Responding for brain stimulation: Stress and desmethylimipramine

1. Stressors influence the activity of biogenic amines and provoke a variety of behavioral disturbances which have been considered as models of human depression.

2. To evaluate the effects of Stressors on reward processes, responding for electrical brain stimulation was assessed after acute or chronic shock, and the modification of performance by desmethylimipramine was determined.

3. While escapable shock did not affect performance, inescapable shock reduced responding from the nucleus accumbens and medial forebrain bundle, but not from the substantia nigra. These deficits were were antagonized by repeated Stressor application or by desmethylimipramine.

4. Uncontrollable Stressors may influence motivational processes subserved by some brain regions, and may thus influence affective state. Chronic stress or desmethylimipramine may Induce adaptive neurochemical changes, thereby preventing the behavioral disturbances otherwise produced by Stressors.     

Efferent connections of the basal forebrain in the cat: the nucleus accumbens.

The efferent connections of the nucleus accumbens in the cat were studied with radioautographic methods. Injections of [³H]leucine were placed throughout the extent of this structure in adult cats. The results revealed the presence of a topographical organization of the projections from the nucleus accumbens to the brain stem. Fibers arising from the dorsomedial sector of the nucleus accumbens project through the medial aspect of the medial forebrain bundle to the rostral end of the ventral tegmental area. Fibers arising from the ventromedial sector of the nucleus accumbens project to slightly more caudal and lateral parts of the ventral tegmentum. In contrast, fibers which arise from lateral parts of the nucleus accumbens project through the lateral aspect of the medial forebrain bundle and medial tip of the internal capsule to terminate primarily within the pars reticulata of the substantia nigra and central tegmental field. The data also suggest that fibers from this part of the nucleus accumbens probably terminate within the dorsolateral aspect of the substantia innominata and adjacent parts of the pallidum. These findings indicate that the nucleus accumbens is linked to both the limbic system and the basal ganglia.     

Evaluation of stressor effects on intracranial self-stimulation from the nucleus accumbens and the substantia nigra in a current intensity paradigm

The effect of uncontrollable footshock was evaluated in animals responding for intracranial self-stimulation from the nucleus accumbens and the substantia nigra (pars compacta) in a descending current intensity paradigm. Responding for brain stimulation from the nucleus accumbens was found to be affected by the stressor at the upper end of the rate-intensity curve. In contrast, responding for brain stimulation from the substantia nigra was unaffected by the stressor at any of the current intensities employed. The variations of responding for self-stimulation from the nucleus accumbens were unrelated to alterations of locomotor activity or rearing. It is suggested that stressor-provoked reductions of responding for intracranial self-stimulation are not a result of the brain stimulation taking on aversive properties, but rather reflect a reduction in the reinforcing or motivational value associated with the stimulation.     

Persistence of the releasable pool of CCK in the rat nucleus accumbens and caudate-putamen following lesions of the midbrain

Previous studies have identified populations of dopamine neurons in the midbrain that colocalize cholecystokinin some of which project to the nucleus accumbens and caudate-putamen. The contribution of dopamine-colocalized peptide to the total releasable pool of cholecystokinin in these brain regions was investigated using microdialysis. Dopamine, dihydroxyphenylacetic acid and cholecystokinin immunoreactive levels in dialysates of the posterior medial nucleus accumbens and medial caudate-putamen were determined following 6-hydroxydopamine lesions of the ventral tegmental area and substantia nigra or transection of the medial forebrain bundle. An 89–99% depletion in basal extracellular dihydroxyphenylacetic acid and an 87–99% decrease in veratridine-evoked extracellular dopamine levels was observed in the nucleus accumbens and caudate-putamen, 4 weeks after 6-hydroxydopamine lesion. No statistically significant difference was observed between lesioned and control animals in the basal or veratridine-evoked extracellular level of cholecystokinin immunoreactivity in either region. Similarly, transection of the medial forebrain bundle failed to significantly deplete the releasable pool of cholecystokinin immunoreactivity in the nucleus accumbens or caudate nucleus despite 89–99% depletions of dopamine and its metabolite. These data suggest that midbrain dopamine or non-dopaminergic cells are not the primary source of releasable cholecystokinin in the posterior medial nucleus accumbens and medial caudate-putamen measured by microdialysis.     

Distribution of glutamate decarboxylase in discrete brain nuclei.

The L-glutamate decarboxylase (GAD) levels of 70 rat brain nuclei were determined. The distribution of GAD is uneven. High AAD activity was found in the substantia nigra, the colliculi, some hypothalamic nuclei (e.g. dorsomedial) some nuclei of the limbic system (e.g. tractus diagonalis and accumbens) and the medial forebrain bundle. The reticular part of the substantia nigra had the highest activity, two-fold higher than any other nucleus. Low GAD activity was found in the nuclei of the pons, the hypothalamic median eminence and the reticular formation. Moderate activity was measured in most areas studied. The biochemical mapping of GAD is discussed in relation to possible GABA pathways in the brain.     

Autoradiographic evidence for nicotine receptors on nigrostriatal and mesolimbic dopaminergic neurons

Rats received unilateral injections of 6-hydroxydopamine into the medial forebrain bundle, resulting in an ipsilateral loss of striatal dopamine and of dopaminergic perikarya. A concimitant reduction of displaceable tritiated nicotine binding was observed autoradiographically in the ipsilateral substantia nigra, ventral tegmental area, striatum, nucleus accumbens, and olfactory tubercle. Thus, nicotine receptors appear to be located on nigrostriatal and mesolimbic dopaminergic neurons at the level of perikarya and terminals.     

Fiber degeneration associated with hyperphagia-inducing knife cuts in the hypothalamus

The pattern of axonal degeneration associated with hyperphagia-producing hypothalamic knife transections was investigated using the Fink-Heimer method for staining of degenerating axons and their terminal endings. Histological analysis of silver-stained material after parasagittal knife cuts which result in hyperphagia and obesity revealed fiber degeneration coursing longitudinally in the medial forebrain bundle including the perifornical component to reach the nucleus accumbens, the diagonal band, the preoptic-anterior hypothalamic junction, the lateral hypothalamus, the zona incerta, the periventricular thalamus, the parafascicular thalamic nucleus, the substantia nigra pars compacta, the central gray matter, the ventral tegmental area of T'sai and the superior colliculus. The data obtained in the present study lend support to the suggestion that projections coursing in the medial forebrain bundle interconnect the anteriomedial hypothalamus and the midbrain tegmentum and may underlie the hyperphagia and obesity produced by hypothalamic knife cuts.     

Efferent connections of the striatum and the nucleus accumbens in the lizard Gekko gecko

The efferent connections of the striatum and the nucleus accumbens of the lizard Gekko gecko were studied with the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L). These structures were found to have segregated output systems. The striatum shows a major projection to the globus pallidus. Striatal fibers which are more caudally directed run through the lateral forebrain bundle and can be traced as far caudally as the pars reticularis of the substantia nigra where they exhibit many varicosities. Along its course, the lateral forebrain bundle issues fibers with varicosities to the anterior and posterior entopeduncular nuclei. The major recipient structure of the nucleus accumbens is the ventral pallidum. The nucleus accumbens, in addition, projects to the portion of the lateral hypothalamus in the path of the medial forebrain bundle and to the ventral tegmental area, which is its most caudal target. Subsequently, the same technique was used in an attempt to study the efferents of the globus pallidus and the ventral pallidum, the major recipient structures of the striatum and the nucleus accumbens. The globus pallidus was found to project to the rostral part of the suprapeduncular nucleus in the ventral thalamus and, in addition, may distribute fibers to the same structures as does the striatum. The ventral pallidum distributes fibers to the ventromedial thalamic nucleus. It probably also projects diffusely to the hypothalamus, the habenula, and the mesencephalic tegmentum.     

Dopaminergic neurons: simultaneous measurements of dopamine release and single-unit activity during stimulation of the medial forebrain bundle

Simultaneous electrical and chemical recordings have been made of dopamine neuronal activity in the rat brain during electrical stimulation of the medial forebrain bundle. Tungsten recording electrodes were placed at the level of the substantia nigra and carbon-fiber, Nafion-coated, voltammetric electrodes were placed in the neostriatum. Dopamine units, verified by histology to be in the zona compacta of the substantia nigra, were identified by previously established electrophysiological criteria. Dopamine release was detected by fast-scan cyclic voltammetry, a technique which allows dopamine to be determined in vivo on a sub-second time scale. The majority of dopamine cells examined (7 out of 10) were antidromically activated by 60 Hz stimulation of the medial forebrain bundle. The same stimulus also elicits dopamine overflow in the caudate nucleus. Following stimulation, dopamine concentrations in the extracellular fluid of the neostriatum rapidly declined to prestimulus levels. In addition, impulse flow in dopaminergic neurons was inhibited for 20 s following stimulation. These measurements represent the first direct observation from a neuronal tract of simultaneous unit activity and chemical release of a neurotransmitter in real time.     

Expression and distribution of CYP2C enzymes in rat basal ganglia

The function and integrity of the basal ganglia is modulated by sex steroids whose activity may be controlled by P450 enzymes, such as members of the CYP2C subfamily. The expression of CYP2C enzymes in rat basal ganglia was examined by immunohistochemistry along with some of the factors that might control their expression. Whereas no CYP2C11 or CYP2C12 immunoreactivity was detected in the basal ganglia of either male or female rats, marked CYP2C13 immunoreactivity was evident in neurones of the subthalamic nucleus, substantia nigra, and interpeduncular nucleus. Strong CYP2C13 immunoreactivity was also expressed in the cortex, olfactory tubercle, hippocampus, dentate gyrus, hypothalamic nuclei, medial habenular nucleus, red nucleus, and medial forebrain bundle. Similar results were found in male and female rats. Following 6-hydroxydopamine lesioning of the nigro-striatal tract, tyrosine hydroxylase immunoreactivity was absent and CYP2C13 immunoreactivity was decreased markedly in the substantia nigra pars compacta, implying its presence in dopaminergic neurones. Modulation of sex steroids, using castrated rats, had no effect on the number of CYP2C13 positive neurones in the substantia nigra pars compacta. These results indicate that CYP2C13 protein is constitutively and widely expressed in rat brain. However, its expression is not sex-specific and is unaffected by castration. The role of CYP2C13 in brain is unknown but it may be involved in the generation of neurosteroids and catecholoestrogens.     

Biochemical mapping of the noradrenergic ventral bundle projection sites: Evidence for a noradrenergic-dopaminergic interaction

Norepinephrine (NE) and dopamine (DA) concentration and dopamine turnover were measured 12 days after a unilateral or bilateral noradrenergic ventral bundle (VB) transection to determine the noradrenergic projection sites and possible interactions with dopaminergic systems.Both bilateral and unilateral VB transection resulted in a significant reduction of NE of the nucleus accumbens, lateral septal nucleus, medial forebrain bundle, ventromedial nucleus, dorsomedial nucleus and medial amygdaloid nucleus. Bilateral transection also decreased NE content of the median eminence and the periventricular and arcuate nuclei. In the medial preoptic nucleus, the nucleus interstitialis striae terminalis and the central gray catecholamine area, bilateral transection significantly decreased NE concentrations while unilateral lesions had no significant effect. The anterior hypothalamic, lateral preoptic, and paraventricular nuclei responded to bilateral VB transection with a decrease in NE concentration and to unilateral lesion with a bilateral increase in NE. In the dorsal hippocampus and the caudate nucleus, bilateral lesions had no effect on NE concentrations while unilateral transection significantly decreased NE concentrations. Regions in which neither bilateral nor unilateral VB transection produced a significant change in NE content are the olfactory tubercle, the nucleus tractus diagonalis, substantia nigra pars compacta and reticulata, ventral tegmental area, habenula, superior colliculus, and the cingulate and piriform cortices.Transection of the noradrenergic ventral bundle also produced changes in dopaminergic systems suggesting a noradrenergic-dopaminergic interaction. Bilateral VB transection decreased the dopamine concentration and turnover in the nucleus accumbens, increased steady-state levels and turnover in the nucleus tractus diagonalis and increased dopamine concentration in the lateral septum. Unilateral VB transection decreased DA concentration bilaterally in the caudate nucleus, olfactory tubercle, nucleus accumbens and the nucleus interstitialis striae terminalis but increased concentrations in the substantia nigra pars reticulata (ipsilateral) and in the ventral tegmental area (bilateral). These results indicate a broad projection field for the noradrenergic ventral bundle and suggest a noradrenergic-dopaminergic interaction.     

Somatostatin in catecholamine-rich nuclei of the brainstem

Somatostatin (SRIF) concentrations in catecholamine-rich nuclei of the rat brainstem were measured by radioimmunoassay. The study was performed both in control or sham operated animals and after transecting the major projections of hypothalamic SRIF-containing neurons. Concentrations of the peptide were found to be relatively high in the locus coeruleus, the parabrachial nucleus and the nucleus of the solitary tract; they were intermediate in the lateral reticular nucleus (A1 cell group) and low in the substantia nigra. Transection of hypothalamic periventricular efferents resulted in a 58% depletion of SRIF content in the locus coeruleus, while concentrations of the peptide in other areas were unaffected. Transection of the medial forebrain bundle at the level of the lateral hypothalamus decreased SRIF content by 55% in the substantia nigra, but not in the other nuclei tested. It is concluded that the hypothalamus contributes significantly to the somatostatinergic innervation of the locus coeruleus and the substantia nigra, whereas SRIF in the other nuclei is intrinsic or originates outside the hypothalamus.     

Distribution of phenylethanolamine-N-methyltransferase-immunoreactive perikarya and fibers in the brain of the lizard Gekko gecko

The distribution of phenylethanolamine N-methyltransferase (PNMT)-immunoreactive (PNMTi) cell bodies and fibers in the brain of the lizard Gekko gecko was studied by antibodies raised in rabbits against purified bovine adrenal PNMT. The PNMTi cell bodies were observed in the ventrolateral rhombencephalic tegmentum at the level of the obex. No immunoreactive perikarya were found in the nucleus of the solitary tract, the medial longitudinal fascicle or the hypothalamus. An extensive network of PNMTi fibers is present throughout the brain, extending rostrally as far as the olfactory peduncle. In the telecenphalon, moderate to dense plexuses of PNMTi fibers were observed in the medial part of the nucleus accumbens, the medial septal nucleus, the nucleus of the diagonal band, the caudoventral septal region and the central amygdaloid nucleus. In the diencephalon, the periventricular and lateral zones of the preoptic and hypothalamic areas, the medial forebrain bundle and the dorsomedial thalamic nucleus contain many PNMTi fibers. Brainstem structures innervated by PNMTi fibers are the ventral tegmental area, the substantia nigra, the periaqueductal gray, the locus coeruleus, the parabrachial region, the nucleus of the solitary tract, the dorsal motor nucleus of the vagus and the ventrolateral region of the caudal brainstem. Although the brain of Gekko appears to lack PNMTi cells in areas comparable to the C2 and C3 cell groups in rats, the distribution of PNMTi fibers is nevertheless strikingly similar in both groups.     

Forebrain projections from cholecystokininlike-immunoreactive neurons in the rat midbrain

The purpose of the present study was to analyze the distribution of cholecystokininlike-immunoreactive (CCK-I) neurons within the rat ventral mesencephalon which project to several forebrain areas. The peroxidase-antiperoxidase immunocytochemical technique was used to examine the anatomical localization of CCK-I within the ventral midbrain and in the following forebrain regions: caudate-putamen, nucleus accumbens, olfactory tubercle, bed nucleus of the stria terminalis, septum, amygdala, and prefrontal, anterior cingulate, and piriform cortices. CCK-I perikarya were distributed throughout the substantia nigra, ventral tegmental area, and several midline raphe nuclei to a greater extent than previously reported, particularly in the substantia nigra pars compacta. Terminallike immunoreactivity for CCK was observed in all of the above forebrain sites. In addition, infrequent CCK-I cell bodies were localized in the caudate-putamen, nucleus accumbens, olfactory tubercle, septum, and bed nucleus of the stria terminalis. To analyze forebrain projections of the ventral midbrain CCK-I neurons, indirect immunofluorescence was combined with fluorescence retrograde tracing. CCK-I neurons of the substantia nigra and/or ventral tegmental area were found to project, to varying extents, to all of the above CCK-I forebrain terminal fields. The nucleus accumbens, olfactory tubercle, and septal and prefrontal cortical projections arose primarily from CCK-I perikarya in the ventral tegmental area whereas the projections to the caudate-putamen and anterior cingulate cortex arose predominantly from immunoreactive neurons in the substantia nigra pars compacta. The amygdala received innervation mainly from CCK-I cell bodies located in the substantia nigra pars lateralis. CCK-I afferents to the bed nucleus of the stria terminalis and piriform cortex originated from perikarya distributed approximately equally across the ventral tegmental area and substantia nigra pars compacta. The general topography of CCK-I forebrain innervation observed in this study is similar to that previously reported for the ascending dopaminergic projections from ventral mesencephalic neurons. CCK-I neurons of the midline raphe nuclei were found to provide relatively minor afferents to the caudate-putamen, bed nucleus of the stria terminalis, septum, and prefrontal cortex and more substantial projections to the amygdala. The results of this study demonstrate that CCK-I neurons of the ventral midbrain supply a much broader innervation of forebrain regions than previously appreciated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Distribution of cytochrome oxidase in response to rewarding brain stimulation: Effect of different pulse durations

Cytochrome oxidase histochemistry was used to evaluate neuronal changes in oxidative metabolism in response to rewarding brain stimulation of the medial forebrain bundle. Rats with single lateral hypothalamic electrodes self-stimulated daily for ten days for trains of either 0.1 or 2.0 ms pulses that corresponded to about 75% of maximum responding. Quantitative comparison of stimulated-to-unstimulated sides revealed differences in relative optical density in few structures, notably in the lateral septal nucleus and the nucleus accumbens, when the brief pulse duration was used. In contrast, the longer pulse duration gave rise to metabolic increases in several dopaminergic projections, including the frontal cortex, olfactory tubercle, and lateral habenula, and also enhanced activity in the lateral septal nucleus. These data suggest that mesocorticolimbic structures may be implicated in medial forebrain bundle self-stimulation.     

Spatial relationship of the striatonigral and mesostriatal pathways: double-label immunocytochemistry for DARPP-32 and tyrosine hydroxylase

Antibodies to tyrosine hydroxylase and DARPP-32 were used to examine the spatial arrangement between mesostriatal dopamine projections and the reciprocal pathway from DARPP-32-containing neurons in the basal forebrain. Use of a double-labeling immunocytochemical procedure demonstrated that the mesostriatal and striatonigral pathways run in close proximity throughout the rostral mesencephalon and basal forebrain. The majority of descending axons immunoreactive for DARPP-32 appear to originate in the striatum, including the nucleus accumbens, and run through the internal capsule to innervate the globus pallidus, entopeduncular nucleus, and all subdivisions of the substantia nigra. The ventral tegmental area is sparsely invested with DARPP-32-immunoreactive axons. At all levels, there are also fascicles of DARPP-32-containing fibers which run ventromedial to the internal capsule in the medial forebrain bundle, and which are coextensive with ascending axons of the mesencephalic dopamine the internal capsule in the medial forebrain bundle, and which are coextensive with ascending axons of the mesencephalic dopamine cell groups. Tyrosine hydroxylase-immunoreactive axons are coextensive with DARPP-32-immunoreactive axons in the internal capsule entopeduncular nucleus, and globus pallidus, as well as much of the remainder of the basal forebrain. Although the main source of descending DARPP-32 immunoreactive axons would appear to be the striatum, other possible sources are also discussed.     

On the origin of dynorphin A and alpha-neo-endorphin in the substantia nigra

The substantia nigra contains among the highest dynorphin A (Dyn A) and alpha-neo-endorphin (alpha-Neo) concentrations in the central nervous system. No dynorphin positive cell bodies are found there, only a dense network of nerve fibers and terminals. The present study provides evidence that the Dyn A and alpha-Neo in the substantia nigra are in neural processes arising from cells located in the head of the caudate nucleus. This neuronal system has been characterized by assaying Dyn A and alpha-Neo in the substantia nigra after a number of surgical transections of neuronal pathways in the rat forebrain and midbrain. Fibers containing dynorphins and neo-endorphins seem to pass through the internal capsule, ansa lenticularis, and medial forebrain bundle on their way from the striatum to the substantia nigra.     

Dopamine and norepinephrine levels in the nucleus accumbens, olfactory tubercle and corpus striatum following lesions in the ventral tegmentalarea.

Dopamine and norepinephrine levels were examined in 3 forebrain regions following unilateral lesions either in the ventral medial tegmental area (VMT) or in the substantia nigra. The dopamine and norepinephrine content of the nucleus accumbens, olfactory tubercle and corpus striatum were assayed ipsilaterally and contralaterally in unilaterally lesioned rats sacrificed 2, 5, 10, and 20 days after the placement of the lesions. In the nucleus accumbens and olfactory tubercle ipsilateral dopamine levels were significantly reduced below the contralateral levels at 2 days, and were decreased by 56% and 65%, respectively, 10 days after the lesion. A 30% reduction of dopamine levels occurred in corpus striatum as well, following lesions in the VMT. Lesions in the substantia nigra decreased ipsilateral dopamine levels by 68% in the corpus striatum, without affecting dopamine levels in the olfactory tubercle or nucleus accumbens. Norepinephrine levels on the side ipsilateral to the lesion did not significantly differ from contralateral levels in any of the 3 regions following lesions either in the VMT or in the substantia nigra. These results demonstrate the specificity of projection in the mesolimbic dopamine system as suggested by the original histofluorescence studies.     

Fos expression following self-stimulation of the medial prefrontal cortex

Self-stimulation of the medial prefrontal cortex and medial forebrain bundle appears to be mediated by different directly activated fibers. However, reward signals from the medial prefrontal cortex do summate with signals from the medial forebrain bundle, suggesting some overlap in the underlying neural circuitry. We have previously used Fos immunohistochemistry to visualize neurons activated by rewarding stimulation of the medial forebrain bundle. In this study, we assessed Fos immunolabeling after self-stimulation of the medial prefrontal cortex. Among the structures showing a greater density of labeled neurons in the stimulated hemisphere were the prelimbic and cingulate cortex, nucleus accumbens, lateral preoptic area, substantia innominata, lateral hypothalamus, anterior ventral tegmental area, and pontine nuclei. Surprisingly, little or no labeling was seen in the mediodorsal thalamic nucleus or the locus coeruleus. Double immunohistochemistry for tyrosine hydroxylase and Fos showed that within the ventral tegmental area, a substantial proportion of dopaminergic neurons did not express Fos. Despite previous suggestions to the contrary, comparison of the present findings with those of our previous Fos studies reveals a number of structures activated by rewarding stimulation of both the medial prefrontal cortex and the medial forebrain bundle. Some subset of activated cells in the common regions showing Fos-like immunoreactivity may contribute to the rewarding effect produced by stimulating either site.     

Cholinergic innervation of the human striatum, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus.

The anatomical organization of cholinergic markers such as acetylcholinesterase, choline acetyltransferase, and nerve growth factor receptors was investigated in the basal ganglia of the human brain. The distribution of choline acetyltransferase-immunoreactive axons and varicosities and their relationship to regional perikarya showed that the caudate, putamen, nucleus accumbens, olfactory tubercle, globus pallidus, substantia nigra, red nucleus, and subthalamic nucleus of the human brain receive widespread cholinergic innervation. Components of the striatum (i.e., the putamen, caudate, olfactory tubercle, and nucleus accumbens) displayed the highest density of cholinergic varicosities. The next highest density of cholinergic innervation was detected in the red nucleus and subthalamic nucleus. The level of cholinergic innervation was of intermediate density in the globus pallidus and the ventral tegmental area and low in the pars compacta of the substantia nigra. Immunoreactivity for nerve growth factor receptors (NGFr) was confined to the cholinergic neurons of the basal forebrain and their processes. Axonal immunoreactivity for NGFr was therefore used as a marker for cholinergic projections originating from the basal forebrain (Woolf et al., '89: Neuroscience 30:143-152). Although the vast majority of striatal cholinergic innervation was NGFr-negative and, therefore, intrinsic, the striatum also contained NGFr-positive axons, indicating the existence of an additional cholinergic input from the basal forebrain. This basal forebrain cholinergic innervation was more pronounced in the putamen than in the caudate. The distribution of NGFr-positive axons suggested that the basal forebrain may also project to the globus pallidus but probably not to the subthalamic nucleus, substantia nigra, or red nucleus. The great majority of cholinergic innervation to these latter three structures and to parts of the globus pallidus appeared to come from cholinergic neurons outside the basal forebrain, most of which are probably located in the upper brainstem. These observations indicate that cholinergic neurotransmission originating from multiple sources is likely to play an important role in the diverse motor and behavioral affiliations that have been attributed to the human basal ganglia.