The current model of basal ganglia organization under scrutiny.
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Animals↗
Biomedical subjects
A Parent
Publications and source records attributed to A Parent.
Calcium-binding proteins in primate cerebellum.
Single and double antigen localization procedures were used to study the distribution of the calcium-binding proteins calretinin, calbindin and parvalbumin in the cerebellum of the squirrel monkey (Saimiri sciureus). The immunostaining experiments have revealed that each of the three calcium-binding proteins occurred, either alone or in various combinations, in many neuronal types of the monkey cerebellum, including the Purkinje cells. Immunoreactivity for calbindin was detected in virtually all Purkinje cells, whereas immunoreactivity for calretinin and parvalbumin was encountered only in some subpopulations of Purkinje cells. In the vermal region, parvalbumin immunostaining appeared in the form of typical weak and strong alternating parasagittal bands. Calretinin immunoreactivity was found in virtually all neurons and fiber systems related to the granular layer, including the monodendritic cells, the granule cells and their parallel fibers, the Golgi and Lugaro cells and the mossy fibers. The Golgi cells also displayed calbindin and parvalbumin immunoreactivity. Parvalbumin was found to labeled both the climbing and mossy fibers, as well as the basket and stellate cells lying in the molecular layer. These results reveal that virtually all the different neuronal types in the primate cerebellum contain at least one of three calcium-binding proteins investigated in the present study. Furthermore, calretinin appears to be a particularly reliable molecular maker for all the neuronal elements associated with the granular layer in the primate cerebellum.
Animals↗
Calretinin gene expression in the human thalamus.
The localization and levels of expression of the calcium-binding protein calretinin (CR) in the human thalamus was studied with an in situ hybridization method applied to formalin-fixed postmortem material from normal individuals. The riboprobe used was generated from a specific fragment of human CR cDNA. As visualized on X-ray film autoradiographs, high levels of CR gene transcript occurred in several thalamic nuclei, including the reticular nucleus, mediodorsal nucleus, rostral intralaminar nuclei (paracentral, central medial and central lateral) and several midline nuclei (paraventricular, reuniens and medioventral nuclei). In the reticular nucleus, neurons expressing CR mRNA were few in number but formed dense and widely distributed clusters. In contrast, virtually all neurons in the rostral intralaminar and midline nuclei expressed very high levels of CR mRNA and formed a prominent rim around the mediodorsal nucleus, which contained scattered clusters of labeled neurons. The caudal intralaminar nuclei, principally the centromedian nucleus, displayed very few neurons expressing CR mRNA. Only the medial part of the parafascicular nucleus expressed moderate levels of CR mRNA. The nuclei of the ventral group (ventral anterior, lateral and posterior nuclei) were virtually devoid of CR gene transcript. This highly heterogeneous pattern of mRNA expression suggests that CR may be heavily involved in the function of the so-called non-specific nuclei, but not in that of the specific relay nuclei of the human thalamus. The data also demonstrate that the presence of CR gene transcript can easily be detected on formalin-fixed sections of the human brain.
Adult↗
The anti-apoptosis bcl-2 proto-oncogene is preferentially expressed in limbic structures of the primate brain.
By virtue of its capacity to prevent apoptosis the protooncogene bcl-2 is believed to play a crucial role in CNS development. Studies in rodents have shown that the anti-apoptosis Bcl-2 protein is widely expressed during CNS development, but undergoes a marked down-regulation during maturation and is present only at low concentrations in adult CNS. In contrast, current data suggest that Bcl-2 protein in adult monkey brain results from microglial expression. In the present immunohistochemical study, however, numerous subsets of Bcl-2-immunoreactive neurons were encountered in the amygdala, hippocampus, hypothalamus, limbic cortices and striatum of squirrel monkeys. Of particular interest was the presence in the basal portion of the amygdala and adjoining piriform cortex of numerous intensely immunoreactive cells with long and thick immunopositive processes that ran into the ventral amygdalofugal pathway. At striatal level Bcl-2-positive neurons were strictly confined to calbindin-poor striosomes, which are specifically innervated by limbic cortices. This study has provided the first evidence for the occurrence of Bcl-2 in mature monkey brain. It has further shown that this protein is preferentially expressed in limbic structures in primate forebrain. The sustained expression of this anti-apoptosis protein may protect limbic system neurons from various injuries or neurodegeneration. It may also be involved in the functional and structural changes that occur throughout adulthood in some regions of the primate limbic system.
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Calretinin-immunoreactive neurons in the human thalamus.
The distribution of the calcium-binding protein calretinin in the thalamus of normal human individuals was studied with immunohistochemistry. Calretinin immunoreactivity was weak in the geniculate bodies and in nuclei of the ventral and posterior groups, moderate in the reticular nucleus and in nuclei of the anterior, medial, and lateral groups, and strong in nuclei of the midline group and anterior intralaminar nuclei. The mediodorsal nucleus was unique among thalamic nuclei because it contained a wide variety of intensely immunostained perikarya embedded in a moderately-labelled neuropil. The reticular nucleus displayed several small and uniformly distributed neuronal clusters composed of immunostained perikarya lying in a moderately-labelled neuropil. Intense and uniform immunostaining was observed in all midline nuclei and in the anterior intralaminar nuclei, including the paracentral and central lateral nuclei. These nuclei, which harboured numerous intensely-stained perikarya lying in a dense immunoreactive neuropil, were the most strongly-immunoreactive structures of the entire human thalamus. At the level of the posterior intralaminar nuclei, the central median nucleus was virtually free of immunostaining whereas the parafascicular nucleus was moderately labelled. The nucleus submedius located just beneath the central median/parafascicular complex displayed a very intense calretinin immunostaining. This study has provided evidence for the presence of the protein calretinin in the human thalamus. The pattern of distribution of calretinin, as delineated in the present study, suggests that this calcium-binding protein may participate in various subcortical and cortical thalamic systems involved in the modulation of emotional and motivational states.
Aged↗
Chemoarchitecture of the primate dorsal raphe nucleus.
The dorsal raphe nucleus (DR) harbours the largest single collection of serotonin (5-HT)-containing neurons in the brain but also comprises other types of chemospecific neurons. The aim of the present study was to characterise morphologically and immunohistochemically the DR in the squirrel monkey (Saimiri sciureus). The morphology of the DR 5-HT-immunoreactive (ir) neurons was analysed and their distribution compared to that of neurons displaying immunoreactivity for either tyrosine hydroxylase (TH), gamma-aminobutyric acid (GABA), substance P (SP), calbindin-D28k (CB), calretinin (CR) or parvalbumin (PV). The 5-HT-ir neurons were distributed in a highly heterogeneous manner throughout the rostrocaudal extent of the DR. The morphology and density of the 5-HT neurons were found to vary significantly in the major subdivisions of the primate DR, that is, the median, ventral, dorsal, ventrolateral, lateral and caudal subnuclei. Numerous SP-, GABA- and PV-ir neurons occurred in all six subnuclei of the DR. The distribution of SP-ir neurons was largely in register with that of 5-HT-ir neurons. Neurons expressing the other neuronal markers (TH, CB, CR) were not present in all six DR subnuclei and their distribution was either complementary to, or in register with, that of 5-HT-ir neurons. The median subnucleus was unique because it contained all the different types of chemospecific neurons. This study has revealed that the primate DR is chemically highly heterogeneous, a finding that may explain the multifarious influence that this nucleus exerts upon various forebrain structures.
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Impaired cerebellar long-term potentiation in type I adenylyl cyclase mutant mice.
Activation of adenylyl cyclase and the consequent production of cAMP is a process that has been shown to be central to invertebrate model systems of information storage. In the vertebrate brain, it has been suggested that a presynaptic cascade involving Ca influx, cAMP production, and subsequent activation of cAMP-dependent protein kinase is necessary for induction of long-term potentiation (LTP) at the cerebellar parallel fiber-Purkinje cell synapse. We have used mutant mice in which the major Ca-sensitive adenylyl cyclase isoform of cerebellar cortex (type I) is deleted to show that this results in an approximately 65% reduction in cerebellar Ca-sensitive cyclase activity and a nearly complete blockade of cerebellar LTP assessed using granule cell-Purkinje cell pairs in culture. This blockade is not accompanied by alterations in a number of basal electrophysiological parameters and may be bypassed by application of an exogenous cAMP analog, suggesting that it results specifically from deletion of the type I adenylyl cyclase.
Adenylyl Cyclases↗
Synaptic transmission and hippocampal long-term potentiation in olfactory cyclic nucleotide-gated channel type 1 null mouse.
Field potential recording was used to investigate properties of synaptic transmission and long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in both hippocampal slices of mutant mice in which the alpha-subunit of the olfactory cyclic nucleotide-gated channel (alpha3/OCNC)1 was rendered null and also in slices prepared from their wild-type (Wt) littermates. Several measures of basal synaptic transmission were unaltered in the OCNC1 knockout (KO), including maximum field excitatory postsynaptic potential (fEPSP) slope, maximum fEPSP and fiber volley amplitude, and the function relating fiber volley amplitude to fEPSP slope and paired-pulse facilitation. When a high-frequency stimulation protocol was used to induce LTP, similar responses were seen in both groups [KO: 1 min, 299 +/- 50% (mean +/- SE), 60 min, 123 +/- 10%; Wt: 1 min, 287 +/- 63%; 60 min, 132 +/- 19%). However, on theta-burst stimulation, the initial amplitude of LTP was smaller (1 min after induction, 147 +/- 16% of baseline) and the response decayed faster in the OCNC1 KO (60 min, 127 +/- 18%) than in Wt (1 min, 200 +/- 14%; 60 min, 169 +/- 19%). Analysis of waveforms evoked by LTP-inducing tetanic stimuli revealed a similar difference between groups. The development of potentiation throughout the tetanic stimulus was similar in OCNC1 KO and Wt mice when high-frequency stimulation was used, but OCNC1 KO mice showed a significant decrease when compared with Wt mice receiving theta-burst stimulation. These results suggest that activation of cyclic nucleotide-gated channels may contribute to the induction of LTP by weaker, more physiological stimuli, possibly via Ca2+ influx.
Animals↗
Parvalbumin and calbindin D-28k in the entopeduncular nucleus, subthalamic nucleus, and substantia nigra of the rat as revealed by double-immunohistochemical methods.
The cellular localization of calbindin D-28k (CB) and parvalbumin (PV) was analyzed by means of double-immunohistochemical techniques applied to single sections in the entopeduncular nucleus (EP), the subthalamic nucleus (STh), and the substantia nigra (SN) of the rat. In EP, PV-positive cells abounded centrally, where CB immunostaining was minimal. The medial and ventral sectors of EP were markedly enriched with CB neuropil but devoid of PV-positive cells. CB-positive neurons abounded particularly in the rostral pole of EP. In STh, PV-positive neurons and neuropil were concentrated in the lateral two thirds of this nucleus. Only a few PV-positive cells were detected in sectors of STh devoid of PV-positive neuropil. The STh was completely devoid of CB immunostaining. In the rostral two thirds of SN, PV-positive neurons were largely confined to the lateral half of the pars reticulata (SNR), and occurred more ventrally and medially in the caudal third. Intense CB-immunoreactive neuropil was found in medial and dorsal parts of rostral SNR, and CB-positive cells were observed in the SN pars compacta and the ventral tegmental area. PV and CB cells were also observed in the pars lateralis of SN. The markedly heterogeneous pattern of distribution of PV and CB in EP, STh, and SN suggests that these two calcium-binding proteins may label distinct functional domains in each of these three components of the rat basal ganglia.
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Re-evaluation of the functional anatomy of the basal ganglia in normal and Parkinsonian states.
In the late 1980s, a functional and anatomical model of basal ganglia organization was proposed in order to explain the clinical syndrome of Parkinson's disease. According to this model, the pathological overactivity observed in the subthalamic nucleus and the output station of the basal ganglia plays a crucial role in the pathophysiology of the motor signs of Parkinson's disease. The hyperactivity of subthalamic neurons in Parkinsonism is viewed as a direct consequence of a pathological hypoactivity of the external segment of the pallidum. This article reviews recent data from different experimental approaches that challenge the established model of basal ganglia organization by reinterpreting the functional interaction between the external segment of the pallidum and the subthalamic nucleus in both the normal and pathological state. Indeed, recent neurobiochemical studies have rather unexpectedly shown that the GABAergic and metabolic activities of the external pallidum are not decreased in human and non-human primates with Parkinsonism. This absence of any decrease in activity might be explained by the functionally antagonistic influences of the striatal and subthalamic afferences within the external pallidum, as suggested by several anatomical studies. In addition, there are clues from electrophysiological studies to suggest that the hyperactivity found in the subthalamic neurons in Parkinsonism may not depend solely on the level of activity in the external pallidum. In such a framework, the hyperactivity of the subthalamic neurons would have to be explained, at least in part, by other sources of excitation or disinhibition. However, any explanation for the origin of the subthalamic overactivity in Parkinsonism remains speculative.
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Distribution of calretinin, calbindin-D28k and parvalbumin in the hypothalamus of the squirrel monkey.
The immunohistochemical approach was used to study the distribution of three calcium-binding proteins of the 'EF hand' family, namely calretinin, calbindin-D28k and parvalbumin, in the preoptico-hypothalamic complex of the squirrel monkey (Saimiri sciureus). These three calcium-binding proteins were found to be heterogeneously distributed in the primate hypothalamus. Neurons expressing high levels of calretinin immunoreactivity were particularly abundant in the infundibular (arcuate) nucleus, the suprachiasmatic nucleus, the lateral area and the dorsomedial nucleus of the hypothalamus. Neurons displaying immunoreactivity for calbindin-D28k were especially numerous in the medial preoptic area and diagonal band nucleus, as well as in the magnocellular subdivision of the paraventricular nucleus, the suprachiasmatic nucleus, the supraoptic nucleus, the infundibular nucleus, the ventromedial nucleus and the mammillary bodies of the hypothalamus. Fibers displaying intense immunoreactivity for either calretinin or calbindin-D28k were very abundant in the median eminence of the hypothalamus. In contrast to calretinin- and calbindin-D28k, parvalbumin was largely absent from the primate preoptico-hypothalamic complex. Parvalbumin-immunoreactive neurons occurred in significant number only in the most lateral portion of the medial mammillary nucleus in the squirrel monkey. The results of the present study suggest that calretinin and calbindin-D28k may act, either in concert or in a complementary manner, so as to participate in some specific aspects of the multifarious role of the hypothalamus in primates. In contrast to the other two calcium-binding proteins, parvalbumin is unlikely to be involved in a significant manner in hypothalamic functions in primates.
Animals↗
[Anatomy and physiopathology of the basal ganglia].
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Basal Ganglia↗
The striatopallidal fiber system in primates.
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Animals↗
The brain in evolution and involution.
This paper provides an overview of the phylogenetic evolution and structural organization of the basal ganglia. These large subcortical structures that form the core of the cerebral hemispheres directly participate in the control of psychomotor behavior. Neuroanatomical methods combined with transmitter localization procedures were used to study the chemical organization of the forebrain in each major group of vertebrates. The various components of the basal ganglia appear well developed in amniote vertebrates, but remain rudimentary in anamniote vertebrates. For example, a typical substantia nigra composed of numerous dopaminergic neurons that project to the striatum already exists in the brain of reptiles. Other studies in mammals show that glutamatergic cortical inputs establish distinct functional territories within the basal ganglia, and that neurons in each of these territories act upon other brain neuronal systems principally via a GABAergic disinhibitory output mechanism. The functional status of the various basal ganglia chemospecific systems was examined in animal models of neurodegenerative diseases, as well as in postmortem material from Parkinson's and Huntington's disease patients. The neurodegenerative processes at play in such conditions specifically target the most phylogenetically ancient components of the brain, including the substantia nigra and the striatum, and the marked involution of these brain structures is accompanied by severe motor and cognitive deficits. Studies of neural mechanisms involved in these akinetic and hyperkinetic disorders have led to a complete reevaluation of the current model of the functional organization of the basal ganglia in both health and disease.
Animals↗
Sparing of striatal neurons coexpressing calretinin and substance P (NK1) receptor in Huntington's disease.
Immunohistochemical studies of the striatum in normal human subjects with a double-antigen localization method have revealed the presence of large and medium-sized aspiny neurons displaying immunoreactivity for both the calcium-binding protein calretinin and substance P (neurokinin-1) receptor. These large and medium-sized cells from two distinct classes of striatal interneurons, which together represent less than 3% of the total neuronal population of the human striatum. Observations made in four cases of Huntington's disease revealed that such doubly labeled interneurons are still present in the striatum of these patients, despite the marked atrophy of the structure. This study provides the first evidence for the existence of interneurons containing calretinin and expressing tachykinin receptors in the human striatum. It also demonstrates the selective sparing of these chemospecific striatal neurons in Huntington's disease.
Adult↗
Corticostriatal projections from layer V cells in rat are collaterals of long-range corticofugal axons.
Corticostriatal projections arising from the infragranular layers of the motor and second somatosensory cortices were studied in rats after labeling small pools of neurons with biocytin. Camera lucida reconstruction of 263 fibers arising from laminae V and VI revealed that all corticostriatal projections derive from collaterals of lamina V cells whose main axons descend into the cerebral peduncle. In contrast, lamina VI cells do not branch upon the striatum, but upon the thalamus. Together with the results obtained in previous tracing studies, the present data raise the possibility that no neuron is exclusively corticostriatal. We therefore propose that all corticostriatal projections are collaterals given off by the axons of two types of neurons: layer V cells whose main axon project to the brainstem and/or spinal cord, and layer III cells that project to the contralateral hemisphere.
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Calretinin as a marker of specific neuronal subsets in primate substantia nigra and subthalamic nucleus.
Neurons immunoreactive for the calcium-binding protein calretinin (CR) were visualized in the substantia nigra (SN) pars compacta (SNc), reticulata (SNr) and lateralis (SNl), the ventral tegmental area (VTA) and the subthalamic nucleus (STN) of squirrel monkeys. The density of CR perikarya was high in VTA, moderate in SNc, low in SNr/SNl, and very low in STN. The SNc/VTA complex also displayed a CR-rich neuropil. Some CR perikarya and fibers occurred in specific sectors of STN. These data suggest that CR may play a role in specific neuronal subpopulations in all components of primate basal ganglia.
Animals↗
Synaptic innervation of midbrain dopaminergic neurons by glutamate-enriched terminals in the squirrel monkey.
The excitatory amino acid, glutamate, has long been thought to be a transmitter that plays a major role in the control of the firing pattern of midbrain dopaminergic neurons. The present study was aimed at elucidating the anatomical substrate that underlies the functional interaction between glutamatergic afferents and midbrain dopaminergic neurons in the squirrel monkey. To do this, we combined preembedding immunocytochemistry for tyrosine hydroxylase and calbindin D-28k with postembedding immunostaining for glutamate. On the basis of their ultrastructural features, three types (so-called types I, II, and III) of glutamate-enriched terminals were found to form asymmetric synapses with dendrites and perikarya of midbrain dopaminergic neurons. The type I terminals accounted for more than 70% of the total population of glutamate-enriched boutons in contact with dopaminergic cells in the dorsal and ventral tiers of the substantia nigra pars compacta as well as in the ventral tegmental area, whereas 5-20% of the glutamatergic synapses with dopaminergic neurons involved the two other types of terminals. The major finding of our study is that the glutamate-enriched boutons were involved in 70% of the axodendritic synapses in the ventral tegmental area. In contrast, less than 40% of the boutons in contact with dopaminergic dendrites were immunoreactive for glutamate in the dorsal and ventral tiers of the substantia nigra pars compacta. Approximately 50% of the terminals in contact with the perikarya of the different populations of midbrain dopaminergic neurons displayed glutamate immunoreactivity. In conclusion, our findings provide the first evidence that glutamate-enriched terminals form synapses with midbrain dopaminergic neurons in primates. The fact that the proportion of glutamatergic boutons in contact with dopaminergic cells is higher in the ventral tegmental area than in the substantia nigra pars compacta suggests that the different groups of midbrain dopaminergic neurons are modulated differently by extrinsic glutamatergic afferents in primates.
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