Differential dopaminergic innervation of the two pallidal segments in the squirrel monkey (Saimiri sciureus)

Immunohistochemical studies with an antiserum raised against tyrosine hydroxylase have allowed us to demonstrate a dense dopaminergic innervation of the globus pallidus in the squirrel monkey. This innervation derived mostly from two fascicles that detached themselves from the major ascending dopaminergic bundle arising from midbrain dopamine cell bodies and running in the lateral hypothalamus. Dopaminergic fibers reached the globus pallidus by coursing along its two major output pathways: the lenticular fasciculus dorsally and the ansa lenticularis ventrally. At pallidal levels, dopaminergic fibers abounded in medullary laminae and arborized profusely within the internal pallidal segment, whereas the external pallidum displayed only few short fibers that prevailed in its dorsal portion. These findings provide the first evidence that the primate globus pallidus receives a massive and diffentially distributed dopaminergic input.     

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

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

GABAergic projection from the ventral pallidum and globus pallidus to the subthalamic nucleus

There exists a topographically organized projection from the globus pallidus and ventral pallidum to the subthalamic nucleus and adjacent lateral hypothalamus. The participation of GABA as a neurotransmitter in this projection was evaluated by retrograde labeling of cells in the pallidal area from an iontophoretic deposit of Fluoro-Gold in the subthalamus combined with in situ hybridization for mRNA of the GABA synthetic enzyme, glutamate decarboxylase (GAD). A rostrocaudal gradient in the contribution of GABA to the projection was demonstrated with a relatively small percentage of retrogradely labeled cells in the rostra1 ventral pallidum containing GAD mRNA (7%) compared to the caudal globus pallidus which had over 70% of the Fluoro-Gold containing cells double-labeled for GAD mRNA. Overall the ventral pallidum contribution to the subthalamic nucleus was less GABAergic than the portion arising from the globus pallidus (35% vs. 61%, respectively). © 1995 Wiley-Liss, Inc.     

The striatopallidal projection displays a high degree of anatomical specificity in the primate

The striatopallidal projection in the squirrel monkey (Saimiri sciureus) was studied with two highly sensitive anterograde tracers, the lectin Phaseolus vulgaris leucoagglutinin (PHA-L) and biocytin. After small PHA-L injections into various sectors of the striatum, the striatopallidal projection was found to display a very precise topographical organization. Fibers from the head of the caudate nucleus emerge as several distinct fascicles that penetrate the dorsal portion of the pallidum at various points along its rostrocaudal extent. Each fascicle arborizes into the dorsal third of the pallidum as dense plexuses composed of numerous fibers that closely entwined the dendrites of pallidal neurons, hence forming typical 'woolly' fiber arrangements. In contrast, fibers from the postcommissural putamen emerge as a few compact bundles that reach the pallidum through its lateral surface. In the pallidum, thin fibers detach themselves from these compact bundles, sweep caudally, and arborize in the form of narrow and elongated bands aligned parallel to the medullary laminae. Each band appears composed of numerous, thin and weakly varicose fibers that make only en passant type of contact with pallidal cell bodies rostrally, but form a dense field of woolly fibers caudally. In cases in which two PHA-L injections were made at two different rostrocaudal levels in the putamen, two rostrocaudally distant fields of woolly fibers, separated one another by thin varicose fibers, occur in each band. Furthermore, each PHA-L injection site in the striatum gives rise to at least two bands in each pallidal segment, indicating that the primate striatum has a dual representation at pallidal level. Finally, injections of PHA-L and biocytin into two small and mediolaterally adjacent areas of the postcommissural putamen lead to the formation of two clearly distinguishable sets of bands in each pallidal segment. Even though they lie very close to one another these two types of bands never really overlap. This experiment shows that, in contrast to previous beliefs, axons of striatal neurons from two small adjacent populations do not converge upon the same pallidal neurons but instead project to several distinct subsets of pallidal neurons. The findings of the present study reveal that the striatopallidal projection system in primates is highly ordered and displays a high degree of specificity with respect to its target sites in the pallidum. Different anatomical strategies are used to maximally exploit the relatively small pallidal space and ensure that the finely tuned corticostriatal information is not blurred as it flows through the funnel-shaped pallidum.     

Efferent connections of the ventral pallidum: evidence of a dual striato pallidofugal pathway

Previous histological and histochemical studies have provided evidence that the globus pallidus (external pallidal segment) as conventionally delineated in the rat extends ventrally and rostrally beneath the transverse limb of the anterior commissure, invading the olfactory tubercle with its most ventral ramifications. This infracommissural subdivision of the globus pallidus or ventral pallidum (VP) is most selectively identified by being pervaded by a dense plexus of substance-P-positive striatofugal fibers; the extent of this plexus indicates that the VP behind the anterior commissure continues dorsally over some distance into the anteroventromedial part of the generally recognized (supracommissural) globus pallidus; the adjoining anterodorsolateral pallidal region, here named dorsal pallidum (DP), receives only few substance-P-positive fibers, but contains a dense plexus of enkephalin-positive striatal afferents that also pervades VP. Available autoradiographic data indicate that VP and DP receive their striatal innervation from two different subdivisions of the striatum: whereas VP is innervated by a large, anteroventromedial striatal region receiving substantial inputs from a variety of limbic and limbic-system-associated structures (and therefore called "limbic striatum"), DP receives its striatal input from an anterodorsolateral striatal sector receiving only sparse limbic afferents ("nonlimbic" striatum) but instead heavily innervated by the sensorimotor cortex. The present autoradiographic study has produced evidence that this dichotomy in the striatopallidal projection is to a large extent continued beyond the globus pallidus: whereas the efferents of DP were traced to the subthalamic nucleus and substantia nigra, those of VP were found to involve not only the subthalamic nucleus and substantia nigra but also the frontocingulate (and adjoining medial sensorimotor) cortex, the amygdala, lateral habenular and mediodorsal thalamic nucleus, hypothalamus, ventral tegmental area, and tegmental regions farther caudal and dorsal in the midbrain. These findings indicate that the ventral pallidum can convey striatopallidal outflow of limbic antecedents not only into extrapyramidal circuits but also back into the circuitry of the limbic system.     

Immunohistochemical study of the serotoninergic innervation of the basal ganglia in the squirrel monkey

A specific antibody raised against 5-hydroxytryptamine (5-HT) conjugated to bovine serum albumin was used to study the serotoninergic innervation of the basal ganglia in the squirrel monkey (Saimiri sciureus). At midbrain level, numerous fine 5-HT-immunoreactive axons were seen to arise from the immunopositive neurons of the dorsal raphe nucleus and less abundantly from those of the nucleus centralis superior. The bulk of these axons formed a rather loosely arranged bundle that arched ventrorostrally through the central portion of the midbrain tegmentum and ascended toward the ventral tegmental area. Several fascicles detached themselves from this bundle to reach the substantia nigra where they arborized into a multitude of heterogeneously distributed 5-HT terminals. The 5-HT innervation was particularly dense in the pars reticulata but much less so in the pars compacta of the substantia nigra. More rostrally other 5-HT fibers swept dorsolaterally and formed a remarkably dense network of varicose fibers within the subthalamic nucleus. A multitude of 5-HT axons continued their ascending course within the lateral hypothalamic area, and many of them swept laterally to invade the lenticular nucleus. At pallidal levels, the 5-HT axons arborized much less profusely in the external segment than in the internal segment, which contained numerous 5-HT varicose fibers and terminals arranged in a typical bandlike pattern. At striatal levels, the 5-HT terminals were particularly abundant in the ventral striatum, including the nucleus accumbens and deep layers of the olfactory tubercle. They also abounded in the ventrolateral region of the putamen and the ventromedial aspect of the caudate nucleus. Overall, the number of 5-HT fibers and terminals decreased progressively along the rostrocaudal axis of the striatum and several large and elongated zones rather devoid of 5-HT immunoreactivity were visualized, particularly in the caudate nucleus and the dorsal putamen. These zones of poor 5-HT immunoreactivity were in register with similar areas devoid of tyrosine hydroxylase immunoreactivity as seen on contiguous sections. These findings reveal that all the core structures of the basal ganglia in primates receive a significant serotoninergic input, but that the densities and patterns of innervation vary markedly from one structure to the other.     

Topographic organization of the ventral striatal efferent projections in the rhesus monkey: An anterograde tracing study

The ventral striatum is considered to be that portion of the striatum associated with the limbic system by virtue of its afferent connections from allocortical and mesolimbic areas as well as from the amygdala. The efferent projections from this striatal region in the primate were traced by using 3H aminoacids and Phaseolus vulgaris-leucoagglutinin (PHA-L). Particular attention was paid to the topographic organization of terminal fields in the globus pallidus and substantia nigra, the projections to non-extrapyramidal areas, the relationship between projections from the nucleus accumbens and the other parts of the ventral striatum, and the comparison between ventral and dorsal striatal projections. This study demonstrates that in monkeys a circumscribed region of the globus pallidus receives topographically organized efferent fibers from the ventral striatum. The ventral striatal fibers terminate in the ventral pallidum, the subcommissural part of the globus pallidus, the rostral pole of the external segment, and the rostromedial portion of the internal segment. The more central and caudal portions of the globus pallidus do not receive this input. This striatal output appears to remain segregated from the dorsal striatal efferent projections to pallidal structures. Fibers from the ventral striatum projecting to the substantia nigra are not as confined to a specific region as those projecting to the globus pallidus. Although the densest terminal fields occur in the medial portion, numerous fibers also extend laterally to innervate the dorsal stratum of dopaminergic neurons of the substantia nigra and the retrorubral area. Furthermore, they project throughout the rostral-caudal extent of the substantia nigra. Projections from the medial part of the ventral striatum reach the more caudally located pedunculopontine tegmental nucleus. Thus unlike the above described terminals in the globus pallidus, the ventral striatum project widely throughout the substantia nigra, a fact that indicates that they may contribute to the integration between limbic and other output systems of the striatum. Finally, the ventral striatum projects to non-extrapyramidal regions including the bed nucleus of the stria terminals, the nucleus basalis magnocellularis, the lateral hypothalamus, and the medial thalamus.     

Convergence of subthalamic and striatal efferents at pallidal level in primates: an anterograde double-labeling study with biocytin and PHA-L

Small injections of two highly sensitive anterograde tracers, Phaseolus vulgaris-leucoagglutinin (PHA-L) and biocytin, into the striatum and the subthalamic nucleus of squirrel monkeys (Saimiri sciureus) have revealed a high degree of convergence of striatal and subthalamic fibers upon single pallidal cells. Both afferent systems formed highly complex band-like patterns that were largely in register with one another. At single cell level, the somata of pallidal neurons were closely surrounded by subthalamic terminal varicosities, whereas the dendrites were entwined mostly by striatal fibers. Typically, a subthalamopallidal fiber coursed in a caudorostral direction and arborized according to a uniform pattern along its trajectory in the pallidum. Numerous thin and markedly varicose axon collaterals detached themselves at right angle from the main subthalamopallidal fiber. These highly branched collaterals were mostly oriented along the mediolateral plane and entwined rather loosely the dendrites but surrounded very closely the somata of pallidal neurons. In contrast, a striatopallidal fiber travelled in a rostrocaudal direction. Its initial segment made only en passant contacts with pallidal cell bodies, whereas its distal end closely entwined the dendrites of pallidal neurons, forming arrangements similar to 'woolly' type fibers. These results suggest that a single subthalamic fiber may influence a rather large collection of pallidal neurons in a similar fashion, compared to the striatal input which appears to exert a more specific control upon selected sets of the same pallidal neurons.     

Efferent projections of the subthalamic nucleus in the squirrel monkey as studied by the PHA-L anterograde tracing method

The organization of the efferent connections of the subthalamic nucleus was studied in the squirrel monkey (Saimiri sciureus) by using the lectin Phaseolus vulgaris-leucoagglutinin (PHA-L) as an anterograde tracer. At the level of the basal forebrain, anterogradely labeled fibers and axon terminals were mostly found in the striatopallidal complex and the substantia innominata. In cases in which the PHA-L injection sites were placed in the central or the lateral third of the subthalamic nucleus, numerous anterogradely labeled fibers were seen to arise from the injection loci and innervate massively the globus pallidus. At pallidal levels the fibers formed bands lying parallel and adjacent to the medullary laminae. The number and the complexity of the topographical organization of these bands varied with the size and the location of the PHA-L injection site. When examined at a higher magnification, the bands of subthalamopallidal fibers appeared as rich plexuses of short axon collaterals with small bulbous enlargements that closely surrounded the cell bodies and primary dendrites of pallidal cells. In contrast, PHA-L injection involving the medial tip of the subthalamic nucleus did not produce bandlike fiber patterns in the globus pallidus. Instead, the labeled fibers formed a diffuse plexus occupying the ventral part of the rostral pole of the globus pallidus as well as the subcommissural pallidal region. The substantia innominata contained a moderate number of labeled fibers and axon terminals following injection of PHA-L in the medial tip of the subthalamic nucleus. A small to moderate number of anterogradely labeled fibers were seen in the putamen after all PHA-L injections. These subthalamostriatal fibers were long, linear, and branched infrequently. At midbrain level the substantia nigra contained a significant number of anterogradely labeled fibers and axon terminals following PHA-L injection in the subthalamic nucleus. The subthalamonigral fibers descended along the ventromedial part of the cerebral peduncle and swept laterally to reach their target. Most of these fibers formed small plexuses along the base of the pars reticulata, whereas a few others ascended along the cell columns of the pars compacta that impinged deeply within the pars reticulata. More caudally in the brainstem, a small number of fibers occurred in the area of the pedunculopontine nucleus and in the periaqueductal gray. These findings indicate that besides its well-known connection with the pallidum, the subthalamic nucleus gives rise to widespread projections to other components of the basal ganglia in primates.     

Connections of the subthalamic nucleus with ventral striatopallidal parts of the basal ganglia in the rat

The present study was undertaken to establish the precise anatomical relationship of the subthalamic nucleus (STh) with limbic lobe-afferented parts of the basal ganglia in the rat. The anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L), injected in the STh, the globus pallidus, the ventral pallidum, the ventral striatum, and the parafascicular thalamic nucleus, and the retrograde tracers Fluoro-Gold (FG) and cholera toxin B (CTb), injected in the globus pallidus, the ventral pallidum, the ventral striatum, and the ventral mesencephalon, were used for this purpose. The results of these tracing experiments confirm the general notion of reciprocal connections between the STh and pallidal areas. Thus the dorsomedial part of the STh is connected with the subcommisural ventral pallidum, whereas a more ventral and lateral part of the medial STh is related to the medial globus pallidus. The lateral hypothalamic area, directly adjacent to the STh, containing neurons with a morphology quite similar to those in the STh, projects to parts of the ventral pallidum related to the olfactory tubercle. The reciprocal projection from this pallidal area to subthalamic regions appears to be very sparse. The medial STh sends strong projections to the medial part of the entopeduncular nucleus and the adjacent lateral hypothalamic area. Sparser projections from the medial STh reach the rostral and medial part of the caudate-putamen and the nucleus accumbens. The nucleus accumbens sends a very sparse projection back to the medial STh. The projections of the medial STh to the ventral mesencephalon appear also to be topographically organized. The lateral hypothalamus and a few cells in the most medial part of the STh project to the ventral tegmental area, whereas progressively more lateral parts of the ventral mesencephalon, in particular the substantia nigra, receive input from successively more lateral and caudal parts of the STh. In addition, a number of STh fibers reach the midbrain extrapyramidal area. The lateral part of the parafascicular thalamic nucleus projects to the lateral part of the STh, whereas parafascicular neurons medial to the fasciculus retroflexus project to the dorsomedial portion of the STh. The medial part of the STh and the adjacent lateral hypothalamus are intimately connected with limbic parts of the basal ganglia in a way similar and parallel to the connections of the lateral STh with motor-related parts of the basal ganglia. These findings suggest a role for the STh in nonmotor functions of the basal ganglia.     

Immunohistochemical demonstration of differential substance P-, met-enkephalin-, and glutamic-acid-decarboxylase-containing cell body and axon distributions in the corpus striatum of the cat

The immunohistochemical localization of neuronal cell bodies and axons reactive for substance P (SP) and methionine-enkephalin (ME) was investigated in the corpus striatum of the adult cat brain and compared with that of glutamate decarboxylase (GAD), synthetic enzyme for gamma-aminobutyric acid. Striatal cell bodies reactive for ME could be identified only in colchicine treated cats, are medium size, ovoid striatal cells, and are found in large numbers in a more or less even distribution throughout the caudate nucleus, putamen, and nucleus accumbens. The striatal region most densely occupied by ME-immunoreactive cells is the ventral and central part of the caudate head. Modest numbers of larger ME-reactive neurons are dispersed throughout the entopeduncular nucleus and the pars reticulata of the substantia nigra. Striatal cells of medium size reactive for SP could be identified, with or without colchicine, in largest numbers in the medial half of the caudal three-fourths of the putamen and in clusters of irregular size and shape in the head of the caudate nucleus. Cells reactive for SP are also common in layer II and the islands of Calleja of the olfactory tubercle. We could not reliably visualize GAD-positive cell bodies in the striatum, even with colchicine treatment; however, they could be seen readily in all pallidal structures such as the globus pallidus, ventral pallidum, entopeduncular nucleus, and substantia nigra. Axons reactive for ME are found mainly in the globus pallidus where they form a dense and even network throughout the nucleus. The globus pallidus is almost devoid of SP reactivity except near its extreme caudal pole. Conversely, SP-immunoreactive axons form dense meshworks in the entopeduncular nucleus and substantia nigra where ME immunoreactivity is minimal. Fewer, but still ample numbers, of SP-reactive axons are present also in the ventral tegmental and retrorubral areas of the midbrain tegmentum and in the ventral pallidum of the basal forebrain, but only sparse ME-reactive axons are present in these areas. This differential distribution of SP- and ME-containing axons in the pallidal and nigral structures stands in contrast to the relatively homogeneous and dense distribution of GAD-containing axons throughout the dorsal and ventral pallidum, entopeduncular nucleus, and substantia nigra.(ABSTRACT TRUNCATED AT 400 WORDS)     

Projections of the globus pallidus and adjacent structures: An autoradiographic study in the monkey

Because the globus pallidus gives rise to the principal efferent system of the corpus striatum and is traversed by several fibers systems, attempts were made to study the projections of its cells by autoradiographic technics. Tritiated amino acids (L-leucine, L-proline and L-lysine) were injected into: (1) the medial pallidal segment (MPS), (2) the MPS and the substantia innominata (SI), (3) portions of the MPS and the lateral pallidal segment (LPS) and (4) parts of the putamen. Cells labeled by injections of the MPS transported isotope to thalamic nuclei (ventral anterior, VApc, ventral lateral, VLo and VLm, and the centromedian, CM), the pedunculopontine nucleus (PPN), and the lateral habenular nucleus (Hbl). Labeled cells of the MPS and SI transported isotope to: (1) thalamic nuclei (VLo, VLm and CM), (2) PPN, (3) Hbl, (4) lateral and posterior regions of the hypothalamus, and (5) extensive dorsal regions of the substantia nigra (SN). Comparisons of label transported from uptake of isotope by cells of the MPS, and cells of both pallidal segments, suggest that the LPS projects fibers only to the subthalamic nucleus (STN). Not all regions of the STN appear to receive fibers from the LPS. Selectively labeled neurons of the putamen transport isotope to broad regions of both pallidal segments and to the pars reticulata of the SN. This study suggests that cells of the MPS project profusely and topographically to: (1) the rostral ventral tier thalamic nuclei (VApc, VLo and VLm), (2) lateral portions of CM, and (3) the PPN. Fibers of the lenticular fasciculus appear to terminate preferentially in VLo. Cells in sublenticular portions of SI, and those extending into the medullary laminae of the pallidum, appear to project to: (1) HBl via the stria medullaris, (2) the pars compacta of SN, (3) lateral and posterior regions of the hypothalamus, and (4) the so-called nucleus of the ansa lenticularis. Some fibers from cells of SI appear to join the dorsal stria terminalis, but none enter the inferior thalamic peduncle and none project to any part of the dorsomedial nucleus of the thalamus.     

The cat neostriatum: relative distribution of cholinergic neurons versus serotonergic fibers

The distribution of choline acetyltransferase (ChAT)-containing neurons and serotonin (5-HT)-containing nerve fibers in the cat neostriatum was investigated by use of immunohistochemical techniques. Both ChAT- and 5-HT-staining techniques were applied to alternate brain sections, thereby allowing a precise comparison of the distribution pattern of ChAT-immunopositive cells (ChAT cells) and 5-HT-immunopositive fibers (5-HT fibers). In the neostriatum, ChAT cells were strongly stained throughout their cell bodies and proximal (first-order) dendrites. The majority of them were multipolar cells with a soma diameter of 20-50 microm (long axis)x10-30 microm (short axis). In the caudate nucleus, ChAT cells were evenly and diffusely distributed except for the dorsolateral region of its rostral half, in which latter region they were distributed in loosely formed clusters. In the rostral portion of the putamen, the density of ChAT-cell distribution was like that in the medial region of the caudate nucleus. In contrast, this distribution was more dense in the caudomedial region of the putamen, adjacent to the globus pallidus. 5-HT fibers in the neostriatum were dark-stained, of quite fine diameter (<0.6 microm), and they contained small, round varicosities (diameter, usually 0.5-1.0 microm, but some >1.0 microm). Such 5-HT fibers were distributed abundantly throughout the caudate nucleus and putamen. In the rostrocaudal portion of the caudate nucleus, their density was high in its dorsal and ventral components, and low in the middle component. Throughout the putamen, 5-HT fibers were distributed homogeneously in the mediolateral and dorsoventral directions. In the caudal portion of the putamen adjacent to the globus pallidus, the 5-HT fibers had a higher density while maintaining their homogenous distribution pattern. In the two main divisions of the striatum, the so-called 'patch' (acetylcholinesterase (AChE)-poor) and 'matrix' (AChE-rich) compartments, there was a near-even distribution of 5-HT fibers and terminals. The above results suggest that the 5-HT-dominated, raphe-striatal pathway is optimally arranged for modulating the activity of both the intrinsic and the projection neurons of the neostriatum.     

Pedunculopontine nucleus in the squirrel monkey: Projections to the basal ganglia as revealed by anterograde tract-tracing methods

The efferent projections of the pedunculopontine nucleus (PPN) to the ganglia have been studied in the squirrel monkey (Saimiri sciureus) with [³H]leucine and Phaseolus vulgaris-leucoagglutinin (PHA-L) as anterograde tracers. Following unilateral injections of [³H]leucine or PHA-L in the central portion of the PPN, numerous autoradiographic linear profiles or PHA-L-labeled fibers ascend to the forebrain, both ipsilaterally and contralaterally. These fibers form a compact bundle that courses in the central portion of the mesopontine tegmentum. At rostral mesencephalic levels, theis bundle splits into ventromedial and dorsolateral fascicles that arborize in basal ganglia and thalamic nuclei, respectively. The substantia nigra and the subthalamic nucleus are by far the most densely innervated structures of the basal ganglia. In these two nuclei, labeled fibers arborize profusely ipsilaterally and less abundantly contralaterally. The labeled fibers in the substantia nigra are thin and varicose and arborize almost exclusively in the pars compacta, where they closely surround the soma and proximal dendrites of dopaminergic neurons. In the subthalamic nucleus labeled fibers are also thin and appear to contact more than one neuron along their course. Numerous labeled fibers also occur in the pallidal complex, where they arborize most profusely in the internal segment. Several thick, labeled fibers oriented dorsolaterally in the pallidal complex give rise to thinner fibers that closley surround the soma and proximal dendrites of pallidal neurons. Some labeled fibers are also scattered in the striatum. These fibers abound in the peripallidal and ventral portions of the putamen, are more sparsely distributed in the remaining portion of the putamen as well as in the caudate nucleus, and are virtually absent in the ventral striatum. These results reveal that the PPN gives rise to a massive and highly ordered innervation of the basal ganglia in the squirrel monkey. This nucleus may thus act as an important relay in the basal ganglia circuitry in primates. © 1994 Wiley-Liss, Inc.     

Topographical and Synaptic Organization of the GABA-Containing Pallidosubthalamic Projection in the Rat

The anterograde transport of Phaseolus vulgaris-leucoagglutinin (PHA-L) was combined with postembedding immunocytochemistry for gamma-aminobutyric acid (GABA) to study the topography, the synaptic organization and the neurotransmitter content of the pallidosubthalamic projection in the rat. After injections of PHA-L in different parts of the globus pallidus a rich plexus of anterogradely labelled fibres and terminals was found in the ipsilateral subthalamic nucleus. The immunoreactive elements were distributed according to a mediolateral and rostrocaudal topography. Injections of PHA-L restricted to the lateral two-thirds of the globus pallidus gave rise to a massive anterograde labelling confined to the lateral half of the subthalamic nucleus. On the other hand, injections of PHA-L strictly confined to the medial part of the globus pallidus resulted in anterograde labelling that occupied the ventromedial pole of the subthalamic nucleus. In some cases a few retrogradely labelled cells were found in the subthalamic nucleus after PHA-L injections in the globus pallidus. The perikarya and the primary dendrites of these labelled cells were sometimes surrounded by anterogradely labelled terminals suggesting a close reciprocal connection between the globus pallidus and the subthalamic nucleus. Electron microscopic analysis of the PHA-L-labelled terminals revealed that they contain many mitochondria, numerous small round or slightly pleomorphic vesicles and occasionally one or two large dense core vesicles. They form symmetrical synaptic contacts predominantly with the proximal dendrites (39%) and less frequently with the perikarya (31%) and the distal dendrites (30%) of the subthalamic cells. Quantitative measurements showed that the pallidosubthalamic varicosities have a diameter ranging from 0.7 to 4.5 microm and a mean cross-sectional area of 0.79 +/- 0.26 microm2 (Mean +/- SD). Postembedding immunocytochemistry for GABA revealed that the PHA-L-immunoreactive pallidosubthalamic axon terminals display GABA immunoreactivity. The results of our study demonstrate that the pallidosubthalamic projection is organized according to a mediolateral and rostrocaudal topography and that the proximal dendrites of the subthalamic cells are the major targets of the GABA-immunoreactive pallidosubthalamic terminals. This suggests that the globus pallidus exerts a powerful control over the subthalamic cells through an inhibitory GABAergic pathway.     

Tyrosine hydroxylase-immunoreactive elements in the human globus pallidus and subthalamic nucleus.

In contrast to the well-established dopaminergic innervation of the neostriatum, the existence of dopaminergic innervation of the subthalamic nucleus and globus pallidus is controversial. In the present study, tyrosine hydroxylase (TH)-immunoreactive elements were observed by light microscopy after antigen retrieval in the subthalamic nucleus and in the internal and external segments of the globus pallidus in postmortem human brain. Small islands of apparent neostriatal tissue with abundant arborization of fine, TH-immunoreactive axons in the vicinity of calbindin-positive small neurons resembling neostriatal medium spiny neurons were present in the external segment of the globus pallidus. Large numbers of medium-large, TH-immunoreactive axons were observed passing above and through the subthalamic nucleus and through both pallidal segments; these are presumed to be axons of passage on their way to the neostriatum. In addition, fine, TH-immunoreactive axons with meandering courses, occasional branches, and irregular outlines, morphologically suggestive of terminal axon arborizations with varicosities, were seen in both pallidal segments, including the ventral pallidum, and the subthalamic nucleus, consistent with a catecholaminergic (probably dopaminergic) innervation of these nuclei. This finding suggests that, in Parkinson's disease and in animal models of this disorder, loss of dopaminergic innervation might contribute to abnormal neuronal activation in these three nuclei.     

A Golgi analysis of the primate globus pallidus. III. Spatial organization of the striato-pallidal complex

An atlas of transverse sections of the globus pallidus and striatum was established in macaque with reference to ventricular coordinates. The three-dimensional geometry of the striato-pallidal complex was investigated by means of sagittal and horizontal reconstructions. Both a personal case studied with autoradiography and data from literature were used to analyze the distribution of cortical axons into the striatum. One may distinguish two striatal territories: one, somatotopically arranged, sensorimotor territory extending over the major part of the putamen; and the other, an associative territory, comprising the caudate nucleus and antero-medial and postero-inferior parts of the putamen. The striato-pallido-nigral bundle was studied using Golgi, Perls, and Fink-Heimer techniques. The bundle is described in four parts: prepallidal (subdivided into caudato-pallidal and putamino-pallidal subparts), transpallidal, pallido-nigral, and nigral. The tracing of the limit between the caudate (associative) and putaminal (essentially sensorimotor) territories shows that the two components are of roughly the same size in the pallidum. The data were compared with geometry and orientation of the dendritic arborizations of large pallidal neurons analyzed in Yelnik et al. ('84). Each pallidal dendritic disc is able to receive axons from a wide region of the striatum. This leads to a convergence on pallidal neurons of striatal axons from different striatal somatotopic strips and from the sensorimotor and associative territories. This is an indication that the globus pallidus may have an integrative role.     

Distribution of cholinergic pallidal neurons in the squirrel monkey (Saimiri sciureus) based upon choline acetyltransferase.

The distribution of cells immunoreactive to choline acetyltransferase (ChAT-IR) in, and around the globus pallidus were studied in the squirrel monkey. Intrinsic pallidal ChAT-IR neurons in the globus pallidus were most numerous in ventrocaudal regions of the lateral pallidal segment (LPS) and in the oral pole of the medial pallidal segment (MPS). Smaller numbers of ChAT-positive cells were seen in portions of the medullary laminae of the pallidum. Computer measurements of somal areas of ChAT-IR cells in the globus pallidus, substantia innominata and putamen were made. Morphological features and somal areas of ChAT-IR cells in the globus pallidus and in the Ch4 group of the substantia innominata were strikingly similar. Cholinergic pallidal neurons appear to be part of the Ch4 cell group and have similar widespread cortical projections. The smaller cholinergic neurons in the striatum are considered to be intrinsic neurons which primarily act upon spiny striatal projection neurons. The possible local interaction of pallidal cholinergic neurons upon GABAergic neurons is unknown.     

Subthalamic projections to the globus pallidus: An electrophysiological study in the rat

The connections between the subthalamic nucleus (STN) and the globus pallidus (GP) were investigated electrophysiologically. By the use of stimulating electrode arrays it was determined that the predominant response of globus pallidus neurons to stimulation of the subthalamic nucleus was inhibition. A smaller proportion of short-latency orthodromic activation was also observed. Antidromic activation from the subthalamic nucleus was seen occasionally, although more laterally located in the pallidum. The results demonstrate the existence of reciprocal connections between these two regions and show that the predominant effect of subthalamic activation is inhibition of pallidal cells.     

Effect of intrastriatal 6-OHDA lesion on dopaminergic innervation of the rat cortex and globus pallidus

The present study examined in the rat the effect of a partial lesion of the nigrostriatal dopaminergic pathway induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA), on the dopaminergic innervation of the cortex and the globus pallidus as revealed using tyrosine hydroxylase (TH) immunoreactivity. Twenty-eight days after unilateral injection of 6-OHDA into the dorsal part of the striatum, TH-positive fiber density was reduced by 41% in the dorsal and central part of the structure, and was accompanied by a retrograde loss of 33% of TH-positive neurons in the substantia nigra (SN), while the ventral tegmental area was completely spared. In the SN, TH-positive cell loss was most severe in the ventral part of the structure (-55%). In the same animals, a substantial loss of TH-positive fibers was evident in the dorsal part of the globus pallidus, and involved both thick fibers of passage and thin varicose terminal axonal branches. In the cortex, a loss of TH-positive fibers was prominent in the cingulate area, moderate in the motor area and less affected in the insular area, while the noradrenergic innervation revealed using dopamine-beta-hydroxylase immunoreactivity was preserved in all of these cortical subregions. These results demonstrate that the intrastriatal 6-OHDA lesion model in rats produces a significant loss of dopaminergic axons in extrastriatal structures including the pallidum and cortex, which may contribute to functional sequelae in this animal model of Parkinson's disease.