Another View of the Brain System

ANOTHER VIEW OF THE BRAIN SYSTEM

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ANOTHER VIEW OF THE BRAIN SYSTEM

TOSHIFUMI KUMAI AND

SHIBUKAWA YOSHIYUKI

Nova Biomedical Books New York

Copyright © 2009 by Nova Science Publishers, Inc.

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Published by Nova Science Publishers, Inc.  New York

Contents

Preface

vii

Acknowledgments

ix

Chapter I

Development of the Nervous System

1

Chapter II

Electrical Properties of Neurons

25

Chapter III

Synaptic Processes and Neurotransmitters

63

Chapter IV

General Organization of the Human CNS

97

Chapter V

Sensory and Motor Nervous System

131

Chapter VI

Dual Properties of the Human Nervous System

165

Index

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Preface Our intelligent life deeply depends on the highly evolved nervous system of the brain, and the brain is one of most exciting themes in science. We, T. Kumai and Y. Shibukawa, have studied the control mechanism of the central nervous system in masticatory movements: Kumai, using electromyogram (EMG) and electroencephalogram (EEG), and Shibukawa, using magnetoencephalogram (MEG). At the same time, we have lectured neurophysiology to students at Matsumoto Dental University and at Tokyo Dental College, respectively. In our lectures we have received many questions about neurophysiology from our students, including questions that specialists in neuroscience had never considered. Although we sometimes found it difficult to answer satisfactorily, we were rewarded with rich viewpoints as well as interesting suggestions for understanding or investigating the mechanism of the nervous system. Recent advances in neuroscience, especially those using new electrical and biochemical technologies, have been great. Yet the students' questions made us aware that many obscure aspects yet remain in the field of neuroscience. This awareness was the impetus for our decision to publish this book, even though there are already many excellent publications on neuroscience. Much of the volume of this book is made up of descriptions of common established knowledge in neurophysiology which we have presented to students, whereas short columns, entitled "A Different Angle”, are interspersed here and there in each chapter. We should state at the outset that some of these "A Different Angle" columns were based on students’ questions, while others were based on ideas that came to us in the process of preparing lectures. So, with few exceptions, we do not provide experimental proofs in the discussions in these columns. We are, however, convinced that many of readers of this book may have had questions like those described in "A Different Angle" at an early stage of their study of neuroscience, but which may have been forgotten. Thus, we hope that everybody, including specialists in neuroscience, will to read this book without formality. We would be very glad if readers are inspired by this small book and feel a deeper interest in neuroscience.

Acknowledgments In preparing this book we have been supported by many experts. First of all, the most difficult thing for us as Japanese in writing this sort of book is how to express the subtle contents in English. We would like to offer great thanks to David Carlson, Professor of English at Matsumoto Dental University, for his kind and continuous support of our writing throughout this book. Next, we are not experts in physics or chemistry, yet neuroscience contains a fair amount of these two subjects. In particular, the sections about the mechanism of membrane potential generation in Chapter 2, and the molecular mechanism of ion channels in Chapter 3 were written with the helpful support of Tadayoshi Tanaka, Lecturer in physics at Matsumoto Dental University, and Naoyuki Takahashi, Professor of biochemistry at Matumoto Dental University. It is a pleasure to acknowledge the help and suggestions of these two experts in expressing difficult content, as well as recognizing the students at Matsumoto Dental University and Tokyo Dental College for giving us many useful hints for this publication. In the preparation of this book we drew on the work of many authors. In particular, we referred to the following words: Chapter 1, "An introduction to Embryology" (Balinsky, B.I., 1970, McGraw-Hill.) and "Foundations of Embryology" (Bradley, M.P. and Carlson, B.M., 1974, W.B. Saunders Co.); Chaper 2, "The conduction of the nervous impulse" (Hodgikin, A.L., 1964 Liverpool University Press), "Membranes, Ions, and Impulses (Translated in Japanese)" (Cole, K.S., 1969, Yoshioka Shoten), and "Biophysics of Neurons (in Japanese)" (Miyagawa, H. and Inoue, M., 2003, Maruzen Inc.); Chapter 3, "The Physiology of Synapses" (Eccles, J.C., 1964, Springer Verlag), "From Neuron to Brain (3rd ed.)" (Nicholls, J.G., Martin, A.R. and Wallace, B.G., 1992, Sinauer Associates Inc.), and "Ion channels of excitable membranes (3rd ed.)" (Hille, B., 2001, Sinauer Associates Inc.); Chapter 4, "Human Brain: An Introduction to Its Functional Anatomy (4th ed.)" (Nolte, J., 1999, Mosby, Inc.), and " Netter’s Atlas of Human Neuroscience" (Felten, D.L. and Józefowicz, R., 2003, Medimedia Inc.); Chapter 5, "Neurophysiology (2nd ed.)" (Shephered, G. M., 1988, Oxford University Press), "Principles of Neural Science (3rd ed.)" (Kandel, E.R., Schwartz, J.H. and Jessell, T.M., 2000, McGraw-Hill), and "Neural Anatomy: text and atlas (3rd ed.)" (Martin, J.H., 2003, McGraw-Hill); and Chapter 6, "Neuroscience: Exploring the Brain (3rd ed.)" (Bear, M.F., Connors, B.W. and Paradiso, M.A., 2007, Lippincott Williams & Wilkins) and "Cognitive Neuroscience: The Biology of the Mind (2nd ed.)" (Gazzaniga, M.S., Ivry, R.B. and Mangun, G.R., 2002, W.W. Norton & Company, Inc.). It is not too much to say that our

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book could not have been produced without referencing these excellent publications. We express special thanks to all of the related authors of these books and to their publishers. We should also add that these publications are very useful not only for teachers of neuroscience, but also for investigators as handy reference works. The knowledge of neurosciences has, of course, been established by a great deal of other earnest investigation in the various subfields, and related articles are also referenced in each chapter. It is impossible, however, in a limited space, to acknowledge all articles which were forerunners. We would, however, like to pay tribute to those forerunners in the establishment of neuroscience, and to beg their pardon if we omitted their articles or publications. Finally, we are grateful to the staff of Nova for giving us an opportunity to publishing this book. T.K. Y.S. Shiojiri, Nagano Inage, Chiba

Chapter I

Development of the Nervous System The human nervous system is quite elaborate anatomically and functionally. The formation of the system, however, starts from simple tubular tissue that originates from an external cell layer of the embryo. The complexity of the human central nervous system (CNS) can be understood more clearly and fully in light of its embryological development. Although there are still many unknown aspects of the developmental process of an embryo, the biologist Ernst Haeckel (1834-1919) long ago noted that the embryonic developmental process (ontogeny) repeats the evolutional history of earlier ancestors (phylogeny) in some abbreviated form. This idea, often restated simply as “ontogeny recapitulates phylogeny”, has influenced research on various aspects of biological formation and function of animal groups. Various physical configurations, at least in their early stages, are similar among vertebrates, in contrast to their mature formations, which are also observed in the configurations of their nervous systems. Whether or not Haeckel’s concept of “recapitulation” is correct, it is certain that embryonic development contains key information for resolving troubles of elaborated and complex architectures and functions of the mature human nervous system. At the beginning of this chapter, we will first take a rough look at the evolution of the nervous system of invertebrates and vertebrates, then at general formations of major components of the central nervous system in embryonic development of vertebrates, and finally at the process of human brain development.

(1) Evolutionary History of the Nervous System One of major differences between plants and animals must be whether or not they have the ability to move. All animals can move to get maximal situation in their surroundings. Reaction in response to stimulation is observed even in organisms at the lowest levels, such as the ameba and paramecium. They have no neurons, so events are mediated by direct ionic flow across their cell membranes: the ionic mechanism has been well analyzed in terms of the beat manner of cilia in the paramecium. With advancing evolutionary stages, this stimulus-

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response connection came to be carried by specific differentiated cells, called neurons, (but they also function on the basis of ionic flow). In succession, the neurons have been organized systematically, which is observed in various evolutionary levels of present animal groups. Before studying the embryonic development of nervous system in mammals including humans, an overview of its progressing features may give us many useful hints on the core thesis “what is the nervous system?”

* Invertebrates Coelenterata was the first division to obtain a true neuron that was able to generate a message, an action potential, and transmit it to other neurons with synaptic properties. Their sensory receptors are isolated, diffuse cells that resemble a net, forming a so called net-nerve system (Fig. 1-1 a). In the nerve-net system, a signal or impulse, starting in one part of the body, can spread in all directions to every part, and there is no critical differentiation of the neurons into sensory and motor types. With the progress of various types of movement, neurons became integrated and concentrated, showing the beginning of cephalization as central ganglia (Fig. 1-1 b). This begins to resemble central nervous system organization, but with ventral location. Most invertebrates have a central nervous system (CNS). These include the annelids (leeches, sandworms, and earthworms), mollusks (squids, bivalves, and snails), and arthropods (insects, crabs, and lobsters). The most primitive configuration of the CNS can be observed in the nervous system of planaria (Platyhelminthes), the lowest invertebrates showing bilateral symmetry (bilateria). The axons and dendrites are arranged in paired, definite nerve cords running longitudinally, which are interconnected by transverse nerve fibers called commissures (Fig. 1-1 c), whereas nerve fibers connecting ganglia longitudinally are called connectives. This prototype of the nervous system is called “orthogon”. Progressive localization of neurons is responsible for the segmental nervous concentrations forming the metameric ganglia, a collection of nervous cell bodies (Fig. 1-1 d). The concentration as ganglia is greater at the anterior end of the animal, and the paired ganglia are interconnected along their length by commissures. There is a differentiation into central and peripheral systems, with separate sensory and motor neurons relayed by synapses allowing nerve impulses to travel systematically. In polychaetes (Annelida), for example, each segment has a ganglion, and the paired nerve cords extend the entire length of the body (a nerve-ladder system) (Fig. 1-1 d), which enables its separate segments to move in a coordinated fashion. As a primitive structure, the ventral nerve cord is completely double throughout. The most anterior part of the cord is an enlarged ganglion, sometimes referred to as the “brain” (or cerebral ganglia), which sends command impulses down the cord. In annelids, the nerve cords are clearly situated in the ventral portion of the body (ventral nerve cord), except for the brain, which is bilobed and lies beneath the dorsal epithelium of the anterior end. A single pair of circumpharyngeal (or circumesophageal) connectives surround the anterior gut and interconnect the brain and the ventral nerve cord. Although there is variation depending upon the degree of development of the sense organs, the brain can generally be divided into three parts: forebrain, midbrain, and hindbrain.

Development of the Nervous System

3

Figure 1-1. Types of nervous systems. a: Nerve net in hydra (coelenterate). b: Concentrated nerve net and the beginning of cepharization in flatworm (polyclad). c: Ladder nerve in freshwater planaria (triclad). d: Segmental ladder nerve with each paired ganglia in sandworm (annelids). e: Ventral segmental nerve cord with each ganglion in shrimp (arthropods). (Based on Barnes 1974.)

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The nervous systems of other higher invertebrates are similar to that of annelids, except for the transverse concentration of the bilateral cords; for example, the paired nerve cords of arthropods tend to fuse longitudinally (Fig. 1-1 e). There is no exception that in invertebrates having the nerve-ladder system, the nerve cord is ventral to the digestive system and without a cavity structure in its center.

* Vertebrates An abrupt and critical change in nerve cord organization occurred at the branching of the invertebrate and vertebrate stages of evolution. In vertebrates, the nerve cord shifted dorsal to the digestive system as the spinal cord and simultaneously became lodged in the bony vertebral canal. Two other important differences between vertebrate and invertebrate nervous systems are a tubular architecture (a central cavity) and the appearance of a notochord in the embryo, giving rise to the vertebral column in the adult. Further, evolution caused the nervous system of vertebrates, especially the brain, to progress. The CNSs of all vertebrates are, however, fundamentally alike: although the degrees of their developments differ between species, all are formed of the same components, such as the spinal cord, medulla, midbrain, cerebellum, and cerebrum. Among the components, the advance of the cerebrum is conspicuous. In higher vertebrates, especially mammals, the cerebrum has expanded with convoluted folding structure of the cerebrum (Fig. 1-2), accompanied simultaneously by functional progress. We can see the highest elaborated architecture of the nervous system in the human brain. Trends in the evolution of nervous systems, including those of invertebrates, can be described using three terms: (1) centralization, (2) cephalization, and (3) specialization. Centralization has tended to form two trunks along the body’s longitudinal axis, which have further tended to become fused, especially in vertebrates, into one major axial trunk: in all vertebrates the fused trunks form the so-called spinal cord, with a longitudinal cavity inside. The centralization process has tended to occur mainly on the cell bodies of neurons, which is the origin of the separation between the peripheral and central nervous system. Cephalization is concentration of neural tissue in the anterior end of the longitudinal body axis, which might, however, be considered to occur near the eyes: it is noticeable that in flatworms the cephalic ganglia are not formed around the pharynx but under the eyes (Fig. 11 b, c). This phenomenon involving cephalic dominance is observed even in invertebrates, but is more pronounced in vertebrates. Specialization is particularly characteristic of vertebrate brains. Each component of vertebrate brains has tended to develop differentially, depending on its function. Some vertebrates have greatly developed the optic lobes, while others, the cerebellum and cerebrum. However, most noticeable specialization has occurred in the human cerebral cortex covering the brain, which doesn’t receive direct fibers from sensory organs, but rather from other parts of the brain, and which correlates the data suitably to control maximal behaviors in various situations.

Development of the Nervous System

5

Figure 1-2. Relative development of major brain parts (dorsal view) in several vertebrate species. A lateral view of the brain is attached in the figure for monkey. @- and *-marks indicate the cerebral hemispheres and cerebellum, respectively, of each animal. Brain sizes are adjusted suitably. (Based on Stark 1982, Romer 1965, and Webster and Webster 1974.)

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(2) General Embryonic Development of Nervous System The CNSs of all vertebrates are fundamentally composed of the same elements. Although the volume and shape of each of the mature components differs among species, the configuration processes are almost the same in their early stages of development. Neurophysiological interest in the development of the embryo starts at the stage of three distinctly-organized layers of cells: endoderm (inner layer), mesoderm (middle layer), and ectoderm (outer layer) as a result of so-called gastrulation. The endoderm forms the alimentary canal and digestive glands; the mesoderm is the source of muscle, the vascular system and the internal skeleton; and the ectoderm gives rise to the epidermis and the nervous system.

* Neurulation in Development of Vertebrates The remarkable differentiation of the nervous system starts with the formation of the socalled neural plate, the result of thickening in the dorsal part of the ectoderm (Fig. 1-3 A). At the same time, the cells of the neural plate change into precursor cells for future neurons: they become elongated and arrange themselves into columnar epithelium. The next event is thickening and raising of the edges of the neural plate, appearing as neural folds which form a neural groove in the neural plate that runs rostral to caudal. The neural folds subsequently move together inward and fuse at the midline, which transforms the neural plate into a tube (Fig. 1-3 B). The formation of the neural tube starts at a level corresponding to the future cervical spinal cord. The neural tube is widened anteriorly as the presumptive brain and narrowed posteriorly as the presumptive spinal cord. The formation and closure of the neural plate is referred to as (primary) neurulation, whose process is believed to be induced by the specific structure called the notochord (Fig. 1-3), which originates from the dorsal endodermal cells. The formation of the notochord, which eventually differentiates into future bony axial structures, starts as an early developmental stage preceding neural plate formation. In the neurulation process, groups of ectodermal cells from the ridge of both folds remain free in the posterior-lateral portion of the neural tube. The tissue of these free ectodermal cells, called the neural crest (Fig. 1-3 B), is the source of neurons in the peripheral nervous system and includes sensory neurons in the ganglia of spinal and cranial nerves, as well as neurons in the autonomic ganglia. Individual cells of both the neural tube and the neural crest differentiate into neuroblasts, which are the precursors of neurons. Neuroblasts migrate until they are close to where they will be located in the mature body, and then differentiate into specific neurons. [A Different Angle 1-1] Neural Tube Formation: In vertebrate embryos, the neural tube cannot be formed as a hollow duct from the first step, but rather is created through a process of fusing the bilateral ridges (neural folds) of the dorsal ectoderm. From the concept that ontogeny recapitulates

Development of the Nervous System

7

phylogeny, this process is thought to reflect the nervous system of the invertebrate stage of evolution. In invertebrate stages, dispersed neurons in the net-nerve system converged into the paired nerve cords running longitudinal in the medial portion of the body. The two ridges in the early stage of vertebrate neural tube formation are thought to reflect the paired nerve cords of the invertebrate nervous system. In the neurulation process of vertebrates, groups of ectodermal cells from the crests remain free as the neural crests in the posterior-lateral portion of the neural tube. The neural crest neurons are believed to give rise to the dorsal spinal ganglia and the cells from the crests remain free as the neural crests in the posterior-lateral portion of the neural tube. The neural crest neurons are believed to give rise to the dorsal spinal ganglia and the neural cords. By extension of this view, the neural plate may reflect the net-nerve system observed in primitive invertebrates. In vertebrate embryos, the fusing of the neural tubes begins from the point corresponding to the occipital region of the embryo (Fig. 1-4 a, 1-5 a), which advances rostrally and caudally, so that eventually both terminal regions of the neural tube remain open at a relatively late stage of the neurulation. What does this mean? From the viewpoint that embryonic development reflects the evolutionary history of the species, the later closure of the two terminals of the neural tube indicates that the brain of the vertebrate CNS, as well as the caudal portion of the spinal cord, progressed in a later stage of evolution.

Figure 1-3. A: Dorsal view sketch of entire chick embryo about 22 hours of incubation, with its longitudinal section through the midline (left drawing) and its cross section through the rostral region of the neural plate formation (upper drawing). B: Outline sketches of three stages in the development of a neural tube in a chick embryo. The upper sketch is for a stage in the appearance of the neural groove; the middle sketch, in the advance of the neural groove; and the lower sketch, in the formation of the neural tube and neural crest. (Adapted from Bradley and Carlson 1974.)

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[A Different Angle 1-2] What is the notochord?: The notochord is an interesting entity that appears in the development process and is restricted to vertebrate embryos. It emerges preceding neural plate formation and is thought to be involved in inducing neural tube formation and subsequent neural vesicle differentiation. The notochord originates from the dorsal wall of the archenterons and differentiates into the vertebrae, hence the term “vertebrate”. At the evolutionary change from invertebrates to vertebrates, the supporting system of the body reversed from an external shell to an internal bony system, and simultaneously the CNS (except for the ganglion of the most rostral region) moved dorsally. An idea arises that notochord formation is a reflection of the external shell system of invertebrates. It is interesting that the notochord differentiates finally to vertebrae that enclose the spinal cord, and that it simultaneously plays a role in supporting the body axis of vertebrates. Similar to the enclosure of the spinal cord by vertebrae, the adult brain is surrounded by the cranium, a rounded structure composed of many bony parts. There has been an argument over whether or not the cranium is part of the vertebrae. Although there are different suggestions about the origin of the cranium, it seems that the cranium may be formed from a few deformed vertebrae. One bit of evidence which supports this theory is the fact that the vertex of the cranium of the newborn is open at the anterior fontanel, which closes gradually until about 18 months of age. The fontanel must be a vestige of the space of vertebral sheathing of the spinal cord.

* Formation of Primary Vesicles of the Brain Soon after establishing the neural tube, the major brain regions and the rostral end of the neural tube become distinct. They develop as three general swellings or primary vesicles called, in rostral to caudal order, the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain) (Fig. 1-4 a. Fig. 1-5 b). Although various specialized outgrowths are later added on to the cephalous, the caudal part of the neural tube from the rhombencephalon remains relatively simple and gives rise to the spinal cord. The original tubular portions of these three brain segments are still recognizable in the adult, but the distinction between three divisions of the brain rests more on functional than on anatomical grounds. In vertebrates, each of the three parts is principally associated with one of the three major sense organs: the procencephalon with the nose, the mesencephalon with the eye, and the rhombencephaon with the ear (and with the lateral line in lower vertebrates). In the mature brains of vertebrates, especially lower vertebrates, the cerebral hemispheres, which are differentiated from the procencephalon, are primarily associated with smell; the midbrain roof and tectum are associated with vision; and the cerebellum, a rhombencephalon outgrowth, is associated with the ear.

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* Formation of Secondary Vesicles and Their Derivatives of the Brain Secondary vesicles differentiate from the primary vesicles. From the rostral region of the prosencephalon, the telencephalic vesicles (telencephalons) expand on both sides, and from

Figure 1-4. Three stages in the development of a chick embryo, at about 30 (a), 42 (b), and 55 (c) hours of incubation. (Redrawn from Balinsky 1970, and Bradley and Carlson 1974.)

Figure 1-5. Three stages in the development of a human embryo, at about 19 (a), 28 (b), and 35 (c) days. (Redrawn from Balinsky 1970, and Bradley and Carlson 1974.)

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the caudal region, optic vesicles. A remnant of the caudal prosencephalon is called the diencephalon. In most mammals, especially in humans, the paired telencephalons grow greatly and eventually cover the diencephalons, which are called the cerebral hemispheres. Each bulge of the telencephalon contains a cavity, which is an extension of the original cavity of the procencephalon. The cavities expanding bilaterally into the cerebral hemispheres are called the lateral ventricles, and the original cavity, which remains at the site of the diencephalons, is called the third ventricle. The ventricles are invaginated by a sort of vascular system, the so called (anterior) choroid plexus. The paired olfactory bulbs develop immediately from the anterior portion of the telencephalons: as described, the telencephalon was originally related with the olfactory sense. The diencephalons give rise to two major structures, the thalamus and the hypothalamus. The right and left thalami differentiate from the dorsal parts of the lateral walls of the diencephalons, and the portion just caudal to the thalamus, the ventral floor of the diencephalons, is called the hypothalamus. The posterior portion of the medial roof of the diencephalons forms dorsally one unpaired outgrowth, called the epiphysis (pineal organ), which becomes, in both function and figure, an eye-like organ, especially in lower vertebrates. There are vertebrates which have another organ similar to the epiphysis (parapineal organ) just anterior to the epiphysis, but its function and relation with the pineal organ are not apparent. The floor of the diencephalons forms a funnel-like depression, called the infundibulum. Part of the wall of the infundibulum becomes segregated from the brain wall and fuses with an outgrowth from the stomodeal invagination, the two together forming an architecture named the hypophysis (pituitary gland).

Figure 1-6. Lateral view of the organization of 5 basic vesicles (telencephalon, diencephalons, mesencephalon, metencephalon, and myelencephalon) and their derivative structures of the principal brain. The outline of the central canal (and ventricles) is shown in gray. (Redrawn from Stark 1982.)

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From the mesencephalon, structures called the tectum and tegmentum are differentiated on the dorsal and ventral sides, respectively, but the organizations are relatively simple. In fishes and amphibians, the tectum develops into paired large swellings that function as the primary visual center, so it is called the optic tectum. The development of the tectum of humans is poor, and produces two paired small swellings -- one pair receiving sensory signals for the eyes, and the other, for the ears. The cavity of the midbrain becomes narrow and it is known as the cerebral aqueduct (aqueduct of Sylvius). The rhombencephalon gives rise to the metencephalon and the myelencephalon (medulla (oblongata)). Owing to the expansion of the membranous roof of the rhombencephalon, the dorsolateral plate lies lateral rather than dorsal to the ventrolateral plate. The metencephalon further differentiates into the cerebellum and the pons. The dorsolateral part of the metencephalon, corresponding to the dorsolateral plate of the spinal cord, gives rise to so called the cerebellum. The bulge of the metencephalon ventral part is called pons: the swelling is largely due to take-up longitudinal nerve fibers running up and down the brain. The cavity of the pons and rostral medulla expands, forming the so called fourth ventricle, which is, as well as the lateral and third ventricles, invaginated by the choroid plexus formation (posterior choroid plexus). The five divisions, telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon, are arranged essentially in a straight line in lower vertebrates: general organization of the cephalons and their derivatives are shown in Fig. 1-6. There is a notable feature in the embryogenic stage of the five brain vesicles as they form, especially for birds and mammals. The brain tube bends strongly upon itself at three levels: the cephalic flexure occurs dorsally at the mesencephalon, the cervical flexure also occurs dorsally at the junction between the medulla (myelencephalon) and the spinal cord, and the pontine flexure that appears latest occurs ventrally at the rhombencephalon (Fig. 1-4 c, 1-5 c). [A Different Angle 1-3] What do the flexures of the embryo brain mean?: The brain-to-body volume ratio tends to increase with the evolution of vertebrates. That the cephalic flexion can make the large volume of the anterior parts pack efficiently within the restricted space of the cranium seems to be a most probable explanation as the physiological background of the flexing phenomenon. An interesting aspect of the cephalic flexures is that they tend to occur strongly in birds and primates, including humans, most of which have been free, more or less, from crawling on four limbs. This suggests that the flexures may relate, in some way, to the alteration of posture from horizontal to perpendicular, accompanying the change in locomotion from four limbs to two. There is another suggestive aspect in the flexures. The flexures caused the position of the telencephalon to move to just in front of the metencephalon (Fig. 1-4 c, 1-5 c). The telencephalons subsequently expanded further and now cover the rostral end of the brain as the cerebral hemispheres. Namely, the cerebral hemispheres come to be able to make connections with wide regions of the caudal brain, with shorter distance compared to the straight arrangement of the vesicles through fusion between the components. (The fusion of neural components is observed typically in the spinal cord architecture, where right and left cords is considered to fuse.) The flexures are merely observed in vertebrates whose development of telencephalon is poor.

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In mammals, the telencephalon has developed greatly as the large cerebral hemispheres, where the folding structure is complexly elaborated. Viewed from another point, the folding structure of the hemispheres can be considered to be a small flexure in the restricted region. The folding structure of the cerebrum surface enables it to connect the cortex neurons situated on opposite sides of the mount with the shortest distance. It is certain that the cephalic flexion can make the large volume of the brain pack efficiently within the restricted space, but the most substantial merit must be the functional connection of relating neurons with the shortest distance.

* Characteristics of Brain Differentiation The basic plan of brain development is common throughout the vertebrates, and the organization of the mature brains of vertebrates shows the following features, if included: 1) Protuberances of major components of the brain tend to be formed on the dorsal side rather than on the ventral side, whereas nerve trunks (cranial nerves) leave the brain ventrally or laterally. (Some species of fishes, however, have fairly large swellings, such as the pituitary gland and inferior lobe of the hypothalamus in the ventral portion of their brains.) The tendency toward dorsal protuberances must relate to the fact that most swellings of the brain are involved in processing sensory information, most signals of which project to neurons located in the roof plate. 2) The cerebrum (telencephlon) of all of vertebrates separates distinctly into right and left hemispheres, whereas the cerebellum tends to be formed as a single bulge on the midline of the dorsal side. In mammals, the cerebellum, however, tends to differentiate into three parts-right and left hemispheres extending laterally and a central region--but the separation between the two hemispheres is not as sharp as the cerebrum separation (Fig. 1-2). The dorsally-medial location of the cerebellum may mean that its main role is the integration of relating sensory signals between the right and left sides, or the regulation of signals of between the caudal and rostral components. 3) Folded (and/or convoluted) structure is observed on the surface of both the cerebrum and cerebellum, especially of mammals. Phylogenetically, the obvious folded structure appears earlier in the cerebellum than in the cerebrum: for example, the cerebrum of mice and birds lacks the conspicuous folded structure that is remarkable on their cerebellum (Fig. 1-2). It is further noticeable that the folded structure of the cerebellum surface tends to be formed crosswise, whereas that of the cerebrum surface tends to be formed lengthwise. 4) All of the major lobes of the brain, excepting the cerebellum, show paired right and left parts, but the epiphysis (pineal organ) and the hypophysis (pituitary gland) of all vertebrates are single swellings. The two structures are arranged in opposite directions along a dorsal-ventral axis, even if various figures and volumes of bulges are differently organized in the brains of animals: the epiphysis is located along (or extends from) the midline on the dorsal surface just anterior to the cerebellum or optic tectum, and the hypophysis along the midline on the ventral surface of the diencephalons. (Although a direct functional connection between the two structures has not been reported, the feature of their locations reminds us of anything like sensory–motor relation.)

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5) In all vertebrates, the 3rd ventricle expands laterally into the telencephalons (the lateral ventricles), and the 4th ventricle widens and opens dorsally from the pons to the medulla (Fig. 1-2) through a thin epithelium roof, even though it is covered by the cerebellum enlargement. Both of the 3rd (and lateral) ventricles and 4th ventricle are invaginated with vascularized mesenchymal tissue (choroid plexus) that plays an important role in maintaining the best state of cerebrospinal fluid circulating through the ventricles. [A Different Angle 1-4] Role of the CNS in organization of body components: The embryonic brain, especially of vertebrates, develops more rapidly than almost any other organ. A generalized structural formation is established very early, upon which the numerous variations of the adult brains of different groups are superposed. The volume ratio of the head to the total body is also great throughout the embryonic stage but decreases gradually after birth. The preceding development of the central nervous system apparently indicates that nervous factors play a command role in the formation of visceral and other various organs. A typical example of the importance of the nervous system in the differentiation of organs is eye formation (Fig. 1-7). Eyes, at the beginning, grow outward on either side from the forebrain area as spherical optic vesicles (a). As each vesicle develops, its outer layer folds inward to form an optic cup (b). As the optic vesicle grows out toward the surface, the overlying ectoderm thickens, and a spherical mass of this tissue sinks into the orifice of the cup to form the lens (c). The optic cup becomes the retina (d), and the lens separates from the epithelium that differentiates the future cornea. It is certain that the stimulus for eye formation is first provided by the approach of the optic vesicle to the ectoderm. A similar inducing process by the nervous system is also observed in the construction processes of the ear, nose, and various internal organs.

Figure 1-7. General developing process of the eye. (a) Outgrowing of the optic vesicle; (b) Induction of the lens epithelium from the opposite ectoderm; (c) Enclosure of the lens vesicle by the optic cap; (d) Completion of basic eye structure with optic nerve. (Adapted from Larsen 1993.)

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* Spinal Cord Formation The caudal part of the neural tube transforms into the spinal cord, the process of which is fairly straightforward compared to the differentiation of the brain. Continued cell proliferation of the spinal cord produces a ventral and a dorsal thickened stratum, termed the mantle layer: the ventral thickening forms the so-called basal plate, and the dorsal thickening forms the so-called alar plate (Fig. 1-8 a). The two plates function differentially in the future nervous system. The cavity of the neural tube becomes the tiny spinal canal with expansion of the tissue in the walls. The mantle layer becomes a configuration, as seen in cross section, roughly like the letter “H”(Fig. 1-8 d). It is in the mantle layer that the neuroblasts, young neuronal cells, become concentrated, so this layer represents the site of cell bodies (and dendrites of the neurons to come). Because the mantle layer contains mainly cell bodies of neuroblasts, this part appears gray, hence the term gray matter. The longitudinal thickenings are referred to as the dorsal gray column and ventral gray column. (The former develops from the alar plate column, and the latter, from the basal plate column.) Axons extending from the neuroblasts in the gray matter invade to the marginal layer called the white matter: most of the axons are wrapped by a sheath called myeline, which is white in appearance, hence the name white matter. The columns of the white matter carry the name “funiculi” and are divided into four areas: the dorsal white funiculus, ventral white funiculus, and two lateral (left and right) white funiluli (Fig. 1-8 d).

Figure 1-8. Cross section of the spinal cord at 4 stages (a-d) in the development of a mammal embryo. (d) is a sketch of the mature spinal cord, while (e) shows the visceral and somatic sensory-motor organizations at the mature medulla. (Redrawn from Balinsky 1970.)

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The functions of the body are commonly divided into two categories, somatic and visceral. The somatic function relates to the events carried on by the skin and its derivatives, as well as the voluntary musculature system. The visceral function relates to the events carried on by internal organs, such as digestion, absorption, circulation, respiration, and so on. Sensory fibers that carry signals from somatic parts to the spinal cord, the somatic sensory fibers, synapse to neurons lying in the posterior portion of the dorsal gray columns. Sensory fibers that carry visceral senses, the visceral sensory fibers, synapse to neurons in the anterior portion of the dorsal columns. The cell bodies of the somatic motor neurons and the visceral motor neurons lie in the ventral column, the former anterior and the latter posterior. As just noted, the neurons in the dorsal gray columns that originate from the alar plate belong for the most part to sensory-relating neurons, and the neurons in the ventral gray columns that originate from the basal plate belong motor neurons whose axons project peripherally to the body. This organization continues principally to the medulla (Fig. 1-8 e).

(3) Brain Development in Human Embryo The outline of development of the human brain is not very different from other vertebrates, but peculiar aspects also exist in the human brain differentiation. This section describes only the essence of human brain organization viewed from a developmental aspect. The development of the major central nervous structures in humans is traditionally categorized as follows, according to vesicular divisions in the embryo. The major components of the human embryonic brain at about 15 weeks are roughly shown in Fig. 1-9.

Figure 1-9. Transparent lateral view of organization of 5 basic vesicles and their derivative structures in a human embryo at about 15 weeks.

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( ◎Ectodermal layer ---> ◎Neural plate ---> ◎Neural tube ---> ) *Procencephalon **Telencephalon ---- cerebral hemispheres, olfactory bulbs, basal nuclei, limbic structures **Optic vesicle ------ optic structures **Diencephalon ----- thalamus, hypothalamus, infundibulum *Mesencephalon ** ---------------------- tectum, tegmentum *Rhombencephalon **Metencephalon ---- cerebellum, pons **Myelencephalon --- medulla (oblongata) It is, however, apparent that this classification is based only on anatomical location, and the brain functions fully in relation to the neural connection among the components.

* Myelencephalon and Metencephalon Differentiation The myelencephalon and the metencephalon differentiate from the rhombencephalon, the most caudal of the primary vesicles. The embryonic myelencephalon becomes the adult medulla. In the early developmental stage, the lumen of this caudal part of the neural tube expands, developing later into a large cavity known as the 4th ventricle. At the same time its roof becomes very thin. Small blood vessels develop and invaginate the lumen of the 4th ventricle, forming the posterior choroid plexus. The lateral and ventral walls thicken gradually, forming the layout of nervous tissue already seen in the general spinal cord-external white matter and internal gray matter. The gray matter is arranged like that in the spinal cord, from dorsal to ventral: somatic sensory, visceral sensory, visceral motor, and somatic motor. These columns continue through the medulla, but in humans, they tend to be broken into nuclei associated with specific functions. Many nuclei of cranial nerves arise directly from the gray matter of this region, the arrangement of which can be considered segmentary, although not readily apparent. The dorso-lateral walls of the metencephalic region (rhombic lip) undergo extensive swelling and give rise to the cerebellum. The human cerebellum develops a cortex, which is a layered surface sheet of gray matter (a cellular component). The cells of the cortical layer originate from the mantle layer at the roof (alar) plate of the 4th ventricle, and non-migrating cells form the cerebellar deep nuclei. The lamellar structure of the cerebellar surface appears during the fourth month, first on the medial part (vermis), then on the hemispheres. In humans, the cerebellum functions as neural centers mainly for maintaining posture and carrying out coordination of muscular movements. Relatively late in the development, groups of fibers appear superficially in the walls of the metencephalon, forming the ventral prominence called the pons. The pons is largely taken up by longitudinal nerve fibers running up and down the brain, most of which are fiber

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bundles connecting the spinal cord and cerebral and cerebellar cortices. Still deeper below the 4th ventricle, there are masses of cells that are clustered in well-defined nuclei for the cranial nerves. [A Different Angle 1-5] Evolution of the cerebellum: The cerebellum develops from the metencephalic alar plates on each side of the embryonic 4th ventricle, which form rather late. In human embryos, the bilateral outgrowths enlarge and become distinct at about 2 months and fuse above the ventricle at about 4 months. The fusion produces the vermis in the midline, while the lateral parts become the cerebellar hemispheres. The mature cerebellum plays an important role in the adjustment of body posture and smooth muscular movements. Considering the appearance of cerebellums through vertebrates, we note that the cerebellar hemispheres (or the corpus cerebelli in lower vertebrates) tend to be larger in animals which are capable of very fine movement, and smaller in animals which are less active or sluggish (Fig. 1-2). Furthermore, it is noticeable that obvious folded (or lamellar) structures tend to appear earlier phylogenetically, as well as ontogenetically, in the cerebellar cortex than in the cerebral cortex: the surface of cerebellums of almost all mammals, as well as birds, shows an elaborated folded-convoluted appearance that is poor or is lacking on the cerebral hemispheres, whereas there are no animals with the reverse configuration (Fig. 1-2). In vertebrates of lower stages than mammal, somatic, auditory, vestibular and visual signals are integrated mainly in the cerebellum. All of these lead to the assumption that the cerebellum was the highest center of the CNS at a certain stage of their evolutions, when the most important thing of their life should be superiority of movement, rather than mentality or intelligence. Isn't it an extra-ordinal view that the lamellar formation of the cerebellar cortex would be the condensed structure of spinal cord segments?

* Mesencephalon Differentiation The mesencephalon was linked originally to vision. In most lower vertebrates, optic fibers project to the roof (or tectum) of the mesencephalon. In humans, the midbrain differentiates poorly, with only 4 observed small swellings: the paired superior colliculuses and the paired inferior colliculuses. The former pair is considered to be the retrograded structures of the optic lobes. (Visual information of humans is processed in the cerebrum (forebrain), first at the thalamus and second in the occipital region of the cerebral hemispheres, whereas in fish, amphibians, reptiles and birds, visual signals from the eyes are input to the tectum or optic lobes of the midbrain.) The inferior colliculi function as relay components of auditory signals to the cerebrum. The floor (basal) plate gives rise to the motor nuclei of some cranial nerves (III, IV). The gray matter of the floor is also formed by the so-called red nucleus and the substantia nigra. The mesencephalic cavity connecting the 3rd and 4th ventricles (Sylvius aquaduct) becomes smaller due to the growth of its wall.

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* Diencephalon Differentiation The epiphysis (pineal organ) protrudes from the roof of the diencephalon in most vertebrates, but that of humans attaches dorsally on the 3rd ventricle rostral to the posterior commissure. Although the epiphysis of lower vertebrates functions as a light receptor, that of humans is regarded as a rudimentary organ, the main role of which is the secretion of the hormone, melatonin, known as the chemical causing circadian rhythm. The melatonin is synthesized depending on daily light-dark cycles, especially in birds and mammals, but the real role of the pineal organ of humans has not yet been established with certainty. The thalamus becomes thickened in the sidewalls of the diencephalons: it is a mass of gray matter and develops fairly well in humans, the main reason for which is the assembly of an amount of sensory fibers ascending from the spinal cord. The human thalamus plays an important role in relaying all somatic information, as well as visual and auditory information, to the cerebrum. In the diencephalon floor, a part of the fibers of each optic nerve crosses to the other side of the midline, at a point known as the optic chiasma. In all vertebrates, including humans, this floor plate gives rise to the sensory primordium of the eye and posterior part of the hypophysis called neural hypophysis. The hypothalamus is thought to be differentiated partly from the alar region below the thalamus and partly from the regressive basal plate. The hypothalamus contains various autonomic nuclei that play a key role in controlling many visceral functions, and the hypophysis secretes various hormones, which is controlled by the hypothalamus.

* Cerebrum (Telencephalon) Configuration Needless to say, the most conspicuous feature of the human brain is the great development of the telencephalon, popularly called the cerebral hemispheres. The hemispheres grow extensively, in a lateral direction (the temporal lobes), in a frontal direction (the frontal lobe), in a hind direction (the occipital lobe), and in a rostral direction (the parietal lobe). The size is so large that these structures cover a wide region of the upper brain, and the surface is greatly elaborated with folded and convoluted structures: each ridge is called a gyrus (plural, gyri), and each groove between the gyri is known as a sulcus (plural, sulci). The most important structure in the cerebrum for humans seems to be the cerebral cortex. The great development of the human cortex, especially of the neocortex, is considered to be the source of all that we call mental or intelligent functions, such as thinking, speaking, programmed movements, learning, memory, and so on. The two cerebral hemispheres are connected by a great transverse fiber tract, the corpus callosum. (As discussed in Chapter 6, severance of the tract produces curious results in intelligent functions.)The base plate of the telencephalon gives rise to the striated gray nuclei, the origin of the basal ganglia: their lateral nuclei develop into the caudate nucleus and putamen, and into its medial nuclei, the globus pallidus, all of which is known to be involved in forming various types of basic movements.

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The original role of the forebrain (prosencephalon) was for processing olfactory information, a function which has remained in many vertebrates, but the olfactory bulbs of humans have become small, as have the afferent signal inputs to the ventral restricted areas of the cerebrum, commonly called the paleocortex. This indicates that the importance of the olfactory sense has decreased in humans, compared to other vertebrates. The most primitive version of the cerebral cortex is called the archicortex, which occupies a wide area of the telencephalon of fishes and amphibians, and is essentially important in olfactory sensation and behavior. In reptiles, the archicortex persists, but a new cortical area, the paleocortex, has appeared: this receives non-olfactory afferents from other sensory centers, and correlates these with olfactory data. In some reptiles there appeared a third version of the cerebral cortex, the neocortex, showing a more complex neural organization than either of the older cortices. As evolution has progressed, the neocortex has been extended, compressing the archicortex on the inside (Fig. 1-10 A). This, in turn, formed the limbic structure, and the paleocortex below, which formed olfactory relating areas like the piriform cortex, entorhinal cortex, and amygdala. This change explains the formation of the human cerebrum. (The regional difference of the cerebrum in function will be discussed widely in later chapters.)

Figure 1-10. A: Diagrammatic cross section of the human cerebral hemispheres showing three types of cortices: archicortex (black enclosures), paleocortex (enclosures with small open dots), and neocortex (white enclosures). B: Hierarchical structure of the human brain. The four brains illustrated correspond to the evolutional stage of fish and amphibians, reptiles, early mammals, and late mammals. The black area (aquarian brain) is involved in most basic functions, and the white area (neomammalian brain) is involved in the highest mental functions of organisms. (Adapted from MacLearn 1967.)

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Toshifumi Kumai and Yoshiyuki Shibukawa [A Different Angle 1-6]

Hierarchical Structure of the Brain: Although the vertebrate forebrain has expanded greatly with evolution, it retains commonalities of neural assemblies that reflect three ancestral relationships, namely to reptiles, lower-stage mammals, and higher-stage mammals. These structures are sometimes called the reptilian brain, paleomammalian brain, and neomammalian brain, respectively (Fig. 1-10 B). Although each corresponding area in the human CNS is not rigidly defined, the reptilian brain roughly occupies the core, such as the medulla, pons, hypothalamus, thalamus, and the deep area of the cerebellum, (also including the spinal cord), which maintain the functions of “basic life ”. The paleomammalian brain corresponds mainly to so called the limbic area of the brain, which, as is frequently stated, functions to maintain “vital life”. Also, the neomammalian brain corresponds to the cerebral cortex (especially to the so-called neocortex), which functions for so-called “civilized life”. (These three sub-brains seem to correspond to the three cerebral cortices: the archicortex, paleocortex, and neocortex.) The reptile brain acts completely automatically, while the neomammalian brain, or neocortex, works with strong consciousness. The paleomammalian brain, the major structure of which is the limbic system, is thought to be involved in emotion, signs of which are recognized as widely distinct from mammals. For instance, in humans emotional events arise fairly automatically, but are never connected with motor events directly. Furthermore, the areas corresponding to fish and amphibian stages in evolution can be deduced to be situated in the deepest (or core) areas surrounding the central canal of the spinal cord and ventricles of the brain, which may be temporarily termed as the “aquarian brain” (Fig. 1-10 B). Although the evolutionary classification of brain configuration differs somewhat according to different investigators, it is certain that the structure and function of the human CNS are organized in a hierarchical fashion reflecting evolution, and the older system situate deeper in the CNS and function automatically.

(4) Formation of the Autonomic Nervous System Activities of most internal organs, blood vessels, and glands are subject to close regulation by two types of visceral nerves, the sympathetic and parasympathetic nerves, which together are known as the autonomic nervous system. (The autonomic nervous system as a whole contains both sensory and motor neurons, but the term "autonomic nerve", in most cases, includes only visceral, not sensory, motor element.) Both the sympathetic and parasympathetic systems exert an influence on the effecter organs through two successive neurons. The first, called the preganglionic neuron, the cell body of which lies in the central nervous system and sends its axon to a peripheral autonomic ganglion, and the second, called the postganglionic neuron, the cell body of which lies in the autonomic ganglion with its axon extending to the effecter organ. Preganglionic fibers are customarily myelinated, whereas postganglionic fibers are usually slightly or not myelinated: the myelinated fibers are whitish and the non-myelinated fibers are graysh in their apperance, hence the so-called “white communicating rami” and “gray communicating rami” which bypass the sympathetic nerve roots (Fig. 1-11 B). Although

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there are controversies concerning their origin, the outlying ganglia of the autonomic system are thought to derive from the embryonic neural crest, which is similar to the spinal ganglia. The sympathetic and parasympathetic systems are different functionally and topographically. Origin and distribution of the sympathetic and parasympathetic efferent nerves are illustrated in Fig. 1-11 A, and following are rough sketches of their features,

* Sympathetic System The preganglionic cell bodies of the sympathetic system lie in the visceral motor area of the spinal cord at the level of the thoracic and lumber vertebrae. The axons leave the spinal cord in the ventral motor roots and then, by way of the white communicating rami, reach sympathetic ganglia, where they terminate on second (postganglionic) neurons. There are two types of sympathetic ganglia that show different locations: one is the ganglia, the so-called sympathetic (chain) ganglia, which are arranged bilaterally in a segmental fashion along the anterolateral surface of the vertebral column; the other is the prevertebral ganglia, such as the celiac ganglia, superior mesenteric ganglia, and inferior mesenteric ganglia, which are irregular aggregations of neurons found in the mesenteric neural plexuses surrounding the abdominal aorta.

* The Adrenal Gland Certain cells migrate ventrally from the neural crest at the time the sympathetic ganglia are formed. They form clusters during development and differentiate to gland cells mainly of the core (medulla) of the adrenal glands, which become positioned on the upward surface of the kidneys. The cells react well with chromic acid salts, often called chromaffin cells. The largest clusters of the chromaffin cells are in the medulla of the adrenal gland, although small clusters are also distributed close to the aorta near the kidneys. (The cortex part of the adrenal gland is derived from the mesoderm adjacent to the developing kidney.) Different from the adrenal cortex, which secretes various types of steroid hormones, the adrenal medulla produces only adrenaline (and noradrenaline). The adrenergic medulla receives preganglionic fibers directly without the intervention of postganglionic fibers. Autonomic preganglionic fibers always secrete acetylcholine, whereas postganglionic sympathetic fibers (with some exceptions) secrete mainly noradrenaline. The three features of the adrenal medulla cells--the origin, the direct connection of pregangionic sympathetic fibers, and the adrenaline secretion--lead us to the understanding that the adrenal medulla cells are homologues to the postganglionic sympathetic neurons.

* Parasympathetic System Different from the sympathetic system, the preganglionic cell bodies of the parasympathetic system lie in the brain and the sacral portion of the spinal cord (Fig. 1-11 A):

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they run to the postganglia close to the effecter organs through cranial nerves (III, VII, IX, and X) and the sacrum spinal nerves, and synapse to the postganglionic neurons. (Of the four cranial nerves, the vagus (X) nerve plays a major and important role in controlling visceral activity.) Excitation of the sympathetic nerves prepares an animal for an emergency situation, for fight or flight, whereas excitation of the parasympathetic nerves causes the opposite effect, promotes digestion, and generally slows down somatic activities. The parasympathetic ganglia are, in general, very minute containing small number of postganglionic neurons and located quite close to the organs themselves, so the postganglionic fibers are quite short. [A Different Angle 1-7] Autonomic nervous system viewed from the developmental aspect: There is a primitive and fundamental question about the autonomic nervous system. Is it impossible for the function of the viscera to be fully controlled by sympathetic nerves alone? If activities of visceral organs need to be suppressed, perhaps they might be induced by decreasing the impulse frequency or by changing the pattern of the impulse sequence of the sympathetic nerves. Parasympathetic nerves collectively flow out from the brain and sacral spinal parts. What does this distribution mean? Some sympathetic nerves project to organs relayed at the sympathetic chain ganglia, and others at the prevertebral ganglia. What do these formations mean? The following facts might answer these questions: 1) The actual formation of the sympathetic chain ganglia starts in earlier stages of embryonic development than that of the formation of spinal cord--brain formation. 2) Lower vertebrates also have a sympathetic nervous system, but most lack an obvious parasynpathetic nervous system. 3) The formation of the sympathetic chain ganglia is similar to the ladder nervous system, and the prevertebral ganglia (the celiac, superior mesenteric, and inferior mesenteric ganglia) are similar to the net nervous system observed in invertebrates. 4) Most viscera receive double autonomic innervations, but the glands of the skin and peripheral blood vessels that are, in a sense, the most primitive and basic organs receive only sympathetic innervation; there are, however, no organs that receive only parasympathetic nerves. 5) The parasympathetic ganglia that are located quite close to the organs themselves are very minute and contain fewer neurons compared with the sympathetic ganglia. All of these features suggest that the sympathetic part of the autonomic nervous system was established phylogenetically at an early stage of nervous system development, and interoperated in the spinal cord system developed later. At the stage when the brain became the highest center of the nervous system, the sympathetic system needed to coordinate with the brain system. The parasympathetic neurons might have developed in the brain for this reason. This leads to such a view about the autonomic nervous system that visceral activities are driven basically (or predominantly) by the sympathetic nerves, and the parasympathetic neurons plays a role in modulation with a suppressive effect, which depends on various environmental situations. This view is slightly different from the traditional understanding that the sympathetic and parasympathetic nervous systems are antagonistic on viscera, where the two parts of the autonomic nervous system have equivalent values in the physiological function.

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Figure 1-11. A: Origin and distribution of sympathetic and parasympathetic efferent nerves. Postganglionic neurons leaving in sympathetic chain ganglia and projecting to the body wall are omitted. Parasympathetic preganglionic neurons are located within the brain stem, which leave through cranial nerves (III, VII, IX, and X), and are located within sacral-2 to sacral-4 segments of the spinal cord. Sympathetic neurons are drawn with filled circles, and parasympathetic neurons, with open circles. CeG, celiac ganglion; IMG, inferior mesenteric ganglion; SMG, superior mesenteric ganglion; SCG, superior cervical ganglion. (Adapted from Parent 1996.) B: Schematic representation of the nervous organization of somatic system (left) and that of sympathetic sensory-motor system (right). Preganglionic sympathetic fiber enters the sympathetic chain ganglion through white communicating ramus, and postganglionic sympathetic fiber projects to effecter organ through gray communicating ramus.

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Why, however, do neurons of the parasympathetic system also exist in the sacral segments of the spinal cord? Possibly the central nervous system developed and was elaborated at the rostral end of (or upward from) the neural tube, with the spinal cord simultaneously developing caudally (or downward) as discussed in "A Different Angle 1-1". (The caudal region was not, however, as greatly developed as the rostral region.) This is suggested in the process of neural tube formation in the embryo: closure of the neural folds is late at both the rostral and caudal edges (Fig. 1-4 a, 1-5 a), suggesting that the sacral spinal region, as well as the brain, is phylogenetically new in the CNS.

References and Suggested Readings Balinsky, B.I. (1970). An introduction to Embryology (3rd ed.). W.B. Saunders Co., Philadelphia. Barnes, R.D. (1974). Invertebrate Zoology (3rd ed.). W.B. Saunders Co., Philadelphia. Bradley, M.P. and Carlson, B.M. (1974). Foundations of Embryology (3rd ed.). McGrawHill, New York. Jacobson, M. (1991). Developmental Neurobiology (3rd ed.). Plenum Press, New York. Larsen, W.J. (1993). Human Embryology. Churchill Livingstone, New York. Lee, K.J. and Jessell, T.M. (1999). The specification of dorsal cell fates in the vertebrate central nervous system. Annu. Rev. Neurosci., 22: 261-294. MacLean, P.D. (1967). The brain in relation to empathy and medial education. J. Nerv. Ment. Dise., 144: 374-382. Noden, D.M. (1991). Vertebrate craniofacial development: The relation between ontogenetic process and morphological outcome. Brain Behav. Evol., 38: 190-225. Parent, A. (1996). Carpenter's Human Neuroanatomy (9th ed.). Williams & Wilkins, United States. Patten, B.M. and Carlson, B.M. (1974). Foundations of Embryology (3rd ed.). McGraw-Hill, New York. Romer, A.S. (1965). The Vertebrate Body (3rd ed.). W.B. Saunders Co., Philadelphis. Schoenwolf, G.C. and Smith, J.L. (1990). Mechanisms of neurulation: Traditional viewpoint and recent advances. Development, 109: 243-270. Stark, D. (1982). Vergleichende Anatomie der Wirbeltiere. Spring-Verlag, Berlin. Tuchman-Duplessis, H., Auroux, M. and Haegel, P. (1974). Illustrated Human Embryology, Vol.3, Nervous System and Endocrine Gland. Masson and Company, Paris. Torrey, T.W. (1971). Morphogenesis of the Vertebrates (3rd ed.). John Wiley & Sons INC., New York. Webster, D. and Webster, M. (1974). Comparative Vertebrate Morphology. Academic Press, New York. Wolpert, L. et. al. (1998). Principle of Development. Oxford Univ. Press, New York.

Chapter II

Electrical Properties of Neurons The nervous system rapidly processes and conveys a great deal of information. The mechanism is similar to electrical circuits composed of hardware such as resistors, capacitors, coils, diodes, transistors and connecting wires, where a substantial carrier of signals is electrons. The nervous system of both invertebrates and vertebrates, however, does not have such hardware, but achieves functions similar to those of electrical circuits using neurons, where the signal is processed by ionic flow across a plasma membrane. Although the behavior of ions has different aspects from the behavior of electrons, the principle law affecting electrical circuits can be applied to the electrical events of neurons. Two types of signals, action potentials and graded potentials, are used in processing information in the nervous system. Action potentials are generated in an all-or-nothing fashion and conducted along a length of nerve fiber without attenuation. On the other hand, graded potentials are generated locally and spread passively, and they play an essential role at neuron-neuron junctions and neuron-muscle junctions (where they are called synaptic potentials), and in cells handling sensory stimuli, (where they are called receptor potentials or generator potentials). This chapter will focus mainly on how action potentials are generated and propagated. Such study can advance our basic understanding of the electrical phenomena of neurons.

(1) General Structure of the Neurons There are two large classes of cells in the CNS: nerve cells (or neurons) and (neuro)glial cells. Neurons are specialized cells for sending and receiving signals, and glial cells are thought to have, in principal, ancillary functions. From the viewpoint of signal processing, neurons seem to be more important so, in most publications, the part of the description for glial cells is usually that they have less volume; however, it has been noted that the number of glial cells in the CNS is actually much greater than that of neurons. Mature neurons diverge greatly, but typically they have 4 main parts: cell body (soma), dendrites, axon, and

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nerve terminal, each of which plays a different role in signal processing (Fig. 2-1). The dendrites receive information from other neurons, the cell body integrates information, the axon conducts the electrical signal, and the nerve terminal transmits it to other neurons.

Figure 2-1. Schematic illustration of a motor neuron of the spinal cord, a typical multipolar neuron composed of various regions. Electrical signals observed at each of the regions are described on the right side of the neuron, and a cross section of the axon wrapped in a myeline sheath, and a longitudinal section of the axon including a Ranvier node, are presented on the left side.

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* Cell Body The cell body of the neuron contains organelles observed normally in other cells such as the nucleus, endoplasmic reticulum, ribosomes, and mitochondria, which support the metabolic and synthetic needs of the neuron. Synthesis of neurotransmitters is especially important in nerve cells; it is carried out in the cell body, and the neurotransmitters are transported to terminals of the axon. The organelles in the neuron are embedded in a network of filamentous proteins that extend throughout the cell body and its extensions, comprising the neural cytoskeleton. From the viewpoint of signal processing in neurons, the cell body integrates synaptic potentials that are locally produced at multiple sites of dendrites and spread electronically. In most neurons, the potential integrated in the cell body is transformed into a digital form, a so-called action potential (or impulse) at a junction between the cell body and the axon, if its value is sufficiently large.

* Axon and Dendrites The cell body of the neuron gives rise to the axon and dendrites in the developing process: dendrites are fine arborizing processes extending from the cell body at its rostral pole, and the axon is a tubular process that extends over a considerable distance and gives rise to a series of terminal branches that form synapses to the next neurons. Along with the axon, messages are conducted in the form of action potentials. Both dendrites and axons are filled with a viscous fluid. The physico-chemical constitution of the axon and dendrites is regarded to be almost the same as that of the cytoplasm of the cell body: the fluid in the axon is called axoplasm, while that of the cell body is known as cytoplasm. Depending on the number and pattern of cell extensions, neurons are commonly distinguished as being unipolar, bipolar, or multipolar. Unipolar neurons, the cell body of which has a single process bifurcating into a peripheral process (dendrite) and a central process (axon), are generally found in cranial and spinal ganglia. The bipolar neurons are similar to the unipolar neurons, but their cell body has an extension at each pole of the cell. This type of neuron is found in the organs of special senses. The majority of the vertebrate CNS is made up of multipolar neurons that have multiple dendritic processes from the cell body and one (or more) axon. Fig. 2-1 shows a typical neuron of this type, a motor neuron in the spinal cord, which has been intensively used in multiple examinations of the nervous system. In all neurons, electrical signals travel in one direction under ordinary physiological conditions (orthodromic direction)--from dendrites (the peripheral process) to the terminals of the axon (the central process).

* Membrane Structure The nerve cell, like all other cells, is bounded by a plasma membrane. The membrane consists of two layers, which are two sheets of oppositely-oriented phospholipid molecules: the hydrophilic phosphorylated heads lie at the exterior surface of the membrane, and the

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hydrophobic lipid acid tails lie at the inferior space of the membrane. The lipids of the membrane form a barrier which retains the cytoplasm, simultaneously forming an electrical capacitance able to store charges of opposite potential. The phospholipid arrangement of the plasma membrane is a fluid matrix in which protein molecules are embedded. The protein components, most of which span the membrane, are involved in multiple functions of the nerves. Most important for excitability of neurons are the proteins that regulate the flow of ions across the membrane. Certain membrane proteins provide channels for the selective movement of ions, which form the basis of the generation of electrical signals of neurons.

* Myelination A short distance from the cell body of the peripheral nerves, axons with a large diameter are enveloped by a lipoprotein sheath of myelin (myelinated fibers) that is formed by glial cells, the so-called Schwann cells. In many instances, especially among vertebrates, the myelin sheath is very strongly developed: the myelin sheath originates from a number of Schwann cells, wrapping the axon with their developmental process. On the other hand, axons of small diameter tend to lack the sheath (unmyelinated fibers). It should, however, be noted that even unmyelinated fibers have an association with neighboring Schwann cells. Many CNS axons are also wrapped in myelin sheaths that are formed by another type of glial cell, oligodendrocytes. The myelin sheath is interrupted at regular intervals by the so-called Ranvier nodes, where the plasma membrane of the axon is exposed (Fig. 2-1). A major function of the myelin sheath is enhancement axonal conduction velocity by providing electrical insulation for the axon. In most neurons, the action potential is considered to be initiated at the initial segment of the axon called the axon hillock (Fig. 2-1, Fig. 3-3).

(2) Electrical Property I: Resting Potential Two facts should be noted about living nerve cells. One is that concentrations of ionic components are different between the inside and outside medium of cells. And the other is that the potential of the inside is usually negative in the order of many tens of mV to the outside in the resting state, producing a so-called resting potential. Cells of animals are surrounded by a medium that is percolated from blood, with ionic components and their concentrations almost the same as those of ancient seawater. The concentration of each species of ion of the inner medium of cells is, however, different from that of the surrounding (outer) medium. For instance, Na+, Cl-, and Ca2+ concentrations of the inside medium are lower than the outside medium, whereas concentration of K+ (and organic anion) of the inside medium is higher than that of the outside medium (Table 2-1). Ionic components and their concentrations of the inner medium of dendrites and axons are suspected to be almost the same as those of the cell body. It is a common and basic understanding that electrical phenomena of living nerve cells are based on the diffusion of ions across the cell membrane,

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and their discussion usually starts from a relation between these two facts -- the concentration difference of ions between the inside and outside medium, and the negative potential inside.

Table 2-1. Approximate Concentrations (mM) of major ions in axoplasm of squid giant axon and mammalian muscle fiber Ion K+ Na+ Ca 2+ Mg 2+ ClA-

Squid Axoplasm 400 50 10-7 10 100 350

Mammalian Muscle 120 10 10-8 15 5 75

Squid Blood 20 400 10 50 500 ---

Sea water 10 450 10 50 500 ---

* Two Different Types of Driving Forces to Make Ions Move Ions in solution diffuse from a region of high concentration to a region of low concentration. The driving force can be understood to originate from the concentration gradient. Flux (the flow of ions) through a unit area during an unit time (fche) is described as fche = ω(-ΔP/Δx) where P is pressure ([N/cm2]) originating from the ionic concentration at site-x ([cm]}, and ωis a proportional constant called a molar mobility ([(mol cm2)/(J sec)]), that is specific for species of ions. The minus sign indicates that the force acts from a high to low concentration. According to van't Hoff, the pressure of a dilute solution of salt is proportional to the molar concentration and temperature (P=RTC (C is concentration [mol/cm3] of a given ion; R is the proportion constant called the gas constant (8.31 [J/(K mol)]); and T is the absolute temperature ([K]) of the solution). Accordingly, the flux (fche) can be described as fche = -ωRT

dC dx

where a unit of fche is [mol cm-2 sec-1] ( [mol cm2 J-1 sec-1]*[J K-1 mol-1]*[K]*[mol cm-3] *[cm1 ]). All ions possess charge(s) that also produce the driving force if in a potential field with gradient (dV/dx). The flux (fele) is known to be described as fele = -ωCZF

dV dx

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where Z is the valence of the ion, F is Faraday's constant (96,500 [Coul(omb) /mol]), and the minus sign means the force acts from a high to a low potential. The unit of fele is [mol cm2 J-1 sec-1]*[mol cm-3]* [Coul mol-1]*[V]*[cm-1]= [mol Coul V]/[J sec cm2]= [mol cm-2 sec-1], which is same as the unit of fche. If the total ionic flow (fche+fele) is understood to be driven by the gradient of the electrochemical potential (μ), it can be described by the following differential equation: dμ dC dV = -(ωRT + ωCZF ) -ωC dx dx dx ∴

dμ dlogeC dV d dC = RT + ZF (∵ logeC=(1/C) ) dx dx dx dx dx

Integrating the left and right sides, we get

μ = U+RTlogeC+ZFV (U: integration constant) In general, the electrochemical potential of ion-n is expressed as

μn = Un+RTloge[Cn]+ZnFV [J mol-1] where Un is the standard potential of ion-n, [Cn] is called molar activity (which is the same as the molar concentration if it is dilute), and μn is understood to be an unitary molar energy of ion-n.

* Equilibrium Potential Let us suppose a situation in which there are two solutions (i,o) of ion-n and a membrane that is permeable to the ion. If the electrochemical potentials of the two solutions for the ion species, μ n,i and μ n,o , are same, the ion cannot move across the membrane in either direction; thus, the following relations are established:

μn,i = μn,o Un+RTloge[Xn]i+ZnFVi = Un+RTloge[Xn]o+ZnFVo ∴ ZnF(Vi-Vo) = RT(loge[Xn]o-loge[Xn]i) ∴ Vi-Vo = (RT/ZnF)loge

[Xn]o [V] [Xn]i

(2-1)

Equation (2-1) is called the Nernst equation, and the voltage difference, Vi-Vo, is called the equilibrium potential for ion-n (En). Equation (2-1) means that the driving force of the

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potential gradient cancels the driving force of the chemical gradient when two solutions are in equilibrium. In calculating the equilibrium potential of a nerve cell, the logarithm to base 10 of the concentration ratio is popularly used, rather than the natural logarithm. To obtain the equilibrium potential (mV) at room temperature (25˚ C), the following equation is often used: [Xn]o [mV] [Xn]i [X ] [X ] ( (RT/ZnF)loge n o = {8.3*(273+25)/(96500*Zn)}*2.30*log10 n o [V] ) [Xn]i [Xn]i

En = (59/Zn)log10

In the resting state of the neuron, the membrane is known to be highly permeable to K+ ions. If the K+ concentration of the outside medium of a cell is 20 [mM], and that of the inside medium is 400 [mM], the equilibrium potential for K+ (Ek) becomes EK = (59/1)log10(20/400) = -77 [mV] This equilibrium potential for K+ is quite close to the actually measured inside voltage of nerve cells in a resting state (resting potential). The actual value of the resting potential varies with neurons, from approximately -50 to -90 mV, due to the difference in the K+ concentration ratio with neurons, and to the permeability of the cell membrane to other ions besides K+. [A Different Angle 2-1] Intuitive explanation of the resting potential: One of the most basic concepts in discussing the ionic mechanism of nervous signals is that both the electrical gradient force and the concentration gradient force drive particles such as ions or molecules, which exert their force on particles independently. First let us consider the ion behaviors of two KCl solutions with different concentrations separated by a membrane. In living neurons, the K+ concentration of the inner medium is estimated to be 15-40 fold higher than that of the outer surrounding medium. When a membrane is not permeable by either K+ or Cl-, no potential across the membrane is produced even though a concentration difference exists. When, however, the membrane allows both K+ and Cl- to permeate, they diffuse together from the inside to the outside until both concentrations become equal. In this case, the potential can be produced across the membrane during continued diffusion because of the difference in mobility between for K+ and for Cl-, but it disappears over time as the concentrations of K+ and Cl- become equal between the inside and outside solutions. If, on the other hand, the membrane allows only K+ ions to pass, what situation gives rise across the membrane? In this condition, K+ ions will diffuse from the inside to the outside (outflux), driven by the force of the concentration gradient. Do K+ ions move until the K+ concentration of the inside solution becomes equal to the outside solution? As the charge of K+ ions is positive, the outer solution becomes more positive (or the inside solution, negative) with the increase in the concentration of the outer solution, which in turn acts on the K+ ions to flow inside (influx), making the K+ outflux weaker with the advance. The outflux of K+ ions,

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however, continues as long as the driving force of the concentration gradient is greater than the driving force of the electrical gradient. The electrical gradient force driving K+ ions inward eventually reaches an equilibrium to the concentration gradient force for driving K+ ions outward, resulting in the stop of K+ ions moving outside. Another interpretation that is possible is that the K+ outflux driven by the concentration gradient force and the K+ influx derived by the electrical gradient force become even. In a situation in which a membrane is permeable to K+, or to other types of ions, alone, it is important to understand that the net flow of K+ ions is zero even if the concentration of the inside solution is higher than that of the outside solution, when the state has once reached the equilibrium. Furthermore, the membrane potential returns to the equilibrium potential decided by the concentration gradient sooner or later, even if it is temporary shifted by another factor, such as an experimental current (or voltage) supply.

* Donnan Equilibrium In two solutions of the same salt, such as KCl, with different concentrations which are separated by a membrane, both K+ and Cl- ions diffuse from the high concentration side to the low concentration side, resulting in equal concentrations of both ions between the both sides, as long as the membrane is permeable to both ions. If, however, an impermeable large organic ion is present on one side, how will the permeable ions be distributed across the membrane? In equilibrium, the following relation between the electrochemical potentials of two regions, inside (i) and outside (o), is established for each of K+ and Cl- ions:

μK,i = μK,o (μK,i = UK+RTln[K]i+FVi; μK,o=UK+RTln[K]o+FVo )

(2-2)

μCl,i = μCl,o (μCl,i=UCl+RTln[Cl]i+(-1)FVi; μCl,o=UCl+RTln[Cl]o+(-1)FVo )

(2-3)

From (2-2) and (2-3): Vi-Vo = (RT/F)(ln[K]o-ln[K]i) Vi-Vo = -(RT/F)(ln[Cl]o-ln[Cl]i) The right paragraphs of the two equations are equal, so ln[K]o-ln[K]i = ln[Cl]i-ln[Cl]o ∴ ln ∴

[K]o [Cl]i = [K]i [Cl]o

[K]o [Cl]i = ln [K]i [Cl]o (2-4)

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The relation expressed in (2-4) is called the Donnan equilibrium, which is applicable to every species of ion permeable to the membrane. If the original concentration of KCl for each side is 200 mM ([200K]o/[200K]i =[200Cl]i/[200Cl]o), and 160 mM Cl- on side-i is replaced by the impermeable ion X-, then the following relations are established: [K]o = [Cl]o [K]i = [Cl]i+160 Substituting these relations into (2-4), we get [K]o [K]i-160 = [K]o [K]i

∴ [K]o2 = [K]i2-160[K]i

∴ ([K]i+[K]o)([K]i-[K]o) = 160[K]i ∴ 400([K]i-(400-[K]i)) = 160[K]i ∴ 1.6[K]i = 400 So, [K]i = 250 mM, [K]o = 150 mM [Cl]i = 90 mM, [Cl]o= 150 mM In other words, when impermeable ions exist on either side, the distribution of permeable ions becomes unbalanced between the inside and the outside of a cell. This is one reason for the unequal distribution of electrolytes across the membrane of nerves (and other living cells). In the Donnan equilibrium electrical neutrality is maintained on each of both sides, but not in an osmotic equilibrium. In the case descried above, [K]i+[Cl]i+[X] =500 mM and [K]o+[Cl]o=300 mM. The osmotic unbalance induces a flow of water into the cell to dilute the electrolyte. Another possible explanation is that water molecules move from a region of high concentration to a region of low concentration, supposing that a solute (in this case, water) is dissolved in a solvent (in this case, an ionic substance). The excess water produces a pressure that can be measured as osmotic pressure, which makes the cell swell and which is not well suited to a living cell: the expansion of cell volume is typically observed in erythrocytes soaked in water, which is produced by strong osmotic pressure due to the existence of hemoglobin, an impermeable protein, inside the cell. In animals, osmotic equilibrium across the cell membrane is achieved by making up the electrolyte deficit on the outside with NaCl.

* Electrical Analog of Ion Channels The amount of ions (measured in moles) which passes across a unit area (cm2) in 1 second is called flux. The flux (J [mol/(cm2 sec)]) of ion-n across the membrane of a cell is proportional to the difference in electrochemical potentials between the inside (i) and outside (o). Thus,

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J = G(μn,i - μn,o) = G{(Un+RTln[Xn]i+ZnFVi) - (Un+RTln[Xn]o+ZnFVo)} = G{RT(ln[Xn]i-ln[Xn]o) + ZnF(Vi-Vo)}

(2-5)

("G" is proportion constant that differs with species of ion.) The flux of ion produces a current (I), which is expressed as I = ZnF*J

(2-6)

Substituting (2-5) to (2-6), we get I = ZnFGZnF{(Vi-Vo) - (RT/ZnF)ln

[Xn]o } [Xn]i

= gn(Vm-En) (gn=GZn2F2 ; Vm=Vi -Vo; En=(RT/ZnF)ln

[Xn]o ) [Xn]i

This equation, I=gn(Vm-En), forms Ohm's law, indicating that the relation between potential and flux of a given ion can be described as an electrical circuit. Also, ionic currents can be measured from voltages applied across the membrane if the equilibrium potential of a given ion (En) and its inner resistance in series with (1/gn) are known. (It is more common to use the term "g (conductance)", which is the reciprocal of resistance, and its unit is "Siemens [S]" or "mho [℧ ]".) Ions are considered to flow through their specific pathway in the membrane, called an ion channel, and the membrane is considered to have the channels specific for each species of ion. The total conductance for ion-n of the cell membrane is equal to the number of channels times the conductance of each individual channel.

* Capacitive Property of the Plasma Membrane The membrane of a cell is composed of a phospholipid bilayer, which is thought to have a capacitive property; that is, it stores electrical charges of opposite signs across the membrane. The potential we record is considered to be the potential due to storage of charge across the membrane capacitance (Cm). The relation between the stored charge (Q) and the potential (Vm) of the capacitor is expressed by the following equation: Q = CmVm If any species of ion moves across the membrane, it builds up a current (Ic), which charges the membrane capacitor. The amount of charge within a short time (Δt) is Ic*Δt, and the voltage of the capacitor changes slightly (ΔV):

Electrical Properties of Neurons Ic*Δt = Cm*ΔVm

35

∴ dVm/dt = (1/Cm)Ic (When Ic>0, dVm>0)

This equation means that the change in membrane potential is proportional to the flux of ions into the membrane capacitor, and that the larger the membrane capacitance is, the slower the potential change becomes. It is important to understand that various types of membrane potential observed in nerve cells are potentials produced by charges (or discharges) on the membrane capacitor.

* Parallel Conductance Model Ion channels for multiple species of ions are distributed in the membranes of nerves. Each ion channel is considered to compose a battery (En) representing the equilibrium potential and a conductance (gn) representing the permeability. The series combination of the battery and the conductance for each species of ions (ordinary Na+, K+, Ca2+, and Cl-) and the capacitance factor of a unitary area of the membrane are frequently represented by the electrical analogue, as illustrated in Fig. 2-2 A, known as the parallel conductance model. In the model, the total ionic current (Iion) through ion channels of the membrane to a membrane potential (Vm) becomes the algebraic sum of the current for each species of the channels according to Kirchhoff's rule: Iion=Σgn(Vm-En) and total current across the membrane (Im) is the addition of ionic currents through the channels (Iion) and through the membrane capacitor (Icap): Im = Iion + Icap = Σgn(Vm-En) + Cm(dVm/dt) This is a fundamental equation representing the electrical property of neurons. In the resting state of neurons, Im=0 and dVm/dt=0. Therefore, 0 =Σgn(Vm-En)

∴ Vm =

Σ g n En Σ gn

This is the equation for calculating the resting potential involving multiple species of ions. (This equation has been commonly used in calculating total voltage in an electrical circuit with multiple batteries and their inner resistances.) If the resting membrane potential (Vrest) is built up by only K+ ions, then Vrest =

g kE k [K] = EK = (RT/F)ln o gk [K]i

This equation indicates that if the resting potential is built up by a species of permeable ions, in this case, K+, it does not depend on its conductance.

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However, the real membrane is more-or-less permeable to ions other than K+ in the resting state. If the resting potential is built up by Na+ and K+ ions, then Vrest =

gNaENa + gKEK gNa + gK

This equation indicates that if the membrane is permeable to two (or more) species of ions, the conductance for each species of ion participates in building up the resting potential. For example, when ENa=+50[mV], gNa=0.8x10-6 [S], EK=-77[mV], and gK=19.2x10-6 [S], then the resting potential becomes -52.9 [mV] {(0.8x10-6 *(+50)+19.2x10-6*(-77)) / (0.8x10-6 +19.2x10-6)}, where the influx of Na+ ions and efflux of K+ ions are equal.

Figure 2-2. A: Electrical equivalent circuit of a patch of the passive neuronal membrane including membrane capacitance (Cm), in which each type of ion channel is represented by a series combination of a battery and a resistor. B1: Electrical equivalent circuit of the passive membrane as a whole of the circuit of A, where each conductance and each battery are included as gl and El, respectively. B2: Current source circuit that is converted from the voltage source circuit of B1. C: Time course of the voltage response (upper graph) of the circuit B2 to a pulse current (lower graph).

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[A Different Angle 2-2] Na/K pump: When two or more species of ions are involved in building up the resting potential, flow across the membrane of each species of ion never stops, regardless if the net ionic current is zero. In the above case where both Na+ and K+ ions are involved in the resting potential, the resting potential is -52.9 [mV] where Na+ ions in the outside medium are driven toward the inside, and K+ ions in the inside medium are driven toward the outside as the equilibrium potential for Na+ is +50 [mV] and that for K+ is -77 [mV]. This allows for a flux of Na+ and K+ in opposite directions, which gradually reduces the concentration differences of the ions between the inside and outside medium, so that eventually the resting potential decreases, even if the amount of the exchange is slight. In order to prevent a decline in concentration gradient, the cell actively transports inside Na+ ions to the outside and outside K+ ions to the inside by means of a mechanism called a Na/K pump. (So, both the Donnan equilibrium and the ion pump system would contribute to maintaining the concentration stability of the inside of the cell.) The Na/K pump works actively against the electrochemical potential gradient, where energy is needed, which is obtained from hydrolysis of adenosine triphosphate (ATP). The two active fluxes, outward transportation of Na+ ions and inward transportation of K+ ions, are known to link in such as manner that 3 units efflux of Na+ are exchanged by 2 units influx of K+. In other words, the Na+:K+ coupling ratio is 3:2, which is not electrically neutral, thereby contributing to the membrane potential. (This uneven transport suggests that the neuron has a need to pump up more Na+ than K+, and this type of pump is called an electrogenic pump, as its work produces a membrane potential.) If the transport ratio is 3(Na):2(K), the pump generates a negative potential inside, so the resting potential shifts to positive (depolarization) when the pumping system stops, as in the case of the application of a chemical transport inhibitor such as ouabain. The pump is known to work depending on the Na+ concentration of inside medium and K+ concentration of outside medium, so the actual resting potential might fluctuate depending on the inside and outside ionic conditions.

* Passive Potential Response of the Membrane to Step Current Ionic current across the membrane produces a membrane potential. If the membrane is composed of a resistance element alone, the time course of the membrane potential is equal to that of the current. The membrane has, however, a capacitor element in parallel with the resistance (Fig. 2-2 B1), where the rise (or fall) of the membrane potential to a step current exhibits a delay. (The resistance in this case does not necessarily mean resistance for ion channels, but total resistance of the membrane in the static state.) A voltage source circuit (Fig. 2-2 B1) can be converted into a current source circuit (Fig. 2-2 B2). If a step current (I0) adds to the current source circuit, it will divide into two components--a current through the resistor (Ir) and a current through the capacitor (Ic), such that I0 = Ir+Ic

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From Ohm's law and from the charge manner in the capacitor, two equations, Ir= V/Rm and Ic=Cm(dV/dt), are respectively established. Substituting these into the equation just above, we get I0 = V/Rm + Cm(dV/dt) ∴ dV/dt = -(1/CmRm)(V-I0Rm) in which Io and Rm are constants. Therefore, -1 d(V-I0Rm) = (V-I0Rm) dt CmRm We can then take the integral of both sides: -1 0Rm) ∫d(V-I =∫ dt V-I0Rm CmRm ∴ log(V-I0Rm) =

-1 t + A (A: integration constant) CmRm

At the start (t=0), the voltage is zero (V=0). Inputting these values into the equation just above, we obtain A= log(-I0Rm) (Io<0). Substituting this relation into the equation above, log(V-I0Rm) =

-1 t +log(-I0Rm) CmRm

∴ log{-V/(I0Rm)+1} =

-1 t CmRm

∴ -V/(I0Rm)+1 = e-t/(CmRm) ∴ V = I0Rm(1-e-t/(CmRm) )

(2-7)

Temporal changes in voltage of the capacitor (Vc) to a step current are shown in Fig. 2-2 C. The voltage increases gradually with time and reaches 63% of the full voltage (I0Rm) at time CmRm (Vc=1*(1-e-1)=0.63). The value, CmRm, is called the time constant (τ), which is an indicator of temporal change in response to the step signal. The larger the time constant is, the slower the response becomes. [A Different Angle 2-3] Relation between voltage and current: The electrical property of a membrane is commonly explained using a current source. This is due to the fact that membrane resistance and membrane capacitance are considered to be in parallel. In general, the voltage response of an RC circuit is explained using a square voltage. In the RC circuit shown in Fig. 2-2 B1, the

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voltage signal (V0) separates into that of resistance (Vr) and that of capacitance (Vc): V0=Vr+Vc=R(dQ/dt)+Q/C (Q: current of charges) This equation can be written as CRdQ + Qdt = CV0dt ∴

CR dQ = dt CV0-Q

We then take the integral of both sides of this equation:

∫

CR dQ =∫dt CV0-Q

∴ -CRlog{(CV0-Q)} = t+A (A: integration constant) At the start (t=0), the stored charge is zero (Q=0). Inputting these values into the equation above, we get A=-CRlog(CV0). Substituting this relation into the equation above, -CRlog{(CV0-Q)} = t-CRlog(CV0) ∴ log(1-Q/CV0) = -t/CR ∴ 1-Q/CV0 = e-t/(CR) ∴ Q = CV0(1-e-t/(CR)) The voltage of the capacitor (Vc) is Q/C, so Vc = Q/C = V0(1-e-t/(CR) ) This equation is the same as in equation (2-7), and the circuit is known as a low path filter for low frequency signals (or for cutting high frequency signals). To indicate the frequency (f0) to path (corner frequency, -3dB; decline curve, -6dB/octave) an alternating voltage (ac voltage) signal in an RC circuit, the equation f0=1/(2πCR) is occasionally used. If approximate values of membrane resistance, R=1.0x103 [Ωcm2], and membrane capacitance, C=1.0x10-6 [F/cm2], of common nerve fibers are used, the frequency range of the alternating signal possible to the path is 0-159 [Hz]. As indicated by the response of the circuit analogue to the plasma membrane to a pulse signal, this value suggests that the nervous membrane cannot easily pass high frequency signals. Neuron, especiially its fiber part overcomes the high-cut property by generating the signal repeatedly along the axon.

Since total resistance and total capacitance throughout the cell membrane depend on the cell volume, this give rise to the impression that the time course of potentials slows with increasing cell size. Is it true? Let consider a spherical cell with radius r, whose resistance of the unit membrane area is Rm [Ω/cm2], and the capacitance of the unit membrane area is Cm

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[F/cm2]. Total resistance (R) is therefore Rm/(4πr2) and total capacitance, Cm*4πr2, so the time constant is R*C = Rm/(4πr2)*Cm*4πr2 = Rm*Cm This indicates that time constant of the cell is independent of the volume of the cell. In other words, electrical response to a step current of large neurons is not necessarily slower. The same thing can be said of axons. This stands to reason because the total capacitance increases but the total resistance decreases with cell volume. [A Different Angle 2-4] Two equations representing the membrane potential: In expressing the potential (Vm) across a membrane permeable to multiple species of ions, such as K+, Na+, and Cl-, the following two equations have been used: Vm =

gKEK + gNaENa + gClECl gK + gNa+ gCl

(2-8)

(gK, gNa, gCl: conductance for each species of ion; EK, ENa, ECl: equilibrium potential for each species of ion ) Vm = (RT/F)*ln

PK[K]o+PNa[Na]o+PCl[Cl]i PK[K]i+PNa[Na]i+PCl[Cl]o

(2-9)

(PK, PNa, PCl: permeability for each species of ion; [K]i,o,[Na]i,o,[Cl]i,o: inside (i) and outside (o) concentration for each species of ion) Equation (2-8) is based on the Ohm's law, where the current (I) of ions with a given concentration (C) is expressed as I = g*(Vm-E), where E=(RT/ZF)*ln(Cout/Cin) This relation is useful in examining electrically the membrane property or analyzing the process of excitation. However, the conductance (or resistance) of a real plasma membrane does not always follow Ohm's law; it can change between influx and efflux of ions (rectification property), which is known to increase with the difference in concentration across the membrane. Thus, equation (2-8) seems more applicable to a situation in which the concentration gradient of ions is not large. Equation (2-9) is assumes that the electric field, or rate of change of potential (dφ/dt) with distance in the membrane, is constant. This is referred to as the constant field hypothesis. In this hypothesis, the relation between ionic current (I) and potential (V) across the membrane with a permeability (P) is described as follows:

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Z2F2V Cout-Cin eZFV/RT * (2-10) 1- eZFV/RT RT When we plot the current to the voltage (I-V relation) according to this equation with changes in the ratio of the outer concentration to the inner concentration, they do not necessarily show a linear relation: the larger the concentration ratio, the stronger the deviation from a straight line. Supposing that the membrane is permeable to Na+, K+, and Cl-, the total current (IT) must be zero in the constant state: I = P*

IT = INa+IK+ICl = 0

(2-11)

Substituting equation (2-10) for each species of ion in equation (2-11) gives equation (29), which is also referred to as the "Goldman - Hodgkin - Katz (GHK) equation". This equation is good at accounting for the behavior of the membrane surrounded by solutions of several electrolytes with various levels of the concentration, and is useful for describing a specific state of the membrane during active or resting states. If the membrane is permeable to only K+, then the equation (2-9) becomes Vm = (RT/F) ln

[K]o [K]i

This is same as the Nernst equation for potassium. (In the resting state of a squid giant axon, it was assumed that PK:PNa:PCl=1:0.04:0.45, and at the peak of the action potential, PK:PNa:PCl=1:20:0.45, according to Hodgkin and Katz (1949).)

(3) Electrical Property II: Generation of Action Potential A neuron can conduct messages along its axon using an electrical signal, action potential. Unlike insulated metal wires, nerve fibers are poor conductors of electricity: the inside medium of a neuron is separated from the outside medium by a cell membrane whose insulation is imperfect and permits some leakage of ions in both directions. How the action potential is generated and propagated is important for understanding neuronal signaling, and the former is the subject of this section. Almost all knowledge on action potential generation has been brought about using the squid giant axon, the generation mechanism of which is applicable to neurons and muscle fibers of most living things. An important feature of the action potential is that it is produced in a self-regenerative manner, and does not decrease in amplitude as it is conducted over distance. These are achieved by selectively changing the ionic permeability of the axon membrane, where ions flow downhill along their electrochemical gradients.

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* Recording of Electrical Signals of Nerve Cells Electrical signals of nerves are ordinary measured as the potentials of the inside medium in reference to the outside medium. Use of a microelectrode is the usual method of observing a potential, where a sharpened tip of a glass capillary filled with ionic solution (recording electrode) is inserted to the inside of the nerve cells (intracellular recording), and a metal wire, typically a silver wire, is soaked in the outer medium as a reference electrode. The objective behind this recording method is to be able to directly amplify constant potential differences, such as the resting potential, as well as the action potential (Fig 2-3 a) or synaptic potential. As the impedance of the glass electrode is very high, the input impedance of the amplifier needs to be more than 1011 [Ω] so as to not shunt the recording signals and observation of the potential.

Figure 2-3. Two methods of action potential recording, intracellular recording and extracellular recording. Typical recording of action potential in each method is shown in a and b, respectively.

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An action potential can be also recorded from the outside of the nerves (extracellular recording) as the potential forms the current field in the external medium around it. The potential can be picked up by contacting the glass electrode (or insulated fine metal) with the surface of the axon, but the simplest arrangement for recording the potential externally is to place an isolated section of nerve fiber (or bundle) on a pair of metal electrodes, typically silver wires, separated by a short distance (Fig. 2-3 b), in a hermetically sealed moist chamber. The ionic flow produces a potential intermediated by the resistance of the solution on the surface of the nerve fiber, which is recorded as a potential difference between the two sites of the recording electrode pair. The magnitude recorded by the paired electrodes over the given distance, ordinary shorter than a few centimeters, is small (typically smaller than 1 mV), unlike that of intracellular recording, the potential of which is ordinary quite large (many tens of mV). The shape of the action potential recorded with the paired electrodes is biphasic (Fig. 2-3 b), where the potential is, in most cases, made up of the summated activity of a number of fibers (compound action potential). However, we can understand the shape of this action potential by considering the activity of a single axon.

* Outline of Action Potential Generation When a single nerve fiber is stimulated by, for instance, an appropriate electrical shock, a transient potential change across the membrane, an action potential, arises at the stimulated site. The action potential is generated in an all-or-nothing manner, depending on the stimulus strength. The value of the weakest voltage that can generate an action potential is called the threshold, and the size of the action potential does not change even if it is stimulated by a voltage greater than its threshold. During the appearance of an action potential, the inside potential in reference to the outside medium changes to positive for a few milliseconds. This change is called depolarization. A typical intracellular action potential is as shown in Fig. 2-3 a: the resting potential is about -60 mV, and the overshoot, the size of the positive phase measured from zero, is about +40 mV. The positive phase of the action potential is followed by the after-potential, resulting in hyperpolarization, which is more negative than the resting potential for a few milliseconds. How is the action potential created? Na+ ions play a key role. In living neurons, the Na+ concentration of the outer surrounding solution is estimated to be about 10 fold higher than that of the inner solution. It is a common understanding that a given ion flows through its specific pathway, ion channel, in the membrane, and that the membrane has channels for each type of ion, which are normally separate and independent. If the membrane of the axon allows only Na+ to pass, what ionic event occurs across the membrane? Na+ ions will diffuse through the channel, in this case from the outside to the inside (influx). In addition to the concentration gradient force, the resting potential also works to drive an Na+ ion influx. The Na+ inward movement, however, does not continue until the inside Na+ concentration becomes equal to the outside. As the charge of Na+ is positive, the potential of the inside medium becomes more positive in reference to the outside medium with the influx, which makes it more difficult for Na+ ions to move toward the inside. The Na+ influx, however, continues as long as the driving force of the concentration

44

Toshifumi Kumai and Yoshiyuki Shibukawa

gradient is greater than the driving force of the electrical gradient. When the electrical force for driving Na+ ions outward reaches equilibrium with the concentration force for driving Na+ ions inward, the Na+ influx stops. From the positive peak of the action potential, it returns to its resting potential level, the phase of which is called a repolarization. The repolarization process is led mainly by the outward flow of K+ ions. As the action potential approaches its peak amplitude, the Na+ channels begin to close, and interchanged by K+ channel activation, which results in outward flow of K+ ions. This in turn makes the inside of the nerve negative and causes a fall of the action potential. (The K+ channel for action potential is thought to be different with that for resting potential.) The K+ permeability gradually decreases through the peak and the action potential approaches the resting level. However, the K+ channel remainsactivated, which gives rise to the undershoot of the action potential, which returns to the resting level with its inactivation.

* Voltage Clamp Method Much of our knowledge of the behavior of ion channels for Na+ and K+ in making up an action potential has been gained using voltage clamps and methodology devised by Kenneth Cole (1949) and his colleagues, and further developed by Alan Hodgkin and Andrew Huxley (1952) and their colleagues. The essential function of the voltage clamp technique is to interrupt the mutual interaction between membrane conductance and membrane potential. When an axon is voltage clamped, the membrane conductance still changes in response to a given voltage applied across the membrane, but the clamp prevents these conductance changes from influencing the membrane potential. The apparatus is built up to supply a current depending on the change in membrane conductance through a negative feed back circuit (Fig. 2-4 A), which can make the membrane potential clamp to various levels. B1 and B2 in Fig. 2-4 show typical records of the current in clamping the membrane potential. If the stepping clamp voltage (depolarization) is small, a small and steady outward current is observed, which is accompanied by a transient outward current at its start, and a transient inward current at its end (B1). The steady current is called leakage current (Il), and the transient currents are produced by discharge and recharge of the membrane capacitor (Ic). The leakage current is produced by passive flow of ions, primarily K+, across the membrane, channels of which are always open and responsible for creating the resting potential. If the clamp voltage is large, the current consists of two phases--an early inward phase and a later outward phase (B2)--which becomes clearer when the Il and Ic subtract the current. Hodgkin and Huxley further revealed that when the experiment was performed by replacing the Na+ ion in the external medium with choline, a large ion impermeable to the membrane, the current consisted of only a later outward phase (Fig. 2-4 B3), which increased in amplitude if the membrane was set at more depolarized levels. They concluded that this later component of the current was carried by K+ ions. When this component was subtracted from the control recording, they obtained an early component that was reversed to the clamp voltage at around +55 mV, which is near the equilibrium potential for Na+. The results obtained from the voltage clump study were confirmed by subsequent pharmacological experiments using selective blockades of the channels for Na+ and K+. One

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chemical, tetradotoxin (TTX) (or saxitoxin (STX)), is a neuroactive poison from the puffer fish that is known to inhibit a generation of action potential due to the blockage of specific Na+ channels, while another chemical, tetraetylammonium (TEA), is known to prolong the time course of the action potential due to blockage of specific K+ channels. When an axon poisoned by TTX was subjected to a depolarizing voltage step, an inward current was not seen, but the delayed outward current was intact. On the other hand, when the axon treated by TEA was subjected to a test pulse, the delayed outward current disappeared, but the early inward current remained intact (Fig. 2-4 B3). It appears that to a depolarizing voltage step, the activation of the Na+ channel rises much more rapidly but decreases soon to zero, even though the membrane is still depolarized. On the other hand, the activation of K+ channels is considerably delayed compared with the activation of the Na+ channels, and remains high throughout the duration of the depolarizing step.

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46

Figure 2-4. A: Diagram of a typical circuit for clamping voltage of an axon. B1-B3: Current pattern in typical voltage clamp recordings. If the clamp voltage is a small and subthreshold depolarization, transient capacitive (Ic) and steady leakage (Il) current are observed (B1). If the clamp voltage is a larger depolarizing step, just after the capacitive and leakage currents, it will give rise to an inward current that declines and gives way to an outward current, which reaches a steady state which it maintains during the clamping (B2). When the voltage step shown in B2 is repeated in the axon treated by TTX (or soaked in Na+ free outside medium), the inward current disappears, and in the axon treated by TEA, the outward current disappears (B3) from the current recording. In the recording of B3, the capacitive current and the leakage current are eliminated by inspection. (From Kandel, Schwartz, and Jessell 2000.)

* Parallel Conductance Model in the Voltage Dlamp Based on their series of voltage clamp experiments, Hodgkin and Huxley (1952) proposed an equivalent circuit diagram for the membrane, which includes passive membrane capacitance (Cm) and leakage conductance (gl), as well as voltage-sensitive gNa and gK channels (Fig. 2-5 A). The currents of the circuit (Im) to clamp voltage (Vm) can be expressed with the following equation: Im = Ic + INa + IK + Il = Cm(dVm/dt) + gNa(Vm-ENa) + gK(Vm-EK) + gl(Vm-El) From the viewpoint of conductance change in the parallel model, the process of action potential generation is interpreted as follows. Depolarization of the membrane causes a rapid increase in sodium conductance (gNa), resulting an inward Na+ current. This current induces further depolarization, which accelerates the increase in gNa and more inward current. This early phase of action potential advances in regenerative fashion. As the depolarization continues, however, inactivation of gNa proceeds, and potassium conductance (gK) is activated with some delay. The inactivation of gNa and activation of gK limit depolarization, causing repolarization, as the former stops inward Na+ current and the latter increases outward K+ current. In most cases, action potentials are followed by a hyperpolarizing after-potential (undershoot), because return of the increased gK during the later phase of the action potential to its resting level shows a delay with a few milliseconds even after the potential reach to the resting level. The relation between the action potential formation and the underlying change in Na+ and K+ conductance has been explained using a famous graph, as presented in Fig. 2-5 B; this was originally presented by Hodgkin and Huxley in 1952.

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Figure 2-5. A: Electrical equivalent circuit of an axon membrane in action potential generation, which is composed of the capacity representing the dielectric properties of the membrane, and the Na+, K+ and leak conductance with their different batteries. B: Action potential (Vm) and underlying behaviors of Na+ and K+ channels (gNa, gK). Approximate equilibrium potentials for Na+ (ENa) and K+ (EK) are also shown in the figure. (Redrawn from Hille 2001.)

48

Toshifumi Kumai and Yoshiyuki Shibukawa [A Different Angle 2-5]

When a nerve fiber is stimulated by a battery or other stimulation device using paired metal wires on the axon, at onset (switch-on) an action potential is generated at the place where the wire contacts the negative pole (cathode) of the battery. On the other hand, at the break (switchoff), an action potential is generated at the place where the wire contacts the positive pole (anode) of the battery (Fig. 2-6 A1). The latter is called the anodal break excitation, and the same phenomenon is observed when a hyperpolarizing pulse is applied inside neurons using microelectrodes, in which the action potential is not elicited at the onset, but elicited at the return of the stimulus to the resting potential level (Fig. 2-6 A2). The action potential generation at the place where the axon contacts the cathode electrode to the onset of the voltage pulse is easily understandable as the outward current flows (or depolarization occurs) across the membrane at the electrode; however, the action potential generation in an anodal break is a curious phenomenon, as the action potential is produced even though the membrane potential does not reach its threshold voltage level. This phenonenon has been interpreted as follows. During pulse stimulation, the inside of the axon at the positive electrode is under hyperpolarization which decreases degree of inactivation of Na+ channels. When hyperpolarization returns to resting revel by break of the stimulus, activation of Na+ channels occurs, which triggers regenerative activation of Na+ channels to produce the action potential. If the membrane possesses an inductance property, another explanation about the anodal break excitation may be possible. An inductor generates a terminal voltage (VL) to prevent the current: it is proportional to the rate of change of the current (VL=-L*di/dt). In a simple circuit composed of a resister and a coil, the coil produces a transient terminal voltage at the onset of a voltage pulse, and that of opposite polar voltage at its break (Fig. 2-6 C1), as the current flows and stops abruptly at both edges of the pulse. The voltage of the inductance in relation to time (t) is expressed as +E*e-Rt/L for the onset and as -E*e-Rt/L, for the break. If the membrane of the axon has an inductance property, the inside positive and negative transient voltages are generated at the place where the electrode connects the cathode of the battery to the onset and to the break, respectively; and an action potential is generated only in the onset, as it is generated in the depolarizing condition of the axon. The opposite potential events occur at the place where the electrode is connected to the positive pole of the battery: the action potential can be generated, restricted in the break of the stimulus. There is another noticeable phenomenon for action potential generation. A slow-rising stimulating current applied across the membrane of an axon fails to trigger the action potential when it depolarizes the membrane to its usual threshold membrane potential (Fig. 2-6 B2), which is called accommodation. The phenomenon is commonly interpreted as following. The stimulation manner fails to generate an action potential because during the slow approach to the threshold membrane voltage, inactivation of the Na+ channel and activation of the K+ channel advance before the threshold voltage is reached. Based on the idea that the membrane possesses an inductance property, another explanation is also possible. (To simplify the discussion, the capacitance factor of the membrane can be omitted.) An essential property of a coil is to generate a voltage to prevent current change, and it is proportional to the rate of change of the current. Slow increments of current are necessary in order not to produce enough voltage to trigger action potential generation. In the circuit shown in Fig 2-6 C1, the potential is produced on the resister, so it might be better to think that the gating property of the Na+ channel would link mainly with the membrane inductance.

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Figure 2-6. A: Anodal break excitation in action potential generation. When an axon is stimulated externally using a paired electrode, the action potential is elicited at the place of the cathode electrode at the switch-on, and at the place of the anode electrode at the break (A1). When the axon is stimulated intracellularly by a hyperpolarizing pulse voltage, an action potential is elicited at the end of the pulse (A2). B: Accommodation. An appropriate pulse current elicits an action potential (B1) when it reaches a threshold voltage, but when the current is supplied in a gradual manner, the action potential fails to arise even when the voltage reaches the threshold (B2). (From Kandel, Schwartz and Jessell 2000.) C: Time course of voltage response to a pulse voltage in a circuit composed of series of a resistor (R) and a coil (L) (C1), and the estimated potential generation across a membrane of neuron at a pair of electrodes to a pulse voltage, supposing that the membrane possesses an inductance component (C2).

In an examination of ionic currents using the voltage clamp method, Na+ current occurs just after the onset of step voltage, which immediately decreases and K+ current follows with a short delay, which increases and reaches a constant level that is maintained during the clamp

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Toshifumi Kumai and Yoshiyuki Shibukawa

voltage (Fig. 2-4 B3). The voltage dependent activation and automatic inactivation of Na+ channels is similar to an inductance response, and the voltage dependent activation of K+ channels is similar to a capacitive response. Roughly speaking, a gating sensor for Na+ channels (Na+ conductance) might be constructed by something like a coil, whereas a gating sensor of K+ channels (K+ conductance) might be constructed by something like a capacitor. Hodgkin and Huxley explained the time dependence of Na+ channels and K+ channels using complex equations. They described the Na+ conductance and K+ conductance using the following equations, respectively. gNa(Vm,t) = GNa*m(Vm,t)3*h(Vm,t), gK(Vm,t) = GK*n(Vm,t)4 where GNa and GK represent the maximum sodium and maximum potassium conductance, respectively; m and n, activation parameters for sodium and potassium conductance, respectively, which are dimensionless and vary from 0 to 1 as a function of voltage and time; and h, an inactivation parameter for sodium conductance that also varies from 0 to 1 as a function of voltage and time. The time dependence of m3h and n4 to a step voltage fits well with the curves for Na+ current and K+ current observed in the voltage clamp tests, respectively, when m, n, and h are given by m=1-exp(-t/τm), n=1-exp(-t/τn), and h=exp(-t/τh). They also clarified that the gate of the Na+ channels would possess three activation "m"-particles and one inactivation "h"-particle, and that the gate of the K+ channels would possess four activation "n"particles as physical analogues.

(4) Electrical Property III: Propagation of the Action Potential An action potential (impulse), generated at a site spreads electrotonically along the axon, but its amplitude diminishes quickly as the insulation of an axon is poor, and the shape also deforms as the membrane possesses capacitance property that works similarly as a high-cut filter on the signal. Discharges of action potential however, reach considerable distances at the axon terminals and cause various effects on organs or tissues, such as muscle contraction. An essential property of action potential discharges is that they do not disappear once they have occurred and propagate along with the axon without diminishing their magnitude and without changing their shape. How an action potential is maintained and propagates along with the axon is a subject of this section.

* Axon as an Analogue to Cable The passive electrical property of nerve fibers is frequently explained by comparing them with undersea cables. In undersea cables, signals in reference to the surrounding seawater diminish gradually with the longitudinal distance from the initial point because current leaks

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continuously along the longitudinal axis even though the inner metal wire is strongly insulated to the outside solution. In addition, the signals are deformed by the capacitance factor across the insulation film. These properties of undersea cables are similar to those of nerve fibers surrounded by a salty medium.

Figure 2-7. A: Cable model for the passive spread of potential in an axon, where the axoplasmic core and extracellular region are represented as chains of resistors, and the region between them as parallel capacitors and resistors. ri (ro), internal (external) resistance of a unit length; rm, membrane resistance of a unit length; Cm, membrane capacitance of a unit length; Ii(Io), internal (external) current; Im, current across the membrane of a unit length; Vi(x,t)(Vo(x,t)), potential of inside (outside) of the membrane. B: Potential distribution (Vm(x,t)) along with the axon (x) to current supply (I0) at x=0 in various times (t). Rough time courses of the potential at five places of the axon are simultaneously presented beneath it. (Adapted from Hodgkin and Rushton 1946.)

The electrical circuit model of a cable is shown in Fig. 2-7 A. In the model, the following differential equations for inside (i) and outside (o) of the cable are formed in relation to voltage (V(x,t)), resistance (r), and current (I(x,t) ), based on Ohm's law. (The voltage

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52

decreases if the current flows in a positive direction, to the right side in this model, along the X-axis.)

∂ Vi ∂ Vo = -riIi and = -roIo ∂x ∂x ∴

∂ Vi ∂ Vo ∂ Vm = = -riIi + roIo ∂x ∂x ∂x

∴

∂ 2 Vm ∂Ii ∂Io + ro 2 = -ri ∂x ∂x ∂x

Current (efflux) that flows at a given point of the membrane (Im(x,t)) is equal to a current flowing inside and to a current flowing outside. Im = -

∴

∂Ii ∂Io = ∂x ∂x

∂ 2 Vm = riIm + roIm = (ri+ro)Im ∂ x2

(2-12)

The current Im is the sum of the current through the membrane resistance (Vm/rm) and the current across the membrane capacitor (Cm*(dVm/dt)): Im =

∂ Vm Vm + Cm rm ∂t

Substituting this to 2-12, then ∴

∂ Vm 1 ∂ 2 Vm Vm + Cm 2 = rm ri+ro ∂x ∂t

∴

∂ Vm rm ∂2Vm = Vm + rmCm ri+ro ∂x2 ∂t

Consequently, the following equation is established

λ2

∂ 2 Vm ∂ Vm -τ - Vm = 0 ∂ x2 ∂t

(2-13)

where λ (= rm/(ri+ro) ) is called the length constant, and τ (=rmCm) is called the time constant.

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When a sufficiently long time has passed (t=∞) after application of the current at x=0, distribution of the potential reaches a steady state along the cable. At this time, the potential change becomes zero (∂Vm/∂t =0), which gives us the following equation:

λ2

∂ 2 Vm - Vm = 0 ∂ x2

The general solution of this equation is Vm = Aex/λ + Be-x/λ (A, B: integration constants) This separates into two parts as the value of Vm should not diverge; A is equal to B as Vm takes the same value at x=0. If x>0, then Vm = Ae-x/λ (∴∂Vm/∂x = -(A/λ)e-x/λ ) If x<0, then Vm = Aex/λ (∴∂Vm/∂x = (A/λ)ex/λ ) These two equations indicate that Vm declines exponentially in both directions along the axon in a symmetrical manner from the point applied with a current (x=0). If a current (I0) is applied to the axon inside at a point (x=0), it would flow separately equal to the opposite directions, so (∂Vm/∂x)x=+0 = -ri(I0/2) (∂Vm/∂x)x=-0 = ri(I0/2) Thus, A/λ= ri(I0/2). Consequently, the membrane potential in the constant state (Vm(x,∞ )) can be described by the following equation: Vm(x,∞) = (I0/2)*λ*ri*e-|x|/λ Resistance of the medium surrounding the axon is very low (ro≑ 0), so this equation becomes Vm(x,∞) = (I0/2)* rm/ri *ri*e-|x|/

rm/ri

For example, if a constant current 10-3 [A] is applied inside the axon with λ= rm/ri =0.25 [cm] and ri=10 [Ω /cm], then the membrane voltage (Vm(0,∞)) passively produced at the applying point (x=0) becomes Vm(0,∞) = 10-3*0.25*10 = 2.5 [mV] :

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The equation Vm(x,∞)= (I0/2)λrie-|x|/λ represents the passive distribution of the potential along the axon in the steady state. (Action potential generation by the applying current is not considered in this situation.) The potential changes not only with distance but also with time. How does the time course progress when a stepping current is applied? We have already seen that the time course of the potential to a maintained current can be expressed by the following equation: Vc = Q/C = V0*(1-e-t/(Cmrm)) = I0*rm*(1-e-t/(Cmrm)) However, this equation is obtained by supposing that all current flows across the two discrete elements, membrane resistance and membrane capacitance, in parallel. To obtain the potential change strictly in an axon analogous to a cable, the differential equation (2-13) must be solved. Although solving the equation is, in general, difficult, it is possible under specific conditions. For example, when x=0, this problem can be solved using the following function, according to Hodgkin and Rushton (1946), and Rall (1960): Vm(0,t) = (I0/2)*λ*ri*erf( t /τ ) Here, erf(t) is a function called an "error function", the curve of which is similar to (1-e-t) and becomes 1 when t= ∞ . Therefore, when a sufficiently long time has passed after application of the current (I0), the potential at the point where the current is supplied, (Vm(0, ∞)), is close to (I0/2)λri . That is, of course, the same as the value calculated from the equation, Vm(x,∞) = (I0/2) λ rie-|x|/ λ , describing the spatial distribution of the membrane potential along the axon. The actual response of nerve fibers takes an intermediate course between these two functions, but it seems to produce no serious problem if we consider that the rising phase takes an exponential property (Vm = Vo(1-e-t/τ)) in response to a pulsating injection of current.

* Outline of Propagation of the Action Potential In nerve fibers, the inside electrotonic voltage (Vx) at a distance along the axon (x) from the site generating the potential (Vo) is given by the following equation, as previously described: Vx = Vo e-x/λ where λis approximately rm/ri (rm, ri: membrane resistance and inner solution resistance for a unit length), which is known as the length constant. If x=λ, then Vx=Vo (1/e); namely, λis the distance where initial voltage decays to 1/e (=37%). The length constant depends on the inner solution resistance that is linked to the size of the axon. In many neurons, the diameter is a few microns and λ is a fraction of a millimeter. This indicates that the

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magnitude of the action potential rapidly diminishes with the longitudinal distance from the place where the potential occurs if it does not regenerate successively. Furthermore, in the axon membrane the capacitive component (Cm) and the resistance component (rm) are considered to exist in parallel, which works as a high-cut filter to electrical signals, resulting in the deformation of its original figure. As discussed already, the effect is apparent when a square pulse is applied to the analogous RC circuit: it makes the rise and fall phases of the pulse slower in a same fashion. The time course of potential (Vt) to a stepping pulse (Vo) is given by the following equation: Vt = Vo (1 - e-t/τ) where τis rmCm (a time constant). In this equation, when t =τ, then Vt = Vo (1-1/e). That is, τis the time when voltage develops to 1-1/e (=63%). These membrane properties, the length constant and the time constant, make the action potential difficult to affect directly (or electrotonically) on the terminal of the axon. How does the action potential move to the neighboring place of the axon successively? To generate action potentials, an influx of Na+ ions is required. The Na+ channel is opened by the depolarization of up to a certain level of voltage (a threshold). During the action potential, Na+ ions flow into the axon. The current spreads out along the inside of the axon and returns at the point of entry through the membrane. Whenever an action potential is set up, electrotonic currents of ions flow through the neighboring membrane. These currents are called a local current. (The carrier of the local current is not necessarily only Na+ ions; all ion species move according to the potential gradient.) These local currents charge the membrane capacitance and make the axon depolarize, resulting in the depolarization gradient along the axon. If the depolarization reaches the threshold, a new action potential is produced at the site. This sequence occurs successively along with the axon like a falling of dominoes, resulting in propagation of the action potential towards the nerve terminal. The larger the length constant of the axon, the greater the distance that the electrotonic potential can spread, and the smaller the time constant, the greater the distance that the shape of the electrotonic potential can be maintained. After all, the large length constant and small time constant of nerve fibers make the propagation velocity of action potential faster.

* Relation Between Axon Diameter and Velocity From equation (2-12), local membrane current of the unit length (im(x,t)) is expressed as im =

1 ∂ 2 Vm 1 ∂ 2 Vm ≑ ri+ro ∂x2 ri ∂ x 2

If the diameter is d, the membrane current of the unitary cross area, Im, and the intracellular resistance of the unitary cross area, Ri, then im= dπIm , ri = Ri/π(d/2)2 = 4Ri/πd2

Toshifumi Kumai and Yoshiyuki Shibukawa

56 ∴ Im = (d/4Ri)

∂ 2 Vm ∂ x2

(2-14)

When an action potential propagates with a constant velocity of α, then the following relation is established: Vm(x,t+t0) = Vm(x-αt,t0) Letting this equation differentiate for time (t) and distance (x), then

∂Vm(x,t+t0)/∂t2 = ∂Vm(x-αt,t0)/∂t2 =α2*d2Vm(x-αt,t0)/d(x-αt)2

∂Vm(x,t+t0)/∂x2 = ∂Vm(x-αt,t0)/∂x2 = d2Vm(x-αt,t0)/d(x-αt)2 The next equation is the obtained:

∂ 2 Vm 1 ∂ 2 Vm = ∂ x2 α 2 ∂ t2

(2-15)

From (2-14) and (2-15), we get Im =

∂ 2 Vm 4Riα2 ∂t2 d

∴ α2 = (d/4Ri)

1 ∂ 2 Vm Im ∂t2

(2-16)

In equation (2-16), Im and∂2Vm,/∂t2 do not depend on the diameter, so this equation indicates that the velocity of the action potential is proportional to the root (√) of d/4Ri. In other words, the velocity increases by a factor of 1.4 times (root(2)) if the diameter of the nerve fiber doubles. [A Different Angle 2-6] Doppler effect in recording the action potential: It is well known that pitch of a sound as heard by an observer is changed if there is a relative motion between the sound source and the observer along the line joining them. This is called the Doppler effect. If the source of the sound is in motion toward the observer, the pitch of the tone heard is higher than when the source is stationary. On the other hand, if the source is receding, the observer hears a sound of lower pitch than when the source is stationary. This phenomenon is common with every type of

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oscillation for which the source is in motion. When the wave source with a velocity of v' and a pitch of f approaches the observer, the pitch (f<) of the sound heard is described as f< = f*(v/(v-v')) v: propagation of the waves as usual If the source is receding, the sign of v' is reversed, so the pitch (f>) of the sound heard is described as f> = f*(v/(v+v')) The wavelength of sound is the reverse of the pitch, so the length in approaching (λ<) and the length in receding (λ>) are as follow, respectively.

λ< = (v-v')/(f*v) λ> = (v+v')/(f*v) The action potential propagating along the axon is considered to be a signal in motion, which gives rise to the question “ Isn't the Doppler effect reflected in the figure of the action potential?” When the action potential is recorded externally by an electrode pair (observer) placed on the surface of an axon with a short distance, the potential is picked up as biphasic, positive (upward) deflection and followed by negative (downward) deflection (Fig. 2-8 A1). (The deflection, however, also can be negative-positive, depending on which electrode is taken as a reference.) The two parts, the former half and latter half of the potential, follow a similar time course, but duration (or wave length) of the first half is slightly shorter than that of the latter half if observed carefully in the recording. This leads one to suspect a reflection of the Doppler effect because the first half wave is the record approaching the electrodes, and the latter half wave, the record receding from the electrodes.

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Figure 2-8. Typical extracellular (A1) and intracellular (A2) recording of an action potential, where a and b express duration of the first half and latter half of the potential, respectively. B: Electrotonical conduction of an action potential estimated roughly from the cable theory. (Adapted from Hodgkin and Rushton 1946, and Koch 1999.)

If we let the duration of the first half and the latter half of the potential be a and b, respectively (Fig. 2-8 A1), the rate of a to b becomes a/b = {(v-v')/(f*v)}/{(v+v')/(f*v)} = (v-v')/(v+v') 17)

(2-

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The velocity of an action potential propagating along axons (v') is known to be approximately 1-100 [m/sec], depending on the types of neurons. Interpretation of "v" in the equation (2-17) is, however, difficult. In this case the value v should be the electrotonic velocity of the potential in solution. Does the electrical signal spread with a velocity almost the same as that of light or electrons? Even if the moving velocity of ions is lower than that of light or electrons, the Doppler effect cannot be detectable in the recording when the value of v in equation (2-17) is great, as the value of a/b approaches 1. As already described, the membrane has a capacitance property, which makes the pulse signal dull. This also means that electrotonic spread of the action potential, especially its high frequency component, is delayed. In other words, the spread of the action potential has a considerable velocity (Fig 2-8 B). Interference of the Doppler effect on action potential recordings can still possibly explain the unsymmetrical biphasic deflection of the action potential. However, it could be ascertained simply by comparing the difference of the wavelengths of the two parts between fast velocity nerves and slow velocity nerves. When the action potential is recorded intracellularly, the potential shown in Fig. 2-8 A2 is typically observed. The shape is almost monophasic, although the positive-going phase of the spike is followed by the after-potential of a small hyperpolarization for a short time. The rate of rise of the positive-going phase is, in most cases, higher than the rate of its fall, which seems essentially the same as the difference in the wavelength between the two parts of the extracellular recording. The faster rising rate and the slower falling rate of the recorded potential is commonly explained from the gating behaviors of Na+ and K+ channels. If the action potential is formed depending on the intrinsic nature of the ion channels, the longer wavelength of the latter half of the extracellular recording stands to reason. However, if any factor, such as the Doppler effect, is intermingled in the recording, an interpretation on the channel mechanism would be effected.

* Saltatory Conduction Velocity of action potential propagation is important for animals to survive, and two mechanisms have developed to optimize it during evolution. To increase the propagation velocity, distant electrotonical spreading of the depolarization for action potential is essential. An increase of the diameter of the axon core would seem to be a rational strategy for achieving this. Equation (2-16) indicates that the larger the diameter, the faster the propagation velocity. This is due to a decrease of the resistance of the unit length of the axon, which makes the length constant large, meaning that the electrotonic potential of the depolarization for the action potential spreads more distant. All consideration about the propagation velocity described up to here is principally for unmyelinated fibers. Another strategy to spread the electrotonic depolarization distantly is insulating the inside from the outside medium. Wrapping the axon in a myeline sheath (myelination) suits this purpose. One key point of myelination is that the axon surface is not entirely wrapped, but there is a gap between the myelinations, called Ranvier nodes (Fig. 21): the range of the internodal distance is approximately 0.5-2 mm. Although the area of each node is quite small (a few μm), it is known to contain a high density of voltage-gated Na+ channels. Local currents produced by an action potential converge at nodes, and if the current

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(or depolarization) is strong enough to generate an action potential, a sudden jump of the action potential occurs (Fig. 2-9). In myelinated nerves, this jump continues successively, which makes the propagation time quite short. This type of propagation is called salutatory conduction. The propagation velocity of myelinated fibers is greater, perhaps more than ten times that of non-myelinated fibers of the same diameter. This salutatory conduction is widely observed in peripheral and central nerve fibers, especially in vertebrates. (The myelination has another effect of decreasing the time constant of the membrane, because the internal and external solutions are separate with longer distance, which makes the membrane capacitance smaller.) Salutatory conduction, however, does not mean that the action potential occurs step by step for each neighboring node. An action potential jumps from one node to the next on its leading edge, but many nodes behind are under an active state, so the action potential propagation of the myelinated fiber is not interrupted by the damage of a few nodes if it is within a safe range.

Figure 2-9. Salutatory conduction in myelinated nerve fiber. Local currents of an action potential converge at nodes of the axon, and the action potential propagates, skipping from node to node. (The real skip would not occur node by node, but would occur included with a few nodes.)

There is another merit, a kind of metabolic merit, in myelination in that less energy is expended by the Na/K pump in restoring the Na+ and K+ concentration gradient that decreases constantly and especially is run down as a result of the action potential, as ionic

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current flows mainly restricted at the node. Myelination is a surprising strategy, but the myeline sheath is known to be weak to such factors as heat, acid, and virus infection, and its peeling or incomplete wrapping frequently causes serious problems for nervous functions, especially of the brain neurons.

References and Suggested Readings Aidley, D.J. (1978). The Physiology of Excitable Cells. Cambridge University Press, Cambridge. Armstrong, C.M. and Hille, B. (1972). The inner quaternary ammonium ion receptor in potassium channels of the node of Ranvier. J. Gen. Physiol. 59: 388-400. Cole, K.S. (1969). Membranes, Ions, and Impulses (Translated in Japanese). Yoshioka Shoten, Tokyo. Cole, K.S. and Moore, J.W. (1960). Ionic current measurements in the squid giant axon membrane. J. Gen. Physiol., 44: 123-169. Goldman, L. (1943). Potential, impedance and rectification in membranes. J. Gen. Physiol. 27: 37-60. Hille, B. (2001). Ion channels of excitable membranes (3rd ed.). Sinauer Associates Inc., Sounderland, Massachusetts. Hodgikin, A.L. (1964). The conduction of the nervous impulse. Liverpool Univ. Press, Liverpool. Hodgikin, A.L. and Huxley, A.F. (1945). Resting and action potentials in single nerve fibers. J. Physiol. 104: 173-195. Hodgikin, A.L. and Huxley, A.F. (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol., 117: 500-544. Hodgikin, A.L. and Huxley, A.F. (1952). Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J. Physiol., 116: 449-472. Hodgikin, A.L., Huxley, A.F. and Katz, B. (1952). Measurement of current-voltage relations in the membrane of the giant axon of Loligo. J. Physiol., 116: 424-448. Hodgkin, A.L. and Rushton, W.A.H. (1946). The electrical constants of a crustacean nerve fibers. Proc. Roy. Soc., B, 133: 444-479. Junge, D. (1976). Nerve and Muscle Excitation. Sinauer Associates Inc., Sunderland. Kandel, E.R., Schwartz, J.H. and Jessell, T.M. (2000). Principles of Neural Science (3rd ed.). McGraw-Hill, New York. Katz, B. (1966). Nerve, Muscle, and Synapse. McGraw-Hill, New York. Koch, C. (1999). Information processing in single Neurons. In: Biophysics of Computation, Oxford University Press, New York. Miyagawa, H. and Inoue, M. (2003). Biophysics of Neurons. Maruzen Inc. More, J.W. (1971). Voltage clamp method. In: Biophysics and Physiology of Excitable Membranes. Van Nostrand Reinhold, New York. Nicholls, J.G., Martin, A.R. and Wallace, B.G. (1992). From Neuron to Brain (3rd ed.). Sinauer Associates Inc, Sounderland.

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Rall, W. (1959). Branching dendritic trees and motoneuron membrane resistivity. Exp. Neurol., 1: 491-527. Rall, W. (1960). Membrane potential transients and membrane time constant of motoneurons. Exp. Neurol., 2: 503-532. Rall, W. (1977). Core conductor theory and cable properties of neurons. In: Handbook of Physiology - A Critical, Comprehensive Presentation of Physiological Knowledge and Concept (E.R. Kandel (ed.)). American Physiological Society, Bethesda, Tasaki, I. (1968). Nerve Excitation. Thomas Books, Springfield. Tuckwell, H.C. (1988). Linear cable theory and dendritic structure. In: Introduction to Theoretical Neurobiology, Vol. 1, Cambridge Univ. Press, Cambridge. Weiss, T.F. (1996). Cellular Biophysics. Vol. 2, The MIT Press.

Chapter III

Synaptic Processes and Neurotransmitters Neurons are anatomically distinct units, and in general, there is no direct structural connection between their cytoplasm. Yet a neuron can send signals to another neuron at the junction between the two neurons, called a synapse that was termed first by Charles Sherrington (1857-1952). A nerve impulse can be propagated in either direction along the axon, whereas transmission at the synaptic region is from the axon terminal of one neuron to a dendrite or cell body of another neuron. In most cases in the animal nervous system, the transmission is intermediated by neuroactive chemical substances, or neurotransmitters, diffusing across the narrow space between the two cells, where a neural signal in digital form, an impulse train, is changed into a signal in analogue form, a synaptic potential. This transfer process is quite interesting from the viewpoint of integration of biological messages. The concept of the chemical transmission was provided by Otto Loewi (1873-1961) in his biochemical experiments on the control of the frog heartbeat in the 1920s, later established by Bernard Katz (1911-2003) and his colleagues in their excellent investigations on the transfer mechanism at the motor neuron-skeletal muscle junction in the frog, and greatly advanced by John Eccles in his earnest research on the transmission process of the spinal motor neurons of cats. At present, synaptic transmission is one of most thrilling topics in the field of neurophysiology, and its understanding is quite important for clarifying why the nervous system works so precisely and elaborately. In particular, mental functions of the human brain, such as learning, memory, attention, cognition, and so on are believed to relate deeply to synaptic transmission.

(1) Morphology of Synapses There are two types of synapses--chemical and electrical. Electrical synapses correspond to gap junctions found in other cells in the body. They interconnect the cytoplasm of two adjacent neurons, where small ions and molecules, as well as water, can move freely

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through the junction. Electrical synapses are commonly observed in the nervous systems of invertebrates, but are thought to be restricted in mammalian nervous systems. (This book will deal only with chemical synapses, but it never denies the importance of electrical synapses, which may be appreciated more in future.) In the mammalian nervous system, chemical synapses are common, in which membranes of a presynaptic neuron and postsynaptic neuron are separated by a narrow space, and the transmission is intermediated by chemical substances. Our first insights into how chemical synapses between neurons might work came from studies of the neuron-muscle junction, the specialized area where a motor nerve terminates on a skeletal muscle. Although a neuron-muscle junction is ontogenetically different from a neuron-neuron junction, both types are called (chemical) synapses. In these two types of chemical synapses, the transmitting region of a presynaptic neuron and the receptive region of a postsynaptic neuron (or muscle) show well-differentiated structures.

* Neuromuscular Junction Skeletal muscle contraction is controlled by nervous signals. The signals are conveyed by motor neurons, situated with their cell bodies in the spinal cord and brainstem. Axons of motor neurons are myelinated. That is, there are wrapped in a sheath of myelin produced by Schwann cells. When entering a muscle, a motor axon branches repeatedly so that it gradually becomes thinner. A nerve ending comes into contact with a single muscle fiber, where it loses its myelin sheath and splits further into finer branches (Fig. 3-1 A). Each branch forms multiple swellings called terminal boutons, which are also covered by Schwann cells. The special region of the muscle fiber contacting the nerve ending is called the neuromuscular junction. The neuromuscular junction is made up of a presynaptic ending of the axon terminal and a postsynaptic element of the muscle, separated by a narrow space approximately 20-50 nm wide (synaptic cleft). An essential feature of the presynaptic ending, the terminal bouton, is an accumulation of clear small vesicles filled with a neurotransmitter substance (Fig. 3-1 B), in this case a small molecule named acetylcholine (ACh). The vesicles are lined up and orderly attached inside the presynaptic membrane, and this region is called the active zone. On the opposite side, across the synaptic cleft, are other characteristic specializations known as postsynaptic folds, which are fine radial extensions of the muscle fiber membrane into the cleft (Fig. 3-1 B). This specific junction between nerve and muscle is frequently called the endplate, a structure not essentially different from the neuron-neuron junction. Receptor molecules for the neurotransmitter substance attach to the specialized endplate region of the muscle fiber membrane, and only one nerve fiber ends on each endplate.

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Figure 3-1. A: Sketch of neuromuscular junction from a large myelinated nerve fiber to skeletal muscle fibers. The nerve fiber branches and contacts with a muscle fiber (end plate), forming terminal swellings called synaptic boutons. B: Sketch of the junction between a bouton and the muscle membrane. The space between the synaptic terminal and the muscle fiber membrane is called the synaptic cleft. The muscle membrane at synapse forms a number of small folds, and one or more Schwann cells cover the end plate. (Adapted from Nicholls, Martin and Wallace 1992.)

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* Neuron-Neuron Synapses in the CNS The human CNS contains an astronomical number of neurons. They differentiate greatly but have in common 4 main functional parts: dendrites, cell bodies (somata), axons, and nerve terminals. One of conspicuous features of neurons in the CNS is the configuration of their dendrites. The number and branching pattern of dendrites of CNS neurons vary greatly (Fig. 3-2), which seems to relate closely to the specific function of the neuron, although the accurate relation has not been fully analyzed. The synaptic contacts are made to all of the four parts (Fig. 3-3), but the dendrites provide the major sites for synaptic terminals. The effect of presynaptic signals on activities of the postsynaptic neuron vary with the contact sites and the numbers.

Figure 3-2. Variation of nerve cell morphologies found in the human nervous system. a is a rough sketch of a spinal cord motor neuron; b, pyramidal cell of motor cortex; c, Purkinje cell of cerebellum; d, pyramidal cell of hippocampus; e, mitral cell of olfactory bulb; and f, retinal amacrine cell. The size of each has been adjusted accordingly. (Redrawn from Kandel, Schwartz and Jessell 2000.)

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Figure 3-3. Diagram of synaptic contact on different sites of neurons.

The synaptic sites are easily distinguished in an electron micrograph, as the presynaptic terminal contains many synaptic vesicles and the postsynapse shows a high density image. The structures and contact sites of nerve-nerve synapses are different among them, but the elements are the same as the nerve-muscle synapse: the presynaptic membrane of the axon terminal and the postsynaptic membrane of the other neuron face across the narrow gap (synaptic cleft), where the presynaptic terminal forms a bouton containing neurotransmitter chemicals, and on the postsynaptic membrane attaches receptor molecules to them. It is known that neurons involving motor function tend to receive synaptic inputs more than neurons involving sensory function, and their dendritic tree is more elaborate. The surface of the dendrites, especially of brain neurons, is covered with a huge number of small protuberances (Fig. 3-2 b, d), called dendritic spines, and it is now thought that most of the synapses on dendrites are made on the spines (Fig. 3-3). Not only do they increase during development, but the number and shape of the dendritic spines are known to change over a time scale of minutes, hours, and days according to various factors. Recent data indicate that the state of the dendritic spines is closely related to cognitive function in the nervous system and possibly to memory, and that development of the dendritic spines depends on the quality of the environment experienced during childhood.

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Why are dendritic spines the main synaptic sites?: Most of the CNS neurons have richly-branched dendritic trees extending and spreading complexly. Their dendritic branches have a large number of spines, most of which are known to form synapses with other fibers. What do the tiny protuberances on dendrites mean, and why are most chemical synapses built up on them? Following is an attempt at resolving this question. If two similar charges, for example electrons, were placed on a metal rod, the two charges would remain separate due to their repelling forces (Fig. 3-4 a). If the same thing were performed with many electrons, they would separate into two groups evenly across the center (Fig. 3-4 b). Let us suppose we have an excess of electrons on a round flat plate. Would they be distributed evenly on the plate? It appears in this case that the electrons would be equidistant at the marginal region, as they all repel one another (Fig. 3-4 c). How would the electrons be distributed if the shape of the plate were a polygon? They would gather at the edges equally (Fig. 3-4 d). In short, charges of same sign are not distributed homogeneously on a plate but gather at protruding or pointed parts, which would occur in three-dimensional materials. This manner of charge distribution in solid materials must also occur for ion distribution in the cytoplasm of living cells. At resting state, the inside of neurons is under an excess of negative charges because of the large K+-conductance. The movable negative charges of the inside medium of the neuron, the majority of which would be Cl-, are estimated to be distributed strongly at the protruding structures such as dendrites and axon terminals: most of the charges in the dendrites must condense at the huge number of the dendritic spines (Fig. 3-3 e). (This suggests that the inside negative discharges of the spines would in turn attract positive ions, maybe mainly Na+ and Ca2+, in the outside medium to the surface of the spine.) Although it is still premature to discuss the role this ununiform ionic distribution plays in synaptic transmission, it is certain that the inside and outside of dendrite spines are under this specific ionic condition.

Figure 3-4. Distribution of same charges in plates of various shapes (a-d) and neuron (e). Two electrons separate and occupy two edges (a). The even numbers of separation occur if the electrons are numerous (b). They are distributed on the marginal region of a round plate (c), and at edges of a polygon plate (d). In neurons, charges of the same polarity are estimated to be distributed in the dendrites, especially spins of the dendrites, and in nerve terminals (e).

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A structure similar to the dendritic spine can also be observed at the neuromuscular junction. The presynaptic terminal containing synaptic vesicles of the motor neuron forms swellings called presynaptic boutons, and the postsynaptic membrane opposing the bouton forms a characteristic folding structure (Fig. 3-1 B). The formation of the small folds of the muscle membrane are believed, in general, to increase the synaptic effect by expanding the surface area on which the synaptic transmitter can act. Viewing the structure from the postsynaptic site, each mount of the folding formation is a protuberance of the postsynaptic membrane and could be considered to be, in a sense, an analogue of the dendritic spine. In actuality, acetylcholine receptor molecules are known to concentrate at the tops of the folds. Furthermore, acetylcholines in medium are thought to be charge positive, suggesting an attraction to the postsynaptic site, possibly the mounts of the folding, which gathers negative charges inside. (It is, however, common understanding that neurotransmitters diffuse toward postsynaptic receptor sites according to the concentration gradient.) The consideration that the specific ionic circumstance of protruding elements of neuron suites to the reception of biological messages may extend to sensory receptor cells. At their apical end, all of receptor cells for taste, smell, hearing, equilibrium, and light have common ciliary structures (Fig. 5-10). The cilia protrude from the receptor cells and are the main elements for receiving the corresponding sensory stimuli. It may, however, seem like a sudden and extraordinary comparison that the signal transmission in the synaptic space is analogous to the phenomena of thunderbolts that happen mostly between clouds and the tops of towers and trees, which are protuberances from the ground.

* Release of Neurotransmitters Chemical synapses transmit an electrical signal on the nerve fiber by secreting neurotransmitter substances from the terminal of presynaptic neurons to the receptor sites of the postsynaptic neurons. It is now established that the secretion of neurotransmitters is triggered by the influx of Ca2+ ions into the presynaptic terminal. The gate for Ca2+ channels is controlled by the inside voltage (voltage dependent Ca2+ channels): in this case, the opening of the gate is linked by the depolarization of the action potential that reaches the terminal. Ca2+ concentration in the outside medium is much greater than inside (more than 10,000 fold), so the opening of the gate for Ca2+ channels causes a transient Ca2+ influx. The increase of the inside Ca2+ concentration is thought to cause synaptic vesicles, in which neurotransmitters are stored, to fuse with the presynaptic plasma membrane, resulting in the release of the neurotransmitters into the synaptic space. The time between the presynaptic action potential and the release of the transmitters has been measured to be as little as 100 μ sec. The train of action potentials aids the Ca2+ entry, resulting in the successive release of the neurotransmitters. Although the mechanism of how the increase in Ca2+ concentration induces exocytosis of neurotransmitters has yet to be elucidated, it is certain in chemical

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synapses that Ca2+ entry into the presynaptic terminal is an indispensable factor for signal transmitting. The neurotransmitters released are believed to diffuse passively towards the postsynaptic receptor molecules according to the concentration gradient.

[A Different Angle 3-2] How do calcium ions act on the exocytos process of neurotransmitters?: Neurons contain much filamentous protein, actin and myosin. In particular, actin filaments are distributed over the cytoplasm and involve nerve formation and movement in the development, and remain as a part of the cytoskeletal structure of mature nerve cells. The two filamentous proteins are well known to be rich in muscle fibers, and they play a key role in contractions. The rough sequence of events in muscle fiber contraction is 1) binding of neurotransmitter (ACh) to receptors on the membrane of muscle fibers; 2) increase of Na+ and K+ conductance at the endplate which produce a synaptic potential in the muscular cell; 3) inducing an action potential in muscle fibers; 4) spread of the action potential along the membrane into myofibrils in tubular form (Tsystem); 5) release of Ca2+ from the terminal cisterns, which are the lateral sacs of sarcoplasmic reticulum next to so called the T-system; 6) binding of Ca2+ to troponin C, uncovering binding sites on actin for the myosin heads; and 7) formation of linkage between actin and myosin filaments, producing muscle force. In addition to containing two filamentous proteins, nerves and muscles have similar properties as excitable tissue in spite of the difference in their appearances. Both tissues receive electrical signals through chemical synapses in the same fashion. Both tissues generate the synaptic potential that produces the action potential, the ionic mechanisms of which are similar between the two. Both tissues can propagate an action potential along the membrane in both directions mediated by local current. And the action potentials of both tissues induce an increase in their internal Ca2+ concentrations; the actual role of Ca2+ entry into the axon part of nerve isn't, however, obvious. Isn't the actin and myosin protein in nerve cells able to work like that of muscle? Ca2+ entry into the presynaptic terminal is an indispensable factor for releasing the neurotransmitter, but the precise cascade from the Ca2+ influx to the transmitter release is still under study. Many functional proteins estimated to responsible for fusion events between the membranes of neurotransmitter vesicles and those of the presynaptic terminals are found within the presynaptic region. Some of the proteins are candidates to start the sequence of neurotransmitter release, as they are capable of binding Ca2+ strongly, while others are supposed to be involved in such processes as endocytotic budding of vesicles from the plasma membrane, neurotransmitter uptake in the vesicles, docking with the presynaptic membrane, and endocytosis of the vesicles. Cascade models of neurotransmitter release have been proposed. Although these models may well explain the sequential aspect of releasing events, the spatial aspect seems weak. How are the neurotransmitter vesicles moved toward the releasing site and pushed into the synaptic space? Isn't it likely that exocytosis would be physically carried out by contraction of presynaptic bouton through a coupling between the filamentous proteins in the bouton? This idea has been hinted at simply from the similarity between the excitable properties of nerves and muscles, but the idea that the local shrinkage of presynaptic terminals actively pushes out

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transmitters seems to have a value of discussing. The actual role of action potentials propagating along nerve fibers may produce a force which ejects neurotransmitters. (However, any evidence that the neuron has a contractile property has not been reported until now.)

* Generation of the Postsynaptic Potential Transmitters that are released reach the postsynaptic membrane within 100 μsec and combine with the receptors. The combination of transmitters and receptors causes a change in the potential of the postsynaptic cytoplasm, a so-called postsynaptic potential (PSP). The process of potential generation varies according to the type of transmitter, but all are mediated by opening (or closing) gates of specific channels for such ions as Na+, K+, Ca2+, and Cl-. Application of a given neurotransmitter causes a specific potential deflection and time course. If we consider polarization, we see that synaptic potential deflects positively (depolarization) or negatively (hyperpolarization). Since the former brings the membrane potential to a threshold initiating an impulse, these responses are called the excitatory postsynaptic potential (EPSP), and since the latter tends to shift the membrane potential away from generating an impulse, these responses are called the inhibitory postsynaptic potential (IPSP). The time course of the synaptic potentials varies with neurotransmitters. It falls into two categories, fast and slow. Accordingly, synaptic potentials are commonly classified as belonging to one of four types: fast EPSP, slow EPSP, fast IPSP, or slow IPSP. (In the central nervous systems of vertebrates (and invertebrates, as well), the fast types of PSP are common, whereas the slow types of PSP are recorded mainly from neurons and effectors for the autonomic nervous system. In this book we will mainly deal with the fast types.) The origin of synaptic potentials is ionic current through membrane pores. The ionic current through the ion channels charges a membrane capacitor that produces the membrane potential. Viewed in terms of ion diffusion theory, an influx of positive ions, and/or efflux of negative ions creates depolarization, and vice versa for hyperpolarization. The time course of the synaptic potential differs with the synaptic current. As the ionic current depends on the change of synaptic conductance for each ion and membrane capacitor, the potential generation shows a delay in some extent from the current. The electrical property of the synaptic membrane of postsynaptic neurons can be described using resister (or conductance) for each ion channel and membrane capacitor (Fig. 3-5). In the constant state (dVm/dt=0), the magnitude of postsynaptic potential (Vm) is known to be expressed in such a general fashion as Vm =

gsynEsyn+grestErest gsyn+grest

where gsyn and Esyn are respectively the total conductance of corresponding ion channels (in usual, gsyn=gNa+gK+gCa+gCl) and the equilibrium potential built up totally by concentration gradients of ions involving the synaptic potential generation and described as Esyn=(gNaENa+gKEK+gCaECa+gClECl)/gsyn. That is, electrical events at the postsynaptic

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membrane are considered to be interpreted using an equivalent circuit composed of two parts in parallel, each of which is composed of a resister with a battery in series: one totally represents ion channels for the resting potential, and the other, ion channels involving the synaptic potential.

* Excitatory Postsynaptic Potential (EPSP) The mechanism of EPSP generation was vigorously studied with the neuromuscular junction of skeletal muscles. When a presynaptic nerve is stimulated, an action potential travels along to the axon to the presynaptic terminal, inducing the release of ACh. This in turn acts on the receptor molecules in the postsynaptic membrane to depolarize the muscle fiber. It has been established that the combination of ACh with receptor molecules on the postsynaptic membrane causes a simultaneous increase in both Na+ and K+ permeability, where the increase in permeability would tend to drive the voltage toward a level between an equilibrium potential for K+ and that for Na+. The whole equilibrium potential of the synapse is called a (synaptic) reversal potential, which can be detected by setting the membrane potential to different levels; for neuromuscular synapses (also for excitatory synapses of almost neurons) this is known to be near zero (Fig. 3-6 B(1)). This depolarization at the synapses of skeletal muscle fiber is termed an endplate potential (EPP) (Fig. 3-6 A(b)(c)), whose amplitude is ordinarily many tens of mV: an example of the calculation is shown in Fig. 3-5 =EPP=. This is sufficient to elicit an action potential and subsequent contraction of the muscle. However, small depolarizations can be observed spontaneously even in the absence of impulse discharge of the motor neurons (Fig. 3-6 A(a)). Known as miniature endplate potentials (MEPPs), they are thought to be due to the random release of a small amount of ACh from the presynaptic terminals. The amplitude of MEPPs shows variation in digital fashion, which is considered to be due to a quantum release of ACh molecules: a single quantum of AChs is considered to correspond to the amount encapsulated in one synaptic vesicle (or a group of synaptic vesicles), and EPPs are considered to be a summation of multiple MEPPs. EPSP at the CNS appears to be generated by a mechanism similar to that found at the neuromuscular junction of skeletal muscles, excepting that ACh is not major neurotransmitter, the amplitude of EPSPs is smaller (Fig. 3-5 =EPSP=), and the flow of Ca2+ participates in producing EPSP in many cases. The smaller amplitude comes from the smaller area of each synapse for EPSP, which means there is high resistance (lower conductance) and little current at the ion channels of the postsynaptic membrane. The depolarization of EPSP is similar to that of an action potential, but the properties are different for the following three points: (1) channels for Na+ and K+ are opened by the binding of a transmitter (ligand-gated type), whereas those for action potentials are opened depending on voltage (voltage-gated type); (2) Na+ and K+ currents are simultaneous, whereas those for action potential are sequential; and (3) the potential magnitude is graded, whereas action potentials generate critically, in all-or-none fashion, at the threshold voltage.

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Figure 3-5. Postsynaptic membrane as electrical circuit, and generation of EPP, EPSP, and IPSP. Potential difference across the membrane (Vm) is represented as a weighted summation of two types of potentials: one is produced by a battery (mainly for K+ ion) in a resting state (Erest) and the other is produced by parallel batteries for ions involving a synaptic event (Esyn) such as Na+, K+, Ca2+, and Cl-. Esyn is also represented as a weighted summation of equilibrium potentials for each ion involved. (Esyn is called the reversal potential as fixation of the membrane potential at the voltage cancels the ionic flow across membrane.) The membrane potential is measured as the amount of charges of membrane capacitance (Cm). Potential change by transmitter binding at the receptor (Vsyn) is calculated by subtracting the resting potential from the membrane potential generated, which is, for example, +66.7 mV for EPS, +5.9 mV for EPSP, -1.7 mV for IPSP. (Adapted from Kandel, Schwartz and Jessell 2000.)

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Figure 3-6. A: Intracellular recording of synaptic potentials from the end-plate (EPP) of skeletal muscle fiber. Small fluctuations of membrane potential (less than 1 mV in size), miniature EPP, are recorded spontaneously in the resting state (a). Stimulation of motor nerve produces a large EPP in the muscle fiber that in an ordinal state surpasses threshold and triggers an action potential (b). The EPP is possible to be isolated from the action potential in the presence of curare that blocks the binding of ACh to its receptor, reducing the amplitude of the EPP below threshold (c). B: Illustration of intracellular recordings of synaptic potentials from a nerve cell in response to stimuli of different types of presynaptic nerve fibers, nerve(1)nerve(4). ("+ "means excitatory synapse, and "-", inhibitory synapse). (1): Stimulation of the presynaptic nerve-(1) (or nerve-(3)) generates EPSP that reverses when the membrane potential is set above the reversal potential. (2): Stimulation of the presynaptic nerve-(2) generates IPSP that reverses when the membrane potential is set below the reversal potential. The EPSP (IPSP) can not be detected when the membrane potential is set just at the reversal potential. (The EPSP and IPSP are drawn exaggerated to make their features more obvious.) The series of the lowest five graphs shows integrations between the two appropriate synaptic potentials, except for graph-(4), which illustrates that presynaptic inhibition results in no potential change in the recording nerve cell.

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Na+ channels for EPSP are apparently different from those for the action potential: activation of the Na+ channels related to EPSP is not prevented by such blockers as tetrodotoxin (TTX), which strongly suppress the opening of Na+ channels involved in the action potential. There is a simple and basic question about whether the Na+ and K+ ions flow via the same channel or different channels. It is commonly understood that channels in the postsynaptic membrane for EPSP can be permeated by both of Na+ and K+ ions, in contrast with ion channels for action potentials, in which Na+ and K+ are considered to flow through different channels.

* Inhibitory Postsynaptic Potential (IPSP) The process of IPSP generation is similar in principle to that of EPSP generation, except that it achieves the inhibitory effect by means of ion channels which are opened by different neurotransmitters and which allow different ions to pass. IPSPs have been investigated using skeletal muscles of crustaceans and spinal motoneurons of cats, where γ-aminobutylic acid (GABA) (or glycine) is identified as the corresponding transmitter. The binding of the transmitter to the receptors induces an increase in the membrane permeability to Cl- ions or (/and) K+ ions. In most nerve cells, the equilibrium potential for Cl- and K+ is more negative (around -70 mV) than the resting potential (around -65 mV), so the release of the transmitter from the presynaptic terminals leads to hyperpolarization (Fig. 3-5 =IPSP=; Fig. 3-6 B(2)), which acts to suppress the generation of an action potential for the postsynaptic neuron. The relationship between the membrane potential and the driving force for a given ion governs the strength of the current flow through the channel and its direction. The equilibrium potential for Cl- is close to the resting potential revel. It is notice that if the IPSP is built up mainly by the Cl- influx and the resting potential is equal to the equilibrium potential for Cl-, the change in synaptic potential for IPSP is not detectable, and if the resting potential is more negative than the equiliblium potential for Cl-, bindings of inhibitory neurotransmitters, in turn, generate depolarizing potentials (Fig. 3-6 B(2)). (This phenomenon of the reverse of direction of the potential deflection is also observed in EPSP, and in the reversal potential frequently used to gain insight into the types of ion channels involved in a synapse.)

* Presynaptic Inhibition Another type of inhibitory mechanism is typically seen in the spinal motor neurons of mammals and in the neuromuscular junctions of crustaceans. In this type, inhibitory nerves form synapses to the terminal (presynaptic) region of the excitatory nerve (Fig. 3-3, 3-6 B). An impulse reaching the terminal of the inhibitory nerve decreases the potential of impulse in the excitatory neuron, reducing Ca2+ entry for the excitatory impulse and the output of transmitter linking (Fig. 3-6 B(1)+(4)). The inhibitory mechanism is considered to be similar to that of ordinal postsynaptic inhibition: the transmitter released from the presynaptic inhibitory axon is estimated to be GABA (or glycine), which induces hyperpolarizing in the

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terminal of the excitatory axon by reducing permeability of K+ or Cl-. This type of inhibition might be common to many animals, including humans, and it plays a role in selective control of the behavior of individual branches of axon. [A Different Angle 3-3] Problems in synaptic integration: Different from muscle fibers, most neurons in the CNS seem to do much computing of information. Most actual potentials of EPSPs and IPSPs of the CNS are very small, on the order of a few mV, which are likely to relate to the computing among synaptic information. Synaptic contacts of a cell differ with neurons; they are estimated to receive on the order of 100-1,000 synaptic inputs from other neurons. The IPSPs and EPSPs are summated spatially and temporally before being transformed into an impulse, so it is generally understood that the small amplitude of each synaptic potential suits the fine computation of many inputs. Synaptic potentials spread electrotonically, and they are, in principal, linearly summated at, for example, the cell body. However, EPSP does not spread fully to the cell body if IPSP synapses that are active are situated on their way to the cell body. In the case, the magnitude at the cell body does not become a simple summation between the two electrotonical potentials, even if the IPSP is not detectable, as the inside local current of the positive charge influxed at the EPSP synapse flows outward across the membrane at the IPSP synapses to bring the membrane potential to the equilibrium potential for Cl- or K+. This is referred to as shunting inhibition. (So, the essential inhibitory action of IPSP synapse seems not to produce a hyperpolarization of the membrane, but rather an increase in ionic conductance which drives the membrane potential toward the equilibrium potential for Cl- or K+.) There is another problem in integration of synaptic potentials. Does a potential generated far from a site initiating the action potential maintain an appropriate level contributing to the action potential generation? Amplitude of synaptic potential decreases exponentially according to the length constant (λ) (Vm=Voexp(-x/λ): Vo is the original potential and Vm is the potential at distance-x from the synaptic site). In ordinal dendrites, the value of λ is estimated to be less than 1mm; for instance, at a point of distance λ from the original site, the potential becomes 1/e (37%). There are many neurons in the CNS, the dendrite lengths of which are more than 10 mm, where the synaptic potentials generated at their distal regions far from the impulseinitiating site would have less weight as synaptic information. In general, the property of dendrites has been considered to be passive. However, dendrites of some neurons, such as motor neurons in the spinal cord, pyramidal cells in cerebral cortex, and Purkinje neurons in the cerebellar cortex, were reported to be able to generate action potentials (dendritic spikes), making the post synaptic event able to be propagated to the cell body without loss of the information. There would be more neurons in the CNS, dendrites of which have the property of generating more impulses than we expected. Variable combinations of synaptic effects among standard EPSP and IPSP and presynaptic IPSP are imagined (series of lowest graphs in Fig. 3-6 B). In the synaptic integration, the role of presynaptic inhibition is relatively understandable. The essential point of the presynaptic inhibition is its contacting site--not the dendrite nor the cell body, but the axonal terminal of an excitatory neuron. It is apparently useful to eliminate selectively some of the inputs without affecting others in a neuron converging from different axonal inputs. This selective depression

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cannot be done through the postsynaptic mechanism that affects the entire cell. Another type of axon-axon synapse that enhances the entry of Ca2+ into presynaptic terminals (presynaptic facilitation) is also known. Different from the dendritic synapses, the synapses on an axon might exert a strong affection on information processing with a small number of synapses.

(2) Neurotransmitters and Their Property It is chemical signaling that mediates much of the intercellular communication among nerve cells within the central nervous system. A number of chemical substances are present in high concentrations in neurons of the CNS, and several of them have been presented unequivocally to act as transmitters at chemical synapses. It is, in actuality, difficult to identify a substance as having real function as neurotransmitter. Stated in an extreme form, almost any chemical in this world can exert an effect of some sort on the physiological properties of a neuron. In particular, it has become evident that many chemicals known as hormones produce transmitter-like effects on target neurons, and those known as neurotransmitters act as hormones. It must be kept in mind that the classical distinction between neurotransmitters and hormones is becoming obsolete. There is another problem for neurotransmitter release. It was believed until relatively recently that a given neuron produced only a single type of neurotransmitter (Dale’s principle). While this is considered to be correct in most adult neurons, even at the present time when chemicals accepted as neurotransmitters have increased greatly, there is also now evidence that many types of neurons contain and release two or more different neurotransmitters, where each class of transmitter tends to be packaged in a separate population of synaptic vesicles. Are the transmitters contained together in presynaptic terminals released simultaneously? One idea is that difference in the frequency of action potentials or pattern of the train may relate to the selection of a specific transmitter.

* Property of Each Neurotransmitter At first, the list of neurotransmitters included such chemicals as epinephrine, norepinephrine, dopamine, and serotonin, in addition to ACh. In recent years, one of the most important findings concerning synaptic transmitters has been the recognition of widespread distribution of so called “neuroactive peptides (neuropeptides)”in the CNS, mostly of the brain. Many, however, were formerly identified as substances having hormonal properties in other tissues and organs. Chemical substances including neuropeptides suspected as neurotransmitters now number over 100. They are classified variously according to such criteria as functional effects on postsynapses, chemical properties, molecule size, and time span of their actions on postsynaptic function. Still, it is difficult to explain systematically the relationship between chemical structure and synaptic functions. The simplest categorization may be as neuropeptides and others (amins and amino acids), most of which are small molecules that are well-known from the past. Followings are some prominent

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neurotransmitters and their notable biochemical and physiological characteristics. (The term "chemical transmitter” might be more accurate than “neurotransmitter”, as the effect of hormones on target cells functions like neurotransmitters, whereas the term “neurotransmitter“ is used here to simplify the explanation of the synaptic mechanism.) -Acetylcholine (Ach)Apart from the classification, it seems proper to first describe the action of acetylcholine (ACh) as a neurotransmitter. ACh was first discovered as a“vagus substance”by Otto Loewi early in the nineteen century. The solution in which the heart of a frog was bathed and its vagus nerve was electrically stimulated also had the effect of slowing the heartbeat of another frog. ACh is now known to be the neurotransmitter of neuromuscular junctions, at synapses of the autonomic nervous system, and at a variety of sites within the CNS. ACh is synthesized in nerve terminals from the co-substrates, acetyl coenzyme A (acetyl-CoA), and choline in a reaction catalyzed by choline acetyltransferase (Fig 3-7). Acetyle-CoA (which is synthesized from glucose) and choline are common metabolites present in all cells, but choline acetyltransferase is not. In most case, the ACh is packaged in synaptic vesicles and is released following the arrival of an action potential at the nerve terminal. The ACh is decomposed by a hydrolytic enzyme, acetylcholinesterase, which produces acetate and choline (Fig. 3-7). This enzyme is clustered at high concentration in the synaptic cleft, and it ensures the brief action of ACh. The choline is taken up again into the presynaptic terminal through a Na+-dependent choline uptake system and utilized for resynthesis into ACh. It is known that synapses that use ACh as a transmitter can be divided into two main classes, depending on whether the combination of the receptor with ACh is blocked by the application of a chemical, either nicotine or muscarine. The two classes are called nicotinic (nACh) synapse and muscarinic (mACh) synapse, and the corresponding receptors are called nicotinic (nACh) receptor and muscarinic (mACh) receptor. Nicotine can act as an agonist at the receptors of neuromuscular junctions in skeletal muscle, and the nicotinic receptors can be blocked by an antagonist, such as hexamethonium and curare (a plant alkaloid). Muscarinic synapses are characteristically found where the synaptic actions are slower because the receptor molecule is not directly coupled to ion channels (but affected through what are known as second messenger systems). Examples of the muscarinic synapses are those of motor neurons to autonomic ganglia, glands, cardiac muscle and smooth muscle. It is well established that the muscarinic receptors are blocked, typically by atropine but not by curare. ACh is also known to be highly concentrated in certain brain neurons, such as in the basal ganglia and Betz cells of the motor cortex, the synapses of which are thought to be of the muscarinic type. Although the action of ACh in the brain is not as well understood as the cholinergic transmission at the neuromuscular junction and ganglionic synapses of the autonomic nervous system, the locations strongly imply that ACh as a neurotransmitter is closely related to motor systems.

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Figure 3-7. Synthesis and inactivation of small molecule transmitters, acetylcholine (ACh), glutamate, γaminobutyric acid (GABA), 5-hydroxytryptamine (serotonin, 5-HT), and histamine.

-Amine TransmittersNeurotransmitters synthesized from amino acids as precursors are named amine transmitters. (ACh is also a sort of amine transmitter.) Dihydroxyphenylethylanine (dopamine), norepinephrine (noradrenaline), and epinephrine (adrenaline) are synthesized in a common pathway that starts from the precursor tyrosine, one of basic amino acids, and consists of several enzymatic steps. The biosynthetic pathway for them takes a course such as tyrosine, dihydroxyphenylalanine (DOPA), dopamine, norepinephrine, and epinephrine. They share the cathechol moiety that composes a benzene combining two OHbases (Fig. 3-8). The latter three neurotransmitters are traditionally called catecholamines.

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The major dopamine-containing area of the brain is the substantia nigra, where most of the cells are believed to project to the corpus striatum, which plays an important role in basic movements of the body. It is well known that the dopaminergic neurons of the substantia nigra degenerate in patients with Parkinson’s disease. The ventral tegmental area of the midbrain, hypothalamus, and some sympathetic ganglia also contain dopamine. Dopaminergic synapses have been also of interest for their relation to psychotic illnesses such as schizophrenia. It is known that dopamine agonists such as amphetamines can induce schizophrenia-like behavior, and that drugs alleviating the symptoms have a common effect of interfering with transmission at dopaminergic synapses in the brain. Norepinephrine is famous as a transmitter in the post-ganglionic neurons of the sympathetic nervous system (visceral motor system). Norepinephrine is also found in neurons of the pons and medulla, and is especially prominent in nerve cell bodies of the locus ceruleus, a collection of pigmented cells located near the floor of the 4th ventricle, which project diffusely to a variety of forebrain areas and is considered to relate to REM (rapid eye movement) sleep. Noradrenergic neurons exist also in the medullary reticular formation, which possibly play a role in maintaining attention. The catecholamines are packed into vesicles at the presynaptic terminal, the release of which occurs by exocytosis following the entry of Ca2+ ions into the nerve terminals, presumably via voltage-dependent Ca2+ channels, as is the case for cholinergic neurons. The size of catecholamine vesicles is larger than that of ACh, and their released space is not as restricted as that of ACh. The actions of catecholamines on the receptors are slower than those of ACh, because the receptor molecule is coupled to ion channels and intermediated by the so-called second messenger system (described in the last section of this chapter). There is no extracellular enzyme decomposing catecholamines, which is different from the case of Ach. Instead, catecholamines are removed from the synaptic space by reuptake into the presynaptic cell or surrounding glial cells by a Na+-dependent transporter. Then, they are catabolized by monoamine oxidase (MAO) and catechol O-methyltransferase (COMT) in the presynaptic terminal (Fig. 3-8). Serotonin (5-HT) and histamine are also classified according to the amine transmitters: the former is synthesized from the amino acid triptophan, and the latter, from the amino acid histidine (Fig. 3-7), both of which are taken up from the blood. Serotonin is found especially in the raphe nuclei of the pons and upper brain stem. It is stored in the synaptic vesicles and released by a mechanism similar to the mechanisms for ACh and catecholamines. The serotonin receptors (5HT-1) are linked to the G-protein and cAMP second messenger systems, which are believed to regulate K+ and Ca2+ channels. Serotonergic neurons in the raphe nuclei innervate virtually all parts of the CNS, and their firing rates seem to play a role in modulating the general activity levels of the CNS. The psychological effect of serotonin has been investigated, as its molecular structure resembles that of the famous hallucinogenic drug, lysergic acid diethylamide (LSD). LSD hallucinations are considered to be due to antagonistic blocking of serotonin receptors in the CNS.

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Figure 3-8. Synthesis and inactivation of catecholamines, DOPA, Dopamine, norepinephrine, and epinephrine, and amino acid sequences of major neuropeptides. Abbreviations of three letters in the neuropeptides indicate different amino acids. COMT: catechol O-methyltransferase, MAO: monoamine oxidase, TRH: Thyrotropin releasing hormone, LHRH: Luteinizing-hormone releasing hormone. (Amino acid sequences are from Iversen 1979.)

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Histamine is found primarily in mast cells, which release it as part of their reaction to allergens, and the receptors are found mostly in the hypothalamus. Histaminergic neurons in the hypothalamus send projections widely to the brain and spinal cord. As stimulation of the posterior hypothalamus in sleeping animals causes awakening, histamine is thought to be involved in maintaining wakeful. High concentrations of histamine are also found in neuron cell bodies in the (neo)cortex and hippocampus, where its action lead to changes in neural metabolism, possibly mediated by the second messenger system using cAMP. In common, amine neurotransmitters are closely involved in brainstem function, especially regulation of the level of consciousness including sleep-wake cycles. -Amino Acid TransmittersThere are amino acids that act as neurotransmitters in the brain. Glutamate (glutamic acid), and γ -amino butyric acid (GABA) are generally acknowledged to be potent transmitters for brain functions. It is estimated that most of the excitatory neurons in the brain are glutamatergic. Glutamate has been known to act as an excitatory neurotransmitter at insect and crustacean neuromuscular junctions, and it has become evident as the major excitatory neurotransmitter in mammalian brains. Glutamate is synthesized from glutamine ( α-Ketoglutamate) (Fig 3-7), which is stored in the vesicles at the terminal and released in a Ca2+-dependent manner. Three distinct types of glutamate receptors are known--kainate receptors, AMPA receptors, and NMDA receptors. These are named after the strong agonists that activate them: kainic acid (and quisqualic acid), α-amino-3-hydroxyl-5-methyl4-isoxazole-propionate (AMPA), and N-methyl-D-aspartate (NMDA). Like nACh receptors, glutamate acts on the receptors to permit Na+, K+, and also Ca2+ to flow through the channels to depolarize the membrane close to 0 mV. (However, it is worth mentioning that application of glutamate commonly induces a depolarizing effect on most other neurons in the CNS, and excess or prolonged exposure of glutamate can injure neurons, as excess Ca2+ entry is thought to become toxic.) GABA was first established as an inhibitory neurotransmitter at invertebrate synapses in crustacean muscle. Now, GABA is known to be the major inhibitory neurotransmitter in the vertebrate and invertebrate CNS. In mammals, GABA is present and condensed in neurons in the basal ganglia, Purkinje cells of the cerebellum, and interneurons in the spinal cord. It is synthesized from glutamic acid via a reaction catalyzed by the enzyme glutamic acid decarboxylase (Fig. 3-7). Through the binding of GABA to the receptors, membrane proteins, cause the postsynaptic membrane potential to become relatively hyperpolarized. There are two categories of GABA receptors: BAGA-A receptors, which are linked directly to the Clchannel; and GABA-B receptors, which are linked to K+ channels (and maybe Ca2+ channels) via the G-protein-cAMP cascade. The GABA-A receptor has high affinity sites for chemicals such as bicucylline, picrotoxine (or strichinine), barbiturates, and benzodiazepines, which are frequently used therapeutically in mental and psychological disorders. Glial cells surrounding the synaptic sites are thought to participate in the uptake and resynthesis of GABA.

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In addition to glutamate and GABA, asparate is a possible neurotransmitter at some excitatory CNS synapses, and glycine a neurotransmitter at some inhibitory CNS synapses. The distributions of GABA and glycine receptors tend to overlap, suggesting that glycine may also have a role in modulating responsiveness at GABAnergic synapses.

-NeuropetidesA lot of short peptides, perhaps as many as one hundred, are localized in neurons of the brain, causing inhibition, excitation, or both. Many of them were previously identified as hormones or as neurosecretions. They include various hypothalamic hormones, such as oxytocin, vasopressin, somatostatin (hypothalamic hormone-inhibiting factor), and many hormone-releasing factors; peptides (hormones) of the pituitary gland, such as adrenocorticotropine (ACTH) and melanocyte-stimulating hormone (MSH); and peptides contained in smooth muscle and nerves of gut, such as substance-P, cholecystokinin (CCK), neurotensin, and enkephaline (Fig. 3-8). In comparison with the transmitter chemicals described above, the synthesis of neuropeptides is more complicated. Certain neuropeptides are involved in the perception of pain, pleasure, feeling, and emotion. In particular, opium and its derivatives have received attention for their usefulness in clinical medicine, such as in pain control. Opiate receptors are found in abundance in the periaquaductal gray, raphe nucleus of the pons, and superficial laminae of the posterior horn of the spinal cord, all of which are considered to be deeply involved in pain sensations. Indeed, the CNS contains endogenous ligands that bind to and activate the opiate receptors. They include, for example, leucine- and methionine- enkephalines, α-and β- endorphins, and dynorphin, compounds of which are multipeptides of similar structure (Fig. 3-8). They have two strong functions -- analgesic and hallucinatory. (In the ligands,β-endorphin has the strongest physiological effects, and receptors for enkephalins are widely distributed in the brain.) Almost all neuropeptides are considered to mediate their effects by activating G-protein coupled receptors described in following section. The localization of neuropeptides in the brain has been identified using mainly immunological methods, but the accurate process from transmitter binding to synaptic potential generation has not been fully advanced for many neuropeptides for various reasons, including the difficulty in locating recording electrodes to the corresponding region, the large number of neuropeptides, and scanty knowledge of their specific agonists and antagonists. [A Different Angle 3-4] Consideration of the diversity of neurotransmitters: Even though there are two critical transmitters acting at human peripheral nerves, Ach and noradrenaline, a lot of chemicals have been determined to be neurotransmitters in the brain. Are all of them which are found in brain neurons really neurotranmitters? It is commonly understood that a substance must fit the following criteria to be accepted as a neurotransmitter: 1) it is synthesized in the neuron and present in the presynaptic processes; 2) it is released in amounts sufficient to exert an influence on the affected neuron or effector organ in response to physiological stimulation such as

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presynaptic depolarization; 3) specific receptors for the chemical must be present on the membrane of the postsynaptic cell; and 4) a specific mechanism must exist for removing it from its site of action within an appropriate time. It is often difficult to demonstrate all of these standards at a given synapse especially in the brain, so it might be better to think that putative transmitters are mixed in the chemicals listed as brain neurotranmitters. The next question that all neuroscientists hope to answer is, "Is there any systematical relation between chemical properties of the neurotransmitters and their functions in the nervous system?" Roughly speaking, small molecule transmitters, such as ACh, catecholamines, and amino acids, tend to function in the peripheral nervous system like visceral organs, tissues such as muscles and glands, and sensory receptor cells, whereas medium molecule transmitters like serotonin and histamine mediate functions of lower levels of the CNS. In contrast. large molecule transmitters, or neuropeptides, mediate higher functions of the brain. More systematic interpretation on the function of neurotransmitters is difficult given our present knowledge. Here, it seems proper to include properties of major neurotransmitters as tables based on multiple aspects (from Table 3-1 to Table 3-4), as common in other publications.

Table 3-1. Major transmitters Amines -------------

Acetylcholine (Ach), Catecholamines (Dopamine, Norepinephrine, Epinephrine), Serotonin (5-HT), Histamine Glutamate, Asparate, γ-amino butyric acid (GABA), Glycine Pituitary peptides (Adenocorticotropic hormone, Growth hormone, Melatonin, Luteinizing hormone, Oxytocin, Prolactine, Vasopressin) Hypothalamic releasing peptides (Growth hormone-releasing hormone, Luteinizing hormone-releasing hormone (LHRH), Somatostatin, Thyrotropine-releasing hormone (TRH)) Gastrointestinal peptides (Bombesin, Cholecystokinin (CCK), Gastrin, Motilin, Neurotensin, Methionine- & Leucine- enkephaline, Secretine, Substance-P) Others (α- & β-endorphin, Angiotensin-II, Bradykinin, Galanin)

Amino acids ------Neuropeptides -----

(Adapted from Kandel, Schwartz and Jessell 2000.)

Table 3-2. Functional features of major neurotransmitters Transmitter ACh Catecholamines Glutamate GABA Glycine 5-HT Histamine Neuropeptide

Effect Excitatory Excitatory Excitatory Inhibitory Inhibitory Excitatory Excitatory Both

(From multiple sources.)

Precursor Choline+acetylCoA Tyrosine Glutamine Glutamate Serine Tryptophan Histidine Amino acids

Remove Ach-esterase MAO, COMT Re-uptake Re-uptake Re-uptake MAO Re-uptake Proteases

Vesicle Small, Clear Medium, Dense Small, Clear Small, Clear Small, Clear Large, Dense Large, Dense Large, Dense

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Table 3-3. Receptor classes and pharmacological effects of major neurotransmitters Transmitter Acetylcholine Norepinephrine Glutamate Serotonin GABA Glycine

Receptor class nicotinic muscarinic α(α1-α2) β(β1-β3) AMPA NMDA 5HT1-5HT4 GABA-A GABA-B Glycine

Agonist (Antagonist) nicotine (curare, hexamethonium,α-bungarotoxin) muscarine (atropin, scopolamine) phenylephrine (phenoxybenzamine) isoproterenol (propranolol) AMPA, D-serine (CNQX, Mg2+ outside) NMDA, glycine (AP5, Mg2+ outside) (identified by clonning) muscimol, barbiturates (bicuculline, picrotoxin) baclofen (phaclofen) ******** (strychinine)

Abbreviations: AMPA, α -amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid; CNQX, 6-cyano-7nitroquinoxaline-2,3-dione; NMDA, N-methyl-D-aspartate; AP5, D-2-amino-5-phosphonovalerate (From Hille 2001, and other multiple sources.)

Table 3-4. Localization of major neurotransmitters Cholinergic ----------

Glutamic -------------

GABAnergic -------Noradrenergic -----Dopaminergic ------Serotonergic -------Histaminergic ------Opiatereceptors -----

(Modified from Nolte 1999.)

Spinal cord motor neurons (nicotinic), Autonomic preganglionic neurons (nicotinic, muscarinic), Parasympathetic postganglionic neurons (muscarinic), Reticular formation (muscarinic), Basal ganglia (muscarinic) Commonly exist in the CNS, Pyramidal cells of cerebral cortex, Primary sensory neurons (labyrinth hair cells, olfactory cells, photoreceptor cells) Basal ganglia, Purkinje cells of cerebellar cortex, Commonly exist in the CNS Sympathetic postsynaptic neurons, Locus ceruleus of the pons, Reticular formation of the brainstem Substantia nigra, ventral tegmental area, Hypothalamus, Amacrine cells of the retina Raphe nuclei of the brainstem, Limbic system Hypothalamus, (neo)cortex, hippocampus Laminae I&II of the Spinal cord, Substantia gelatinosa of trigeminal spinal tract, Solitary nucleus, Locus cerleus, Pretectal area, Parabrachial nucleus, Infundibulum, thalamus, Amygdala, Basal ganglia

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What does the abundance of different neuropeptides in the brain mean?: Since we can elicit appropriate actions in response to surrounding stimuli within a second, we all have the impression that our nervous system works very rapidly. Actually, an action potential propagates on the nerve fiber very fast, at speeds that can exceed 100 m/sec. Investigations into synaptic mechanisms started with the study of how skeletal muscles contract after receiving nerve impulses, and it was revealed the neuromuscular junction also achieves the transmission within a few milliseconds. Until fairly recently, the fast and restricted transmission between nerve and muscle was thought to be principally applicable on the brain nervous system. One of the surprising discoveries concerning the brain nervous system is, in addition to traditional neurotransmitters, the wide and abundant distribution of a variety of neuroactive peptides, many of which were identified in other organs and known to work regulatively on their physiological functions in a hormonal fashion. In actuality, many chemicals known as hormones were included among the neuropeptides discovered. Most neuropeptides are understood to exert their effects through the second messenger system intermediated by so called G-proteins, which is principally the same as the effecting process of hormones, of peptide types, in the cytoplasm of target cells. In contrast to the neuromuscular junction using nACh, the actions of neuropeptides take, in most cases, a fairly long time, the range of which could be from a few second to many days, as the sequence is constructed of many steps of enzymatic reactions. It is certain that the brain nervous system is able to process information with high speed. However, actual human behavior involves a wide range of time courses for action. We can move our hands and our feet very quickly, in the millisecond range. On the other hand, when we observe something while standing, the appropriate muscles must remain contracted to maintain our posture. It seems to be an ordinal interpretation that the slow time course of postsynaptic potentials for most neuropeptides would be involved in types of slow movements. Another view, however, may be possible. The basic function of hormones is the regulation of organs and tissues to maintain them in the best physiological condition. When we perform any action, the best condition of related organs or tissues must be prepared beforehand according to the aim of the action. The autonomic nervous system plays this role, where (nor)epinephrine and ACh act on the organs like hormones. Different from a hormonal effect mediated via blood circulation, the autonomic nervous exerts its effect more rapidly and prescriptively using the nervous system. In the brain nervous system, the state of neurons also seems to be continuously adjusted with changes in the internal conditions and the external surroundings. Many of the brain neuropeptides would be involved in adjusting the physiological state of neurons rather than participating in actual signal processing. It can be said that the brain is, as a whole, a great hormonal gland. When we drive a car, the adequate neurons of our brain must be kept in high tension to be able to respond quickly, depended on varying situations. Likewise, when we play football, corresponded regions in our brain must remain active for us to perform our best, and when we enter a dark room, certain neurons must increase their tension so prevent our taking a false step. When we enjoy music, unconcerned neurons must be silent. In awaking (and maybe even while sleeping) all neurons of our brain must be continuously adjusted and suitable to perform appropriate behaviors depending on our internal and external surroundings. The brain can be likened to a sort of biological computer processing signals with high speed, but the excellent function is achieved only when the

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corresponding neurons are regulated to their best states, which might be a major reason why the brain contains so many varieties of neuropeptides. Such a phylogenetical consideration makes possible the notion that part of the hormone system evolved and became specialized as the nervous system, where the bloodstream was substituted for the nerve fiber to carry the information faster and in a more restricted fashion. The fact is suggestive that information in the nervous system is carried electrically by action potentials, but they are made up substantially using ions in blood fluid. The hormonal aspect of the nervous system is well observed in the autonomic nervous system and neurosection of the hypothalamus neurons. Furthermore, a view may be also possible that the synaptic process, where information is carried by diffusion of neurotransmitters, would be a residue of the hormonal system. After all, the brain can be considered to be a complex of two hierarchical systems: the advanced nervous system that can process information with high speed, and the old hormonal system that supports the function as its base. Actually, it is known that most neurons of the brain contain simultaneously both neurotransmitters that were well defined and neuropeptides that work like hormones. Brain neurons need to be regulated differentially from visceral organs. For typical example, the heart and lungs must work even during sleep, and appropriate regions of the brain must remain in an active state even when the visceral organs relax. To make the brain function orderly, hormonal circumstance within the brain must be separated from that for visceral organs, which must be a main reason why the fluid of the brain neurons is protected chemically from the blood stream of the body by the blood-brain barrier system.

(3) Structures of Synaptic Receptors A transmitter molecule released from the presynaptic terminal diffuses to and binds with a specific site, a neurotransmitter receptor, on the postsynaptic membrane. The receptor gives rise to excitatory or inhibitory potentials by opening (or closing) specific ion channels in the postsynaptic membrane. The receptors, molecules of specific proteins, are classified into two types. One is called ionotropic receptors. These receptors are linked directly to ion channels as a single molecular entity, so they are also called ligand-gated ion channels. Postsynaptic electrical events of this type are very quick, and they are observed typically in EPP at neuromuscular junctions and fast EPSPs and fast IPSPs at various postsyapses. The other type is called metabotropic receptors. This type of receptor does not include ion channels as part of its structure, but links with an intermediate molecule, called a G-protein (guanine nucleotide (GTP)-binding proteins), the activation of which is carried out by binding neurotransmitters interacting with ion channels through metabolic steps. Accordingly, the postsynaptic electrical event for this type is relatively slow.

* Voltage-Gated Ion Channels Before discussing the neurotransmitter receptors, it is useful to study structures of ion (Na , K+, and Ca2+) channels making up action potentials. Although evidence suggests that the channels responsible for action potentials are also able to sense neurotransmitters, they +

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are believed to be distinct from synaptic channels. The channels for action potentials are sensitive to the electrical potential difference across the membrane, and are therefore referred to as voltage-gated ion channels, whereas the channels involving synaptic events are presumed to be sensitive only to the action of a transmitter substance released from other neurons. Opening or closing of the voltage-gated ion channels depends on the magnitude of the membrane potential, allowing the membrane permeability to be regulated by the potential. Na+ channel: The membrane proteins for voltage-gated Na+ channel were first isolated by solubilizing them with detergents and purifying them on the basis of their ability to bind TTX with high affinity. The molecule for voltage-gated Na+ channel has almost been completely established to be composed typically of 3 subunits, one large glycoprotein (α) that has four domains repeating similarly in the membrane (I, II, III, IV) and 2 smaller subunits of polypeptides (β1, β2). Each of the 4 domains of α-subunit is considered to have 6 alpha-helical-formed regions (named S1-S6) (Fig. 3-9 A), of which S5 and S6 are connected by another hydrophobic region, called P-loop. It is estimated that the 4 domains form centrally the channel pore to pass Na+ ions, the narrow space enclosed with 4 P-loops forms an selective filter, and the S4 region is thought to work as a voltage sensor. Ca2+ channel: The membrane proteins for Ca2+ channels were first purified using dihydropyridine blockers as the specific marker, and successively several voltage-gated Ca2+ channels have been identified. The basic structure of the Ca2+ channels is quite similar to that of Na+ channel. Ca2+ channels are commonly composed of five subunits, named α1, α2, β, γ, and δ. Components of the α1-subunit are almost the same as those of the α-subunit of the Na+ channel: the α 1 subunit is also composed of 4 repeating domains which are considered to form the channel pore, and each domain is composed of 6 hydrophobic transmembrane regions and 1 P-loop. The similarity of amino acid sequences of the α1subunit of Ca2+ channels to those of the α-subunit of Na+ channels suggests that the two receptors have evolved from a common ancestral channel protein. K+ channel: Many different types of voltage-gated K+ channels have been reported, and similarly, the molecular structures of K+ channels show diversity. The basic structure of most of them, however, resembles that for Na+ or Ca2+ channels; principally, they are composed of four subunits. The subunits span the membrane 2-7 times, depending on the types. Four of these K+ channel subunits aggregate together, as tetramers, to form a single functional ion channel, forming centrally a single channel pore, which is identical to that of Na+ and Ca2+ channels. The amino acid sequence of receptor molecules is encoded in DNA within the cell's nucleus. Many different genes have been discovered for each type of voltage-gated ion channel. In mammals, approximately 10 different genes for Na+ channel are estimated to exist, with nearly the same number for Ca2+ channels and over 70 for K+ channels. In each of the channel families, the diversity of genes is expressed in a tree, a dendrogram, on the basis of similarity of their amino acid sequences.

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Figure 3-9. Model of molecular structure of the voltage-dependent sodium channel (A) and ligand-gated ACh receptor (B). In each drawing, the lowest diagram indicates hydrophobicity (upward of the base line) of amino acids in the sequence of the unit molecule; the middle drawing illustrates the topology of ion channels in the membrane, estimated from the amino acid sequence; and the upper drawing is its threedimensional structure estimated from the topology. (Adapted from Schofield et al. 1987, Catterall 2000, and Hille 2001.)

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Would the channel variations for each ion really be identical? : Many different types of voltage-dependent ion channels have been identified for each ion. In particular, the variation of K+ channels (conductances) is tremendous, which many researchers investigating the mechanism of ion channels find bewildering. Such channels include the following: K+ channels, mediating fast and slow delayed rectifiers; KA channels, (for fast transient current (IA)); KD channels, (for delay current (ID)); Ca2+ dependent K+ channels; inward rectifying K+ channels; K+ channels, mediating leak conductance; and K+ channels, for slow delayed rectifiers (IM) linking with mACh receptor. Would all K+ channels reported be really identical? Could the divergence be accounted for as something originating from an uncertain factor, such as the difference in the state of location in the membrane with the channels? For example, if the channels are located at a wall with a hollow-like structure (or in more intricate regions) or if the channels are surrounded tightly by other neurons or glial cells, it is difficult for them to permit passage of the ions (low conductance) or test current even if they have a fully permeable property; also, effects of test chemicals become weak even if they have a high affinity with them. This discussion is possible in various scales of the membrane of postsynaptic neurons, from large to quite restricted levels of the area. It does not seem to reject completely that a considerable extent of the wide variation of voltage-dependent K+ channels would be a reflection of any anatomical factor or experimental uncertainty. This is, however, still just a probability because gene analysis of channel molecules has also revealed the great variation of the K+ channels.

* Ligand-Gated Ion Channels Among the ligand-gated ion channels, nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction in skeletal muscle is best understood. The nAChR elicits excitatory postsynaptic potentials, as they are nonselective cation channels, which give rise to currents with a reversal potential near zero mV. Many toxins, for example α -bungarotoxin, specifically bind to nAChR, which was utilized in purifying nAChR molecule. It is now known that it is composed of a large protein complex consisting of five subunits arranged around a central membrane-spanning pore for ion permeation. They are two same-subunit polypeptides, designated α, and one each of three polypeptides, designated β,γ and δ. In addition, there is one ACh binding site on each of the α-subunits. Also, each subunit polypeptide has 4 separate alpha helical formed regions (M1-M4) (Fig. 3-9 B). (The formation of the subunits of nAChR molecule is similar to but different from the formation of the voltage-dependent Na+ channel, where four domains of one α-subunit molecule compose centrally the ion channel.) Binding of ACh to the α-subunits would cause changes of their conformation of structure and distribution of the charges within the subunits affecting the state of the central pore formed by the pentamer, which is considered to be the base for controlling the flow of cations. The tight association of ACh binding with the molecule presumably accounts for the rapid response of the nACh synapses.

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The primary structures of other ligand-gated ion channels for such neurotransmitters as glutamate (NMDA, AMPA, Kainate), GABA(A), and glycine, have also been confirmed. There are similarities to the nAChR molecule: they are composed of 4-7 subunits with the receptor types; almost all contain 4 hydrophobic alpha helices; and they form a central pore for the flow of ions. A comment which seems be useful is that the basic structures of voltagegated ion channels and ligand-gated ion channels are similar, and their actions are analogous, except that channel gates of the former are controlled by the voltage across the membrane (Fig. 3-10 A), and the latter, by ligand combining on certain sites of the subunits (Fig. 3-10 B).

* Metabotropic Receptors and G-protein System Different from voltage-gated ion channels or ligand-gated ion channels, metabotropic receptors are considered to be monometric proteins composed of seven membrane-spanning domains of amino acid sequences. The proteins contain an extracellular transmitter binding site and an intracellular G-protein binding site (Fig. 3-10 C). Well-known examples include muscarinic ACh receptor (mAChR), GABA-B receptor, metabotropic glutamate receptors, catecholamine receptors, and neuropeptide receptors, as well as odorant receptors in the olfactory system, light receptors in retina cells, and receptors for peptide hormones. Bindings of neurotransmitters activate G-proteins adjacent the inside region of the metabotropic receptor molecules, regulating the opening and closing of postsynaptic ion channels indirectly, and usually inducing slower and long-lasting electrical responses. [A Different Angle 3-7] About three-dimensional models of ion channels: The three-dimensional models of ion channels that have been proposed are very attractive for explaining the mechanism of ion transportation across the plasma membrane, and are accepted by most researchers investigating synaptic mechanisms. There are two distinct approaches to determine amino acid sequences of ion channel proteins. The classical approach takes the following steps: 1) find a tissue containing the receptor protein in high concentration; 2) solubilize and purify it with appropriate detergents; 3) dissociate the subunits with denaturing detergents, such as sodium dodecyl sulfate together with protease inhibitors, and purify the subunits; and 4) determine the sequence of amino acids using amino-acid sequencing techniques. The steps of the other approach are as follows: 1) extract messenger RNA from tissues containing a large amount of the receptor protein, and make their complementary DNA(cDNA) transcripts; 2) insert the cDNA into the plasmid vectors and transfect them into E. coli cells to make a cDNA library; 3) screen a huge amount of bacterial colonies by hybridization to find sequences matching individual probes; 4) guide construction of a new prove using each selected plasmid DNA, and successively determine longer sequences of the original cDNA until an entire coding region appears; and 5) decide the sequence of amino acids from the triplet codons of the completed cDNA.

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Three-dimensional conformations of the amino acid sequences and structures of receptors with them were estimated using such techniques as X-ray analysis or electron micrography adding the chemical property of each amino acid of the sequence, where there are repeating regions composed by hydrophobic amino acids (Fig. 3-9). The three-dimensional structure of receptors estimated from the molecular studies has illustrated that they are large protein complexes commonly consisting of subunits arranged around a central pore that is permeable to ions. Each of the subunits is composed of hydrophobic amino acid sequences spanning the plasma membrane. This channel model, however, has one problem: How could the pores select specific ions and exclude others? One possible answer is that the mobility of ions in solution does not depend simply on their sizes in a crystal state, but rather on those including their water shell surrounding. This resolves how the pore can select K+ and exclude Na+, but the question remains of how it can select Na+ and exclude K+. Another idea is that electrostatic interaction of ions with charged amino acid residues that line the wall of the pore could work as a filter selecting specific ions. This mechanism is probable but has yet to be demonstrated. Another simple question is why the hydrophobic membrane-spanning domains of molecules for metabotropic receptors do not form subunits like voltage-gated ion channels or ligand-gated ion channels. Would something be expedient if metabotropic receptors were composed of subunits arranged circularly? The three-dimensional models of ion channels that are widely accepted have many attractive aspects, but it may be better to keep in mind that they are constructed inherently on the basic concept that something in a particle state should pass along a narrow space like a canal. Would ions in solution be really particles like ball bearings?

Typically, the G-proteins are composed of three units (α,β,γ), and a transmitter binding to a metabotropic receptor causes dissociation of a (α-) subunit, which is then able to move laterally in the postsynaptic membrane and exert various physiological effects. In the simplest case, the G-protein subunit directly influences the state of ion channels, for example making K+ or Ca2+ channels open. However, in most cases the G-protein subunit enhances (or suppresses) the activity of an enzyme that synthesizes (or degrades) so-called intracellular second messengers, triggering the complex biochemical signaling cascade. The well-known enzymes include adenylate cyclase, guanylate cyclase, and phospholipase C, and second messengers induced are Ca2+, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and inositol triphosphatase (IP3) (Fig. 3-10 C). A well-understood second messenger system is the type that uses a cAMP: cAMP is synthesized from ATP by the enzyme adenylate cyclase coupling with G-protein, termed Gs. Binding of a neurotransmitter to a receptor protein causes an allosteric change that activates G-protein linking of the receptor to preferentially bind GTP instead of GDP. Activated Gprotein (α-subunit) then moves to and associates with the adenylate cyclase, synthesizing cAMP from ATP. The second messenger, cAMP, then binds to the regulatory units of cAMPdependent protein kinase, dissociating the catalytic units. The protein kinase mediates many physiological responses of cells including regulation of ion channels of neurons by phosphorelating target proteins. The free catalytic units can catalyze the transfer of terminal phosphate from ATP to serine and threonine residues on the target protein, to produce a phosphoprotein. This system is turned off by the enzymes phosphodiesterase and protein phosphatase. The cAMP system is virtually universal in cells, but it appears to be particularly important in the CNS, as adenylate cyclase activity is very high in the brain.

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Figure 3-10. Illustration of three types of ion channels. A is a voltage-gated ion channel that opens and closes depending on the voltage difference across the membrane; B is a ligand-gated ion channel that is directly regulated by the binding of neurotransmitters to receptor sites of the channel molecule; and C is a metabotropic ion channel that is controlled by an intracellular signal transduction system. (Modified from Hall 1996.)

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Analogue of the second messenger system to the nervous system: The nervous system, typically the somatic nervous system, follows a fixed sequence of information flow: external stimulus, receptor cells, sensory nerves, interneurons, motor neurons, and effectors. The signal flow sequence is similar to that for the G-protein-2nd messenger system. The following correspondence between the somatic nervous system and the G-protein-2nd messenger system is possible: [2nd messenger system] Neurotransmitter receptor molecule G-protein effector protein 2nd messenger target molecule physiological function

[Somatic nervous system] external stimulus receptor cell sensory neuron interneuron motor neuron effector (muscle) potential generation

In other words, the G-protein-2nd messenger system is a nervous system within neurons (and other cells); hence, it is named the intracellular signal transduction system. The signal pathway in the (somatic) nervous system diverges from a simple circuit-like spinal cord reflex to a circuit containing many interneurons. Similarly, different pathways from the transmitter reception which produce physiological effects are known in the G-protein-2nd messenger system. In the nervous system, messages travel successively along with nerve fibers and reach critical target cells or tissues. In the G-protein-2nd messenger system, the cascade of molecules involved has been well studied, but how a given molecule in the cascade moves to an object molecule or to suitable sites within the cytoplasm remains unclear.

References and Suggested Readings Catterall, W.A. (2000). From ionic currents to molecular mechanisms: The structure and function of voltage-gated Ca2+ channels. Annu. Rev. Cell Dev. Biol.,16: 521-555. Claudio, T. (1989). Molecular genetics of acetylcholine receptor-channels. In: Frontiers in Molecular Biology: Molecular Neurobiology (Glover, D.M. and Hames, B.D. (Eds)). pp.63-142, IRL Press, Oxford. Eccles, J.C. (1964). The Physiology of Synapses. Springer Verlag, Berlin. Fatt, P. and Katz, B. (1951). An analysis of the end-plate potential recorded with an intracellular electrode. J. Physiol., 115: 320-370. Hall, Z.W. (1996). Molecular neurobiology. Sinauer Associates Inc. (Japanese edition), Tokyo. Hille, B. (2001). Ion channels of excitable membranes (3rd ed.). Sinauer Associates Inc., Sunderland.

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Hubbard, J.I., Llinas, R. and Quastel, D.M.J. (1969). Electro-physiological Analysis of Synaptic Transmission. Edward Arnold LTD. Iversen, L. (1979). Chemistry of the brain. Sci. Am.,241: 118-129. Kandel, E.R., Schwartz, J.H. and Jessell, T.M. (2000). Principles of neural science (4th ed.). McGraw-Hill, New York. Katz, B. (1966). Nerve, Muscle, and Synapse. MacGraw-Hill, New York. Landis, D.M.L., Hall A.K., Weinstein, L.A. and Reese, T.S. (1988). The organization of cytoplasm at the presynaptic active zone of a central nervous system synapse. Neuron,1: 201-209. Miller, C. (1989). Genetic manipulation of ion channels: A new approach to structure and mechanism. Neuron, 2: 1195-1205. Mishima, M. et al. (1985). Location of functional regions of acetylcholine receptor αsubunit by site-directed mutagenesis. Nature, 313: 364-369. Nicholls, J.G., Martin, A.R. and Wallace, B.G. (1992). From Neuron to Brain (3rd ed.). Sinauer Associates Inc., Sunderland. Noda, M. et al. (1984). Primary structure of Electrophorus electrius sodium channels deduced from cDNA sequence. Nature, 312: 121-127. Nolte, J. (1999). The Human Brain: an introduction to its functional anatomy (4th ed.). Mosby Inc., St. Louis. Schofield, P.R. et al. (1987). Sequence and functional expression of the GABA-A receptor shows a ligand-gated receptor super-family. Nature, 328: 221-227. Schwarz, T.L. et al. (1988). Multiple potassium-channel components are produced by alternative splicing at the Shaker locus in Drosophila. Nature, 331: 137-142. Siegel, G.J., Agranoff, B.W., Albers, R.W., Fisher, S.K. and Uhler, M.D. (1999). Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th ed.). Lippincot-Raven, Philadelphia. Takeuchi, A. and Takeuchi, N. (1960). On the permeability of end-plate membrane during the action of transmitter. J. Physiol., 154: 52-67. Trimble, W.S., Linial, M. and Scheller, R.H. (1991). Cellular and molecular biology of the presynaptic nerve terminal. Annu. Rev. Neurosci., 14: 93-122. Pierce, K.L., Permont, R.T. and Lefkowitz, R.J. (2002). Seven- transmembrane receptors. Nat. Rev. Mol. Cell Biol., 3: 639-650. Rall, W. (1959). Branching dendritic trees and motoneuron membrane resistivity. Exp. Neurol, 1: 491-527. Unwin, N. (1989). The structure of ion channels in membranes of excitable cells. Neuron, 3: 665-676.

Chapter IV

General Organization of the Human CNS The nervous system is composed of two main parts: the peripheral nervous system (PNS) and the central nervous system (CNS). This classification is based simply on location in the body, and almost all nerves of the PNS function intermediated by the CNS. The CNS is generally classified into the spinal cord and the brain, which are protected by bony structures--the vertebral column and the skull, respectively--indicating the importance of the CNS for all vertebrates. From the viewpoints of appearance and function, the brain of adult humans can be generally divided into five main parts: the brain stem, cerebellum, diencephalon, and two cerebral hemispheres. In this chapter, the main elements and functions of the CNS will be overviewed according to this traditional classification.

(1) Spinal Cord The spinal cord occupies the lowest part of the CNS and runs dorsally the length of the body. It is composed of segmental structures of a unitary nervous system. The principle neural system of the segmental units involves the reflex between sensory (input) and motor (output) signals, the mechanism of which is simple but basic to all animals. The nervous organization and function of the spinal cord can be applicable to higher levels of the nervous system.

* Basic Formation of the Spinal Cord The spinal cord is composed of, in cross section, two different appearances as described in chapter 1. The more peripheral region appears white, comprising the so-called white matter, and internal to the white matter lies an H-shaped mass which appears dark, forming the so-called gray matter (Fig. 4-2). The white matter is mainly the region where longitudinal fibers run, and the gray matter is mainly the region where cell bodies of spinal

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Figure 4-1. A: Dorsal view of the right half of the spinal cord and left half of vertebrae, where the origins of the roots of the spinal nerves are roughly shown (left-sided drawing), and left sided view of the spinal cord with cauda equina and spinal nerves (right-sided drawing). C: cervical nerve, T: thoracic nerve, L: lumbar nerve, S: sacral nerve. (Adapted from Nolte, 1999.) B: Approximate dermatomes (cutaneous territories) for trigeminal nerves (V1-V3) and spinal nerves (C, T, L, S, and Co) in the posture stretching four limbs. (C1 normally lacks a dorsal root.) (Adapted from Chusid 1982.)

cord neurons exist. (The same difference in appearance coming from the collection of fibers or cell bodies of neurons is also observed in various portions of the brain, where whitish areas

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are rich in axons, and grayish areas, in cell bodies.) The ratio of white to gray matter increases with the rostral direction of the spinal cord because of the increase of longitudinal running fibers: ascending fibers gather from various body parts and descending fibers leave graded as they descend from the brain. There are two enlargements in the spinal cord, the cervical enlargement and lumbosacral enlargement (Fig. 4-1 A), which might be related to controls of movements of the forelimbs and hindlimbs, respectively.

Figure 4-2. A: Schematic cross section of the cervical spinal cord, where ascending tracts are shown in white enclosures, and descending tracts in black enclosures. B: Schematic cross section of the thoracic spinal cord, where major nuclei in the gray matter are shown. (Adapted from House and Pansky 1967.)

Paired spinal nerves are present in every segment of the spinal cord. Each of the spinal nerves is composed of two roots, called the dorsal root and the ventral root (Fig. 1-8 d). It is well established that the dorsal root contains visceral and somatic sensory fibers whose cell bodies lie outside the spinal cord in clusters, known as spinal (root) ganglia, and the ventral root contains somatic and visceral motor fibers, whose cell bodies are located respectively in

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the ventral and lateral column of the gray matter of the spinal cord. (The areas corresponding to the gray columns in each segment are named the ventral horn and the lateral horn, respectively, and its dorsal column, the dorsal horn (Fig. 1-8 d).) The sensory and motor nerves enter and leave at each of 31 vertebral segments (Fig. 4-1). They are traditionally classified into 8 cervical (C), 12 thoracic (T), 5 lumbar (L), 5 sacral (S), and 1 coccygeal (Co). The trunk of the spinal cord, however, ends just below the L1 vertebral body (conus medullaris), so the lumbar, sacral and coccygeal roots traverse a considerable distance (cauda equina) through the lumbar cistern space to reach the appropriate intervertebral foramina of exit. [A Different Angle 4-1] Why does’t the spinal cord continue to the sacral part?: In the early stage of the embryonic development, the neural tube and vertebral canal develop almost in parallel: the spinal cord occupies the entire length of the caudal region of vertebral column, and the spinal nerves emerge perpendicular between the vertebral bodies. In about the 4th month, growth of the neural tube slows, while that of the vertebral canal continues. This difference in growing speeds produces a vertebral canal not occupied by spinal cord, and drags down spinal nerves of the lumbar and sacral parts (cauda equina) below the spinal cord. It is well known that aberrations or distortions of vertebra originate disorders of viscera and muscles corresponding, which is apparently due to pressing the spinal nerves or spinal cord mechanically. Although the view might be teleological, the curious (but interesting) formation of the lower part of the spinal cord is, as a result, advantageous in bending the waist, in which posture the nervous tissue might be strongly pressured by vertebra and tissues surrounding the spinal cord if the corresponding parts of the core were massive. The protection of the nervous tissue from mechanical pressure due to bending the head is also observed at the junction between the skull and cervical vertebra. In this case, the bony structures of the skull and the vertebra are suitably formed to avoid direct mechanical pressure. (Nevertheless, humans tend to suffer lower back pain and disorders of the neck.)

[A Different Angle 4-2] About dermatomal distribution: The cutaneous area supplied by a single spinal nerve root is called a dermatome. It is a unitary area giving rise to sensations of temperature, pain, and touch corresponding to one spinal segment. (The innervation of sensory and motor spinal nerves into skeletal muscles also follows systematically to the spinal segments, which corresponds complexly to the cutaneous dermatomes.) Dysfunction of a single dorsal root diminishes sensation on the corresponding cutaneous area but does not produce a total loss, probably due to overlap between neighboring dermatomes. It is known that the area of tactile loss tends to be wider than the area of loss of pain and thermal sensations, which seems to be the result of the stronger overlap of the dermatome for pain and thermal sensation than the overlap for tactile sensation. So it is, in actuality, difficult to define critically the territory of each dermatome. In addition, the distribution pattern of the sensory peripheral nerves in the cutaneous region exhibits variation among people. (Indeed, details of the pattern differ from

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publication to publication.) Although the coding mechanism of the sensory sensation in the CNS depends on multiple factors, including this overlapping distribution, it is, at least, certain that in many cases damage of one dorsal root does not result in the complete loss of sensation of the corresponding cutaneous territory. Approximate dermatomal distribution is as follows: cervical roots dominate the posterior surface of the head, neck, and upper limbs and hands; thoracic roots dominate the medial side of upper limbs, and most of the ventral and dorsal surfaces of the thoracic; lumbar roots dominate the anterior and inner surfaces of lower limbs, and feet; and sacral roots dominate the posterior side of lower limbs, lateral margin of foot, and perineum. The anterior surface of the head also receives a dermatomal supply of the trigeminal nerve (V): the ophthalmic branch (V1) dominates around eyes, nose bridge, and forehead; the maxillary branch (V2) around the upper lip and lateral side of nose; and the mandibular branch (V3) around the chin, lower lip, and ears. After all, dermatomes (of humans) assume a parallel pattern in each other in the quadruped posture (Fig. 4-1 B).

* Ascending Tracts in the Spinal Cord Many ascending and descending tracts, or bundles of axons, are known to exist in the spinal cord. (There are, however, tracts whose functions are not fully understood.) Among ascending tracts, the function and running manner of the dorsal funiculus (or column) tracts (fasciculus gracilis and fasciculus cuneatus) are well established (Fig. 4-2 A, Fig. 4-3). The tracts are a collection of branches of somatic sensory nerves entering from the dorsal roots, which are strongly myelynated, and convey tactile, pressure, and proprioceptive information of muscles: branches of the sensory nerves for legs and lumber ascend in the bundle of fasciculus gracilis, and those for thoracic and hands, in the bundle of fasciculus cuneatus. The fibers ascend the dorsal side of the spinal cord ipsilaterally and synapse to the second order neurons at the caudal end of the medulla. The sensory information for the proprioception of muscles is conveyed mainly to the cerebellum. The sensory fibers conveying the proprioceptive information from muscles is known to synapse on neurons of Clarke’s nucleus in the dorsal horn (Fig. 4-2 B), and they send their axons into the lateral funiculus of the same side, forming the spinocerebellar tract, the most characterized tract of which is the dorsal spinocerebellar tract, which ascends to the cerebellum through the inferior cerebellar peduncle. Sensory neurons of the spinal dorsal root conveying more primitive (or basic) sensations, such as pain and temperature, synapse to cells in the posterior horn, and the second (and higher) order neurons send their axons across the midline to the anterolateral region. They form ascending pathways in the anterolateral white column, the spinothalamic tract. Both the spinothalamic tract and the dorsal funiculus tracts convey sensory signals to the thalamus via the medial lemniscus. It is worth noticing that dorsal funiculus fibers cross at the medulla, whereas the spinothalamic fibers cross at the segment of the spinal cord, mostly of segments to which the first order fibers enter (Fig. 4-3).

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Figure 4-3. Schematic representation of the ascending pathway of the medial lemniscus system and the descending pathway of the corticospinal tract system in the spinal cord, brainstem, and cerebrum. Open circles indicate sensory nuclei or cells, and filled circles indicate motor nuclei or cells. n.: nucleus or nuclei; t.: tract.

Other tracts of sensory fibers for cutaneous sensations are also identified in the spinal cord. They ascend to reticular formations in the brainstem (spinoreticular tract), to the superior colliculus (spinotectal trac), and to the inferior olivary nuclei (spinoolivary tract). They are considered to ascend the ipsilateral (spinoreticular tract) or contralateral (spinotectal tract and spinoolivary tract) white column after terminating on the second order neurons in the gray matter of the spinal cord on the same side. (A part of these tracts is thought to be

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composed of branches of the spinothalamic fibers, but there are unclear aspects in the functional relation between these and the spinothalamic tract.) The approximate locations of these ascending tracts in the cross section of the spinal cord (cervical potion) are shown in the right half of Fig 4-2 A.

* Descending Tracts in the Spinal Cord Among tracts descending the spinal cord, the corticospinal tract must be the most important and best understood. The fibers arise mainly from the primary motor area (and probably the supplementary and premotor cortices) of the cerebral cortex. They go down the ipsilateral ventral side of the brain stem; the tract in the caudal medulla is called popularly the pyramidal tract (Fig.4-3). Just caudal to the medulla-spinal cord junction, most of them cross and then swing laterally, forming the lateral corticospinal tract. The crossing site is called the motor (or pyramidal) decussation, which is just caudal to the sensory decussation. (There are uncrossed fibers in the pyramidal tract, which go down the spinal cord ventrally. Thus, this tract is called the anterior corticospinal tract.) Fibers of the lateral corticospinal tract synapse to somatic motor neurons in the ventral horns of each segment of the spinal cord. Descending pathways that originate from nuclei in the brainstem and terminate at motor neurons in the spinal cord are also identified. They include the reticulospinal tract (from the reticular formations), tectospinal tract (from the superior colliculus), olivospinal tract (from the inferior olivary nucleus), rubrospinal tract (from the red nucleus), and vestibulospinal tract (from the vestibular nuclei). These tracts might be involved in various types of coordinative movements or in maintaining posture. Approximate locations of these descending tracts in the cross section of the spinal cord (cervical potion) are shown in the left half of Fig 4-2 A. Viewing largely, spinal tracts can be classified into two groups, one is ascending and descending tracts having relation to the cerebrum nervous system and the other, those having relation to the brainstem nervous system. [A Different Angle 4-3] Topographical arrangement observed in tracts of the spinal cord: The sensory fibers entering from the dorsal root synapse to the neurons in the dorsal gray column. Somatic fibers of the dorsal roots branch medially (medial division) immediately after entering the dorsal column, and ascend ipsilaterally. During their ascending course, they are steadily pushed in a more medial direction by the fibers entering at succeeding rostral levels. Consequently, the ascending fibers of the dorsal funiculus in the spinal cord at the junction with the medulla show a segmental arrangement from the medial to lateral side: sacral, lumber, thoracic, and cervical (Fig. 4-4). In other words, sensory fibers entering the dorsal funiculi add on laterally to those already present. The topographical arrangement is also observed in the spinothalamic tracts in the anterolateral white column of the spinal cord: the fibers from the sacral and lumber segments of the body are pushed laterally by fibers crossing the midline at successively higher levels, so that

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the cervical to sacral segments are located from a medial to lateral position (Fig. 4-4). This is in contrast to the arrangement of the dorsal funiculus; the dorsal funiculus is a graded collection of ipsilateral fibers, whereas the spinothalamic tract is a graded collection of the contralateral fibers.

Figure 4-4. Somatotopical organiation of the dorsal white column (gracile fascicle and cuneate fascicle), anterior spinothalamic tract, and lateral corticospinal tract at the middle cervical level. (Adapted from Martin 2003.)

Lateral corticospinal fibers, major fibers descending the spinal cord, are also known to be arranged somatotopically. Fibers that project to lumbosacral levels are lateral, whereas those traveling to cervical levels are medial (Fig. 4-4). The corticospinal tract is formed by pyramidal tract fibers just after decussating at the junction between the medulla and spinal cord, so the tract is a collection of the contralateral descending fibers. The order, from lateral to medial, sacral, lumber, thoracic, and cervical, leads to the estimation that the decussation of the pyramidal tracts starts from fibers commanding leg movements, followed by the fibers commanding movements of the higher body parts, successively. The view that in the organization of the tracts, ispilateral fibers added later push others medially, and the fibers that come from the contralateral side push others laterally would be applicable to all of the other tracts, and would give a hint at their origins and functions.

(2) Brainstem (Medulla, Pons, Midbrain) The spinal cord continues rostrally to the so-called brainstem, and it is commonly classified, caudal to rostral, into three portions: the medulla (oblongata), pons, and midbrain. The nervous organization of the brainstem is essentially an extension of the spinal cord, based on the alar and basal plates of the embryonic development. This is the region which performs the function on the head and neck parts, like the spinal cord. Another conspicuous feature of the brainstem is the running of large tracts connecting the spinal cord and components of the cerebellum and cerebrum. The central canal of the spinal cord

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continues into the medulla, the rostral part of which expands as the fourth ventricle. The fourth ventricle continues to the roof of the pons but becomes narrow again in the midbrain (cerebral aqueduct).

* Cranial Nerves in the Brainstem In the same way that the spinal cord functions through segmental spinal nerves, the brainstem functions through cranial nerves, which are identified by 12 roots, numbered with Roman numerals I-XII. The leaving and entering features of the 12 cranial nerves in the brainstem are, however, not as uniformly observed in the spinal cord. They contain visceral and somatic sensory and motor fibers differentially. (Details of the running manner, fiber type components, and function of each cranial nerve are described in many other publications.) The cranial nerve nuclei are located in distinct regions of the brainstem, but primary sensory signals input to nuclei originate from the alar plate, and motor signals arise from the nuclei originating from the basal plate. Nuclei of the alar plate group, however, are distorted laterally due to the expansion of the 4th ventricle (Fig. 1-8 e). Most nuclei for the visceral system in the brainstem are located between the somatic afferent and somatic efferent nuclei, which principally have the same organization as in the spinal cord. (Fig. 4-5 shows the principle organization of the cranial nerve nuclei in the brainstem viewed from the dorsal and left side.)

Figure 4-5. Position of the sensory nuclei (open enclosure) and motor nuclei (closed enclosure) in the brainstem viewed simultaneously from the dorsal and lateral direction. Roman numbers indicate cranial nerve numbers. (Adapted from Chusid 1982.)

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* Descending and Ascending Tracts in the Medulla The dorsal funiculi (fasciculus gracilis and fasciculus cuneatus) of the spinal cord ascend the dorsal side of the spinal cord ipsilaterally and synapse to the second order neurons in the so-called dorsal column nuclei (nucleus gracilis and nucleus cuneatus) in the caudal end of the medulla: the dorsal column nuclei appear as small swellings just caudal to the obex on the dorsal surface of the medulla. The second order fibers from the dorsal column nuclei swing likewise in the anteromedial direction and immediately cross the midline; this is called sensory decussation. Among the 12 cranial nerves, the trigeminal nerve (V) conveys general somatic sensory information of the face and oral region. Lateral to the cuneatus nuclei of the dorsal column nuclei, there is the spinal trigeminal tract, and internal to the spinal tract is the spinal trigeminal nucleus. The trigeminal tract corresponds to the dorsal funiculus, and the trigeminal nucleus, to the dorsal column nucleus. (Similarly, the trigeminal ganglion corresponds to the dorsal root ganglion of the spinal cord). Second order fibers from each of the gracile, cuneate, and trigeminal nuclei cross midline to form the so-called medial lemniscus, which projects to the ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei of the thalamus (Fig. 4-3). This ascending system is popularly called the dorsal column - medial lemniscus system.

Figure 4-6. Schematic illustration of the cross section at three levels of the medulla. Both sensory and motor nuclei (n.) are shown with filled enclosures, open enclosures, ascending and descending tracts (t.), and roman numbers, cranial nerves or their nuclei. (Redrawn from Felten and Józefowicz 2003.)

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On the contrary, the system conveying the somatic information mainly for nondiscriminative sensation such as pain and temperature is called the anterolateral system as the corresponding fibers ascend in the anterolateral portion of the lateral column of the spinal cord. The fibers of the anterolateral system are thought to terminate in the reticular formation of the pons and medulla, the midbrain, and the thalamus. The anterolateral system has been paid attention especially from a pain clinic, as nociceptive input to the dorsal horn of the spinal cord is thought to be relayed to pain centers in the brain by projection neurons of this system. On the ventral surface of the medulla there are conspicuous bilateral swellings called pyramids. The pyramids are tracts that are composed of bundles of descending fibers which originated mainly from large cells in the motor cortex. At the caudal region of the medulla, most fibers of the pyramidal tracts cross the anterior midline as the motor (or pyramidal) decussation to form the lateral corticospinal tracts, which descend contralaterally in the spinal cord (Fig. 4-3). (The motor decussation is a short distance below (caudal) to the sensory decussation.) These features of nuclei and tract organization in the medulla are illustrated with three successive cross-sections in Fig. 4-6. [A Different Angle 4-4] What is the characteristic structure of the inferior olivery nuclei in the medulla?: Posterolateral to the pyramidal tracts are bilateral oval elevations, known as the inferior olivary nuclei (Fig. 4-6 a). This architecture is a part of the gray matter, and it occupies a relatively large area of the medulla. The form of the inferior olivary nuclei, which shows strong convolutions in spite of being situated completely in the medulla tissue, is conspicuous and, as neurophysiologists have noted, seems quite similar to the formation of deep nuclei, especially dentate nuclei, of the cerebellum. Actually the inferior olivary nuclei are known to have strong neural and functional connections with the cerebellum. The cells of the inferior olivary nuclei are known to receive sensory inputs from the spinal cord (spinoolivary tract) and the cerebral cortex (corticoolivary fibers), and send fibers medially across the midline to enter the cerebellum through the inferior cerebellar peduncle. (The climbing fibers that are afferents projecting to the cerebellum cortex are thought to be composed mainly of fibers originating from the inferior olivary nuclei.) Here, a view originates that the olivery nucleus structure was phylogenetically a part of the cerebellum, which retrograded and absorbed into the medulla during an evolutionary stage. The structure we observe in the medulla must be its residue retrograded. In “A Different Angle 1-5”, it was argued that the highest central function of the human CNS may have shifted from the cerebellum to the cerebrum at some stage of human evolution. The appearance, location, and input/output organization of the inferior olivary nuclei appear to support this view.

* Architecture of the Pons The medulla continues rostrally to the pons. The ventral surface of the pons forms a bulge called the pontine protuberance. The dorsal surface forms the rostral portion of the 4th ventricle, which is covered by the cerebellum. The ventral bulge is due to a lot of nerve

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fiber bundles. The corticospinal fibers arise from the cerebral cortex path through the ventral side of the pons, but they do not form obvious bundles as cerebral peduncles of the midbrain and pyramidal tracts of the medulla. (In general, the dispersed running pattern of axons in the CNS would reflect many varied connections with the neurons in the surrounding region, whereas the appearance as a distinct bundle in the CNS might mean a pass-through and poor connection of the fibers with other neurons in the surrounding region.)

Figure 4-7. Schematic illustration of the cross section at three levels of the pons. Both sensory and motor nuclei (n.) are shown with filled enclosures, open enclosures, ascending and descending tracts (t.), and Roman numbers, cranial nerves or their nuclei. (Redrawn from Felten and Józefowicz 2003.)

Many transverse fibers in the ventral bulge converge on each side to form the middle cerebellar peduncle. The basal part of the pons contains a small mass of nerve cells called pontine nuclei. Corticopontine fibers are also a large group of fibers that originate from a wide area of the cerebral cortex. They project onto the ipsilateral pontine nuclei, fibers of which enter the cerebellum via the middle cerebellar peduncle after crossing the midline on their way to the cerebellum. These fibers of the pontine nuclei are understood to give origin to the transverse fibers of the basal pons. On the lateral surface of the pons, the trigeminal nerve (V) emerges on each side. In the border between the pons and the medulla, the cranial nerves emerge; medial to lateral, they are as follows: the abducent (VI); facial (VII); and vestibulocochlear (VIII) nerves, the nuclei of which are variously positioned, lateral or ventral to the 4th ventricle. The dorsal surface of the pons forms the caudal portion of the floor of the 4th ventricle, which is limited laterally by the superior cerebellar peduncles. The dorsal part of the pons is composed largely

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of the reticular formation, which is believed to be involved in arousal and consciousness. These features in organization of nuclei and tracts in the pons are illustrated by three successive cross-sections in Fig. 4-7.

* Architecture of the Midbrain The pons continues to the midbrain, the ventral surface of which is marked by the bilateral runnings of massive fiber bundles, the cerebral peduncles. They carry fibers originating from cerebral cortices to the brainstem (the corticopontine and corticobulbar tract) and spinal cord (corticospinal tract). (“Bulb” indicates the medulla or the brainstem.) Between the cerebral peduncles lie the paired occulomotor nerves (III). The trochlear nerves (IV), cranial nerves for controlling eye movement, leave the midbrain in a somewhat peculiar manner: they emerge from the dorsal side of the midbrain, curve around, and appear at the lateral borders of the cerebral peduncle. On the ventral surface, optic nerves (II) and their chiasm pass. Pigmented nuclei, named the substantia nigra, are situated inside dorsal to the cerebral peduncles throughout the midbrain, and reddish nuclei, named the red nuclei, are medial-dorsal to the substantia nigra; both nuclei are a mass of gray matter having motor function. These features in organization of nuclei and tracts in the midbrain are illustrated in three successive cross-sections in Fig. 4-8.

Figure 4-8. Schematic illustration of the cross section at three levels of the midbrain. Both sensory and motor nuclei (n.) are shown with filled enclosures, open enclosures, ascending and descending tracts (t.), and Roman numbers, cranial nerves or their nuclei. (Redrawn from Felten and Józefowicz 2003.)

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The dorsal part to the cerebral aqueduct of the midbrain is called the tectum. There are four swellings in the tectum: the caudal pairs are the inferior colliculi, and the rostral pairs are the superior colliculi. The inferior colliculus is the major relay nucleus in the auditory pathway, and the superior colliculus plays a role in the visual reflex. The midbrain originally functions for processing visual inputs from eyes, and is differentiated largely as either the optic tectum or optic lobe in many vertebrates. In humans, the major visual center shifts to the cerebral cortex, and only the function for eye reflexes has remained, which are carried by the superior colliculus. [A Different Angle 4-5] The role of reticular formation: Peculiar architectures, so called reticular formations, are scattered medial-longitudinally in the brainstem, and they extend to near the thalamus. They receive numerous collaterals of lemniscal fibers and receive projections of fibers from deep nuclei of the cerebellum. (Reticular formations situated in the core zone of the brainstem are called raphe nuclei.) They show a matrix appearance mixed with neurons and fibers, which form definite nuclear groups in the brainstem. The reticular formations are understood to be a mass of intermeshed, pooly organized neurons and nerve fibers. As most reticular formation is organized at medial regions of the brainstem, it is probable to represent the rostral extension of the interneuronal network found in the spinal cord. Although there are unclear aspects in the functional role of the reticular formations, it has been widely believed that the reticular core is an activating system regulating the activity level of the brain. At present, the formations are understood to have multiple functions, such as modulation of motor signals, gating sensory inputs, regulation of the autonomic system, and control of sleep, all of which are, in a sense, related to consciousness or wakefulness. As described in “A Different Angle 1-6”, the human brain shows hierarchical organization where the nervous system located medially or deeply, in the core area, is phylogenetically old, and it acts automatically to maintain basic aspect of the nervous system. The unsystematic mixing feature of human reticular formations certainly resembles an interneuronal network around the central canal of the spinal cord (and the net nervous system observed in invertebrates). As neural formation like the reticular formation is not observed at higher levels than the thalamus in the human brain, it is certain that the reticular formations have some basic functions for supporting the work of higher centers of the CNS.

(3) Cerebellum The cerebellum lies over the dorsal surface of the pons and medulla, forming the roof of the 4th ventricle, whose surface shows a conspicuous folding structure (Fig. 4-9). It is composed of internal white matter, and superficial gray matter (cerebellar cortex), which is similar in composition to the cerebrum. The cerebellum is traditionally divided into transverse and longitudinal zones: transversely, it is composed of a midline vermis and two laterally-placed hemispheres; and longitudinally, it is subdivided into three portions, anterior, posterior, and flocculonodular lobes (Fig. 4-9 A). The flocculonodular lobe is the oldest zone, and the posterior lobe is the most recent zone phylogenetically, but the citoarchitectual formation of the anterior and posterior lobes is almost uniform over the lobes.

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Figure 4-9. A: Superior surface appearance of the cerebellum and its regional classification. The flocculus, nodulus, and tonsil are hidden to the inferior surface. B: Cytearchitecture of the cerebellum represented by both midsaggital and lateral saggital section. (Redrawn from Felten and Józefowicz 2003.)

* Neural Connections The cerebellum is connected to the brainstem by three pairs of peduncles: the superior, middle, and inferior peduncle. The major inputs to the cerebellum are as follows. 1) Somatic sensory signals from the spinal cord are input through mainly to the anterior lobe via the dorsal and ventral spinocerebellar tracts, so the corresponding portion is frequently called the “spinocerebellum”. These tracts are believed to convey information mainly for muscular proprioception, (including pain, temperature, and touch) of the upper and lower limbs. 2) Vestibular sensory signals arise from the primary vestibular end organ as well as from vestibular nuclei in the brainstem input mainly to the flucculonodular lobe through the inferior cerebellar peduncles on the same side. The corresponding portion is frequently called the “vestibulocerebellum”. 3) Signals arising from the brain cortex are input mainly to the

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posterior lobe via the pontine nuclei, inferior oliva nuclei, and reticular formation through the inferior and middle cerebellar peduncles. The corresponding portion is frequently called the “cerebrocerebellum”.

Figure 4-10. Schematic representation of inputs to and outputs from the cerebellum. Open circles indicate sensory nuclei or cells and filled circles, motor nuclei or cells. (Some of axons of Purkinje cells, arising in the flocculonodular lobe end in the vestibular nuclei axons of which then project to motor neurons of the spinal cord via the vestibulospinal tracts, which are omitted in this representation.) n.: nucleus or nuclei, t.: tract

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These three sorts of inputs are segregated into two fiber systems in the white matter of the cerebellum: the climbing fiber system or the mossy fiber system. Climbing fibers, the main inputs of which are thought to come from the contralateral cerebral cortex, synapse to the neurons called Purkinje cells, which lie in the cortex; one of conspicuous characteristics of climbing fibers is its strong excitatory effect on Purkinje cells. Mossy fibers, the main inputs of which are believed to come from the spinal cord and the vestibular system, synapse to neurons in the granule cell layer of the cortex. Fibers of granule cells also exert an excitatory effect on the Purkinje cells, but the effect is known to be weaker than that for climbing fibers.

* Outputs of the Cerebellum Purkinje cells project a strong inhibitory effect on cerebellar deep nuclei that are bilaterally embedded in the cerebellar white matter. The following nuclei are known as the extracerebellar targets of the deep nuclei outputs: the vestibular nuclei and reticular nuclei of the brainstem (from the fastigial nucleus); the red nucleus in the midbrain (from the dentate nuclei); the inferior olivary nucleus in the medulla (from the interposed nucleus); and the thalamus (from the dentate nuclei and interposed nuclei), (as well as perhaps the hypothalamus (from all deep cerebellar nuclei)). These features of inputs and outputs are included in Fig. 4-10: whether the input (output) fibers come from (project to) the ipsilateral side or contralateral side is very complex and some of their pathways seems to be estimation. [A Different Angle 4-6] Similarities between the cerebellum and the cerebrum: In some ways, the cerebellum and the cerebrum appear similar. First of all, the surface of both architectures elaborates with a folded or convoluted structure, although their patterns are different in their details. In addition of the surface appearance, their neural organizations are similar, too. The cerebellar cortex, that is the gray matter, contains various types of neural cell bodies and covers the sphere surface, and inside of the cerebellum is the white matter that is composed of ascending and descending fibers, where groups of nuclei are situated, which principally have the same neural organization as the cerebrum. Inside the cerebrum, the ventricle expands widely as the bilateral and 3rd ventricles, where the choroid plexus invades at many places. Similarly, the ventricle expands as the 4th ventricle between the cerebellum and the brainstem, where the ventricle has also small lateral enlargements and is abundant in the choroid plexus. As discussed in “A Different Angle 1-5”, these similarities further support the consideration that the cerebellum was once the highest center of the nervous system. (So, it seems proper to call the cerebellum the “old brain” or “little brain”.) From the developmental aspect, the original function of the cerebellum is thought to have been the processing of vestibular information. This is also suggested by the fact that the flucculonodular lobe is phylogenetically the oldest portion of the cerebellum (and is therefore frequently called the “archicerebellum”), and the lobe is yet the region processing vestibular information. With advancing evolutional stages, the cerebellum integrated other sensory information, especially for the somatic system, which relates to the development of the anterior and posterior lobes,

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(called the “paleocerebellum” and the “neocerebellum”, respectively). Evolution of the human nervous system has further developed the telencephalon, which might have induced the shift of the highest center from the cerebellum to the cerebrum. To perform the cerebrum function fully as the highest center of the CNS, the cerebellum, however, must be controlled under the cerebrum. This is reflected in the strong suppressive effect of Purkinje fibers on the deep nuclei, the output nuclei of the cerebellum. It is understood that the climbing fibers convey the information mainly from the cerebral cortex, whereas the mossy fibers convey the spinal or vestibular signals. It is noticeable that the suppressive effect of the climbing fibers on the deep nuclei via Purkinje neurons is much stronger than that of the mossy fibers. The nuclei of the brainstem -- such as the red nuclei, reticular nuclei, and vestibular nuclei, which mainly receive the cerebellum outputs -- might have been the main motor nuclei in the old CNS system, where their activities were dominated by the cerebellum. At the stage where the cerebellum was the highest center of the CNS, excellent agility might have been important for capturing game or running away from enemies. At present, the highest center of the nervous system is the cerebrum, which has progressed most in modern humans. The main function of the cerebrum can be said to be intelligence, where activities of the cerebellum need to be suppressed in various situations to sufficiently execute cerebral functions. This neural relation between the cerebrum and cerebellum is similar, in some aspects, to the relation between the parasympathetic and sympathetic nervous system: the sympathetic nervous system, the main center of which lies in the spinal cord, must be suppressed by the parasympathetic nervous system, the main center of which lies in the brain, to make visceral organs and tissues function more suitably, depending on complex and multiple human behaviors that came to develop, as discussed in the “A Different Angle 1-7 ”.

(4) Diencephalon The midbrain continues rostrally to the diencephalon, which belongs developmentally to the embryonic prosencephalon (forebrain). The diencephalon lies deep in the cerebrum as an enlargement of the cerebral hemispheres. The central canal widens as the 3rd ventricle, which occupies the medial portion of the diencephalon. The diencephalon is composed of identical structures, and both the hypothalamus and thalamus are important and, as such, are described in detail in most textbooks. In the diencephalon, there are also the main parts of the so-called limbic system, which surrounds the hypothalamus and bilateral thalami, composing the marginal region of the diencephalon.

* Hypothalamus The hypothalamus is a restricted area of the ventral diencephalon, which is closely involved in the neuroendocrine regulation and control of various visceral functions with the autonomic system. So, this area is frequently referred to as the “visceral brain”. It is composed of many discrete nuclei and diffuse cell bodies, which are subdivided commonly into rostral-caudal zones, as well as medial-lateral zones. The most ventral portion continues to the pituitary gland (hypophysys). Input signals to the hypothalamus arise in such

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architectures as the limbic system, brainstem, and spinal cord, and outputs of the hypothalamus project to such the architectures as the hippocampus, amygdala, brainstem, and spinal cord. (Some of the pathways are based on estimation and have not been commonly established.) Among the zones of the hypothalamus, the nucleus in the region just above the optic chiasma (supraoptic nucleus (SON)) and the nucleus dorsal to it and lateral to the 3rd ventricle (paraventricular nucleus (PVN) are well known to contain large cells that produce the peptide hormones vasopressin (antidiuretic hormone (ADH)) and oxytocin. Axons of the cells reach the posterior pituitary through the infundibulum, transporting the hormones. The hormones are elaborated in the nuclei and released from the terminal of the axons into the vasculature of the posterior lobe of the pituitary gland (Fig. 4-11). The cells in the SON and PVN are excitable electrically, and action potentials conducted to the terminal act on the releasing process of the hormones. This system is called neurosecretion, although it is not principally different from the synaptic process of other neurons, except that the neurosecretory neurons do not release the chemicals into the synaptic space, but rather into the vascular system. ADH acts on the kidneys to increase water reabsorption, and oxitocin causes contraction of uterine smooth muscle (and promotes milk ejection from the mammary glands). (The function of oxitocin in males is not known.)

Figure 4-11. Architecture of the hypothalamus and nearby regions. Rough location of arcuate nucleus that produces and releases factors controlling secretions of anterior pituitary hormones and neurosecretory cells of magnocellular and parvocellular neurons (filled circles) and their runnings to the posterior pituitary gland are also drawn in the figure.

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The relation between vasopressin (ADH) and oxitocin: We might have a sense of incongruity concerning the secretion of the two different hormones, vasopressin and oxitocin, from the same site (posterior pituitary) and in the same manner (neurosecretion). The target organs and physiological effects of the two hormones are certainly different, but their chemical compositions are substantially quite similar: each contains nine amino acids, although two of the nine are different. The chemical components, as well as the loci of the neurons synthesizing them in the hypothalamus and the releasing process in the posterior pituitary, are almost the same for the two hormones. It is, therefore, natural to think that there might be a physiological relationship between vasopressin and oxitocin. Vasopressin facilitates water re-absorption from the collecting ducts (and convoluted tubules) of the kidneys by increasing their permeability to water, but vasopressin is known to have another interesting effect. High concentration of vasopressin causes contraction of smooth muscles, especially for the vascular system, an effect similar to that of oxitocin. (The term “vasopressin” originates from this physiological effect.) Although it is difficult to explain how the contraction of smooth muscle caused by of vasopressin is involved in accelerating water intake, it is known that both vasopressin and oxitocin cause an increase of Ca2+ permeability of adequate cells. An increase of inside Ca2+ concentration is, in many cases, based on various physiological functions of cells. It is certain that the water re-absorption in the kidneys and contraction of uterine smooth muscle are induced through the Ca2+ influx. Apart from the similarity of chemical components and their effective mechanism, the fact is further suggestive that the excretory and reproductive systems have the same origin in embryonic development: both differentiate from the so-called pronephron (Fig 1-5), located dorsal to the coelom between the somites and lateral plate mesoderm. Vasopressin and oxitocin might not be such different biogenic chemicals as we conceive them to be.

Secretion of most anterior pituitary hormones is controlled by chemicals synthesized mainly by cells locating at the floor of the 3rd ventricle (arcuate nucleus), which release their chemical products into the capillaries of the median eminence, from which they reach the anterior pituitary via the hypophyseal portal circulation (Fig. 4-11). As the chemicals act on the appropriate cells to release or inhibit the secretion of most of anterior pituitary hormones, they are commonly called releasing factors (or hormones) and inhibiting factors (or hormones), respectively. Most of the factors are small peptides, and many other peptides of neurological interest, like endorphins, enkephalins, angiotensin, substance-P, and neurotensin, are also found in the neurons in this area, appearing to function more or less like releasing and inhibiting factors. (The secretion cells in the arcuate nucleus that are relatively small are frequently referred to as the parvocellular neurosecretion cells, whereas the large neurons in the SON and PVN that produce vasopressin and oxitocin are referred to as the magnocellular neurosecretion cells.) Organisms also need to continuously monitor intrinsic conditions, such as temperature of the hypothalamus, blood pressure, osmotic pressure, and concentration of glucose (or certain hormones) in the blood. Receptor cells for sensing lie in the hypothalamus, the information

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from which activates appropriate neurons, maintaining homeostasis of organisms: the neurons activated are autonomic motor neurons in the brainstem and the spinal cord, and parvocellular and magnocellular neurons for neurosecretion in the hypothalamus.

* Thalamus The main role of the thalamus is transmission of ascending signals from the spinal cord and the brainstem to the cerebral cortex. It is composed of numerous nuclei. (The term “hypothalamus” and “thalamus” give the impression that there is a functional relation between the two components, but the function of the thalamus is quite different from that of the hypothalamus.) The following projections of afferent signals to the thalamus nuclei are well known: auditory signals project to the medial geniculate bodies, visual signals to the lateral geniculate bodies, somatic sensory signals from the trigeminal nerve to the ventral posterior medial nucleus (VPM), and somatic sensory signals from the spinal cord to the ventral posterior lateral nucleus (VPL). Most fibers from these nuclei of the thalamus run to the cerebrum through the posterior part of the internal capsule (Fig. 4-12, Fig. 4-16). The ventral anterior portion of the thalamus is considered to have a connection with nuclei relating to the cerebellum and the brainstem, and the medial portion of the thalamus is considered to have connections with the prefrontal and cingulate cortex. It may be noticed that inputs from and outputs to neurons in the anterior portion of the thalamus are relatively uncertain and show diversity compared to those of neurons in the posterior portion, and that the thalamus is also thought to receive feedback signals from the cerebral cortex, which might modulate its sensory outputs.

Figure 4-12. Three-dimensional anatomical relation (viewed from the left posterior side) among the thalamus, corpus striatum, and hippocampus formation in the core region of the brain. Internal capsule of the left side, which descends and ascends between the thalamus and the lentiform nucleus (putamen) is also drawn. (Adapted from Carpenter, 1983.)

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* Limbic System Although agreement on a critical definition is still lacking, the medial and basal areas of the cerebral hemisphere forming a border around the thalamus and hyopothalamus are called the limbic nervous system. The major components are the amigdala, cingulate gyrus, hippocampal formation, mammillary body, and the connections with their related architectures. Among them, the hippocampal formation, which consists of the hippocampus, dentate gyrus, and parahippicampul gyrus, is conspicuous (Fig. 4-12). The hippocampus shows a primitive cortical structure of gray matter, and it extends the length of the floor of the inferior horn of the lateral ventricle. Its anterior end is called the pes hippocampus. (The name “hippocampus” comes from its resemblance to a sea horse.) The dentate gyrus is also gray matter that lies on the upper surface of the parahippocampal gyrus. Many of the limbic structures and their pathways form a ring encircling the diencephalons. Neural connections among the components within the limbic system and input-output relation with other architectures remain obscure, as do their function. Originally the limbic system was assigned a purely olfactory function, but is believed at present to also play an important role in emotional behaviors and memory. [A Different Angle 4-8] About the structure and function of the limbic system: Among the components of the limbic system, the architecture of the hippocampus formation is the most conspicuous. Construction of memories, especially of relatively long-term memory, is suggested as an important function of the hippocampal formation, whereas emotional behaviors arise from the limbic system. (A substantial mechanism of memory and emotion in the neural system, however, has yet to be fully explained.) Are memory and emotion independent items for nervous function? It stands to reason that sensory perception is the first step of the memory process. Sensory signals enter the spinal cord and brainstem, elicit simply reflex-like behaviors, but disappear immediately. Emotion is also elicited through sensory perception but is accompanied with something like "feelings", which are thought to be a biological factor specific to higher vertebrates. (The term “emotion” here means feelings such as happiness, sadness, or anger, which are triggered by external inputs; it excludes feelings such as starvation, thirst, or sexual desire, which are principally driven by intrinsic factors.) Can we maintain sensory experience without some accompanying emotional factor? To construct a memory of a sensory experience elsewhere (in the brain), an appropriate emotion, irrespective of being weak or strong, must be attached to the sensation. For instance, most mammals, such as dogs or monkeys, as well as humans, avoid places where they have previously experienced danger, whereas fish or flies will repeatedly approach a place where they have experienced danger. This is apparently due to a lack of the ability to construct memory, which is related with the lack of ability of generating emotion to the sensory perception. If limbic architectures are compressed artificially by removing the thalamus and hypothalamus, the formation becomes simple. The fornix, thought to be the pathway of the hippocampal formation, curves into the anterior pole of the diencephalons and connects to the mammillary bodies that are situated side by side at the ventral region, caudal to the optic chiasm of the diencephalon. The reorganization leads to the view that the anatomical relation

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between the hippocampus and the mammillary bodies is similar to the organization of sensory and motor nuclei in the dorsal and ventral horn of the spinal cord, where the fornix and its commissure correspond to the connective and cross fibers of spinal cord segments, respectively. The hippocampal formation is a laterally-curved extension of the gray matter, the anterior end (pes hippocampus) of which shows a weak folding structure (Fig. 4-12). (The surface structure of the dentate gyrus can also be considered as a sort of folding structure). These structural features of the hippocampal formation are, in a sense, similar to those of the temporal lobe of the cerebral hemisphere, which is also a lateral extension of the cerebral cortex. The hippocampus could be seen as an analogue to the temporal lobe at the lower level, strongly suggesting its sensory function. (The temporal lobe, its inferior medial region, is also estimated to be involved in learning and higher level memory.) Emotion can be regarded as a sort of motor function, and memory as a sort of sensory function. Thus, one might say that the limbic system, especially hippocampal formations, should be the architecture for transforming sensation to emotion. Thus, we might suppose that anterior components of the limbic system such as, for example, the amygdala and mamillary body, would be deeply involved in the generation of emotion. Humans perform highly-elaborated tasks such as speaking, calculation, painting, singing, crafting works, and so on whose functions might be assumed under the term “intelligence”(or “mentality”). The intelligence that is thought to be the highest function of the human CNS is apparently different from emotion. It is possible to consider that animals produce three types of behavior in response to sensory inputs, that is (1) reflex movement, (2) emotion, and (3) intelligent behaviors, which are organized hierarchically in the brain system of humans. Although fish repeatedly approach a dangerous place, dogs never approach a place where they have previously experienced danger. And humans can avoid places where they have not experienced danger by simply using estimation. The avoidance behavior of dogs owes something to their ability to produce emotion, while that of humans involves intelligence, as well as emotion.

(5) Cerebrum The term “cerebrum” indicates, in most cases, the cerebral cortex that covers the cerebral hemispheres, the surfaces of which contain many sulci. (Deeper and longer sulci are frequently called fissures that become visible earlier in embryonic development and separate large functional areas of the adult brain.) The portions lying between the sulci are called gyri. The gross patterns of the sulci and gyri are fairly constant among people. The cortex is a layer of gray matter composed mainly of cell bodies. Three types of cortices, the neocortex (most recent), archicortex (oldest), and paleocortex, are classified phylogenetically (Fig. 110 A). In humans, the neocortex has expanded greatly, which has caused the rotation of the cerebral hemispheres, and has pushed the paleocortex and archicortex to the medial inferior portion. On the basis of cytoarchitectural characteristics, the cortices are divided into layers. The neocortex, including the primary somatosensory cortex, primary motor cortex, and visual cortex, comprises six layers; the archicortex, made up of the piriform cortex and primary olfactory cortex, (and also hippocampal formation) comprises three layers; and

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the paleocortex, including the singulate gyrus, entorhinal cortex, and orbital cortex, comprises intermediated numbers of layers. Layer V of the motor cortex is sometimes called the giant pyramidal layer, a layer containing large pyramidal cells known as Betz cells, which have long apical dendrites and send their axons to other areas. The cortex of each hemisphere is traditionally divided into four regions: the frontal, parietal, occipital, and temporal lobe, where the three prominent sulci, the central sulcus, lateral sulcus, and parietooccipital sulcus, are marked (Fig. 4-13).

Figure 4-13. Rough sketch of the left cerebral hemisphere (left sided view) and approximate location of major areas for motor and sensory functions in the cerebral cortex. Areas involving in gustatory and olfactory function are represented with dotted closures.

* Somatosensory Area Sensory information from the body projects through the medial lemniscus mainly to the nuclei of thalamus named VPL and VPM via two major ascending systems: the dorsal column pathways and the anterior lateral ascending (spinothalamic) pathways. The third order neurons of the VPL/VPM project to the primary somatosensory cortex (S-I) of the cerebral hemisphere (Fig.4-13). All somatic sensory signals reach the cortex from the contralateral side of the body via the thalamus, but sensations from the oral region, pharynx, larynx, and perineum are thought to reach to the S-I on both sides. (In general, cutaneous sensations of the zone along the midline of the body surface tend to project bilaterally to the corresponding nuclei of the CNS, one reason possibly being the innervations of sensory peripheral nerves beyond the midline of the body to the opposite side.) The primary somatosensory cortex is located in the postcentral gyrus of the parietal lobe (Brodmann’s areas 1 and 2) and in the depths of the central sulcus (Brodmann’s areas 3a and 3b). (Hereafter,“Brodmann’s area” is described simply as “area”.) The contralateral half of the

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body is represented in a precise (but disproportionate fashion) in the S-I, which is frequently expressed as the sensory homunculus (Fig. 4-14). The restricted area in the superior lip of the posterior limb of the lateral fissure (lateral and posterior to the S-I) is called the secondary somatosensory cortex (S-II), which also receives inputs from VPL/VPM of the thalamus and possibly from the S-I. (The term “S-II” refers to the processing area next to S-I, but its functional significance is not clearly understood and normally is not classified as the area for sensory association.) The region posterior to the S-I is also known to process somatic sensory information, where different sensory modalities are associated. This is the so-called ”sensory association area”(of the posterior parietal lobe) (Fig. 4-13). (In general, the terms “anterior” and “posterior“ are used in the anatomical description of the brain, because the “ventral/dorsal” relation of the spinal cord becomes distorted in the brain.)

Figure 4-14. Schematic illustration of somatosensory homunculus on the postcentral gyrus. Areas for tongue and pharynx are extended into the insula cortex. (Adapted from Penfield & Boldrey 1937.)

[A Different Angle 4-9] Is the right side up face orientation of the sensory homunculus correct?: The somatotopical organization in the primary somatosensory area is expressed occasionally as a homunculus. The order from medial to lateral in the sequence is foot, leg, trunk, arm, hand, thumb, neck, face, mouth, tongue, and pharynx, where the face is usually represented right side up in the lateral area. However, an upside down orientation for the face part seems to be more natural considering the sequence of the representation of body parts. If the face is represented upside down, where are the oral components such as lips, tongue, palate, and pharynx (and larynx) represented? Such organization, in which the oral components are positioned between the neck and face, also seems irregular. After all, the sensory homunculus would posture as having four limbs (Fig. 4-14) like the dermatomal distribution of spinal nerve roots (Fig. 4-1 B).

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All descriptions for the sensory homunculus we know end at the pharynx (and larynx) positioning the inside area of the lateral sulcus, the parietal opeculum. Where are the sensations of the continual structures for digestion, such as the esophagus, gut, duodenum, and intestines, coded in the brain? Are they represented continuously to the region of insular cortex, or do the sensory signals not project to the cerebral cortex? Although there has been no accurate descriptions about visceral sensory projection in the brain, it is natural to think that the continuance to the pharynx (and larynx) of the sensory homunculus should be represented in any region in the brain. We are certainly unconscious of visceral activities, but perceive more or less their sensation, especially pain. It is not so peculiar an idea that a “visceral homunculus” might exist somewhere, such as in a posterior portion of the hypothalamus, an area strongly involved in visceral function and close to the insular cortex. It is interesting that the sensory signals from pharynx and larynx, which have intermediate properties of between somatic and visceral organs, project to the area hidden from the brain surface.

* Areas for Special Sensations of Vision, Sound, Balance, Taste, and Olfaction The optic tracts conveying visual signals from retina terminate in the lateral geniculate body of the thalamus, neurons of which send axons to the ipsilateral calcarine (striate) cortex (primary visual area, area 17) of the occipital lobe. The fibers run to the occipital visual center forming radiating patterns (optic radiations) through the temporal loop (Mayer’s loop). Neurons in the primary visual cortex send axons anterior and the signals associated with other sensations. Auditory signals relayed at the medial genuculate body of the thalamus input ipsilaterally to the restricted area of the superior temporal gyrus of the temporal lobe (primary auditory area, area 41, 42). The secondary auditory area exists posterior to the primary auditory cortex in the lateral sulcus and in the superior temporal gyrus (area 22). The area around the posterior end of the left lateral sulcus, which is situated posterior to the second auditory cortex and extends into the parietal region, is called the sensory speech area, or Wernicke’s area. This area is important for understanding written and spoken language. (It is noticeable that the sensory speech area is adjacent to both the visual association and somatic association area.) The vestibular signals from the ventral posterior area of the thalamus project to the lateral postcentral gyrus (vestibular area, area 2), which is known to be involved in motion perception and spatial orientation, and possibly project to the insular cortex and temporoparietal cortex, all of which are close medially to the primary auditory cortex. (The neurons for the vestibular system and the cochlear system tend to be situated in a set from the receptor level to the cerebral cortex.) All of these sensory areas for vision, hearing, and vestible are located in the posterior half of the cerebral hemispheres (Figure 4-13). Olfactory information is processed in such areas as the anterior olfactory nucleus, amygdala, olfactory tubercle, piriform cortex, and entorhinal cortex, which are located at the ventromedial region across the posterior frontal lobes and the temporal lobes. (In the olfaction-relating nuclei, their accurate order in the synaptic relay remains uncertain

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compared with other sensory systems.) The gustatory center, whose inputs are thought to originate from the ventral posteriomedial (VPM) nuclei of the thalamus, is located in the anterior insular cortex extending to the frontal operculum, which is rostral and deep to the somatosensory representation of the tongue, and is proximal to the olfactory relating areas.

* Areas for Motor Function Motor functions collect in the anterior half (frontal lobe) of the cerebral hemisphere. An elongated convolution just anterior to the central sulcus (area 4) is known as the primary motor cortex (M-I). Motor functions of the contralateral half of the face, limbs, and trunk is represented in the M-I in a precise manner, giving rise to the motor homunculus in the same fashion as the organization in the S-I. Just anterior to the M-I is an area that corresponds to area 6, called the premotor area. The premotor area is concerned with voluntary motor function dependent on sensory inputs or coordinative rough movements among many muscles. The medial surface of the frontal lobe, anterior to the M-I (area 4) and extensions of the premotor area (area 6), is called the supplementary motor area. This area plays an important role in the sequential formation of multiple movements. Two areas giving rise to districted movements are known: the motor speech area (Broca’s area, area 44, 45) and the frontal eye field (area 8). The motor speech area is located mainly in the inferior frontal gyrus of the left hemisphere, which can be considered to be a part of the premotor area. The motor speech area plays a key role in speech behaviors that are formed by receiving the information from Wernicke’s area through connecting fibers named the arcuate fasciclus. The frontal eye field is bilaterally located in the middle frontal gyrus, anterior to the premotor area. The activity of this area initiates intentional saccades to the visible target. (Saccade eye movements are rapid refixations of visual attention from point to point, where the visual interest shifts discontinuously.) The most anterior portion of the frontal lobe, including the frontal pole, is called the prefrontal (association) cortex, which is well developed, especially in humans. Terms applied to the function of this cortex include judgment, will, motivation, expectation, initiation, planning, preparation, thought, memory, and so on, which can be subsumed by the term “intrinsic motor function”. Approximate locations of areas for these motor functions are shown in Fig. 4-13. [A Different Angle 4-10] Two sensory homunculi--the somato homunculus and face homunculus: In the brain, sensory signals are processed separately from sensory modalities, and the responsible neurons tend to be arranged in the order of the cellular organization of their receptors. Somatotopic representation of the receptors of the body and head in the primary somatosensory cortex of primates, including humans, is the most typical example, which is expressed as a picture of a small human, called homunculus (Fig. 4-14). The orderly representation is also observed in the visual and auditory nuclei of the brain, the retinotopic organization of retina cells and tonotopic

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organization of tonal frequencies. The somatotopic, retinotopic, and tonotopic organizations are topographies within the single sensory modalities. However, areas for processing sensory information from the eyes, ears, nose and tongue are also topographically organized among them in the posterior half of the cerebral hemispheres. The primary visual cortex is located around the calcarine sulcus of the occipital lobe. Although the signals spread variously to the anterior, there is no doubt that almost all visual information is processed in the posterior regions of the posterior half. The superior surface of the temporal lobe is involved in analyzing auditory information. The olfactory relating nuclei collect at the medial floor of the forebrain. The gustatory center is located in the anterior insular cortex with an extension to the frontal operculum, which is rostral and deep to the somatosensory representation of the tongue, and proximal to the olfactory areas. Considering these locations in total, we are aware that their organization is analogous to the arrangement of their receptor organs—the eyes, ears, nose, and tongue—in the face with the front side back. The representations form what might be termed a “sensory face homunculus”, oriented backward in the posterior half of the brain, as illustrated in Fig. 4-15. This leads to the following three discussions.

Figure 4-15. Shematic illustration of the two sensory homunculi, “face” and “somato”, represented in the posterior half of the brain. The “face sensory homunculus” is expressed in the sensory lobes (posterior half) with the front side back, where the areas for processing vision, hearing, olfactory, and taste information are expressed respectively with their receptor organs, eyes, ear, nose, and tongue. The classic “somatosensory homunculus” that also appears to be oriented backward is drawn together in the primary sensory cortex.

The first concerns the orientation of the somatosensory homunculus in the primary somatosensory cortex. The organization of body parts and the head in the medio-lateral representation of the area is known in detail, but it is not clear in which direction the homunculus is oriented, forward or backward. Which side of the foot is indicated at the foot area? At its sole or instep? At the trunk area? At its abdomen or back? At the hand area? And at its palm or back? It seems to be natural to consider that the somatosensory homunculus is also oriented in the same direction as the sensory face homunculus. Kaas and co-workers demonstrated in primates that complete and systematic representations of the body parts exist in

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area 3b and 1, which are roughly mirror-images of each other: the abdomen is represented at the 3b-1 border and the back is represented at both the rostral border of area 3b and the caudal border of area 1. However, they concluded that area 3b is the proper area for cutaneous sensation in the primary sensory cortex, considering the evolutionary aspect of the somatosensory cortex of primates, which consists of the traditional understanding and fits to the orientation of the face homunculus. Second is representation of motor functions in the frontal lobes (or anterior half) of the brain. Do they also form a face homunculus as in the sensory half? Many motor functions are, in general, difficult to correlate with a single sensory modality. For example, mouth movements are involved in vocalization and mastication. However, there are areas, the functions of which connect fairly directly with the sensory information of single modality. The frontal eye field and neighboring supplementary eye field are such examples. They are located in the dorsal surface of the anterior portion of the frontal lobe, and are involved in various types of eye movements, where the feedback of visual information might play an important role. In general, the anterior portion of the frontal lobe is involved in functions for future action, such as judgment, will, motivation, expectation, initiation, planning, preparation, memory, and so on, most of which are accompanied more or less with an intrinsic imaginary process that can be considered to be a sort of visual motor function. The motor area for speech, known as Broca’s area, is located in the inferior lateral region of the left frontal lobe. The area functions fully supported by the sensory speech area, known as Wernicke’s area, which is a part of the auditory cortex of the left temporal lobe. Areas for oral functions such as chewing, swallowing, and tongue movements, which relate deeply with gustatory sensation, are understood to be located in the frontal orbital cortex that is more rostral to the gustatory sensory cortex. (In the olfactory system, it is uncertain to which motor architecture the nuclei belong.) Although the shape is fairly fuzzy, these organizations suggest that motor functions are also arranged like the face formation (the motor face homunculus) that orients forwards. Third is the orientation of the homunculus in the primary motor cortex, the somatomotor homunculus. Contraction of the skeletal muscles of the body and head is controlled by descending signals mostly from the contralateral primary motor cortex located just anterior to the central sulcus. The body and head are represented in the area with the homunculus in a fashion similar to the primary somatosensory area, but its abdomen-back (or flexor-extensor muscle) representations are uncertain. It also seems to be rational to consider that the somatic motor homunculus orients in the same direction as the motor face homunculus. This consideration is not beyond estimation, but it is worth examining whether any functional differences exist in the anterior-posterior organization of the primary motor cortex. It can be concluded that sensory and motor functions in the cerebral cortex compose a back-to-back mirror image across the central sulcus, which will be discussed more in Chapter 6.

* Basal Ganglia Masses of gray matter situated within the cerebral hemispheres are collectively called the basal ganglia (nuclei), which are involved in motor functions. Although definitions of the term “basal ganglia” differ between neurophysiologists and anatomists, three structures, caudate nucleus, putamen, and globus pallidus, are held in common (Fig. 4-16).

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Functionally, the substantia nigra, subthalamic nucleus, and amygdaloid nucleus are frequently included in the basal ganglia. The caudate nucleus is an elongated extension of the putamen, so together the two are frequently called the (neo)striatum (or corpus striatum). The globus pallidus is frequently called the paleostriatum. The amygdaloid complex that is phylogenetically oldest in the basal nuclei is the archistriatum. The major function of the basal ganglia is the control of movements coordinating with the cerebellum and the corticospinal system, and this system is referred to as the extrapyramidal system, as descending fibers originating from these nuclei do not run down in pyramidal tracts. The outline of the neural connection of the basal ganglia to other structures is as follows. The caudate nucleus and putamen (neostriatum), neurons of which have an enormous number of dendrites covered with spines, are thought to receive inputs mainly from a wide area of the cerebral cortex through the corticostriatal pathway, through the internal capsule. Output signals from the neostriatum descend into such nuclei as the globus pallidus, substantia nigra, retricular formation, and possibly the thalamus. (Although part of the substantia nigra is located in the midbrain, its main connections are thought to be with the neostriatum.) The output of the globus pallidus is thought to direct mainly to the thalamus, and that of the substantia nigra back to the neostriatum. The neostriatal neurons receive the excitatory effect of glutamate from the corticostriatal fibers, and exert a suppressive effect of gammaaminobutyric acid (GABA) on neurons in the substantia nigra.

Figure 4-16. Horizontal section of the cerebrum, to show main cell groups of the thalamus and the anatomical relation of major components (caudate nucleus, putamen, and globus pallidus) of the basal ganglia. (Redrawn from Felten, and Józefowicz 2003.)

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[A Different Angle 4-11] Disease of the basal ganglia: Input-output signal flows among the basal ganglia, and their related structures are drawn quite complexly in most publications dealing with brain function, but it seems to be difficult to understand from diagrams how the neural circuits correlate with the specific motor functions of the basal ganglia. The essential point of the basal ganglia system seems to be that neurons in the cerebral cortex exert a strong suppressive effect on many nuclei located in the deep region of the brain through so called glutamic and GABAnergic neurons of the basal ganglia. We aware that this is, in a sense, similar to the affection of the cortex on the cerebellum neurons: inputs from the cerebral cortex via climbing fibers exert suppression strongly on output nuclei located deep in the cerebellum through cerebellar cortex neurons, Purkinje neurons, where GABA is also used as the neurotransmitter. The similarity between these two suppressive systems leads to the following estimation. The cerebellum and basal ganglia are older nervous systems involved in basic (or primitive) movements. Muscular movements of humans are quite elaborated, which apparently is due to the highly-organized nervous system of the cerebral cortex, where some functions of the cerebellum and the basalganglia-relating neurons must be suppressed to execute the elaborate movements controlled by the cerebrum system. This cerebrum dominance in highly organized movements of humans must be the main reason why the GABAnergic neurons exist more specifically in both the cerebellum and the basal ganglia. It has been noticed that certain species of abnormal movements in humans are closely related with disease of the basal ganglia and related structures. They include chorea, hemiballism, Huntinton’s disease, and Parkinson’s disease. The disorders are characterized by various irregular movements. They can be also explained to be the state of losing the balance between the excitatory and suppressive effects on neurons controlling the corresponding muscles, and perhaps the best description about basal ganglia disorders might be “involuntary unwilling movements”. The state of involuntary unwilling musculature movements can be explained to be due to the loss of the suppressive effect of the cerebral cortex on the lower motor system relating the basal ganglia. For example, Huntington’s disease that is accompanied with choreiform movements is characterized by involuntary jerking movements, and it is estimated to arise mainly from degeneration of GABAnergic neurons (and partially cholinergic neurons) in the neostriatum. Most movement disorders related to the basal ganglia system are accompanied by positive (or hyperkinetic) irregular movements, which must be produced by releasing lower motor systems from the suppression of the cerebral cortex. Parkinson’s disease is a well-known movement disorder that is also deeply related to illness of the basal ganglia. The disease accompanies such syndromes as rhythmical tremor (especially in a fixed posture), a kind of rigidity, and hypokinegia. Reduction of the neurotransmitter dopamine in nuclei, mainly of the substantia nigra, is thought to attack this disorder. How dopamine acts in the basal ganglia system is not completely understood, but intravenous dosages of L-dopa, a precursor of dopamine, can improve symptoms in many patients. The disorder might not completely deny the participation of GABAnergic neurons. Neurons in the substantia nigra are thought to project to the neostriatum, so degeneration of its dopaminergic neurons may weaken the suppressive effect of the basal ganglia.

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Kunzle, H. (1975). Bilateral projections from precentral motor cortex to the putamen and other parts of the basal ganglis: An autoradiographic study in Macaca fascicularis. Brain Res., 88: 195-209. Martin, J.H. (2003). Neuroanatomy (3rd ed.). McGraw-Hill, New York. Merzenich, M.M., Kaas, J.H., Sur M. and Lin, C.S. (1978). Double representation of the body surface with cytoarchitectonic areas 3b and 1 in “SI” in the owl monkey (Aotus trivirgatus). J. Comp. Neurol.,181: 41-74. Moore, R.Y. (1997). Circadian rhythm: basic neurobiology and clinical applications. Annu. Rev. Med., 48: 253-266. Mushiake, H., Inase, M. and Tanji, J. (1990). Selective coding of motor sequence in the supplementary motor area of monkey cerebral cortex. Exp. Brain Res., 82: 208-210. Nelson, R.I., Felleman, D.J. and Kaas, J.H. (1980). Representations of the body surface in postcentral parietal cortex of Macaca fascicularis. J. Comp. Neur.,192: 611-643. Nolte, J. (1999). Human Brain: An Introduction to Its Functional Anatomy (4th ed.). Mosby, Inc., St. Louis. Penfield, W. and Boldrey, E. (1937). Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain, 60: 389-443. Penfield, W. and Rasmussen, T. (1950). A clinical study of localization of function. In: The Cerebral Cortex of Man. Macmillan Pub. Co., New York. Rizzolatti, G., Luppino, G. and Matelli, M. (1998). The organization of the cortical motor system: new concepts. Electroencephalo.Clin. Neurophysiol.,106: 283-296. Sakurai, M. (1987). Synaptic modifiability of parallel fiber-Purkinje cell transmission in vitro guinea-pig cerebellar slices. J. Physiol., 349: 463-480. Schall, J.D., Morel, A. and Kaas, J.H. (1993). Topography of supplementary eye field afferents to frontal eye field in macaque: implications for mapping between saccade coordinate systems. Visual Neurosci.,10: 385-393. Swanson, L.W. and Sawchenko, P.E. (1983). Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu. Rev. Neurosci., 6: 269-324. Tanji, J. and Hoshi, E. (2001). Behavioral planning in the prefrontal cortex. Curr. Opin. Neurobiol., 11: 164-170. Ungerleider, L.G. and Haxby, J.K. (1994). "What” and “where” in the human brain. Curr. Opin. Neurobiol., 4:157-165. Vandesande, F. and Dierickx, K. (1979). The activated hypothalamic magnocellular neurosecretory system and the one neuron – one neurohypophysial hormone concept. Cell Tissue Res., 200: 29-33. Wallis, J.D. and Miller, E.K. (2003). Neuronal activity in primate dorsolateral and orbital prefrontal cortex during performance of a reward preference task. Eur. J. Neurosci.,18: 2069-2081.

Chapter V

Sensory and Motor Nervous System Various types of receptors exist in the human body. They can be generally classified into the three groups: interoceptors, proprioceptors, and exteroceptors. Interoceptors monitor the inside situation of the body, such as chemical and physical conditions of the blood or distention of the various internal organs. Propioceptors monitor tension of muscles and joint ligaments, which play an important role especially in movements of the body parts. Exteroceptors monitor external environments, such as vision, hearing, smell, taste, and touch (or pressure), former four senses of which are frequently called special senses. (Vestibular receptors are commonly classified as proprioceptors, whereas receptors for pain and temperature receptors, as well as touch receptors are frequently called contact, or mechanical, receptors.) Receptor cells produce an electrical potential (also known as a receptor potential or generator potential) in response to an appropriate stimulus, which is changed into electrical discharges (impulses or action potentials) through a synaptic transudation process in most sensory systems. The discharges, the frequency of which corresponds to the intensity of sensory stimulus, are conducted on the axons of neurons. Almost all of the primary sensory information enters the CNS and is processed and relayed to the motor system. Proprioceptors and exteroceptors are involved mainly in the control of skeletal muscle through the somatic motor nervous system, whereas interoceptors are involved mainly in controling or adjusting the function of internal organs and tissues through the autonomic (motor) nervous system.

(1) Somatic Sensory-Motor System Spinal segments are related systematically to areas of skin and muscles that originate from somites of the mesoderm. Proprioceptors and exteroceptors are inclusively called somatic sensory receptors. These receptors have been well investigated since their locations and stimulus qualities are simple and clear. Muscles are supplied with two types of proprioceptors, the muscle spindle and the tendon organ, and the cutaneous is innervated by a wide variety of sensory end organs (exteroceptors), such as the Merkel ending, Ruffini ending, Pacinian corpuscle, Meissner corpuscle, Krause ending, and free nerve ending.

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(There are also receptors on and under the cutaneous, whose forms do not necessarily adapt to any of the classified receptors.) Although these receptors respond best to one stimulus quality (adequate stimulus) of touch, pressure, vibration, pain, and temperature, many show more or less multiple sensitivities to the stimuli. Sensory signals (discharge forms) from these receptors enter the spinal cord and brainstem and project to the cerebrum (and cerebellum) through ascending tracts and intermediate nuclei, which turn to the motor neurons in the brainstem and the spinal cord through descending tracts. This somatic sensory-motor system primarily plays a role in the control of skeletal muscles. The pathways of the somatic ascending and descending fibers in the CNS are described in Chapter 4. In this section it will be quickly overviewed once more from the viewpoint of sensory-motor relations.

* Somatic Sensory Pathways Neural signals from receptors in the skin and muscle enter the spinal cord via the dorsal roots of spinal nerves, which are segregated into two main general sensory systems in the spinal cord. One is the dorsal column system, which carries signals concerned with discriminative aspects of sensation, such as touch, pressure, and proprioceptive sensations, such as the position or movement of limbs (Fig. 4-3). Most fibers of this type in the dorsal roots of spinal nerves are strongly myelynated. In this system, branches of the primary sensory fibers enter the ipsilateral dorsal funiculi (the fasciculus gracilis and the fasciculus cuneatus) and ascend to the nuclei (the nucleus gracilis and the nucleus cuneatus) in the lower medulla. Second order axons from these nuclei decussate in the medulla and ascend as the medial lemniscus to the ventral posterolateral nucleus (VPL) of the thalamus. The other general sensory system is the anterolateral (or spinothalamic) system, which carries signals for pain, temperature, and less discriminative mechanical sensations (Fig. 4-3). Myelination of fibers of this type in the spinal dorsal roots is generally weak, which might indicate that this system is older physolgentically than the dorsal column system. In this system, the spinal dorsal root fibers synapse to neurons at the dorsal gray horn. The spinal neurons give rise to secondary fibers that cross the midline and ascend in the opposite anterolateral white column (anterolateral pathways) (Fig. 4-2 A). The anterior spinothalamic tract is one of the major anterolateral pathways, which run together with the medial lemniscus and also end in the VPL nucleus of the thalamus. There is a fiber bundle called the spinoreticular tract in the anterolateral pathways, which projects mainly to the reticular formation of the brainstem, and then projects to the thalamus nuclei: the spinotericular fibers are known to relate dominantly to pain sensation. Thalamic neurons for the dorsal column and spinothalamic systems project to the same side of primary somatosensory cortex (S-I) (and maybe to the same side of secondary sensory cortex (S-II) and the parietal association cortex, as well). The S-I is subdivided into area 3a, area 3b, area 1, and area 2, and a major projection of VPL neurons for cutaneous sensation is considered to be areas 3b and 1. After all, somatosensory pathways, representing spinal nerves project to the contralateral S-I. This crossing of sensory pathways, which is quite a curious property, results in the sensory loss of the side of the body opposite to a damaged side of the S-I.

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[A Different Angle 5-1] Why is pain sensation conveyed by low velocity (unmyelinated) fibers? : Fibers in the spinal dorsal roots for discriminative sensations such as touch and pressure are strongly myelinated, and they ascend in the dorsal funiculi, whereas fibers for pain and temperature are weakly myelinated, and their information ascends via the anterior spinothamic tract. The somatosensory information conveyed by the dorsal funiculi is involved in consciousness and in fine movements of the foot and hand, whereas the main information conveyed by the spinothalamic system is about nociception, and it plays an important role in the protection of organisms. From the viewpoint of maintaining the organism’s life, the nociceptive sensation is more important. Further, the spinothalamic tract runs through the ventral portion of the spinal cord, whereas the dorsal funiculi, its dorsal portion. From the viewpoint of protection of the nervous system, the ventral pathway seems to be more profitable. The major merit of the myelination of axons is an increase of conduction velocity of the impulse: it is apparent that myelinated nerves are phylogenetically new and functionally progressive. The question arises about why the nociceptive sensation, which seems to be quite important in protecting the organism, is conveyed by the slower velocity fibers. The myelinated fibers certainly exhibit a fine property in the conduction of impulses, but they are known to be weak, especially to virus infection, and are known to be inferior in their regeneration ability. Actually, uncompleted myelimation of nervous fibers in the brain is known to cause serious disability in mental function, and when the myeline sheath is stripped from peripheral sensory fibers, to cause disorders of sensory perception. The fact that pain and temperature are conveyed by unmyelinated fibers indicates that organisms have a priority toward certainty rather than advantage.

Primary somatosensory axons for proprioception from muscles and joints of mainly lower limbs terminate at restricted neurons in the dorsal horn, at the so-called Clarke’s nucleus (Fig. 4-2 B). Most of the secondary fibers ascend as the dorsal spinocerebellar tract (Fig. 4-2 A) which projects to the ipsilateral vermis of the cerebellum through the inferior cerebellar peduncle. Primary somatosensory axons for proprioception of arm and thoracic muscles project to the so-called lateral cuneate nucleus (Fig. 4-10) in the caudal medulla, which is analogous to Clarke’s nucleus of the spinal cord. Secondary fibers from this nucleus form the cuneocerebellar tract, whose projection manner to the cerebellum is similar to that of the dorsal spinocerebellar tract. The sensory information from receptors in muscles and joints is considered to project also to the S-I, mainly areas 3a and 2, through the dorsal column-medial lemniscus system, as well as to the cerebellum. The proprioceptive sensation, as well as the cutaneous sensation, play a key role in controling muscular actions. Somatic sensory information of the facial region projects to the ventral posteromedial nucleus (VPM) of the thalamus. Three sensory nuclei are associated with trigeminal afferents. The main sensory nucleus receives heavily myelinated afferents concerned with discriminative tactile and proprioceptive sensations, which is the trigeminal homologue of the dorsal column nuclei. It gives rise to two ascending pathways: one is the collection of fibers that cross the midline, join the medial lemniscus, and terminate in the VPM nucleus of the thalamus, and the other is the collection of fibers, called the dorsal trigeminal tract, that

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project ipsilaterally to the VPM (Fig. 4-3). Trigeminal afferents conveying pain and temperature descend through the spinal trigeminal tract and synapse to neurons in the spinal trigeminal nucleus. Second-order neurons of the spinal trigeminal nucleus, homologous to spinothalamic tract neurons, give rise to a crossed ascending pathway, join the spinothalamic tract and also terminate in VPM (Fig. 4-3). The third sensory nucleus is called the mesencepharic nucleus that is thought to be essentially a bit of the trigeminal ganglion located within the midbrain. The neurons are pseudounipolar: their peripheral processes are distributed mainly to muscle spindles in jaw closer muscles and their central processes connect directly with neurons in the trigeminal motor nucleus. Third-order neurons for the trigeminal system in the VPM project to the same side of the lateral portion of S-I.

* Somatic Motor Pathways Most descending neurons originate from the primary motor cortex (M-I) (and maybe also from other areas of the frontal lobe such as the supplementary motor and the premotor cortices). They descend to the basal ganglia, red nucleus, pontine nuclei, motor cranial nerve nuclei (on both sides), and the ventral horn neurons of the spinal cord (contralateral side), whose fibers form various descending tracts. A major one of these tracts is the corticospinal tract. Among fibers in the corticospinal tract, large myelinated fibers originate from so-called Betz cells (large pyramidal cells) in layer-V of the primary motor cortex. They descend through the internal capsule, cerebral peduncle, basis pons, and medulla pyramid. Most fibers of the pyramid (pyramidal tract) decussate at the junction between the medulla and the spinal cord (pyramidal motor deccusation) and descend in the lateral corticospinal tract to project to the α- (and γ-) motor neurons in the ventral horn of the spinal cord (Fig. 43): α - motor neuron controls directly muscle contraction and γ -motor neuron adjusts suitably its strength via proprioception process of the muscle. Although most fibers of pyramidal tracts decussate, there are fibers that do not cross in the pyramidal decussation, and continue to descend ipsilaterally, forming the anterior corticospinal tract, which also terminates on motor neurons or interneurons of the anterior horn. Most of these neurons are understood to cross in the anterior white commissure before synapsing. In some respects, the descending manner of the lateral corticospinal tract and the anterior corticospinal tract resemble the ascending manner of the dorsal funicului and the spinothalamic tract, which leads to the estimation that the lateral corticospinal fibers may be driven dominantly by the sensory signals conveyed by the dorsal funiculi, and the anterior corticospinal fibers, by the signals conveyed by the anterior spinothalamic tract. Fiber collection in the corticospinal tract, which originates mainly from the lateral portion (face area) of M-I, is called the corticobulbar tract (Fig. 5-1 A). This tract projects to the motor nuclei of cranial nerves, commonly in bilateral fashion. (The facial nerve and the hypoglossal nerve are understood, however, to receive predominantly contralateral signals.) The corticobulbar tract function in controlling muscles in the face, head and neck.

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Figure 5-1. A: Diagramatic presentation of descending pathways of the so-called pyramidal (left half of the figure) and extrapyramidal (right half of the figure) systems. B: Diagramatic representation of three hierarchical sensory-motor systems--cerebral system, cerebellum system, and actual system--and estimated signal flow among them. In each figure, “t.” means tract, and “n.”stands for nucleus or nuclei.

The brainstem contains many motor nuclei, axons of which also project to motor neurons of the spinal cord: most of them receive inputs from the M-I and simultaneously project to spinal motor neurons. Fibers originating from the red nucleus form the rubrospinal tract, and they decussate in the ventral portion of the tegment, descending laterally in the brain stem and the dorsolateral column of the spinal cord (Fig. 4-2 A), and terminating on motor neurons in the dorsolateral area of the spinal gray matter, probably on the neurons for controlling distal muscles of the limbs. Fibers originating from vestibular nuclei (medial and lateral) form the vestibulospinal tract (medal and lateral); fibers from the pontine reticular formation (medial and lateral) form reticulospinal tracts (medial and lateral); and fibers from the superior colliculus form the tectospinal tract. These three tracts descend in the ventral column (Fig. 4-2 A): their decussation is not obvious, but the neurons might partially cross. The vestibulospinal, reticulospinal, and tectrospinal tracts are understood to function in controlling basic postures or movements, and thought to be phylogenetically the oldest component of the somatic motor system. (So the ascending anterolateral pathways might have strong connection to these motor tracts.)

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Difference in the projection of motor neurons between limbs and facial areas: All descending fibers in the corticospinal tract cross and project to spinal motor neurons on the contralateral side. On the contrary, the corticobulbar tract, which originates mainly from the face area of M-I, projects bilaterally to motor nuclei of the cranial nerves. It is difficult for us to control separately one of the paired muscles distributing the facial area. For instance, most people cannot move only one eyebrow, cannot shut only one eye, cannot move differentially their two eyes balls, cannot move differentially their two ears, and cannot twitch only one nostril. In addition, chewing muscle activities on the balancing side never cease even in lateral mastication. These difficulties in independent movement between the right-sided and left-sided elements of the organs in the facial region apparently correlate with the bilateral projection of corticobulbar fibers on neurons innervating the muscles for the movements. On the contrary, it is easy for us to control separately the movements of our paired legs or paired arms. This owes to the fact that almost all descending fibers in the corticospinal tract project to spinal motor neurons predominantly on one (contralateral) side of the spinal cord. This difference in the projection manner of descending fibers for the face area and limbs is also observed in sensory nerve projections (Fig. 4-3). Almost all ascending fibers of dorsal funiculi and the anterior spinothalamic tract, which convey general somatic sensory information of limbs and trunk, project to the opposite half of the thalamus (and of the cerebral hemisphere). On the contrary, sensory fibers of the trigeminal nerve, which convey tactile and proprioceptive sensations for the face and head, are thought to ascend bilaterally to the thalamus and cerebral hemisphere. Furthermore, in our visual, auditory, and vestibular systems, our primary sensory fibers are known to ascend bilaterally and project to the corresponding nuclei (via contralateral dominance). (Projections of the taste and olfactory information to the cerebral hemisphere are understood to be ipsilateral, but secondary taste fibers of the solitary nucleus project to the hypogrossal and dorsal motor nucleus bilaterally, and neurons of the anterior olfactory nucleus, are known to send their axons to the opposite olfactory bulb.) In any case, mono-lateral distribution of sensory and motor neurons in the facial part is weak, which may relate to the position of the pyramidal motor decussation and the medulla sensory decussation in the CNS.

* Sensory-Motor System in the Cerebellum The major inputs to the cerebellum are from three sources: (1) somatic sensory signals of mainly the muscular proprioception from the spinal cord; (2) sensory signals arising from the primary vestibular end organs as well as from vestibular nuclei in the brainstem; and (3) signals arising from the brain cortex. They are considered to input, respectively, to the anterior lobe (spinocerebellum), flucculonodular lobe (vestibulocerebellum), and posterior lobe (cerebrocerebellum) (Fig. 4-9 A). These three inputs are segregated within the cerebellar white matter into two fiber systems: the climbing fiber system and the mossy fiber system (Fig. 4-10). Climbing fibers, the main origins of which are thought to be the contralateral inferior olivary nucleus via the inferior cerebellar peduncle, exert a strong excitatory effect on Purkinje cells, which lie widely in the cerebellar cortex. Mossy fibers,

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the main origins of which are thought to be the spinal cord (via the spinocerebellar tracts), brainstem reticular nuclei, pontine nuclei, and the vestibular system, synapse to neurons in the granule cell layer of the cortex, and fibers of granule cells also synapse to the Purkinje cells through called the parallel fiber pathway. Although the distinct origin of input fibers for each of the climbing and mossy system remains yet uncertain aspect, it is certain that Purkinje cells receive excitatory effects from both the climbing and mossy system, in which the effect of the climbing system is stronger than that of the mossy system. Activation of Purkinje cells then project a strong inhibitory effect on deep cerebellar nuclei that are bilaterally embedded in the cerebellar white matter: ascending fibers in both the climbing and mossy systems are also known to send collaterals to cells of deep nuclei before continuing to cerebellar cortex (Fig. 4-10) and activate them appropriately. Although deep nuclei of the cerebellum receive both the excitatory and inhibitory effects complexly from the two segregated sensory systems, key point of these connections is that the climbing fiber system suppresses strongly activities of the deed nuclei. Extracerebellar targets of the deep nuclei outputs are distributed widely from the medulla to diencephalons: they are the vestibular and reticular nuclei of the brainstem (from the fastigial nucleus), the red nucleus in the midbrain and the inferior olivary nucleus in the medulla (from the interposed nucleus), the thalamus (from the dentate and interposed nuclei), and the hypothalamus (from all deep cerebellar nuclei). The projection of fibers originating from the fastigial nucleus is known to be ipsilateral, whereas fibers originating from the dentate and interposed nucleus decussate at the superior cerebral peduncles. [A Different Angle 5-3] The extrapyramidal system and the hierarchical structure of motor function: The main fibers of the corticospinal tract originate from the region of the primary motor cortex, where the upper and lower limbs are represented. They pass through the internal capsule, cerebral peduncle, pons, and pyramid of the medulla, then decussate and descend in the lateral column of the spinal cord. This is popularly called the pyramidal system (Fig. 5-1 A), which is deeply involved in voluntary movements of the limbs. Basal ganglia, composed of nuclei situated under the cerebral cortex, are known to carry an important aspect of movement too. Although the functional role of their individual components is not completely understood, the basal ganglia, as a collective whole, work in collaboration with the cerebral cortex in various types of movements. Damage of the basal ganglia elicits characteristic abnormal movements, most of which arise involuntary (“A Differential Angle 4-11”). Such movements are often referred to as extrapyramidal disorders, and the motor system related to the basal ganglia is popularly called the extrapyramidal system (Fig. 5-1 A). However, extrapyramidal disorders are known to occur not only due to damage to the basal ganglia but also to brainstem nuclei, such as the substancia nigra, red nucleus, reticular formation, and vestibular nucleus, all of which have tight connections with cerebellar deep nuclei. Therefore, there might be disorders whose origins lie within the cerebellum among the so-called extrapyramidal disorders. Every movement can be organized more or less hierarchically from simple to complex. Most voluntary (goal-directed) movements are performed through the smooth coordination of body parts, but constructed by reflex and stereotypical (involuntary) movements as their background. For example, walking is voluntary leg movement controlled by the cerebral

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cortex, but our paired legs move alternatively through the excitatory and inhibitory spinal reflex circuit, where the factors such as our walking rhythm, which is stereotypical and almost unconscious, might be formed at a higher level of the CNS, such as in the brainstem, basal ganglia or cerebellum. Mastication is also a voluntary movement of the jaw, controlled by the cortical mastication area (chewing center) of the cerebral cortex. However, the actual neural base is a sensory-motor reflex (jaw-opening and jaw-closing reflexes), and the chewing rhythm is thought to be formed at the rhythm-formation area in the brainstem. It appears as if movements in vertebrates, especially in humans, are constructed hierarchically from the highest (conscious) to lowest (automatic) levels. The idea of a hierarchical construction of the motor system was first formulated by John Hughlings Jackson (1853-1911). From a study of epileptic seizures, he concluded that motor function has evolved from simple to elaborate, as reflected in the human nervous system in our ability to control automatic movements at lower levels, such as the spinal cord and brainstem, and to control purposive movements at higher levels, such as the primary motor cortex, premotor cortex, and prefrontal cortex. He also suggested that the higher levels normally exert control over the lower levels, and that this control can be either excitatory or inhibitory. This leads to the notion that interruption of higher levels could release the function of lower levels, if the control is inhibitory, and that such interrupted release might result in hyperactivity of relating muscles, as occasionally observed in extrapyramidal (basal ganglion) disorders and epileptic seizures. Many neural components, such as motor regions of the cerebral cortex, basal ganglia, cerebellum, various brainstem nuclei, and spinal cord motor neurons, need to work cooperatively to execute movements sufficiently. The neural mechanism of movements can be understood in a more straightforward manner if the motor components of the CNS are reclassified hierarchally into the following three systems: (1) the cerebral system, including the cerebral motor cortex and basal ganglia; (2) the cerebellum system, including cerebellar deep nuclei and brainstem neclei; and (3) the actual system that includes the spinal cord and brainstem reflex circuits (Fig. 5-1 B). In these hierarchical systems, which are arranged based on Jackson’s concept, the cerebral system makes the plan of movement which is changed adequately through sensory feedback; the cerebellum system forms the stereotypical movement that is modulated by the cerebral system; and the actual system directly practices the movement ruled by the two higher systems through spinal cord reflex circuits. The basal ganglia and Purkinje cells, which show a strong inhibitory effect on the relating nucleus, suggest strong control of the cerebrum system on the cerebellum system (“A Different Angle 4-11”), and the control of the cerebellum system on the actual system is suggested from the fact that γ-motor neurons in the ventral horn of the spinal cord, which adjust muscular activities through the proprioceptive information, receive complex effects of inhibition and excitation from the brainstem nuclei. When we walk voluntary toward an object or our destination, for instance, the following sequence is estimated. How we move legs is first programmed and the movement is then triggered, both events being performed by the cerebrum system; then our two legs move alternatively due to the spinal cord reflex system, where the basic stepping rhythm and velocity is constructed almost unconsciously by the cerebellum system, which is maintained until the aim and situation of the movement behavior change. Movements, especially quick or short time movements, could be achieved only by the pyramidal system, but most voluntary movements are performed more satisfactory if the extrapyramidal system would participate in them.

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(2) Taste (Gustatory) and Olfactory Systems We are surrounded by many different chemicals, which are sampled by the olfactory and taste systems. Their taste aspect is sensed mainly by the tongue, and odor aspect by the nose, which respectively produce gustatory sensations and olfactory sensations in the CNS. The chemical sensations are, in a sense, somewhat primitive but important in detecting and selecting nutritive substances, and their information is conveyed by corresponded cranial nerves. The tongue and oropharyngeal cavity also sense somatosensory stimuli such as thermal, tactile, pressure, and pain, and the somatosensory system contributes to olfactory experiences like irritating smell. The information of somatosensory stimuli is relayed to the brain by a different nerve, the trigeminal nerve, branches of which innervate oral and nasal mucosa.

* Taste System Taste receptor cells (Fig. 5-2 A1) are located in taste buds (Fig. 5-2 A2) that are found mainly on papillae distributed on the tongue, and less frequently on the palate and epiglottis. Primary fibers in the facial (VII), glossopharyngeal (IX), and vagus (X) nerves innervate taste buds, respectively, in the anterior two-thirds of the tongue, in the posterior third of the tongue, and in the epiglottis, whose cell bodies lie in the geniculate ganglion, petrosal ganglion (inferior ganglion of the glossophryngeal nerve), and nodose ganglion (inferior ganglion of the vagus nerve) (Fig. 5-2 B2), respectively. Sensory signals of these fibers are input to the nucleus of the rostral part of the solitary tract in the medulla, which send ipsilateral projections to the ventral posteromedial nucleus (VPM) of the thalamus (Fig. 5-2 B2). The thalamus fibers project to the so-called gustatory cortex, located in the insula cortex near the base of the central sulcus (Fig. 5-2 B1). Neurons in the gustatory cortex project in turn to the orbital cortex of the frontal lobe, where the gustatory information might participate in voluntary aspects of motor functions, such as chewing, swallowing, and tongue movements. Other types of ascending gustatory fibers are known. They project to the hypothalamus and the amygdaloid nucleus (possibly via the parabrachial, or reticular nucleus in the pons) without intermediating the thalamus and are involved mainly in emotional behaviors in humans. Tongue movements that are controlled by the hypoglossal nerve (XII) and the salivary secretion that is induced through the facial (VII) and glossopharyngeal (IX) nerves are the most direct reactions to the gustatory inputs. Axons originating from the solitary nucleus for taste sensations also project to neurons in hypoglossal nuclei and salivatory nuclei (Fig. 5-2 B2). Taste stimulation is necessarily accompanied with mechanical stimulation at the tongue surface. In actuality, mechanical receptors, Merkel endings and free nerve endings exist in each of the papillae distributed on the tongue. These are trigenimal nerve endings monitoring the food texture, the position of chewed food on the tongue, and the clustering grade of food in mastication.

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Figure 5-2. Structure of the taste bud (A1), cross section of fungiform papilla (A2), projection area of taste neurons of the thalamus (VPM) to the cerebral cortex (cross section through near the central sulcus) (B1), and afferent pathways of the taste signal in the brainstem (dorsal view) (B2). B2 shows simultaneously peripheral taste nerves, the chorda tympani nerve (a branch of the facial nerve (VII), glossopharyngeal nerve (IX), and vagus nerve (X), and their ganglia, geniculate ganglion, petrosal ganglion, and nodos ganglion (n.; nerve, g.; ganglion). The cranial nerves respectively supply taste buds on the anterior two-thirds of the tongue, those on the posterior third of the tongue, and those on the epiglottis. (Adapted from Pansky, Allen and Budd, 1988, and other multiple sources.)

The trigeminal sensory signals from these mechanosensitive receptors form reflex circuits with motor neurons for mastication (V), salivary secretion (VII, IX), tongue movement (XII), swallowing (X) via the spinal nucleus, the main sensory nucleus, and the mesencephalic nucleus of the trigeninal nerve. In addition, the trigeminal sensory signals are conveyed to the orofacial area of the S-I through the thalamus. [A Different Angle 5-4] Cording mechanism in taste substances: Traditionally, four taste qualities, salty, sour, sweet, and bitter, have been identified as basic taste sensations. (More recently, five basic taste qualities have been proposed, mainly by Japanese investigators, where “umami (in Japanese)” a flavor-taste produced typically by amino acids, such as glutamate, is added to the four basic qualities.) This classification fits the general feeling of human taste, but seems to lack a scientific basis along the lines of the classification of colors into the three basic colors (red, green, blue) used in color production, which might have been the original idea

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behind the four basic taste qualities. Mixing of different wave forms generates new wave forms, but a new taste quality cannot be produced from the mixture of taste substances, whatever the change in their combination and the ratio of mixture among them. It simply results in their blend, as far as some chemical reactions occur among them. (However, new discharge patterns or receptive potentials can be produced on nerves by the stimulation of mixed tastants, because neural signal like the action potential is a sort of wave.) Setting aside the problem of basic taste qualities, we are exposed to a huge number of taste (or chemical) substances. We can also discriminate between most of them. How can the taste system identify so many tastants? If one peripheral fiber corresponds to one chemical, a great number of taste fibers are needed, which would be impossible. An idea referred to as the across fiber pattern theory has been proposed, where different spectra of response across many taste fibers entering into the gustatory center (generally meaning the gustatory cortex at the insula) correspond to each taste sensation. This notion would certainly account for a great number of taste substances. In actuality, most primary taste fibers, as well as taste receptor cells, respond to all of the four (or more) taste qualities with different sensitivities. Apart from whether this across fiber pattern theory is proper or not in actual coding of taste quality, electrical devices for discriminating between chemical substances have been designed and utilized based on this theory. Where output spectra of an array of sensors are analyzed; each of the sensors is designed to have different sensitivities with chemicals of groups, for example, certain chemicals of sweetness. When the sensing property of the sensor array is variously designed, interesting applications might be possible.

* Olfactory System Olfactory receptor cells lie in the olfactory epithelium in the nasal wall of the nasal cavity (Fig. 5-3 A2). The cell body of the receptor cell is situated in the base of the epithelium. The dendritic process with cilia extends to the epithelial surface, and the axon projects to cells (mitral cells) in the olfactory bulb (Fig. 5-3 A1). (The olfactory bulb is an outgrowth from the telencephalon, which develops well in most animals but relatively poorly in humans.) Secondary sensory fibers originating from the olfactory bulb project to the socalled paleocortex (the primary olfactory cortex) through the olfactory tract. The main components of the primary olfactory cortex are the anterior olfactory nucleus situated in the olfactory tract, and the olfactory tubercle (anterior perforated substances), as well as the piriform cortex, entorhinal cortex, and periamigdaloid area in the temporal lobe (Fig. 5-3 B2). Fibers from these in turn project to the hypothalamus, limbic structure (such as the hypocampus), which might relate mainly to emotional responses. Some neurons in the olfactory cortices are considered to send axons to the thalamus (possibly to its dorsomedial nucleus), and then the thalamus neurons (and perhaps neurons in the other olfactory nuclei) send fibers to the orbital surface of the frontal lobe (orbitofrontal olfactory area) (Fig. 5-3 B1), which extends to the anterior insula adjacent to the gustatory cortex.

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Figure 5-3. A1: Neural relation of the olfactory bulb and olfactory epithelium. A2: Location of the olfactory epithelium (filled enclosure) on the superior nasal cavity. B1: Flow of olfactory signal in the ventromedial region of the cerebral hemisphere. B2: Ventral view of main olfactory cortical areas (filled enclosures) terminated by the olfactory tract. (Adapted from Pansky, Allen and Budd, 1988, and other multiple sources.)

First order olfactory neurons, as well as the higher order neurons, respond to multiple odorants, which are similar to taste neurons in their early stage. There is a huge number of odorants in our surroundings, but each odorant is thought to be received by a corresponding specific receptor protein coupled with G-protein. Setting aside the simple question of whether it is possible that receptor proteins for all odorants for human olfactory sensation are present beforehand in olfactory receptor cells, it has been reported that there are approximately 1,000 genes for olfactory reception proteins in the chromosome of the mouse. The entire coding mechanism of the primary olfactory signals is not obvious, but they first converge at so called the glomerulus of the olfactory bulb, and any discrimination is performed as a population of odorants (population coding). Although it is rarely the case that odorants stimulate the olfactory receptors mechanically, sensory endings of the trigeminal nerve (V1 or V2) are innervating into the olfactory epithelium, which might be responsible for the noxious sensation elicited by irritant substances like ammonia.

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[A Different Angle 5-5] Specificity of the olfactory system: Our understanding of fiber pathways and relating nuclei of the olfactory system in the brain is fairly shallow compared with our understanding of other sensory systems. One reason for this fact might be their deep locations in the brain, (and another could be the experimental factor that the stimulating timing of odors cannot be decided critically in the same manner as light or auditory stimuli, which cannot easily be summated as responses, for example, in brain wave recording). It is, however, commonly agreed that olfactory cortical projections of vertebrates, including humans, principally do not relay to the thalamus, which is in contrast with all other types of sensory projection. The olfactory bulb protrudes from the rostral end of the telencephalon, so it makes sense that olfactory signals project to cerebral cortices, taking a short cut without relaying to the thalamus. The direct projection of the olfactory signals to the cerebral cortex seems to be due to the specificity of its location in the development. However, the thalamus is not only architecture which simply relays ascending signals to the cortex, but rather it processes and changes them suitably. Actually, it has been shown that olfactory cortices send axons to the thalamus. The thalamus neurons for olfactory sensation send fibers to the orbitofrontal region adjacent to the area for oral functions such as chewing, swallowing, and tongue movements. This indicates that the olfactory system participates in actual behavior coordinated with the taste system through the thalamus. Another specificity of the olfactory system is the strong neural connection with the limbic system. The limbic system is well known to receive many olfactory inputs and it is estimated to be involved in emotional behaviors. In actuality, many odorants elicit specific emotions. What, however, is “emotion”? Although the definition of "emotion" is fairly vague, an emotion can be interpreted simply to be a transformed action that cannot be achieved in actuality. All emotions, such as sadness, happiness, anger, hatred, and goodwill, are virtual behaviors without movements of the legs and arms. The motor function of the olfactory system was originally the search for food (or prey) and mating, most of which has become indirect in humans. As discussed in “A Different Angle 4-8”, motor behaviors in response to olfactory signals might be changed to virtual behaviors, an emotional response, through the limbic system, and the factors for foods and sexual events occupy yet the large part of our emotions.

(3) Auditory and Vestibular System The auditory sensation arises from the cochlea, and the sensation for position and movement of the head, or vestibular sensation, arises from the vestible. The two sensory organs combine tightly to compose the (membranous) labyrinth, embedded in the temporal bone (Fig. 5-4 A). The auditory signals are conveyed by the cochlear division, and the vestibular signals by the vestibular division of the eighth cranial nerve (vestibulocochlear nerve). The sensory qualities are very different between the two systems, but their structures of receptor cells, called hair cells that are specialized mechanoreceptor cells, and their reception mechanisms are quite similar.

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* Auditory System The cochlea shows a characteristic helical structure. Sound waves incoming to the cochlea through transmitting apparatuses (ossicles) of the middle ear vibrate a fluid (perilymph) in the cochlear duct, which resonates with the site of the basilar membrane corresponding to the frequency. The perilymph vibration stimulates hair cells, the actual receptor neurons, in the so-called Corti organ arranged along the basilar membrane (Fig. 5-4 (B3)). Cell bodies of the primary auditory fibers lie in the cochlea ganglion located in the bony core of the cochlear spiral, peripheral processes of which innervate hair cells of the spiral organ. The central processes of the spiral ganglion neurons project to the dorsal and ventral cochlear nuclei in the pons. Auditory signals from the cochlear nuclei reach bilaterally (contralateral dominant) to the medial geniculate bodies of the thalamus intermediated by such nuclei and pathways as the trapezoid body (crossing point), superior olive (nucleus of the lateral lemniscus), lateral lemniscus (major ascending auditory pathway), and inferior colliculus. Fibers originating from the medial geniculate body project tonotopically to the same side of primary auditory cortex (transverse temporal gyri of Heschl, area 41) on the superior surface of the temporal lobe via auditory radiations (Fig. 55 A). It is known that the vestibulocochlear nerve (VIII) contains efferent fibers too: they originate in the contralateral superior olive and periolivary nuclei in the pons, and terminate on the hair cells, controlling the sensitivity of hair cells, whose mechanism is called an “auditory servomechanism”. It is also known that a loud sound to one ear contracts reflexly both stapedius muscles that are attached to the neck of the stapes through the facial nerves of both sides. The main function of the reflex might be the protection of inner ear apparatuses. Neurons in the primary auditory cortex send axons to the posterolateral region (secondary auditory cortex, area 42) adjacent to so-called the planum temporale that situates caudal to the transverse giri, and the neurons in the secondary auditory cortex project to higher auditory centers in the cortex. In humans, the auditory system is closely related to speech behavior. The posterior part of the superior temporal gyrus (area 22) is called Wernicke’s area or sensory speech area (Fig. 4-13), which is concerned with the comprehension of language. The angular gyrus (ara 39) and adjacent regions, which in part includes the Wernicke’s area, are concerned with comprehension of written language. The posterior part of the triangular gyrus (area 45) and the adjacent opecular gyrus (area 44) in the inferior frontal gyrus, called Broca’s area or motor speech area (Fig. 4-13), is concerned with programming speech. Areas corresponding to Wernicke’s area and Broca’s area cannot be identified in the right hemisphere, so language function is, in most persons, dominant in the left cerebral hemisphere. Damage to Wernicke’s area results in difficulty understanding language, whereas damage to Broca’s area results in difficulty of speech expression. Wernicke’s area and Broca’s area are connected by a fiber bundle, the arcurate fasciclus.

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Figure 5-4. A: Formation of the membranous labyrinth of the right ear. Filled circles indicate the locations of three ampullae and two otolith organs. B1: Structure of ampulla of a semicircular duct. B2: Structure of otolith organ. B3: Anatomical relation among main components, including Corti organ (hair cells, tectorial membrane, and basilar membrane), cochlear ducts, and ganglion cells, in an auditory receptor unit of the cochlea. (Adapted from Pansky, Allen and Budd, 1988, and other multiple sources.)

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Figure 5-5. Ascending pathways of auditory signal (A) and vestibular signal (B) on both sides of the higher CNS. Approximate areas of their relating nuclei are shown with filled closures. Two figures illustrate that signal projection areas (nuclei) in the pons, midbrain, thalamus, and cerebral cortex are quite similar between the auditory and vestibular systems.

[A Different Angle 5-6] Origin of the sound receptor organ: Many investigators think that the sound receptor organ is differentiated from the lateral line organs of aquatic animals, such as fishes and amphibians, and specialized fit to sound reception in evolutionary stages of vertebrates. The lateral line system, the receptors of which are hair cells that show almost the same structure as the cochlear hair cells in higher vertebrates, is an apparatus for monitoring water flow and water vibration. Some of the hair cells are distributed directly on the body surface (free neuromasts), and others are situated in the canal (lateral line canal) running just under the epithelium (canal neuromasts) (Fig. 5-6 A). Hair cells of the lateral lines are distributed mainly along the length of the trunk and tail part of aquatic animals. (They do not receive innervations of spinal (or trigeminal) nerves: most hair cells on the head are innervated by the facial and glossopharyngeal nerves, and those on the body line by the vagus nerves.) In invertebrates, for example insects, antennae at the head and tympanic organs and subgenual organs in the legs sense sound waves, and the vibration is translated directly into impulse discharges of the corresponding sensory neurons. In the auditory system of humans, tympanic vibration is, however, translated to fluid vibration of the perilymph filling the cochlear duct. Why must air vibrations be translated to fluid vibrations? This can be explained by supposing that the lateral line canal of aquatic vertebrates has condensed as a cochlear duct in higher vertebrates. Actually, the internal ears of humans appear as ectodermal thickenings on either side of the head in early stages of development, which is similar to the developmental

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process of the lateral line organs. The architecture of the membranous labyrinth exists on both sides of the head in all vertebrates, but that of fishes lacks the conspicuous cochlear part that shows progress with advancing vertebrate stages (Fig. 5-6). This indicates that the original function of the membranous labyrinth was probably not audition but sensing the equilibrium. Equilibrium that is built up in relation to gravity, whose action on the body is the same throughout all animals, is a basic function from fish to humans. Actually, formations of vestibule part of the labyrinth are essentially the same in fish and mammals (Fig. 5-6). After all, it is possible to think that in an early stage of evolution of vertebrates, the lateral line canal of the head region differentiated as the vestibule architecture, and the rest developed gradually as the cochlear part with the shift in living environment from water to land.

Figure 5-6. A: Structure of lateral line organ with canal in fishes. a1-a6: Formational change of membranous labyrinth with the progress of vertebrate stages. The lagena (cluster of dots) is thought to be a prototype auditory organ. In most vertebrates, the hearing organ (filled enclosure) includes both the Corti organ, an advanced hearing component, and the basilar papilla, a primitive hearing component. The obvious vestibular apparatus has already emerged in teleost, but the basic structure does not change largely throughout the evolutionary stage, whereas the development of the cochlear apparatus is remarkable. (Redrawn from Stark, 1982.)

* Vestibular System The receptor organ of the vestibular sense exists in the inner ear united with the auditory organ, the cochlea. The apparatus consists of two small vesicles (otolith organs), the utricle, and the saccule, and three circular ducts (semicircular ducts) (Fig. 5-4 A). Each of the

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semicircular ducts has a swelling called the ampulla on the end close to the utricule. Sensory epithelium, with hair cells that are principally the same architecturally as those in the cochlea, is found at five places: the utricle, saccule, and three ampullas in the vestibular apparatus. Each of the hair cells has a number of long cilia at the apex that is covered by a jellylike mass that is called the cupula in semicircular ducts (Fig. 5-4 B1) and the otholithic membrane in otholith organs (Fig. 5-4 B2). As the formation is suitable to sense gravitational force, the vestibular apparatus is thought to be used in perceiving motion (with semicircular ducts) and in positioning the head (with otolith organs). Therefore, the vestibular apparatus is not normally classified as an organ for monitoring the external environment, but as a proprioceptive organ. The signals emitted by vestibular hair cells are conveyed to the four vestibular nuclei, the superior, inferior, medial, and lateral vestibular nuclei, expanding from the pons to medulla on their lateral side by the vestibular division of the vestibulocochlear nerve, which is a collection of central processes of bipolar cells in the vestibular gangla near the labyrinth. The vestibular system has a strong relationship originally with cerebellum function, but the accurate difference in the function and projection pattern among the four vestiblar nuclei is less clear. Some of the vestibular primary fibers project directly to the flocculonodular lobe of the cerebellum, and vestibular nuclei receive inputs from the cerebellum (in addition to the spinal cord and the contralateral vestibular nuclei). These interconnections are related to the coordinative movement of two legs. The vestibular system is also involved in eye and head movements (vestibulo-ocular reflex). Many secondary vestibular fibers project directly to motoneurons of the oculomotor, trochlear, and abducens nuclei (Fig. 5-5 B), affecting or modulating eye movements. Ascending vestibular signals from the vestibular nuclei are suspected of reaching the lateral region of postocenral gyrus (area 2) and so-called the primary vestibular cortex in the temporal lobe situating at the base of the central sulcus, adjacent to the primary auditory cortex, via the thalamus (Fig. 5-5 B). The vestibular area in the thalamus is estimated to be located near VPL and VPM, close to the medial geniculate body, and the vestibular centers in the cortex are thought to play a role in motion perception or spatial orientation. Similar to cochlear hair cells, vestibular hair cells also receive efferent fibers, and they are thought to be involved in modulating the process of the receptor potential transduction. [A Different Angle 5-7] Why does the vestibular apparatus attach to the cochlea?: The vestibular apparatus is understood to be an organ for monitoring motion and decline of the head and body in relation to gravity. Why does the organ for sensing gravity connect tightly with the organ for hearing? Thinking superficially, the vestibular sensation and the auditory sensation are quite different for organisms. In addition to the neighboring location of the two organs, the structure of receptor cells (hair cells), the manner of receptor potential generation, the innervations of the primary sensory nerve to the hair cells, and signal projection areas in the pons, midbrain, thalamus, and cerebral cortex are quite similar between the two systems (Fig. 5-5 A, B). It is reasonable to think that the two systems have something of a strong relation. Further, the vestibular apparatus is paired, which would not be necessary if its role were only the perception of gravitational

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force. All other sensory receptors, including somatic ones, are situated symmetrically on both sides of the body, which are needed for analyzing multiple aspects of their information, but a single form, in theory, would be sufficient for sensing gravity, as its action on the body would be homogeneous. The viewpoint has been put forth that the vestibular apparatus is deeply associated with searching for sound sources. It is believed that sound sources are located using such clues as differences of the intensity, arrival time, and phase of the wave produced between the bilateral ears. The location of a sound source estimated from such clues is, however, only in the horizontal plane, that is to the right or left of the midsagittal plane. The location of sound sources in three-dimensional space becomes more accurate if the information of the head (or body) decline participates in the analysis. There is no doubt that the vestibular apparatus functions as the gravity sensor, but it is proper to consider that the function was originally for sound location in three-dimensional (water and air) space. Almost all nuclei for the vestibular sensation in the CNS are situated adjacent to the auditory relating nuclei, suggesting the existence of an close interaction of signals between the vestibular and auditory systems at the multiple levels.

(4) Visual System The visual sense is especially important for most animals. Many volumes have been assigned to descriptions of visual systems in the literature on the nervous system. The organ for vision is the eye, and its photoreceptive component is the retina (Fig 5-7 A1). Objects focus in reverse on the retina through lens of eyes, which, however, presents no problem, as the entire world is perceived in reverse. The retina is differentiated from the telencephalon and it shows a synaptic network among different types of retina neurons. Thus, it is principally a part of the central nervous system rather than a peripheral organ. In mammals, visual information originates in retina receptor cells and then is conveyed mostly to the brain, first to the occipital lobes, via the thalamus. Throughout the pathway, a precise retinotopic arrangement of fibers is maintained.

* Photoreceptors in the Retina Retinal neurons and their synaptic connections are organized into many layers: the photoreceptor cells are located in the back of the eye, immediately in front of the pigment epithelium, and all other retina cells are located anterior to the photoreceptors (Fig. 5-7 A2). There are two types of photoreceptor cells, the rod and cone, both of which are differentiated into an outer and inner segment. The outer segment is the region for sensing light, and the inner segment, which contains a cell nucleus, forms synaptic contacts with neurons in the next layer. A narrow cytoplasmic neck containing ciliary structures connects the two segments. Rods are predominantly for night vision, and cones, predominantly for daylight and color vision. Both contain hundreds to thousands of stacked membranous discs in their outer segments, which are believed to play a role in increasing the surface area of the

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membrane to enlarge the sensitivity to photons. (It is a common understanding that the inside of the cone discs is continuous with the extracellular medium, and the rod discs are intracellular floating structures.)

Figure 5-7. A1: General structure of the eye from a sagittal view. A2: Shematic illustration of layers of the neural retina. The outer nuclear layer is composed of cell bodies of cone and rod cells; the inner nuclear layer of horizontal cells, bipolar cells, and amacrine cells; and the ganglion cell layer of cell bodies of the optic nerve fibers. Layers between the cell layers are called plexiform layer. (Adapted from Pansky, Allen and Budd, 1988.)

Rod cells contain a visual pigment, called rhodopsin, which is arranged in the discs of the outer segment, absorbing photons quite strongly. (Cones also contain visual pigments that do not yet have universal names.) Light exposure on the rod cell elicits a hyperpolarizing receptor potential that is produced mainly by a decrease in Na+ conductance of the outer segment. The fact that the photoreceptor cell is depolarized in the resting (or dark) state by a high permeability of the membrane to Na+ is the basis of this unique response. The decrease

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in Na+ conductance removes the depolarizing influence, and returns to the equilibrium potential of primarily K+. Cone cells also generate a hyperpolarizing receptor potential, which is principally the same as the response of rod cells, but which changes with a graded manner in response to successive spectra of light. Color is sensed by three different types of cone cells, each of which has maximal sensitivity to the spectra: red, green, or blue light. Existence of the different sensitivity of cone cells to light spectra is believed to be the basis of color coding in higher visual centers of the brain.

* Visual Pathways of the CNS The rod cells and cone cells project with convergence to the ganglion cells via different types of intermediate neurons called bipolar cells, horizontal cells, and amacrine cells. Axons of the ganglion cells in the retina gather together and form the optic nerves. The right and left optic nerves come together at the optic chiasma, where a nasal portion of axons crosses at the midline, so each optic tract conveys visual information from both sides. Fibers of the optic tract project to such regions as the lateral geniculate body of the thalamus, superior colliculus and pretectal area of the midbrain, and suprachiasmatic nucleus of the orbital cortex of the frontal lobe of the cerebral hemisphere (Fig. 5-8).

Figure 5-8. Location of visual areas (filled enclosures) in the cerebral hemisphere and brainstem and flow of the signals. Mt; middle temporal area: V1; primary visual cortex: V2, V3, and V4; higher-order visual areas: E-W; Edinger-Westphal nucleus: III, IV, and VI; cranial nerves innervating extraocular muscles.

Among them, the pathway relayed at the lateral geniculate body is strongly involved in conscious interpretation of the visual information. Fibers from the lateral geniculate body project to the ipsilateral calcarine (striate) cortex (primary visual cortex, V1, area 17) of the occipital lobe through the optic radiations in the temporal lobe. Throughout this course, a retinotopic arrangement of fibers is maintained. Visual signals then flow forward through

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many nuclei in the occipital and temporal lobes (Fig. 5-8). Areas containing those nuclei are collectively called the secondary visual areas or the visual association areas. Neurons in the V1 send axons to the visual association areas (V2, V3), which are located on the lateralmedial aspect of the posterior portion of the hemisphere: V2 corresponds approximately to area 18, and V3, area 19. V2 and V3 project separately to the middle temporal area (MT) and inferior occipitotemporal area (V4). MT and V4 neurons further extend axons anteriorly along parietal cortex and along inferior region of the temporal lobe, respectively. [A Different Angle 5-8] Flows of visual information in the posterior half of the cerebral cortex: Visual signals originating from the primary visual cortex (V1) flow forward through many cortical nuclei in the posterior lobes. Two roots, the dorsal root and ventral root, have been confirmed. The former extends from V1 to the parietal cortex, so it is often called the parietal pathway, and the other extends from V1 to the inferior temporal cortex, so it is often called the temporal pathway. (Both pathways start from the primary visual cortex, but their distal ends are fuzzy.) The two pathways are known to have different functions. A typical understanding about their functions is that the parietal pathway is involved in analyzing where an object is, and the temporal pathway, analyzing what an object is. There has been another explanation, in which the parietal pathway extracts the motion of an object and is concerned with motor action such as pursuing an object, whereas the temporal pathway extracts static characteristics, such as the color, shape, and size of an object and is concerned with its recognition. There is something unsatisfying, however, in these interpretations as functional roles, as the relations between the function and the topographical organization in the two pathways cannot be fully understood. The difference in function between the two roots can possibly be interpreted more simply as that the parietal pathway runs toward the primary somatosensory cortex, where somatic (or substantial) reality increases gradually in the visual sensation with the approach, and the temporal pathway runs towards the auditory (or/and vestibular) cortex, where sound space reality or linguistic reality increases gradually in the visual sensation with the approach. This view leads to the possibility of existence of other visual pathways that run toward the olfactory cortex and the gustatory cortex (Fig. 6-3). (So the root known as the temporal pathway might mingle with the root toward the olfactory area or taste area.) Furthermore, existence of visual pathways toward the foot area, hand area, face area, and so on of the somatic sensory cortex is also supposed. A similar discussion about central pathways must be possible for all other sensory modalities. For example, auditory signals may have flow roots toward the visual, olfactory, taste, and somatic cortex. So-called sensory association cortices apparently correspond to these pathways of mixing different sensations. For example, Wernicke’s area can be considered to be a sort of association cortex. Compared to the primary auditory cortex, Wernicke’s area is situated more closely to the parietal cortex. This seems to add substantial reality to the auditory information, which might imply a function in language interpretation. The angular gyrus that caps the superior temporal sulcus is closer to the visual-relating areas than Wernicke’s area. Left, dominant-hemisphere damage of the angular gyrus is known to result in an inability to name drawn objects or in an inability to read letters, indicating the incomplete combination between visual and auditory (language) information.

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More-or-less every object possesses somatic, gustatory, olfactory, auditory, and visual factors which should be associated variously in the cerebral cortex according to the purpose of motor events. The cortex contains a huge number of neurons and many nuclei, and understanding of its actual work is difficult only from a statement of function of the nuclei and pathways in each sensation. One way of understanding the sensory functions in the brain is that each of the six (visual, auditory, vestibular, olfactory, gustatory, and somatic) sensations is altered gradually with the topographical extension from its primary cortex to the other primary cortices. In other words, through suitable mixing among the five basic sensations it is possible to produce different types of sensations, similar to trichromacy theory in color production.

* Voluntary Eye Movements Eye movements are driven by the oculomotor (III), trochlear (IV), and abducens (VI) cranial nerves. For most movements, the eyes move in the same direction simultaneously, and a saccadic type of eye movement occurs most frequently in living animals, including humans, and is achieved by central control. (Saccadic movement is the rapid direction of the eyes, from point to point, to a target of interest inside a visual field.) Electrical stimulation of the frontal eye field in the frontal lobe (area 8) and visual relating areas in the parieto-occipital area are known to elicit saccadic eye movement, where the efferent signals are intermediated by the superior colliculus. (In the nervous network, it is, however, difficult to decide strictly on the actual function of its site only from the stimulus-response relationship. It remains unclear whether the parieto-occipital area has a directly motor function, as the eye movement may possibly be elicited, intermediated by, for example, the frontal eye field.) The supplementary eye field is also known to influence saccades, but an actual function of the field might be the programming of coordinative movements among legs and/or hands responding to visual inputs. The vertical saccades are concerned with the midbrain motor nuclei, such as the oculomotor nerve (III) and the trochlear nerve (IV), whereas the lateral saccades are concerned with nuclei in the pons, such as the pontine reticular formation and the abducens nuclei (VI). The pontine reticular formation also relates to another type of eye movement, in which the so-called gaze center receives input from various sources, such as the vestibular nucleus, cerebellum, tegmentum, and superior colliculus.

* Light Reflex Visual signals of certain optic nerve fibers enter the pretectal area, just rostral to the superior colliculus, via the optic tract. Pretectal neurons project bilaterally to the so called Edinger-Westphal nucleus, a subnucleus of the occulomotor nucleus on both sides. Edinger-Westphal neurons run in the ipsilateral occulomotor nerve and project to the ciliary ganglion, which supplies the ciliary muscle for controlling the focus of the lens, and the pupillary constrictor muscle for controlling the pupil (Fig. 5-8). In a normal state, when light is applied to the eye on one side, both pupils constrict. This is a parasympathetic reflex,

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and pupils are also controlled by sympathetic nerves from the superior cervical sympathetic trunk ganglion. The pupillary light reflex is useful to test brainstem and cranial nerve function or their lesion, and popularly used in the clinical side. [A Different Angle 5-9] Role of the optic chiasm in stereographic vision: When somatic sensory receptors covering only one of paired legs or arms are harmed, we loose sensation on the corresponding side. On the other hand, in the case of visual perception, most of the visual field of the ipsilateral half never disappears when we shut only one eye, but the stereographic image is lost. As the visual image perceived by each of the paired eyes is flat, the main role of the binocular view is apparently the stereographic perception of objects, based on the difference in view angle between the right and left eyes. The flow of binocular visual information through the optic chiasm is shown in Fig. 5-9 A, where the small letters “a” and “b” refer to flat images projected on half of the retina, while“(l)” and “(r)” mean the left and right sided view angle respectively. The capital letters “A” and “B” refer to stereographic images of half of an object (or scene). In the presentation, object-BA focuses in reverse, with different angles on the left retina (a(l)b(l)) and on the right retina (a(r)b(r)), and the information for the nasal half (b(l) and a(r)) crosses at the chiasm and enters the opposite tract, becoming a(l) a(r) for the left tract and b(l)b(r) for the right tract; a(l)a(r) represent a stereographic image of the right half (A), and b(l)b(r), the left half (B) of the object-AB, which would be constructed at higher visual centers. It is noticeable that the visual image of the right side (A) project to the left side, and that of the left side (B) to the right side of higher centers. Visual defections by damage at specific locations in the pathways are estimated, as shown in Fig. 5-9 B1-B3, where B1 represents damage at the right optic nerve, B2 at the optic chiasm, and B3 at the right optic tract. (In actuality, such clear-cut damage might rarely occur.) In the case of B1, which represents the shutting of the right eye, the left and right tracts convey images for the temporal and nasal half viewed from the left eye (a(l)@ and b(l)@, respectively; the symbol ”@”indicates no information), which means that the CNS image of the object-AB becomes flat (a(l)@+b(l)@). In the case of B2, the combination of information for the right and left tracts becomes a(l)@+b(r)@, which might mean that it is impossible to construct the image as one stereographic representation. In the case of B3, the combination becomes a(l)a(r)+@@ (=A+@@), which means only the right half of the object can be perceived as the stereographic image. In B4, possible combinations of the temporal and nasal half of the visual information between the left and right retina are shown, where it is indicated that combination between different view angles of same half of the object (a(l)a(r) or b(l)b(r)) produces the stereographic image ([A] or [B]), but different angles of different halves of the object produce nonsense images (*), which must mean the separation of images of the object. The manner in visual perception by which external sights are reconstructed in reverse in the brain produces the important conclusion that all other sensations relating the external environment must be projected in reverse to the brain, too, to coincide with the visual sensation. This must be the explanation for why almost all major ascending tracts (and descending tracts, as well,) decussate. The reversal projection of visual images comes from a

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property of the lens of the eyes, where reverse focusing on the retina is inevitable. Thus, the right and left sided information of other sensations must be coded in reverse in order to adjust the visual sensation. (From this view point, the ascending fibers for taste and olfactory sensation must decussate at any level.) This further leads to the estimation that sensations having no relation with the visual system do not need to be reversed, and that, for instance, ascending fibers conveying cutaneous sensation in beings at lower evolutional stages, whose eye organs, such as ocellus and compound eye, can sense the visual world straightly (not reversal), do not need to decussate principally. There is another important suggestion concerning visual perception through the lens, namely that the reverse focusing on the retina also occurs not only in the right-left direction, but also in the upward-downward direction. The nervous system also needs to adjust the vertical reverse with other types of sensation. Although the corresponding arrangement in the ascending and descending nervous system has not yet been described, an appropriate mechanism to achieve the adjustment would exit in the central nervous network. Anyway it is an actual fact that our brain perceive surroundings reversibly.

Figure 5-.9. A: Schematic diagram in constructing stereographic images of an object-AB through a pair of lenses (and retinas), optic nerves, optic chiasm, and optic tracts. In this figure, a(l) and b(l) indicate the information of flat vision for each half of the object viewed from the left eye, and a(r) and b(r), viewed from the right eye. A combination of a(l) and a(r) (or b(l) and b(r)) can produce a stereographic image (A (or B) of right (or left) half of the object in any higher-order visual area. B1B3: Damage (wave line) at the optic nerve (B1), optic chiasm (B2), and optic tract (B3) and their estimated visual defections (@-mark means no information on their optic tracts). B4: possible combinations of the temporal and nasal halves of the visual information between the left and right retina, where [A] and [B] indicate the stereographic images of each half of the object and [*] indicates that it is impossible to construct a stereographic image.

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(5) Receptor Potential Generation in Special Senses Sensory stimulus is transduced into an electrical signal, a receptor potential, by sensory receptor cells. All receptor potentials are generated on the basis of an ionic mechanism of a medium across a membrane of receptor cells. The magnitude of receptor potential depends on the stimulus intensity. A receptor potential that is an analogue signal is transformed digitally into a train of action potentials of the next neuron or of itself, whose frequency depends on the magnitude of the receptor potential; that is, it depends on the stimulus intensity. In general, sensory stimulus cannot act directly on ion channels, so an appropriate interface is needed in the receptor cell for each sensation. A contact area of receptor cells with sensory stimuli differentiates suitably with sensations for transmitting the stimulus effectively to the receptor-ion channel complex. The rough process from the sensory stimulation to the action potential generation in taste, olfactory, auditory (and vestibular) and visual sensations is shown in Fig. 5-10 a, b, c, and d, respectively.

* Taste Reception Taste receptor cells are located in taste buds embedded in papillae that are scattered on the surface of the tongue. The receptor cells have microvilli that extend to the taste pores, where they make contact with taste solutions. Specificity of taste reception is the possibility of direct interaction of taste stimulants with ion channels in the microvilli. In a taste response, ions such as Na+, K+, Cl-, H+, and Ca2+ of salty chemicals are able to flow directly through the appropriate ion channels on the apical membrane of the microvilli, but chemicals of large molecules, such as sugars or alkaloids, interact at the first step with specific receptors, which activate the second messenger system. In the microvilli of taste cells, there are ligand-gated K+ channels that are closed by binding of some bitter substances inducing the decrease of K+ conductance. These processes generate in most cases depolarization potentials in the receptor cells, which induce Ca2+ influx from the surrounding medium or Ca2+ release from inside the Ca2+ store. It is general understood that the taste cell can generate action potentials, and that a Ca2+ influx (or increase) in the taste cells is its result. The increase of the internal Ca2+ concentration triggers the release of a neurotransmitter. (The neurotransmitter, however, has not yet been determined.) The receptor potential is translated into an action potential discharge on peripheral endings of taste nerves through the synaptic process. (Some investigators assert that the potential produced by the contact of stimulus solutions with the mucus matter covering the microvilli is able to directly affect the synaptic process.)

* Olfactory Reception An olfactory receptor is a bipolar neuron with a slender dendrite and a long axon process. The dendrite extends to the olfactory vesicle, from which cilia spread out to the epithelium surface, which is covered by a mucus layer. Most odorants are large molecules, so direct

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interaction of ion channels of olfactory receptor cells with them is in most cases impossible. Odorants interact with receptors, specific with proteins on the cilia, in which a mucus substance covering the olfactory epithelium may play a role. The translation to the receptor potential that is produced by cation (Na+, Ca2+) influx for almost all odorants is performed by a G-protein coupled mechanism and 2nd messenger system. The receptor potential, normally depolarization, produced in the distal process of the olfactory neuron, spreads its proximal part, inducing action potential generation in its axonal process. The (unmyelinated) axons of olfactory receptor cells enter directly into the olfactory bulb, so the olfactory system lacks a formation corresponding to the sensory ganglion. The receptor potential tends to decrease rapidly compared to the potential for other sensory receptors, even if the odorant stimulation continues. The rapid adaptation may be simply due to less fluidity of the stimulants, which makes it difficult to remove combined substances from the receptor protein rather than the ion chennel property of the receptor cell.

* Auditory and Vestibular Reception As stated previously, the structure of receptor cells and the manner of receptor potential generation are quite similar between the auditory and vestibular systems. The first step of auditory and vestibular reception is performed on the so-called hair cells. Sounds are received by the hair cells of the Corti organ in the cochlea, acceleration is received by those of ampulla in semicircular ducts, and the equilibrium is received by those of otolith organs in the utricle and saccule. The basic formations of the hair cells are the same: all have an array of microvilli projecting as a bundle from the apical end into the endolymph. In the vestibular hair cells, the array is composed of many microvilli called stereocilia and one large villus called a kinocilium. Gating ion channels sensitive to direct mechanical deflection produce receptor potentials: the mechanoelectrical transduction channels are presumed to be nonselective to small cations. The bundles of hair cells are bathing in the endolymph with its high concentration of K+, and most transduction currents for mechanical stimulation are carried by K+. This ionic mechanism in potential generation is different from that for typical neurons. This is due to the high K+ and low Na+ concentration of the endolymph, which is in contrast to the external medium for common cells including neurons. The ion channels lie collectively at the tips of the cilia, and the elicited depolarization at the tip spreads to the body of the hair cell, which induces Ca2+ influx through voltage-dependent Ca2+ channels. The increase of the internal Ca2+ concentration accelerates the release of a neurotransmitter (probably glutamate) onto endings of the 8th nerve, whose ganglia, the spiral ganglion and vestibular ganglion, are located close to each component. The increase of free Ca2+ of the hair cell, in turn, induces an outward K+ current through Ca2+ dependent K+ channels, followed by acceleration of a Ca2+ pump activity, which rapidly repolarizes the hair cell. (To maintain an appropriate cytoplasmic Ca2+ concentration, the Ca2+ must be pumped from the cell.) The receptor potential of hair cells is known to follow well the oscillation of the cilia. In the case of vestibular reception, the polarization of the receptor potential of hair cells to deflection of their stereocilia is known to depend on their bending directions: deflection of the stereocilia toward (or away from) the kinocilium produces the depolarization (or

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hyperpolarization) through the change in the gating state of K+ channels in the apical portions of the cilia. The depolarization (hyperpolarization) increases (decreases) the rate of Ca2+ influx, increasing (decreasing) the firing rate of afferent fibers. A most specific characteristic in the receptor potential generation of hair cells is no participation of Na+ ions throughout its process. [A Different Angle 5-10] Ionic base of sensorymotor behavior in ciliate Paramecium: We can see an archetype of a hair cell in the protozoa ciliate Paramecium, and the basic process of generating a receptor potential in the ciliate movements. When the paramecium collides with an object, the beat of its cilia reverses, causing the paramecium to swim backward a short distance, whereas a mechanical stimulus to its posterior region causes it to swim forward with greater velocity. The ciliary beat manner in these avoidance and escape reactions are brought about without participation of a nervous system; they directly depend on membrane potential. Mechanical stimulation at the anterior region of the paramecium elicits a depolarization graded in intensity with the stimulus strength, whereas stimulation of the posterior region elicits a graded hyperpolarization. These two electrical responses underlie the adaptive behaviors of the paramecium. Mechanical stimulation of the anterior region causes an increase in permeability of the mechanically-activated Ca2+ channel distributed in the anterior region, resulting in a transient influx of Ca2+, which depolarizes the anterior region inside the cell. (Hyperpolarization is produced by a local increase in permeability of the K+ channels distributed in the posterior region.) The receptor potentials, originating locally, spread to the entire cell electrotonically. The depolarizing receptor potential activates voltage-gated Ca2+ channels distributed on numerous cilia, through which Ca2+ ions flow into the cilia. The elevation of intraciliary Ca2+ ions resulting from the Ca2+ influx acts upon the ciliary motor apparatus to cause reversal of the beat direction of the cilia. (The nature of the effect of Ca2+ on the ciliary machinery remains to be determined.) The process of receptor potential generation in cochlear and vestibular hair cells, and in the paramecium, is similar in terms of the following points: 1) mechanical stimulation activates mechanical-sensitive cation (Ca2+ in paramecium or K+ in hair cells) channels; 2) receptor potential activates voltage-sensitive Ca2+ channels; 3) an increase of Ca2+ concentration brings about organic function of the cell (neurotransmitter release for hair cells of cochlear and vestibular organs and a change in the beating of paramecium cilia; 4) Na+ never perticipates in the receptor potential generation throughout the process. An ionic mechanism in the simple stimulus-response connection of the paramecium that lives in a fresh-water Na+-poor solution indicates that Ca2+ (and also K+) plays a major role in exerting the physiological function of the cell, which has yet been maintained in the receptor potential generation, especially of hair cells of the cochlear and vestibular organs.

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* Light Reception Photoreceptors are of two types, rods and cones, both of which contain stacked disc membranes in their outer segments. The disc membranes contain photopigment substances: rhodopsin in rods; and related substances sensitive to red, green, and blue wavelengths in cones. The mechanism of transduction of photons into the electrical response of the photoreceptor is involved in a second messenger system. In darkness, rods show a large inward current that flows through cGMP-gated ion channels on the discs in the outersegment mainly for Na+ ions. The inward Na+ current maintains the cell in a relatively depolarized state (about –30mV) in the dark. Light stimulation (absorption of light by visual pigments) activates a phosphodiesterase (PDE), an enzyme for hydrolyzing cGMP, which lowers the concentration of cGMP in the cytoplasm. The reduction in the cGMP concentration closes the Na+ channels, thus hyperpolarizing the photoreceptor. (Darkness or black color is suspected to be the most fundamental sense in visual sensation, if the interpretation of relation between the receptor potential recorded and the current field produced by light stimulation is correct.) Cone cells also generate a receptor potential similar to rod cells, normally hyperpolarization, in a graded manner to successive spectra of light. The color is thought to be discriminated by three different types of cone cells, each of which contains a different photo pigment having maximal sensitivity to the spectra: red, green, or blue light. The signal of each cone of the three types is considered to be transmitted separately to the brain’s visual center, and combined to generate a variety of color sensations. The entire retina is described as many layered structure (Fig. 5-7 A2): some are layers of cell bodies (nuclear layers), and others, layers of axons and rich-synapses (plexiform layers). The rod cells and cone cells project with convergence to the ganglion cells via different types of intermediate neurons called bipolar cells, horizontal cells, and amacrine cells. Axons of the ganglion cells gather together and form the optic nerves. Visual signals are processed progressively from photoreceptors to ganglion cells through the intermediate neurons. Among the cells in the retina, only the ganglion cells generate obvious action potentials, which is consistent with their role as the output neurons of the retina. Individual ganglion cells have a receptive field, which in this case refers to the retinal area in which changing conditions of illumination produce an alteration of the cell's activity. Their receptive fields are a characteristic concentric center-surrounded organization. The receptor field is roughly circular: illumination of the center of this circle causes either an increase or a decrease in the background firing rate, whereas illumination of the surrounding area has the opposite effect. This center-surrounded receptive field would function in enhancing contrast sensitivity in the visual system and is considered to be the result of processing by the synaptic circuits in the retina, principally those through the horizontal and amacrine cells.

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[A Different Angle 5-11] About color cording mechanisms: It is a common understanding that color perception is based on three types of cones sensitive to different spectra. This perception mechanism seems to be constructed by consulting the so-called trichromacy theory, by which a suitable mixture of three different colors can produce every color. The retina has a huge number of cone cells. Are all of them classified distinctly into any of the three types? When the theory is adapted to color perception in the retina, three different kinds of cones for red, green, and blue light must situate side by side as a set, like the color-dot arrangement in a television system, although this seems very artificial. Is it somehow possible that the stacked discs in the outer segment function as architecture for resonating with light waves? In soundwave perception at the cochlea, the frequencies are considered to be discriminated through the resonance system in the cochlea. Sound waves conducted to the cochlea resonate with the basilar membrane, which cause displacement of the hair cells relative to the tectorial membrane, bending the cilia of the hair cells, which induces receptor potentials. It is also thought that the resonance occurs according to the physical property of the basilar membrane, the thickness of which changes gradually, and each hair cell is best activated by tones within a narrow range of frequencies. This suggests that the resonation mechanism is suitable for perceiving wavy stimulants. Light is a collection of photons, but color is represented by their wave aspect. The diameter of each stacked disc in a cone cell changes in a graded manner, reminding one of the structural features of the cochlear basilar membrane. (On the contrary, same size discs are stacked in rod cells that sense the strength of light.) The magnitude of the receptor potential (orderly hyperpolarization) of individual cone cells changes successively with maximal peaks in response to light spectra. This has been popularly interpreted to be due to the difference in sensitivity of photopigments to light spectra, where the receptor potential is produced homogeneously inside the outer segment, depended on the stimulus magnitude. Another explanation on the successive potential change of the photoreceptor cell may be possible, supposing that a certain spectrum of light resonates specifically with the restricted discs of suitable sites in the outer segment. Under this assumption, the (hyperpolarizing) potential produced locally shifts along the outer segment, depending on the resonation site. The folded structure of the outer segment is suspected of giving the inside medium a high resistance, which makes it difficult for the receptor potential to spread a great distance. The locally-generated receptor potential and the high resistance of the inside medium of the outer segment might be the reason for the successive change of receptor potential with light spectra in the recording at the inside of the inner segment. Although the role of photosensitive proteins for three colors cannot be explained fully in this discussion, the idea that one cone cell codes widely for the wavelength of light, where the magnitude of the receptor potential corresponds to the light spectra, might not be completely irrelevant. (The magnitude of the receptor potentials represents their stimulus intensity in all other sensations, but it is known that bipolar cells of the retina, which receive the potential of cones, show less sensitivity to the intensity of illumination.)

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Figure 5-10. Schematic representation of transduction (stimulation-receptor potential-action potential) processes at receptor cells for taste (a), olfactory (b), vestibular (or auditory) (c), and visual system (d). The cascade advances along the explanation from upwards to downwards in each sense. (Adapted from Nolte, 1999.)

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[A Different Angle 5-12] Common features in generating receptor potentials of special senses: Thoroughly observing shapes of the receptor cells for taste, olfactory, auditory, vestibular, and visual cues, we are aware that all possess ciliary structures at the apical end of the receptor cells, the forms of which, however, vary with the sensations (Fig. 5-10). (Photoreceptor cells also possess ciliate structures at the junction between the inner and outer segments, and the view is widely accepted that the rod and cone, the outer segments, are modified cilia.) The ciliate structures apparently play a key role in sensing adequate stimuli and generating receptor potentials. As discussed in “A Different Angle 3-1”, the cilia element of a neuron must, under specific conditions, be highly sensitive to sensory stimuli. The detail mechanism of generating a receptor potential is different according to sensation, but interaction of stimuli and their receptor apparatuses induces, after all, a Ca2+ increase in the inside of receptor cells in all sensations except photoreceptor cells. The Ca2+ increase of the inside medium is already observed in the depolarizing process in protozoa, where the majority of Ca2+ ions influx through the membrane of cilia element. From the phylogenetical viewpoint, it is certain that Ca2+ plays a fundamental role in the potential generation of receptor cells. (The Ca2+ role in photoreception is not obvious, but is likely to contribute in some way to the process of potential generation. One suggestion is that Ca2+ may play a role in visual adaptation, because prolonged illumination decreases the Ca2+ influx. As Ca2+ inhibits the production of cGMP, a decrease of Ca2+ concentration allows the membrane potential to recover from its hyperpolarization.) Viewed as a whole, the sensory reception system is similar to the common synaptic system of neurons, where sensory stimuli correspond to neurotransmitters, and ciliate membranes to the postsynaptic membranes.

References and Suggested Readings Haines, D.E. (2002). Fundamental neuroscience (2nd ed.). Churchill Livingstone (Harcourt, Inc.) Kandel, E.R., Schwartz, J.H. and Jessell, T.M. (2000). Principles of Neural Science (4rd ed.). McGraw-Hill, New York. Martin, J.H. (2003). Neural Anatomy: text and atlas (3rd ed.). McGraw-Hill, New York. Nolte, J. (1999). Human Brain: An Introduction to Its Functional Anatomy (4th ed.). Mosby, Inc., St. Louis. Pansky, B., Allen, D.J. and Budd, G.C. (1988). Review of Neuroscience (2nd ed.). Macmillan Pub. Co., New York Penfield, W. and Boldrey, E. (1937). Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain, 60: 389-443. Shephered, G. M. (1988). Neurophysiology (2nd ed.). Oxford Univ. Press, New York. -Taste & olfactionBeidler, L.M. (1971). Handbook of Sensory Physiology IV: Chemical senses 2 Taste. Springer-Verlag, Berlin. Benjamin, R.M. and Burton, H. (1968). Projection of taste nerve afferents to anterior opercular-insular cortex in squirrel monkey (Saimiri sciureus). Brain Res., 7: 221-231.

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Buck, L.B. (1996). Information coding in the vertebrate olfactory system. Annu. Rev. Neurosci., 19: 17-554. Hayashi, K., Yamanaka, M., Toko, K. and Yamafuji, K. (1990). Multichannel taste sensor using lipid membranes. Sens. Actuators, B2: 205-213. Laurent, G. (1997). Olfactory processing: maps, time and codes. Curr. Opin. Neurobiol., 7: 547-553. Lund, J.P. and Enomoto, S. (1988). The generation of mastication by the mammalian central nervous system. In: Neural Control of Rhythmic Movements in Vertebrates (Cohen,A., Rossignol, S. & Grillner, S. (Eds.)). pp. 41-72, Wiley, New York. Martin, R.E. & Sessle, B.J. (1993). The role of cerebral cortex in swallowing. Dysphagia, 8: 159-202. Ogawa, H., Ito, S. and Nomura, T. (1985). Two distinct projection areas from tongue nerves in the frontal operculum of macaque monkeys as revealed with evoked potential mapping. Neurosci. Res., 2: 447-459. Ottoson, D. (1983). Physiology of the nervous system. Oxford Univ. Press. New York. Pfaffmann, C. (1955). Gustatory nerve impulses in rat, cat, and rabit. J. Neurophysiol., 18: 429-440. Ressler, J., Sullivan, S.L. and Buck, L.B. (1993). A zonal organization of odorant receptor gene expression in the olfactory epithelium. Cell, 73: 597-609. Sato, T. (1980). Recent advances in the physiology of taste cells. Prog. Neurobiol., 14: 2567. Scott, T.R., Plata-Salaman, C.R., Smith, V.L. and Giza, B.K. (1991). Gustatory neural coding in the monkey cortex: stimulus intensity. J. Neurophysiol., 65: 76-86. Shephered, G. M. (1972). Synaptic organization of the mammalian olfactory bulb. Physiol. Rev., 52: 864-917. -Hearing and vestibuleArt, J.J., Fettiplace, R. and Fuchs, P.A. (1984). Synaptic hyperpolarization and inhibition of turtle cochlear hair cells. J. Physiol., 356: 525-530. Assad, J.A., Shepherd, P.G. and Corey D.P. (1991). Tip-link integrity and mechanical transduction in vertebrate hair cells. Neuron, 7: 985-994. Brodal, A. (1981). Neurological Anatomy in Relation to Clinical Medicine, (3rd ed.). Oxford Univ. Press, New York. Crawford, A.C. and Fettiplace, R. (1985). The mechanical properties of ciliary bundles of turtle cochlear hair cells. J. Physiol., 364: 359-379. Hudspeth, A.J. (1983). Transduction and tuning by vertebrate hair cells. Trends Neurosci., 6: 366-369. Merzenich, M.M. and Burugge, J.F. (1973). Representation of the cochlear partition on the superior temporal place of the macaque monkey. Brain Res., 50: 275-296. Moore, J.K. and Osen, K.K. (1979). The human cochlear nuclei. In: Experimental Brain Research, Supple. II: Hearing mechanisms and Speech (Creutzfeld, O., Scheich, H. and Schreiner, C. (Eds)). Springer-Verlag, New York. Penfield, W. & Roberts, L. (1958). In: Speech and Brain Mechanisms. Princeton Univ. Press, Princeton. Stark, D. (1982). Vergleichende Anatomie der Wirbeltiere. Spring-Verlag, Berlin.

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Woolsey, T.A. and van der Loos (1970). The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex: The description of a cortical field composed of discrete cytoarchitectonic units. Brain Res., 17: 205-242. VisionBaylor, D.A., Lamb, T.D. and Yau, K.W. (1979). The membrane current of single rod outer segments. J. Phsiol., 288: 589-611. Burns, M.E. and Baylor, D.A. (2001). Activation, deactivation, and adaptation in vertebrate photoreceptor cells. Ann. Rev. Neurosci., 24: 779-805. De Renzi, E., Colombo, A., Faglioni, P. and Gibertoni, M. (1982). Conjugate gaze paresis in stroke patients with unilateral damage. An unexpected instance of hemispheric asymmetry. Arch. Neurol., 39: 482-486. Dowling, J.E. and Werblin, F.S. (1971). Synaptic organization of the vertebrate retina. Vision Research Suppl., 3: 1-15. Hubel, D. and Wiesel, T. (1962). Receptive fields, binocular interaction and functional architecture in the cat's visual cortex. J. Physiol., 160: 106-154. Kuffler, S.W. (1953). Discharge patterns and functional organization of mammalian retina. J. Neurophysiol., 16: 37-68. Matthews, H.R., Torre, V. and Lamp, T.D. (1985). Effects on the photoresponse of calcium buffers and cyclic GMP incorporated into the cytoplasm of retinal rods. Nature, 313: 582-585. Merigan, W.H. and Maunsell, J.H. (1993). How parallel are the primate visual pathways? Annu. Rev. Neurosci., 16: 369-402. Olson, C.R. and Gettner, S.N. (1995). Object-centered direction selectivity in the macaque supplementary eye field. Science, 269: 985-988. Robertis, De E. (1961). Ultrastructure and chemical organization of photoreceptors: The structure of the eye. Academic Press, New York. Roland, P.E. and Skinhoj, E. (1981). Extrastriate cortical areas activated during visual stimulation in man. Brain Res., 222: 166-171. Schiller, P.H., True, S.D. and Conway, J.L. (1980). Deficits in eye movements following frontal eye-fiels and superior colliculus ablations. J. Neurophysiol., 44: 1175-1189. Schnapf, J.L., Kraft, T.W., Nunn, B.J. and Baylor, D.A. (1988). Special sensitivity of primate photoreceptors. Vis. Neurosci., 1: 255-261. Stone, J., Dreher, B. and Leventhal, A. (1979). Hierarchial and parallel mechanisms in the organization of visual cortex. Brain Res. Rev., 1: 345-394. Stryer, L. (1986). Cyclic GMP cascade of vision. Ann. Rev. Neurosci. 9: 87-119. Ungerleider, L.G. and Mishikin, M. (1982). Two cortical visual systems. In: Analysys of Visual Behavior (Ingle, D.J., Goodale, M.A. & Mansfield, R.J.W. (Eds)). pp.549-586, MIT Press, Cambridge, MA. Wässel, H. and Boycott, B. (1991). Functional architecture of the mammalian retina. Physiol. Review, 71:447-480. Zeki, S., et al. (1991). A direct demonstration of functional specialization in human visual cortex. J. Neurosci., 11: 641-649. Zeki, S. (1993). A vision of the brain. Blackwell Scientific, London.

Chapter VI

Dual Properties of the Human Nervous System The nervous system has multiple functions--from those which are global (such as the motor system, visual system, and visceral system) to those which are restrictive (finger movement, color discrimination, heart beat control, and so on). Although they are executed in relation to one another, each unit functional system corresponds to an exclusive nucleus (or nuclei) and pathway(s). Their nuclei and pathways are not located or do not run randomly but are organized orderly in a network. In this chapter, three major concepts that rule the functional organization of the nervous system are discussed. They include (1) left-right specialization of the cerebral hemispheres, (2) input-output organization in the CNS, and (3) virtual-physical differentiation in the total nervous system.

(1) Left-Right Specialization of the Cerebral Hemispheres The two cerebral hemispheres in humans (and in other animals) appear symmetrical. The two are, at least superficially, almost equal in size and show a similar surface appearance. In contrast to the anatomical symmetry, the brain function of humans shows laterality, an obvious and simple example of which is control of limb movements. Muscles of the hands and legs are projected by the contralateral motor cortex of the cerebrum. The distribution of the muscles and the projection manner of spinal motor neurons are almost the same between the right and left hands, but most people can control movements of the right hand more skilfully than those of the left hand. Similarly, most people have better control over their right leg than their left leg. These preferences are considered to relate deeply to the functional differentiation of the right and left cerebral hemisphere. Another conspicuous lateralization of the human brain which has long been noticed is language function. It is well known that language disorders are far more likely to occur by damage to the left hemisphere than by damage to the right hemisphere, so the left hemisphere has frequently been called the dominant hemisphere. (This naming arises, however, from the impression that the right

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hemisphere is inferior, which has been shown to be false as the right hemisphere has been shown to have excellent ability in other types of function.) Let us first focus on the different function between the right and left hemispheres of the brain as one of the major properties of the human nervous system.

* Effects of Brain Damage in Language Ability To estimate the function of a site in the brain, we can examine the effect caused by damage at the corresponding area. Investigation began in the later half of eighteen century. Paul Broca was the first to report the relation between a damaged site in the brain and language ability, concluding that the left frontal lobe plays an important role in speaking. Later, Carl Wernicke showed two types of language aphasia. One is sensory aphasia, the lack of ability to formulate words, which was caused by damage to the upper region of the temporal lobe, and another is motor aphasia, the inability to speak language, which is caused by damage to the lateral region of the frontal lobe (Fig. 6-1). Although the boundary of the two areas is not clearly defined, it is accepted that Broca’s area is involved in vocalization or speech, thus it is often called the motor speech area; and Wernicke’s area, in interpretation of speech, and thus called the sensory speech area. As the two areas are connected by a bundle of nerve fibers, the arcuate fasciculus (Fig. 6-1), it is judged that Broca’s area cannot fully achieve its function without the sensory information of language processed in Wernicke’s area. The two language areas are, in most people, located in the left hemisphere, so language ability has been understood to be dominant in the left hemisphere.

Figure 6-1. A: Location of areas involved in language tasks, viewed from the left side of the brain. Approximate location of the planum temporale is also represented on the superior surface of the temporal lobe. B: Horizontal relation between Wernicke’s area and Broca’s area. (Adapted from Geschwind, 1979.)

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These findings give rise to a simple question of whether or not there is an anatomical asymmetry in the corresponding areas between the left and right hemispheres. Norman Geschwind and Walter Levitsky (1968) indicated that an area called the “planum temporale”, the cortical area on the upper border of the temporal lobe, extending deep into the Sylvian (lateral) fissure and containing Wernicke’s area (Fig. 6-1 A), is considerably larger in the left hemisphere. (The reported rate of enlargement of the planum temporale was found to be 65% in the brains of right-handed subjects.) The larger planum temporal has been also confirmed by recent MRI (magnetic resonance imaging) technology, by which threedimensional images of the brain can be constructed. Although it is difficult to strictly prove a correlation between volume dominance and functional dominance, it is certain that the areas for language function of the right and left temporal lobes show an anatomical asymmetry. Another simple question is whether the speech dominance of the left hemisphere is correlated with handedness or not. Are language events of left-handed people performed through analogous areas in the right hemisphere? Examinations using a Wada-test (described later in this section) have shown that the correlation between language dominance of the left hemisphere and handedness is weak. Differences in other factors, such as the size of cells, number of synapses, elaboration of dendrites, and amount of neurotransmitter between the left and right hemisphere, have been also examined. All of these factors tended to be dominant in the left hemisphere, but the degree of every factor was quite small. The question also arises as to what sort of functions are involved in the homologues of Broca’s and Wernicke’s areas in the nondominant hemisphere (mostly in the right). Are they also activated in some way during language tasks? The accurate functions of the two right homologues in language events is not yet understood. As far as language tasks, lesions of the right hemisphere tend to produce problems that are not as serious as those caused by left hemisphere lesions. Patients with lesions of the inferior right parietal lobe are, however, known for frequently failing to appreciate emotional aspects of speech such as tone, loudness, intonation, and rhythm, and for a tendency to speak robotically. As described later, the right hemisphere plays major role in space recognition or totality of events, rather than language function.

* Effects of Damage of the Parietal Lobe in Space Recognition It is certain that damage to the left hemisphere causes serious problems in many aspects of language events. On the contrary, it has been noticed that damage to the parietal lobe tends to cause abnormalities of body image and space cognition (popularly called parietal lobe syndrome). In particular, damage to the inferior region of the right parietal lobe results in a lack of appreciating sensory information from the left side of the body as well as information from the visual field on the left side. This condition is known as “neglect syndrome”, and it occurs only rarely with damage to the left hemisphere. Despite their retention of peripheral somatic and visual sensations, such patients ignore the world of their left visual field. For typical examples, they leave untouched the left half in such tasks as wearing, shaving, washing, and eating (Fig. 6-2 a). They are unable to recognize even a simple object using

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Figure 6-2. Deficit of the right parietal lobe causes various types of inability in spatial recognition. Patients have difficulty, for example, focusing their attention on the left side of the body (a), recognizing an object with tactile sensation (b), constructing three-dimensional architecture (c), drawing cubical shapes (d), and copying the left half of picture (e). (All results of these tasks presented in this figure were not obtained from actual patients, but from supposition.)

three-dimensional architecture (asterognosis) (Figure 6-2 c), cannot draw the depth of a cubic object (constructional apraxia) (Figure 6-2 d), cannot copy a picture of its left side

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(Figure 6-2 e), cannot correctly orient an object when instructed vocally, and cannot accurately tactile sensation (tactile agnosia), especially with the left hand (Fig. 6-2 b). Furthermore, they read a map, even though their visual fields are intact. These inabilities can be said to fall under the term “loss of spatial organization”. We are able to properly understand these disorders produced by lesions of the parietal lobe, as the lobe is the region in which the association between visual and somatic sensations is formed. The disorders are caused by lesions mainly of the right lobe. What function is affected in spatial recognition if the left parietal lobe is damaged? Most probably a loss of understanding of written letters, considering that the left hemisphere is involved in language ability. In actuality, patients with damage restricted to the left parietal lobe tend to be unable to read sentences smoothly (alexia). Especially, severe damage to Wernicke’s area and that to the angular gyrus, which is the junction of the parietal, occipital, and temporal lobes, are well known to accompany strong alexia. This seems to be due to a difficulty in recognizing sequences of letters with linguistic logic. (However, patients can still recognize what they see as drawings). The question arises of whether the parietal lobe of the left hemisphere even participates in the recognition of objects in surroundings. In addition to the analytical function of language, the left parietal lobe is, in the present, considered to function in analyzing components of objects or drawings. The left parietal lobe, however, cannot associate them as a whole, where, for example, letters cannot be formed fully as a sentence, and parts cannot be constructed as a meaningful object. It is now understood extensively that visual patterns or spatial objects, as well as various sorts of sounds (including vocal sounds), are recognized analytically (or linguistically) by the left hemisphere, and recognized synthetically and artistically by the right hemisphere. [A Different Angle 6-1] Visual disorders viewed from visual pathways: Loss of spatial organization caused by a deficit of the parietal lobe can also be understood from the viewpoint of visual pathways, as the dorsal visual root runs forward in the parietal lobe. “A Different Angle 5-8” touched on the possibility that visual sensations might be associated with taste and olfactory sensations. Although such areas have yet to be demonstrated, the temporal visual pathway may contain the roots running toward taste and olfactory cortices (Fig. 6-3). If the suspected visual-taste association area were damaged, association between a substance and its taste would not be formed, and patients would not recognize whether they were eating an apple, peach, pear or mango only from the cue of taste sensation. This might mean that the patients would not be able to discriminate whether the food in their mouth was edible or noxious. If the suspected area for visual-olfactory association were damaged, the patient would not be able to recall the object corresponding to a certain scent. Whether or not these syndromes actually exit is uncertain, although they are plausible. The following discussion might be also possible. As discussed in “A Different Angle 5-8”, the visual root of the parietal pathway running toward the somatosensory area would separate further into sub-pathways such as the lower limb pathway, upper limb pathway, and face pathway (Fig. 6-3). The so-called parietal visual pathway might correspond mainly to the upper limb pathway, because recognition of objects deeply depends on the somatic sensation of the fingers. What happens when the lower limb pathway is damaged? Since a basic function of the feet is to

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perceive the state of the ground, patients damaged at the lower limb pathway appear to fall in feeling of floating. They may find it difficult to walk or run in an ordinary manner on terrain with obstacles or on stairs. What sort of disorder occurs if the facial pathway is damaged? The most likely disorder might be an inability to recognize faces. In fact, neurons responding specifically to visual patterns of the face are reported to exist in the ventral region of the medial occipital and temporal lobes. There have been discussions about whether such face-recognition neurons really exist in the brain or not, but it seems probable, supposing that a part of visual information would flow toward the face area of the primary somatosensory cortex. Lateral functional specialization is apparently observed in such functions as language work, spatial recognition, and hand and foot manipulation. In this discussion about the visual roots for taste and smell, as well as for the lower limbs, upper limbs and face, lateral specifications have not be considered. However, each of these roots is also estimated to be differentiated functionally, such as analytically and synthetically, between the left and right hemispheres, although the accurate specializing properties are difficult to state at the present.

Figure 6-3. Probable streams of visual information from the primary visual area in the posterior half of the cerebral hemisphere. Visual signals originated from the primary visual area would stream towards each of the primary sensory cortices, such as somatosensory cortex (lower limb pathway, upper limb pathway, and face pathway), auditory cortex (language pathway), olfactory cortex (olfactory pathway), and gustatory cortex (gustatory pathway).

* Split-Brain Operation The cortices of two cerebral hemispheres are interconnected by a great number of fibers, the largest cerebral commissure, which is called the corpus callosum. Most fibers of the callosum connect principally homotopic (and partially hererotopic) sensory and motor areas of both hemispheres. Although the manner of communication is not completely understood, it

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is obvious that the callosum serves to integrate the functions of the left and right cortices. (Gross anatomy indicates that the frontal lobes, parietal lobes, and occipital lobes are connected through the callosum, but the connection between temporal lobes is uncertain.)

Figure 6-4. Different functional specialization of the left and right hemispheres. Specialization of sensory function is represented in the lower halves, and specialization of motor function in the upper halves. (Some of the functions are based on speculation.) Opposite conceptual terms corresponding to their functional differences are also presented under each hemisphere. (Adapted from Sperry, 1974.)

If two hemispheres are separated by sectioning the corpus callosum, functions of one hemisphere are expected to become clearer, as interference from the other hemisphere is eliminated without destroying any cortical tissue. From this perspective, Roger Sperry and his

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colleagues examined functions of each hemisphere in patients treated with split-brain operation for preventing the spread of epileptic seizures. They devised ingenious tasks for this purpose using called a tachistoscope, a device which is able to send visual information separately into either of the two hemispheres by quickly flashing the stimulus. Typically, an examination using tachistoscopic visual stimuli (a visuospatial test) requires the patient to report a word, for example, “cup”, which is presented to either of the right and left visual fields. In such tests, the split-brain patients were able to report words if they were presented in the right visual field (left hemisphere). On the other hand, the patients could not report correctly, or they said “I see nothing” if the word stimuli were presented in the left visual field (right hemisphere). Still, they were able to correctly choose a cup from many different objects before them. Although the split-brain method is fairly radical, it furthered our understanding on the functional difference between the two hemispheres. The outline of the results for functional laterality are the following: the left hemisphere is specialized for such functions as speech, language interpretation, reading, writing, and arithmetic tasks, whereas the right hemisphere is widely specialized for nonverbal recognition, such as pattern and shape recognition, direction in space, musical audition, and sense of intuition. These results can be stated more comprehensively to say that the left hemisphere processes information sequentially (or analytically), and the right hemisphere, more spatially (or synthetically). These features are represented in Fig. 6-4: in discussing the lateral specialization, sensory and motor function, in general, tends to be intermingled, so in the figure specialization an attempt is made to separate between motor and sensory functions. The left-right functional specialization obtained from examinations in the sprit-brain operation is principally accepted with almost no alterations and is based on studies of brain function up to the present. [A Different Angle 6-2] Functional separation viewed from the preference side of arm and leg: Apart from the results of laboratory studies on brain laterality, functional differences between the right and left hemispheres can be simply estimated based on the movement of our arms and legs in everyday life. In walking, in which we easily swing both arms, there is no difference in the movement manner between both legs and both arms, but a difference emerges when we perform elaborate tasks or complex operations using our hands and legs. In crafting something with our hands, such as when we carve a statue, the left hand holds the grip of the chisel and the right hand hits the pommel. In kicking something, such as a soccer ball, the left foot supports the body and the right foot can kick the ball in various ways. It is apparent that right (dominant or preferred) limbs can function fully only when they are supported by the left (non-dominant or nonpreferred) limbs. This is essentially equal to the functionally different property between the left and right cerebral hemispheres. The analytic function of the left cerebral hemisphere cannot be achieved sufficiently if there is no support by the right hemisphere. In watching a picture of a face, we can make analytical recognition of eyes, ears, a nose and a mouth only when the figure is as a whole recognized as a face, which is performed by the right hemisphere. When we speak the name of any object, recognition of the being itself is necessary before we can join it with the proper noun and its vocalization; this is a function of the right hemisphere. The evolutionary origin of lateral specialization is not obscure, but it is certain that the lateral

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specialization of hands and feet has made their operations more elaborate. If right and left limbs move in the same fashion, which must occur if brain functional lateralization is poor, our complex and intelligent works are impossible to be achieved. This is applicable to other higher functions such as speaking, singing, playing, painting, and so on. In addition to the definitions of function as “analytic (sequential)” and “synthetic (spatial)”, there are also adaptive terms, such as “dynamic (active) ” and “static (passive)”, or “expressive” and “supporting”, respectively, for the left and right hemisphere (Fig. 6-4). Usage depends on functional types. The phenomenon that a unit of matter or a system separates into two parts, each of which shows different function but depends on in each other, is observed in many aspects of this world (even in social systems). The lateralization of the brain is also a good example.

* Lateral Specialization Viewed Using Other Interesting Methods The sodium amytal (amobarbital) test ("Wada test”) was designed by Juhn Wada to determine which hemisphere is dominant for speech functions in patients with epilepsy. In this test, the chemical is injected into either the left or right internal carotid artery to produce a brief anesthesia on the ipsilateral side of the injection (Fig. 6-5 a). If the injected hemisphere is dominant for language, the subject is unable to speak under anesthesia. This test revealed that more than 95% of right-handed people have language dominance in the left hemisphere, and a fairly high percentage (70%) of left-handed people also have lefthemisphere language ability. (In other words, approximately 93% of all people have language dominance in the left hemisphere, given that about 90% of all people are right handed.) This method needs careful treatment in its execution, but seems to have a possibility of wide application on various functions other than speaking. The dichotic listening task was initially designed by Doreen Kimura to compare hemispheric specialization in auditory perception. In the test, subjects are presented with a series of different words in their left and right ears simultaneously, and then asked to repeat as many words as possible (Fig. 6-5 b). Results of the test have demonstrated that words presented to the right ear are usually better discriminated than those presented to the left ear. Furthermore, this test revealed a right-ear (left hemisphere) dominance for a song’s lyrics and a left-ear (right hemisphere) dominance for the melody. This test is excellent at a point of examining the lateral specialization of hearing function easily with a simple apparatus. The “Tsunoda test” was designed by Tadanobu Tsunoda to examine the right-left specialization of hearing function, where the dichotic listening task was combined with a tapping audiometry device. In the test of tapping audiometry, a subject voluntarily continues to tap a key with a certain rhythm, each time triggering a short tone that feeds back to the ears of the subject through earphones. The subject, however, can not maintain the steady rhythm of tapping when the feedback tones are delayed by an electrical delay circuit. In the Tsunoda test, the synchronized tone with tapping feedback to one ear, and various sort of delayed signals such as vowels, words, noises, pure tones, instrumental sounds, insect chirps, bird songs, and so on, are sent to the other ear in successive tapping (Fig. 6-5 c). This procedure, when done twice, changes between the right and left ears, and it is used to examine which ear

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stimulus of the delayed signal disturbs the tapping rhythm more greatly. The test proved that the affected ear (the dominant hemisphere) in disturbances is different depending on the type of sound. As expected, language input (such as vowels, articulations and words) dominate the right ear (left hemisphere), whereas musical, mechanical and noise sounds dominate the left ear (right hemisphere). In addition, the test revealed the interesting fact that Japanese tend to perceive insect chirps, bird songs, animal barks, cries and laughter dominantly in the left hemisphere, whereas Western people perceive them dominantly in the right hemisphere.

Figure 6-5. Diagrammatic representation of various tests for examining the functional laterality of the cerebral hemispheres without damage of nervous tissue. They are the sodium amytal test (Wada test) (a), dichotic listening (Kimura) test (b), Tsunoda test (c), and local-global stimuli test (d). (a, b, c and d are drawn respectively based on Wada, Clarke, and Hamm 1975; Kimura, 1973; Tsunoda, 1975; and Navon, 1977.)

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Many interesting tasks using visual presentation have been designed to examine hemispherical differences in visual function. Results of a “local-global stimuli test”, for instance, created first by David Navon, were suggestive for the process of functional differentiation. The test was designed to examine how the brain perceives hierarchical stimuli, where visual patterns containing both analytical (local) and synthetic (global) elements are presented in a short time (Fig. 6-5 d). This test suggested that the perceptual system of the brain tends to recognize firstly the global element, rather than the local element. As expected, this test on patients with hemispheric lesions proved that right hemisphere damage produces difficulty in recognizing the global element of the hierarchical stimuli, and left hemisphere damage, its local element. These various methods were excellent in estimating the lateral specialization without damage of brain tissue, but they left unclear the neural mechanisms and the accurate location of function. Modern imaging techniques, such as PET (positron emission tomography) and fMRI (functional magnetic resonance imaging), have made possible the observation of the relation between neural function and its activated location without damage to brain tissue. The techniques have provided us with a greater understanding of the functional laterality of the human brain. In addition, brain imaging techniques simultaneously revealed that perceptive and cognitive processes in the brain are more complex than we thought. For example, language processing, although dominant in the left hemisphere, relies simultaneously on synchronized interactions among various cortical areas and, in addition, among subcortical structures. [A Different Angle 6-3] Left-right specialization of internal organs: Internal organs that are innervated by peripheral nerves of the autonomic nervous system can be regarded as a deployment of the brain. They appear in different forms, show different internal structures, are situated separately from each other in the body cavity, and have different functions with the organs. Is there any laterality in physiological function among internal organs, similar to that observed in brain hemispheres? The representative internal organs situated on the left side are the heart and stomach (Fig. 6-6). In the circulatory system, actual work is performed by the distal members, the capillary vessels, which are distributed throughout the body, while blood circulation continues through the work of the heart. In the digestive system, foods taken in are stored in the stomach and changed into a state suitable for the subsequent digestive processes. The function of the heart and stomach can be considered as a sort of “collective function”. On the other hand, the representative organ situated on the right side is the liver, most of the volume of which is located on the right side of the stomach (Fig. 6-6). Various functions of the liver are known, but its main function is the filtration and detoxification of various substances, such as old red blood cells, metabolic products, and noxious chemicals. The collective function of the heart and stomach is similar to the synthetic function of the right hemisphere, and the function of the liver, to the analytic function of the left hemisphere. (From this point of view, the functional lateralization of the internal organs is considered the reverse of that of the brain, which is similar to the specialization in tasks of the right and left limbs.)

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The semi-fluid mixture of food with gastric secretions (chyme) in the gut is then transported to the duodenum, which is the place where digestion proceeds under multiple digestive enzymes secreted from the pancreas. It is suggestive that the duodenum is situated right of the gut. Furthermore, the following view for the function of the intestines, which occupy a large area of the abdominal cavity across the left and right sides, may be possible. Chyme in the duodenum is propelled to the small intestine, winding downward to the left and right, where digestion further advances and nutritive components are extracted. In the small intestine, both the analytic process (selection of nutritive components) and synthetic process (including the remainder) advance at the same time. The contents of the small intestine then enter the large intestine, which runs first upwards on the right side of the abdominal cavity, moves to the left side across the midline, and then runs downward on the left side to the anus. In the proximal (right) half of the large intestine, water and electrolytes are absorbed from the chyme, and in the distal (left) half the remainder is included as feces. The contents of the large intestine rotate clockwise, and its right half exhibits a selective function and its left half, a collective function.

Figure 6-6. Approximate location of major internal organs in the body space.

Another extensive discussion may be permitted, namely that organs of paired formation might show a functional differentiation between the two. The lungs, kidneys, and reproductive organs of males and females form pairs. The most rational explanation for the paired system is that it allows for the maintaining of safe physiological function by one compensating for the other. Although this is a plausible explanation, there are many internal organs that are single. Yet another interpretation of the paired system, by which the two parts play different roles from each other within a certain function, might also be possible. Eyes and ears are paired sensory organs, each of which shows almost the same figure. However, when we shut either of our

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paired eyes (or stop up our ears), an important factor of our visual (or hearing) sensation is lost, (but a certain level of the sensation is also kept). Setting aside the outward appearance, no one is likely to think that either of the eyes (or ears) is unnecessary. On the other hand, we tend to think that the loss of one of paired internal organs does not produce a serious problem on the organism: we think that it isn't qualitative, but quantitative, if a problem would result. It is, however, probable that the paired types of internal organs would be accompanied, more or less, with functional differentiation, which has not yet been discovered.

(2) Input-Output (I/O) Organization of the CNS The spinal cord has a modular organization, in which every segment has a similar basic structure. Each spinal cord segment contains a pair of nerve roots, the dorsal and ventral roots. Dorsal roots contain afferent nerve fibers that convey sensory inputs, and ventral roots contain efferent fibers that conduct motor signals away from the spinal cord. On each dorsal root there is a swelling called the dorsal root ganglion, which contains the cell bodies of both somatic and visceral afferent neurons, whereas the cell bodies of somatic efferent neurons are located in the anterior horns, and those of visceral efferent neurons are in the lateral horns of the spinal cord. The organization, in which the dorsal roots contain sensory fibers and the ventral roots contain motor fibers in the spinal cord, is known as the Bell-Magendie law. (The Bell-Magendie law includes both the somatic and visceral systems.) Is the Bell-Magendie law restricted to the spinal cord? The nervous organization analogous to the spinal cord is widely observed in various nervous systems of the brain if the Bell-Magendie law is understood to mean that neural signals principally flow from the dorsal (posterior) side to the ventral (anterior) side in a unit functional nervous system. The functional differentiation in the right and left halves of the brain was examined in the previous section, and the functional differentiation in the ventral and dorsal halves of the CNS will be addressed in this section.

* Neural Organization of the Brainstem The Bell-Magendie law can be also described from the developmental aspect of the spinal cord. As explained in Chapter 1, spinal neurons develop from precursor cells in the ventricular zone of the neural tube cavity that forms from a specialized region of the ectoderm called the neural plate. These developing cells migrate and form 2 zones of developing neurons: the alar plate (in the dorsal portion of the neural tube wall), and the basal plate (in the ventral portion of the neural tube wall). Neurons that develop from the alar plate comprise the interneurons and projection neurons of the dorsal horn of the mature spinal cord, which receive sensory information from the dorsal root ganglion neurons. Neurons that develop from the basal plate comprise the interneurons and motor neurons of the ventral horn of the mature spinal cord, which exit through the ventral roots. The brainstem (medulla, pons, and midbrain) receives sensory information from cranial nerves,

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and their efferent neurons mainly control the muscles of the orofacial region. The basic plan of brainstem development is the same as that of spinal cord development. Although the arrangement of nuclei in the brainstem involved in sensory and motor function is distorted because of the extensive lateral spread of the 4th ventricle, the organization of the roots and the location of nuclei of the cranial nerves in the brainstem are analogous to their counterparts in the spinal cord.

* Sensory–Motor Organization Across the Central Sulcus of the Cerebral Cortex The sensory-motor organization of the spinal cord and brainstem is not simply adaptive to the brain, as its neural structure and function are complexly elaborated. However, there are also nuclear groups (or areas) whose function and interconnection are fairly simple. First of all, the neural organization fitted to the Bell-Magendie law can be clearly observed in the relation between the primary somatosensory area and primary motor area in the cerebral cortex. Somatic sensory inputs from limbs, the trunk and the head project finally to neurons in the contralateral cerebral cortex of the posterior region of the central sulcus, and neurons in its anterior region descend to the brainstem and spinal cord, controlling mainly the skeletal muscles. The primary somatosensory cortex and the primary motor cortex are similarly somatotopically organized. The primary motor cortex is estimated to receive input from the primary somatosensory cortex, mainly from the corresponding opposite site, through short association fibers. Although the dorsal-ventral relation of the brain is distorted, there is little objection among neurologists to the view that the organization between the primary somatosensory area and the primary motor area across the central sulcus is analogous to the sensory-motor organization in the spinal cord (1 in Fig. 6-7). (In discussing the brain portion of the CNS, the terms “posterior” and “anterior” are used instead of “dorsal” and “ventral” in this chapter.)

* Organization of Visual Pathways in the Cerebral cortex The primary visual cortex is located in the calcarine area of the occipital lobe, and the signals then flow forward through many nuclei in the occipital, parietal, and temporal lobes (Fig. 5-8). The visual function of humans is highly differentiated, and various aspects of visual information are progressively analyzed during the transmission in the posterior region of the hemispheres. Setting aside the difference in visual function between the right and left hemispheres, these visual areas are thought to be located in both hemispheres in a similar fashion. Among the many diverse actions associated with visual sensation, eye movements appear to be the most direct response. Three areas in the frontal lobe, the frontal eye field, the supplementary eye field, and the dorsolateral prefrontal cortex, are known to participate in eye movements. The frontal eye fields (area 8), located anterior to the premotor cortex, are strongly associated with voluntary eye movement. The supplementary eye fields, anterior part of the supplementary motor area situated on the medial surface of the

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hemisphere, are involved in saccadic movements concerned with complex motor programming, such as those made during head or body movements. The dorsolateral prefrontal cortex (area 46) is believed to be activated by various types of visual inputs mainly during fixation of the eyes. Although visual inputs to these eye movement control centers of the frontal lobe have not fully been confirmed, it is reasonable to postulate that the visual motor areas have some connection with nuclei of visual sensory areas in the posterior lobes (2 in Fig. 6-7).

* Sensory-Motor Organization in the Hearing System Auditory signals, relayed via the medial geniculate body that is part of the thalamus, terminate at the superior surface of the temporal lobe, which is called the primary auditory cortex. In the left temporal lobe, the auditory information then flows to a posterior part of the superior temporal gyrus: this area is famous as the sensory speech area, which is thought to play an important role in interpretation of speech. On the other hand, an area that plays important roles in articulation of speech and language is the motor speech area, which is located in the inferior frontal gyrus of the left frontal lobe. The two areas are functionally connected through a specific fiber bundle (Fig. 6-1 A). The relationships in function and location between the two language areas are essentially the same as the corresponding relationship between the primary somatosensory area and primary motor area (3 in Fig. 6-7). The two language areas are always described as restricted in the left hemisphere, but the auditory signals are input to the homologous area of the right hemisphere. Among the auditory signals, non-linguistic sounds, such as instrumental sounds and harmonic tones, are known to be perceived dominantly in the right hemisphere. However, there has been little description of motor areas corresponding to these non-linguistic auditory sensations. Musical representations such as singing and emotional vocalization such as cry, for example, are thought of as non-linguistic motor functions, which might be dominantly performed through the homologous area of the right hemisphere to the motor speech area of the left hemisphere.

* Organization of Gustatory and Olfactory Pathways in the Cerebral Cortex The primary gustatory cortex is known to be located in the anterior insular cortex extending to the frontal operculum, which is rostral and deep to the primary somatosensory representation of the tongue. Areas for oral functions such as chewing, swallowing, and tongue movements, which are closely related to gustatory sensation, are believed to be located in the lateral part of cortical area 4 (the orofacial region of primary motor cortex), area 6 (the premotor area), and the frontal orbital cortex, all of which are located more anterior to the gustatory sensory cortex. Concerning the olfactory pathways, areas projected by fibers from the olfactory bulb are collectively located in the medial portion of the ventral surface across the frontal and temporal lobes. They include the olfactory tubercle, piriform cortex, entorhinal cortex,

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and amygdala. It is, however, difficult to discuss their sensory-motor organization because what is a motor event in the olfactory system cannot be clearly defined. The most conspicuous reaction of humans to odorants is the emotional response, but little of this reaction is accompanied by the direct movement of body parts. (Axons of olfactory relating neurons in the olfactory cortices and in the thalamus are known to project the orbital surface of the frontal lobe, which is close to areas for mastication movements.)

Figure 6-7. Input-output organizations observed in the brain nervous system: (1) primary somatosensoryprimary motor areas in the cerebral cortex; (2) occipital visual area-frontal eye field; (3) Wernicke’s areaBroca’s area; (4) thalamus-basal ganglia; (5) hypothalamus-hypophysis connection; and (6) retina cell layers. Major fiber bundles connecting the anterior and posterior halves are also superimposed in the illustration of the left hemisphere.

* Functional Relation Between the Anterior Half and Posterior Half of the Cerebral Hemisphere Through our global overview of the sensory and motor organization in the somatic, auditory, visual, and gustatory system, it appears that most sensory information is processed in the posterior half of the brain and that most motor signals arise from the anterior half of the brain. Furthermore, it is possible to hold the view that in the posterior half of the cerebral cortices, sensory modality changes from wavy to somatic, proceeding from marginal areas to the central sulcus, and in the anterior half, motor function changes from abstractive to concrete proceeding from marginal areas to the central sulcus. From this viewpoint, the sensory cortex can be classified into 3 large areas: i) the marginal area, which contains the majority of occipital and temporal lobe neurons, and which processes information about wavy stimulants such as light and sound; ii) the primary somatosensory area, which is immediately posterior to the central sulcus, and which mainly processes information about mechanical senses of various parts of the body; and iii) the intermediate area between the marginal area and primary somatosensory area, which is involved in various associations

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among different modalities of sensory signals, and which corresponds to traditionally-named association areas. (This classification is similar to the concept of peripersonal and extrapersonal spaces in space cognition. The intermediate area near the primary somatosensory area might correspond to peripersonal space cognition, and the intermediate area near the marginal area, to extrapersonal space cognition.) From the functional aspect, the motor cortex of the frontal lobe can be similarly classified as follows: i) the prefrontal area including the frontal pole, which is involved in the generation of abstractive motor events such as volition, will, motivation, expectation, and intention; ii) the primary motor cortex, which is located immediately anterior to the central sulcus, and which is directly involved in movement of feet, hands, neck, and organs of the face; and iii) the area intermediate between areas i and ii, which is involved in coordination of body movement or its programming. Concerning motor areas i and iii, it is certain that the anterior regions of the frontal lobe are mainly involved in giving rise to the intrinsic motor event, considering that damage to the anterior portion of the frontal lobe causes loss or impairment of the ability to initiate voluntary action. In brain wave recording, generation of negative potential, called the readiness potential (RP) or the contingent negative variation (CNV), is normally recorded in the anterior half of the brain preceding actual movements during cognitive tasks, of which processes are thought to be mediated by the prefrontal cortex, supplementary cortex, and premotor cortex. (Excitatory synaptic potential is recorded as negative potential on the surface of the skull.) We are aware that the three areas in the posterior sensory cortex and the three areas in the anterior motor cortex compose functionally mirror images of each other across the central sulcus. When a human performs any controlled and skilled action (e.g., grasping an object), the following processes occur: i) generation of the purpose of the movement; ii) programming how to coordinate the involved body parts; and iii) actual movement. Each of those processes requires adequate sensory information to advance the movement smoothly. The generation of the purpose or motivation is triggered, for instance, by visual inputs to the occipital lobe. The prefrontal area of the frontal lobe might play an important role in generating such an intrinsic motor event. Programming for coordination of different body parts to perform the action must be mediated by the premotor area or supplementary motor area, and appears to require input from several different senses via the intermediate area of the sensory cortex. Actual movement of the hands, feet and/or head is executed with reference to direct sensory information for the state of body parts used. Although the above description is a rough sketch of interrelations between the sensory and motor areas, and the movement process is successively corrected by feedback of sensory information, it appears certain that signals arising in motor areas are strongly dependent on input from the opposite sensory area. Indeed opposite areas of the posterior and anterior halves of the cortex tend to be connected via association bundles (or fibers) within the hemisphere. The marginal areas of the posterior and anterior halves are connected via the superior longitudinal fasciculus, inferior occipitofrontal fasciculus, and uncinate fasciculus; the intermediate areas are connected via the superior occipitofrontal fasciculus; and the primary areas are connected via short association fibers (Fig. 6-7). The terms “input” and “output” might be more proper than the terms “sensory” and “motor” in talking about the central nervous system, as most neurons involved have both

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sensory and motor aspects in the sequence of signal flow. The manner that input signals are processed in the posterior portion, as well as output signals in the anterior portion, can be also seen in various areas or structures of the brain other than the cerebrum cortex. Hereafter, this input-output relation in the brain is referred to as the “I/O organization law”.

* Nervous Organization in the Thalamus and Basal Ganglia The connections and functions of deep areas of the brain generally remain unclear mainly due to the difficulty in conducting studies of those areas. The thalamus, an oval-shaped structure in the diencephalon, is known as a nodal point for transmission of sensory information to the cerebral cortex. It is situated on each side of the third ventricle and contains several defined nuclei. Somatic sensory information projects to nuclei mainly in the posterior portion of the thalamus. The ventral posterolateral nucleus (VPL), a lateral division of the ventral posterior nucleus, receives input from the medial lemniscus system for mechanical sensory information of the limbs and trunk. The ventral posteromedial nucleus (VPM), a medial division of the ventral posterior nucleus, mainly receives input from the trigeminal nerve, which conveys mechanical sensory data from the face and head. Outputs from both nuclei project to the primary somatic sensory cortex (and partially to the secondary somatic cortex) via the posterior portion of the internal capsule. The optic nerve projects to nuclei of the lateral geniculate body, and neurons in the inferior colliculus (origin of third order auditory fibers) project to nuclei of the medial geniculate body; both bodies are swellings on the posterior surface of the thalamus beneath the pulvinar part. Although the function of nuclei in the anterior portion of the thalamus is less clear than the function of the posterior nuclei, neurons in the anterior nuclei are thought to diffusely project mainly to portions of the frontal lobe, such as the frontal cortex, premotor cortex, supplementary motor cortex and primary motor cortex, and perhaps the cingulate gyrus. These features strongly suggest that the organization of the thalamus also conforms to the I/O organization law. One clearly established fact is that most ascending (sensory) signals pass through nuclei in the posterior region of the thalamus. In the antero-lateral region of the thalamus, there are functional groups of neurons that are collectively known as the basal ganglia. They are the caudate nucleus, putamen, and globus pallidus (and the substantia nigra is frequently included). Although the precise input-output organization of the basal ganglia is not clearly understood, it is certain that the nuclei receive descending signals mainly from the anterior half of the cerebral cortex, and that signals modulated in the basal ganglia project to cell groups involved in motor function mainly in the brainstem. (Also, some of the output signals from the basal ganglia are believed to relay basal ganglion signals to the thalamus, conforming feedback circuits in the motor cortex.) One certain fact is that the major role of the basal ganglia is the control of basal aspect of body movements. Indeed, pathological changes are frequently found in the subcortical nuclei from patients with extrapyramidal disorders such as Parkinson’s disease, Huntington’s disease and hemiballismus ("A different Angle 4-11"). Thus, the basal ganglia are intermediate structures that modulate descending motor signals from the cerebral cortex, whereas the thalamus is an intermediate structure that

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processes ascending sensory signals just before they enter the cerebral cortex. Although detailed synaptic connection between the thalamus and the basal ganglia remains unclear, it is possible that the relation between the two structures in the subcortical region is analogous to the sensory and motor organization of the cerebral cortex (4 in Fig. 6-7). This view seems not to be so unusual, because the thalamus, from the beginning, has its origin in the alar plate of the neural tube of the diencephalon, and the basal ganglia are estimated to originate mainly from its basal plate.

* Signal Flow in the Cerebellum The cerebellum lies posterior to the 4th ventricle of the pons and medulla, and it is thought to play an important role in maintaining posture and coordinative aspects of various movements. It is commonly divided into 3 functional regions: the spinocerebellum receives mainly somatic sensory information from the spinal cord; the cerebrocerebellum, from the cerebral cortex; and the vestibulocerebellum, from the vestibular labyrinth. Sensory information entering the cerebellum is conveyed by 2 main types of afferent fibers: the climbing fibers originate mainly from the inferior olivary nucleus, and the mossy fibers originate mainly from nuclei in the spinal cord and caudal brainstem including vestibular nuclei. The climbing and mossy fibers, respectively, project to 2 different types of cells that are widely distributed throughout the cerebellar cortex: Purkinje cells and granullar cells (Fig. 4-10). Beneath the cerebellar cortex lies white matter within which 4 bilaterally paired nuclei (the deep cerebellar nuclei) are embedded. These 4 nuclei function as final output nuclei of the cerebellum. The Purkinje cells project their inhibitory signals to the deep cerebellar nuclei. (Both the climbing fibers and mossy fibers are also believed to conduct signals directly to the deep nuclei via their branches.) The output of the deep nuclei projects diversely to structures including the thalamus and hypothalamus, the red nucleus in the midbrain, the vestibular and reticular nuclei of the brainstem, and maybe the inferior olivary nucleus in the medulla. These patterns of signal flow are fairly complicated but can be roughly characterized as follows: sensory signals project first to the cellular layers of the cerebellar cortex covering the dorsal cortex of the cerebellum, then project ventral to the deep nuclei via the Purkinje cells, and exit anterior to the brainstem (Fig. 6-8). The cerebellum apparently evolved to integrate multiple types of sensory information for posture control. Viewed simply, the cerebellum can be described as one great bump at the dorsal surface of the metencephalon, suggesting that its main function is processing sensory information. This can be understood from the developmental aspect of the cerebellum: most of this architecture develops from neurons located in the rhombic lips, which are specialized regions of the alar plate of the dorsolateral metencephalon. It is proper to think of the output of the cerebellum deep nuclei as highly integrated sensory signals rather than as motor signals. Viewing glossary neural connections between the deep nuclei and the relating nuclei in the brainstem, such as the vestibular nuclei, reticular formation nuclei, and red nucleui (and possibly the substantia nigra), they are regarded as composing the sensory (input)-motor (output) organization.

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Figure 6-8. Diagrammatic representation of signal flow in the cerebellum, brainstem, and spinal cord. The relevant nuclei are drawn with filled closures. A cross section of the caudal medulla and spinal cord are superimposed.

* Other Structures to which the I/O Organization Law Can Be Applied The hypothalamus, which contains a variety of nuclei, is situated at the anterior end of the diencephalons, below the thalamus. Its main functions are control of hormone production and regulation of the autonomic nervous system. The anterior pituitary gland (hypophysis) is regulated indirectly by the hypothalamus. A group of neurons located mainly in the medial zone of the hypothalamus secrete 2 types of peptide hormones (releasing hormones and release-inhibiting hormones) into the hypophyseal portal circulation, which carry blood from the hypothalamus to the anterior pituitary gland. In the anterior pituitary gland, those peptide hormones control the release of most of the anterior pituitary hormones. Also, neurons in the paraventricular and supraoptic nuclei in the hypothalamus project to the posterior pituitary gland. The bodies of those neurons synthesize the neurohypophyseal hormones oxytocin and vasopressin, which travel down the axons and are released into the general circulation via the posterior pituitary (neurosecretion process). Although the hypothalamus itself is located in the anterior portion of the diencephalons, the connection between the hypothalamus and the pituitary gland via the circulatory system or neurosecretion (5 in Fig. 6-7) is consistent with the I/O organization law, if it restrictively views the two structures. The neural structure of the retina, which is the receptor for light, is a peculiar example of a pattern that is consistent with the I/O organization law. The retina is thought to be part of the central nervous system, rather than a peripheral organ, and its synaptic organization is

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similar to that of other CNS structures. Retinal neurons and their synaptic connections are organized into many layers (Fig. 5-7 A2). The photoreceptor cells, rods and cones, are located in the back of the eye, immediately in front of the pigment epithelium, and all other retina cells processing and transmitting the receptor signals are located between the photoreceptors and the lens. Thus, light must travel through layers of other retinal neurons before striking the photoreceptor cells, and the neural message flows from the back to frontal of the retina layers (6 in Fig. 6-7). Most neurologists feel that this neural organization is very curious. The arrangement of retina neurons is difficult to understand unless viewed in terms of the I/O organization law. Dorsal column axons that convey somatic sensory information of limbs and trunk ascend the spinal cord and synapse on neurons in the dorsal column nuclei, the gracile nucleus and cuneate nucleus (Fig. 4-3), which are swellings at the dorsal surface of the caudal portion of the medulla. The axons of second-order neurons run ventrally and decussate. Immediately after crossing the midline, the fibers ascend to the thalamus in the medial region of the medulla, which is called the medial lemniscus. On the other hand, the lateral corticospinal tract is the principal pathway for skeletal muscle control, the neurons of which originate mainly in the primary motor cortex. The descending axons run through the cerebral hemisphere in the internal capsule and then along the ventral brainstem surface. They appear as a large bundle on the ventral surface of the medulla, in the shape of a pyramid. Axons of the pyramid descend immediately ventral to the medial lemniscus, which is particularly easily visible in the caudal part of the medulla. This organization of the large ascending and descending bundles in the medulla can be considered to be another aspect of the I/O organization law (Fig. 6-8). At the junction of the spinal cord and medulla, the pyramidal axons decussate (pyramidal decussation) and descend in the dorsolateral portion of the lateral column of the spinal cord (lateral corticospinal tract). The axons synapse to motor neurons mainly in the ventral horn of the spinal cord, where the corticospinal fibers go out of the way to project them from the dorsal direction. A similar type of projection is observed in the running manner of rubrospinal fibers (Fig. 4-2 A), which originate from the red nucleus in the midbrain, and are the main fibers conveying motor signals from the cerebellum to spinal motor neurons. [A Different Angle 6-4] About the function of the mammillary body and pineal organ: It is possible to use the I/O organization law to estimate functions of nuclei or other structures in the brain. For example, the mammillary bodies are paired, small, rounded swellings at the anterior medial portion of the midbrain. The mammillary bodies are thought to connect with the anterior nuclear group of the thalamus, the tegmantal nucleus in the midbrain, and the hippocampal formation, but its precise input-output relations and functions remain uncertain. From the I/O organization low, its location in the midbrain strongly suggests the mammillary body having some motor function. No cranial nerve is, however, known to originate directly from it. Just above the mammillary bodies is situated the hypothalamus, and the bodies are thought to have a close relation architecturally to the limbic system as discussed in "A Different Angle 4-8". These facts give

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rise to the impression that the mammillary body is involved in the endocrine or autonomic control relating to emotion. The following prominent swellings are located at the dorsal side of the midbrain: the paired inferior and superior colliculei and the pineal organ located centrally just above the superior colliculei (Fig. 4-8). The 4 paired swellings process sensory information from the auditory and visual system, but the precise role of the pineal organ is not certain. The pineal organ is commonly classified as part of the human endocrine gland because it contains granular cells that produce the hormone melatonin, which is thought to be involved in the generation of circadian rhythms. However, the location of the pineal organ strongly suggests that it functions mainly in the processing of sensory information. In lower vertebrates, such as fishes, amphibians and reptiles, the pineal organ functions as a light sensor. It is located on the top of the head and is exposed to light penetrating the thin cranium. The human pineal organ may possibly still have the sensory function of processing any aspect of light information, even if it is intermediated by the suprachiasmatic nucleus.

* Past-Future Differentiation The I/O organization law can be further characterized by stating that nervous signals flow from the past (posterior side) to the future (anterior side), because the sensory perception process searches for past states, and every action directs future effects. Sensory information, such as a 1kHz sound, red light, bitter taste, pressure on a finger, and so on, cannot change, because the past occurrence cannot change, whereas action of a person to the sensory inputs varies with various inner and outer situations, because the future can be selective.

Figure 6-9. Functional dichotomies of the brain in three dimensions. The sagittal, coronal, and transverse axes are labeled with biological relevant terms such as discrimination, I/O, and evolution axis, respectively.

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[A Different Angle 6-5] I/O organization observed in the circular system: The distribution feature of vessels of the circular system in the body is similar to that of fibers of the nervous system. Actually, almost all fiber bundles, from large to fine, of peripheral nerves are attached by circular vessel and run together. In the nervous system, the motor component drives various tissues and organs, and the change of their situation feeds back to the brain through the sensory component. In a sense, the motor and sensory systems form, as a whole, an electrical circuit that is regulated by the CNS. There is no objection that the center of circular system is the heart: the systemic blood enters into the right atrium, passes into the right ventricle, and then is pumped through the pulmonary artery to the lungs, returning through the pulmonary veins to the left atrium (pulmonary circulation), passing into the left ventricle, where it is then pumped out through the aorta to all parts of the body, except the lungs. The blood percolated from the capillary vessels of arteries (arteriole) is absorbed by those of veins (venules), where it collects and returns through the superior and inferior vein (systemic circulation) to the right atrium. When we observe the heart from an upward direction (Fig. 6-10 a), the relation of the inflow (input) and outflow (output) of blood in the heart can be understood to be similar to the input/output signal flow manner of the CNS: the tricuspid valve, which marks the entrance of the superior and inferior veins into the right atrium, is situated posterior to the pulmonary valve, which is the exit of the pulmonary artery, and the mitral valve, which is the entrance of the pulmonary vein situated posterior to the aortic valve, the exit of the aorta.

Figure 6-10. Entrance-exit organization of main circular ducts in the heart (a), lungs (b), and kidneys (c). The heart is viewed from the upper direction; lungs, from the frontal direction; and kidneys, from the frontal direction. The lungs are drawn rotated (arrows) to allow observation of the entrance of arteries and the exit of the veins. (Redrawn from Larsen, 2002.)

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The lungs and kidneys are especially conspicuous as organs connecting to main trunks of the vascular system. Both organs function as important parts of the circular system. The lungs eliminate carbon dioxide from and supply oxygen to blood through the pulmonary circular system. The pulmonary artery enters and the pulmonary vein leaves medially from each lung, where the entrance of the artery as a whole is situated posterior to the exits of the vein (Fig. 610 b). The kidneys function in maintaining the balance of sodium and water of blood, and they excrete toxic wastes. They are situated bilaterally in the posterior wall of the abdominal cavity, and the aorta and the inferior vena cava join together in the center between the kidneys. These two great vessels supply the large branches, renal arteries and renal veins, to both kidneys medially. Each renal vein, through which the blood flows from the kidney, runs in front of each renal artery, through which the blood flows into the kidney (Fig. 6-10 c). The inflow and outflow manner of blood circulation in the heart, lungs, and kidneys can be also adapted to the I/O organization law of signal flow in the nervous system.

(3) Virtual-Physical Differentiation of the Total Nervous System All beings in the universe have dual aspects, wave and particle. This nature appears, especially in particles, such as electrons, and in electromagnetic field waves, such as light. There seems to be no doubt that electrons have a wave aspect and light has a particle aspect. In principle, this nature is supposed to be applicable to things such as stones, plants, animals, and even artificial products such as golf balls. Although the nuance is different from the wave-particle duality in the physical field, a similar dual function, which we might call “virtual and physical duality”, exists in the human nervous system. The term “duality” indicates a simultaneous being of two natures, but the two natures in the nervous system are not represented at a particular area simultaneously. They polarize in graded fashion on various organizations of the nervous system, so in the nervous system the term “gradation” is preferred to “duality”. In the previous sections, two major concepts regarding the nervous system, the left-right specialization and input-output organization, were discussed. In this section, the third concept, “virtual-physical gradation” observed on nervous function, will be taken up.

* Wavy-Material Gradation of Sensory Modality We continuously sense the external environment through sensory organs on our body surface. Most sensations are identified by a particular type of stimulus. Each sensory modality is received by its specific receptor organ and mediated by a distinct neural system. There is an interesting relation between the arrangement of sensory organs on the body and their sensory modalities. Somatic sensations of the trunk and limbs, such as touch, pressure, pain, and temperature are, in a sense, the most basic (or primitive) sensations in our sensory experience. They are received by a variety of exteroceptors that are distributed widely in the

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skin and subcutaneous tissue. The somatic sensory information is conveyed through dorsal root neurons of the spinal cord to the central nervous system. Light is sensed by retina cells of the eyes. Visual information is conveyed by the optic nerves and tracts to cortical areas through the lateral geniculate bodies. Sound waves collected by the auricle are transmitted to the inner ear and the vibration is received by hair cells in the cochlea. The auditory information is conveyed first to the brainstem by the cochlea nerve. Furthermore, we are exposed continuously to molecules released into our environment. Taste and smell sensations provide us with important information about these molecules. Taste stimuli are sensed by taste cells of the taste buds embedded in the papilla on the tongue. Odors are detected by the apical process of olfactory neurons that are embedded in a restricted area of specialized epithelium in the dorsal posterior recess of the nasal cavity. Each type of information for taste and smell is conveyed by the corresponding cranial nerve to the brain. The organization order of the receptor organs downward in the body is eyes, ears, nose, tongue, and somatic sensory organs. (Exteroceptors for somatic sensation exist also in the head part, but there might not be strong opposition that the main distribution is on the limbs and trunk.) Their corresponding stimuli are light, sound, floating molecules, dissolved molecules, and direct contact of matter, respectively. Here, we aware that the more materialistic the stimulant quality is, the more downward the corresponding receptors are located. In other words, humans sense the wave aspect of their environment using more upward sensory organs, and the material aspect, using more downward sensory organs (Fig. 6-11 A). (The sensory organs in non-human animals, however, are not necessarily arranged in the order as observed in humans, so this discussion is applicable to humans alone.) The hierarchical view of sensory modality and sensory organs make the understanding for a sensory perception system clearer. When discussing the sensory system, it seems proper to classify three hierarchies: the wave receptor system, molecule receptor system, and mechanical receptor system. (Frequencies of wavy stimulants such as light or sound are separated into the components by their receptor cells, and material stimulants such as mechanical stimuli or taste (or olfactory) substances are synthesized at their receptor cells.) [A Different Angle 6-7]

Function of the pineal organ viewed from the sensory modality: As described, the pineal organ of humans is located posterior in the roof of the third ventricle of the brain, and normally classified as an endocrine gland because it contains granular cells that produce the hormone melatonin. Secretion of melatonin is known to induce a circadian rhythm in mammals and a protective coloration in lower vertebrates, both of which are closely related to light sensing. In lower vertebrates such as fishes, amphibians and reptiles, it is located on the top of their head, which is externally identified by a small spot in the skin between the eyes. It is covered over by the roofing bones of the skull and presumably is exposed to light penetrating the thin cranium. Owing to the location and appearance, it is frequently called a “third eye”. Indeed the stacked formation of disc structure, as observed in the retina cells, is also observed in cells of their pineal organ, and nerve impulses are generated (or suppressed) when it is exposed to light. From the viewpoint that sensory organs located upward in the body sense more wavy stimulation, its location in lower vertebrates suggests that the pineal organ perceives higher frequency spectra of

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light than do the eyes. (It is interesting that the snake pit organ that senses infrared light is located slightly lower than the eyes.) Concerning the human pineal organ, it might be impossible to directly detect light of the visible spectrum range, about 400-700 nm, as it is deeply embedded in the brain. However, the possibility that this organ still possesses an ability to sense electromagnetic waves of quite short wavelength which can permeate the skull and brain matter might not be completely denied, as this organ yet closely relates with our circadian rhythm. Further, the pineal organ is unpaired, suggesting perception of a static aspect of the stimulus

* Wavy-Somatic Gradation of Sensory Function in the Posterior Half of the Brain Most nerve signals from the sensory organs enter the posterior lobes. The predominant area processing each sense is, describing roughly once more, as follows: somatic sensory inputs from limbs and trunk project to the primary somatosensory cortex, the elongated narrow region just posterior to the central sulcus of the parietal lobes; visual information to the wide area of the occipital lobe, which is the most posterior portion of the brain; auditory information to the temporal lobe, which is the lateral region of the brain; olfactory information to the medial portion of the ventral surface across the frontal and temporal lobes; and gustatory information to the insular cortex near the primary somatosensory cortex, which is adjacent to the olfactory cortex. The intermediate wide region of the parietal lobe between the primary somatosensory area and the occipital and temporal lobes is called the sensory association area, where the somatosensory information is believed to mix with other sensory information, mainly visual information. These arrangements are generalized as sensory modality in the posterior half of the brain changes from wavy to somatic approaching the central sulcus (Fig. 6-11 B).

* Abstractive-Concrete Gradation of Motor Function in the Anterior Half of the Brain Most motor signals arise from the anterior half (frontal lobe) of the brain. A rough sketch of localization of motor functions in the anterior half is, describing roughly once more, as follows. Neurons of the elongated narrow region just anterior to the central sulcus (primary motor cortex) control skeletal muscles of the foot, hands, trunk and head through the spinal or brainstem motor neurons. This primary motor cortex and the primary somatosensory cortex are similarly somatotopically organized. The anterior wide area of the frontal lobe, including the frontal pole, called the prefrontal area, is involved in generation of motor events such as volition, will, motivation, memory, thought, expectation, and intention, which do not directly associate with muscle contraction. Many distinct areas for various functions are identified between the primary motor area and prefrontal area: they are the supplementary motor area, supplementary eye field, frontal eye field, premotor area, and motor speech area. The common feature of their functions is

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programming for coordinating various body parts to perform actions smoothly. Functional difference of the anterior half of the brain can be generalized as motor function in the anterior half of the brain changes graded from abstractive to concrete approaching the central sulcus (Fig. 6-11 B).

Figure 6-11. A: Relation between the location of sensory organs on the human body surface and their adequate stimuli. The stimulus modality changes from wavy to materialistic as the sensory organs progress downward. B: Location of sensory and motor functions in the posterior and anterior halves of the brain viewed from the left side. In the posterior half, the processed sensory modality changes from wavy to somatic as it approaches the central sulcus, and in the anterior half, the motor function changes from abstract to concrete approaching the central sulcus. (The olfaction relating area and the primary gustatory cortex, both of which are located inside the brain, are shown with dotted enclosures.)

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[A Different Angle 6-8] Function of motor areas estimated from the mirror image: As described in section (2) of this chapter, the abstractive-concrete gradation of motor function in the anterior half of the brain is a mirror image of the wavy-somatic gradation in sensory processing of the posterior half. From this viewpoint, the anterior region of the frontal lobe (prefrontal cortex) is considered to be involved in most abstractive motor function, which may be something like visual images. When we perform any goal-directed action, first of all we are struck with an image of the situation to be achieved before programming the process of the behavior and before actually moving the arms and feet. When we taste, smell, and hear, any related image emerges indefinably in our mind, which may be most abstractive visual motor function. The visual image would be closely connected to our will (or motivation) that is well known to be produced in the prefrontal cortex, including the frontal pole. The widely elongated area anterior to the primary motor cortex is called the premotor cortex. The premotor cortex is also known to show approximate maps of the body (somatic homunculus) similar to the primary motor cortex. The medial surface of the hemisphere just anterior to the representation of the foot in the primary motor cortex is called the supplementary motor cortex. The position of the supplementary motor cortex strongly indicates its main function to be coordinative foot movements. Anterior to the supplementary motor cortex is the so-called the supplementary eye field, which is fairly close to the frontal pole. Here the thought arises that the intrinsic visual image originating from the region of the frontal pole flows dispersedly towards the primary motor cortex, and the supplementary eye field and the supplementary motor cortex are on the way to the foot area of the primary motor cortex. Similarly, many pathways toward the primary motor cortex are thought to exist: for example, the frontal eye field may be an intermediate nucleus of the pathway toward the hand area, for example, capturing moving objects, and Broca' s area may be an intermediate nucleus of the pathway toward the mouth or tongue for adding a factor of visual event to the linguistic event .

* Mental-Actual Gradation of Nervous Function in the CNS Viewing the CNS as a whole, the level of nervous function gradually changes from basic to elaborate with progression from lower to upper regions along the transverse axis. The spinal cord and brainstem are directly associated with the activity of internal and external organs and various tissues, which are integrated at the core region of the brain, such as the thalamus, hypothalamus, and basal ganglia. The limbic system, a marginal area of the brain core region, is associated with producing emotion, thought to be a sort of intrinsic behavior without direct movement of the body. The rostral end of the CNS, the cerebral cortex, is thought to be the place for highly conscious function. Most human conscious behaviors are controlled by the cerebral cortex. This functional change in the transverse axis of the CNS can be referred to as “mental-actual gradation” (Fig. 6-12).

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Figure 6-12. Rough sketch of internal organs and the central nervous system (CNS) of humans. The illustration indicates that nervous function of CNS changes from mental to actual, and physiological function of internal organs including the brain changes from spiritual to substantial with downward positioning.

* Virtual-Physical Differentiation in the Nervous System These dualities in the human nervous system, the wavy-material gradation in sensory receptor organs, wavy-somatic gradation of sensory function in the posterior half of the cerebral cortex, abstractive-concrete gradation of motor function in the anterior half of the cerebral cortex, and mental-actual gradation of the CNS in the transverse axis, can be discussed inclusively as “virtual-physical differentiation”. Different from the wave-particle duality in electrons and light, the differentiation between the two properties of each duality in the human nervous system is graded. It is certain that the nervous system of humans is polarized into two properties, and that the function is maintained on the effective connection or communication between the two. Just as the concept of wave-particle duality in physics has made the explanation of various phenomena of nature more rational, the view of virtual-physical differentiation in the nervous system would advance the understanding of its mechanism. [A Different Angle 6-9] Functional differentiation in the organization of internal organs: From the viewpoint of physiological function, the human body can be largely divided into three parts: abdomen, head, and thorax. In the abdomen, there are the gut, intestines, pancreas, liver, gall, and so on. Most of them are involved in nutrition intake or metabolism, which can be stated to be “substantial”

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functions. On the other hand, the function of the brain is to integrate various forms of information from the internal and external environments and to control the organism adequately. Brain function is mediated by the electrical signals of neurons, which are, as a whole, wavy processes, which can be stated to be a “spiritual” function. Furthermore, it is noticeable that prior to being consumed, foods are packed with chemical energy, which decreases gradually while traveling downward through the digestion organs. Likewise, the spiritual aspect of the central nervous system grows weaker with increasing distance from the brain cortex, and the spinal cord is strongly associated with actual physical functions. Both of these can be considered to be the “substantiation”. The function of the lungs is to exchange oxygen and carbon dioxide through respiration, and the function of the heart is to circulate blood. Both the brain and the abdominal organs need blood to function fully. It is possible to consider that the heart and lungs work as the interface apparatuses between the brain and the abdominal organs through their rhythmical movements. The internal organs, including the brain, are also considered to polarize into two properties--spiritual and substantial functions (Fig. 6-12).

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Index A Aβ, 74 abdomen, 125, 199 abdominal, 22, 179, 191, 199 ablations, 167 abnormalities, 171 absorption, 15, 118, 161 accommodation, 50 accounting, 42 acetate, 80 acetylcholine, 22, 66, 69, 80, 81, 93, 97, 98 acetylcholinesterase, 80 Ach, 80, 82, 85, 86 acid, 22, 30, 63, 77, 81, 82, 84, 86, 87, 90, 91, 92, 94, 128 actin, 72 action potential, 2, 27, 29, 30, 42, 43, 44, 45, 46, 48, 49, 50, 53, 58, 59, 62, 63, 64, 71, 72, 74, 75, 77, 78, 79, 80, 88, 90, 117, 133, 142, 158, 159, 161, 164 activation, 45, 48, 50, 77, 89 activation parameters, 50 activity level, 83, 112 adaptation, 159, 162, 166 adenosine, 39, 95 adjustment, 17, 156 adrenal cortex, 22 adrenal gland, 22 adrenaline, 22, 82 adult, 4, 8, 13, 16, 79, 99, 121 afferent nerve, 181 afferent nerve fiber, 181 age, 8 agnosia, 172

agonist, 80 air, 148, 150 alexia, 173 alimentary canal, 6 alkaloids, 158 allergens, 84 allosteric, 95 alpha, 90, 93, 94 alternative, 98 amine, 82, 84 amino, 80, 82, 84, 85, 86, 87, 90, 92, 94, 118, 142 amino acid, 80, 82, 84, 85, 90, 92, 94, 118, 142 ammonia, 145 ammonium, 63 amphetamines, 82 amphibia, 20 amphibians, 11, 18, 19, 20, 148, 189, 196 amplitude, 43, 45, 48, 53, 74, 77, 78 ampulla, 147, 150, 159 amygdala, 19, 117, 120, 125, 184 analgesic, 85 anatomy, 98, 175 anger, 120, 145 angiotensin, 86, 118 animals, 1, 12, 17, 30, 35, 62, 78, 84, 99, 120, 143, 148, 151, 155, 169, 193, 194 anion, 30 anode, 50 antagonist, 80 antagonistic, 24, 83 antagonists, 85 anterior pituitary, 118, 188

Index

200 antidiuretic, 117 antidiuretic hormone, 117 anus, 179 aorta, 22, 191 aortic valve, 191 aphasia, 170 application, 39, 56, 57, 64, 80, 84, 177 apraxia, 173 aquatic, 148 archetype, 160 argument, 8 arithmetic, 176 arousal, 111 arteries, 191 artery, 177, 191 arthropods, 2, 3, 4 articulation, 183 artificial, 161, 193 Asian, 130 aspartate, 84, 87 associations, 184 asymmetry, 166, 171, 200, 202 atlas, 130 atrium, 191 atropine, 81 attention, 65, 82, 85, 109, 125, 172 audition, 148, 176 auditory cortex, 124, 125, 146, 147, 150, 154, 173, 183 auditory stimuli, 145 autonomic, 6, 18, 21, 24, 73, 80, 81, 88, 112, 117, 119, 133, 179, 188, 189 autonomic nerve, 21 autonomic nervous system, 21, 24, 73, 80, 81, 88, 179, 188 avoidance, 120, 160 avoidance behavior, 120 axon, 21, 27, 28, 29, 30, 31, 40, 42, 43, 44, 45, 46, 47, 48, 49, 50, 53, 54, 56, 57, 58, 59, 62, 63, 64, 65, 66, 69, 71, 72, 74, 78, 143, 159 axon terminals, 53, 69, 71 axonal, 30, 78, 159 axons, 2, 14, 15, 21, 29, 30, 42, 59, 68, 101, 103, 110, 115, 117, 122, 124, 133, 134, 135, 137, 144, 145, 147, 153, 154, 159, 161, 188, 189

B back pain, 102 bacterial, 94

barbiturates, 84, 87 barrier, 30, 88 basal ganglia, 19, 81, 84, 87, 128, 129, 130, 136, 139, 184, 186, 198 basal nuclei, 16, 128 basilar membrane, 146, 147, 161 batteries, 37, 49, 76 battery, 37, 39, 50, 74, 76 beating, 160 behavior, 19, 27, 42, 46, 78, 82, 88, 120, 139, 145, 147, 160, 197, 198 bending, 102, 160, 161 benzene, 82 benzodiazepines, 84 bilateral, 2, 4, 6, 17, 109, 111, 115, 116, 136, 137, 150, 200 binding, 72, 75, 76, 77, 84, 85, 89, 93, 94, 95, 96, 158 bindings, 77 biochemical, 65, 80, 95 biological, 1, 65, 69, 88, 120, 191 biological form, 1 biology, 98, 201 bipolar, 29, 150, 152, 153, 159, 161 bipolar cells, 150, 152, 153, 161 birds, 11, 12, 17, 18 birth, 13 black, 20, 101, 161 blocks, 77 blood, 16, 21, 24, 30, 82, 88, 119, 133, 179, 188, 191, 199 blood flow, 191 blood pressure, 119 blood stream, 88 blood vessels, 16, 21, 24 blood-brain barrier, 88 bloodstream, 88 body image, 171 bone, 145 boutons, 66, 67, 69 brain development, 1, 12 brain functions, 16, 84 brain imaging techniques, 179 brain stem, 23, 82, 99, 105, 137 brainstem, xi, xii, 66, 84, 87, 104, 105, 106, 107, 111, 112, 113, 115, 117, 119, 120, 134, 137, 138, 139, 142, 153, 156, 181, 182, 186, 187, 188, 189, 193, 197, 198 brainstem nuclei, 139 branching, 4, 68

Index budding, 72 bulbs, 10, 16, 19 butyric, 84, 86 bypass, 21

C Ca2+, 30, 37, 69, 72, 73, 74, 76, 78, 82, 84, 90, 93, 95, 97, 118, 158, 159, 160, 162 cables, 54 calcium, 72, 166 cAMP, 82, 84, 95 candidates, 72 capacitance, 30, 36, 37, 38, 40, 41, 42, 48, 50, 53, 54, 57, 58, 59, 63, 76 capacity, 49 capillary, 44, 179, 191 capital, 156 capsule, 119, 120, 128, 136, 139, 186, 189 carbon, 191, 199 carbon dioxide, 191, 199 cardiac muscle, 81 carrier, 27, 58 catalytic, 95 catechol, 82, 84 catecholamine, 82, 94 catecholamines, 82, 84, 85, 86 categorization, 80 cathode, 50 cation, 93, 159, 160 cations, 93, 159 cats, 65, 77 cauda equina, 100, 102 cavities, 10 cDNA, 94, 98 cell, 1, 2, 4, 14, 15, 21, 24, 25, 27, 29, 30, 33, 35, 36, 39, 41, 42, 43, 65, 66, 68, 72, 77, 78, 82, 84, 85, 90, 97, 100, 101, 102, 115, 117, 121, 128, 131, 138, 141, 143, 151, 152, 158, 159, 160, 161, 181, 184, 186, 201 cell body, 21, 27, 29, 30, 65, 78, 143 cell fate, 25 cell membranes, 1 central nervous system, 1, 2, 4, 13, 21, 24, 25, 73, 79, 98, 99, 151, 165, 185, 189, 193, 198, 199 cephalization, 2, 4 cerebellum, 4, 5, 8, 11, 12, 13, 16, 17, 20, 68, 84, 99, 103, 107, 109, 110, 112, 113, 115, 119, 128, 129, 134, 135, 137, 138, 139, 150, 155, 187, 188, 189

201

cerebral cortex, 4, 17, 19, 20, 78, 87, 105, 109, 110, 112, 115, 119, 120, 121, 122, 123, 124, 125, 128, 129, 130, 131, 139, 142, 145, 148, 150, 154, 165, 166, 182, 184, 186, 187, 191, 198, 200, 201, 202 cerebral function, 115 cerebral hemisphere, 5, 8, 10, 11, 16, 17, 18, 19, 20, 99, 116, 120, 121, 122, 125, 128, 137, 144, 148, 153, 169, 173, 174, 176, 178, 189 cerebrospinal fluid, 13 cerebrum, 4, 11, 12, 18, 19, 104, 105, 107, 109, 112, 115, 116, 119, 121, 128, 129, 134, 139, 169, 186 certainty, 18, 135 cervical, 6, 11, 23, 100, 101, 102, 105, 156 channels, 30, 36, 37, 39, 45, 46, 48, 49, 50, 59, 62, 63, 64, 72, 73, 74, 75, 77, 78, 81, 82, 84, 89, 90, 92, 93, 94, 95, 96, 97, 98, 158, 159, 160, 161 chemical, 18, 29, 33, 39, 48, 65, 69, 71, 72, 79, 80, 85, 94, 118, 133, 141, 142, 167, 177, 199 chemical composition, 118 chemical energy, 199 chemical properties, 80, 85 chemical reactions, 142 chemicals, 69, 79, 80, 84, 85, 88, 93, 117, 118, 141, 142, 158, 179 chewing, 125, 137, 139, 141, 145, 183 chiasma, 18, 117, 153 childhood, 69 cholecystokinin, 85 cholinergic, 81, 82, 129 cholinergic neurons, 82, 129 chorea, 129 choroid, 10, 11, 13, 17, 115 chromaffin cells, 22 chromosome, 144 chyme, 179 cilia, 1, 69, 143, 150, 159, 160, 161, 162 ciliate, 160, 162 circadian, 18, 189, 196 circadian rhythm, 18, 189, 196 circadian rhythms, 189 circulation, 15, 88, 118, 179, 188, 191 classes, 27, 80, 87 classical, 79, 94 classification, 16, 20, 80, 99, 113, 142, 185 classified, 73, 80, 82, 89, 99, 102, 105, 106, 121, 123, 133, 134, 150, 161, 184, 185, 189, 196 clinical, 85, 131, 156

202 closure, 6, 24 clouds, 69 clustering, 142 clusters, 22, 102 Co, 25, 100, 102, 131, 165 cochlea, 145, 146, 147, 150, 159, 161, 193 codes, 161, 165 coding, 94, 102, 131, 142, 144, 153, 165 codons, 94 coelom, 118 coenzyme, 80 cognition, 65, 171, 185 cognitive, 69, 179, 185 cognitive function, 69 cognitive process, 179 cognitive tasks, 185 coil, 50 collaboration, 139 colors, 142, 161 commissure, 18, 120, 136, 174 communication, 79, 130, 174, 199 communication systems, 130 complementary, 94 complexity, 1 components, 1, 4, 6, 11, 12, 13, 15, 16, 18, 30, 39, 50, 98, 107, 118, 119, 120, 123, 128, 139, 144, 147, 173, 179, 194 composition, 112 compositions, 118 compound eye, 156 compounds, 85 comprehension, 147 computation, 78 computer, 88 computing, 78 concentration, 2, 4, 30, 31, 32, 33, 34, 35, 39, 42, 45, 63, 69, 72, 74, 80, 94, 118, 119, 158, 159, 160, 161, 162 concrete, 184, 195, 197, 198 conductance, 36, 37, 38, 39, 42, 46, 48, 49, 50, 69, 72, 73, 74, 75, 78, 93, 153, 158 conduction, 30, 59, 62, 63, 64, 135 conductor, 64 configuration, 2, 6, 14, 17, 20, 68 connectivity, 130, 200 consciousness, 20, 84, 111, 112, 135 construction, 13, 94, 139 consulting, 161 continuing, 139 contractions, 72

Index contracts, 146 contrast sensitivity, 161 control, 4, 48, 65, 78, 85, 112, 117, 128, 133, 134, 137, 139, 155, 169, 182, 183, 186, 187, 188, 189, 197, 199, 200, 201 controlled, 18, 24, 66, 72, 94, 96, 115, 118, 125, 129, 139, 142, 156, 185, 198 convergence, 153, 161 coordination, 17, 139, 185 cornea, 13 corpus callosum, 19, 174, 175 correlation, 171 cortical, 17, 19, 120, 130, 131, 139, 144, 145, 154, 166, 167, 171, 175, 179, 183, 193, 201, 202 corticospinal, 104, 105, 109, 110, 111, 128, 136, 137, 139, 189 coupling, 39, 72, 95 covering, 4, 156, 158, 159, 187 cranial nerve, 6, 12, 17, 18, 23, 24, 107, 108, 109, 110, 111, 112, 136, 137, 141, 142, 145, 153, 155, 156, 181, 189, 193 craniofacial, 25 cranium, 8, 11, 189, 196 crustaceans, 77, 78 crystal, 94 cues, 162 cycles, 18, 84 cytoplasm, 29, 30, 65, 69, 72, 73, 88, 97, 98, 161, 166 cytoskeleton, 29

D danger, 120 deficit, 35, 173 definition, 120, 145 deformation, 58 degenerate, 82 degree, 2, 50, 171 dendrite, 29, 65, 69, 78, 159 dendrites, 2, 14, 27, 29, 30, 68, 69, 78, 122, 128, 171 dendritic spines, x, 69 density, 62, 69 dentate gyrus, 120 depolarization, 39, 45, 47, 50, 58, 62, 72, 73, 74, 75, 85, 158, 159, 160 depression, 10, 78 derivatives, 11, 15, 85

Index dermatome, 102 desire, 120 detergents, 90, 94 detoxification, 179 developmental process, 1, 30, 148 deviation, 42 dielectric, 49 differential equations, 55 differentiated cells, 2 differentiation, 2, 6, 8, 13, 14, 15, 169, 179, 181, 191, 199 diffusion, 30, 33, 73, 88 digestion, 15, 24, 123, 179, 199 digestive enzymes, 179 digestive process, 179 dihydroxyphenylalanine, 82 diodes, 27 disability, 135 discharges, 37, 53, 69, 133, 148 discrimination, 144, 169, 191, 201 discs, 152, 161 disorder, 129, 173 displacement, 161 dissociation, 95, 200 distal, 78, 137, 154, 159, 179 distortions, 102 distribution, 21, 23, 24, 35, 54, 56, 57, 69, 80, 88, 93, 102, 123, 137, 169, 191, 194 divergence, 93 diversity, 85, 90, 91, 119 division, 2, 105, 145, 150, 186 dogs, 120 dominance, 4, 129, 137, 171, 177 dopamine, 80, 82, 129 dopamine agonist, 82 dopaminergic, 82, 129 dopaminergic neurons, 82, 129 Doppler, 59 dorsal horn, 102, 103, 109, 135, 181 dorsolateral prefrontal cortex, 182 dorsomedial nucleus, 144 drosophila, 98 drugs, 82 D-serine, 87 duality, 193, 199 duodenum, 123, 179 duration, 48, 59

203

E E. coli, 94 ears, 11, 102, 125, 137, 148, 150, 176, 177, 179, 194 earthworms, 2 eating, 171, 173 ectoderm, 6, 13, 181 education, 25 efferent nerve, 21, 23 elaboration, 171 electric field, 42 electrical, 27, 28, 29, 30, 33, 35, 36, 37, 40, 42, 43, 45, 50, 54, 55, 58, 59, 64, 65, 71, 72, 74, 76, 89, 90, 94, 131, 133, 142, 158, 160, 161, 165, 177, 191, 199, 200, 201 electricity, 43 electrochemical, 32, 34, 35, 39, 43 electrodes, 44, 50, 59, 85 electrolyte, 35 electrolytes, 35, 42, 179 electromagnetic, 192, 196 electromagnetic wave, 196 electromagnetic waves, 196 electron, 69, 94 electrons, 27, 59, 69, 192, 199 electrostatic, 94 embryo, 1, 4, 6, 7, 9, 11, 15, 16, 24 embryonic, 1, 2, 6, 13, 15, 16, 17, 21, 24, 102, 106, 116, 118, 121 embryonic development, 1, 2, 6, 24, 102, 106, 118, 121 embryos, 6, 8, 17 emission, 179 emotion, 20, 85, 120, 145, 189, 198 emotional, 20, 120, 142, 144, 145, 171, 183, 184 emotional responses, 144 emotions, 145 empathy, 25 encapsulated, 74 encoding, 201 endocrine, 189, 196 endocytosis, 72 endoderm, 6 endogenous, 85 endoplasmic reticulum, 29 endorphins, 85, 118 energy, 32, 39, 63, 199 enkephalins, 85, 118 enlargement, 13, 101, 116, 171

Index

204 entorhinal cortex, 19, 122, 125, 144, 183 environment, 69, 148, 150, 156, 193, 194 environmental, 24 enzymatic, 82, 88 enzyme, 80, 82, 84, 95, 161 enzymes, 95, 179 epidermis, 6 epiglottis, 141, 142 epilepsy, 177 epileptic seizures, 139, 176 epinephrine, 80, 82, 84, 88 epiphysis, 10, 12, 18 epithelium, 2, 6, 13, 143, 144, 145, 148, 150, 151, 159, 165, 189, 193 equilibrium, 32, 33, 34, 35, 36, 37, 39, 42, 45, 48, 49, 50, 69, 74, 76, 77, 78, 148, 153, 159 erythrocytes, 35 esophagus, 123 esterase, 86 estimating, 179 evidence, 8, 72, 79, 90, 201 evoked potential, 165 evolution, 1, 4, 6, 11, 19, 20, 62, 109, 148, 191 evolutionary, 1, 6, 8, 20, 109, 125, 148, 176 examinations, 29, 176 excitability, 30 excitation, 24, 42, 50, 64, 85, 139 excitatory postsynaptic potentials, 93 excitatory synapses, 74 execution, 177 exocytosis, 72, 82 exponential, 57 exposure, 84, 152 extensor, 125 external environment, 133, 150, 156, 193, 199 extinction, 201 extracellular, 44, 54, 59, 82, 94, 152 extraocular muscles, 153 eye, 8, 10, 13, 18, 82, 111, 112, 125, 131, 137, 150, 151, 152, 155, 156, 166, 167, 182, 184, 189, 196, 197, 201, 202 eye movement, 82, 111, 125, 150, 155, 167, 182 eyes, 4, 11, 18, 102, 112, 125, 137, 151, 155, 156, 176, 179, 183, 193, 194, 196

F facial nerve, 136, 142, 146 false, 88, 170 family, 98

feces, 179 feedback, 119, 125, 139, 177, 185, 186 feelings, 120 feet, 88, 102, 173, 176, 185, 197 females, 179 Feynman, 200 fiber, 17, 19, 23, 27, 31, 40, 44, 45, 50, 59, 63, 66, 67, 71, 72, 74, 77, 88, 107, 110, 111, 115, 131, 134, 138, 139, 142, 145, 148, 183, 184, 191 fiber bundles, 17, 110, 111, 184, 191 film, 54 filtration, 179 fish, 18, 20, 48, 120, 148 fixation, 76, 183 flatworms, 4 flavor, 142 flexor, 125 flight, 24 floating, 152, 173, 194 flow, 1, 24, 27, 30, 31, 32, 33, 35, 36, 39, 43, 44, 45, 48, 50, 56, 58, 74, 76, 77, 84, 93, 94, 97, 137, 148, 153, 154, 156, 158, 160, 173, 181, 182, 186, 187, 188, 190, 191 fluctuations, 77 fluid, 13, 29, 30, 88, 146, 148, 179 fMRI, 179 focusing, 156, 172 folding, 4, 11, 69, 112, 120 food, 142, 145, 173, 179 football, 88 forebrain, 2, 8, 13, 18, 19, 20, 82, 116, 125 fornix, 120 freshwater, 3 frog, 65, 80 frontal cortex, 186 frontal lobe, 19, 125, 136, 141, 144, 153, 155, 170, 175, 182, 183, 184, 185, 186, 197 frontal lobes, 125, 175 functional architecture, 166 functional magnetic resonance imaging, 179 fusion, 11, 17, 72

G gamma-aminobutyric acid, 128 ganglia, 2, 3, 4, 6, 19, 21, 22, 23, 24, 29, 81, 82, 84, 87, 102, 127, 128, 129, 130, 136, 139, 142, 159, 184, 186, 187, 198

Index ganglion, 2, 3, 8, 21, 23, 108, 136, 139, 141, 142, 146, 147, 152, 153, 156, 159, 161, 181, 186 gas, 31 gastric, 179 gastrulation, 6 gene, 93, 165 gene expression, 165 generation, 30, 43, 48, 49, 50, 57, 73, 74, 76, 77, 78, 85, 97, 120, 150, 158, 159, 160, 162, 165, 185, 189, 197 genes, 90, 144 genetics, 97 gland, 10, 12, 22, 85, 88, 117, 118, 188, 189, 196 glass, 44 glial, 27, 30, 82, 84, 93 glial cells, 27, 30, 82, 93 globus, 19, 128, 186 glomerulus, 144 glossopharyngeal nerve, 142, 148 glucose, 80, 119 glutamate, 81, 84, 85, 93, 94, 128, 142, 159 glutamatergic, 84 glutamic acid, 84 glutamine, 84 glycine, 77, 78, 85, 87, 93 glycoprotein, 90 goal-directed, 139, 197 G-protein, 82, 84, 85, 88, 89, 94, 95, 97, 144, 159 gracilis, 103, 108, 134 granule cells, 115, 138 graph, 39, 50, 77 gravitational force, 150 gravity, 148, 150 gray matter, 14, 17, 18, 100, 101, 102, 105, 109, 111, 112, 115, 120, 121, 128, 137 groups, 1, 2, 6, 13, 17, 69, 105, 112, 115, 128, 133, 142, 182, 186 growth, 18, 102 guanine, 89 gustatory, 122, 125, 141, 142, 144, 154, 173, 183, 184, 195, 196 gut, 2, 85, 123, 179, 199 gyri, 19, 121, 146 gyrus, 19, 120, 122, 123, 124, 125, 147, 150, 154, 173, 183, 186

H hair cells, 87, 146, 147, 148, 150, 159, 160, 161, 166, 193

205

hallucinations, 83 handedness, 171 handling, 27 hands, 88, 102, 103, 155, 169, 176, 185, 197 happiness, 120, 145 head, 13, 102, 106, 125, 136, 137, 145, 148, 150, 182, 183, 185, 186, 189, 194, 196, 197, 199 hearing, 69, 125, 133, 148, 150, 177, 179 heart, 80, 88, 169, 179, 191, 199 heartbeat, 65, 80 heat, 63 hemisphere, 120, 122, 125, 137, 144, 148, 153, 154, 169, 170, 171, 173, 175, 176, 177, 179, 183, 184, 185, 189, 197 hemispheric asymmetry, 166, 202 hemoglobin, 35 hippocampal, 120, 122, 189 hippocampus, 68, 84, 87, 117, 120 histamine, 81, 82, 84, 85 histidine, 82 homeostasis, 119 homogeneous, 150 hormone, 18, 84, 85, 86, 88, 117, 131, 188, 189, 196 hormones, 18, 22, 79, 80, 85, 88, 94, 117, 118, 119, 188 horse, 120 house, 101, 130 human, 1, 4, 9, 15, 16, 17, 18, 19, 20, 65, 68, 85, 88, 109, 112, 115, 120, 125, 130, 131, 133, 139, 142, 144, 166, 167, 169, 179, 185, 189, 191, 193, 194, 195, 196, 198, 199, 200, 201, 202 human animal, 194 human behavior, 88, 115 human brain, 1, 4, 15, 19, 20, 65, 112, 131, 169, 179, 191, 200, 202 human cerebral cortex, 4 human subjects, 201 humans, 2, 10, 11, 15, 17, 18, 19, 20, 78, 99, 102, 112, 115, 120, 122, 125, 129, 139, 142, 143, 145, 147, 148, 155, 169, 182, 184, 191, 194, 196, 198, 199, 202 hybridization, 94 hydro, 29 hydrolysis, 39 hydrophilic, 29 hydrophobic, 30, 90, 94 hydrophobicity, 92 hydroxyl, 84, 87

Index

206 hyperactivity, 139 hypoglossal nerve, 136, 142 hypoglossal nuclei, 142 hypothalamic, 85, 130, 131 hypothalamus, 10, 12, 16, 18, 20, 82, 84, 88, 115, 116, 117, 118, 119, 120, 123, 139, 142, 144, 184, 187, 188, 189, 198 hypothesis, 42

I illumination, 161, 162 images, 125, 156, 171, 185, 197 imaging, 171, 179 imaging techniques, 179 immunological, 85 in vitro, 131 inactivation, 45, 50, 81, 84, 201 incongruity, 118 incubation, 7, 9 inductor, 50 infection, 63, 135 inferior frontal gyrus, 125, 148, 183 inferior vena cava, 191 information processing, 78 infrared, 196 infrared light, 196 infundibulum, 10, 16, 117 inhibition, 77, 78, 85, 139, 166 inhibitor, 39 inhibitors, 94 inhibitory, 73, 77, 78, 84, 85, 89, 115, 139, 187 inhibitory effect, 77, 115, 139 initiation, 125, 130 injection, 57, 177 inner ear, 146, 150, 193 innervation, 24, 102 inositol, 95 insects, 2, 148 insight, 78 inspection, 47, 50 insulation, 30, 43, 53, 54 integration, 12, 32, 40, 56, 65, 71, 78, 131 integrity, 166 intelligence, 17, 115, 120 intensity, 133, 150, 158, 160, 161, 165 interaction, 46, 94, 150, 158, 159, 162, 166 interactions, 179, 201 interface, 158, 199 interference, 175

interneuron, 97 interneurons, 84, 97, 136, 181 interpretation, 33, 59, 85, 88, 154, 161, 170, 176, 179, 183 interrelations, 185 intervention, 22 intestine, 179 intonation, 171 intravenous, 129 intrinsic, 50, 59, 119, 120, 125, 185, 197, 198 intuition, 176 invaginate, 16 invertebrates, 1, 2, 4, 6, 8, 24, 27, 66, 73, 112, 148 Investigations, 88 ion channels, 37, 39, 46, 59, 73, 74, 75, 77, 78, 81, 82, 89, 90, 92, 93, 94, 95, 96, 98, 158, 159, 161 ion transport, 94 ionic, 1, 27, 30, 31, 32, 33, 35, 36, 37, 39, 42, 43, 44, 45, 50, 63, 69, 72, 73, 76, 78, 97, 158, 159, 160 ions, 27, 30, 31, 33, 34, 35, 37, 38, 39, 42, 43, 45, 48, 50, 58, 59, 64, 65, 69, 72, 73, 74, 76, 77, 82, 88, 90, 93, 94, 158, 160, 161, 162 ipsilateral, 104, 105, 110, 115, 124, 134, 135, 137, 139, 141, 154, 155, 156, 177

J Japan, 200 Japanese, 64, 97, 142, 178 joints, 135 judgment, 125

K K+, 30, 31, 33, 34, 37, 38, 39, 42, 45, 46, 48, 49, 50, 59, 63, 69, 72, 73, 74, 75, 76, 77, 78, 82, 84, 90, 93, 94, 95, 153, 158, 159, 160 kainate receptor, 84 kainic acid, 84 kidney, 22, 191 kidneys, 22, 117, 118, 179, 191 kinase, 95 Kirchhoff, 37

Index

L L1, 102 laboratory studies, 176 lamellar, 17 land, 148 language, 124, 130, 147, 154, 169, 170, 171, 173, 176, 177, 178, 179, 183, 200 language processing, 179 large intestine, 179 larynx, 122, 123 laterality, 169, 176, 178, 179 laughter, 178 law, 27, 36, 40, 42, 49, 55, 181, 182, 186, 188, 189, 190, 191 lead, 17, 22, 84 leakage, 43, 47, 48 leaks, 54 learning, 19, 65, 120, 201 left atrium, 191 left hemisphere, 12, 125, 169, 170, 171, 173, 176, 177, 178, 179, 182, 183, 184, 200 left ventricle, 191 left visual field, 171, 176 left-handed, 171, 177 left-hemisphere, 177 lens, 13, 151, 156, 189 lenses, 156 lesions, 171, 173, 179, 201 leucine, 85 ligand, 75, 89, 92, 93, 94, 96, 98, 158 ligands, 85 limbic system, 20, 116, 117, 120, 145, 189, 198 linear, 42 linguistic, 154, 173, 183, 197 linguistically, 173 linkage, 72 links, 89 lipid, 30, 165 lipoprotein, 30 listening, 177, 178 literature, 151 liver, 179, 199 living environment, 148 lobsters, 2 localization, 2, 85, 131, 197 location, 2, 12, 16, 93, 99, 109, 118, 122, 145, 150, 170, 179, 182, 183, 189, 195, 196 locomotion, 11 locus, 82, 98

207

London, 130, 167 long-term memory, 120 lumbar, 100, 102 lumen, 16 lung, 191 lungs, 88, 179, 191, 199 lying, 15, 121 lysergic acid diethylamide, 83

M M1, 93 machinery, 160 magnetic resonance imaging (MRI), 171, 179 maintaining attention, 82 males, 117, 179 mammal, 15, 17 mammalian, 31 mammalian brain, 84 mammals, 2, 4, 10, 11, 12, 17, 18, 20, 78, 84, 90, 120, 148, 151, 196 mandibular, 102 mango, 173 manipulation, 98, 173 mantle, 14, 17 mapping, 131, 165, 201 Massachusetts, 64 mast cell, 84 mastication, 125, 137, 139, 142, 165, 184 matrix, 30, 112 maxillary, 102 mechanical, 102, 133, 134, 142, 159, 160, 166, 178, 184, 186, 194 mechanical properties, 166 median, 118 medicine, 85 medulla, 4, 11, 13, 15, 16, 20, 22, 82, 103, 105, 106, 108, 109, 110, 111, 112, 115, 134, 135, 136, 137, 139, 141, 150, 181, 187, 188, 189 melatonin, 18, 189, 196, 201 melody, 177 membrane permeability, 77, 90 membranes, 1, 37, 64, 66, 72, 98, 161, 162, 165 memory, 19, 65, 69, 120, 125, 130, 197, 200, 201 mesencephalon, 8, 10, 11, 18 mesenchymal, 13 mesoderm, 6, 22, 118, 133 messages, 29, 43, 65, 69, 97 messenger RNA, 94 messengers, 95

208 metabolic, 29, 63, 89, 179 metabolism, 84, 199 metabolites, 80 metabotropic glutamate receptor, 94 metabotropic glutamate receptors, 94 methionine, 85 Mg2+, 87 mice, 12 microelectrode, 44 microelectrodes, 50 midbrain, 2, 4, 8, 11, 18, 82, 106, 109, 110, 111, 112, 115, 116, 128, 136, 139, 148, 150, 153, 155, 181, 187, 189 milk, 117 mirror, 125, 185, 197 mitochondria, 29 mitral, 68, 143, 191 mitral valve, 191 mixing, 112, 154 mobility, 31, 33, 94 modalities, 123, 125, 154, 185, 193 modality, 125, 184, 193, 194, 195, 196 models, 72, 94, 130 modulation, 24, 112 molecular biology, 98 molecular mechanisms, 97 molecular structure, 83, 90, 92 molecules, 29, 30, 33, 35, 65, 66, 69, 72, 74, 80, 89, 90, 93, 94, 97, 158, 159, 193, 194 mollusks, 2 momentum, 193 monkeys, 120, 130, 165, 200, 201 monoamine oxidase, 82, 84 morphological, 25 motion, 59, 120, 124, 150, 154 motivation, 125, 185, 197 motor area, 21, 105, 125, 131, 174, 182, 183, 184, 185, 197, 202 motor behavior, 145 motor fiber, 102, 107, 181 motor function, 69, 111, 120, 125, 128, 129, 139, 141, 145, 155, 175, 176, 182, 183, 184, 186, 189, 195, 197, 198 motor neurons, 2, 15, 21, 65, 66, 74, 78, 81, 87, 97, 105, 115, 119, 134, 136, 137, 139, 142, 169, 181, 189, 197 motor system, 23, 81, 82, 129, 131, 133, 134, 137, 139, 169, 201 mouse, 144, 166 mouth, 123, 125, 173, 176, 197

Index movement, 2, 17, 30, 45, 72, 82, 111, 120, 129, 130, 134, 137, 139, 142, 145, 150, 155, 169, 176, 182, 184, 185, 198, 201, 202 movement disorders, 129, 130 mucosa, 141 mucus, 158, 159 multiple factors, 102 muscarinic receptor, 81 muscle, 6, 27, 31, 43, 53, 65, 66, 67, 69, 72, 74, 77, 78, 80, 84, 85, 88, 93, 97, 117, 118, 125, 133, 134, 136, 137, 156, 189, 197 muscle contraction, 53, 66, 136, 197 muscle force, 72 muscles, 72, 74, 77, 85, 88, 102, 103, 118, 125, 129, 133, 135, 136, 137, 139, 146, 153, 169, 182, 197 music, 88 mutagenesis, 98 myelin, 30, 66 myelination, 62, 63, 135 myosin, 72

N Na+, 30, 31, 37, 38, 39, 42, 45, 46, 47, 48, 49, 50, 58, 59, 62, 63, 69, 72, 73, 74, 75, 76, 77, 80, 82, 84, 90, 93, 94, 153, 158, 159, 160, 161 N-acety, 200 NaCl, 35 naming, 71, 170 nasal cavity, 143, 144, 193 natural, 33, 118, 123, 125 neck, 102, 106, 123, 136, 146, 151, 185 neglect, 171, 200 neocortex, 19, 20, 121 neostriatum, 128, 129 nerve cells, 27, 29, 30, 33, 37, 44, 72, 77, 79, 110 nerve fibers, 2, 11, 17, 40, 43, 54, 57, 58, 62, 64, 72, 77, 97, 112, 152, 155, 170, 181 nerve trunk, 12 nervous system, 1, 2, 3, 4, 6, 13, 14, 21, 24, 25, 27, 29, 65, 66, 68, 69, 73, 79, 80, 81, 82, 85, 88, 97, 98, 99, 105, 112, 115, 120, 129, 133, 135, 139, 151, 156, 160, 165, 169, 170, 179, 181, 184, 185, 188, 189, 191, 193, 198, 199, 200 network, 29, 112, 151, 155, 156, 169 neural connection, 16, 128, 145, 187 neural crest, 6, 7, 21, 22 neural function, 179

Index neural mechanisms, 179 neural tissue, 4 neural tubes, 6 neuroactive peptides, 80, 88 neurobiology, 97, 131 neuroblasts, 6, 14 neuroendocrine, 117 neuronal cells, 14 neuropeptide, 94 neuropeptides, 80, 84, 85, 88 neurophysiology, 65 neuroscience, 164 neuroscientists, 85 neurosecretory, 117, 118, 131 neurotensin, 85, 118 neurotransmitter, 66, 69, 71, 72, 73, 74, 79, 80, 81, 84, 85, 89, 90, 95, 129, 158, 159, 160, 171 neurotransmitters, 29, 65, 69, 72, 73, 77, 79, 80, 82, 84, 85, 86, 87, 88, 89, 90, 93, 94, 96, 162 New York, 25, 64, 98, 130, 131, 165, 166, 167, 200, 201, 202 nicotine, 80, 87 Nicotine, 80 NMDA receptors, 84, 87, 93 N-methyl-D-aspartate, 84, 87 nociception, 135 nociceptive, 109, 135 node of Ranvier, 63 nodes, 30, 62, 63 noise, 178 non-human, 194 nonverbal, 176 noradrenaline, 22, 82, 85 norepinephrine, 80, 82, 84 normal, 156 notochord, 4, 6, 8 nuclear, 112, 152, 161, 182, 189 nuclei, 16, 17, 18, 19, 82, 87, 101, 104, 105, 107, 108, 109, 110, 111, 112, 114, 115, 117, 119, 120, 122, 125, 128, 129, 130, 131, 134, 135, 136, 137, 138, 139, 142, 144, 145, 146, 148, 150, 154, 155, 166, 169, 182, 186, 187, 188, 189 nucleus, 18, 19, 29, 85, 87, 90, 103, 104, 105, 108, 109, 112, 115, 117, 118, 119, 120, 125, 128, 130, 134, 135, 136, 137, 138, 139, 141, 142, 144, 146, 151, 153, 155, 169, 186, 187, 189, 197, 200 nutrition, 199

209

O obsolete, 79 occipital lobe, 19, 124, 125, 151, 154, 175, 182, 185, 196 ocellus, 156 oculomotor, 150, 155 oculomotor nerve, 155 odorants, 144, 145, 159, 184 odors, 145 olfaction, 125, 165, 195 olfactory, 10, 16, 19, 68, 87, 94, 120, 122, 125, 137, 141, 143, 144, 145, 154, 156, 158, 159, 162, 164, 165, 173, 183, 193, 194, 196 olfactory bulb, 10, 16, 19, 68, 137, 143, 144, 145, 159, 165, 183 olfactory epithelium, 143, 144, 145, 159, 165 olfactory receptor, 144, 159 oligodendrocytes, 30 olive, 146 ophthalmic, 102 opium, 85 opposition, 194 optic chiasm, 18, 117, 120, 153, 156 optic nerve, 13, 18, 111, 152, 153, 155, 156, 161, 186, 193 oral, 108, 122, 123, 125, 141, 145, 183 organ, 10, 12, 13, 18, 21, 23, 85, 114, 133, 146, 147, 148, 150, 151, 159, 179, 189, 193, 196 organelles, 29 organic, 30, 34, 160 organism, 135, 179, 199 organization, 2, 4, 10, 11, 12, 13, 15, 16, 19, 23, 98, 99, 105, 106, 107, 109, 111, 112, 115, 120, 123, 125, 131, 154, 161, 165, 166, 167, 169, 173, 181, 182, 184, 186, 187, 188, 189, 190, 191, 193, 194, 199, 200, 201, 202 organizations, 11, 15, 115, 125, 184, 193 orientation, 123, 124, 125, 150, 201 oscillation, 59, 160, 193 osmotic, 35, 119 osmotic pressure, 35, 119 ossicles, 146 oxygen, 191, 199 oxytocin, 85, 117, 188

Index

210

P pain, 85, 102, 103, 109, 114, 123, 133, 134, 135, 136, 141, 193 pain clinic, 109 pancreas, 179, 199 parameter, 50 parasympathetic, 21, 23, 24, 115, 156 parasympathetic nervous system, 24, 115 paraventricular, 117, 130, 131, 188 paraventricular nucleus, 117 paresis, 166 parietal, 171, 201 parietal cortex, 130, 131, 154, 200 parietal lobe, 19, 123, 171, 172, 173, 175, 196 parietal lobes, 175, 196 Paris, 25 Parkinson, 82, 129, 186 particles, 33, 50, 94, 192 partition, 166 passive, 38, 48, 54, 57, 78, 176, 200 pathways, 97, 103, 105, 115, 117, 120, 122, 134, 135, 137, 142, 145, 146, 148, 154, 156, 166, 169, 173, 183, 197 patients, 82, 129, 166, 171, 172, 173, 176, 177, 179, 186 peptide, 88, 94, 117, 188 peptides, 80, 85, 86, 88, 118 perception, 85, 120, 124, 135, 150, 156, 161, 177, 190, 194, 196, 201 performance, 131 perineum, 102, 122 peripheral blood, 24 peripheral nerve, 30, 85, 102, 123, 179, 191 peripheral nervous system, 6, 85, 99 permeability, 33, 37, 42, 43, 45, 74, 77, 78, 90, 98, 118, 153, 160 permeation, 93 permit, 84, 93 personal, 201 pharmacological, 48, 87 pharynx, 4, 122, 123 Philadelphia, 25, 98, 130, 200 phosphate, 95 phosphodiesterase, 95, 161 phospholipase C, 95 phosphoprotein, 95 photons, 152, 161 photoreceptor, 87, 151, 153, 161, 162, 166, 189 photoreceptor cells, 87, 151, 162, 166, 189

photoreceptors, 151, 161, 167, 189 photoresponse, 166 phylogeny, 1, 6 physics, 199 physiological, 11, 24, 29, 79, 80, 85, 88, 95, 97, 98, 118, 160, 179, 198, 199, 201 physiology, 165 pig, 131 pigment epithelium, 151, 189 pigments, 152, 161 pineal, 10, 12, 18, 189, 196 pineal organ, 10, 12, 18, 189, 196 pitch, 59 pituitary, 10, 12, 85, 117, 118, 188 pituitary gland, 10, 12, 85, 117, 118, 188 planning, 125, 131, 202 plants, 1, 193 planum temporale, 147, 170, 171 plasma membrane, 27, 29, 30, 40, 42, 50, 72, 94 plasmid, 94 Platyhelminthes, 2 play, 13, 18, 27, 45, 72, 82, 88, 120, 125, 133, 135, 150, 152, 159, 162, 179, 183, 185, 187 pleasure, 85 plexus, 10, 11, 13, 17, 115 poison, 48 polarity, 69 polarization, 73, 160 polarized, 199 polypeptide, 93 polypeptides, 90, 93 pons, 11, 13, 16, 17, 20, 82, 85, 87, 106, 109, 110, 111, 112, 136, 139, 142, 146, 148, 150, 155, 181, 187 poor, 11, 17, 43, 53, 110, 160, 176 population, 79, 144 pore, 90, 93, 94 pores, 73, 94, 158 positron, 179 positron emission tomography, 179 postsynaptic, 66, 68, 69, 71, 72, 73, 74, 75, 77, 78, 80, 84, 85, 87, 88, 89, 93, 94, 95, 162 posture, 11, 17, 88, 100, 102, 105, 123, 129, 187 potassium, 42, 50, 63, 64, 98 potassium channels, 63 precursor cells, 6, 181 preference, 131, 176 prefrontal cortex, 131, 139, 183, 185, 197, 202 premotor cortex, 139, 182, 185, 186, 197 preparation, 125

Index pressure, 31, 35, 102, 103, 119, 133, 134, 135, 141, 190, 193 presynaptic, 66, 68, 69, 71, 72, 74, 77, 78, 79, 80, 82, 85, 89, 98 primary visual cortex, 124, 125, 153, 154, 182 primate, 130, 131, 166, 167, 200, 201, 202 primates, 11, 125, 130 probability, 93 production, 142, 154, 162, 188 programming, 148, 155, 183, 185, 197 progressive, 135 proliferation, 14 propagation, 58, 59, 62, 63 property, 36, 37, 40, 42, 50, 53, 54, 57, 59, 72, 74, 78, 93, 94, 135, 142, 156, 159, 161, 176 propionic acid, 87 propranolol, 87 protease inhibitors, 94 protection, 102, 135, 146 protein, 30, 35, 72, 82, 84, 85, 89, 90, 93, 94, 95, 97, 144, 159 protein binding, 94 proteins, 29, 30, 72, 84, 88, 89, 90, 94, 95, 144, 159, 161 prototype, 2, 148 protozoa, 160, 162 proximal, 125, 159, 179 psychological, 83, 84 psychotic, 82 pulmonary circulation, 191 pulse, 39, 40, 48, 50, 58, 59 pumping, 39 pupil, 156 pupils, 156 Purkinje, 68, 78, 84, 87, 115, 129, 131, 138, 139, 187 Purkinje cells, 84, 87, 115, 138, 139, 187 pyramidal, 68, 78, 105, 109, 110, 122, 128, 136, 137, 139, 189 pyramidal cells, 78, 122, 136

Q quantum, 74 quaternary ammonium, 63

R radical, 176

211

radius, 41 rain, 20 random, 74, 193 range, 40, 62, 63, 88, 161, 196 raphe, 82, 85, 112 rat, 165 reaction time, 201 reading, 176 reality, 154 recall, 173 reception, 69, 71, 97, 144, 146, 148, 158, 159, 160, 162 receptive field, 161 receptor sites, 69, 71, 96 receptors, 2, 72, 73, 77, 80, 82, 84, 85, 89, 90, 94, 98, 125, 133, 134, 135, 142, 145, 148, 150, 156, 158, 159, 194 recognition, 80, 154, 171, 172, 173, 176 rectification, 42, 64 red blood cells, 179 red light, 190 reduction, 161 reflection, 8, 59, 93 reflexes, 112, 139 regenerate, 58 regeneration, 135 regional, 19, 113 regular, 30 regulation, 12, 21, 84, 88, 95, 112, 117, 188 relationship, 77, 80, 118, 150, 155, 183 relationships, 20, 183 renal, 191 repolarization, 45, 50 reproductive organs, 179 reptile, 20 reptiles, 18, 19, 20, 189, 196 research, 1, 65 researchers, 93, 94 residues, 94, 95 resistance, 36, 39, 40, 41, 42, 44, 50, 54, 55, 57, 58, 62, 75, 161 resistivity, 64, 98 respiration, 15, 199 responsiveness, 85 resting potential, 30, 33, 37, 38, 39, 44, 45, 48, 50, 74, 76, 77 retention, 171 reticulum, 29, 72 retina, 13, 87, 94, 124, 125, 151, 152, 153, 156, 161, 166, 167, 184, 189, 193, 196

Index

212 retinohypothalamic tract, 200 returns, 33, 45, 50, 58, 153, 191 rhodopsin, 152, 161 rhythm, 18, 131, 139, 171, 177, 196 rhythms, 189 ribosomes, 29 right atrium, 191 right hemisphere, 148, 169, 171, 173, 175, 176, 177, 178, 179, 183 right ventricle, 191 right visual field, 176 rigidity, 129 rings, 160 rods, 161, 166, 189 room temperature, 33

S saccades, 125, 155 saccadic eye movement, 155 sacrum, 24 sadness, 120, 145 salt, 31, 34 salts, 22 scalp, 202 scalp topography, 202 schizophrenia, 82 Schwann cells, 30, 66, 67 science, 98 scientific, 142 search, 145 searches, 190 searching, 150 seawater, 30, 54 secrete, 22, 188 secretion, 18, 22, 72, 118, 142 seizures, 139, 176 selecting, 94, 141 selectivity, 166 sensation, 19, 102, 109, 120, 123, 125, 134, 135, 142, 144, 145, 150, 154, 156, 158, 161, 162, 172, 173, 179, 182, 183, 194 sensations, 85, 102, 103, 104, 122, 123, 124, 134, 135, 137, 141, 142, 154, 156, 158, 161, 162, 171, 173, 183, 193 sense organs, 2, 8 sensing, 119, 142, 148, 150, 151, 162, 196 sensitivity, 146, 152, 153, 161, 167 sensors, 142 sensory cortices, 173

sensory data, 186 sensory experience, 120, 193 sensory modalities, 123, 125, 154, 193 sensory modality, 125, 184, 193, 194, 195, 196 sensory nerves, 97, 103 sensory projection, 123, 145 sensory systems, 125, 133, 134, 139, 145, 191 sentences, 173 separation, 4, 12, 69, 156, 176 sequencing, 94 series, 29, 36, 37, 38, 48, 50, 74, 77, 78, 177 serine, 87, 95 serotonin, 80, 81, 82, 85, 86, 87 shape, 6, 44, 53, 58, 59, 69, 125, 154, 176, 189 shock, 45 shrimp, 3 Siemens, 36 sign, 31, 32, 59, 69, 202 signal transduction, 96, 97 signaling, 43, 79, 95 signals, 11, 12, 15, 17, 18, 27, 28, 29, 30, 33, 40, 44, 54, 58, 65, 66, 68, 71, 72, 88, 99, 103, 107, 112, 113, 115, 117, 119, 120, 122, 123, 124, 125, 128, 134, 136, 138, 141, 142, 144, 145, 146, 150, 153, 154, 155, 161, 173, 177, 181, 182, 183, 184, 185, 186, 187, 189, 190, 196, 197, 199 signs, 20, 36 silver, 44 similarity, 72, 90, 91, 118, 129 sites, 29, 44, 68, 69, 71, 72, 80, 84, 94, 96, 97, 161 skeletal muscle, 65, 66, 67, 74, 77, 80, 88, 93, 102, 125, 133, 134, 182, 189, 197 skeleton, 6 skin, 15, 24, 133, 134, 193, 196 sleep, 82, 84, 88, 112 sleep-wake cycle, 84 small intestine, 179 smooth muscle, 81, 85, 117, 118 soccer, 176 social systems, 176 sodium, 50, 64, 92, 94, 98, 177, 178, 191 solutions, 32, 33, 34, 42, 63, 158 solvent, 35 somata, 68 somatic nervous system, 97 somatomotor, 125 somatosensory, 122, 123, 125, 130, 134, 135, 141, 154, 166, 173, 182, 183, 184, 196, 197

Index somatostatin, 85, 86 sounds, 173, 177, 183 spatial, 57, 72, 124, 150, 172, 173, 176, 191, 202 spatial processing, 202 specialization, 4, 167, 169, 173, 175, 176, 177, 179, 191, 193, 202 specialized cells, 27 species, 4, 5, 6, 12, 30, 31, 32, 35, 36, 37, 38, 39, 42, 58, 129 specificity, 145 spectra, 142, 153, 161, 196 spectrum, 161, 196 speculation, 175 speech, 124, 125, 147, 170, 171, 176, 177, 183, 197 speed, 88 spinal cord, 4, 6, 8, 11, 14, 15, 17, 18, 20, 21, 23, 24, 28, 29, 66, 68, 78, 84, 85, 87, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 112, 113, 115, 117, 119, 120, 123, 134, 135, 136, 137, 138, 139, 150, 181, 182, 187, 188, 189, 191, 193, 198, 199 spinal trigeminal tract, 108, 136 spindle, 133 spine, 69 spines, 69, 128 spiritual, 198, 199 St. Louis, 98, 131, 165 stability, 39 stages, 1, 4, 6, 7, 9, 15, 17, 20, 24, 115, 148, 156 standards, 85 stapes, 146 starvation, 120 steady state, 47, 56, 57 stereotypical, 139 steroid, 22 steroid hormone, 22 steroid hormones, 22 stimulant, 194 stimulus, 1, 13, 45, 50, 97, 133, 155, 158, 160, 161, 165, 176, 177, 193, 195, 196 stomach, 179 storage, 36 streams, 173 strength, 45, 71, 77, 136, 160, 161 stretching, 100 striatum, 82, 120, 128 stroke, 166 structural formation, 13 subcortical nuclei, 186

213

subcortical structures, 179 subcutaneous tissue, 193 substances, 65, 66, 71, 79, 80, 141, 142, 144, 145, 158, 159, 161, 179, 194 substantia nigra, 18, 82, 87, 111, 128, 129, 186, 187 substrates, 80 sugars, 158 sulfate, 94 superior temporal gyrus, 124, 147, 183 superiority, 17 supply, 33, 46, 54, 102, 142, 191 suppression, 129 suprachiasmatic nucleus, 153, 189, 200 surface area, 69, 152 surface structure, 120 swallowing, 125, 141, 142, 145, 165, 183 swelling, 11, 17, 150, 181 symmetry, 2, 169 sympathetic, 21, 22, 23, 24, 82, 115, 156 sympathetic fibers, 22 sympathetic nervous system, 24, 82, 115 symptoms, 82, 129 synapse, 15, 24, 65, 67, 69, 71, 74, 75, 77, 78, 80, 85, 98, 103, 105, 108, 115, 134, 136, 138, 189 synapses, 2, 29, 65, 69, 71, 72, 74, 78, 79, 80, 81, 82, 84, 85, 93, 161, 171 synaptic transmission, 65, 69 synaptic vesicles, 69, 72, 74, 79, 80, 82 syndrome, 171 synthesis, 85, 201 synthetic, 29, 176, 179 systematic, 85, 125 systemic circulation, 191 systems, 1, 2, 3, 4, 21, 24, 66, 73, 81, 82, 88, 115, 118, 122, 125, 129, 130, 131, 133, 134, 137, 138, 139, 141, 145, 148, 150, 151, 159, 167, 176, 181, 191, 201, 202

T target organs, 118 targets, 115, 139 task conditions, 201 taste, 69, 125, 133, 137, 141, 142, 144, 145, 154, 156, 158, 162, 164, 165, 173, 190, 193, 194, 197 technology, 171 telencephalon, 10, 11, 19, 115, 143, 145, 151

214 television, 161 temperature, 31, 33, 102, 103, 109, 114, 119, 133, 134, 135, 136, 193 temporal, 19, 40, 120, 122, 124, 125, 144, 145, 146, 147, 150, 153, 154, 156, 166, 170, 171, 173, 175, 182, 183, 184, 196, 201, 202 temporal lobe, 19, 120, 122, 124, 125, 144, 146, 150, 154, 170, 171, 173, 175, 182, 183, 184, 196, 201 tendon, 133 tension, 88, 133 terminals, 6, 29, 53, 68, 69, 71, 72, 74, 77, 78, 79, 80, 82 territory, 102 textbooks, 116 thalamus, 10, 16, 18, 20, 87, 103, 108, 109, 112, 115, 116, 119, 120, 122, 123, 124, 125, 128, 130, 134, 135, 137, 139, 141, 142, 144, 145, 146, 148, 150, 151, 153, 183, 184, 186, 187, 188, 189, 198 theory, 8, 59, 64, 73, 142, 150, 154, 161 thermal, 102, 141 thinking, 19 third order, 122, 186 thoracic, 21, 100, 101, 102, 103, 105, 135 thorax, 199 three-dimensional, 69, 92, 94, 150, 171, 172, 173 threonine, 95 threshold, 45, 50, 58, 73, 75, 77 time, 6, 16, 22, 31, 33, 36, 39, 40, 41, 42, 48, 50, 54, 56, 57, 58, 59, 62, 64, 69, 72, 73, 79, 80, 85, 88, 139, 150, 165, 177, 179, 201 timing, 145 tissue, 1, 4, 6, 13, 14, 17, 72, 94, 102, 109, 175, 178, 179, 193 Tokyo, 64, 97, 200 tongue, 142 topology, 92 toxic, 84, 191 toxins, 93 transcripts, 94 transduction, 96, 97, 150, 159, 161, 164, 166 transfer, 65, 95 transference, 71 transistors, 27 translation, 159 transmembrane, 90, 98 transmission, 65, 66, 69, 71, 81, 82, 88, 119, 131, 182, 186 transmits, 28

Index transport, 39 transportation, 39, 94 travel, 2, 29, 97, 188, 189 trees, 64, 69, 98, 201 tremor, 129 tricuspid valve, 191 trigeminal, 87, 100, 102, 108, 110, 119, 135, 137, 141, 142, 145, 148, 186 trigeminal nerve, 100, 102, 108, 110, 119, 137, 141, 145, 186 trigeminal system, 136 triggers, 50, 77, 158 triptophan, 82 trochlear, 111, 150, 155 trochlear nerve, 111, 155 tryptophan, 86 tubular, 1, 4, 8, 29, 72 turtle, 166 tyrosine, 82, 86

U uncertainty, 93 uniform, 69, 113 unilateral, 166 United States, 25 universe, 192 utricle, 150, 159

V vagus, 24, 80, 141, 142, 148 vagus nerve, 80, 141, 142, 148 valence, 32 values, 24, 40 variation, 2, 74, 93, 102, 185, 202 vascular, 6, 10, 117, 118, 191 vascular system, 6, 10, 117, 118, 191 vasculature, 117 vasopressin, 85, 117, 118, 188 vein, 191 velocity, 30, 58, 59, 62, 135, 139, 160, 193 ventricle, 10, 11, 13, 16, 17, 18, 82, 107, 110, 111, 112, 115, 116, 117, 118, 120, 182, 186, 187, 191, 196 ventricles, 10, 11, 13, 18, 20, 115 ventricular, 181 ventricular zone, 181 venules, 191

Index vertebrae, 8, 21, 100 vertebrates, 1, 4, 6, 8, 10, 11, 12, 13, 15, 17, 18, 19, 24, 27, 30, 62, 73, 99, 112, 120, 139, 145, 148, 189, 196 vesicle, 8, 13, 16, 74, 159 vessels, 16, 21, 24, 179, 191 vestibular system, 115, 124, 137, 138, 148, 150, 159 vestibulocochlear nerve, 145, 146, 150 vibration, 134, 146, 148, 193 villus, 159 virus, 63, 135 virus infection, 63, 135 viscera, 24, 102 visible, 121, 125, 189, 196 vision, 8, 18, 125, 133, 151, 152, 156, 167 visual, 11, 17, 18, 112, 119, 122, 124, 125, 137, 151, 152, 153, 154, 155, 156, 158, 161, 162, 164, 166, 167, 169, 171, 173, 176, 179, 182, 184, 185, 189, 196, 197, 199, 201, 202 visual area, 124, 153, 154, 156, 173, 182, 184, 199 visual attention, 125 visual field, 155, 156, 171, 173, 176 visual images, 156, 197 visual perception, 156, 201 visual stimuli, 176, 201 visual system, 151, 156, 161, 164, 167, 169, 189, 202 visuospatial, 176, 201

W walking, 139, 176 water, 31, 35, 65, 94, 117, 118, 148, 150, 160, 179, 191 wavelengths, 59, 161 white matter, 14, 17, 99, 112, 115, 138, 139, 187 wires, 27, 43, 44, 50 workers, 125 working memory, 200, 201 writing, viii, 176

X X-axis, 55 X-ray analysis, 94

215

Z Zn, 33