Calcium-binding proteins in primate basal ganglia.

This paper describes the distribution of the calcium-binding proteins calbindin-D28k. Parvalbumin and calretinin in primate basal ganglia. The data derive from immunocytochemical studies undertaken in squirrel monkeys (Saimiri sciureus) and in normal human individuals. In the striatum, calbindin labels medium-sized spiny projection neurons whereas parvalbumin and calretinin mark two separate classes of aspiny interneurons. The striatal matrix compartment is markedly enriched with calbindin while striatal patches (striosomes) display a calretinin-rich neuropil. In the pallidum, virtually all neurons contain parvalbumin but none express calbindin. Calretinin occurs only in a small subpopulation of both large and small pallidal neurons. In the subthalamic nucleus, there exists a multitude of parvalbumun-positive cells and fibers but the number of calretinin and calbindin-positive neuronal elements is small. In the substantia nigra/ventral tegmental area complex, calbindin and calretinin occur principally in dopaminergic neurons of the dorsal tier of the pars compacta and in those of the ventral tegmental area. Parvalbumin is strictly confined to the GABAergic neurons of the pars reticulata and lateralis. Calbindin-rich fibers abound in the pars reticulata and lateralis, while calretinin-positive axons are confined to the pars compacta. These results indicate that calbindin and parvalbumin are distributed according to a strikingly complementary pattern in primate basal ganglia. Calretinin is less ubiquitous but occurs in all basal ganglia components where it labels distinct subsets of neurons. Such highly specific patterns of distribution indicate that calbindin, parvalbumin and calretinin may work in synergy within primate basal ganglia.

Limbic system-associated membrane protein (LAMP) in primate amygdala and hippocampus.

The distribution of the limbic system-associated membrane protein in the amygdaloid complex and hippocampal formation of cynomolgus monkeys (Macaca fascicularis) was studied with immunohistochemical procedures. A highly complex and heterogeneous staining pattern is encountered in the macaque amygdala. The basal, lateral, and accessory basal nuclei display the most intense immunostaining with local heterogeneities. The lateral division of the central nucleus also stains intensely, whereas the medial division of the central nucleus and the medial nucleus are more weakly stained. The dorsal division of the bed nucleus-amygdala continuum (extended amygdala) is strongly immunoreactive. The hippocampus displays the strongest immunoreactivity encountered so far in the primate brain. The intensity of the immunostaining is highest in the cornu Ammonis (Ammon's horn; CA1-CA3 fields) and gradually decreases toward the dentate gyrus or the subicular area. In the hippocampus proper, the stratum radiatum, the pyramidal layer, the stratum oriens, and the alveus all display intense immunoreactivity. The immunostaining is much less prominent in the dentate gyrus, whose granule cell layer is completely devoid of labeling. In the subicular area, there is a lateromedial decreasing gradient in immunostaining intensity, the subiculum being moderately stained and the parasubiculum weakly stained. These results reveal that the limbic system-associated membrane protein labels structures that form the core of the limbic system in primates. Within each of these structures, however, the labeling is highly heterogeneous and appears to be confined to specific functional domains.

Distribution of limbic system-associated membrane protein immunoreactivity in primate basal ganglia.

The limbic system-associated membrane protein is a 64,000-68,000 mol.wt molecule known to be preferentially expressed by neurons in limbic structures of rats and cats. The present immunohistochemical study describes the distribution of this protein in the basal ganglia of Macaca fascicularis. The ventral striatum of the cynomolgus monkey displays a very intense immunostaining, whereas the dorsal striatum is much more weakly stained, except for some small zones scattered in the caudate nucleus and, to a lesser extent, in the putamen. These protein-rich zones are in register with striosomes, as visualized on adjacent sections immunostained for calbindin. At pallidal levels, immunostaining for the protein is observed only in the subcommissural regions, at the ventromedial tip of the internal pallidum, and in the caudoventral portion of the external pallidum. At nigral levels, the immunostaining is highly heterogeneous with a marked decreasing rostrocaudal gradient. The staining is most intense in nigral regions that receive striatal inputs and are enriched with calbindin. Nigral sectors populated by dopaminergic neurons, as visualized on adjacent sections immunostained for tyrosine hydroxylase, are largely devoid of immunoreactivity. In contrast, the immunostaining is uniformly intense in the ventral tegmental area. This study provides the first neuroanatomical evidence for teh existence of the limbic system-associated membrane protein in primate brain. It reveals that this glycoprotein is distributed in a highly heterogeneous manner in primate basal ganglia, where it preferentially labels regions that are anatomically and functionally linked to the limbic system.

Chemical anatomy of primate basal ganglia.

This paper provides an overview of the anatomical and functional organization of the most prominent chemospecific neuronal systems that compose the basal ganglia in primates. Emphasis is placed on the heterogeneity and diversity of small-molecule transmitters, neuroactive peptides and proteins used by basal ganglia neurons. Dopaminergic, serotoninergic and cholinergic neuronal systems are shown to comprise multiple subsystems organized according to highly specific patterns. These subsystems differentially regulate gene expression of several neuroactive peptides, including tachykinins, enkephalins, dynorphin, somatostatin, and neuropeptide Y, that are used by distinct subsets of basal ganglia neurons. Glutamatergic excitatory inputs establish distinct functional territories within the basal ganglia, and neurons in each of these territories act upon other brain neuronal systems through a GABAergic disinhibitory output mechanism. A striking complementary pattern of distribution of the calcium-binding proteins parvalbumin and calbindin D-28k is noted in all basal ganglia components. The limbic system-associated membrane protein (LAMP) is confined chiefly to basal ganglia sectors that are anatomically and functionally related to limbic system structures; these may serve as functional interfaces between the basal ganglia and the limbic system. The functional status of the various basal ganglia chemospecific systems in neurodegenerative diseases, such as Parkinson's disease and Huntington's chorea, is examined. It is concluded that these multiple transmitter-related systems cannot be analyzed separately as they form highly complex and interactive neuronal networks. These complexities should be taken into account to reach a better understanding of the functions of primate basal ganglia in health and disease.

Mesencephalic grafts partially restore normal nigral dynorphin levels in 6-hydroxydopamine-lesioned rats treated chronically with L-dihydroxyphenylalanine.

An increase of dynorphin levels is commonly observed in the substantia nigra of 6-hydroxydopamine-lesioned rats chronically treated with daily injections of L-DOPA. This study investigates the potential of fetal mesencephalic grafts to restore normal levels of dynorphin in such cases. After 19 consecutive days of treatment with L-DOPA, lesioned rats with the most severe nigral cell loss showed increased levels of dynorphin in the substantia nigra ipsilateral to the lesion, as expected. The changes were assessed by standard immunohistochemical techniques combined with the use of an image analysis system. Such changes were not observed in the substantia nigra of rats that received fetal mesencephalic cells in the striatum six months prior to the beginning of the chronic treatment. However, only animals displaying heavy loss of dopaminergic neurons in the substantia nigra pars compacta showed significant changes of dynorphin levels in the substantia nigra following drug treatment. Our results show that fetal nigral cells transplanted into the striatum have the potential to prevent biochemical changes observed in the basal ganglia induced by the lesion of the nigrostriatal pathway and chronic treatment with L-DOPA. It is still hypothesized from studies in rodents that this peptide may play a role in the appearance of DOPA-induced dyskinesia, because dynorphin levels increase in the substantia nigra pars reticulata after L-DOPA treatment. If this happens to be the case, then the use of fetal nigral grafts could therefore be an important step to prevent the induction of dyskinesia after chronic L-DOPA treatment.

Striatal changes in preproenkephalin mRNA levels in parkinsonian monkeys.

Levels of preproenkephalin (PPE) mRNA were measured in different sectors of the striatum with in situ hybridization histochemistry in both normal and parkinsonian (MPTP-treated) squirrel monkeys. In parkinsonian monkeys, a marked increase in PPE mRNA levels was noted in the dorsolateral third of the precommissural putamen and in most of the postcommissural putamen. These regions largely correspond to the sensorimotor striatal territory. The other striatal sectors, including the caudate nucleus, did not exhibit significant changes, despite the fact that the loss of the dopaminergic input was severe in most of the striatum. These results reveal that PPE mRNA expression is specifically altered in striatal regions involved in sensorimotor processing in parkinsonian monkeys.

Calbindin D-28k and choline acetyltransferase are expressed by different neuronal populations in pedunculopontine nucleus but not in nucleus basalis in squirrel monkeys.

Single- and double-immunostaining procedures were used to study the distribution of the acetylcholine synthesizing enzyme choline acetyltransferase (ChAT) and the calcium binding protein calbindin D-28k in the nucleus basalis of Meynert (nbM) and in the pedunculopontine nucleus (PPN) of the squirrel monkey (Saimiri sciureus). As expected from previous studies in other primates, including humans, the nbM in the squirrel monkey is enriched with large ChAT-immunoreactive neurons that form clusters in the substantia innominata. Some ChAT-positive neurons are also scattered more dorsally within the internal and external medullary laminae of the pallidal complex. A smaller number of calbindin-immunoreactive cells occur in the same locations and their mean cross-sectional somatic area (424 microns 2) is not significantly different from that of the ChAT-immunoreactive cells (450 microns 2). Furthermore, 60% of the ChAT-immunopositive cells in the nbM display calbindin immunoreactivity. Most of these double-immunoreactive neurons occur in the typical clusters of the nbM, whereas the large neurons scattered in between the clusters display ChAT immunoreactivity only. In the PPN, ChAT-positive neurons are scattered around and partly within the superior cerebellar peduncle and also form a dense cluster in the lateral portion of the mesopontine tegmentum. Calbindin-immunoreactive cells also abound around the superior cerebellar peduncle, but they are more sparsely distributed and cover a larger sector of the tegmentum than the ChAT-positive neurons. These calbindin-immunoreactive cells are significantly smaller (200 microns 2) than the ChAT-immunoreactive cells (471 microns 2) and no double-immunostained neurons are present in the PPN.(ABSTRACT TRUNCATED AT 250 WORDS)

Dystrophin-like immunoreactivity in monkey and human brain areas involved in learning and motor functions.

Two antidystrophin antibodies against different fragments of dystrophin were used to detect this polypeptide in monkey and human brains. Dystrophin was revealed by immunoperoxidase amplified with the biotin/avidin system and by immunoblotting. A dystrophin-like immunoreactivity was uniformly expressed in several brain regions implicated in learning and motor functions. Dystrophin function is not clear but our results raise the possibility that this protein may be involved in the cognitive impairment observed in several Duchenne muscular dystrophy (DMD) patients.