Topographic projections from the basal ganglia to the nucleus tegmenti pedunculopontinus pars compacta of the cat with special reference to pallidal projections

Summary Projections from the basal ganglia to the nucleus tegmenti pedunculopontinus pars compacta (TPC) were studied by using anterograde and retrograde tracing techniques with horseradish peroxidase conjugated with wheat germ agglutinin (WGA-HRP) in the cat. Following WGA-HRP injections into the medial TPC area, a substantial number of retrogradely labeled cells were seen in the entopeduncular nucleus (EP) and medial half of the substantia nigra pars reticulata (SNr), whereas following WGA-HRP injections into the lateral TPC area, labeled cells were marked in the caudal half of the globus pallidus (GP) and lateral half of the SNr. To confirm the retrograde tracing study, WGA-HRP was injected into the EP or the caudal GP, and anterograde labeling was observed in the TPC areas. Terminal labeling was located in the medail TPC area in the EP injection case, while terminal labeling was observed in the lateral TPC area in the caudal GP injection case. Projections from the striatum to the pallidal complex (the EP and the caudal GP) were also studied autoradiographically by injecting amino acids into various parts of the caudate nucleus and the putamen. Terminal labeling was distributed over the whole extent of the EP and the rostral GP following injections into the rostral striatum (the head of the caudate nucleus or the rostral part of the putamen), while terminal labeling was distributed over the caudal GP following injections into the caudal striatum (the body of the caudate nucleus or the caudal part of the putamen). From these findings, we conclude that there exists a medio-lateral topography in the projection from the basal ganglia to the TPC: The EP receives afferent projections from the rostral striatum and projects to the medial TPC area, whereas the caudal GP receives projections from the caudal striatum and sends fibers to the lateral TPC area.Abbreviations BC brachium conjunctivum - CD caudate nucleus - CP cerebral peduncle - DBC decussation of the brachium conjunctivum - EP entopeduncular nucleus - GP globus pallidus - IC internal capsule - ICo inferior colliculus - LH lateral habenular nucleus - ML medial lemniscus - PN pontine nuclei - PUT putamen - SCo superior colliculus - SI substantia innominata - SN substantia nigra - SNc substantia nigra pars compacta - SNr substantia nigra pars reticulata - STN subthalamic nucleus - TH thalamus - TPC nucleus tegmenti pedunculopontinus pars compacta     

Comparative activities of tetanus and botulinum toxins

Using immunohistochemical methods we have studied the distribution of substance P fibers, terminals and perikarya throughout the basal ganglia of baboons and at selected levels of the human brain. Immunoreactivity in the substantia nigra pars reticulata, internal segment of the globus pallidus and ventral pallidum was dense and of a characteristic, “woolly-fiber” morphology. The caudate nucleus and putamen contained sharply circumscribed patches of dense immunoreactivity superimposed on a moderately stained background. The external division of the globus pallidus displayed very little immunoreactivity. Two morphological types of immunoreactive cell bodies were present in the caudate nucleus, putamen and nucleus accumbens, and were clustered within the dense patches. The distribution of immunoreactive perikarya within the striatum differed from that reported for rats, as immunoreactive neurons were distributed evenly throughout the rostrocaudal extent rather than being concentrated in the rostral portions.     

Organization of the striatal projections from the rostral caudate nucleus to the globus pallidus,the entopeduncular nucleus,and the Pars reticulata of the substantia nigra in the cat

This study explores the organization of the striatal projections from the rostral caudate nucleus to the output nuclei of the basal ganglia in the cat. Tracer deposits were stereotaxically injected in different dorsoventral, mediolateral, and rostrocaudal sectors of the head of the caudate nucleus using horseradish peroxidase (HRP) conjugated with wheat germ agglutinin (HRP-WGA) either alone or mixed with free HRP. After the injections, a detailed analysis of the terminal labeling was carried out within the globus pallidus (GP), the entopeduncular nucleus (Ep), and the substantia nigra (SN) pars reticulata (SNR). Our findings illustrate how different dorsoventral, mediolateral, and rostrocaudal parts of the rostral caudate nucleus project primarily to similarly positioned but spatially segregated parts of GP. The striatoentopeduncular pathway was also organized topographically, but there was overlapping by projections from different parts of the rostral caudate nucleus. Areas of topographical segregation and zones of overlap were detected in the organization of the striatal projections from the rostral caudate nucleus to SNR. These results raise the possibility of distinct striatal actions upon different sectors of the output nuclei of the basal ganglia and, indirectly, upon their targets in the thalamus and brainstem. © 1994 Wiley-Liss, Inc.     

Initial observations on the distribution of cannabinoid receptor binding sites in the human adult basal ganglia using autoradiography.

The distribution of cannabinoid receptor binding sites has been studied in the basal ganglia of 3 human adults using the synthetic cannabinoid agonist [3H]CP55,940 and autoradiography. The [3H]CP55,940-specific labeling was found in the caudate, putamen, accumbens, substantia nigra pars reticulata, and globus pallidus. The binding was consistently higher in the medial over the lateral part of the globus pallidus.     

Behavioral effects of unilateral basal gangliar lesions in neonatal rats

Two-day-old rats were given unilateral lesions of the caudate-putamen, globus pallidus, or hippocampus and their postural orientation was observed for 30 min immediately after surgery. All groups with damage to the caudate-putamen and/or globus pallidus showed a significant postural deviation toward the side ipsilateral to the lesion. At this age, neurogenesis in the basal ganglia is complete but synapses, neurotransmitters, and enzymes for neurotransmitter synthesis are far below adult levels. These results indicate that the basal ganglia have a role in motor function prior to their full maturation as measured by neuroanatomical and biochemical techniques.     

Role of globus pallidus and substantia nigra efferent pathways in striatally evoked head turning in the rat

Summary These studies have examined the role of brain areas that receive efferent projections from the globus pallidus (GP) and substantia nigra (SN) in producing the contralateral head turning evoked by unilateral electrical stimulation of the neostriatum in the conscious rat. Two parameters were studied: the latency for a 90 ° head turn and changes in the normal latency evoked by administration of the GABA drugs picrotoxin and muscimol in GP. Electrolesions in the ipsilateral ventromedial and centromedian thalamic nuclei had no effect on the head turn parameters. Although small electrolesions in the SN slowed, but did not abolish the head turn, it prevented the changes in the response latency brought about by GABA drugs in GP. Treatment with 6-hydroxydopamine, which partly destroyed the nigrostriatal dopamine neurones, had no effect on the head turn. Areas of the brainstem that receive basal ganglia efferents were lesioned. An electrolesion of the nucleus tegmenti pedunculopontinus had no effect on the head turn latencies. The head turning was abolished by a lesion in the lateral periaqueductal grey (PAG); a more rostral PAG lesion, on the same level as SN, was ineffective. It is concluded that the head turning is mediated by basal ganglia efferents which pass close to the nigra without synapsing and project to the PAG. The GABA-sensitive GP efferents which modulate the response, probably project to SN.     

The organization of nucleus tegmenti pedunculopontinus neurons projecting to basal ganglia and thalamus: a retrograde fluorescent double labeling study in the rat

The organization of nucleus tegmenti pedunculopontinus (PPN) projections to the basal ganglia and thalamus was studied in the rat by using retrograde transport of fluorescent dyes. Fast blue was injected into the substantia nigra (SN) while Nuclear yellow was delivered to one of the following nuclei: globus pallidus (GP), entopeduncular nucleus, subthalamic nucleus (STN) or parafascicular nucleus of the thalamus. Retrogradely labeled cells were observed throughout the PPN without topographical arrangement. The cells labeled from the SN outnumbered those labeled from other structures. In all cases the majority of cells were single labeled and only a few cells double labeled from SN-GP or SN-STN were found. Labeled cells were either fusiform or multipolar in shape. These data suggest that distinct PPN cells project to their basal ganglia and thalamic targets without a prominent branched organization.     

苍白球功能变化与帕金森症

As an important nucleus of basal ganglia, globus pallidus was concerned to involve in the neural mechanism of Parkinss disease (PD). Previous studies of PD patients and animal model indicate that neurotransmitters and receptors are changed in globus pallidus neurons, the balance between inhibition and excitation is broken in the output nuclei of basal ganglia, and globus pallidus neurons display bursting and oscillatory discharge, the synchronous tendency of neighboring neurons enhances. These neurophysiological changes are associated with PD symptoms, such as bradykinesia, rigidity and tremor, which reflects that globus pallidus plays an important role in the process of PD. In the present paper, the recent advances in pathophysiology in globus pallidus, its clinical application in treatment of Parkinsons disease, and the study direction in the future are reviewed.     

Direct projections from the central amygdaloid nucleus to the globus pallidus and substantia nigra in the cat.

Employing both anterograde and retrograde axonal tracing, we investigated direct projections from the central amygdaloid nucleus to the basal ganglia in the cat. The anterograde axonal tracing of Phaseolus vulgaris-leucoagglutinin revealed that projection fibers from the central amygdaloid nucleus to the basal ganglia ended in the globus pallidus (the feline homolog to the external segment of the globus pallidus of primates) and substantia nigra. The amygdalopallidal fibers terminated chiefly in the medial most part of the globus pallidus at its caudal level. The amygdalonigral fibers terminated densely in the substantia nigra pars lateralis, and moderately in the dorsolateral part of the substantia nigra pars reticulata; none of them were found to end in the substantia nigra pars compacta. Both of the amygdalopallidal and amygdalonigral projections were ipsilateral. These neuronal connections were confirmed by retrograde axonal tracing of cholera toxin B subunit in the second set of the experiments: The cells of origin of the amygdalopallidal and amygdalonigral projections were located predominantly in the lateral part of the central amygdaloid nucleus, and additionally in the intercalated cell islands of the amygdala. Most of them were of small bipolar or multipolar type. The cells projecting to the globus pallidus were preferentially distributed at the rostral levels of the central nucleus and intercalated cell islands of the amygdaloid complex, while those projecting to the substantia nigra were mainly located at the caudal levels of these amygdaloid subdivisions. In the third set of the experiments, sequential double-antigen immunofluorescence histochemistry for transported cholera toxin B subunit and horseradish peroxidase showed that some single neurons in the lateral part of the central amygdaloid nucleus, particularly at its middle level, issued axon collaterals to both the globus pallidus and substantia nigra pars lateralis. The results of the present study indicate that the central amygdaloid nucleus sends projection fibers to the globus pallidus and substantia nigra possibly to exert a limbic influence upon forebrain motor mechanisms.     

Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network

The subthalamic nucleus-globus pallidus network plays a central role in basal ganglia function and dysfunction. To determine whether the relationship between activity in this network and the principal afferent of the basal ganglia, the cortex, is altered in a model of Parkinson's disease, we recorded unit activity in the subthalamic nucleus-globus pallidus network together with cortical electroencephalogram in control and 6-hydroxydopamine-lesioned rats under urethane anaesthesia. Subthalamic nucleus neurones in control and 6-hydroxydopamine-lesioned animals exhibited low-frequency oscillatory activity, which was tightly correlated with cortical slow-wave activity (approximately 1 Hz). The principal effect of dopamine depletion was that subthalamic nucleus neurones discharged more intensely (233% of control) and globus pallidus neurones developed low-frequency oscillatory firing patterns, without changes in mean firing rate. Ipsilateral cortical ablation largely abolished low-frequency oscillatory activity in the subthalamic nucleus and globus pallidus. These data suggest that abnormal low-frequency oscillatory activity in the subthalamic nucleus-globus pallidus network in the dopamine-depleted state is generated by the inappropriate processing of rhythmic cortical input. A component (15-20%) of the network still oscillated following cortical ablation in 6-hydroxydopamine-lesioned animals, implying that intrinsic properties may also pattern activity when dopamine levels are reduced. The response of the network to global activation was altered by 6-hydroxydopamine lesions. Subthalamic nucleus neurones were excited to a greater extent than in control animals and the majority of globus pallidus neurones were inhibited, in contrast to the excitation elicited in control animals. Inhibitory responses of globus pallidus neurones were abolished by cortical ablation, suggesting that the indirect pathway is augmented abnormally during activation of the dopamine-depleted brain. Taken together, these results demonstrate that both the rate and pattern of activity of subthalamic nucleus and globus pallidus neurones are altered profoundly by chronic dopamine depletion. Furthermore, the relative contribution of rate and pattern to aberrant information coding is intimately related to the state of activation of the cerebral cortex.     

Influence of globus pallidus on arm movements in monkeys. II. Effects of stimulation

The effect of changing basal ganglia activity with electrical stimulation in and around the globus pallidus (GP) was studied in monkeys trained to make rapid arm-reaching movements to a visual target in a reaction time task. As was the case following kainic acid (KA) lesions of the globus pallidus (30), stimulation changed movement times (MT) without affecting the pattern of sequential activation of muscles involved in the task or, in most cases, the reaction times (RT). Stimulation in the ventrolateral internal segment of the globus pallidus (GPi) or in the ansa lenticularis reduced movement times, whereas stimulation at many sites in the external pallidal segment (GPe), dorsal GPi, and putamen increased movement times for the contralateral arm. These results are consistent with the hypothesis that arm movements are speeded up when the critical output of GPi is increased and arm movements are slowed down when critical GPi output is reduced, either by an inhibitory process (via stimulation-induced activation of inhibitory elements presynaptic to GPi) or by destroying GPi neurons (via kainic acid). The influence of the basal ganglia on the scaling of electromyographic (EMG) amplitude, as opposed to the spatiotemporal organization of EMG activation, is discussed.     

MRI in schizophrenia: basal ganglia and white matter T1 times

The T1 relaxation time of the basal ganglia (putamen, globus pallidus and head of caudate) and of the frontoparietal centrum semiovale was compared between 49 schizophrenic patients and 36 healthy controls. Previous reports of increased T1 time in the basal ganglia were not confirmed, and group differences were not detected within the white matter. Within patients T1 values could not be related to tardive dyskinesia or other clinical features. Normal variation seen in basal ganglia T1 times is described for the first time: lowest values occur in the globus pallidus and highest in the caudate, and values within the putamen increase rostrally.     

Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons.

In the infant and adult human basal ganglia, the finding of mRNA exclusively in the striatal medium-sized neurons together with the detection of [3H]CP55,940 binding sites in the caudate-putamen, accumbens, substantia nigra pars reticulata and globus pallidus suggests cannabinoid receptor localization on the striatal intrinsic enkephalinergic and substance P-projecting neurons and on their nigral and pallidal terminals. However, the consistent finding of higher binding in the substantia nigra pars reticulata and medial part of the globus pallidus over its lateral segment suggests cannabinoid receptor enrichment on the striatal substance P neurons which express selectively the dopamine D1 receptor.     

The role of the globus pallidus D2 subfamily of dopamine receptors in pallidal immediate early gene expression.

The globus pallidus plays an important role in basal ganglia circuitry, representing the first relay nucleus of the 'indirect pathway' of striatal efferents. In contrast to the well-characterized actions of dopamine on striatal neurons, the functional role of the dopamine innervation of globus pallidus is less well understood. Previous research showed that systemic administration of either a dopamine D2 receptor antagonist or combined dopamine D1 and D2 receptor agonists induces Fos, the protein product of the immediate early gene c-fos, in neurons of globus pallidus [Ruskin and Marshall (1997) Neuroscience 81, 79-92]. To determine whether the ability of the D2 receptor antagonist, sulpiride, to induce Fos in rat pallidal neurons is mediated by D2-like receptors in striatum or globus pallidus, intrastriatal or intrapallidal sulpiride infusions were conducted. The diffusion of intrastriatal sulpiride was estimated by measuring this antagonist's competition for N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-induced D2 receptor inactivation. The phenotype of the striatal neurons expressing Fos after intrastriatal infusion was assessed by combining Fos immunocytochemistry with D2 receptor mRNA in situ hybridization. Intrastriatal infusions of (-)-sulpiride (10-200 ng) dose-dependently increased the number of striatal cells expressing Fos; and the Fos-immunoreactive striatal cells were D2 receptor mRNA-expressing, the same population in which systemic D2 receptor antagonists induce Fos. Intrastriatal infusions of high (5 microg), but not low (10-200 ng), (-)-sulpiride doses also induced Fos in globus pallidus cells but the sulpiride appeared to spread to the globus pallidus. Direct intrapallidal infusions of (-)-sulpiride (50-100 ng) dose-dependently induced Fos in globus pallidus with minimal influence on striatum or other basal ganglia structures. Using sensitive in situ hybridization conditions, prominent labeling of D2 receptor mRNA was evident in globus pallidus. D2 receptor mRNA was densest in a lateral 200 microm wide band that follows the curvature of the pallidal/striatal boundary. Cellular analysis revealed silver clusters associated with D2 receptor mRNA labeling over globus pallidus neurons that were immunoreactive for neuron-specific nuclear protein. These results strongly suggest that the dopaminergic innervation of globus pallidus, acting through D2-like receptors internal to this structure, can control gene expression in pallidal neurons.     

Alterations of neuronal activity in the superior colliculus of rotating animals

We have investigated the relationship between alterations in neuronal activity in the superior colliculus and behavioral responses which occur following disruption of basal ganglia circuitry. These changes were analysed following unilateral suppression of the immediate early genes, c-fos and ngfi-a, in the striatum and/or the globus pallidus. Animals with unilateral suppression of immediate early gene expression in the striatum exhibited robust circling activity, following administration of D-amphetamine, that was directed towards the side of suppression. The intensity of rotation was inversely related to the length of the recovery period following antisense infusion and increased significantly when the globus pallidus was infused simultaneously with the striatum. The difference between ipsiversive (towards the antisense-infused hemisphere) and contraversive rotations was calculated and animals were grouped by number according to their ipsiversive bias: I, <50 turns; II, 50-500 turns; III, 500-1000 turns; IV, >1000 turns. Immunohistochemical localization of Fos was used as an indicator of neuronal activity in the superior colliculus. While group I animals showed diffuse Fos-like immunoreactivity throughout the intermediate layers of the superior colliculus, those animals in groups II-IV showed increasing suppression of Fos-like immunoreactivity in the stratum album intermediale and marked enhancement in the stratum griseum intermediale. Correlation and regression analysis revealed a significant positive relationship between the number of ipsiversive rotations and the number of Fos-positive nuclei in the stratum griseum intermediale of the ipsilateral superior colliculus. These data suggest that the degree of rotation elicited in an animal may depend on reciprocal suppression/stimulation of adjacent intermediate strata of the superior colliculus. This study provides the first demonstration, using Fos immunohistochemistry, of changes in tectal activity produced by alterations in basal ganglia function. These findings support previous electrophysiological studies in this region and suggest that the nigrotectal projection may be an important site of altered basal ganglia output.     

Correlated multisecond oscillations in firing rate in the basal ganglia: modulation by dopamine and the subthalamic nucleus

Previous studies from this laboratory have shown that many neurons in the basal ganglia have multisecond (<0.5 Hz) periodicities in firing rate in awake rats. The frequency and regularity of these oscillations are significantly increased by systemically injected dopamine (DA) agonists. Because oscillatory activity should have greater functional impact if shared by many neurons, the level of correlation of multisecond oscillations was assessed by recording pairs of neurons in the globus pallidus and substantia nigra pars reticulata in the same hemisphere, or pairs of globus pallidus neurons in opposite hemispheres in awake, immobilized rats. Cross-correlation (90-180 s lags) and spectral analysis were used to characterize correlated oscillations. Thirty-eight percent of pairs recorded in baseline (n=50) demonstrated correlated multisecond oscillations. Phase relationships were near 0 or 180 degrees. DA agonist injection significantly increased the incidence of correlation (intra- and interhemispheric) to 94% (n=17). After DA agonist injection, phase relationships of globus pallidus/substantia nigra neuron pairs were exclusively concentrated near 180 degrees, and phases of interhemispheric pairs of globus pallidus neurons were concentrated near 0 degrees. After subthalamic nucleus lesion (n=8), the incidence of correlated multisecond oscillations (or of multisecond oscillations per se) was not changed, although the consistent phase relationship between the globus pallidus and substantia nigra pars reticulata was disrupted. Subthalamic lesion also blocked apomorphine-induced decreases in oscillatory period and increases in oscillation amplitude, and significantly attenuated apomorphine-induced changes in mean firing rate. The data demonstrate that multisecond oscillations in the basal ganglia can be correlated between nuclei, and that DA receptor activation increases the level of correlation and organizes internuclear phase relationships at these multisecond time scales. While the subthalamic nucleus is not necessary for generating or transmitting these slow oscillations, it is involved in DA agonist-induced modulation of mean firing rate, oscillatory period, and internuclear phase relationship. These data further support a role for DA in modulating coherent oscillatory activity in the basal ganglia, and for the subthalamic nucleus in shaping the effects of DA receptor stimulation on basal ganglia output.     

Localization of cells containing transforming growth factor-alpha precursor immunoreactivity in the basal ganglia of the adult rat brain

Transforming growth factor-alpha-like immunoreactivity (TGF-alpha-ir) was visualized in the adult rat forebrain using three antisera directed against carboxyterminal sequences in the TGF-alpha precursor. Using immunoperoxidase and immunofluorescence techniques with all three antisera, TGF-alpha-ir was found to be present in a subpopulation of astrocytes in the forebrain. Striatal and pallidal regions of the basal ganglia were studied in detail. In the striatum, there was an uneven distribution of astrocytes containing TGF-alpha-ir, with the greatest number in the dorsal medial third of the caudate-putamen and the overlying corpus callosum/external capsule. In addition, the region of the caudate-putamen bordering the globus pallidus contained numerous clusters of TGF-alpha-ir astrocytes. The globus pallidus itself contained numerous and more evenly distributed TGF-alpha-ir astrocytes. Other pallidal structures--including the ventral pallidum, entopeduncular nucleus, and substantia nigra pars reticulata--contained moderate numbers of TGF-alpha-ir astrocytes. These results suggest that TGF-alpha precursor is present and, perhaps, synthesized in astrocytes. A related growth factor, epidermal growth factor (EGF), has also been reported to be present in pallidal regions of rat brain. Therefore, the TGF-alpha/EGF family of trophic factors may play a role in the function of the central nervous system.     

The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease

In order to investigate the sequence and pattern of neurodegeneration in Huntington's disease, the distribution and density of cannabinoid CB(1), dopamine D(1) and D(2), adenosine A(2a) and GABA(A) receptor changes were studied in the basal ganglia in early (grade 0), intermediate (grades 1, 2) and advanced (grade 3) neuropathological grades of Huntington's disease. The results showed a sequential pattern of receptor changes in the basal ganglia with increasing neuropathological grades of Huntington's disease. First, the very early stages of the disease (grade 0) were characterized by a major loss of cannabinoid CB(1), dopamine D(2) and adenosine A(2a) receptor binding in the caudate nucleus, putamen and globus pallidus externus and an increase in GABA(A) receptor binding in the globus pallidus externus. Second, intermediate neuropathological grades (grades 1, 2) showed a further marked decrease of CB(1) receptor binding in the caudate nucleus and putamen; this was associated with a loss of D(1) receptors in the caudate nucleus and putamen and a loss of both CB(1) and D(1) receptors in the substantia nigra. Finally, advanced grades of Huntington's disease showed an almost total loss of CB(1) receptors and the further depletion of D(1) receptors in the caudate nucleus, putamen and globus pallidus internus, and an increase in GABA(A) receptor binding in the globus pallidus internus.These findings suggest that there is a sequential but overlapping pattern of neurodegeneration of GABAergic striatal efferent projection neurons in increasing neuropathological grades of Huntington's disease. First, GABA/enkephalin striatopallidal neurons projecting to the globus pallidus externus are affected in the very early grades of the disease. Second, GABA/substance P striatonigral neurons projecting to the substantia nigra are involved at intermediate neuropathological grades. Finally, GABA/substance P striatopallidal neurons projecting to the globus pallidus internus are affected in the late grades of the disease. In addition, the finding that cannabinoid receptors are dramatically reduced in all regions of the basal ganglia in advance of other receptor changes in Huntington's disease suggests a possible role for cannabinoids in the progression of neurodegeneration in Huntington's disease.