Pigeon basal ganglia: insights into the neuroanatomy underlying telencephalic sensorimotor processes in birds

This paper reviews the organization of the avian and mammalian striatum. The striatum receives input from virtually the entire rostrocaudal and mediolateral expanse of the cerebral cortex. The corticostriatal projections appear to be glutamatergic, forming excitatory synapses in the striatum. Another major projection to the avian striatum that also appears to be glutamatergic stems from a set of nuclei in the dorsal zone of the avian thalamus that are comparable to the mammalian intralaminar, mediodorsal, and midline nuclei. Furthermore, the striatum receives a massive projection from dopaminergic neurons of the ventral tegmental area and substantia nigra in the midbrain tegmentum. In return, the midbrain tegmentum receives a direct GABAergic/substance P-ergic/ dynorphinergic projection from the striatum, as well as an indirect one formed by GABAergic/substance P-ergic/ dynorphinergic and GABA-ergic/enkephalinergic striatal neurons projecting to the pallidum in the first step, and pallidal GABAergic/LANT6/parvalbumin neurons projecting to the midbrain tegmentum in the second step. In addition to its projection neurons, the striatum possesses GABAergic and cholinergic interneurons. One motor output pathway of the striatum runs via the pallidum and dorsal thalamic ventral tier nulei to the motor cortex. In addition to this pathway, birds possess a major descending pathway from the basal ganglia to the tectum via the GABAergic nucleus spiriformis lateralis in the pretectum. On hodological and topological grounds, similar nuclei, although not GABAergic, can be found in mammals. Finally, an other striatal motor output is formed by a sequential GABAergic pathway from the basal ganglia via the substantia nigra to the tectum. In conclusion, it appears that the organization of the avian and mammalian basal ganglia is similar rather than different.     

Role of the subthalamo-nigral input in the control of amygdala-kindled seizures in the rat

The substantia nigra pars reticulata (SNpr) is a critical site for the control of epileptic seizures. Potentiation of the inhibitory GABAergic input from the striatum to the SNpr suppresses primary or secondary generalized seizures in the rat. The purpose of this study was to examine the possible involvement of the excitatory glutamatergic input from the subthalamic nucleus to the SNpr in the control of both the electroencephalographic and the motor components of amygdala-kindled seizures in the rat. Microinjections of either an N-methyl-D-aspartate (NMDA) antagonist in the substantia nigra or a GABAA agonist in the subthalamic nucleus, significantly reduced motor seizures but did not modified the afterdischarges. These results provide evidence for the involvement of the subthalamo-nigral projection in the modulation and the propagation of the motor components of amygdala-kindled seizures.     

Involvement of basal ganglia transmitter systems in movement initiation

The basal ganglia have been implicated in a number of important motor functions, in particular in the initiation of motor responses. According to the current model of basal ganglia functions, motor initiation is supposed to be associated with an inhibition of basal ganglia output structures (substantia nigra pars reticulata/entopeduncular nucleus) which, in turn, might be brought about by corresponding striatal activity changes conveyed via direct and indirect intrinsic pathways to the substantia nigra pars reticulata and the entopeduncular nucleus. Rodent studies using neuropharmacological manipulations of basal ganglia transmitter systems by neurotoxins or drugs provide converging evidence that dopamine within the caudate-putamen, but also within extrastriatal basal ganglia nuclei, is involved in motor initiation by modulating the activity of direct and indirect intrinsic pathways. However, the striatal segregation of dopamine D1 and D2 receptors in control of the direct and indirect projection neurons seems not to be maintained throughout the basal ganglia. In dopamine intact animals, striatal glutamate plays a major role in response initiation probably through actions on striatopallidal neurons involving N-methyl-D-aspartate, but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. Striatal adenosine might also contribute to movement initiation by acting on adenosine A2A receptors located on striatopallidal neurons. Analysis of two integral parts of the indirect pathway revealed that inactivation of the subthalamic nucleus was found to facilitate response initiation, while inactivation of the globus pallidus resulted in facilitation as well as inhibition of response initiation indicating a complex contribution of this latter nucleus. Glutamate and gamma-amino-butyric acid (GABA) controlling the activity of the substantia nigra pars reticulata could be involved in control of response initiation in a way predicted by the simplified model of basal ganglia functions. In contrast, the role of the entopeduncular nucleus in response initiation and its control through GABA and glutamate is at variance with this hypothesis, suggesting functional differences of the output structures. Taken together, neurochemical systems of the basal ganglia significantly contribute to intact response initiation by mechanisms which are only partly consistent with predictions of the current functional scheme of the basal ganglia. This suggests that a more complex model is required to account for these disparate findings.     

Localization of serotonin-4 receptors in the striatonigral pathway in rat brain

Rats were injected unilaterally with 6-hydroxydopamine either in the medial forebrain bundle or in the dorsolateral substantia nigra. Another group was injected unilaterally with kainate in the striatum. The loss of neurons was assessed by a reduction in tyrosine hydroxylase-like immunoreactivity for dopaminergic neurons, and choline acetyltransferase-like and glutamate decarboxylase-like immunoreactivities for cholinergic and GABAergic neurons, respectively. Brain sections also were analysed by autoradiography on 20 micron sections with the radio-iodinated serotonin-4 receptor antagonist [125I]SB 207710 [Brown A. M. et al. (1993) Br. J. Pharmac. 110, 10P]. Kainate injections in the striatum resulted in loss of choline acetyltransferase- and glutamate decarboxylase-like immunoreactive cell bodies in this area. There was also a decrease in glutamate decarboxylase-like immunoreactivity on the ipsilateral side in the substantia nigra and entopeduncular nucleus. These changes were accompanied by substantial (> 50%) decreases in [125I]SB 207710 binding in both the ipsilateral striatum (confined to the lesioned area) and substantia nigra, with no change in either the nucleus accumbens or the globus pallidus. There was also significant loss of [125I]SB 207710 binding in the ipsilateral entopeduncular nucleus. 6-Hydroxydopamine lesions placed either in the medial forebrain bundle or in the substantia nigra failed to decrease [125I]SB 207710 binding in any of these areas, although there was total loss of tyrosine hydroxylase-like immunoreactive terminals in the striatum and cell bodies in the nigra. We conclude that serotonin-4 receptors are present on projection neurons, both on their perikarya in the striatum and terminals in the nigra and entopeduncular nucleus. It is likely that these receptors are located on the GABAergic projection neurons and possibly on cholinergic and GABAergic interneurons. However, serotonin-4 receptors are not located on dopaminergic neurons, either on their cell bodies in the substantia nigra or terminals in the striatum.     

Sex and the substantia nigra: administration, teaching, patient care, and research

The immature brain is most susceptible to the development of seizures. The substantia nigra may play a crucial role in the control of seizures as a function of age. In the adult substantia nigra pars reticulata (SNR), there are two regions that mediate opposing effects on seizures after infusions of GABA(A) agents. One region is located in the anterior SNR, and localized muscimol infusions mediate anticonvulsant effects. These anticonvulsant effects use a circuitry that may involve the ventromedial thalamic nucleus, the deep layer of the superior colliculus, or both. The second region is in the posterior SNR, and muscimol infusions produce proconvulsant effects, perhaps mediated by the striatum, the globus pallidus, the deep layer of the superior colliculus, or all three. In developing male rats, only the proconvulsant region is present up to the age of 21 days. In ongoing studies, it has been shown that, in the male rat, the transition from the immature to mature SNR-mediated seizure control occurs between the ages of 25 and 30 days, just before adolescence. In male rats castrated on the day of birth, the ensuing depletion of testosterone accelerates the development of the anterior SNR with its anticonvulsant features. Castration does not alter the development of the proconvulsant region. In the developing female SNR, muscimol infusions produce only anticonvulsant effects. The data indicate that gonadal hormones may have an important role in the maturation of systems involved in the containment of seizures.     

Systemic morphine-induced Fos protein in the rat striatum and nucleus accumbens is regulated by mu opioid receptors in the substantia nigra and ventral tegmental area

To characterize how systemic morphine induces Fos protein in dorsomedial striatum and nucleus accumbens (NAc), we examined the role of receptors in striatum, substantia nigra (SN), and ventral tegmental area (VTA). Morphine injected into medial SN or into VTA of awake rats induced Fos in neurons in ipsilateral dorsomedial striatum and NAc. Morphine injected into lateral SN induced Fos in dorsolateral striatum and globus pallidus. The morphine infusions produced contralateral turning that was most prominent after lateral SN injections. Intranigral injections of [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), a mu opioid receptor agonist, and of bicuculline, a GABAA receptor antagonist, induced Fos in ipsilateral striatum. Fos induction in dorsomedial striatum produced by systemic administration of morphine was blocked by (1) SN and VTA injections of the mu1 opioid antagonist naloxonazine and (2) striatal injections of either MK 801, an NMDA glutamate receptor antagonist, or SCH 23390, a D1 dopamine receptor antagonist. Fos induction in dorsomedial striatum and NAc after systemic administration of morphine seems to be mediated by dopamine neurons in medial SN and VTA that project to medial striatum and NAc, respectively. Systemic morphine is proposed to act on mu opioid receptors located on GABAergic interneurons in medial SN and VTA. Inhibition of these GABA interneurons disinhibits medial SN and VTA dopamine neurons, producing dopamine release in medial striatum and NAc. This activates D1 dopamine receptors and coupled with the coactivation of NMDA receptors possibly from cortical glutamate input induces Fos in striatal and NAc neurons. The modulation of target gene expression by Fos could influence addictive behavioral responses to opiates.     

The activation of cannabinoid receptors in striatonigral GABAergic neurons inhibited GABA uptake

Cannabinoid receptors (CNRs) in basal ganglia are located on striatal efferent neurons which are gamma-aminobutiric acid (GABA)-containing neurons. Recently, we have demonstrated that CN-induced motor inhibition is reversed by GABA-B, but not GABA-A, receptor antagonists, presumably indicating that the activation of CNRs in striatal outflow nuclei, mainly in the substantia nigra, should be followed by an increase of GABA concentrations into the synaptic cleft of GABA-B receptor synapses. The present study was designed to examine whether this was originated by increasing GABA synthesis and/or release or by decreasing GABA uptake. We analyzed: (i) GABA synthesis, by measuring the activity of glutamic acid decarboxylase (GAD) and GABA contents in brain regions that contain striatonigral GABAergic neurons, after in vivo administration of CNs and/or the CNR antagonist SR141716; (ii) [3H]GABA release in vitro in the presence or the absence of a synthetic CN agonist, HU-210, by using perifusion of small fragments of substantia nigra; and (iii) [3H]GABA uptake in vitro in the presence or the absence of WIN-55,212-2, by using synaptosomes obtained from either globus pallidus or substantia nigra. Results were as follows. Delta9-tetrahydrocannabinol (delta9-THC) and HU-210, did not alter neither GAD activity nor GABA contents in both the striatum and the ventral midbrain at any of the two times tested, thus suggesting that CNs apparently failed to change GABA synthesis in striatonigral GABAergic neurons. A similar lack of effect of HU-210 on in vitro [3H]GABA release, both basal and K+-evoked, was seen when this CN was added to perifused substantia nigra fragments, also suggesting no changes at the level of GABA release. However, when synaptosome preparations obtained from the substantia nigra were incubated in the presence of WIN-55,212-2, a decrease in [3H]GABA uptake could be measured. This lowering effect was specific of striatonigral GABAergic neurons since it was not observed in synaptosome preparations obtained from the globus pallidus. In summary, the activation of CNRs located on striatonigral GABAergic neurons, which primarily access to GABA-B receptor synapses, was accompanied by a reduction in neurotransmitter uptake, thus prolonging the presence of GABA into the synaptic cleft. This mechanism might underly the CN-induced motor inhibition through the potentiation of the inhibitory effect of GABA on neuronal activity, in particular of nigrostriatal dopaminergic neurons.     

Regulation of substantia nigra dopamine neurons

A substantial amount of research has focused on determining the factors that alter the activity of substantia nigra dopamine neurons. Much of this research has indicated that several mechanisms that regulate dopamine neuron activity have the capability to maintain the baseline activity of dopamine cells at a fairly constant rate. For example, the intrinsic membrane conductances present on dopamine neurons, which generate the spike activity of these cells, appear to maintain the activity of spontaneously active neurons and suppress the induction of activity in quiescent cells. In addition, dopamine cell activity can be regulated by afferent systems that appear to be capable of preventing dopamine neurons from displaying sustained variations in electrophysiological activity. Specifically, inputs from the striatum or from the subthalamic nucleus may each exert opposing influences on dopamine cell activity via direct vs. indirect afferent projection pathways. In addition, the dendritic release of dopamine may provide negative feedback; dopamine cell firing may increase the dendritic release of dopamine within the substantia nigra, providing a local feedback inhibition of dopamine neuron activity. Factors such as the intrinsic membrane properties, afferent input, and the dendritic release of dopamine all work together in a complex manner to regulate the activity level of dopamine neurons.     

Striatal dopamine-glutamate interactions reflected in substantia nigra reticulata firing

To gain insight into the role of striatal dopamine in basal ganglia functioning, dopaminergic drugs alone and in combination with the glutamate receptor agonist kainic acid were infused in the lateral striatum via a microdialysis probe, while single-unit recordings of substantia nigra reticulata neurons were made in chloral hydrate-anaesthetized rats. Striatal infusion of dopaminergic drugs did not significantly affect the firing rate of substantia nigra reticulata neurons, which was related to the low activity of striatal cells under basal conditions, illustrated by the lack of effect of striatal infusion of TTX on substantia nigra reticulata activity. Under glutamate-stimulated conditions, striatal infusion of d-amphetamine potentiated the inhibition of substantia nigra reticulata neurons induced by striatal kainic acid. Thus, under stimulated but not basal conditions, the modulatory role of dopamine in the striatum could be demonstrated. Dopamine potentiated the inhibitory effect of striatal kainic acid on the firing rate of the basal ganglia output neurons.     

Selection, optimization, and compensation as strategies of life management: correlations with subjective indicators of successful aging

To understand better how the brainstem may influence thalamocortical activity, we have examined the projection patterns of different brainstem nuclei to the thalamic reticular nucleus. Iontophoretic injections of biotinylated dextran were made into various nuclei of the brainstem (superior colliculus, periaqueductal grey matter, parabrachial nucleus, pedunculopontine tegmental nucleus, laterodorsal tegmental nucleus, substantia nigra, ventral tegmental area, and locus coeruleus) of Sprague-Dawley rats by using stereotaxic coordinates. Our results show that afferents from each brainstem nucleus make distinct zones within the reticular nucleus. For example, the superior colliculus projects largely to the dorsal parts of the reticular nucleus, whereas the pedunculopontine nucleus projects to the ventral parts of the reticular nucleus. The substantia nigra, on the other hand, projects to the ventrolateral edge of the reticular nucleus. We also examined the distribution of these brainstem afferents within the dorsal thalamus and compared these distributions with those seen in the reticular nucleus. We found three different patterns. First, a given brainstem nucleus projects to a particular dorsal thalamic nucleus as well as to the corresponding, functionally associated, reticular sector (e.g., from the substantia nigra). Second, a given brainstem nucleus projects to a particular dorsal thalamic nucleus but not to the corresponding reticular sector (e.g., from the superior colliculus). Finally, a given brainstem nucleus projects to a given reticular sector but not to the corresponding dorsal thalamic nucleus (e.g., from the midbrain reticular nucleus). In general, our results indicate that various brainstem nuclei project to particular territories of the thalamic reticular nucleus. Through these reticular projections, brainstem nuclei may influence distinct thalamocortical pathways in addition to those that are influenced by their direct projection to the dorsal thalamus.     

Occurrence of heat shock response in deafferented neurons in the substantia nigra of rats

The substantia nigra is innervated by massive inhibitory GABAergic projections from the striatum and globus pallidus, deafferentation of which is supposed to lead to anterograde trans-synaptic degeneration of the nigral neurons. An immunohistochemical method was used to examine the induction of 72,000 mol. wt heat shock protein in the substantia nigra following cerebral hemitransection or transient middle cerebral artery occlusion. At three and four days post-transection, strong immunoreactivity for 72,000 mol. wt heat shock protein was found in the ipsilateral substantia nigra pars reticulata. Light microscopic observation revealed a number of pars reticulata neurons showing strong immunoreactivity for 72,000 mol. wt heat shock protein in their perikarya and proximal processes. In addition, Golgi-like stained neurons with dystrophic features were occasionally observed in the ipsilateral substantia nigra pars reticulata. The immunoreactivity for 72,000 mol. wt heat shock protein in the ipsilateral pars reticulata gradually declined and almost disappeared by 15 days after transection. No apparent induction of 72,000 mol. wt heat shock protein was found in the substantia nigra pars compacta throughout the time period examined. Massive striatal ischemic injury produced by transient middle cerebral artery occlusion also induced expression of 72,000 mol. wt heat shock protein in the pars reticulata neurons three and four days postoperatively. These findings suggest that deafferentation of the striatal or striatopallidal inputs per se is a harmful stress for the substantia nigra pars reticulata neurons, inducing 72,000 mol. wt heat shock protein synthesis. The present data may contribute to our understanding of the molecular basis of the pathomechanism of the transneuronal regression of substantia nigra pars reticulata neurons, which may occur after removal of inhibitory GABAergic inputs.     

Significance of the paralemniscal tegmental area for audio-motor control in the moustached bat, Pteronotus p. parnellii: the afferent off efferent connections of the paralemniscal area

The paralemniscal tegmental area has been determined in the brain of the New World moustached bat, Pteronotus p. parnellii, by electrical microstimulation eliciting echolocation calls and pinna movements. It is located in the dorsal tegmentum rostral and medial to the dorsal nucleus of the lateral lemniscus and is characterized by medium sized and large neurons. Tracer injections (WGA-HRP) showed that the most intense input to the paralemniscal tegmental area originates in the intermediate and deep layers of the homolateral superior colliculus. The strong projections from the ipsi- and contralateral nucleus praepositus hypoglossus most probably contributes vestibular information. Further inputs in descending order of intensity are from the substantia nigra, the contralateral paralemniscal tegmental area, the putamen, the ventral reticular formation in its lateral portions, the medial cerebellar nucleus and the dorsal reticular formation. Efferent projections of the paralemniscal tegmental area reach the putamen bilaterally, the nucleus accumbens and other parts of the basal ganglia, the pretectal area, the substantia nigra, the intermediate and deep layers of the superior colliculus bilaterally and the tegmental area ventral to it. Connections to the dorsal part of the periaqueductal grey, the cuneiform nucleus and the parabrachial region are important in the context of vocal control, whereas projections to the medial portion of the contralateral facial nucleus may interfere with the control of pinna movement. The findings suggest that the paralemniscal tegmental area is involved in audio-motor control of vocalization and pinna movements in bats; connectional and functional similarities and disparities to tegmental regions described in other mammals are discussed.     

Intrinsic GABAergic neurons in the rat central extended amygdala

The present study examined the distribution, morphology, and connections of gamma-aminobutyric acid-immunoreactive (GABA-IR) neurons in the three principal components of the central extended amygdala: the central amygdaloid nucleus, the bed nucleus of the stria terminalis (BNST) and the sublenticular substantia innominata. In the central nucleus, large numbers of GABA-IR neurons were identified in the lateral, lateral capsular, and ventral subdivisions, though in the medial subdivision, GABA-IR neurons were only present at very caudal levels. Combined immunocytochemistry-Golgi impregnation revealed that GABA-IR neurons in the lateral central nucleus were medium-sized spiny neurons that were morphologically similar to GABAergic neurons in the striatum. Injections of horseradish peroxidase into the bed nucleus of the stria terminalis labeled a major proportion of the GABA-IR neurons in the central nucleus. In the bed nucleus, the majority of GABA-IR neurons were located in the anterolateral subdivision, ventral part of the posterolateral subdivision and the parastrial subdivision. GABA-IR neurons in the anterolateral bed nucleus were of the typical medium-sized spiny type. Injections of horseradish peroxidase into the central nucleus labeled a few GABA-IR neurons in the posterior part of the anterolateral bed nucleus. GABA-IR neurons were identified in the sublenticular substantia innominata and medial shell of the nucleus accumbens and contributed to the continuum of GABA-IR extending from the central nucleus to the bed nucleus. Injections of horseradish peroxidase (HRP) into the central nucleus, but not the BNST, labeled a few GABA-IR neurons in the substantia innominata. The data point to GABA-IR neurons being a characteristic feature of the central extended amygdala and that GABA-IR neurons participate in the long intrinsic connections linking the major components of this structure. Since lesions of the stria terminalis and basolateral amygdaloid nucleus failed to deplete GABA-IR terminals in the central nucleus, the role of GABA in local and short intrinsic connections in the central extended amygdala is discussed. Further, physiological findings implicating the intrinsic GABAergic system of the central extended amygdala in the tonic inhibition of brainstem efferents are reviewed.     

Dorsal raphe, substantia nigra and locus coeruleus: interconnections with each other and the neostriatum

Using a retrograde axonal transport method, direct projections to the neostriatum were demonstrated from the dorsal raphe nucleus, a large area of the ventral midbrain tegmentum (including the ventral tegmental area of Tsai, the substantia nigra pars compacta, reticulata and suboculomotoria), and the tegmentum ventral to the caudal red nucleus. A direct projection was also found from the mediodorsal part of the substantia nigra to the rostral part of the dorsal raphe nucleus. Projections from the entopeduncular nucleus (pallidum) and the lateral hypothalamic area to the lateral habenular nucleus, and from the latter to the dorsal raphe nucleus were also found. This habenular projection arises primarily from large neurons in the medial part of the lateral habenula and also from another group of small cells immediately adjacent to the medial habenular nucleus. A non-reciprocal connection of the dorsal raphe nucleus to the locus coernuleus was also found. On the basis of these results and the data available in the literature on the possible neurotransmitters used by these various structures, it is suggested that the dorsal raphe nucleus may play an important role in brain stem modulation of neostriatal function.     

Role of the subthalamic nucleus in cannabinoid actions in the substantia nigra of the rat

The effect of cannabinoids on the excitatory input to the substantia nigra reticulata (SNr) from the subthalamic nucleus was explored. For this purpose a knife cut was performed rostral to the subthalamic nucleus to isolate the subthalamic nucleus and the SNr from the striatum, a major source of cannabinoid receptors to the SNr. The data showed that the cannabinoid agonist WIN55,212-2 blocked the increase in the firing rate of SNr neurons induced by stimulation of the subthalamic nucleus with bicuculline. Furthermore, the cannabinoid antagonist SR141716A antagonized the effect of the cannabinoid agonist. This study showed that cannabinoids regulate not only the striatonigral pathway, as previously reported, but also the subthalamonigral pathway. The opposite influences of these two inputs to the SNr, inhibitory and excitatory respectively, suggest that endogenous cannabinoids play a major role in the physiological regulation of the SNr.     

The connections of the primate subthalamic nucleus: indirect pathways and the open-interconnected scheme of basal ganglia-thalamocortical circuitry

The current view of basal ganglia organization holds that functionally corresponding subregions of the frontal cortex, basal ganglia and thalamus form several parallel segregated basal ganglia-thalamocortical circuits. In addition, this view states that striatal output reaches the basal ganglia output nuclei (the substantia nigra pars reticulata (SNR) and the internal segment of the globus pallidus (GPi)) via a 'direct' pathway, and via an 'indirect pathway' which traverses the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). However, the topographical relationships of GPe and STN, and their topographical relationships with the basal ganglia-thalamocortical circuits are still unclear. The present work reviewed primate data on the topographical organization of STN afferents from GPe, and STN efferents to the pallidum, striatum and SNR, and examined these data with respect to a tripartite (motor, associative and limbic) functional subdivision of the striatum and pallidum. This examination indicated the following. (1) On the basis of its efferent connections, the STN may be divided into a motor and an associative territories, as well as a smaller limbic territory, each projecting to corresponding areas in the pallidum and striatum. (2) Efferents from GPe are in a position to contact subthalamic cells projecting to GPi/SNR, thus providing anatomical support for the existence of indirect pathways. (3) Moreover, given the tripartite division of the striatum, pallidum, and STN, the available data indicate the existence of indirect pathways connecting functionally corresponding subregions of the striatum, pallidum, and STN, as well as indirect pathways connecting functionally non-corresponding subregions. On the basis of the above we suggested that there may be two types of indirect pathways, one which terminates in the same subregion in GPi/SNR as the direct pathway arising from the same striatal subregion, and another which terminates in a different GPi/SNR subregion than the direct pathway arising from the same striatal subregion. We termed the former a 'closed indirect pathway' and the latter an 'open indirect pathway'. The application of these concepts to the surveyed data suggested the existence of three closed indirect pathways, each connecting the corresponding functional (motor, associative, and limbic) regions of the striatum, pallidum, STN, and SNR, as well as of two open indirect pathways, one connecting the associative striatum to the motor subregions of the basal ganglia, and the other connecting the associative striatum to the limbic subregions of the basal ganglia. While the organization of the closed indirect pathways fits the closed segregated arrangement of basal ganglia-thalamocortical circuitry, the organization of the open indirect pathways fits the recently suggested open interconnected scheme of basal ganglia thalamocortical circuitry. The clinical implications of this scheme for Huntington's disease are discussed.     

Synaptic input and output of parvalbumin-immunoreactive neurons in the neostriatum of the rat

Previous studies have demonstrated that the calcium-binding protein parvalbumin, is located within a population of GABAergic interneurons in the neostriatum of the rat. Anatomical studies have revealed that these cells receive asymmetrical synaptic input from terminals that are similar to identified cortical terminals and that they innervate neurons with the ultrastructural features of medium spiny cells. Furthermore, electrophysiological studies suggest that some GABAergic interneurons in the neostriatum receive direct excitatory input from the cortex and inhibit medium spiny cells following cortical stimulation. The main objectives of the present study were (i) to determine whether parvalbumin-immunoreactive neurons in the rat receive direct synaptic input from the cortex, (ii) to determine whether parvalbumin-immunopositive axon terminals innervate identified striatal projection neurons and (iii) to chemically characterize this anatomical circuit at the fine structural level. Rats received stereotaxic injections of biocytin in the frontal cortex or injections of neurobiotin in the substantia nigra. Following an appropriate survival time, the animals were perfused and the brains were sectioned and treated to reveal the transported tracers. Sections containing the neostriatum were treated for simultaneous localization of the transported tracer and parvalbumin immunoreactivity. Tracer deposits in the cortex gave rise to massive terminal and fibre labelling in the neostriatum. Parvalbumin-immunoreactive elements located within fields of anterogradely labelled terminals were examined in the electron microscope and corticostriatal terminals were found to form asymmetrical synaptic specializations with all parts of parvalbumin-immunoreactive neurons that were examined. Tracer deposits in the substantia nigra produced retrograde labelling of a subpopulation of striatonigral neurons. Areas of the neostriatum and nucleus accumbens containing retrogradely labelled neurons and parvalbumin-immunoreactive structures were selected for electron microscopy. Parvalbumin-immunopositive axon terminals formed symmetrical synaptic specializations with the perikarya of retrogradely labelled medium spiny projection neurons. Postembedding immunocytochemistry for GABA revealed that parvalbumin-immunoreactive boutons in synaptic contact with medium spiny neurons were GABA-positive. These data demonstrate directly a neural circuit whereby cortical information may be passed to medium spiny cells, via GABAergic interneurons, in the form of inhibition and provide an anatomical substrate for the feed-forward inhibition that has been detected in spiny neurons in electrophysiological experiments.     

Selective innervation of neostriatal interneurons by a subclass of neuron in the globus pallidus of the rat

A subpopulation of neurons in the globus pallidus projects to the neostriatum, which is the major recipient of afferent information to the basal ganglia. Given the moderate nature of this projection, we hypothesized that the pallidostriatal projection might exert indirect but powerful control over principal neuron activity by targeting interneurons, which comprise only a small percentage of neostriatal neurons. This was tested by the juxtacellular labeling and recording of pallidal neurons in combination with immunolabeling of postsynaptic neurons. In addition to innervating the subthalamic nucleus and output nuclei, 6 of 23 labeled pallidal neurons projected to the neostriatum. Both the firing characteristics and the extent of the axonal arborization in the neostriatum were variable. However, light and electron microscopic analysis of five pallidostriatal neurons revealed that each neuron selectively innervated neostriatal interneurons. A large proportion of the boutons of an individual axon (19-66%) made contact with parvalbumin-immunoreactive interneurons. An individual parvalbumin-immunoreactive neuron (n = 27) was apposed on average by 6.7 boutons (SD = 6.1) from a single pallidal axon (n = 2). Individual pallidostriatal boutons typically possessed more than one symmetrical synaptic specialization. In addition, 3-32% of boutons of axons from four of five pallidal neurons contacted nitric oxide synthase-immunoreactive neurons. Descending collaterals of pallidostriatal neurons were also found to make synaptic contact with dopaminergic and GABAergic neurons of the substantia nigra. These data imply that during periods of cortical activation, individual pallidal neurons may influence the activity of GABAergic interneurons of the neostriatum (which are involved in feed-forward inhibition and synchronization of principle neuron activity) while simultaneously patterning neuronal activity in basal ganglia downstream of the neostriatum.     

Glutamate receptor binding sites in MPTP-treated mice

Changes in excitatory amino acid (EAA) neurotransmission are thought to play an important role in the development of parkinsonian symptoms. We examined EAA receptor binding sites in substantia nigra, striatum, globus pallidus, and cortex at 2 weeks and 2 months after MPTP (1-methyl-4-phenyl-1,2,3,6-tetra-hydroxypyridine) injection in C57bl6 mice. At 2 weeks striatal dopamine content in MPTP-treated mice was reduced to 7% of control and N-methyl-D-aspartate (NMDA)-sensitive [3H]glutamate and [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) binding sites were decreased in substantia nigra to 57 and 76% of control, respectively. In globus pallidus only [3H]AMPA binding sites were decreased to 80% of control; no significant changes were found in striatum or cortex. [3H]Kainate binding sites remained unchanged. At 2 months striatal dopamine content was reduced to 31% and no changes in EAA binding sites could be detected in any of the structures examined. [3H]Mazindol binding to striatal monoamine-uptake sites was decreased to 17% of control at 2 weeks versus 37% at 2 months. Our data indicate that modulation of NMDA and AMPA binding sites in substantia nigra and globus pallidus, the major projection areas of the subthalamic nucleus, takes place only after severe impairment of the nigrostriatal system.     

Electrophysiological studies of rat substantia nigra neurons in an in vitro slice preparation after middle cerebral artery occlusion

We studied sequential changes in electrophysiological profiles of the ipsilateral substantia nigra neurons in an in vitro slice preparation obtained from the middle cerebral artery-occluded rats. Histological examination revealed marked atrophy and neurodegeneration in the ipsilateral substantia nigra pars reticulata at 14 days after middle cerebral artery occlusion. Compared with the control group, there was no significant change in electrical membrane properties and synaptic responses of substantia nigra pars reticulata neurons examined at one to two weeks after middle cerebral artery occlusion. On the other hand, there was a significant increase in the input resistance and spontaneous firing rate of substantia nigra pars compacta neurons at 13-16 days after middle cerebral artery occlusion. Furthermore, inhibitory postsynaptic potentials evoked by stimulation of the subthalamus in substantia nigra pars compacta neurons was suppressed at five to eight days after middle cerebral artery occlusion. At the same time excitatory postsynaptic potentials evoked by the subthalamic stimulation was increased. Bath application of bicuculline methiodide (50 microM), a GABA(A) receptor antagonist, significantly increased the firing rate of substantia nigra pars compacta neurons from intact rats. These results strongly suggest that changes in electrophysiological responses observed in substantia nigra pars compacta neurons is caused by degeneration of GABAergic afferents from the substantia nigra pars reticulata following middle cerebral artery occlusion. While previous studies indirectly suggested that hyperexcitation due to deafferentation from the neostriatum may be a major underlying mechanism in delayed degeneration of substantia nigra pars reticulata neurons after middle cerebral artery occlusion, the present electrophysiological experiments provide evidence of hyperexcitation in substantia nigra pars compacta neurons but not in pars reticulata neurons at the chronic phase of striatal infarction.