs in these cognitive—we might even say today ‘conscious’—tasks, the effect of nAChR blockers was tested in the rat on delayed-response tasks (Granon et al. 1994, 1995). The performance on two distinct tasks was compared. First, a delayed-non-matching-to-sample task (NMTS) was used as reference. The tasks depend on the tendency of

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the animal to spontaneously alternate, on a second run, to the branch it did not visit on the first time. This behaviour makes sense on an evolutionary basis, since the rat will not visit a place where it already consumed the food reward. As a consequence, the delayedPhil. Trans. R. Soc. B (2006)

matching-to-sample task (MTS), which consists in visiting the arm where the food reward was, is an effortful task. As anticipated, lesions of the prefrontal cortex selectively impaired the performance of the MTS task, caused errors and perseverations, while

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100 ng nicotine Figure 5. Nicotinic receptors and content of consciousness: consequences of the deletion of the b2 subunit and of its stereotaxic re-expression in the ventral tegmental area on self-administration of nicotine and on the navigatory behaviour of the mouse (from Maskos et al. 2005); VEC, re-expressed b2 subunit.

preserving the performance of the NMTS tasks (Granon et al. 1994). Interestingly, injection of neuronal bungarotoxin into the prelimbic area of the prefrontal cortex produced a significant performance deficit in the MTS, but not in the NMTS. In contrast, an inhibitor of the muscarinic receptor, scopolamine, impaired performance in both tasks. nAChRs in the prefrontal cortex are thus necessary to the successful performance of the delayed-response tasks, requiring effortful processing for response selection (Granon et al. 1995). Is this a sufficient demonstration of the Turing test for consciousness? Mice do not pass MTS versus NMTS tasks as easily as rats, possibly because, as we shall see, of their compulsive tendency to explore. The specific contribution of particular species of nAChR to such complex cognitive functions was nevertheless examined in mutant versus WT mice (Picciotto et al. 1995, 1998; Granon et al. 2003). The b2K/K mice were selected because both high-affinity nicotine-binding sites and electrophysiological responses to nicotine were almost completely absent from the brain (Picciotto et al. 1995). The Moris watermaze evaluates spatial orientation learning. The performance of b2K/K mice in the test did not differ from that of WT mice when tested both on the visible platform task and on the hidden one, indicating an intact spatial memory (Picciotto et al. 1995). Retention of an inhibitory avoidance response was then assessed because of its known sensitivity to nicotine administration. The mouse was placed in a well-lit chamber of a shuttle box, and the latency to enter the adjacent dark chamber measured. Upon entry to the dark chamber, a mild inescapable foot shock was delivered and nicotine (versus saline) injected into the mouse. After 24 hours, retention was assessed by measuring the latency to enter the dark chamber. Interestingly, treatment with nicotine after foot shock consistently aided retention and nicotine administration was completely ineffective in b2K/K mice. Control experiments confirmed that the b2K/K mice did not differ from their non-mutant siblings by sensory sensitivity, pain threshold or increased emotionality (see also Granon et al. 2003; S. Granon, unpublished work 2006). The effect of nicotine on memory Phil. Trans. R. Soc. B (2006)

retention may only indirectly concern the issue of consciousness in the mouse, yet an unexpected though relevant observation was made. Retention latency was significantly longer for mutant mice than for their nonmutant-injected siblings (Picciotto et al. 1995). The learning abilities of the b2K/K versus WT mice were further investigated in a maze equipped with four dissociable arms. Animals learned to reach food from any location in a given configuration of the arms. The configuration of the arms was then changed and the starting point as well, without changing the position of the goal arm in the absolute space. Yet, here as well, quite unexpectedly, b2K/K mice learned the task more rapidly than WT mice (Granon et al. 2003). Explanation of this paradoxical behaviour, noted in both the multiple configuration maze and the avoidance learning task (Picciotto et al. 1995; which, in addition, becomes amplified with age; Zoli et al. 1999; Caldarone et al. 2000), came out from a closer analysis of the organization behaviour in b2K/K versus WT mice. Exploratory activity is a spontaneous behaviour that does not involve explicit reinforcement (Renner 1990; Thinus-Blanc 1996; Poucet & Hermann 2001; even though it mobilizes, as we shall see, endogenous reward processes). It serves to gather and store spatial information, which allows allocentric coding of space, itself, necessary for flexible navigational processes. In one experiment, mice were placed in the centre of an empty arena and their spontaneous trajectories recorded with a camera fixed to the ceiling and connected to a video track system. The system was set up to break down each trajectory into navigation (large movements at fast speeds 14.4 cm sK1), fast exploration (small movements at a speed between 6.8 and 14.4 cm sK1) and slow exploration (small movements at a speed up to 6.8 cm sK1). A complementary ‘automatic’ analysis by ‘symbolic’ quantification of trajectories (Faure et al. 2003) was carried out in parallel. It included the definition of the position of the animal, its two-dimensional path and its instantaneous velocity. Statistical analysis revealed a modification in the organization of displacements in the b2K/K mice. The balance between navigation and exploration was shifted in the b2K/K mice in favour of navigation to the detriment of more precise exploration of the

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Review environment. The symbolic analysis further revealed a reduction of the trajectories in the centre of the arena for the b2K/K mice, due to high-speed crossing without slowing down in the centre. In other words, the b2K/K mice were more rigid and exhibited less behavioural flexibility than the WT (Granon et al. 2003; Maskos et al. 2005), and the apparent faster learning in the above-mentioned situations simply results from the absence of time-consuming exploration of the apparatus used. These aspects were further evaluated by placing the mice in more sophisticated environments. First, a single object was presented in the arena. No difference of exploratory behaviour was noted, indicating no gross sensory or memory impairment in the recognition process. But, when two objects were placed in the environment, the b2K/K mice exhibited an exploratory behaviour different from WT mice. Symbolic analysis revealed a striking reorganization of the transitions between sequences of action in the WT, which was absent in the b2K/K mice. WT mice increased the number of trajectories between the two objects, while b2K/K mice did not; in other words, they display a spontaneous flexibility of behaviour, an increased curiosity (Denton 2005), that requires the presence of b2
-nAChR (Granon et al. 2003). Last, the cognitive behaviour of the b2K/K mice was analysed further in conflict-behaviour paradigms that requires strategic choice. Two situations were considered. In a first series of experiments, the multiple arms maze was used and the same learning protocol, except that objects were inserted in the maze as attentional distractors. WT mice reacted to novelty by increasing exploratory activity, whereas, again, b2K/K mice did not show this adaptative flexibility to a change in the environment. In a last series of experiments, the sequences of socalled ‘social’ interactions were examined between a test resident mouse and a social intruder. In short, among the diverse types of interactions tested, the b2K/K mice showed significantly higher rates of approach behaviours, and lower rates of escape behaviours. In other words, the b2K/K mice display more ‘automatic’ interactions: faster rates of approach and impaired capacity for interrupting ongoing behaviour (Granon et al. 2003). Lesion experiments (S. Granon unpublished work) reveal that mice with prefrontal lesions do not show significant alteration in spatial learning, but display evident deficit in conflict-resolution situations in the maze paradigm with an unexpected object. The prefrontal lesion creates a behavioural phenotype that displays several features in common with the loss of b2
-nAChR, which affects behavioural flexibility and ability to hierarchize competing motivations. Along these lines, different related experimental paradigms, referred to as delay versus trace conditioning (Clark et al. 2002), were applied to the mouse by another group, yet without the above pharmacological and genetic analysis (Han et al. 2003a). They will be mentioned here for methodological reasons. In trace conditioning, a time gap was introduced between the end of the conditioned stimulus (such as a tone) and the unconditioned stimulus (like a foot shock), while in Phil. Trans. R. Soc. B (2006)

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delay fear conditioning, the conditioned stimulus was immediately followed by the unconditioned stimulus. A visual distraction of flash of light was introduced at randomly selected intervals. Interestingly, the distraction interfered selectively with trace but not delay conditioning. Trace conditioning, which is thought as requiring conscious awareness, was expectedly found associated with increased neuronal activity in the anterior cingulate cortex and was selectively impaired by lesion of this structure in the medial prefrontal territories at variance with delay conditioning (Han et al. 2003a,b). Interestingly, similar experiments have been carried out in humans, in whom an explicit requirement for attentive awareness was demonstrated for the trace, but not delay conditioning task (Carter et al. 2003). Moreover, the phenotypes observed with the b2K/K mice and characterized by alterations of behavioural flexibility and adaptative behaviours coupled with unimpaired memory and anxiety may reproduce the cognitive impairments observed in human diseases (Granon et al. 2003); for instance, in attention deficit hyperactivity disorders (ADHD; Granon & Changeux in press) and even in autism (Frith 2001; Andres 2002; Booth et al. 2003). Both groups of patients show a reduced activation of prefrontal and cingulate cortices (Frith 2001; Giedd et al. 2001), and autistic children further show a substantial decrease of a4b2-containing nAChR in their prefrontal cortex (Perry et al. 2001). The b2K/K mice thus might represent a useful animal model for the study of ADHD and autism (Granon et al. 2003; Granon & Changeux in press; but see §8). In conclusion, mice under these experimental conditions do far more than to simply react to sensory information. They engage in complex extended behaviours geared towards far removed goals. They use processes that override or differentially select routines (Thinus-Blanc 1996) and, according to Denton (2005), orchestrate locomotor behaviours according to ‘conscious intentions’, a behaviour consonant with, though far more elaborate, than Koch’s Turing test for consciousness. Further studies are of course needed to further complement, I would even say justify, these conclusions (see §8).

7. THE JOINT RECOVERY OF EXPLORATORY BEHAVIOUR AND REWARD FUNCTION BY TARGETED RE-EXPRESSION OF nAChR SUBUNIT To further understand the specific role of nAChR subunits in mediating the effects of nicotine and endogenous acetylcholine on higher cognitive functions in the mouse, a method of selective re-expression of a nAChR subunit by stereotaxic injection of a lentiviral vector in a defined territory of the brain of a knockout (KO) mouse was developed (Maskos et al. 2005). Lentivirus-based expression systems, initially developed for gene therapy purposes (Naldini et al. 1996), provide several advantages over other virusbased in vivo transgene expression strategies. In particular, they are capable of stable integration into the genome of non-dividing cells, such as neurons, facilitating the potential for long-term, stable transgene expression. The lentiviral expression vector was derived

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from the pHR 0 expression vectors of Naldini et al. (1996), yet with several modifications: it contained a bi-cistronic cassette simultaneously expressing the b2 subunit and the enhanced green fluorescent protein facilitating efficient detection of transduced cells (Maskos et al. 2002). The vector was stereotaxically injected into the VTA of mice carrying b2-subunit deletions. The ligand-binding nAChR protein was found quantitatively re-expressed in DA-containing neurons of the VTA, using epibatidine as a ligand. Its functionality was assessed by recording in vivo the effect of nicotine on the electrophysiological activity of DA neurons in the VTA. The well-established rapid 1.5-fold increase in firing frequency upon intravenous injection of nicotine, which disappeared in the b2K/K mice, was recovered. However, instead of lasting on average nearly 10 min as in WT, this effect did not persist for more than 2 min. These data show that the re-expression of the b2 subunit exclusively in the VTA suffices to recover an effect of nicotine on DA neurons. Furthermore, using in vivo intracerebral microdialysis in awake, freely moving mice, nicotine-elicited DA release from the nucleus accumbeus (NuAcc) was found completely restored by the re-expressed b2 subunit in the b2K/K mice. To assess whether the nicotine-elicited responses observed in the VTA and NuAcc following reexpression of the b2 subunit were sufficient to support nicotine reinforcement, an intra-VTA nicotine self-administration paradigm in the mouse, as described for morphine self-administration (David & Cazala 1994), was used. WT mice exhibited a clear nicotine-seeking and self-administration behaviour, which disappeared in the b2K/K mice. Interestingly, the lentivirus-injected mice recovered intra-VTA nicotine self-administration behaviour and improved their performance over learning sessions, yet they displayed a delay in the acquisition of self-administration and their discrimination performance was slightly lower than that observed for WT mice. Therefore, reexpression of b2
-nAChR in the VTA is not only necessary, but also sufficient to re-establish sensitivity to nicotine reward in drug-naive mice. Having established that VTA re-expressed b2
nAChR respond to nicotine in vivo, the spontaneous exploratory behaviour of the injected mice was examined. As mentioned, b2K/K mice exhibit modified spatio-temporal organization of displacements, with increased navigatory and decreased exploratory behaviour (Granon et al. 2003). Interestingly, the lentivirus-injected mice showed a selective restoration of exploration, bringing this measure up to the level of WT without a significant modification of navigation. In addition, they exhibited transitions between fast and slow movements in the central portion of the arena that were similar to WT. The targeted expression of b2
nAChR in the VTA thus generated, at least, a partial dissociation between exploratory and navigatory behaviour. These results demonstrate that nAChRs in neurons originating in the VTA and/or their axonal projections suffice for the differential restoration of the cognitive executive function, as studied in our paradigm. This behaviour therefore appears to be mediated by Phil. Trans. R. Soc. B (2006)

endogenous acetylcholine acting on b2
-nAChR expressed on VTA neurons and their axonal projections, in particular to the NuAcc. It suggests the implication of DA as the endogenous neuromodulatory substance for this executive function. In conclusion, this study shows that re-expression of functional b2
-nAChRs, specifically in the VTA and its axonal projections, suffices to simultaneously restore the self-administration of nicotine and the ability to perform an executive behaviour under endogenous cholinergic modulation, thus bringing a first experimental demonstration of the proposed theoretical mechanisms, implying a causal link between cognitive learning, motivation and reward processes (Dehaene & Changeux 1989, 2000; see also Damasio 1995). Moreover, it underlines a rather unclassical, yet predicted (Dehaene et al. 1998), but still hypothetical connection between reward neurons and consciousness. 8. IS THE MOUSE A USEFUL ANIMAL MODEL TO INVESTIGATE CONSCIOUSNESS? The issue of mouse consciousness is not simply philosophical (Block 1990). The obvious limitation of the mouse model in the scientific study of consciousness is its reduction to a minimal level and thus of the impossibility to investigate some of its most characteristic human features like self-recognition and reflective consciousness. On the other hand, as we saw, it gives access to a large spectrum of methods, in particular to recombinant DNA technologies (gene deletion, gene exchange and targeted gene expression), which provide the means to explore, at the molecular, cellular, neuronal networks and behavioural levels what I referred to as the fundamentals of minimal consciousness. In this paper, data on the contribution of neuronal nAChRs to these fundamentals have been reviewed. The main conclusions may be summarized as follows. (a) States of vigilance: sleep & arousal, epilepsy, general anaesthesia Multiple states of vigilance (such as wakefulness, sleep, coma, general anaesthesia, epileptic seizures, etc.) and the regulation of their reversible transitions occur in the mouse as in all mammals, including humans; the circadian sleep–waking cycle is controlled in these species by brainstem reticular formation and intralaminar nuclei of the thalamus (Bogen 1995; Jones, E. 1998; Jones, B. 1998), with complex patterned releases of neuromodulatory substances. The use of mice deleted for the b2-subunit gene gave us the opportunity to demonstrate the positive contribution of b2
nAChR to the phasic expression of arousal promoting mechanisms by endogenous acetylcholine (Cohen et al. 2002; Lena et al. 2004). Similar phenotypes as those noticed in b2K/K mice are observed after chronic in utero exposure of the fetus to nicotine. These mice thus offer, in addition, a plausible animal model of SIDS, the prevalence of which is known to increase in smoking pregnant women (Cohen et al. 2005). Furthermore, as discussed, knockin mice where point mutations were introduced in the a4-subnit gene by homologous recombination may constitute relevant

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Review though still primitive animal models for human familial frontal lobe epilepsies (Labarca et al. 2001; Steinlein 2004). Interestingly, these mutations cause rather paradoxical ‘gain of function’, pleiotropic, phenotypes characterized by higher affinity of acetylcholine and nicotine, loss of desensitization and conversion of the response to some nicotinic antagonists into an activatory response (Revah et al. 1991; Bertrand et al. 1992; Devillers-Thie´ry et al. 1992). These complex phenotypes are simply accounted for by the MWC mechanism for signal transduction. Homologous gain of function mutations were also identified as responsible for congenital myasthenic syndromes (Engel & Sine 2005), and as well viewed as either differentially changing the intrinsic properties of the ion channel in the different conformation of the nAChR or altering the kinetic parameters of the transition from the resting to the active open-channel conformation (Edelstein et al. 1997; Changeux & Edelstein 2005). These observations unambiguously demonstrate that the allosteric properties of the nicotinic receptor protein may gate, when altered, the transition from a state of slow-wave sleep to an epileptic state of vigilance. In a more general manner, bottom-up causal determination may exist between the molecular dynamics of a critical receptor protein and the transitions between states of vigilance. Last, nAChRs are inhibited by some volatile anaesthetics and ketamine (Tassonyi et al. 2002). On muscle nAChR, the latter acts mostly as open-channel blockers, but on neuronal nAChRs, it may also bind to allosteric sites located outside the ion channel where they inhibit activation and/or enhance desensitization. The direct role of brain nAChR (a4b2
) as targets of general anaesthetics to cause losses of consciousness has been challenged (see Tassonyi et al. 2002). On the other hand, their potential contribution to the analgesic component of general anaesthesia has received support from both pharmacological and in vivo animal model experiments (Cordero-Erausquin et al. 2000; Cordero-Erausquin & Changeux 2001), even if GABAA receptors are thought to be a primary target for general anaesthetics. The mouse and its mutants may thus become convenient animal models to investigate the pharmacology of general anaesthesia. In many instance, both the chemistry and molecular biology of the various states of vigilance are currently under investigations. (b) Content of consciousness: behavioural flexibility and the rudiments of ‘intentionality’ in the mouse? Classically, in the waking conscious state, a ‘graded global integration of multiple cognitive functions is assumed to take place that yields an unified representation of the world, of the body and of the self’ (modified from Hobson 1999, see also Changeux 1983; Edelman 1989, 2002, 2004). This notion, which deals now with the content of consciousness, has been approached, still in a rather rudimentary form, by the qualitative and quantitative analysis of a spontaneous behaviour displayed by mice and rats and referred to as exploratory behaviour (Granon et al. 2003; Maskos et al. 2005). These behaviours were up to now investigated in the context of animal spatial Phil. Trans. R. Soc. B (2006)

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cognition (Renner 1990; Thinus-Blanc 1996; Poucet & Hermann 2001), but without explicit reference to consciousness. I will take the risk to discuss here the notion that they might be plausibly relevant to the study of what I referred to as minimal or ‘level 1’ (Barresi & Moore 1996) consciousness. Exploratory behaviour expresses, in one way or another, a reaction to novelty. It may also, to some extent, implement the spontaneous (Dehaene & Changeux 2005) or basal activity of the brain (Gusnard & Raichle 2001). A mouse or a rat placed in a new environment displays intense investigatory activity: contact with objects, sniffing, stopping, rearing up on hind paws and so on. In humans, young children, for example, display a need to seize and touch any unfamiliar object and extensively visit their environment as soon as they can crawl and walk. Exploratory activity, in general, decreases overtime—it habituates—but it also dishabituates when some spatial relationships between the elements of the situation are modified. It is currently assumed that the organism detects spatial novelty by comparing the actual perceived arrangement and a representation or stored ‘internal model’ of the initial situation (ThinusBlanc 1996). Intensive studies of the neurobiological bases of exploratory behaviour are consistent with a multistage processing of spatial inputs: from the visual cortices for the perception of local views, the associative parietal cortex for the extraction of spatial invariants, the prefrontal cortex for holding the information to plan and execute a trajectory and the hippocampus as a comparator (or detector) of mismatches between stored representations and currently perceived situations (Poucet 1993). In a more general manner, exploratory activity, as its habituation and dishabituation in reaction to spatial changes, is viewed as relying on multisensory perception of the environment matched with movement-related information or, in other words, as an ‘active information-seeking structure’ (Neisser 1976), in constant updating of its representations, a manifestation of behavioural flexibility (Thinus-Blanc 1996; Granon et al. 2003). In its very nature, exploratory behaviour would then be organized along an egocentric reference frame (e.g. go ahead, turn left) and sequentially ordered (go ahead, then turn left) bearing of the goal determined on the basis of ‘abstract’ exocentric representation of the physical world (see also Berthoz 2003). In a broader philosophical context, exploratory behaviour might be tentatively considered as a first sign of ‘intentionality’ in a simple animal species (for a discussion of classical literature, see Boakes 1984). Indeed, according to the Viennese philosopher Brentano, intentionality would be the signature of consciousness as being the tractable feature of recognizing a difference between one’s own thoughts and the sensory information coming from the outside. In other words, intentional representations would differ from other purposive thoughts where the aim is clearly in view. Koch (2004), as mentioned earlier, has suggested as a Turing test for conscious behaviour in animals the ability to maintain information through a delay period. In light of what was mentioned about exploratory behaviour, one may further say that, with the course of exploration, as well as in the case of trace conditioning

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(Clark et al. 2002; Han et al. 2003a), the organism has to keep the information ‘on line’ through delays, but also to exploit delays to elaborate, select and evaluate plans, organize a programme of actions, which would ultimately let it respond in a natural environment to inner motivations as, for instance, Denton (2005) primordial emotions. Accordingly, the so-called minimal Turing test should be re-formulated as ‘the maintenance of information through delay plus selection of a relevant plan’ (Changeux 2005). Denton (2005) has underlined that, in the wild, simple species like mice, and sometimes, under special circumstances, human beings themselves might be under the ‘totalitarian occupancy’ of primordial emotions which signals that their very existence is threatened. These primordial emotions basically organize the primitive functions necessary for survival: hunger, thirst, compulsion to sleep or to find a sex partner, which, in a natural environment, require constant efforts of attentive awareness. At some stage, the drive caused by some physical impairment or imperious sensation—for instance thirst—may create some organized effort to achieve a ‘particular purpose’, an intentional behaviour—for instance satisfy thirst. But, taking into account stored past memories, such as the map of the environment where, for example, a source of water would be located, or confronted with the unpredicted sight of a predator, the organism may have to display behavioural flexibility, define action priorities which match internal motivations and actual environment conditions to reach some kind of ‘mental synthesis’ and take the decision, for instance, to flee (or to keep going). For the evolutionary biologist and for the philosopher, the behaviour of the ‘simple-minded’ mouse may thus become an outstanding topic to approach the neurobiological bases as well as the origins of minimal consciousness. At least the question is raised! More specifically, the observations that, in the mouse, the exploratory behaviour may be dissociated from the more automatic navigatory behaviour by the deletion of the b2-subunit gene of the nAChR (Granon et al. 2003; Maskos et al. 2005) illustrates: (i) the specialization of neural circuits engaged in such executive ‘conscious’ functions; (ii) the ‘gating’ of these functions (which mobilize, in particular, the prefrontal cortex) by nAChRs activated through endogenously released acetylcholine; last, (iii) the joint recovery of exploratory behaviour and reward functions by targeted re-expression of the b2 subunit in the VTA DA nucleus. This important result points to an issue, insufficiently recognized in altogether behavioural, psychological and philosophical studies on cognition in general and consciousness in particular, that a fundamental connection may exist between the activity of reward processes and the selection of plans, the maintenance of a goal, or in a philosophical and even more speculative manner, the content of consciousness in an intentional behaviour. On the clinical side, these conclusions may also lead to a plausible interpretation of drug (nicotine) addiction. It may be viewed as an escape from the ‘voluntary’ control of drug-taking behaviour, for instance, as a consequence of the disconnection of a reciprocal-loop Phil. Trans. R. Soc. B (2006)

linking prefrontal cortex, DA neurons and striatum, thus uncovering the compulsive non-conscious aspect of drug addiction (for discussion, see Gutkin et al. 2006). Moreover, as noted earlier, the b2K/Kmice which are compulsively navigating without pausing for exploration may offer an animal model for human ADHD behaviour, in which hyperactivity symptoms are known to improve with nicotine treatment (Shytle et al. 2002; rev. Granon & Changeux in press). (c) Social relationships in the mouse? Behavioural scientists together with philosophers have primarily considered intentionality in the framework of social relationships. Social organisms, including humans, represent intentional relations of themselves and other agents, yet at different levels. They unambiguously distinguish their own intentional relations (or first person information) from the qualitatively different informations available about another agent’s intentional relations (or third person information). In this respect, one should remember that the analysis of the exploratory behaviour leads to the distinction between allocentric and exocentric motor behaviour (Thinus-Blanc 1996) pointing to the still highly speculative occurrence of a ‘self ’ in the mouse, yet oriented towards the outer physical world. Furthermore, the so-called ‘social relationship’ we examined in WT and mutant mice were reduced to rather crude sequences of interactions between a resident mouse and a social intruder of the same sex. Higher rates of approach behaviour and lower rates of escape behaviour were noticed in b2K/K mice compared to WT, as if again the b2K/K mice were impaired in their behavioural flexibility for interrupting ongoing behaviours (Granon et al. 2003). No evidence was found, at this stage, with the mouse, for comparability between the actions of self and others, no sign of imitating goaldirected activity nor of ‘understanding’ the view point of others (Barresi & Moore 1996). In other words, the presently available evidence does not support the occurrence of authentic social relationships in the mouse. The human infant at birth seems already at a stage more advanced than the adult mouse in this respect. Indeed, as mentioned earlier, he or she may already distinguish between his own and others’ movements, in particular, by touch and he/she displays rudiments of imitations (Meltzoff & Gopnik 1993, but see Barresi & Moore 1996; Lagercrantz 2005). Thus, the mouse cannot be a good animal model to investigate intentional relations and social understanding, where highest level is reached exclusively in humans with the theory of mind. On the other hand, it may serve as baseline to define the neural circuits mobilized by these intentional relationships in higher mammals and humans. It may thus hardly become a reliable model of autism (at variance with what was suggested before). If autistic children show a strong need for stereotyped routines in daily life that evokes the dominant navigatory behaviour of the b2K/K mice, their most characteristic deficits concern the understanding of other minds (Leslie & Frith 1990; Baron-Cohen 1991). They do not show social pretend play, which in normal children develop during the first

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Review 2 years of life (Sigman & Ungerer 1984), neither do they express joint attention and adequate imitation. They fail standard theory of mind tasks. According to Barresi & Moore (1996), they would never attain an understanding of intentional relations at the level 2, ‘recursive consciousness’, level. In other words, following this reasoning, the WT mouse would already constitute some kind of animal model analogue of the autistic child. (d) The neuronal workspace hypothesis, blindsight and the laboratory mouse? As discussed by Baars (2001) and Dehaene & Changeux (2003), in humans the standard observational index of consciousness is an accurate, verifiable report by pressing a button or any other voluntary response mediated or not by language. Reporting responses have also been used with some animal species. It is, for instance, the ‘commentary key’ report method developed by Weiskrantz (1991) and Cowey & Stoerig (1995) to demonstrate blindsight in macaque by forced-choice responses. Yet a still unanswered question is whether or not reportability would be demonstrated in simpler species like the mouse. Since it does not require any kind of social relationship, it looks plausible, but a reliable assay still needs to be invented. On the other hand, if the neuronal workspace hypothesis was initially designed to account for access to consciousness and reportability, it obviously deals with important features of minimal consciousness. It accounts, for instance, for the active maintenance of ‘abstract rules’ through top-down amplification and the flexible control of tasks that require a novel interconnection of existing processors as it typically occurs in the Stroop task (rev. Dehaene & Changeux 2004). It deals, a fortiori, with the active maintenance of information during a delay period and, thus, with the ‘Turing test’ for conscious behaviour of Koch (2004) (see Han et al. 2003a). Even though the relevant simulations have not been carried out, the neuronal workspace architecture would adequately fit exploratory behaviour and offers an appropriate mechanism for the ultimate stage of spatial processing as introduced by Poucet’s model (1993), where unified location-independent representation with one unique reference direction is being built. The model also offers simple explanation for the observed ‘disconnection’ between exploratory and navigatory behaviour. It may, for instance, result from a deficit of the VTA–NuAcc pathway activation, within the more elaborate circuit linking this system to the ‘prefrontal workspace’. Such an interpretation may hold as well for autism as long as it, primarily, affects primary consciousness and secondarily social understanding. Alternatively, as suggested (Changeux & Edelstein 2005), it may affect the development of the prefrontal workspace itself. The formation of the longrange axonal projection of the supragranular pyramidal neurons might be highly vulnerable to the process of epigenesis by selective stabilization of synapses (Changeux & Danchin 1976), as found with the visual pathways (Rossi et al. 2001; Grubb et al. 2003; Mrsic-Flogel et al. 2005). This interpretation may fit for the brain phenotype of the adult b2K/K mouse, Phil. Trans. R. Soc. B (2006)

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but also, still in a speculative manner, for that of mentally retarded children, including autistic children (but see §8c), where postnatal cortical development would be altered by mutations affecting synapse formation and/or stabilization (X-fragile (Mandel & Biancalana 2004), autism (Bourgeron), Retts syndrome (Neul & Zoghbi 2004)). Functional brain imaging data from the mouse and its mutants are still at the stage of being developed (S. Suarez & S. Granon, unpublished work). In humans and monkeys, the available MRI and PET data are consistent with the observed link between cortical areas which are found active in conscious effortful tasks and areas particularly rich in workspace neurons with long-distance connections (i.e. prefrontal, parietal and superotemporal, cingulate entries; Goldman-Rakic 1988; Pardo et al. 1990; Cohen et al. 1997; Paus et al. 1998). These areas show the most intense and consistent spontaneous activity in the awake state (Gusnard & Raichle 2001; Mazoyer et al. 2001) and the greatest drop in metabolism during various types of transitions away from the awake state, during anaesthesia, sleep, coma or vegetative state (Maquet & Phillips 1998; Fiset et al. 1999; Laureys et al. 2000; Paus 2000; Balkin et al. 2002; Shulman et al. 2003). These areas also show the greatest contrast between conscious versus non-conscious processing of visual stimuli (Dehaene et al. 2001; Dehaene & Naccache 2001; Marois et al. 2004). These studies should thus offer the opportunity to further dissect, already with the mouse, the abovementioned multiplicity of states and of levels in consciousness. This might be of considerable help for the cognitive neuroscientist and the philosopher to clarify situations or experimental paradigms, in which the word consciousness is used with rather different meanings (for instance, Block 2005; Fiset et al. 1999; Paus 2000; Lamme 2003; Zeki 2003; Dehaene & Changeux 2004). The use of neurocomputational models might, in this respect, be of some help (Dehaene & Changeux 2004, 2005). Indeed, one may view the various graded states of consciousness (from deep anaesthesia and coma to full awareness) as directly related to the spontaneous activity of recurrent thalamo-cortical loops and reticular thalamic nuclei (see Llinas & Pare 1991; Steriade et al. 1993) under brainstem control. Simulations help to characterize several states of activity (Dehaene & Changeux 2005): (i) one of quiet vigilance with moderate spontaneous activity; I may tentatively suggest—at my own risk—that it suffices for the access of Ze´ki’s levels of ‘micro-’ and ‘macro-consciousness’ for colour perception or visual motion; (ii) another state that one may refer to as full conscious access occurs at higher levels of the neuromodulation parameter, where spontaneous ‘ignited’ states appear originating from higher association cortices and where sensory inputs become selfamplified above a threshold; again, it may account for access to Ze´ki’s ‘unified consciousness’. On the other hand, the model predicts that the content of consciousness builds up from the processing of both ‘exogenous’ sensory signal and ‘endogenous’ spontaneous activity as long as they give rise to above threshold ignition; in other words, considerable processing may remain

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below access to consciousness. This is expected to be the case for Ze´ki’s ‘micro- and macro-levels’ for processing of visual perception as well as for all processes of exploratory behaviour which in Poucet’s model do not reach the prefrontal cortex. These different states or levels in the WT mouse would therefore display electrophysiological signals of ignition in its neuronal workspace under conditions of exploration, while these ignition signals would disappear in the b2K/K mice. In other words, the b2K/K mice would be in a state of ‘quiet vigilance’ below threshold. Could it be called using Koch metaphor ‘a mouse zombie’? Would it be a simple-minded model of blindsight in an animal species able to carry on minimal vision without having full access to consciousness? In any case, these studies may have, as a principal consequence, given rise to a re-evaluation of some of the key paradigms of the scientific studies on human consciousness, in particular on blindsight, in a phylogenetic and developmental perspective. It has been confirmed since the famous experiments of Friedrich Goltz on dogs at the end of the nineteenth century (see Clarke & O’Malley 1968) that the removal of the cerebral cortex has vastly different consequences on visual perception in lower mammalian species than in humans and monkeys. Moreover, recent evidence on face detection in the awake human newborn reveals rather unanticipated subcortical processings ( Johnson 2005, see, however, Bartocci et al. 2006). Would then Goltz statement that ‘the decerebrated dog is essentially nothing but a child of the moment’ bear some truth? Would the mouse and its mutants be of some help in these investigations? Empirical and theoretical studies on all these issues, including genetically modified mice and the human newborn, are urgently needed. On neuroanatomical grounds, as noted earlier, a strong correlation exists between the development of consciousness and the expansion (or maturation) of the neocortex and more specifically of the prefrontal cortex (comparatively to the bulk of the neocortex), both in the course of evolution (see Elston 2003; Changeux 2004) and during development (Zelazo 1996). An interesting correlation moreover has been established between the increased complexity of pyramidal neurons from layer III (largely long-axon neuron possibly contributes to the workspace) and their distribution from occipital to temporal and prefrontal areas and, in prefrontal areas, from lower species (rabbit, marmoset) to humans (Elston 2003). In mouse and rat, the prefrontal cortex occupies a relatively small area of the cerebral cortex. Yet, its role in exploratory behaviour and conflict resolution problems is documented even in these simple species (see Granon et al. 1994; Dias & Aggleton 2000; Robbins 2000; S. Granon unpublished work). To conclude, the mouse and its genetically modified variants may become a convenient, though simple, model to investigate the molecular biology of behaviours associated with minimal consciousness but also to test neurocomputational models, such as the neuronal workspace hypotheses for states and access to consciousness. It may become a convenient model system, yet with the above-mentioned important limitations, to establish a causal relationship—not Phil. Trans. R. Soc. B (2006)

simply ‘neural correlates’—between neuronal architectures, their activity processes and the access to minimal consciousness. Would the mouse ever become the Drosophila of minimal consciousness? I thank M. Besson, S. Dehaene, P. Faure, S. Granon, H. Lagercrantz and B. Molles for helpful comments. Support was provided by Centre National de la Recherche Scientifique, Colle` ge de France, Ministe` re de la Recherche, Association pour la Recherche contre le Cancer, European Communities.

REFERENCES Andres, C. 2002 Molecular genetics and animal models in autistic disorder. Brain Res. Bull. 57, 109–119. (doi:10. 1016/S0361-9230(01)00642-6) Baars, B. J. 1998 Metaphors of consciousness and attention in the brain. Trends Neurosci. 21, 58–62. (doi:10.1016/ S0166-2236(97)01171-5) Baars, B. J. 2001 The brain basis of a “consciousness monitor”: scientific and medical significance. Conscious Cogn. 10, 159–164. (doi:10.1006/ccog.2001.0510) Balfour, D. J. 2002 Neuroplasticity within the mesoaccumbens dopamine system and its role in tobacco dependence. Curr. Drug Targets CNS Neurol. Disord. 1, 413–421. (doi:10.2174/1568007023339076) Balkin, T. J., Braun, A. R., Wesensten, N. J., Jeffries, K., Varga, M., Baldwin, P., Belenky, G. & Herscovitch, P. 2002 The process of awakening: a PET study of regional brain activity patterns mediating the re-establishment of alertness and consciousness. Brain 125, 2308–2319. (doi:10.1093/brain/awf228) Baron-Cohen, S. 1991 The development of a theory of mind in autism: deviance and delay. Psychiatr. Clin. North Am. 14, 33–51. Barresi, J. & Moore, C. 1996 Intentional relations and social understanding. Behav. Brain Sci. 19, 107–122. Barto, A. G., Sutton, R. S. & Anderson, C. W. 1983 Neuronlike adaptive elements that can solve difficult learning control problems. IEEE Trans. Syst. Man Cybern. 13, 834–846. Bartocci, M., Bergqvist, L., Lagercrantz, H. & Anand, K. J. S. 2006. Pain activates cortical areas in the preterm newborn brain. Pain. Mar 10 [EPub ahead of print]. Berthoz, A. 2003 La de´cision. Paris, France: O. Jacob. Bertrand, D., Devillers-Thie´ry, A., Revah, F., Galzi, J.-L., Hussy, N., Mulle, C., Bertrand, S., Ballivet, M. & Changeux, J.-P. 1992 Unconventional pharmacology of a neuronal nicotinic receptor mutated in the channel domain. Proc. Natl Acad. Sci. USA 89, 1261–1265. Bianchi, L. 1921 La me´canique du cerveau et la fonction des lobes frontaux. Paris, France: Louis Arnette. Block, N. 1990 Consciousness and accessibility. Behav. Brain Sci. 13, 596–598. Block, N. 2005 Two neural correlates of consciousness. Trends Cogn. Sci. 9, 46–52. (doi:10.1016/j.tics.2004.12.006) Boakes, R. 1984 From Darwin to behaviourism: psychology and the minds of animals. Cambridge, UK: Cambridge University Press. Bogen, J. E. 1995 On the neurophysiology of consciousness: I. An overview. Conscious Cogn. 4, 52–62; see also pp. 137– 158. (doi:10.1006/ccog.1995.1003) Booth, R., Charlton, R., Hughes, C. & Happe, F. 2003 Disentangling weak coherence and executive dysfunction: planning drawing in autism and attention-deficit/hyperactivity disorder. Phil. Trans. R. Soc. B 358, 387–392. (doi:10.1098/rstb.2002.1204) Brejc, K., van Dijk, W. J., Klaassen, R. V., Schuurmans, M., van Der Oost, J., Smit, A. B. & Sixma, T. K. 2001 Crystal

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Review structure of an ACh-binding protein reveals the ligandbinding domain of nicotinic receptors. Nature 411, 269–276. (doi:10.1038/35077011) Broide, R. S., Salas, R., Ji, D., Paylor, R., Patrick, J. W., Dani, J. A. & De Biasi, M. 2002 Increased sensitivity to nicotineinduced seizures in mice expressing the L250T alpha 7 nicotinic acetylcholine receptor mutation. Mol. Pharmacol. 61, 695–705. (doi:10.1124/mol.61.3.695) Caldarone, B. J., Duman, C. H. & Picciotto, M. R. 2000 Fear conditioning and latent inhibition in mice lacking the high affinity subclass of nicotinic acetylcholine receptors in the brain. Neuropharmacology 39, 2779–2784. (doi:10.1016/ S0028-3908(00)00137-4) Carter, R. M., Hofstotter, C., Tsuchiya, N. & Koch, C. 2003 Working memory and fear conditioning. Proc. Natl Acad. Sci. USA 100, 1399–1404. (doi:10.1073/pnas. 0334049100) Celie, P. H. N., van Rossum-Fikkert, S. E., van Dijk, W. J., Brejc, K., Smit, A. B. & Sixma, T. K. 2004 Nicotine and carbamylcholine binding to nicotinic receptors studied by AChBP structures. Neuron 41, 907–914. (doi:10.1016/ S0896-6273(04)00115-1) Chalmers, D. J. 1998 The problems of consciousness. Adv. Neurol. 77, 7–16. Champtiaux, N. & Changeux, J.-P. 2004 Knockout and knockin mice to investigate the role of nicotinic receptors in the central nervous system. Prog. Brain. Res. 145, 235–251. Changeux, J.-P. 1981 The acetylcholine receptor: an “allosteric” membrane protein. Harvey Lect. 75, 85–254. Changeux, J.-P. 1983 L’Homme neuronal. Paris, France: Fayard. Changeux, J.-P. 1990 Functional architecture and dynamics of the nicotinic acetylcholine receptor: an allosteric ligandgated ion channel. Fidia Res. Found. Neurosci. Award Lect. 4, 21–168. Changeux, J.-P. 2002 L’Homme de Ve´rite´ (English transl. by M. Debevoise. The physiology of truth. Harvard University Press, Cambridge MA, 2005). Paris, France: O. Jacob. Changeux, J.-P. 2004 Clarifying consciousness. Nature 428, 603–604. (doi:10.1038/428603a) Changeux, J.-P. 2005 Pre´face. In Les e´motions primordiales et l’e´veil de la conscience (ed. D. Denton), pp. 73–94. Paris, France: Flammarion. Changeux, J.-P. & Danchin, A. 1976 Selective stabilization of developing synapses as a mechanism for the specificication of neuronal networks. Nature 264, 705–712. (doi:10.1038/ 264705a0) Changeux, J.-P. & Edelstein, S. J. 1998 Allosteric receptors after 30 years. Neuron 21, 959–980. (doi:10.1016/S08966273(00)80616-9) Changeux, J.-P. & Edelstein, S. J. 2005 Allosteric mechanisms of signal transduction. Science 308, 1424–1428. (doi:10.1126/science.1108595) Cheng, X., Lu, B., Grant, B., Law, R. J. & McCammon, J. A. 2006 Channel opening motion of a7 nicotinic acetylcholine receptor as suggested by normal mode analysis. J. Mol. Biol. 355, 310–324. (doi:10.1016/j.jmb.2005.10.039) Clark, R. E. & Squire, L. R. 1998 Classical conditioning and brain systems: the role of awareness. Science 280, 77–81. Clark, R. E., Manns, J. R. & Squire, L. R. 2002 Classical conditioning, awareness, and brain systems. Trends Cogn. Sci. 6, 524–531. (doi:10.1016/S1364-6613(02)02041-7) Clarke, P. B. 1993 Nicotine dependence—mechanisms and therapeutic strategies. Biochem. Soc. Symp. 59, 83–95. Clarke, E. & O’Malley, C. D. 1968 The human brain and spinal cord. Berkeley, CA: UCLA Press. Cohen, G., Malcolm, G. & Henderson-Smart, D. 1997 A comparison of the ventilatory response of sleeping Phil. Trans. R. Soc. B (2006)

J.-P. Changeux

2255

newborn lambs to step and progressive hypoxaemia. J. Physiol. 503, 203–213. (doi:10.1111/j.1469-7793. 1997.203bi.x) Cohen, G., Han, Z. Y., Grailhe, R., Gallego, J., Gaultier, C., Changeux, J.-P. & Lagercrantz, H. 2002 Beta 2 nicotinic acetylcholine receptor subunit modulates protective responses to stress: a receptor basis for sleep-disordered breathing after nicotine exposure. Proc. Natl Acad. Sci. USA 99, 13 272–13 277. (doi:10.1073/pnas.192463599) Cohen, G., Roux, J. C., Grailhe, R., Malcolm, G., Changeux, J.-P. & Lagercrantz, H. 2005 Perinatal exposure to nicotine causes deficits associated with a loss of nicotinic receptor function. Proc. Natl Acad. Sci. USA 102, 3817–3821. (doi:10.1073/pnas.0409782102) Cordero-Erausquin, M. & Changeux, J.-P. 2001 Tonic nicotinic modulation of serotoninergic transmission in the spinal cord. Proc. Natl Acad. Sci. USA 98, 2803–2807. (doi:10.1073/pnas.041600698) Cordero-Erausquin, M., Marubio, L. M., Klink, R. & Changeux, J.-P. 2000 Nicotinic receptor function: new perspectives from knockout mice. Trends Pharmacol. Sci. 21, 211–217. (doi:10.1016/S0165-6147(00)01489-9) Cowey, A. & Stoerig, P. 1995 Blindsight in monkeys. Nature 373, 247–249. (doi:10.1038/373247a0) Crick, F. & Koch, C. 2003 A framework for consciousness. Nat. Neurosci. 6, 119–126. (doi:10.1038/nn0203-119) Damasio, A. R. 1995 Descartes error: emotion, reason, and the human brain. New York, NY: Gosset/Putnam. David, V. & Cazala, P. 1994 A comparative study of selfadministration of morphine into the amygdala and the ventral tegmental area in mice. Behav. Brain Res. 65, 205–211. (doi:10.1016/0166-4328(94)90106-6) De Fusco, M., Becchetti, A., Patrignani, A., Annesi, G., Gambardella, A., Quattrone, A., Ballabio, A., Wanke, E. & Casari, G. 2000 The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat. Genet. 26, 275–276. (doi:10.1038/81566) Dehaene, S. & Changeux, J.-P. 1989 A simple model of prefrontal cortex function in delayed-response tasks. J. Cogn. Neurosci. 1, 244–261. Dehaene, S. & Changeux, J.-P. 1991 The Wisconsin card sorting test: theoretical analysis and simulation of a reasoning task in a model neuronal network. Cereb. Cortex 1, 62–79. Dehaene, S. & Changeux, J.-P. 1995 Neuronal models of prefrontal cortical functions. Ann. NY Acad. Sci. 769, 305–319. Dehaene, S. & Changeux, J.-P. 1997 A hierarchical neuronal network for planning behavior. Proc. Natl Acad. Sci. USA 94, 13 293–13 298. (doi:10.1073/pnas.94.24.13293) Dehaene, S. & Changeux, J.-P. 2000 Reward-dependent learning in neuronal networks for planning and decision making. Prog. Brain Res. 126, 217–229. Dehaene, S. & Changeux, J. P. 2004 Neural mechanisms for access to consciousness. In The cognitive neurosciences III (ed. M. S. Gazzaniga), pp. 1145–1158. Cambridge, MA: MIT Press. Dehaene, S. & Changeux, J.-P. 2005 Ongoing spontaneous activity controls access to consciousness: a neuronal model for inattentional blindness. PLoS Biol. 3, e141. (doi:10. 1371/journal.pbio.0030141) Dehaene, S. & Naccache, L. 2001 Towards a cognitive neuroscience of consciousness: basic evidence and a workspace framework. Cognition 79, 1–37. (doi:10.1016/ S0010-0277(00)00123-2) Dehaene, S., Kerszberg, M. & Changeux, J.-P. 1998 A neuronal model of a global workspace in effortful cognitive tasks. Proc. Natl Acad. Sci. USA 95, 14 529–14 534. (doi:10.1073/pnas.95.24.14529)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

2256

J.-P. Changeux

Review

Dehaene, S., Naccache, L., Cohen, L., Bihan, D. L., Mangin, J. F., Poline, J. B. & Riviere, D. 2001 Cerebral mechanisms of word masking and unconscious repetition priming. Nat. Neurosci. 4, 752–758. (doi:10.1038/89551) Dehaene, S., Sergent, C. & Changeux, J.-P. 2003 A neuronal network model linking subjective reports and objective physiological data during conscious perception. Proc. Natl Acad. Sci. USA 100, 8520–8525. (doi:10.1073/pnas. 1332574100) Denton, D. 2005 Les Emotions primordiales et l’e´veil de la conscience. Paris, France: Flammarion. Devillers-Thie´ry, A., Galzi, J.-L., Bertrand, S., Changeux, J.-P. & Bertrand, D. 1992 Stratified organization of the nicotinic acetylcholine receptor channel. Neuroreport 3, 1001–1004. Dias, R. & Aggleton, J. P. 2000 Effects of selective excitotoxic prefrontal lesions on acquisition of nonmatching- and matching-to-place in the T-maze in the rat: differential involvement of the prelimbic–infralimbic and anterior cingulate cortices in providing behavioural flexibility. Eur. J. Neurosci. 12, 4457–4466. (doi:10.1046/j.0953-816X. 2000.01323.x) Di Chiara, G. 2000 Role of dopamine in the behavioural actions of nicotine related to addiction. Eur. J. Pharmacol. 393, 295–314. (doi:10.1016/S0014-2999(00)00122-9) Edelman, G. 1989 The remembered present. New York, NY: Basic Books. Edelman, G. 2004 Biochemistry and the sciences of recognition. J. Biol. Chem. 279, 7361–7369. (doi:10. 1074/jbc.X400001200) Edelstein, S. J., Schaad, O. & Changeux, J.-P. 1997 Myasthenic nicotinic receptor mutant interpreted in terms of the allosteric model. C. R. Acad. Sci. III 320, 953–961. Ellis, J. R., Ellis, K. A., Bartholomeusz, C. F., Harrison, B. J., Wesnes, K. A., Erskine, F. F., Vitetta, L. & Nathan, P. J. 2005 Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans. Int. J. Neuropsychopharmacol. 9, 1–15. (doi:10.1017/S146 1145705005407) Elston, G. N. 2003 Cortex, cognition and the cell: new insights into the pyramidal neuron and prefrontal function. Cereb. Cortex 13, 1124–1138. (doi:10.1093/ cercor/bhg093) Engel, A. G. & Sine, S. M. 2005 Current understanding of congenital myasthenic syndromes. Curr. Opin. Pharmacol. 5, 308–321. (doi:10.1016/j.coph.2004.12.007) Faure, P., Neumeiste, H., Faber, D. S. & Korn, H. 2003 Symbolic analysis of swimming trajectories reveals scale invariance and provides a model for fish locomotion. Fractals 11, 233–243. Fiset, P., Paus, T., Daloze, T., Plourde, G., Meuret, P., Bonhomme, V., Hajj-Ali, N., Backman, S. B. & Evans, A. C. 1999 Brain mechanisms of propofol-induced loss of consciousness in humans: a positron emission tomographic study. J. Neurosci. 19, 5506–5513. Franks, N. P. & Lieb, W. R. 1994 Molecular and cellular mechanisms of general anaesthesia. Nature 367, 607–614. (doi:10.1038/367607a0) Friston, K. J., Tononi, G., Reeke Jr, G. N., Sporns, O. & Edelman, G. M. 1994 Value-dependent selection in the brain: simulation in a synthetic neural model. Neuroscience 59, 229–243. (doi:10.1016/0306-4522(94)90592-4) Frith, U. 2001 Mind blindness and the brain in autism. Neuron 32, 969–979. (doi:10.1016/S0896-6273(01) 00552-9) Giedd, J. N., Blumenthal, J., Molloy, E. & Castellanos, F. X. 2001 Brain imaging of attention deficit/hyperactivity disorder. Ann. NY Acad. Sci. 931, 33–49. Phil. Trans. R. Soc. B (2006)

Gil, Z., Sack, R. A., Kedmi, M., Harmelin, A. & OrrUrtreger, A. 2002 Increased sensitivity to nicotineinduced seizures in mice heterozygous for the L250T mutation in the alpha7 nicotinic acetylcholine receptor. Neuroreport 13, 191–196. (doi:10.1097/00001756-200202 110-00004) Giraudat, J., Dennis, M., Heidmann, T., Chang, J. Y. & Changeux, J.-P. 1986 Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptor: serine-262 of the delta subunit is labeled by [3H]chlorpromazine. Proc. Natl Acad. Sci. USA 83, 2719–2723. Goldman-Rakic, P. S. 1988 Topography of cognition: parallel distributed networks in primate association cortex. Annu. Rev. Neurosci. 11, 137–156. (doi:10.1146/annurev.ne.11. 030188.001033) Granon S. & Changeux, J.-P. In press. Attention-deficit/ hyperactivity-disorder: a plausible mouse model? Acta Pediatr. Granon, S., Vidal, C., Thinus-Blanc, C., Changeux, J.-P. & Poucet, B. 1994 Working memory, response selection, and effortful processing in rats with medial prefrontal lesions. Behav. Neurosci. 108, 883–891. (doi:10.1037/0735-7044. 108.5.883) Granon, S., Poucet, B., Thinus-Blanc, C., Changeux, J.-P. & Vidal, C. 1995 Nicotinic and muscarinic receptors in the rat prefrontal cortex: differential roles in working memory, response selection and effortful processing. Psychopharmacology (Berlin) 119, 139–144. (doi:10.1007/BF022 46154) Granon, S., Faure, P. & Changeux, J.-P. 2003 Executive and social behaviors under nicotinic receptor regulation. Proc. Natl Acad. Sci. USA 100, 9596–9601. (doi:10.1073/pnas. 1533498100) Grubb, M. S., Rossi, F. M., Changeux, J. P. & Thompson, I. D. 2003 Abnormal functional organization in the dorsal lateral geniculate nucleus of mice lacking the beta2 subunit of the nicotinic acetylcholine receptor. Neuron 18, 8008–8018. Gusnard, D. A. & Raichle, M. E. 2001 Searching for a baseline: functional imaging and the resting human brain. Nat. Rev. Neurosci. 2, 685–694. (doi:10.1038/35094500) Gutkin, B., Dehaene, S. & Changeux, J. P. 2006 A neurocomputational framework for nicotine addiction. Proc. Natl Acad. Sci. USA 103, 1106–1111. Halasz, P. 1998 Hierarchy of micro-arousals and the microstructure of sleep. Neurophysiol. Clin. 28, 461–475. Han, C. J., O’Tuathaigh, C. M., van Trigt, L., Quinn, J. J., Fanselow, M. S., Mongeau, R., Koch, C. & Anderson, D. J. 2003a Trace but not delay fear conditioning requires attention and the anterior cingulate cortex. Proc. Natl Acad. Sci. USA 100, 13 087–13 092. (doi:10.1073/pnas. 2132313100) Han, Z. Y., Zoli, M., Cardona, A., Bourgeois, J.-P., Changeux, J.-P. & Le Novere, N. 2003b Localization of [3H]nicotine, [3H]cytisine, [3H]epibatidine, and [125I]alpha-bungarotoxin binding sites in the brain of Macaca mulatta. J. Comp. Neurol. 461, 49–60. (doi:10. 1002/cne.10659) Hauser, M. 2000 Wild minds: what animals really think? New York: Henry Holt. Hobson, J. A. 1999 Dreaming as delirium: how the brain goes out of its mind. Cambridge, MA/London: A Bradford Book/ The MIT Press. Hucho, F., Oberthur, W. & Lottspeich, F. 1986 The ion channel of the nicotinic acetylcholine receptor is formed by the homologous helices MII of the receptor subunits. FEBS Lett. 205, 137–142. (doi:10.1016/0014-5793(86) 80881-X)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Review Huxley, T. H. 1874. On the hypothesis that animals are automata, and its history, vol. 1, p. 199 in Collected Essays of T.H. Huxley. New York, NY: D. Appleton. Itier, V. & Bertrand, D. 2002 Mutations of the neuronal nicotinic acetylcholine receptors and their association with ADNFLE. Neurophysiol. Clin. 32, 99–107. Jasper, H. H. 1998 Sensory information and conscious experience. Adv. Neurol. 77, 33–48. Johnson, M. H. 2005 Subcortical face processing. Nat. Rev. Neurosci. 6, 766–774. (doi:10.1038/nrn1766) Jones, B. E. 1998 The neural basis of consciousness across the sleep–waking cycle. Adv. Neurol. 77, 75–94. Jones, E. G. 1998 Viewpoint: the core and matrix of thalamic organization. Neuroscience 85, 331–345. (doi:10.1016/ S0306-4522(97)00581-2) Jones, M. W. 2002 A comparative review of rodent prefrontal cortex and working memory. Curr. Mol. Med. 2, 639–647. (doi:10.2174/1566524023361989) Jones, B. E. 2004 Paradoxical REM sleep promoting and permitting neuronal networks. Arch. Ital. Biol. 142, 379–396. Klink, R., de Kerchove d’Exaerde, A., Zoli, M. & Changeux, J.-P. 2001 Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J. Neurosci. 21, 1452–1463. Kobayashi, Y. & Isa, T. 2002 Sensory–motor gating and cognitive control by the brainstem cholinergic system. Neural Netw. 15, 731–741. (doi:10.1016/S08936080(02)00059-X) Koch, C. 2004 The quest for consciousness: a neurobiological approach. Englewood, CO: Roberts and Publishers. Labarca, C. et al. 2001 Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proc. Natl Acad. Sci. USA 98, 2786–2791. (doi:10.1073/pnas.041582598) Lagercrantz, H. 2005 I barnets hja¨rna. Stockholm: Bonnier fakta. Lagercrantz, H., Hanson, M., Evrard, P. & Rodeck, C. (eds) 2002 The newborn brain: neuroscience and clinical applications. Cambridge, UK: Cambridge University Press. Lamme, V. A. 2003 Why visual attention and awareness are different. Trends Cogn. Sci. 7, 12–18. (doi:10.1016/S13646613(02)00013-X) Laureys, S. et al. 2000 Auditory processing in the vegetative state. Brain 123, 1589–1601. (doi:10.1093/brain/123.8. 1589) Lawrence, N. S., Ross, T. J. & Stein, E. A. 2002 Cognitive mechanisms of nicotine on visual attention. Neuron 36, 539–548. (doi:10.1016/S0896-6273(02)01004-8) Lee, S. L., Ralston, H. P., Drey, E. D., Partridge, J. C. & Rosen, M. A. 2005 Fetal pain: a systematic multidisciplinary review of the evidence. JAMA 294, 947–953. (doi:10.1001/jama.294.8.947) Lena, C., de Kerchove D’Exaerde, A., Cordero-Erausquin, M., Le Novere, N., del Mar Arroyo-Jimenez, M. & Changeux, J.-P. 1999 Diversity and distribution of nicotinic acetylcholine receptors in the locus ceruleus neurons. Proc. Natl Acad. Sci. USA 96, 12 126–12 131. (doi:10.1073/pnas.96.21.12126) Lena, C., Popa, D., Grailhe, R., Escourrou, P., Changeux, J.-P. & Adrien, J. 2004 Beta2-containing nicotinic receptors contribute to the organization of sleep and regulate putative micro-arousals in mice. J. Neurosci. 24, 5711–5718. (doi:10.1523/JNEUROSCI. 3882-03.2004) Le Novere, N., Grutter, T. & Changeux, J.-P. 2002 Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2C-binding sites. Proc. Natl Acad. Sci. USA 99, 3210–3215. (doi:10.1073/pnas.042699699) Phil. Trans. R. Soc. B (2006)

J.-P. Changeux

2257

Leslie, A. M. & Frith, U. 1990 Prospects for a cognitive neuropsychology of autism: Hobson’s choice. Psychol. Rev. 97, 122–131. (doi:10.1037/0033-295X.97.1.122) Levin, E. D. 1992 Nicotinic systems and cognitive function. Psychopharmacology (Berlin) 108, 417–431. (doi:10.1007/ BF02247415) Levin, E. D. 2002 Nicotinic receptor subtypes and cognitive function. J. Neurobiol. 53, 633–640. (doi:10.1002/neu. 10151) Llinas, R. R. & Pare, D. 1991 Of dreaming and wakefulness. Neuroscience 4, 521–535. (doi:10.1016/0306-4522(91) 90075-Y) Maggi, L., Le Magueresse, C., Changeux, J.-P. & Cherubini, E. 2003 Nicotine activates immature “silent” connections in the developing hippocampus. Proc. Natl Acad. Sci. USA 100, 2059–2064. (doi:10.1073/pnas.0437947100) Maggi, L., Sola, E., Minneci, F., Le Magueresse, C., Changeux, J.-P. & Cherubini, E. 2004 Persistent decrease in synaptic efficacy induced by nicotine at Schaffer collateral-CA1 synapses in the immature rat hippocampus. J. Physiol. 559, 863–874. Maia, T. V. & Cleeremans, A. 2005 Consciousness: converging insights from connectionist modeling and neuroscience. Trends Cogn. Sci. 9, 397–404. (doi:10. 1016/j.tics.2005.06.016) Mandel, J. L. & Biancalana, V. 2004 Fragile X mental retardation syndrome: from pathogenesis to diagnostic issues. Growth Horm. IGF Res. 14, S158–S165. (doi:10. 1016/j.ghir.2004.03.034) Maquet, P. & Phillips, C. 1998 Functional brain imaging of human sleep. J. Sleep Res. 7, 42–47. (doi:10.1046/j.13652869.7.s1.7.x) Marois, R., Chun, M. M. & Gore, J. C. 2004 A common parieto-frontal network is recruited under both low visibility and high perceptual interference conditions. J. Neurophysiol. 92, 2985–2992. (doi:10.1152/jn.01061. 2003) Maskos, U., Kissa, K., St Cloment, C. & Brulet, P. 2002 Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice. Proc. Natl Acad. Sci. USA 99, 10 120–10 125. (doi:10.1073/pnas.152266799) Maskos, U. et al. 2005 Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436, 103–107. (doi:10.1038/nature03694) Mazoyer, B. et al. 2001 Cortical networks for working memory and executive functions sustain the conscious resting state in man. Brain Res. Bull. 54, 287–298. (doi:10. 1016/S0361-9230(00)00437-8) McGehee, D. S. & Role, L. W. 1996 Presynaptic ionotropic receptors. Curr. Opin. Neurobiol. 6, 342–349. (doi:10. 1016/S0959-4388(96)80118-8) McMahon, L. L., Yoon, K. W. & Chiappinelli, V. A. 1994 Electrophysiological evidence for presynaptic nicotinic receptors in the avian ventral lateral geniculate nucleus. J. Neurophysiol. 71, 826–829. Meltzoff, A. N. 1990 Towards a developmental cognitive science. The implications of cross-modal matching and imitation for the development of representation and memory in infancy. Ann. NY Acad. Sci. 608, 1–31. Meltzoff, A. N. & Gopnik, A. 1993 The role of imitation in understanding persons and developing a theory of mind. In Understanding other minds: perspectives from autism (ed. S. Baron-Cohen, H. Tager-Flusberg & D. J. Cohen), pp. 335–366. Oxford, UK: Oxford University Press. Mitchell, B. D. & Macklis, J. D. 2005 Large-scale maintenance of dual projections by callosal and frontal cortical projection neurons in adult mice. J. Comp. Neurol. 482, 17–32. (doi:10.1002/cne.20428)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

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J.-P. Changeux

Review

Monod, J., Wyman, J. & Changeux, J.-P. 1965 On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12, 88–118. Montague, P. R., Dayan, P., Person, C. & Sejnowski, T. J. 1995 Bee foraging in uncertain environments using predictive hebbian learning. Nature 377, 725–728. (doi:10.1038/377725a0) Montague, P. R., Dayan, P. & Sejnowski, T. J. 1996 A framework for mesencephalic dopamine systems based on predictive Hebbian learning. J. Neurosci. 16, 1936–1947. Mrsic-Flogel, T. D., Hofer, S. B., Creutzfeldt, C., CloezTayarani, I., Changeux, J.-P., Bonhoeffer, T. & Hubener, M. 2005 Altered map of visual space in the superior colliculus of mice lacking early retinal waves. J. Neurosci. 25, 6921–6928. (doi:10.1523/JNEUROSCI.1555-05. 2005) Mulle, C. & Changeux, J.-P. 1990 A novel type of nicotinic receptor in the rat central nervous system characterized by patch-clamp techniques. J. Neurosci. 10, 169–175. Mulle, C., Vidal, C., Benoit, P. & Changeux, J.-P. 1991 Existence of different subtypes of nicotinic acetylcholine receptors in the rat habenulo-interpeduncular system. J. Neurosci. 11, 2588–2597. Nagel, T. 1974 What is it like to be a bat? Phil. Rev. 83, 435–450. Naldini, L., Blomer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F. H., Verma, I. M. & Trono, D. 1996 In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267. Neisser, U. 1976 Cognition and reality: principles and implications of cognitive psychology. New York, NY: W.H. Freeman. Neul, J. L. & Zoghbi, H. Y. 2004 Rett syndrome: a prototypical neurodevelopmental disorder. Neuroscientist 10, 118–128. (doi:10.1177/1073858403260995) Nordberg, A. & Winblad, B. 1986 Reduced number of [3H]nicotine and [3H]acetylcholine binding sites in the frontal cortex of Alzheimer brains. Neurosci. Lett. 72, 115–119. (doi:10.1016/0304-3940(86)90629-4) Norman, D. A. & Shallice, T. 1980 Attention to action: willed and automatic control of behaviour. In Consciousness and self regulation (ed. R. Davidson, G. E. Schwartz & D. Shapiro), pp. 1–15. New York, NY: Plenun times. Paas, Y., Gibor, G., Grailhe, R., Savatier-Duclert, N., Dufresne, V., Sunesen, M., de Carvalho, L. P., Changeux, J.-P. & Attali, B. 2005 Pore conformations and gating mechanism of a Cys-loop receptor. Proc. Natl Acad. Sci. USA 102, 15 877–15 882. (doi:10.1073/pnas. 0507599102) Pardo, J. V., Pardo, P. J., Janer, K. W. & Raichle, M. E. 1990 The anterior cingulate cortex mediates processing selection in the Stroop attentional conflict paradigm. Proc. Natl Acad. Sci. USA 87, 256–259. Passetti, F., Dalley, J. W., O’Connell, M. T., Everitt, B. J. & Robbins, T. W. 2000 Increased acetylcholine release in the rat medial prefrontal cortex during performance of a visual attentional task. Eur. J. Neurosci. 12, 3051–3058. (doi:10. 1046/j.1460-9568.2000.00183.x) Paus, T. 2000 Functional anatomy of arousal and attention systems in the human brain. Prog. Brain Res. 126, 65–77. Paus, T., Koski, L., Caramanos, Z. & Westbury, C. 1998 Regional differences in the effects of task difficulty and motor output on blood flow response in the human anterior cingulate cortex: a review of 107 PET activation studies. Neuroreport 9, R37–R47. Perry, E. K. & Perry, R. H. 2004 Neurochemistry of consciousness: cholinergic pathologies in the human brain. Prog. Brain Res. 145, 287–299. Phil. Trans. R. Soc. B (2006)

Perry, E., Walker, M., Grace, J. & Perry, R. 1999 Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci. 22, 273–280. (doi:10. 1016/S0166-2236(98)01361-7) Perry, E. K. et al. 2001 Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am. J. Psychiatry 158, 1058–1066. (doi:10.1176/appi.ajp. 158.7.1058) Phillips, H. A. et al. 2001 CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am. J. Hum. Genet. 68, 225–231. (doi:10.1086/316946) Picciotto, M. R. et al. 1995 Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature 374, 65–67. (doi:10.1038/374065a0) Picciotto, M. R., Zoli, M., Rimondini, R., Lena, C., Marubio, L. M., Pich, E. M., Fuxe, K. & Changeux, J.-P. 1998 Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391, 173–177. (doi:10.1038/34413) Pickworth, W. B., Fant, R. V., Butschky, M. F. & Henningfield, J. E. 1997 Effects of mecamylamine on spontaneous EEG and performance in smokers and nonsmokers. Pharmacol. Biochem. Behav. 56, 181–187. (doi:10.1016/S0091-3057(96)00183-9) Poucet, B. 1993 Spatial cognitive maps in animals: new hypotheses on their structure and neural mechanisms. Psychol. Rev. 100, 163–182. (doi:10.1037/0033-295X. 100.2.163) Poucet, B. & Herrmann, T. 2001 Exploratory patterns of rats on a complex maze provide evidence for topological coding. Behav. Process. 53, 155–162. (doi:10.1016/S03766357(00)00151-0) Preyer, W. 1894 Mental development in the child. New York, NY: D. Appleton. Renner, M. J. 1990 Neglected aspects of exploratory and investigatory behavior. Psychobiology 18, 16–22. Revah, F., Bertrand, D., Galzi, J.-L., Devillers-Thie´ry, A., Mulle, C., Hussy, N., Bertrand, S., Ballivet, M. & Changeux, J.-P. 1991 Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor. Nature 353, 846–849. (doi:10.1038/353846a0) Robbins, T. W. 2000 From arousal to cognition: the integrative position of the prefrontal cortex. Prog. Brain Res. 126, 469–483. Rochat, P. 2003 Five levels of self-awareness as they unfold early in life. Conscious Cogn. 12, 717–731. (doi:10.1016/ S1053-8100(03)00081-3) Rodrigues-Pinguet, N. O., Pinguet, T. J., Figl, A., Lester, H. A. & Cohen, B. N. 2005 Mutations linked to autosomal dominant nocturnal frontal lobe epilepsy affect allosteric Ca2C activation of the alpha 4 beta 2 nicotinic acetylcholine receptor. Mol. Pharmacol. 68, 487–501. (doi:10.1124/mol.105.011155) Rossi, F. M., Pizzorusso, T., Porciatti, V., Marubio, L. M., Maffei, L. & Changeux, J.-P. 2001 Requirement of the nicotinic acetylcholine receptor b2 subunit for the anatomical and functional development of the visual system. Proc. Natl Acad. Sci. USA 98, 6453–6458. (doi:10.1073/pnas.101120998) Sacco, K. A., Bannon, K. L. & George, T. P. 2004 Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders. J. Psychopharmacol. 18, 457–474. (doi:10.1177/0269881104047273) Schaeffer, P., Prabonnaud, V., Roux, M., Gully, D. & Herbert, J. M. 1994 CCK-JMV-180 acts as an antagonist of the CCKA receptor in the human IMR-32 neuroblastoma cell line. FEBS Lett. 354, 203–206. (doi:10.1016/ 0014-5793(94)01114-1)

Downloaded from rstb.royalsocietypublishing.org on May 31, 2010

Review Schultz, C., Koppers, D., Braak, H. & Braak, E. 1997 Cytoskeletal alterations in the aged human neurohypophysis. Neurosci. Lett. 237, 93–96. (doi:10.1016/S03043940(97)00817-3) Searle, J. R. 2000 Consciousness. Annu. Rev. Neurosci. 23, 557–578. (doi:10.1146/annurev.neuro.23.1.557) Semba, K. 1999 The mesopontine cholinergic system: a dual role in REM sleep and wakefulness. In The handbook of behavioral state control: cellular and molecular mechanisms (ed. R. Lydic & H. A. Baghdoyan), pp. 161–180. Boca Raton, FL: CRC Press. Semba, K. 2004 Phylogenetic and ontogenetic aspects of the basal forebrain cholinergic neurons and their innervation of the cerebral cortex. Prog. Brain Res. 145, 3–43. Shallice, T. 1988 From neuropsychology to mental structure. New York, NY: Cambridge University Press. Shulman, R. G., Hyder, F. & Rothman, D. L. 2003 Cerebral metabolism and consciousness. C. R. Biol. 326, 253–273. Shytle, R. D., Silver, A. A., Sheehan, K. H., Sheehan, D. V. & Sanberg, P. R. 2002 Neuronal nicotinic receptor inhibition for treating mood disorders: preliminary controlled evidence with mecamylamine. Depress. Anxiety 16, 89–92. (doi:10.1002/da.10035) Sigman, M. & Ungerer, J. A. 1984 Cognitive and language skills in autistic, mentally retarded, and normal children. Dev. Psychol. 20, 293–302. (doi:10.1037//0012-1649.20. 2.293) Steinlein, O. K. 2004 Genetic mechanisms that underlie epilepsy. Nat. Rev. Neurosci. 5, 400–408. (doi:10.1038/ nrn1388) Steinlein, O. K., Mulley, J. C., Propping, P., Wallace, R. H., Phillips, H. A., Sutherland, G. R., Scheffer, I. E. & Berkovic, S. F. 1995 A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 11, 201–203. (doi:10.1038/ ng1095-201) Steriade, M. 2004 Slow-wave sleep: serotonin, neuronal plasticity, and seizures. Arch. Ital. Biol. 142, 359–367. Steriade, M., McCormick, D. A. & Sejnowski, T. J. 1993 Thalamocortical oscillations in the sleeping and aroused brain. Science 262, 679–685. Taly, A., Delarue, M., Grutter, T., Nilges, M., Le Novere, N., Corringer, P.-J. & Changeux, J.-P. 2005 Low frequency normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism. Biophys. J. 88, 3954–3965. (doi:10.1529/biophysj.104.050229) Tapper, A. R. et al. 2004 Nicotine activation of alpha4
receptors: sufficient for reward, tolerance, and sensitization. Science 306, 1029–1032. (doi:10.1126/science. 1099420) Tassonyi, E., Charpantier, E., Muller, D., Dumont, L. & Bertrand, D. 2002 The role of nicotinic acetylcholine receptors in the mechanisms of anesthesia. Brain Res. Bull. 57, 133–150. (doi:10.1016/S0361-9230(01)00740-7) Terzano, M. G. & Parrino, L. 2000 Origin and significance of the cyclic alternating pattern (CAP). Sleep Med. Rev. 4, 101–123. (doi:10.1053/smrv.1999.0083) Thinus-Blanc, C. 1996 Animal spatial cognition: behavioral and neural approaches. Singapore: World Scientific.

Phil. Trans. R. Soc. B (2006)

J.-P. Changeux

2259

Thorndike, E. L. 1898 Animal intelligence: an experimental study of the associative processes in animals. New York, NY: Macmillan (Psychological Review, Monograph Supplements, No. 8). Trivers, R. 1985 Social Evolution. Menlo Park, CA: Benjamin. Unwin, N. 2000 The Croonian Lecture 2000. Nicotinic acetylcholine receptor and the structural basis of fast synaptic transmission. Phil. Trans. R. Soc. B 355, 1813–1829. (doi:10.1098/rstb.2000.0737) Unwin, N. 2005 Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J. Mol. Biol. 346, 967–989. (doi:10.1016/j.jmb.2004.12.031) Vidal, C. & Changeux, J.-P. 1989 Pharmacological profile of nicotinic acetylcholine receptors in the rat prefrontal cortex: an electrophysiological study in a slice preparation. Neuroscience 29, 261–270. (doi:10.1016/0306-4522(89) 90056-0) Vidal, C. & Changeux, J.-P. 1993 Nicotinic and muscarinic modulations of excitatory synaptic transmission in the rat prefrontal cortex in vitro. Neuroscience 56, 23–32. (doi:10. 1016/0306-4522(93)90558-W) Weiskrantz, L. 1991 Disconnected awareness for detecting, processing, and remembering in neurological patients. J. R. Soc. Med. 84, 466–470. Wonnacott, S., Go¨thert, M., Chahl, L. A., Willow, M. & Nicholson, G. M. 1995 Modulation of neurotransmitter release by some therapeutic and socially used drugs; Go¨thert M: ethanol (alcohol). In Neurotransmitter release and its modulation (ed. D. A. Powis & S. J. Bunn), pp. 293–327. Cambridge, UK: Cambridge University Press. Woolf, N. J. 1997 A possible role for cholinergic neurons of the basal forebrain and pontomesencephalon in consciousness. Conscious Cogn. 6, 574–596. (doi:10.1006/ ccog.1997.0319) Yamamoto, K. I. & Domino, E. F. 1965 Nicotine-induced EEG and behavioral arousal. Int. J. Neuropharmacol. 4, 359–373. (doi:10.1016/0028-3908(65)90016-X) Yerkes, R. M. 1916 The mental life of monkeys and apes. New York, NY: H. Holt. Zeki, S. 2003 The disunity of consciousness. Trends Cogn. Sci. 7, 214–218. (doi:10.1016/S1364-6613(03)00081-0) Zelazo, P. D. 1996 Towards a characterization of minimal consciousness. New Ideas Psychol. 14, 63–80. (doi:10. 1016/0732-118X(96)00004-9) Zelazo, P. D. 2004 The development of conscious control in childhood. Trends Cogn. Sci. 8, 12–17. (doi:10.1016/j.tics. 2003.11.001) Zhou, W. X., Sornette, D., Hill, R. A. & Dunbar, R. I. 2005 Discrete hierarchical organization of social group sizes. Proc. Biol. Sci. 272, 439–444. (doi:10.1098/rspb.2004.2970) Zoli, M., Lena, C., Picciotto, M. R. & Changeux, J.-P. 1998 Identification of four classes of brain nicotinic receptors using beta2 mutant mice. J. Neurosci. 18, 4461–4472. Zoli, M., Picciotto, M. R., Ferrari, R., Cocchi, D. & Changeux, J.-P. 1999 Increased neurodegeneration during ageing in mice lacking high-affinity nicotine receptors. EMBO J. 18, 1235–1244. (doi:10.1093/emboj/18.5.1235) Zucconi, M. & Ferini-Strambi, L. 2000 NREM parasomnias: arousal disorders and differentiation from nocturnal frontal lobe epilepsy. Clin. Neurophysiol. 111, S129–S135. (doi:10.1016/S1388-2457(00)00413-2)

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Phil. Trans. R. Soc. B (2006) 361, 2261 doi:10.1098/rstb.2006.1896

Erratum Phil. Trans. R. Soc. B 361, 1857–1875 (2006) (doi:10.1098/rstb.2006.1896) Implications of a 3.472–3.333 Gyr-old subaerial microbial mat from the Barberton greenstone belt, South Africa for the UV environmental conditions on the early Earth Frances Westall, Cornel E. J. de Ronde, Gordon Southam, Nathalie Grassineau, Maggy Colas, Charles Cockell and Helmut Lammer The following author addresses were omitted from the above article. 6

Planetary and Space Sciences Research Institute, The Open University, Milton Keynes, MK7 6AA, UK Space Research Institute, Austrian Academy of Sciences, Schmiedlstr. 6, A-8042 Graz, Austria

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