No title

Animal Models of Neurological Disorders Kathryn

C. Todd and Roger F. Bufterworfh

1. Introduction Of primary concern to an investigator of neurological disorders is that of the selection of the most relevant animal model to achieve his or her research goals. According to Kornetsky (19771, three different types of animal models are typically used in medical research. Homologous models are those in animals which the etiology, symptoms, and outcome of the model duplicate those of the human disorder m every major aspect. Isomorphic models are those that resemble the human disorder, but are artificially produced in the laboratory in a way that does not reflect normal human etiology, and predictive models are those that do not necessarily resemble the human disorder in many respects, but are valuable in terms of predicting some aspect of the disorder such as the response to various drugs. The selection of the model depends on the goal of the experimenter. A predictive model allows the investigator to make certain predictions about the disorder it models; an isomorphic model permits not only predictions, but also allows the study of underlying mechanisms; and a homologous model serves as a basis for studying all aspects of a disorder, including its causes. Once the purpose of the experiment is defined, the type of model to be selected becomes apparent. It is also important that the model of choice be relatively easy to establish, be reproducible, and economical, and respect relevant ethical guidelines. Any investigation employing animal models should be conducted in such a manner that the control of con-

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founding variables is optimized, ensuring definitive results, and planned in such a way as to minimize distress and use the fewest numbers of animals possible. Although fulfilling these conditions seems somewhat daunting, their consideration is obligatory. For a detailed discussion on the ethics of animal models in neurological diseases, the reader is referred to Olfert (1992). Although numerous animal models exist for a wide variety of diseases for practical purposes, only those models representing the most intensive areas of research into neurological diseases are presented in this chapter.

2. Surgical

and Pharmacological

Considerations

Many animal models of neurological disorders involve surgical techniques. One of the primary concerns in surgical undertakings is the choice of anesthesia. As most anesthetic agents depress cerebral metabolic rate, introducing a possible confound, their selection is somewhat dependent on the disease modeled and the goal of the experiments. Commonly used anesthetic agents include barbiturates such as sodium pentobarbital and inhalation anesthetics such as halothane. Barbiturates in particular may be problematic in terms of confounding variables, as they have been reported to protect against neuronal loss (Hallmayer et al., 1985). Models that involve craniotomy and direct manipulations in the brain always introduce the risk of extraneous injury and infection. These undesirable effects may be minimized by sound surgical techniques and postoperative care. Physiological parameters such as PO,, PCO,, body temperature, and blood pressure should be controlled, and kept within a defined range. Often, it is also relevant to monitor brain temperature, as fluctuations in brain temperature may produce variations in outcome. Overnight fasting of the animal is helpful in controlling blood glucose, and an acclimatization period of 2-3 d after shipment combined with gentle handling aid in preventing metabolic differences produced by stress. Postoperative care is also an important consideratron, and the degree of care required is somewhat dependent upon the disease modeled. Postoperatrve procedures should include the application of an antibiotic to reduce the possibility of infection, body temperature monitoring to avoid hypothermia, administration of a saline/dextrose solution to prevent dehydration, and either free availability of food (chow) and water or intubation feeding to avoid starvation.

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Models

Surgical methodologies are primarily used to model Alzheimer’s, Huntington’s and Parkinson’s diseases, as well as cerebral ischemia, hypoxia, hepatic encephalopathy, and cerebellar ataxia. These protocols, depending upon the disease modeled, involve the administration of neurotoxins, ablation or lesioning of specific brain nuclei, and interference with blood supply or peripheral organ isolation. In addition to surgical methodologies, pharmacological manipulation may also be an appropriate method of modeling neurological disease. The major research strategy involving pharmacological agents is to administer drugs that either increase or decrease the effects of particular neurotransmitters. Systemic administration of drugs requires consideration of route of administration and drug disposition, appropriate dosage, and the possibility of multiple drug effects. As some drugs may render the animal incapable of food seeking because of impaired motor function, care must be taken to ensure the animal obtains sufficient nourishment.

3. Alzheimer

Disease

3.1. Neuropathology Alzheimer disease (AD) is the most common cause of progressive intellectual failure in aged humans. Animal models of AD have been designed to reproduce some of the neuropathological, biochemical, and behavioral changes that have been observed in the brains of patients with AD. Although no model has been successful in replicating all of the pathological and biochemical changes associated with AD, they have been useful in identifying specific aspects of the disease. Typically, AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis (Games et al., 1995). These changes are found in a variety of neural systems, including brainstem catecholaminergic nuclei, the basal forebrain cholinergic system, amygdala, hippocampus, and specific regions of the neocortex (Price, 1986). The most consistent and greatest changes have been associated with magnocellular neurons of the nucleus basalis of Meynert, medial septal area, and diagonal band of Broca (Coyle et al., 1983). These neurons provide the primary cholinergic innervation to the neocortex, hippocampus, and other limbic and paralimbic regions, thus implicating this system in the pathogenesis of AD (seeFig. 1)

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Fig. 1. Neurofibrillary tangle (center) surrounded by abnormal neurite processes from the hippocampal region in Alzheimer disease. (From Graham et al., [19951, with permission.)

3.2. Surgical Models of AD A number of models exist to induce Alzheimer-like neuropathologies. Aluminum salts injected either intrathecally or intracerbroventricularly (ICV) have produced neurofibrillary abnormalities in susceptible species (Pendelbury et al., 1988; Troncoso et al., 1982). The relevance of this model remains controversial, however, as the location of the neurofibrillary tangles produced by aluminum in the susceptible animal species does not reflect that observed in human AD. Aged animals, who typically show many of the same behavioral and cognitive impairments identified in early stage AD (Rapp et al., 19871, have not proven to be a particularly valuable model, as they lack they the typical neuropathology observed in agerelated AD (Markowska, et al., 19891, and are often cost-prohibitive. A commonly used model employs young animals in which a subset of the pathological or biochemical changes similar to those observed in AD are produced by lesioning specific brain regions. Lesions may be produced by the administration of specific neurotoxins or by the application of an electrical current (electrolytic

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lesions). The areas usually targetted for lesioning include the basal forebrain cholinergic system, noradrenergic locus coeruleus, serotonergic raphe nuclei, or a combination of these regions. Lesions of the fimbria and fornix by electric current, horizontal knife cuts, or aspiration result in disconnection of the hippocampus, an apparent pathology in AD (Hyman et al., 1984). Direct neurotoxin application to the hippocampus has also been used as a model for AD-like pathology (Jarrard et al., 1984). Both rats and monkeys have been used in models of AD. The most commonly employed models involve lesions of the basal forebrain structures using either neurotoxins for destruction of cell bodies or electrical current for destruction of fibers of passage and cell bodies. The excitatory amino acids ibotenic, kainic, quinolinic, and quisqualic acids and N-methyl-D-aspartate have proven to be the most reliable neurotoxins for destruction of cell bodies within specific basal forebrain nuclei (Kohler and Schwartz, 1983). Dependmg on the species used, the number of mjections required for lesioning may vary from 1 (rat) to 14 (monkey) per nuclei (Wenk, 1992). 3.3. Pharmacological

Models of AD

Correlated with the progressive deterioration of cognitive functioning observed in AD is the loss of cholinergic function (Collerton, 1986). The most common pharmacological agent used to produce a representative cognitive deficit in animals is the muscarinic antagonist scopolamine (Preston et a1.,1988). The effects of scopolamine on cognitive functioning (particularly learning and memory) are transient, and studies using this drug have resulted in putative pharmacotherapies for the enhancement of cognitive functioning in AD. 3.4. Transgenic

Models of AD

Recently, studies have reported the production of transgenic mice that develop significant aspects of the AD-like pathology, including amyloid plaques and early stages of tangles (Crowther, 1995). In AD, the amyloid plaques are composed of amyloid betapeptide, a 40-42-amino acid fragment of the beta-amyloid precursor protein (API’). Games et al. (1995) have produced transgenic mice that express high levels of human mutant APP, that progressively develop many of the pathological hallmarks of AD, includ-

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ing neurite plaques, synaptic loss, astrocytosis, and mrcrogliosis, creating a useful model of AD. Another recent development utilizes the mouse trisomy 16 (Ts 161, an animal model of Down’s syndrome which, similar to AD, shows degeneration of cholmergic forebrain neurons. As Ts 16 mice do not survive birth, and in an attempt to produce a useful model of for AD, Holtzman and colleagues (1992) transplanted Ts 16 basal forebrain neurons into the hippocampus of young adult mice. Their results showed that the transplanted neurons survived and grew neurites in all grafts. Over time however, the cholinergic neurons in Ts 16 grafts selectively atrophied and denervatron of the hippocampus increased the size of the lesion, suggesting that hippocampal-derived neurotrophic factors prevented degeneration of the cholinergic neurons. These studies, and others of their kind, should provide more salient models for AD 4. Parkinson

Disease

4.1. Neuropathology

Parkinson disease (PD) occurs primarily m middle age, usually beginning between 40 and 70 yr of age with the peak of onset in the sixth decade (Wiederholt, 1995). Familial cases of PD are rare, the idiopathic form being the most common. The disorder is characterized pathologically by the presence of cytoplasmic inclusions (Lewy bodies) and progressive loss of dopamine (DA)-synthesizing neurons in the zona compacta of the substantra nigra that project to the caudate and putamen (Hornykiewicz and Kish, 1986). As a consequence, dopamine is depleted in the neostriaturn. The behavioral manifestations of PD include expressionless face, infrequent blinking, tremor (particularly resting tremor), rigidity, bradykinesia, and disturbances of gait and posture. Many attempts have been made to reproduce PD in both rodent and primate animal models, with varying degrees of success. The l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model has been the most useful to date (see Fig. 2) 4.2. Animal

Models

of PD

Early models of PD, induced lesions of the ventromedial tegmental area (Poirier, 1960). This and a number of other investigations led to the identification of the dopaminergic nigral-striatal system as the primary culprit in this disorder. From then on, the use of surgical lesioning was rendered somewhat obsolete, and

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Fig. 2. Characteristic neuropathology of Parkinson’s disease: shrinkage and discoloration of the substantia nigra (bottom) in contrast to a normal age matched control (top). (From Graham et al. [1995l, with permission.)

the generation of models focused on compounds effective in depleting striatal DA levels. Intrastriatal and systemic injections of reserpine, a drug that results in the depletion of DA, noradrenaline (NA), and serotonin (5-hydroxytryptamine, 5-FIT), produces hypokinesia, muscle rigidity, and tremors in animals (Duvoisin and Marsden, 1974; Goldstein et al., 1975), but no degeneration of catecholaminergic fibers was observed, reducing the validity of this compound as a model of PD. 4.3. 6-Hydroxydopamine

lesions

Currently, the most commonly used models of PD depend on the species of animal selected. In rats, the preferred model of PD

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involves either unilateral or bilateral microinjection of the neurotoxin 6-hydroxydopamine (6-OHDA) (Ungerstedt et al., 1973) This compound has also been shown to be effective in mice (Von Voigtlander and Moore, 1973). Unilateral administration of 6-OHDA in the substantia nigra, ventral tegmentum, or medial forebrain bundle results in degeneration of the nigrostriatal pathway (Ungerstedt et al., 1973) and produces episodic head and neck tremors and abnormal body posturing (Buonamicl et al., 1986). 6-OHDA is often injected directly into the striatum (Przedborski et al, 1995). A critical component of the 6-OHDA model of I’D is the subsequent administration of DA-stimulating drugs that induce whole-body circling, directionally dependent on the nature of the drug administered. DA-releasing drugs, such as amphetamine, produce circlmg ipsilateral to the lesloned side, whereas duect DA receptor agonists, such as apomorphine, produce rotations contralateral to the lesioned side. L-DOPA, the precursor of DA and a pharmacological treatment for PD, produces contralatera1 rotations (Ungerstedt et al., 1973). The most likely explanation for these effects is the stimulation of hypersensitive striatal DA receptors because of presynaptic denervation. Although a valuable investigatory tool, the drawbacks to the unilateral 6-OHDA model include the obvious unilateral nature of the model, the fact that these animals do not exhibit hypokinesra and rigidity, and the findings that the ability of drugs to induce circling (by stimulating whatever DA receptors remain), does not always correlate with their potency in attenuating the symptoms of I’D in humans. Bilateral administration of 6-OHDA in the medial forebram bundle at the level of the hypothalamus is also used as a model of PD, and results in severe behavioral effects, including hypokinesia (Butterworth et al., 19780, muscular rigidity (Rondeau et al., 19781, tremor (Jolicoeur et al., 1991), and severe aphagia and adipsia (Smith et al., 1972). These symptoms are temporarily reversed by the administration of DA receptor agonists, including apomorphine and bromocriptme and by L-DOPA (Butterworth et al., 1978), indicating behavioral and pharmacological profiles of this model similar to those observed in PD.

4.4. MPTP Model The I’D model of choice for use in primates and mice is the lmethyl-4-phenyl-1,2,3,6-tetrahydropyridine model (MPTP); this

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toxin is ineffective in the rat. Intravenous or subcutaneous injection of MPTP in primates induces symptoms almost identical to those seen in PD patients (Burns et al., 1983). The active component of this nigrostriatal toxin appears to be l-methyl-4phenylpyridinium ion (MPP+), a metabolite produced by the enzyme monamme oxidase B. A review of the current literature suggests that the 6-OHDA model in rats and mice, and the MPTP model in mice and primates continue to be used extensively for investigations of the underlying mechanisms of, and potential pharmacological and transplantation therapies for PD. 4.5. Protocol of Parkinson

for the MPTP Model Disease (Bedard et al., 7992)

Either MPTP salts or base may be used. The base is easily soluble in saline. Because of its extreme toxicity, MPTP should be weighed in a fume hood, and cautionary measures such as chemical-proof masks and rubber gloves are required. The exact amount necessary for the experiment is calculated, and dissolved (1 mg/mL) in saline. It is advisable to first place the relevant amount of powder in a bottle and cap the bottle with a rubber cover through which the saline vehicle may be injected. The animals are restrained, injected intravenously or subcutaneously, and placed in a room equipped with separate ventilation. Care must also be taken in postinjection handling of the animals, as MPTP is excreted through the feces and urine for 48 h. Excrement from the animals should be collected and disposed of separately. Appropriate dosage seems to be somewhat variable, therefore for their primate model Bedard et al. (1992) suggest commencing with 0.3 mg/kg/d for 3 d. If the animal becomes maximally akinetic, this dose is sufficient. With other animals it may be necessary to repeat the same dose every three to four days. After three trials, the dose is increased to 0.6 mg/kg and if still not sufficient, increased to 0.9 mg/kg. A cumulative dose of 40 mg/kg is not unusual. An effective dose in mice is .003 mg/kg/d for 3 d (Date et al., 1995). For a period of lo-30 min postinjection, the animals typically exhibit agitation, ataxia, myoclonus, lingual dyskinesia, and in the primate, periodic vomiting. Most animals require repeated administration of MPTP, and akinesia becomes evident in the days following the last dose. In the primate, the akinesia manifests initially as aphagia and adipsia followed by immobility and

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stooped posture. At this point, many animals require assistance to eat and drink. If the animal is unable to swallow, it must be fed by gavage. If after a few days the symptoms have not resolved, treatment with L-DOPA must be initiated. If the aim of the experiment is to test anti-Parkinson’s agents, a stabilization period of 1-2 wk for mice and 6-8 wk for primates is suggested. A visible Parkinsonian syndrome requires a greater than 90% loss of DA in the striatum

5. Cerebrovascular

Disorders:

Stroke

5.1. Neuropathology The term stroke refers to any severe, sudden attack, and because damage from disorders of the cerebral circulatory system frequently occurs with great suddenness and severity, stroke is commonly used as a synonym for cerebrovascular disorder. However, that being said, not all cerebrovascular disorders are characterized by sudden onset, and not all cerebral disorders of sudden onset are vascular in origin. There are many ways of classifying and categorizing cerebrovascular disorders, the simplest being into two main types; intracerebral hemorrhage and cerebral ischemia. Intracerebral hemorrhage (bleeding) occurs when a cerebral blood vessel is ruptured and blood seeps into the surrounding neural tissue, damaging it, and leaving areas beyond the rupture deprived of their blood supply. Aneurysms are frequent causes of intracerebral hemorrhage. In this condition, a pathological balloon-like dilation forms in the wall of a blood vessel at a point where the elasticity of the vessel wall is defective. These are points of weakness in the cerebrovascular system, and sometimes they burst, causing bleeding into the surrounding tissue. The second type of cerebrovascular disorder, cerebral ischemia, is a disruption of the blood supply to an area of the brain, which eliminates its supply of glucose and oxygen, resulting in brain cell death. An area of ischemic brain damage is called an infarct. Three

main

causes

of infarcts

exist:

thrombosis,

a type

of “plug,”

often composed of a blood clot, fat, oil, air bubble, or tumor cells that block blood flow at the site of formation; embolism, similar to thrombosis, except the plug is carried by the blood from a larger vessel, where it was formed, to a smaller one where it becomes lodged; and arteriosclerosis, in which the walls of blood vessels

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thicken, often as a result of fatty deposits, producing a narrowing of the vessels that may eventually become completely blocked. This classification may be somewhat redundant, however, as regardless of the underlying etiology (a plug or a rupture of a blood vessel), in the development of a stroke a certain part of the brain does not receive an adequate blood supply for a period of time and ischemia ensues. If brain tissue is thus deprived of blood supply for lo-20 min, infarction will occur. Occlusion of a given artery does not necessarily imply infarction of brain tissue m the perfusion territory of the blood vessel, as often adequate collateral circulation may exist. Patients whose brains are supplied with excellent collateral circulation may show no neurological deficit, whereas the unfortunate patient with extremely poor collateral circulation may be left with a devastating neurological deficit after a stroke. Four different types of ischemia-induced brain damage have been described (Seta et al., 1992): autolysis (mainly alterations of neurons); generalized neuronal necrosis (GNN, necrotic neurons surrounded by normal glia); selective neuronal necrosis (similar pattern to GNN, but identifies neurons extremely sensitive to ischemia); and infarction (death of all cells, including neurons, glia, and endothelia cells). Cerebral ischemia also causes widespread alterations in physiological, metabolic, and biochemical systems. Further comphcating the picture are the added alterations to brain tissue caused by recirculation and reintroduction of oxygen and glucose to the deprived system such that reperfusion injury is believed to represent an important facet of brain disease initiated by ischemia (Dietrich, 1994). 5.2.

Global

Models

of lschemia

Global models of ischemia result in, as their name implies, global or diffuse brain damage. Most often, the animal of choice for these models is the rodent, particularly the rat or gerbil. Physiological monitoring is difficult and multiple blood sampling is simply not feasible in smaller rodents. Three main models for global ischemia have been employed: unilateral occlusion of the common carotid artery (CCA); bilateral occlusion of the CCA; and four-vessel occlusion. The unilateral occlusion of the CCA is commonly performed in gerbils as they lack a complete circle of Willis because of the absence of the posterior communicating arteries (Kahn, 1972;

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Kitagawa et al., 1989). The procedure produces severe neurological deficits and unilateral hemispheric infarction that has the advantage of an intra-animal control. The drawbacks to this models are a rather low success rate (only 30-40% develop lesions) and the tendency of seizure activity in the gerbil (Seta et al., 1992). The bilateral CCA occlusion or two-vessel occlusion (2VO) is commonly performed on both rats and gerbils. This model will cause global ischemia in the gerbil, but in the rat only if additional stress such as reduced arterial pressure is placed on the cerebral circulation (Seta et al., 1992). In this model, both common

carotid

arteries

are occluded,

and in rats blood

pressure

is

reduced to 50 mmHg employing a servo-system such as that described by Kagstrom and colleagues (1983). The lesion produced in this model involves the forebrain, caudate and putamen, neocortex, and selectively vulnerable areas such as the CA1 region of the hippocampus (Smith et a1.,1984). The drawbacks to this model are the same as those of the unilateral occlusion, namely postischemic seizures. The main advantage to both the unilateral and bilateral CCA occlusion models is the relatively small amount of necessary specialized equipment. The four-vessel occlusion model (4VO) was initially developed as a method for producing incomplete forebrain ischemia in the awake animal. Although the lesion produced in this model is similar to that produced in the bilateral 2V0, the protocol is more complicated, and involves two stages of surgery. In the first stage, clasps or loops are placed around the carotid arteries of anesthetized animals and exteriorized through a neck incision. Additionally, during this stage, the vertebral arteries are electrocauterized. One day later, the ischemic episode is produced by tightening the clasps or loops. The advantage of this procedure is that the ischemic episode is performed on an awake animal. The disadvantages include the technically demanding electrocoagulation of the vertebral arteries, a high mortality rate (approx 50%), and postischemic seizure activity. Researchers

have also found outcome

variabilities

between

and

even within strains of rats, but Wistar rats appear to be the animal of choice for this approach. Other, less commonly used models for global ischemia such as decapitation ischemia, the tourniquet model, compression ischemia, and graded unilateral ischemia exist. For a further description of these models, the reader is referred to Seta et al, (1992).

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5.3. Focal Models of lschemia Many different strategies are used to induce cerebral ischemia, but the focal, transient occlusion of the middle cerebral artery (MCA) has been reported to result in neuropathology most similar to that seen in clinical cerebral ischemia (Borlongan et al., 1995). This model may be used in virtually any species, with the surgical approach made relevant to the animal size. In rodents, the MCA model is typically performed in the subtemporal region by making a vertical incision midway between the eye and the ear. The skin and underlying musculature are then retracted, and a portion of the jawbone removed. The MCA is then exposed by means of a craniotomy. For an irreversible MCA occlusion, the artery is permanently occluded by thermocoagulation. Several reversible MCA procedures also exist which require, instead of the removal of a portion of the jawbone, the drilling of a small hole into the bone at the zygomatic arch. In a procedure described by Shigeno et al. (1985), a 10-O suture is passed behind the MCA and drawn up through a polyethylene catheter placed m the jawbone hole. The artery is then occluded by tightening the suture and gluing it to the catheter, and blood flow is re-established by cutting the suture Because of its difficulty, this procedure has not been widely employed, and has since been modified by Welsh and colleagues (1987). The modification employs a snare ligature to occlude the MCA. The snare is produced in a manner similar to the Shigeno method, in that the 10-O suture is pulled through a polyethylene tube, but instead of being glued to the catheter, it is tied around a small piece of proline suture placed across the top of the catheter, thus snaring the artery. Reflow is then easily re-established by removing the proline suture and allowing the artery to fall back into place. More recently, Selman et al. (1990) detailed a procedure combining the methods of Tamura and Welsh, which involves the removal of a portion of the jawbone, craniotomy just rostra1 and lateral to the foramen ovale, followed by either permanent occlusion by electrocauterization (or tight ligature) or reversible occlusionby snare method. For a detailed protocol of this model, the reader is referred to Seta et al. (1992) and to Ginsberg and Busto (1989) for a summary of rodent models of MCA occlusion (seeFig. 3). The advantages to this model of cerebral ischemia include the clinical relevance, relatively low cost per animal, use of general anesthesia, production of blood pressure and blood gas data, and the generation

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Fig. 3. “Snaring” of the middle cerebral artery. Top: The 10-O suture captures the MCA, and is brought back through the silastic tubing (St). Bottom: A piece of 4-O prolene suture (p) is placed across the top of the silastic tube, and the 10-O suture is tied off, kinking and occluding the MCA. Recirculation is achieved by removing the prolene suture and the silastic tube (From Seta et al. 119921 with permission).

of adequate sample sizes. The disadvantages are the difficult surgical procedures, variable response in size and location of lesion, specialized postoperative care, and the requirement of specialized equipment. In larger animals such as primates and cats, the method of choice for MCA occlusion is the transorbital approach, which avoids the necessity of a craniotomy. Here, the eye is removed, the optic foramen enlarged, and the dura opened to expose the MCA at its origin (O’Brien and Waltz, 1973). It is then possible to occlude the artery either permanently by cauterization or reversibly with a clip. Many variations of this basic procedure exist. Advantages to

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this model are that it is relatively easy to perform, involves minimal brain retraction, and thus is one of the least traumatic models of focal ischemia. The drawbacks include routine surgical complications and injury to surrounding tissue, and, most importantly, the ethical concern of removal of an eye. Other models of focal ischemia exist that are variations of embolism models. In an embolism model, either a homologous blood clot fragment or microspheres made of carbon, silastic or other material are injected into the internal carotid artery (Kudo et a1.,1982; Kogure et al., 1974; Lyden and Lonzo, 1994). Another model utilizes a photochemical method to induce a nonocclusive platelet thrombosis in the CCA that travels to produce a distal embolism, producing a cortical infarction (Futrell, 1988). The main advantage of these procedures is that they do not involve craniotomy; however they are somewhat less frequently employed as the lesions they produce are unpredictable in both size and location, and the occlusion is permanent. Longa et al. (1989) described a variation of the embolism model that allows reversible occlusion of the MCA. The basic procedure involves the introduction of a 4-O nylon intraluminal suture into the cervical internal carotid artery and advancing it 17 mm intracranially to block blood flow into the MCA; collateral blood flow was reduced by interrupting all branches of the external carotid artery and all extracranial branches of the internal carotid artery. Blood flow was restored by withdrawing the suture. Because of increased collateral branching in older rats, younger animals (300-400 g) were preferred. This model has proven to be a reliable, relatively noninvasive means of reversible MCA occlusion. However, as with most ischemia models, the extent of infarction is somewhat variable. More recently, a strain of rats has been produced that develop a pathology similar to that observed in patients with stroke. This strain, the Spontaneously Hypertensive Rats-Stroke Prone, or SHRSP, has mainly been used to study a variety of drugs aimed at reducing the deleterious effects of stroke. These animals must be fed a stroke-inducing diet (Hernandez et a1.,1994); seeFig. 4.

6. Other Neurological

Disorders

Models for a vast array of other neurological disorders also exist, including those for Huntington’s disease, epilepsy, demyelinating diseases, and metabolic diseases. A brief discussion of these disorders is presented in the following sections.

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Fig. 4. Multifocal prone spontaneously with permission.)

disruption of the blood-brain barrier in a strokehypertensive rat. (From Graham and Latntos 119971,

6.1. Hun tingon Disease Like Parkinson disease, Huntingon disease (HD) is a progressive disorder of motor function; but unlike Parkinson disease, it is relatively rare, it has a strong genetic basis, and it is always associated with severe dementia. The initial motor symptoms take the form of increased fidgetiness, slowly worsening until the patient’s behavior is characterized by incessant involuntary performance of a variety of rapid, complex, jerky movements that involve entire limbs rather than individual muscles. HD is passed from generation to generation by a autosomal dominant gene, so all individuals carrying the gene develop the

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disorder as do about half of their offspring. There is no cure for HD, and death occurs approx 15 yr after the appearance of the first symptoms. The neuropathology typically associated with HD is a gross generalized atrophy of the cortex and basal ganglia, affecting both gray and white matter. Histological evaluation of postmortem HD brain has revealed an extensive gliotic reaction, and loss of small neurons in both the striatum and in layers 3,5, and 6 of the frontal and parietal cortices. Severe damage to the neostriatum causes compensatory, secondary hydrocephalus with a gross dilation of the ventricular system (Vonsattel et al., 1985). Other brain regions affected in HD to a lesser extent include the pars reticulata of the substantia nigra, thalamic nuclei, subthalamic nucleus, cerebellum, hypothalamus, hippocampus, superior olive, and red nucleus (Emerich and Sanberg, 1992). A number of animal models of HD exist, primarily pharmacological manipulatrons or lesions of the striatum. Mechanically or electrolytically leslonmg various brain structures such as the striaturn in an attempt to mimic the symptoms of HD typically also damages supportive neuronal structures in addition to fibers that pass through and terminate in the damaged area. Thus, these models have been less employed, and the focus has turned to pharmacological strategies. The most relevant pharmacological approaches involve the intrastriatal injection of the selective cytotoxic compounds kainic acid (McGeer and McGeer, 1982) or quinolinic acid (Beal et al, 1986; Beal et al., 1988), and the systemic administration of 3-nitroproprionic acid, an inhibitor of the mitochondrial citric acid cycle (Schulz and Beal, 1994). Although all three compounds have been reported to provide valid models of HD, quinolinic acid exerts a more selective degenerative effect in the striatum than kainic acid, and 3-nitroproprionic acid has been suggested to result in lesions that more closely replicate the neurochemical, histological, and clinical features of HD (Schulz and Beal, 1994). For a more detailed discussion of animal models of HD the following sources are recommended: Emerich and Sanberg (1992); Sanberg et al. (1993); Antal and Bodis-Wollner (19931, Dunnett and Svendsen (19931, and Schulz and Beal (1994). 6.2. Epilepsy The primary symptom of epilepsy is the epileptic seizure, but not all persons who suffer seizures are considered to have epi-

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lepsy. The term epilepsy is applied only to those patients whose seizures appear to be generated by their own chronic brain dysfunction. Seizure disorders are classified mto partial seizures or generalized seizures. Partial seizures do not involve the entire brain, and are further categorized mto simple seizures (primarily sensory and/or motor in which there is no change in consciousness) and complex seizures (in which there is a change in consciousness. Similarly, generalized seizures are further categorized as either convulsive, characterized by violent tonic-clonic or myoclonic convulsions (often referred to as grand ma1 seizures), or nonconvulsive, in which there is an absence of convulsions. To induce either simple partial acute or chronic seizures, application of topical convulsants, including penicillin, tetanus toxin, strychnine, alumina, cobalt, tungstic acid, or iron are employed. Depending on the convulsant selected, administration is either by direct cortrcal bathing with a pledget (filter paper or cotton) or intracranial injection. Because a variety of anesthetics are known anticonvulsants, careful selection and control of anesthesia is required. The induction of complex partial or generalized clonic-tonic seizures has been produced using systemically administered convulsants including kainic acid, bicuculline, bemegride, isoniazid, methionine sulfoximine, pentylenetetrazole, picrotoxm and flurothyl. The advantages of systemic convulsants are the ease of adminrstration and elimination of a preliminary surgery that requires the use of anesthesia. Genetically based animal models of seizures also exist that develop various forms of seizure disorders. For example, the El mouse model, an autosomal dominant model, exhibits complex partial seizures, whereas the tottering mouse mutant, an autosoma1 recessive model, develops simple partial seizures. The quaking mouse model, an autosomal recessive trait developed in the DBA/2J strain, is a model of generalized seizures. Several rat strains also produce genetically epilepsy-prone (GEPR) rats, and two of these, GEPR-9 and GEPR-3, have been the most widely studied. The GEPR-9 rats exhibit a severe audiogenic tonic-clonic seizure, whereas the GEPR-3 rats exhibit clonus (Reigel et al., 1986). For a detailed description of these methodologies, the reader is referred to McCandless and Finesmith, (1992) and to Abel and McCandless (1992). Kindling is another means for modeling epilepsy. This procedure involves repeated subconvulsive stimulation of the brain by

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electrical current or pharmacological agents to produce seizure activity of gradually increasing intensity, finally culminating in full, clonic, motor seizures. Electrical kindling is produced by bipolar electrodes typically made of approx 0.25 mm of stainless steel or platinum iridium insulated with teflon except at the tip. The most common electrode placement is either the amygdala or hippocampus, regions considered to be the primary foci for many clinical seizure syndromes. A common proctoral for stimulation is application of a 1-2 s train of a 50-60 Hz square wave, l-ms duration at an amplitude of 200-1000 PA. A critical component to this model is the interval between stimulations, as the probability that seizures will develop increases with the intertrial time and, the number of trials required to elicit the first convulsron decreases as the intertrial times increases to 24 h (Abel and McCandless, 1992). A common methodology is to use a schedule of one stimulation per day, 5/wk. Chemical kindling is also used to model epilepsy, and mvolves drug delivery either through systemic injection or direct brain application using a cannula. Lidocaine (Post et al. 1975), cocaine (Post et al. 1988), and bicuculline (Dworsky and McCandless, 1987) are administered by ip injection, and the excitatory amino acids L-aspartate and L-glutamate are typically delivered directly into the amygdala (Mori and Wada, 1987). 6.3. Rem yelina ting Diseases: Multiple Sclerosis Demyelinating diseases were first identified as a group of related diseases in the early 192Os, with the most common, multiple sclerosis (MS), being known for nearly 160 years. Charcot made the definitive synthesis of the clinical and pathological features of the disease in 1868. The pathological basis of MS is the sequential development of multifocal lesions characterized by demyelination, relative preservation of axons, inflammation, gliosis, and variable remyelination. Clinally, MS is characterized by relapses and remissions of neurological disturbance with gradual accumulation of residual impairment later. The mean age of onset is about 30 yr, but occasional cases begin over 50 yr and under the age of 15. Women are more often affected by the disease than men (female:male, 1.5:1). The course of the disease varies from death within a few months of onset to asymptomatic survival until death from another cause. The average expectation of life from onset is about 25 yr. The etiology of MS has yet to be completely under-

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stood, but two factors are clearly involved: genetics and environment. One possibility is that any one of a number of common infectious agents, that are successfully eliminated in most people, interacts with a genetically primed immune system to produce an abnormal response that leads to recurring episodes of focal immune-mediated attack on myelinated nerve fibers. Four pathological variants of MS exist: chronic variants, acute and subacute variants, MS diagnosed by biopsy, and MS associated with hypertrophic polyradiculoneuropathy. Most cases of MS satisfy the classic diagnostic criterion that lesions exhibit multiplicity in time and space (Lumsden, 1970; see Fig. 5). Animal models of MS may be divided into either genetic or nongenetic models. The genetic or mutant models are important for the identification of myelin constituents, clarification of major features of myelin metabolism and myelinogenesrs, and in elucidating the pathogenesis of inherited human diseases. Most of these mutations have been identified in mice, and are characterized pathologically by a deficiency in myelin production, resulting in diffuse or tract hypomyelination, that is, myelin sheaths that are absent or abnormally thin and malformed, with or without myelin breakdown. Four of the most commonly used mutant models are the jimpy and related PLP gene mutants, twitcher mutant, quaking mutant, and shivever mutant. Recessive mutations of PLP, an integral component of CNS myelin, include the jimpy mouse and myelin-deficient rat disease Both these mutations exhibit severe hypomyelination of the CNS together with evidence of myelin breakdown. Jimpy mice live for approx 2-3 wk followmg the appearance of progressive neurological signs 12 d postpartum and have almost no myelin visible in hrstological preparations (Sidman et al., 1964). The twitcher mutant is an autosomal recessive mouse mutation, that produces a severe deficiency of galactosylceramidase pgalactosidase, resulting in impaired myelin formation in both the central and peripheral nervous systems and eventual myelin breakdown. These mice exhibit progressive neurological signs from 30 d of age until death l-2 mo later Myelin formation proceeds normally until 10 d postnatally, followed by the appearance of abnormally thin myelin sheaths and myelin breakdown (Scaravilli, 1985). The quaking mutant is a nonlethal autosomal recessive trait causing tremor and seizures in mice beginning at postpartum d 12.

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Fig. 5. Multiple sclerosis, shown by lack of myelin staining in a C5-6 spinal cord section obtained from a patient with a 3-yr history of the disease. (From Graham and Lantos 119971, with permission.)

Very little myelin is visible in the CNS, although the axons are largely left intact (Harrison and McDonald, 1977). The shiverer mutant

is also an autosomal

recessive mouse

mutation,

in this case

with deletions within the myelin basic protein (MBP) gene resulting in an absence of MBP in both peripheral and central nervous systems, but with morphological changes primarily restricted to the CNS. These mice show signs of the disease from 12 d of age, and die when 2-3 mo old. Histological evaluation shows that central

axons lack myelin

uncompacted

sheaths

oligodendrocyte

or are surrounded

by spirals

of

cytoplasm. In this mutant, there

are no reactive changes in astrocytes, nor is there evidence of myelin breakdown. Interestingly, peripheral myelin, although

lacking MBP, appears normally compact (Privat et al., 1979; Rosenbluth, 1980; Roach et al., 1983). Konat and Wiggins (19921 and Miller (1992) have provided excellent and more detailed descriptions of these and other myelin models. 6.4. Metabolic

Disorders

Many models exist for a wide variety of metabolic disorders, and are too numerous to present here in their entirety. That being said, interesting and well-documented models are present in the literature for disorders including various vitamin deficiencies,

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(vitamins B,, and E; thiamine deficiency syndromes such as beriberi, Wernicke-Korsakoff syndrome, and alcoholic neuropathies), pyrrdoxine and niacin deficiencies; systemic disorders including hepatrc encephalopathy, Reye’s syndrome, and inherited metabolic defects such as Leigh’s disease, Wilson’s disease, the hyperammonemias, porphyria, and Menkes’s disease. There are a published protocols to model each of these disorders. This list is by no means exhaustive, but is presented to provide an idea of the vast number of metabolically induced cerebral insults. For investigators interested in this area, a description of the pathology associated with each of the above disorders included with the animal models used may be found m separate chapters of Neuvomethods volumes 21 and 22.

7. Summary The purpose of this chapter was to provide a brief description of the most intensely studied neurological disorders and their current animal models. Wherever possible, additional references that expand on these topics have been provided to assist investigators in their endeavors. Whatever the disease process studied, certain considerations are common to all; selection of the most appropriate model given the goals of the study, ethical concerns in terms of minimizing the pain and suffering and the number animals used, and employing the appropriate controls to allow for definitive results. Although studying an animal model is often rife with difficulties, it remains a necessary means for investigations leading to the understanding, prevention, and treatment of neurological diseases.

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Neurochetn 49,846-851 Wenk, G L (1992) Animal models of Alzhermer’s disease, m Neuromethods vol 21 Antmal ModelsqfNeurologrca1Dtsease,I (Boulton, A A , Baker, G B , and Butterworth, R F., eds.) Humana, Clifton, NJ, pp. 29-63 Wrederholt, W C (1995) Neurology for Non-Neurologzsts,3rd ed Saunders, Phrladephra