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At least 19 recordsLinked to original sources
PubMed1997

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.

Animals↗
PubMed1997

Synaptic integration of functionally diverse pallidal information in the entopeduncular nucleus and subthalamic nucleus in the rat.

To determine the principles of synaptic innervation of neurons in the entopeduncular nucleus and subthalamic nucleus by neurons of functionally distinct regions of the pallidal complex, double anterograde labeling was carried out at both light and electron microscopic levels in the rat. Deposits of the anterograde tracers Phaseolus vulgaris-leucoagglutinin and biotinylated dextran amine were placed in different functional domains of the pallidal complex in the same animals. The tracer deposits in the ventral pallidum and the globus pallidus gave rise to GABA-immunopositive projections to the entopeduncular nucleus, the subthalamic nucleus, and the more medial lateral hypothalamus that were largely segregated but overlapped at the interface between the two fields of projection. In these regions the proximal parts of individual neurons in the entopeduncular nucleus, lateral hypothalamus, and subthalamic nucleus received synaptic input from terminals derived from both the ventral pallidum and the globus pallidus. Furthermore, the analysis of the afferent synaptic input to the dendrites of neurons in the subthalamic nucleus that cross functional boundaries of the nucleus defined by the pallidal inputs, revealed that terminals with the morphological and neurochemical characteristics of those derived from the pallidal complex make synaptic contact with all parts of the dendritic tree, including distal regions. It is concluded that functionally diverse information carried by the descending projections of the pallidal complex is synaptically integrated by neurons of the entopeduncular nucleus, lateral hypothalamus, and subthalamic nucleus by two mechanisms. First, neurons located at the interface between functionally distinct, but topographically adjacent, projections could integrate diverse information by means of the synaptic convergence at the level of the cell body and proximal dendrites. Second, because the distal dendrites of neurons in the subthalamic nucleus receive input from the pallidum, those that extend across two distinct domains of pallidal input could also provide the morphological basis of integration.

Afferent Pathways↗
PubMed1997

Glutamate-enriched cholinergic synaptic terminals in the entopeduncular nucleus and subthalamic nucleus of the rat.

Several lines of evidence suggest that the cholinergic neurons of the mesopontine tegmentum contain elevated levels of glutamate and are the source of cholinergic terminals in the subthalamic nucleus and entopeduncular nucleus. The object of this study was to test whether cholinergic terminals in the entopeduncular nucleus and subthalamic nucleus, also express relatively high levels of glutamate. To address this, double immunocytochemistry was performed at the electron microscopic level. Perfuse-fixed sections of rat brain were immunolabelled to reveal choline acetyltransferase by the pre-embedding avidin-biotin-peroxidase method. Serial ultrathin sections of cholinergic terminals in both the entoped uncular nucleus and subthalamic nucleus were then subjected to post-embedding immunocytochemistry to reveal glutamate and GABA. Quantification of the immunogold labelling showed that choline acetyltransferase-immunopositive terminals and boutons in both regions were significantly enriched in glutamate immunoreactivity and had significantly lower levels of GABA immunoreactivity in comparison to identified GABAergic terminals. Furthermore, the presumed transmitter pool of glutamate i.e. that associated with synaptic vesicles, was significantly greater in the choline acetyltransferase-positive terminals than identified GABA terminals, albeit significantly lower than in established glutamatergic terminals. In the entopeduncular nucleus, a small proportion of cholinergic terminals displayed high levels of GABA immunoreactivity. Taken together with other immunocytochemical and tracing data, the elevated levels of glutamate in cholinergic terminals in the entopeduncular nucleus and subthalamic nucleus, is further evidence adding weight to the suggestion that acetylcholine and glutamate may be co-localized in both the perikarya and terminals of at least a proportion of neurons of the mesopontine tegmentum.

Animals↗
PubMed1998

Distribution of glutamate receptor subunits at neurochemically characterized synapses in the entopeduncular nucleus and subthalamic nucleus of the rat.

Glutamatergic neurotransmission in the subthalamic nucleus (STN) and in the output nuclei of the basal ganglia is critical in the expression of basal ganglia function, and increased glutamate transmission in these nuclei has been implicated in the pathology of Parkinson's disease. In order to determine the precise spatial relationship of subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors to nerve terminals enriched in glutamate or gamma-aminobutyric acid (GABA) in one of the output nuclei, the entopeduncular nucleus (EP), and the STN, postembedding immunolabelling for glutamate receptor subunits and for glutamate and GABA was carried out in the rat. Immunolabelling for the AMPA glutamate receptor subunits 1, 2/3, and 4 (GluR1, GluR2/3, and GluR4) and the NMDA receptor subunit 1 (NR1) was localized predominantly within asymmetrical synapses in both the EP and STN. Quantitative analysis revealed that, on average for the whole population, each of the receptor subunits was evenly distributed along the synaptic specialization. Multiple AMPA receptor subunits and the GluR2/3 and NMDA (NR1) subunits were co-localized within individual synapses. The combination of immunolabelling for glutamate and GABA with the receptor immunolabelling revealed that the majority of axon terminals presynaptic to the receptor-immunoreactive synapses were enriched in glutamate immunoreactivity and were GABA-immunonegative. However, at some NR1- and GluR2/3-positive synapses, the level of glutamate immunoreactivity was low in the presynaptic terminal and, in the STN, some of them were GABA-immunopositive. It is concluded that glutamatergic transmission at individual synapses of different origins in the EP and STN is mediated by a combination ofAMPA and NMDA glutamate receptors.

Animals↗
PubMed1994

The projections from the parafascicular thalamic nucleus to the subthalamic nucleus and the striatum arise from separate neuronal populations: a comparison with the corticostriatal and corticosubthalamic efferents in a retrograde fluorescent double-labelling study.

The parafascicular thalamic nucleus projects to the subthalamic nucleus and the striatum. Double-retrograde fluorescent tracing was used to determine whether these projections arise from the same neurons via axon collaterals. True Blue was injected into the subthalamic nucleus and Nuclear Yellow was injected into the striatum of each rat and the parafascicular thalamic nucleus was examined under the fluorescence light-microscope. Individual parafascicular neurons were not double-labelled with the tracers. The True Blue- and Nuclear Yellow-labelled neurons wee located in different parts of the parafascicular nucleus ipsilateral to the injections. In the rostral part of the parafascicular nucleus, True Blue-labelled neurons were located ventral to the fasciculus retroflexus, and in the caudal part of the nucleus. True Blue-labelled neurons were located close to the medial and lateral borders of fasciculus retroflexus. Nuclear Yellow-labelled neurons were found mainly to encircle the fasciculus retroflexus in the rostral part of the parafascicular nucleus and in the dorsolateral sector of the caudal part of the parafascicular nucleus. Double-labelled neurons were, however, found in the cortex. The proportion of neurons projecting to both the subthalamic nucleus and the striatum accounted for 38% of the total number of cortiscosubthalamic neurons in the prefrontal cortex, 15.5% in the cingulate cortex and 9% in the sensorimotor cortex. The present finding of an individualization between the parafascicular efferents to the subthalamic nucleus and the striatum emphasize the importance of this projection and provides further evidence of the associative functions attributable to the subthalamic nucleus.

Animals↗
PubMed2000

Morphological study of the tegmental pedunculopontine nucleus, substantia nigra and subthalamic nucleus, and their interconnections in rat organotypic culture.

The morphological organization of the tegmental pedunculopontine nucleus, midbrain extrapyramidal area, substantia nigra and subthalamic nucleus and their interrelationships were studied in rat organotypic culture using immunohistochemistry and NADPH-diaphorase histochemistry. Three coronal sections, one containing the tegmental pedunculopontine nucleus/midbrain extrapyramidal area, another with the substantia nigra and the third with the subthalamic nucleus, were obtained from postnatal 1-2-day-old rats. These sections were co-cultured for 3-4 weeks using the roller-tube technique. In the tegmental pedunculopontine nucleus/midbrain extrapyramidal area, the distribution pattern of cholinergic neurons was similar to that found in the in vivo study. We could, therefore, identify the subdivisions of the tegmental pedunculopontine nucleus (i.e., pars compacta and pars dissipata) and the midbrain extrapyramidal area. As in the in vivo situation, glutamate immunoreactive neurons were also located in these areas. Approximately 10% of NADPH-diaphorase positive neurons in the tegmental pedunculopontine nucleus, were glutamate immunoreactive. In the substantia nigra, as in the in vivo, tyrosine hydroxylase immunoreactive (putative dopaminergic) neurons were identified predominantly in the substantia nigra pars compacta, and parvalbumin immunoreactive neurons (putative GABAergic) mainly in the substantia nigra pars reticulata. The subthalamic nucleus was ladened with glutamate immunoreactive neurons. NADPH-diaphorase stained axons originating from the tegmental pedunculopontine nucleus were traced into the substantia nigra and subthalamic nucleus. They were often in close apposition to tyrosine hydroxylase immunoreactive neurons in the substantia nigra. Parvalbumin immunoreactive fibers from the substantia nigra projected heavily to the midbrain extrapyramidal area, but only sparsely to the tegmental pedunculopontine nucleus and the subthalamic nucleus. These findings indicate that the tegmental pedunculopontine nucleus/midbrain extrapyramidal area, substantia nigra and subthalamic nucleus in the organotypic culture have retained a basic morphological organization and connectivity similar to those seen in the in vivo situation. Therefore, this preparation could be a useful model to conduct further studies to investigate functional circuits among the structures represented.

Animals↗
PubMed1998

Ipsilateral turning behavior induced by unilateral microinjections of a cannabinoid into the rat subthalamic nucleus.

The subthalamic nucleus contains cannabinoid receptors and cannabinoid receptor mRNA. However, the role of cannabinoid receptors in this nucleus has not been examined. In order to investigate the functional role of cannabinoid receptors in the rat subthalamic nucleus, turning activity was observed following unilateral microinjection of the synthetic cannabinoid CP 55,940. CP 55,940 (10 microg) induced ipsilateral turning. This effect was blocked by coadministration of the cannabinoid receptor antagonist SR141716A (5 microg). These results suggest that cannabinoid receptors in the subthalamic nucleus mediate an inhibition of motor activity.

Animals↗
PubMed1994

Lesions of the entopeduncular nucleus and the subthalamic nucleus reduce dopamine receptor antagonist-induced catalepsy in the rat.

The role of the entopeduncular nucleus (EP) and the subthalamic nucleus (STN) in mediating dopamine receptor antagonist-induced catalepsy in the rat was investigated. Five days after bilateral lesions of EP and STN respectively with the excitotoxin quinolinic acid (15, 30 nmol/0.5 microliter/side and 24 nmol/0.5 microliter/side, respectively) rats were injected intraperitoneally with the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) or the dopamine D2 receptor antagonist haloperidol (0.5 mg/kg). Complete EP lesions prevented both SCH 23390- and haloperidol-induced catalepsy. STN lesions exerted pronounced anticataleptic effects in case of haloperidol-induced catalepsy, but less pronounced in case of SCH 233390-induced catalepsy. Further characterization of these anticataleptic effects in an open field demonstrated, that neither EP- nor STN lesions reversed bradykinesia, which occurred after selective dopamine receptor blockade. In conclusion, both EP and STN participate in the mediation of catalepsy induced by dopamine D1- and dopamine D2 receptor antagonists. Thereby these nuclei preferentially mediate rigidity and akinesia, but to a lesser extent bradykinesia.

Animals↗
PubMed1992

Cholinergic innervation of the human striatum, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus.

The anatomical organization of cholinergic markers such as acetylcholinesterase, choline acetyltransferase, and nerve growth factor receptors was investigated in the basal ganglia of the human brain. The distribution of choline acetyltransferase-immunoreactive axons and varicosities and their relationship to regional perikarya showed that the caudate, putamen, nucleus accumbens, olfactory tubercle, globus pallidus, substantia nigra, red nucleus, and subthalamic nucleus of the human brain receive widespread cholinergic innervation. Components of the striatum (i.e., the putamen, caudate, olfactory tubercle, and nucleus accumbens) displayed the highest density of cholinergic varicosities. The next highest density of cholinergic innervation was detected in the red nucleus and subthalamic nucleus. The level of cholinergic innervation was of intermediate density in the globus pallidus and the ventral tegmental area and low in the pars compacta of the substantia nigra. Immunoreactivity for nerve growth factor receptors (NGFr) was confined to the cholinergic neurons of the basal forebrain and their processes. Axonal immunoreactivity for NGFr was therefore used as a marker for cholinergic projections originating from the basal forebrain (Woolf et al., '89: Neuroscience 30:143-152). Although the vast majority of striatal cholinergic innervation was NGFr-negative and, therefore, intrinsic, the striatum also contained NGFr-positive axons, indicating the existence of an additional cholinergic input from the basal forebrain. This basal forebrain cholinergic innervation was more pronounced in the putamen than in the caudate. The distribution of NGFr-positive axons suggested that the basal forebrain may also project to the globus pallidus but probably not to the subthalamic nucleus, substantia nigra, or red nucleus. The great majority of cholinergic innervation to these latter three structures and to parts of the globus pallidus appeared to come from cholinergic neurons outside the basal forebrain, most of which are probably located in the upper brainstem. These observations indicate that cholinergic neurotransmission originating from multiple sources is likely to play an important role in the diverse motor and behavioral affiliations that have been attributed to the human basal ganglia.

Acetylcholinesterase↗
PubMed1982

Electron microscopy of the subthalamic nucleus in the baboon. I. Synaptic organization of the subthalamic nucleus in the baboon.

Our study of the synaptic organization of the baboon subthalamic nucleus has revealed at least nine different types of synapses. Most frequently encountered is the type I (F) axo-dendritic or axo-somatic synapse. It is characterized by scattered flat vesicles and many large mitochondria. The axon terminal is either elongated, tubule shaped (type IF en passant), and undergoes many short button-like en passant junctions with a parallel running dendrite, or it is spindle shaped with similar synaptic contacts (type IFa). In other cases a more compact bouton forms many short junctions at the same time with a dendrite and a beak-shaped spine springing from it. A smaller bouton with flat vesicles, which show a tendency to fuse together (type IIF) usually undergoes slightly asymmetric contacts with two vesicles-free dendrites between which they frequently appear wedged. Three types of boutons with small, round vesicles have extended asymmetric contacts forming elongated (type III), star-shaped (type IV), or oval (type V) synapses. The latter form contacts mostly with dendritic terminals or spines. Another type of synapses contain larger, pale, pleomorphic vesicles (VI (SO)): The bouton is more compact and often in contact with a dendritic terminal. Type VII (LO) shows a looser arrangement of vesicles intermingled with more dense core vesicles. Type VIII (F) is a dendritic terminal with loosely arranged, flat vesicles and is in contact either with a type VI or with a type VII P bouton. Finally, there is an axo-spinous microsynapse type IX, which partly degenerates after contralateral pallidum externum coagulation. A few axon preterminals filled with dense core vesicles do not undergo synaptic contacts.

Animals↗
PubMed2000

Postural and anticonvulsant effects of inhibition of the rat subthalamic nucleus.

The subthalamic nucleus (STN) plays a crucial role as a regulator of basal ganglia outflow by providing excitatory glutamatergic input into the two output nuclei of the basal ganglia, substantia nigra pars reticulata (SNpr), and entopeduncular nucleus. This study examined the effects of suppressing activity in the STN of the awake, behaving rat. Specifically, we evaluated the effects of unilateral and bilateral focal inhibition of STN on posture, locomotion, and susceptibility to limbic motor seizures. Unilateral microinjection of a GABA(A) receptor agonist (muscimol, 200 pmol) into STN produced a site-dependent contralaterally directed postural asymmetry without locomotor activation. This effect differed from responses produced by the same dose of muscimol placed into SNpr, which included locomotor activation in addition to contralaterally directed postural asymmetry. Locomotor activation and postural asymmetry were obtained also after blockade of glutamate transmission in SNpr by the unilateral application of kynurenate (100 nmol). Our observation that STN inhibition did not induce the locomotor activation characteristic of SNpr inhibition suggests that there are glutamatergic inputs to SNpr, other than those from STN, that are responsible for controlling locomotion. Bilateral, but not unilateral, injection of muscimol (200 pmol) into STN protected against limbic motor seizures evoked either by intravenous bicuculline or by focal application of bicuculline into anterior piriform cortex (area tempestas). These results demonstrate that focal inhibition of STN reproduces the postural asymmetry and anticonvulsant actions that are obtained with the inhibition of SNpr. This provides behavioral support for the concept that STN contributes a crucial tonic excitatory (glutamatergic) drive to the rat SNpr.

Animals↗
PubMed2000

Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus.

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in normal motor function, as well as in pathological conditions such as Parkinson's disease (PD) and related disorders. Development of a complete understanding of the roles of the STN in motor control and the pathophysiological changes in STN that underlie PD will require a detailed understanding of the mechanisms involved in regulation of excitability of STN neurons. Here, we report that activation of group I metabotropic glutamate receptors (mGluRs) induces a direct excitation of STN neurons that is characterized by depolarization, increased firing frequency, and increased burst-firing activity. In addition, activation of group I mGluRs induces a selective potentiation of NMDA-evoked currents. Immunohistochemical studies at the light and electron microscopic levels indicate that both subtypes of group I mGluRs (mGluR1a and mGluR5) are localized postsynaptically in the dendrites of STN neurons. Interestingly, pharmacological studies suggest that each of the mGluR-mediated effects is attributable to activation of mGluR5, not mGluR1, despite the presence of both subtypes in STN neurons. These results suggest that mGluR5 may play an important role in the net excitatory drive to the STN from glutamatergic afferents. Furthermore, these studies raise the exciting possibility that selective ligands for mGluR5 may provide a novel approach for the treatment of a variety of movement disorders that involve changes in STN activity.

Animals↗
PubMed2001

Activation of groups I or III metabotropic glutamate receptors inhibits excitatory transmission in the rat subthalamic nucleus.

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in the normal motor function, as well as in pathological conditions such as Parkinson's disease. Development of a complete understanding of the role of the STN in motor control will require a detailed understanding of the mechanisms involved in the regulation of excitatory and inhibitory synaptic transmission in this nucleus. Here, we report that activation of groups I or III metabotropic glutamate (mGlu) receptors, but not group II, causes a depression of excitatory transmission in the STN. In contrast, mGlu receptor activation has no effect on the inhibitory transmission in this nucleus. Further characterization of the group I mGlu receptor-induced effect on EPSCs suggests that this response is mediated by mGlu1 and not mGlu5. Further, paired pulse studies suggest that both the mGlu1 receptor and the group III mGlu receptor-mediated effects are due to a presynaptic mechanism. If these receptors are involved in endogenous synaptic transmission in the STN, these results raise the exciting possibility that selective agents targeting mGlu receptors may provide a novel approach for the treatment of motor disorders involving the STN.

Animals↗
PubMed1993

Descending efferent connections of the sub-pallidal areas in the cat: projections to the subthalamic nucleus, the hypothalamus, and the midbrain.

The efferent connections of the sub-pallidal regions to the mediodorsal thalamic nucleus, the subthalamic nucleus, the lateral hypothalamic area, and the midbrain were investigated in the cat, using Phaseolus vulgaris--leucoagglutinin (PHA-L) as an anterograde label. The results indicate that the sub-pallidal regions of the cat project to the (dorso)medial tip of the subthalamic nucleus and the adjoining lateral hypothalamic area as well as to the ventral tegmental area and the greater extent of the dorsolateral tier of the substantia nigra pars compacta. Extensive projections were also found to the peripeduncular nucleus. The central gray as well as the mesencephalic locomotor region receive some input from the basal forebrain too. In contrast only very limited projections were found to the mediodorsal thalamic nucleus. The results are discussed in view of the possible role of these output regions in oro-facial dyskinesia.

Animals↗
PubMed2000

Characterization of Ca(2+) channels in rat subthalamic nucleus neurons.

The subthalamic nucleus (STN) plays a key role in motor control. Although previous studies have suggested that Ca(2+) conductances may be involved in regulating the activity of STN neurons, Ca(2+) channels in this region have not yet been characterized. We have therefore investigated the subtypes and functional characteristics of Ca(2+) conductances in STN neurons, in both acutely isolated and slice preparations. Acutely isolated STN cells were identified by retrograde filling with the fluorescent dye, Fluoro-Gold. In acutely isolated STN neurons, Cd(2+)-sensitive, depolarization-activated Ba(2+) currents were observed in all cells studied. The current-voltage relationship and current kinetics were characteristic of high-voltage-activated Ca(2+) channels. The steady-state voltage-dependent activation curves and inactivation curves could both be fitted with a single Boltzmann function. Currents evoked with a prolonged pulse, however, inactivated with multiple time constants, suggesting either the presence of more than one Ca(2+) channel subtype or multiple inactivation processes with a single channel type in STN neurons. Experiments using organic Ca(2+) channel blockers revealed that on average, 21% of the current was nifedipine sensitive, 52% was sensitive to omega-conotoxin GVIA, 16% was blocked by a high concentration of omega-agatoxin IVA (200 nM), and the remainder of the current (9%) was resistant to the co-application of all blockers. These currents had similar voltage dependencies, but the nifedipine-sensitive current and the resistant current activated at slightly lower voltages. omega-Agatoxin IVA at 20 nM was ineffective in blocking the current. Together, the above results suggest that acutely isolated STN neurons have all subtypes of high-voltage-activated Ca(2+) channels except for P-type, but have no low-voltage-activated channels. Although acutely isolated neurons provide a good preparation for whole cell voltage-clamp study, dendritic processes are lost during dissociation. To gain information on Ca(2+) channels in dendrites, we thus studied Ca(2+) channels of STN neurons in a slice preparation, focusing on low-voltage-activated channels. In current-clamp recordings, a slow spike was always observed following termination of an injected hyperpolarizing current. The slow spike occurred at resting membrane potentials and was sensitive to micromolar concentrations of Ni(2+), suggesting that it is a low-threshold Ca(2+) spike. Together, our results suggest that STN neurons express low-voltage-activated Ca(2+) channels and several high-voltage-activated subtypes. Our results also suggest the possibility that the low-voltage-activated channels have a preferential distribution to the dendritic processes.

Action Potentials↗