Pallidal Segment Research Articles

Infrequent types of pallidal discharges during pallidotomy.

Pallidal discharges of patients with Parkinson's disease have been characterized as slow irregular or bursting discharges for the external pallidal segment (GPe) and fast discharges for the internal pallidal segment (GPi). Tremor-synchronous cells have also been described. Using microrecording techniques on 70 patients who underwent pallidotomy, we have recorded other types of pallidal discharges. In GPe, we recorded cells which fired fast, cells which were silent, and cells which fired tonically. In GPi, we recorded cells which burst following short segments of fast tonic discharges. We will demonstrate these cells and discuss their clinical significance.

Characteristics and somatotopic organization of kinesthetic cells in the globus pallidus of patients with Parkinson's disease.

Information is limited on the characteristics and topographic localization of pallidal kinesthetic cells in patients with Parkinson's disease. The authors analyzed the data from 298 neurons recorded in 38 patients with Parkinson's disease who underwent pallidotomy via microrecording techniques. Sixty-five neurons (22%) responded to passive movement of contralateral limbs. Of 17 kinesthetic cells that were tested in six patients, seven (41%) responded to ipsilateral limb movement as well. Nineteen cells (6%) fired synchronously with tremor. More kinesthetic cells were activated (63%) than inhibited (28%) by movement of single (68%) rather than multiple (32%) joints, and proximal (75%) rather than distal (25%) joints. The lateral globus pallidus externus (GPe) and medial globus pallidus internus (GPi) pallidal segments contained similar proportions of kinesthetic cells, activated or inhibited cells, arm- or leg-activated cells, and cells responding to single or multiple joints. Significantly more kinesthetic cells that responded to distal joints were recorded in GPi compared to GPe segments (p = 0.01). Arm and leg cells had similar characteristics pertaining to activation versus inhibition and responses to single, multiple, proximal, or distal joint movements. Arm and leg cells were somatotopically organized in GPi. Arm cells were clustered at the rostral and caudal segments of GPi and leg cells were clustered centrally. In GPe, leg cells were clustered at the caudal border. No somatotopic organization was identified for activated or inhibited cells; cells that responded to single, multiple, proximal, or distal joints; tremor-synchronous cells; or cells responding to specific joints within somatotopic arm or leg cells. It is concluded that kinesthetic cells provide a roadmap that localizes limb cells during pallidotomy. More studies are needed to identify the clinical significance of the different characteristics of kinesthetic cells.

Changes in the control of arm position, movement, and thalamic discharge during local inactivation in the globus pallidus of the monkey.

1. To examine the effect of disruption of basal ganglia output on limb stability and movement, muscimol was injected into the internal globus pallidus (GPi) of monkeys trained to make arm movements to visible or remembered targets in a two-dimensional workspace. 2. Injections of as little as 0.25 micrograms muscimol at GPi sites at which pallidal neurons with arm movement activity had been recorded were followed by drift of the contralateral arm within < 10 min. Drift was usually in the flexor direction. Injections at a few sites in or near the external pallidal segment sometimes were followed by extensor drift. 3. Drift was active (accompanied by activation of agonist muscles), but could be overcome by the animal, resulting in an oscillating movement off and on the required position. 4. The pallidal-receiving (PR) area of the thalamus was identified by recording the response of thalamic neurons to stimulation in the globus pallidus. The activity of 15 neurons identified as PR cells (n = 6) or within the PR region was recorded both before and after injection of muscimol into GPi. After the injection, the tonic discharge increased during the hold period in 47% of the cells studied. When postural drift also occurred, there was a close temporal correlation between the postinjection time at which drift occurred and the time at which the tonic discharge rate increased in thalamic neurons that were clearly related to arm movement. 5. The peak velocity of arm movements to visible or remembered visual target locations was decreased after injection of muscimol into GPi, sometimes with an increase in movement time. 6. The firing rate of PR thalamic neurons after injection of muscimol was also increased during the perimovement period. Because of the increase in the tonic discharge rate, however, the phasic movement-related change in activity could stay the same or even decrease. Postinjection changes in this movement-related phasic activity, however, were not necessarily coincident with changes in peak movement velocity. 7. Changes in reaction time were variable after injection of muscimol. In some cases it was increased, and in others decreased. The time of onset of phasic movement-related changes in the activity of PR neurons studied was not altered by the injection. 8. Our data indicate that the tonic inhibitory output of GPi, in particular to the cortical motor areas, is especially important in the maintenance of postural stability. In the absence of normal pallidal output, desired limb position can be achieved on the basis of either current or prior visual cues, but targeted movements are slowed.

Contrasting locations of pallidal-receiving neurons and microexcitable zones in primate thalamus.

1. In two awake, juvenile male Macaca fascicularis monkeys, microstimulation was applied in ventralis anterior (VA), ventralis lateralis (VL), or ventralis posterior lateralis (VPL) of the thalamus. Thalamic recording was used to identify the region that contained pallidal-receiving (PR) thalamic neurons, cells that responded orthodromically to stimulation in the internal pallidal segment (GPi). Thalamic stimulation was used to elicit motor responses. Penetrations in the thalamus and the pallidum focused on areas with activity related to contralateral arm movement. Fifty-one PR cells were identified electrophysiologically in VL oralis (VLo), VL caudalis (VLc) and VA pars parvocellularis (VApc). 2. With a subject at rest, trains of stimuli were applied through the thalamic microelectrode. Palpable or visible muscle twitches or joint movements were evoked by short trains (12 pulses) of stimuli applied in VLc and VPL oralis (VPLo); thresholds there ranged from 5 to 75 microA. In VA and VLo, areas where PR neurons were located, even longer trains (24 pulses) of stimuli with currents up to 200 microA usually failed to evoke movement. In the caudal portions of VLo, near VPLo, there were some microexcitable sites found near PR cells where stimuli at approximately 50 microA elicited movement. 3. From microstimulation studies combined with histological reconstruction, Ashe and co-workers hypothesized that microexcitable zones were cerebellar receiving areas (CR) and nonexcitable zones were PR areas. Our data support theirs and add electrophysiological identification of PR areas. Further, we injected wheat germ agglutinin-horseradish peroxidase (WGA-HRP) into the thalamus at one of the more rostral microexcitable sites, just caudal and lateral to identified PR cells. The tetra-methyl benzidine-reacted HRP label was found in the contralateral deep cerebellar nuclei (DCN) but not in ipsilateral GPi, showing that even this rostral microexcitable zone was a CR area. 4. Together with evidence from the literature, the data are consistent with the hypothesis that PR cells have relatively weak access to spinal-destined motor outputs, whereas thalamocortical neurons from VPLo and VLc have more secure access. In addition to characteristics of cell discharge and responses to somatosensory stimulation, microexcitability may be a further aid in tentative electro-physiological identification of PR versus CR areas of the motor thalamus without necessarily recording thalamic neuronal responses to stimulation in GPi or the DCN.

Differential synaptic innervation of striatofugal neurones projecting to the internal or external segments of the globus pallidus by thalamic afferents in the squirrel monkey

It is well established that the centromedian nucleus (CM) is the major source of thalamic afferents to the sensorimotor territory of the striatum in monkeys. However, the projection sites of striatal neurones contacted by thalamic afferents still remain to be determined. We therefore carried out an anatomical study aimed at elucidating the hodology of striatal neurones that receive input from the CM in squirrel monkeys. Our approach was to combine the anterograde transport of Phaseolus vulgaris-leucoagglutinin (PHA-L) or biocytin from the CM with the retrograde transport of biotinylated dextran-amine (bio-dex) or PHA-L from the internal (GPi) or external (GPe) segments of the globus pallidus. Following CM injections, rich plexuses of anterogradely labelled, thin varicose fibres aggregated in the form of bands that were confined to the postcommissural region of the putamen. On the other hand, injections into the GPe or GPi led to profuse retrograde labelling of a multitude of medium-sized spiny neurones. In cases where the injections involved the caudoventral two-thirds of the GPe or GPi, the retrogradely labelled striatopallidal cells and the anterogradely labelled thalamostriatal fibres occurred in the sensorimotor territory of the putamen. After injections into either pallidal segments, clusters of retrogradely labelled cells were in register with bands of anterogradely labelled thalamic fibres. However, electron microscopic analysis of striatal regions containing both anterogradely labelled thalamic afferents and retrogradely labelled cells revealed that terminals from the CM frequently form asymmetric synapses with dendritic shafts and spines of striato-GPi cells but rarely with those of striato-GPe cells. In conclusion, our findings demonstrate that thalamic afferents from the CM innervate preferentially striatopallidal neurones projecting to the GPi in monkeys. These results indicate that the striatopallidal neurones contributing to the “direct” and “indirect” output pathways are differentially innervated by thalamic afferents in primates. © 1996 Wiley-Liss, Inc.

Differential synaptic innervation of striatofugal neurones projecting to the internal or external segments of the globus pallidus by thalamic afferents in the squirrel monkey

It is well established that the centromedian nucleus (CM) is the major source of thalamic afferents to the sensorimotor territory of the striatum in monkeys. However, the projection sites of striatal neurons contacted by thalamic afferents still remain to be determined. We therefore carried out an anatomical study aimed at elucidating the hodology of striatal neurones that receive input from the CM in squirrel monkeys. Our approach was to combine the anterograde transport of Phaseolus vulgaris-leucoagglutinin (PHA-L) or biocytin from the CM with the retrograde transport of biotinylated dextran-amine (bio-dex) or PHA-L from the internal (GPi) or external (GPe) segments of the globus pallidus. Following CM injections, rich plexuses of anterogradely labelled, thin varicose fibres aggregated in the form of bands that were confined to the postcommissural region of the putamen. On the other hand, injections into the GPe or GPi led to profuse retrograde labelling of a multitude of medium-sized spiny neurones. In cases where the injections involved the caudoventral two-thirds of the GPe or GPi, the retrogradely labelled striatopallidal cells and the anterogradely labelled thalamostriatal fibres occurred in the sensorimotor territory of the putamen. After injections into either pallidal segments, clusters of retrogradely labelled cells were in register with bands of anterogradely labelled thalamic fibres. However, electron microscopic analysis of striatal regions containing both anterogradely labelled thalamic afferents and retrogradely labelled cells revealed that terminals from the CM frequently form asymmetric synapses with dendritic shafts and spines of striato-GPi cells but rarely with those of striato-GPe cells. In conclusion, our findings demonstrate that thalamic afferents from the CM innervate preferentially striatopallidal neurones projecting to the GPi in monkeys. These results indicate that the striatopallidal neurones contributing to the "direct" and "indirect" output pathways are differentially innervated by thalamic afferents in primates.

Pallido-thalamo-motor cortical connections: an electron microscopic study in the macaque monkey

We combined the retrograde transport of horseradish peroxidase conjugated to wheat germ agglutinin (WGA-HRP) technique and degenerating electron microscopic investigations to confirm the motor cortical area projection from the medial pallidal segment (GPm) via the thalamic nucleus ventralis lateralis pars oralis (VLo). We found first degenerated boutons arising from the GPm make synaptic contact with the somata and proximal dendrites of VLo neurons containing WGA-HRP reaction products transported retrogradely from motor area.

Single striatofugal axons arborizing in both pallidal segments and in the substantia nigra in primates

The striatofugal fiber system in primates is believed to be composed of separate subsystems terminating in either the external (GPe) or internal (GPi) segment of the globus pallidus, or in the substantia nigra (SN). At variance with this concept is the present demonstration of single biocytin-labeled striatofugal axons that arborize in the three major target structures of the striatum in cynomolgus monkeys. Out of nine single-labeled axons that were analyzed in detail, one terminated exclusively in GPe, another in both GPe and GPi, whereas the rest arborized in GPe, GPi and SN. The axons that branched in the three sites had one preferential recipient structure where they arborized profusely and formed typical woolly fibers. These findings suggest that, in contrast to previous beliefs based on results of retrograde double-labeling studies, most striatofugal axons arborize within more than one striatal target structures in primates.

Neuronal activity in the striatum and pallidum of primates related to the execution of externally cued reaching movements

We studied changes in basal ganglia neuronal activity associated with reaching movements of the arm in two monkeys. Data were obtained from 427 single neuronal units in putamen, 199 in caudate nucleus, and 216 in globus pallidus with multiwire electrodes allowing simultaneous recordings from multiple neurons. In all structures, changes in activity related to movement occurred most often after the onset of EMG: 43% of tested neurons in the putamen, 32% in the caudate nucleus, and 38% in the globus pallidus. Less frequently, changes began before EMG activation: 20% of neurons in the putamen, 19% in caudate nucleus, and 17% in globus pallidus. In general, these changes in neuronal activity lasted longer than EMG activity associated with reaching. The proportions of neurons activated were significantly larger in the putamen than the caudate nucleus. In the pallidum, the proportions were not statistically different from either the putamen or caudate nucleus, and no significant difference was found between the internal and external pallidal segments. Significant selectivity for movements to different targets was observed in 36% of neurons in the putamen, 28% in the caudate nucleus and 9% in the globus pallidus. The lower proportion in the globus pallidus compared to the striatum was significant ( P < 0.002). Clusters of activated neurons were found in the striatum, however, the timing of changes was often different for individual neurons in these clusters. A cross-correlation analysis of the activity of neurons in the clusters revealed no evidence of common inputs, suggesting that striatal neurons in close proximity with neurons showing similar changes in activity are driven by different populations of neurons. In the putamen, the anatomical locations of neurons with changes in activity related to movement execution were on average significantly more posterior and lateral than neurons with changes related to the preparation of movement described earlier [31]. These findings support the view that the putamen and the caudate nucleus contain distinct functional areas. The present studies show that most anatomical regions in both the striatum and palladum participate in the control of executing reaching movements.

Differential synaptic innervation of neurons in the internal and external segments of the globus pallidus by the GABA- and glutamate-containing terminals in the squirrel monkey.

The present study aimed at comparing the pattern of synaptic innervation of neurons in the external (GPe) and internal (GPi) pallidum by gamma-aminobutyric acid (GABA)- and glutamate-immunoreactive terminals in the squirrel monkey. Four major populations of terminals were encountered in GPe and GPi. Our findings combined with those obtained in previous tract-tracing studies reveal that the synaptic innervation of perikarya in GPe is strikingly different from that in GPi. Although the GABA-positive type I boutons (from the striatum) represent 85% of the terminals in contact with somata in GPe, only 32% of the axosomatic synapses involve this type of terminal in GPi. However, the type II terminals (from GPe), which display a moderate level of GABA and glutamate immunoreactivities, account for 48% of the boutons in contact with perikarya in GPi but only 10% in GPe. In both pallidal segments, less than 10% of the axosomatic synapses involve the glutamate-immunoreactive type III terminals (from the subthalamic nucleus). Finally, the type IIa boutons (unknown source), which show levels of immunoreactivities similar to the type II terminals, account for 12% of the boutons in contact with perikarya in GPi but only 4% in GPe. In contrast to perikarya, the innervation of dendritic shafts is similar in both GPe and GPi; more than 80% of the axodendritic synapses involve the type I terminals, 10-15% involve the type III terminals, less than 5% are formed by the type II boutons, and less than 1% involve the type IIa terminals. Three other categories of boutons (types IV, V, VI) account for less than 1% of the total population of terminals in GPe and GPi. In conclusion, our findings demonstrate a differential synaptic innervation of neuronal perikarya in GPe and GPi in primates. These data suggest that the two pallidal segments are separate functional entities of which the neuronal activity is largely controlled by extrinsic inputs that are differentially distributed at the level of single cells.

Activity of pallidal neurons in the monkey during dyskinesia induced by injection of bicuculline in the external pallidum.

The present study was undertaken to determine whether dyskinesia, resulting from injection of the GABA antagonist bicuculline into the external globus pallidus of intact monkeys, is induced by hyperactivity of local external pallidal neurons and ensuing hypoactivity of neurons in the internal globus pallidus, at the output of the basal ganglia. Accordingly, 86% of responding external pallidal neurons increased and 56% of internal pallidal neurons decreased their activity, either exclusively or within biphasic responses. Whereas 29% of external pallidal neurons decreased and as much as 85% of internal pallidal neurons increased their activity. The latter unpredicted responses may be explained by diffusion of bicuculline from the external to the internal pallidum and by lateral monosynaptic inhibition within the external and its mirror image in the internal pallidum. With respect to individual injection sites, the hypoactive neurons in the internal pallidum tended to be grouped together and surrounded by hyperactive or unresponsive neurons. The changes occurred before and persisted during dyskinesia, suggesting that they were required to induce and maintain the dyskinesia. There were also changes in firing patterns, comprising long periods of silence, especially in external pallidal neurons close to the injection site. The periods of silence did not appear to result from depolarization block but rather from activation of receptors of inhibitory neurotransmission other than type A GABA. Dyskinesia therefore does not appear to result exclusively from a simple imbalance of activity between the pallidal segments, with hyperactivity in the external and hypoactivity in the internal segment, but also from imbalances within each pallidal segment, possibly with a center-surround organization.

Increased glutamate decarboxylase mRNA levels in the striatum and pallidum of MPTP-treated primates

The mRNA levels encoding for the enzyme glutamate decarboxylase (GAD67) were measured by computerized image analysis after in situ hybridization histochemistry and radioautography in the striatum and pallidum of normal squirrel monkeys (Saimiri sciureus), or after treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). All MPTP-injected monkeys exhibited profound motor deficits including akinesia. The dopaminergic innervation, as visualized and quantified on x-ray films after 3H-mazindol binding on tissue sections, was uniformly lost throughout the striatum of MPTP-treated monkeys. Brain sections processed with a probe synthesized from a feline or human GAD67 cDNA exhibited intense radioautographic labeling throughout the striatum. When measured on x-ray films, the intensity of GAD67 mRNA labeling was increased in the striatum of MPTP-treated versus control monkeys. Increased labeling reached statistical significance in the dorsolateral sector of the rostral putamen and throughout the putamen and the caudate at the caudal, postcommissural, level. Analysis of emulsion radioautographs demonstrated that the increase in GAD67 mRNA labeling in MPTP-treated monkeys occurred in individual neurons of the striatum. In the external and internal segments of the pallidum, numerous neurons labeled with the GAD67 cRNA probe were visualized on emulsion radioautographs. The intensity of GAD67 mRNA labeling in single neurons of both pallidal segments was increased in MPTP-treated versus control monkeys. Construction of the histograms of frequency distribution of labeling indicated that this increase occurred in a majority of labeled neurons. The present study demonstrates that GAD67 mRNA levels are significantly altered in the striatum and pallidum of parkinsonian monkeys. The preferential increase of GAD67 mRNA labeling in the dorsolateral putamen, which receives afferents from the sensorimotor cortex, provides further evidence of the involvement of GABAergic transmission in the expression of the motor deficits elicited after MPTP. In addition, increased GAD67 mRNA levels in the internal segment of the pallidum support the hypothesis of an increased activity of GABAergic neurons in the output structures of the basal ganglia in parkinsonism.

Selective vulnerability in Huntington's disease: preferential loss of cannabinoid receptors in lateral globus pallidus.

Selective neuronal vulnerability is a key feature of the neuropathology of Huntington's disease. We used [3H]CP-55,940, a synthetic cannabinoid, to label cannabinoid receptors in tissue sections from individuals dying with Huntington's disease and from normal control subjects. The density of cannabinoid receptors in striatum and pallidum was measured using quantitative autoradiography. There was a greater loss of cannabinoid receptors on striatal nerve terminals in the lateral pallidum compared to the medial pallidum, in Huntington's disease of all neuropathological grades. The disparity in binding density between the lateral and medial pallidum increased with higher grades of disease. There was also a greater loss of receptors in the lateral pallidum than in the putamen. The disproportionate loss of receptors in the lateral pallidum compared to the putamen increased in magnitude with severity of neuropathological grade. These data support the relative preferential loss or dysfunction of striatal neurons projecting to the lateral pallidum compared to neurons projecting to the medial pallidum. Terminals in the lateral pallidum containing cannabinoid receptors may be affected earlier or more severely than terminals in the medial pallidum, and both pallidal segments may be affected before or more severely than cell bodies or dendrites in the striatum. Terminal loss of markers may represent a response to perikaryal injury or dysfunction, or less likely, may indicate the primary site of neuronal damage in Huntington's disease.

Synaptic innervation of neurons in the internal pallidal segment by the subthalamic nucleus and the external pallidum in monkeys

In order to better understand the way by which the subthalamic nucleus interacts with the globus pallidus to control the output of the basal ganglia, we carried out a series of experiments to investigate the pattern of synaptic innervation of the pallidal neurones by the subthalamic terminals in the squirrel monkey. To address this problem we used the anterograde transport of biocytin. Following injections of biocytin in the subthalamic nucleus, rich plexuses of labelled fibres and varicosities formed bands that lay along the medullary lamina in both segments of the ipsilateral pallidum. At the electron microscopic level, two populations of biocytin-containing terminals were identified in the internal pallidum (GPi). A first group of small to medium-sized terminals (type 1; mean cross-sectional area +/- S.D. = 0.41 +/- 0.04 microns 2) contained round vesicles and formed asymmetric synapses with dendritic shafts (95%) of mixed sizes (maximum diameter ranging from 0.3 to 4.0 microns) and spine-like structures (5%). The second group of terminals (type 2) contained pleiomorphic vesicles, had a larger cross-sectional area (mean +/- S.D. = 0.9 +/- 0.4 micron 2) and formed symmetric synapses predominantly with perikarya (41%) and large dendrites (57%). In some cases, the two types of terminals converged at the level of single GPi neurones. Postembedding immunogold method revealed that the type 2 terminals displayed gamma-aminobutyric acid (GABA) immunoreactivity, whereas the type 1 terminals did not. In the external pallidum (GPe), injections in the subthalamic nucleus labelled both type 1 or type 2 terminals. However, the labelled type 2 boutons were much less abundant in GPe than in GPi. The presence of biocytin-labelled perikarya in GPe and the fact that the type 2 terminals displayed GABA immunoreactivity led us to suspect that these terminals were derived from axons of GPe neurones. In agreement with this hypothesis, injections of Phaseolus vulgaris-leucoagglutinin (PHA-L) in GPe labelled terminals in GPi that displayed the morphological features and a pattern of synaptic organization similar to the type 2 terminals. In conclusion, the results of our study demonstrate that the subthalamopallidal terminals form asymmetric synapses that are distributed along the dendritic tree of GPe and GPi neurones. In contrast, the GPe projection to GPi gives rise to large GABA-containing terminals that form symmetric synapses predominantly with the proximal region of pallidal neurones.(ABSTRACT TRUNCATED AT 400 WORDS)

Brainstem dopaminergic, cholinergic and serotoninergic afferents to the pallidum in the squirrel monkey

The retrograde tracer cholera toxin B subunit (CTb) was used in combination with immunohistochemistry for tyrosine hydroxylase (TH), calbindin D-28k (CaBP), choline acetyltransferase (ChAT) and 5-hydroxytryptamine (5-HT) to determine the distribution and relative proportion of brainstem chemospecific neurons that project to the pallidum in the squirrel monkey ( Saimiri sciureus). Large injections of CTb involving both pallidal segments produce numerous retrogradely labeled neurons in the substantia nigra (SN), the pedunculopontine tegmental nucleus (PPN) and the dorsal raphe nucleus (DR). Labeled neurons are distributed uniformly in SN with a slight numerical increase at the junction between the pars compacta (SNc) and the ventral tegmental area (VTA). Retrogradely labeled neurons abound also in PPN, principally in its pars dissipata, whereas other CTb-labeled cells are scattered throughout the rostrocaudal extent of DR. After CTb injection involving specifically the internal pallidal segment (GPi), the same pattern of cell distribution is found in SN, PPN and DR, except that the number of retrogradely labeled cells is lower than after large pallidal complex injections. Approximately 70% of all CTb-labeled neurons in SNc-VTA complex display TH immunoreactivity, whereas 20% are immunoreactive for CaBP. About 39% of all retrogradely labeled neurons in PPN are immunoreactive for ChAT, whereas approximately 38% of the labeled neurons in DR display 5-HT immunoreactivity. Following CTb injection in the external pallidal segment (GPe), the number of labeled cells is much smaller than after GPi injection. The majority of CTb-labeled cells in SNc-VTA complex are located in the lateral half of SNc and approximately 93% of these neurons display TH immunoreactivity compared to 10% that are immunoreactive for CaBP; very few CTb-labeled cells occur in PPN. Retrogradely labeled cells in DR are located more laterally than those that projects to the GPi and about 25% of them are immunoreactive for 5-HT. These results suggest that, in addition to their action at striatal and/or nigral levels, the brainstem dopaminergic, cholinergic and serotoninergic neurons influence the output of the primate basal ganglia by acting directly upon GPi neurons.

Input-output organization of the sensorimotor striatum in the squirrel monkey

The basal ganglia receive massive inputs from the neocortex and send outputs that exert both inhibitory and disinhibitory control over parts of the frontal cortex and brainstem. Between these basal ganglia inputs and outputs lies the striatum, which receives most of the cortical afferents and projects to the basal ganglia output nuclei--the globus pallidus and substantia nigra. To analyze this system we conjointly labeled, in squirrel monkeys, sensorimotor cortical inputs to the striatum and striatal outputs to the globus pallidus. Anterograde tracers were injected into the motor (MI) and somatosensory (SI) cortical body maps, at sites determined by electrophysiological stimulation and recording. Retrograde tracers were stereotaxically injected into the external and internal pallidal segments (GPe and GPi). We found that multiple dispersed modules ("matrisomes") in the putamen that all received inputs from single body-part representations in sensorimotor cortex could, in turn, send convergent outputs to single sites in the pallidum. This divergence-reconvergence pattern was found for both GPe and GPi sites, and for inputs from both SI and MI cortex. Thus, information from a single functional region in the cortex can be split up at the striatal stage only to be brought back together in the pallidum. The temporary divergence may increase lateral interactions between sensorimotor matrisomes, as well as between matrisomes and striosomes. One function of striatal modularity may thus be to set up an associative network in the striatum, which might contribute to sensorimotor learning. We also found that some sets of matrisomes did not receive strong sensorimotor inputs, even though they projected to regions of GPe and GPi that are near the sensorimotor-recipient zones described above. Thus, the matrisomal system may sort MI/SI inputs and other inputs before transfer to paired regions of GPe and GPi.

Efferent projections from medial pallidal segment in the monkey: An anterograde tracing study with biotinylated dextran

Efferent projections from medial pallidal segment in the monkey: An anterograde tracing study with biotinylated dextran

Toward an understanding of the role of glutamate in experimental parkinsonism: Agonist‐sensitive sites in the basal ganglia

Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease. However, the mechanisms by which activation of glutamate receptors produce parkinsonism are unknown. Therefore, we examined whether the glutamate agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate produce parkinsonism in rats after microapplication into different subregions of the basal ganglia. Electromyographic activity was used as a measure of parkinsonian rigidity. We found that in the rostral striatum, excitation mediated by NMDA but not by non-NMDA receptors led to parkinsonism. In the substantia nigra pars reticulata, internal pallidal segment/entopeduncular nucleus, and subthalamic nucleus, activation of AMPA/kainate and metabotropic receptors but not of NMDA receptors led to parkinsonian rigidity. Rigidity occurred also in animals bearing ibotenate-induced lesions of the posterior part of the striatum and of the external pallidal segment, but not in animals with lesions of the anterior striatum, subthalamic nucleus, internal pallidal segment/entopeduncular nucleus, or substantia nigra pars reticulata. These observations suggest that the activation of glutamate receptor subtypes in the basal ganglia may be differentially involved in the expression of parkinsonian symptoms.

Output architecture of the primate putamen

The basal ganglia act through direct and indirect striatopallidal output pathways that have different effects on cortical activity. This division has been proposed to underlie the fundamental distinction between hyperkinetic and hypokinetic movement disorders such as Parkinson's disease and Huntington's disease. Evidence to date does not favor a relationship between this dual organization and the division of the striatum into striosome and matrix compartments. However, the possibility has been raised that the division of striatopallidal output paths reflects a compartmentalization of the matrix itself into clusters of different striatopallidal projection neurons. We directly tested this hypothesis in squirrel monkeys by comparing the distributions of striatal output neurons retrogradely labeled from the two pallidal segments. Striatopallidal neurons labeled by small injections confined to either the external pallidum (GPe) or the internal pallidum (GPi) formed small clusters ("matrisomes") in the matrix compartment of the putamen. However, contrary to previous predictions, labeled matrisomes projecting to GPe were not systematically separated from those projecting to GPi. They could overlap extensively, and within individual matrisomes GPe-projecting neurons and GPi-projecting neurons were extensively intermixed. Double-retrograde labeling analysis in single sections demonstrated that only 2.1 +/- 2.7% of labeled striatal neurons were doubly labeled from both GPe and GPi--a number not significantly different from zero. GPe-projecting and GPi-projecting neurons in the putamen also differed sharply in their expression of enkephalin-like immunoreactivity: 71.3 +/- 7.6% of the neurons labeled by GPe injections were enkephalin positive, in contrast to 10.0 +/- 3.6% of the neurons labeled by GPi injections. These results suggest that in the primate, populations of striatopallidal output neurons are grouped in clusters in the matrix, but that individual neurons in any given cluster project either to GPe or to GPi. Matrisomal clustering may thus coordinate signals sent into the direct and indirect pathways of the basal ganglia from distributed populations of projection neurons in the striatum.

Cortical connections of the motor thalamic nuclei in the Japanese monkey, Macaca fuscata.

Our findings revealed the nucleus ventralis lateralis pars oralis (VLo) projection to motor area, and the nucleus ventralis anterior pars principalis (VApc) projections to the premotor and supplementary motor areas (SMA). The VLo gave rise to thalamocortical projections terminating in the superficial half of layer I, mainly in the forelimb motor area. The VApc gave rise to the superficial projections to the post-arcuate premotor area around the arcuate genu and arcuate spur as well as SMA. We suggested that the medial pallidal segment projects to the motor area via VLo, and to the premotor area and SMA via VApc. We also proposed that the premotor area and SMA receive cerebellar afferents via nucleus ventralis lateralis pars caudalis and area X.