Bilateral cerebral metabolic effects of pharmacological manipulation of the substantia nigra in the rat: Unilateral intranigral application of the putative excitatory neurotransmitter substance P

The metabolic activity of several anatomically distinct brain areas was investigated by means of the quantitative autoradiographic 2-deoxy-d[1-¹⁴C]glucose method in awake rats following unilateral intranigral application of the putative excitatory neurotransmitter substance P. The primary goal was to determine the metabolic effects of substance P on the substantia nigra and its targets. Intranigral injection of 1 mM substance P (1.5 μl) induced metabolic activation locally in the substantia nigra reticulata by 117% and substantia nigra compacta by 35%, as well as distally in the contralateral substantia nigra reticulata by 22% and contralateral substantia nigra compacta by 21%. All the basal ganglia components, the striatum, pallidum, entopeduncular, subthalamic nucleus and nucleus accumbens displayed bilateral metabolic activations after unilateral intranigral substance P injection. Among the principal reticulata efferent projections, the ventromedial, ventrolateral, parafascicular, mediodorsal and centrolateral thalamic nuclei, as well as the pedunculopontine nucleus displayed bilateral metabolic activations after intranigral substance P application. Moreover, unilateral intranigral substance P injection elicited metabolic activations in the thalamic and cortical components of the reticular, intralaminar, limbic and prefrontal systems, mostly bilateral.

It is suggested that substance P applied into one substantia nigra reticulata activates the compacta nigrostriatal dopaminergic and the reticulata nigrothalamic GABAergic outputs inducing distal metabolic effects, similar to those elicited by unilateral nigral electrical stimulation [Savaki et al. (1983) J. comp. Neurol.213, 46–65] and, opposite to several of those induced by intranigral injection of the inhibitory GABA_A agonist muscimol [Savaki et al. (1992) Neuroscience50, 781–794]. Furthermore, it is suggested that the ipsilateral basal ganglia effects induced by intranigral substance P application are mediated via both the compacta dopaminergic nigrostriatal projection and the reticulata GABAergic nigro-thalamo-cortico-striatal loop, whereas the contralateral basal ganglia and associated thalamocortical effects are due to the activation of the GABAergic reticulata efferents and are mediated via an interthalamic circuitry involving the motor, reticular and intralaminar thalamic nuclei.     

Projections to the rostral reticular thalamic nucleus in the rat

Summary Afferent pathways to the rostral reticular thalamic nucleus (Rt) in the rat were studied using anterograde and retrograde lectin tracing techniques, with sensitive immunocytochemical methods. The analysis was carried out to further investigate previously described subregions of the reticular thalamic nucleus, which are related to subdivisions of the dorsal thalamus, in the paraventricular and midline nuclei and three segments of the mediodorsal thalamic nucleus. Cortical inputs to the rostral reticular nucleus were found from lamina VI of cingulate, orbital and infralimbic cortex. These projected with a clear topography to lateral, intermediate and medial reticular nucleus respectively. Thalamic inputs were found from lateral and central segments of the mediodorsal nucleus to the lateral and intermediate rostral reticular nucleus respectively and heavy paraventricular thalamic inputs were found to the medial reticular nucleus. In the basal forebrain, afferents were found from the vertical and horizontal limbs of the diagonal band, substantia innominata, ventral pallidum and medial globus pallidus. Brainstem projections were identified from ventrolateral periaqueductal grey and adjacent sites in the mesencephalic reticular formation, laterodorsal tegmental nucleus, pedunculopontine nucleus, medial pretectum and ventral tegmental area. The results suggest a general similarity in the organisation of some brainstem Rt afferents in rat and cat, but also show previously unsuspected inputs. Furthermore, there appear to be at least two functional subdivisions of rostral Rt which is reflected by their connections with cortex and thalamus. The studies also extend recent findings that the ventral striatum, via inputs from the paraventricular thalamic nucleus, is included in the circuitry of the rostral Rt, providing further evidence that basal ganglia may function in concert with Rt. Evidence is also outlined with regard to the possibility that rostral Rt plays a significant role in visuomotor functions.Abbreviations ac anterior commissure - aca anterior commissure, anterior - Acb accumbens nucleus - AI agranular insular cortex - AM anteromedial thalamic nucleus - AV anteroventral thalamic nucleus - BST bed nucleus of stria terminalis - Cg cingulate cortex - CG central gray - CL centrolateral thalamic nucleus - CM central medial thalamic nucleus - CPu caudate putamen - DR dorsal raphe nucleus - DTg dorsal tegmental nucleus - EP entopeduncular nucleus - f fornix - Fr2 Frontal cortex, area 2 - G gelatinosus thalamic nucleus - GP globus pallidus - Hb habenula - HDB horizontal limb of diagonal band - IAM interanterodorsal thalamic nucleus - ic internal capsule - INC interstitial nucleus of Cajal - IF interfascicular nucleus - IL infralimbic cortex - IP interpeduncular nucleus - LC locus coeruleus - LDTg laterodorsal tegmental nucleus - LH lateral hypothalamus - LHb lateral habenular nucleus - ll lateral lemniscus - LO lateral orbital cortex - LPB lateral parabrachial nucleus - MD mediodorsal thalamic nucleus - MDL mediodorsal thalamic nucleus, lateral segment - Me5 mesencephalic trigeminal nucleus - MHb medial habenular nucleus - mlf medial longitudinal fasciculus - MnR median raphe nucleus - MO medial orbital cortex - mt mammillothalamic tract - OPT olivary pretectal nucleus - pc posterior commissure - PC paracentral thalamic nucleus - PF parafascicular thalamic nucleus - PPTg pedunculopontine tegmental nucleus - PrC precommissural nucleus - PT paratenial thalamic nucleus - PV paraventricular thalamic nucleus - PVA paraventricular thalamic nucleus, anterior - R red nucleus - Re reuniens thalamic nucleus - RRF retrorubral field - Rt reticular thalamic nucleus - Scp superior cerebellar peduncle - SI substantia innominata - sm stria medullaris - SNR substantia nigra, reticular - st stria terminalis - TT tenia tecta - VL ventrolateral thalamic nucleus - VO ventral orbital cortex - VP ventral pallidum - VPL ventral posterolateral thalamic nucleus - VTA ventral tegmental area - 3 oculomotor nucleus - 3V 3rd ventricle - 4 trochlear nucleus     

Topographic distribution of the axonal endings from the sensorimotor and associative striatum in the macaque pallidum and substantia nigra

The striatopallidonigral connection was studied by injecting anterograde tracers into either the associative or the sensorimotor striatum in ten macaques. The results were analyzed using a precise cartographic method. Injections into various parts of the associative striatum (caudate nucleus and ventromedial putamen) produced a labeling of axons in the dorsomedial and ventral pallidal regions. These associative regions occupied two-thirds of the lateral pallidum and one-third of the medial pallidum. Bands of labeled axons from the sensorimotor striatum (dorsolateral putamen) were found in the remaining, central part of the two pallidal nuclei. In the substantia nigra, the rostral associative striatum projected medially to the pars reticulata, while the caudal parts projected laterally. The whole pars reticulata and lateralis thus appeared to receive associative striatal inputs. The sensorimotor striatal territory projected to the central part of the pars reticulata/lateralis. It was concluded that the two functional territories remain separate in the two pallidal nuclei but overlap in the middle third of the substantia nigra. However, due to their great size, the pallidal neurons located at the border of the two territories may receive striatal inputs from both the associative and the sensorimotor components in the same way that nigral neurons do.     

The pathways connecting the hippocampal formation, the thalamic reuniens nucleus and the thalamic reticular nucleus in the rat

Most dorsal thalamic nuclei send axons to specific areas of the neocortex and to specific sectors of the thalamic reticular nucleus; the neocortex then sends reciprocal connections back to the same thalamic nucleus, directly as well indirectly through a relay in the thalamic reticular nucleus. This can be regarded as a 'canonical' circuit of the sensory thalamus. For the pathways that link the thalamus and the hippocampal formation, only a few comparable connections have been described. The reuniens nucleus of the thalamus sends some of its major cortical efferents to the hippocampal formation. The present study shows that cells of the hippocampal formation as well as cells in the reuniens nucleus are retrogradely labelled following injections of horseradish peroxidase or fluoro-gold into the rostral part of the thalamic reticular nucleus in the rat. Within the hippocampal formation, labelled neurons were localized in the subiculum, predominantly on the ipsilateral side, with fewer neurons labelled contralaterally. Labelled neurons were seen in the hippocampal formation and nucleus reuniens only after injections made in the rostral thalamic reticular nucleus (1.6-1.8 mm caudal to bregma). In addition, the present study confirmed the presence of afferent connections to the rostral thalamic reticular nucleus from cortical (cingulate, orbital and infralimbic, retrosplenial and frontal), midline thalamic (paraventricular, anteromedial, centromedial and mediodorsal thalamic nuclei) and brainstem structures (substantia nigra pars reticularis, ventral tegmental area, periaqueductal grey, superior vestibular and pontine reticular nuclei). These results demonstrate a potential for the thalamo-hippocampal circuitry to influence the functional roles of the thalamic reticular nucleus, and show that thalamo-hippocampal connections resemble the circuitry that links the sensory thalamus and neocortex.     

Bilateral cerebral metabolic effects of pharmacological manipulation of the substantia nigra in the rat: unilateral intranigral application of the inhibitory GABAA receptor agonist muscimol.

Rates of cerebral glucose utilization were measured by means of the autoradiographic 2-deoxy-d[1-¹⁴C]glucose technique in the rat brain in order to determine the metabolic effects of unilateral intranigral application of the GABA_A agonist muscimol upon the substantia nigra and its targets. Intranigral injection of 1.5 μl 0.3 M muscimol (52 μg total dose) induced local metabolic activation in the injected substantia nigra reticulata (by 87% as compared to the control group), and distal metabolic depressions in the nucleus accumbens, striatum, globus pallidus and subthalamic nucleus only ipsilaterally to the injected nigra. The remaining basal ganglia components, including the substantia nigra compacta and the entopeduncular nucleus were bilaterally unaffected. Among the principal efferent projections of the substantia nigra reticulata, the ventromedial and centrolateral thalamic nuclei as well as the deep layers of the superior colliculi were metabolically depressed bilaterally, whereas the ventrolateral, parafascicular and mediodorsal thalamic nuclei as well as the pedunculopontine nucleus displayed metabolic depressions ipsilateral to the muscimol-injection nigra. The ventromedial and centrolateral thalamic nuclei were depressed by 41 and 42%, respectively, in the ipsilateral side, and by 30 and 26% in the contralateral side, when compared to the respective values of the control group of rats. Furthermore, unilateral intranigral injection of 0.3 M muscimol induced metabolic depressions in reticular, intralaminar and prefrontal thalamocortical areas mostly ipsilateral to the injected nigra, as well as in limbic areas bilaterally.

It is suggested that the present findings are due to a postsynaptic effect of muscimol on the nigral GABAergic cells and to a consequent metabolic depression of the basal ganglia and associated thalamocortical areas, in contrast to an earlier suggested presynaptic nigral effect of lower doses of intranigrally injected muscimol which induced metabolic activations within the same network.¹⁸ This suggestion is further supported by the fact that intranigrally injected substrate P¹⁹ induced similar effects to those elicited by the lower doses of intranigral muscimol and opposite to those induced at present by the higher muscimol dose. Moreover, it is further substantiated that the nigrothalamic GABAergic system is responsible for considerable transfer of information from one substantia nigra reticulata to the ipsilateral basal ganglia and associated thalamocortical components as well as to bilateral motor, intralaminar and limbic areas.     

3H]SCH 23390 binding to D1 dopamine receptors in the basal ganglia of the cat and primate: delineation of striosomal compartments and pallidal and nigral subdivisions

The distribution of D1 dopamine receptors was studied autoradiographically in the basal ganglia of the cat, monkey and human. These receptor binding sites were labeled directly with the D1-selective antagonist [3H]SCH 23390, and ligand-binding assays were performed concurrently. Serial- or same-action analysis permitted comparisons among D1 binding distributions, acetylcholinesterase staining and tyrosine hydroxylase immunoreactivity. In all species studied, the dorsal striatum exhibited patches of particularly dense D1 binding in correspondence with acetylcholinesterase-poor striosomes. Highly patterned binding was present in the ventral striatum. Distinctions in binding density were observed among the subdivisions of the globus pallidus and of the substantia nigra. The external segment of the pallidum was extremely sparse in D1 binding, whereas the internal segment (or entopeduncular nucleus in the cat) was a site of high D1 binding density. The binding density was greatest in the core of the internal segment, and tyrosine hydroxylase-positive fibers surrounded and weakly dispersed themselves through this core. Weak binding was present in the ventral pallidum. In the substantia nigra, the pars reticulata demonstrated the densest binding, particularly medially. The pars compacta showed much sparser binding, though some of its tyrosine hydroxylase-positive neurons had dendrites extending ventrally into the zone of dense D1 binding in the pars reticulata. We conclude that [3H]SCH 23390-defined D1 binding is compartmentalized in the dorsal striatum and that, particularly in relation to the reported distributions of striatal D2 dopamine receptors, this is likely to be of functional significance in the dopaminergic modulation of intrastriatal neurotransmission as well as of afferent and efferent neurotransmission. The segregated localizations of D1 receptors in the substantia nigra suggest predominant activation of the pars reticulata, including ventral and medial regions adjacent to the densocellular zone. Specific pathways from compartments in the striatum to subdivisions of the pallidum may also be differentially modulated by dopamine acting via distinct receptor subtypes. At the level of the pallidum, such D1 modulation appears to be restricted to the internal segment, which projects to the thalamus, rather than to the external pallidum, which projects to the subthalamic nucleus.     

A horseradish peroxidase study of afferent connections of the globus pallidus in Macaca mulatta

Summary The high tonic discharge rates of globus pallidus neurons in awake monkeys suggest that these neurons may receive some potent excitatory input. Because most current electrophysiological evidence suggests that the major described pallidal afferent systems from the neostriatum are primarily inhibitory, we used retrograde transport of horseradish peroxidase (HRP) to identify possible additional sources of pallidal afferent fibers. The appropriate location was determined before HRP injection by mapping the characteristic high frequency discharge of single pallidal units in awake animals. In animals with injections confined to the internal pallidal segment, retrograde label was seen in neurons of the pedunculopontine nucleus, dorsal raphe nucleus, substantia nigra, caudate, putamen, subthalamic nucleus, parafascicular nucleus, zona incerta, medial and lateral subthalamic tegmentum, parabrachial nuclei, and locus coeruleus. An injection involving the external pallidal segment and the putamen as well resulted in additional labeling of cells in centromedian nucleus, pulvinar, and the ventromedial thalamus.Abbreviations AC anterior commissure - CG central grey - CM centromedian nucleus - CN caudate nucleus - DM dorsomedial nucleus - DR dorsal raphe nucleus - DSCP decussation of superior cerebellar peduncle - GPe globus pallidus, external segment - GPi globus pallidus, internal segment - LC locus coeruleus - LL lateral lemniscus - MG medial geniculate nucleus - ML medial lemniscus - NVI abducens nucleus - OT optic tract - Pbl lateral parabrachial nucleus - Pbm medial parabrachial nucleus - Pf parafascicular nucleus - PPN pedunculopontine nucleus - PuO oral pulvinar nucleus - RN red nucleus - SCP superior cerebellar peduncle - SI substantia innominata - SNc substantia nigra, pars compacta - SNr substantia nigra, pars reticulata - STN subthalamic nucleus - TMT mamillothalamic tract - VA ventral anterior nucleus - VLc ventral lateral nucleus, pars caudalis - VLm ventral lateral nucleus, pars medialis - VLo ventral lateral nucleus, pars oralis - VPI ventral posterior inferior nucleus - VPM ventral posterior medial nucleus - VPLc ventral posterior lateral nucleus, pars caudalis - ZI zona incerta     

An autoradiographic study of topographical relationships between pallidal and cerebellar projections to the cat thalamus

Summary Injections of ³H-leucine were made in the entopeduncular nucleus or dentate nucleus of the cerebellum in eight cats. The terminal projection zones of both pathways in the thalamus were studied using the sagittal plane and their relationships to one another as well as to cytoarchitectural boundaries of thalamic nuclei were compared. The data indicate that the territories controlled by the two projection systems are almost entirely segregated. The segregation is mainly along the antero-posterior axis as the main pallidal projection zone occupies the medio-ventral VA while the main dentate projection zone lies posterior to it in the VL. Furthermore, the dorsolateral part of the VA not occupied by pallidal projections receives dentate projections. In the VM, both afferent systems terminate in the lateral part of the nucleus with pallidal territory located anteriorly and dentate territory located posteriorly, again without overlap. As the delineations of nuclear subdivisions in the ventral thalamus of the cat have been a subject of some controversy, it is suggested that the boundaries of the VA, VL and VM in the cat thalamus be defined on the basis of basal ganglia and cerebellar projection zones.Abbreviations used in the Text and in Fig. 5 AM anterior medial nucleus - AV anterior ventral nucleus - BC brachium conjunctivum - CA anterior commissure - CC crus cerebri - CP posterior commissure - CD caudate nucleus - CE centrum medianum - CLN central lateral nucleus - DN dentate nucleus - EPN entopeduncular nucleus - FF Forel's field - FN fastigial nucleus - FR fasciculus retroflexus - HL lateral habenular nucleus - HM medial habenular nucleus - INA anterior interposite nucleus - INP posterior interposite nucleus - IC internal capsule - LD lateral dorsal nucleus - LG lateral geniculate body - MD medial dorsal nucleus - MTT mamillothalamic tract - NR red nucleus - OT optic tract - PAC paracentral nucleus - PF parafascicular nucleus - PV pulvinar - RT reticular thalamic nucleus - SM submedian nucleus - SN substantia nigra - SNr substantia nigra pars reticularis - STN subthalamic nucleus - VF ventral posterior nucleus - VA ventral anterior nucleus - VL ventral lateral nucleus - VM ventral medial nucleus - ZI zona incerta Supported in part by a grant from the American Parkinson Disease Association and NIH grant R01NS19280     

An autoradiographic study of efferent connections of the globus pallidus in Macaca mulatta

Summary Radioactive amino acids were injected into restricted regions of the globus pallidus of rhesus macaques to allow identification of the organization and courses of efferent pallidal projections. The previously identified projection of the internal pallidal segment (GPi) to ventral thalamic nuclei showed a topographic organization, with the predominant projection from ventral GPi being to medial and caudal ventralis anterior (VA) and lateralis (VL) and from dorsal GPi to lateral and rostral VA and VL. Pallidal efferent fibers also extended caudally and dorsally into pars caudalis of VL, but they spared the portion of pars oralis of VL shown by others to receive input from the cerebellum. In addition to centromedian labeling in all animals, the parafascicular nucleus was also labeled when isotope was injected into dorsal GPi. The medial route from GPi to the midbrain tegmentum was more substantial than has been shown before, and along this route there was an indication that some fibers terminated in the prerubral region. The projection to the pedunculopontine nucleus was extensive, and fibers continued caudally into the parabrachial nuclei.Pallidal projections to the thalamus seem to be topographically organized but spare thalamic regions that interact with area 4. Caudally directed efferent fibers follow multiple routes and extend more caudally than to the pedunculopontine nuclei.Abbreviations Cd caudate nucleus - CM centromedian nucleus - CT central tegmental tract - DPCS decussation of superior cerebellar peduncle - F fornix - FLM medial longitudinal fasciculus - GPe globus pallidus, pars externa - GPi globus pallidus, pars interna - HbL lateral habenular nucleus - HbM medial habenular nucleus - Is interstitial nucleus - LM medial lemniscus - MD dorsomedial nucleus - PbL lateral parabrachial nucleus - PbM medial parabrachial nucleus - PCS superior cerebellar peduncle - Pf parafascicular nucleus - PPN pedunculopontine nucleus - Put putamen - R reticular nucleus - Rmg red nucleus, pars magnocellularis - Rpc red nucleus, pars parvocellularis - S stria medullaris - SI substantia innominata - SNc substantia nigra, pars compacta - SNr substantia nigra, pars reticulata - St subthalamic nucleus - ST stria terminalis - THI habenulointerpeduncular tract - TM tuberomamillary nucleus - TMT mamillothalamic tract - VA nucleus ventralis anterior - VAmg nucleus ventralis anterior, pars magnocellularis - VAp nucleus ventralis anterior, pars principalis - VI nucleus ventralis intermedius - VLc nucleus ventralis lateralis, pars caudalis - VLm nucleus ventralis lateralis, pars medialis - VLo nucleus ventralis lateralis, pars oralis - VPL nucleus ventralis posterior lateralis - X area X Supported by National Institutes of Health, grant RR00166, Rehabilitation Services Administration, grant 16-P-56818, and PHS grant NS10804     

A GABA immunocytochemical study of rat motor thalamus: light and electron microscopic observations.

A light and electron microscopic study of GABA-immunoreactive neurons and profiles in the ventroanterior-ventrolateral and ventromedial nuclei of rat dorsal thalamus was conducted using antiserum raised against GABA. Less than 1% of the neurons in these motor-related nuclei exhibited GABA immunoreactivity, confirming previous reports that these nuclei are largely devoid of interneurons. Immunoreactive neurons in the ventral anterior-ventral lateral complex and ventromedial nucleus were bipolar or multipolar in shape, and tended to be smaller than non-immunoreactive neurons. GABA immunoreactivity in the neuropil consisted of labeled axon terminals and myelinated and unmyelinated axons, and was lower in the ventral anterior-ventral lateral complex and ventromedial nucleus than in neighboring thalamic nuclei. The density of neuropil immunolabeling was slightly higher in ventral anterior-ventral lateral complex than in ventromedial nucleus. GABA-immunoreactive axon terminals, collectively termed MP boutons for their medium size and pleomorphic vesicles (and corresponding to "F" profiles of some previous studies of thalamic ultrastructure), formed symmetric synapses and puncta adhaerentia contacts predominantly with large and medium-diameter (i.e. proximal) non-immunoreactive dendrites. Approximately 12 and 18% of boutons in the ventral anterior-ventral lateral complex and ventromedial nucleus, respectively, were GABA-immunopositive. Many of these immunoreactive profiles probably arose from GABAergic neurons in the thalamic reticular nucleus, substantia nigra pars reticulata and entopeduncular nucleus. Two types of non-immunoreactive axon terminals were distinguished based on differences in morphology and synaptic termination sites. Boutons with small ovoid profiles and round vesicles that formed prominent asymmetric synapses onto small-diameter dendrites were observed. Mitochondria were rarely observed within these boutons, which arose from thin unmyelinated axons. These boutons composed approximately 82 and 74% of boutons in the ventral anterior-ventral lateral complex and ventromedial nucleus, respectively, and were considered to arise predominantly from neurons in the cerebral cortex. In contrast, boutons with large terminals that contained round or plemorphic vesicles and formed multiple asymmetric synapses predominantly with large-diameter dendrites were also observed. Puncta adhaerentia contacts were also common. Mitochondria were numerous within large boutons with round vesicles, which arose from myelinated axons. Many of the large boutons were likely to have originated from neurons in the cerebellar nuclei. Approximately 6% of the boutons in the ventral anterior-ventral lateral complex and 8% in ventromedial nucleus were of the large type.(ABSTRACT TRUNCATED AT 400 WORDS)     

Laminar organization of the substantia nigra pars reticulata in the cat

Using a semihorizontal section plane tangential to the ventral surface of the cerebral peduncle, the authors re-examined cyto-, myelo- and dendroarchitecture, acetylcholinesterase activity, afferent fibers, and efferent projection neurons of the substantia nigra pars reticulata. In the semihorizontal section plane, the substantia nigra pars reticulata was a disc-shaped nucleus and contained two to three myelinated fiber bundles running from anteromedial to posterolateral. Bands of high acetylcholinesterase activity existed parallel to the anteromedial-posterolateral direction. The Golgi silver impregnation study revealed that many nigral neurons extended their varicose dendrites anteromedially and posterolaterally. In cases with injections of wheat germ agglutinated horseradish peroxidase into the neostriatum or injections of tritiated leucine into the subthalamic nucleus, anterogradely labeled afferent fibers and axon terminals in the substantia nigra pars reticulata were organized into bands in the same anteromedial-posterolateral direction. In cases with injections of wheat germ agglutinated horseradish peroxidase into either the superior colliculus, the pedunculopontine tegmental nucleus or the ventromedial nucleus of the thalamus, retrogradely labeled neurons were also clustered along the anteromedial-posterolateral direction with their dendrites extending anteromedially and posterolaterally. The present findings strongly suggest that the substantia nigra pars reticulata has a laminar organization.     

Excitatory amino acid projections to the nucleus accumbens septi in the rat: a retrograde transport study utilizing D[3H]aspartate and [3H]GABA

Afferents to the nucleus accumbens septi utilizing glutamate or aspartate have been investigated in the rat by autoradiography following injection and retrograde transport of D[3H]aspartate. Parallel experiments with the intra-accumbal injection of [3H]GABA were employed to establish the transmitter-selective nature of the retrograde labelling found with D[3H]aspartate. The topography of cortical and thalamic perikarya labelled by D[3H]aspartate was extremely precise. D[3H]Aspartate labelled perikarya were found in layer V of agranular insular cortex; bilaterally within prelimbic and infralimbic subareas perikarya, but predominantly ipsilaterally. Ipsilateral labelling was observed in dorsal, ventral and posterior agranular insular cortices, and in perirhinal cortex. Injections into ventral accumbens labelled perikarya in ipsilateral entorhinal cortex, while infusion of D[3H]aspartate into anterior caudate-putamen resulted in labelling of perikarya in ipsilateral cingulate and lateral precentral cortices. Following infusion of D[3H]aspartate, ipsilateral midline thalamic nuclei contained the highest density of labelled perikarya; infusions centred on nucleus accumbens resulted in heavy retrograde labelling of the parataenial nucleus, but labelling was sparse from a lateral site and not observed after injection into anterior caudate-putamen. Less prominent labelling of perikarya was seen in other thalamic nuclei (mediodorsal, central medial, rhomboid, reuniens and centrolateral), mostly near the midline. Perikaryal labelling was also found in the ipsilateral amygdaloid complex, particularly in basolateral and lateral nuclei. Only weak labelling resulted in ventral subiculum. Numerous labelled cells were present bilaterally in anterior olfactory nucleus, although perikarya were more prominent ipsilaterally. Labelled perikarya were not consistently observed in other regions (ventral tegmental area, medial substantia nigra, raphe nuclei and locus coeruleus) known to innervate nucleus accumbens. Presumptive anterograde labelling was detected in ventral pallidum/substantia innominata, ventral tegmental area and medial substantia nigra. [3H]GABA was generally not retrogradely transported to the same regions labelled by D[3H]aspartate; an exception being the anterior olfactory nucleus, where large numbers of labelled perikarya were found. [3H]GABA failed to label perikarya in thalamus and amygdala, and a topographic distribution of label was absent in neocortex.(ABSTRACT TRUNCATED AT 400 WORDS)     

An analysis of potentially converging inputs to the rostral ventral thalamic nuclei of the cat

Summary Potentially convergent inputs to cerebellar-receiving and basal ganglia-receiving areas of the thalamus were identified using horseradish peroxidase (HRP) retrograde tracing techniques. HRP was deposited iontophoretically into the ventroanterior (VA), ventromedial (VM), and ventrolateral (VL) thalamic nuclei in the cat. The relative numbers of labeled neurons in the basal ganglia and the cerebellar nuclei were used to assess the extent to which the injection was in cerebellar-receiving or basal ganglia-receiving portions of thalamus. The rostral pole of VA showed reciprocal connections with prefrontal portions of the cerebral cortex. Only the basal ganglia and the hypothalamus provided non-thalamic input to modulate these cortico-thalamo-cortical loops. In VM, there were reciprocal connections with prefrontal, premotor, and insular areas of the cerebral cortex. The basal ganglia (especially the substantia nigra), and to a lesser extent, the posterior and ventral portions of the deep cerebellar nuclei, provided input to VM and may modulate these corticothalamo-cortical loops. The premotor cortical areas connected to VM include those associated with eye movements, and afferents from the superior colliculus, a region of documented importance in oculomotor control, also were labeled by injections into VM. The dorsolateral portion of the VA-VL complex primarily showed reciprocal connections with the medial premotor (area 6) cortex. Basal ganglia and cerebellar afferents both may modulate this cortico-thalamo-cortical loop, although they do not necessarily converge on the same thalamic neurons. The cerebellar input to dorsolateral VA-VL was from posterior and ventral portions of the cerebellar nuclei, and the major potential brainstem afferents to this region of thalamus were from the pretectum. Mid- and caudo-lateral portions of VL had reciprocal connections with primary motor cortex (area 4). The dorsal and anterior portions of the cerebellar nuclei had a dominant input to this corticothalamo-cortical loop. Potentially converging brainstem afferents to this portion of VL were from the pretectum, especially pretectal areas to which somatosensory afferents project.List of Abbreviations AC central amygdaloid nucleus - AL lateral amygdaloid nucleus - AM anteromedial thalamic nucleus - AV anteroventral thalamic nucleus - BC brachium conjunctivum - BIC brachium of the inferior colliculus - Cd caudate nucleus - CL centrolateral thalamic nucleus - CM centre median nucleus - CP cerebral peduncle - CUN cuneate nucleus - DBC decussation of the brachium conjunctivum - DR dorsal raphe nuclei - EC external cuneate nucleus - ENTO entopeduncular nucleus - FN fastigial nucleus - FX fornix - GP globus pallidus - GR gracile nucleus - IC internal capsule - ICP inferior cerebellar peduncle - IP interpeduncular nucleus - IVN inferior vestibular nucleus - LD lateral dorsal thalamic nucleus - LGN lateral geniculate nucleus - LH lateral hypothalamus - LP lateral posterior thalamic complex - LRN lateral reticular nucleus - LVN lateral vestibular nucleus - MB mammillary body - MD mediodorsal thalamic nucleus - MG medial geniculate nucleus - ML medial lemniscus - MLF medial lengitudinal fasciculus - MT mammillothalamic tract - MVN medial vestibular nucleus - NDBB nucleus of the diagonal band of Broca - NIA anterior nucleus interpositus - NIP posterior nucleus interpositus - OD optic decussation - OT optic tract - PAC paracentral thalamic nucleus - PPN pedunculopontine region - PRO gyrus proreus - PRT pretectal region - PT pyramidal tract - PTA anterior pretectal region - PTM medial pretectal region - PTO olivary pretectal nucleus - PTP poterior pretectal region - Pul pulvinar nucleus - Put putamen - RF reticular formation - RN red nucleus - Rt reticular complex of the thalamus - S solitary tract - SCi superior colliculus, intermediate gray - SN substantia nigra - ST subthalamic nucleus - VA ventroanterior thalamic nucleus - VB ventrobasal complex - VL ventrolateral thalamic nucleus - VM ventromedial thalamic nucleus - III oculomotor nucleus - IIIn oculomotor nerve - 5S spinal trigeminal nucleus - 5T spinal trigeminal tract - VII facial nucleus     

Bilateral cerebral metabolic effects of pharmacological manipulation of the substantia nigra in the rat: Unilateral intranigral application of the inhibitory GABAA receptor agonist muscimol

Rates of cerebral glucose utilization were measured by means of the autoradiographic 2-deoxy-d[1-¹⁴C]glucose technique in the rat brain in order to determine the metabolic effects of unilateral intranigral application of the GABA_A agonist muscimol upon the substantia nigra and its targets. Intranigral injection of 1.5 μl 0.3 M muscimol (52 μg total dose) induced local metabolic activation in the injected substantia nigra reticulata (by 87% as compared to the control group), and distal metabolic depressions in the nucleus accumbens, striatum, globus pallidus and subthalamic nucleus only ipsilaterally to the injected nigra. The remaining basal ganglia components, including the substantia nigra compacta and the entopeduncular nucleus were bilaterally unaffected. Among the principal efferent projections of the substantia nigra reticulata, the ventromedial and centrolateral thalamic nuclei as well as the deep layers of the superior colliculi were metabolically depressed bilaterally, whereas the ventrolateral, parafascicular and mediodorsal thalamic nuclei as well as the pedunculopontine nucleus displayed metabolic depressions ipsilateral to the muscimol-injection nigra. The ventromedial and centrolateral thalamic nuclei were depressed by 41 and 42%, respectively, in the ipsilateral side, and by 30 and 26% in the contralateral side, when compared to the respective values of the control group of rats. Furthermore, unilateral intranigral injection of 0.3 M muscimol induced metabolic depressions in reticular, intralaminar and prefrontal thalamocortical areas mostly ipsilateral to the injected nigra, as well as in limbic areas bilaterally.It is suggested that the present findings are due to a postsynaptic effect of muscimol on the nigral GABAergic cells and to a consequent metabolic depression of the basal ganglia and associated thalamocortical areas, in contrast to an earlier suggested presynaptic nigral effect of lower doses of intranigrally injected muscimol which induced metabolic activations within the same network.¹⁸ This suggestion is further supported by the fact that intranigrally injected substrate P¹⁹ induced similar effects to those elicited by the lower doses of intranigral muscimol and opposite to those induced at present by the higher muscimol dose. Moreover, it is further substantiated that the nigrothalamic GABAergic system is responsible for considerable transfer of information from one substantia nigra reticulata to the ipsilateral basal ganglia and associated thalamocortical components as well as to bilateral motor, intralaminar and limbic areas.     

Locomotor activity induced by the non-competitive N-methyl-D-aspartate antagonist, MK-801: role of nucleus accumbens efferent pathways

We have recently shown that focal administration of dizocilpine hydrogen maleate (MK-801, a non-competitive N-methyl-D-aspartate antagonist) within the nucleus accumbens increases locomotor activity in a dopamine-independent manner. The purpose of this study was to investigate the neural network underlying locomotor stimulation induced by N-methyl-D-aspartate receptor blockade in the accumbens. In the first experiment, we examined the effect of different doses (1, 5 and 25 nmol) of the active and inactive enantiomers of the N-methyl-D-aspartate antagonist, (+)- and (-)-MK-801, respectively, focally administered in the nucleus accumbens. Only the active enantiomer induced a significant increase in locomotor activity; furthermore, the effect induced by the two highest doses of (+)-MK-801 was significantly different from that induced by (-)-MK-801. In the second part of the study, we performed ibotenic acid lesions to the major output nuclei of the accumbens, the ventral pallidum, mediodorsal thalamus, ventrolateral/ventromedial thalamus and pedunculopontine tegmental nucleus, to observe their effect on locomotor activity induced by focal (+)-MK-801 (25 nmol) administration into the accumbens. None of the lesions had any effect on spontaneous locomotor activity. Hyperactivity induced by accumbens MK-801 administrations was unaffected by ibotenic acid lesions of the pedunculopontine tegmental nucleus, while lesions of the mediodorsal thalamus induced only a partial inhibition. In contrast, ibotenic acid lesions of the ventral pallidum and ventrolateral/ventromedial thalamus completely blocked the motor response induced by accumbens MK-801.These data indicate that the intact mediodorsal thalamus, which has been proposed as a part of the loop that relays accumbens information to the prefrontal cortex, does not seem to be a structure of primary importance in MK-801 locomotor activity. On the contrary, the motor nuclei of the thalamus appear to play a more relevant role, suggesting that different neural substrates may mediate dopamine and glutamate functional output from the nucleus accumbens.     

Long collateral branches of substantia nigra pars reticulata axons to thalamus,superior colliculus and reticular formation in monkey and cat. Multiple retrograde neuronal labeling with fluorescent dyes

In order to gain some impressions about the degree to which individual neurons of the pars reticulata of the substantia nigra send long collateral branches to more than one of its three major targets (thalamus, superior colliculus, reticular formation), two, or all three targets were injected with fluorescent dyes (Evan's blue, granular blue, nuclear yellow, propidium iodide) in six squirrel monkeys and four cats. The best results were obtained in the monkey brain with injections of Evan's blue in the thalamus, granular blue in the colliculus and nuclear yellow in the reticular formation. Whereas nigrothalamic and nigroreticular neurons are numerous and widely scattered throughout all parts of the pars reticulata, cells projecting only to the superior colliculus are fewer in number and restricted to a rostral-lateral zone. These results are consistent with earlier data obtained with the horseradish peroxidase method.² Although double-labeled cells with projections to both the thalamus and reticular formation occur throughout the pars reticulata, such cells are somewhat more abundant at caudal levels of the nucleus. Cells containing dyes from both the superior colliculus and reticular formation are less common and restricted to the lateral part of the pars reticulata. A small number of cells near the rostral pole of the pars reticulata contain dye from both the tectal and thalamic injection. Typically, less than two dozen cells in any case can be confidently identified as containing all three dyes and these cells are located in the rostrolateral half of the pars reticulata. Fewer than 20% of the labeled nigral cells contain more than one dye.In the cat, thalamic injection of granular blue and tectal injection of nuclear yellow indicate that most nigrotectal cells are located in the middle of the mediolateral expanse of the pars reticulata in its rostral half. Nigrothalamic cells flank the nigrotectal group medially, laterally and caudally. Where these groups border one another, several cells contain both dyes indicating that they project to both the thalamus and colliculus. In both the cats and monkeys, a less extensive cell-labeling occurs in the contralateral nigra with a pattern similar to that in the ipsilateral substantia nigra.The results indicate that several neurons of the substantia nigra's pars reticulata send long collateral branches to two or even all three of the major targets. Many reticulata cells, however, appear to project either to the thalamus, or to the superior colliculus or to the reticular formation.     

Biochemical evidence for γ-aminobutyrate containing fibres from the nucleus accumbens to the substantia nigra and ventral tegmental area in the rat

Glutamate decarboxylase activity, a specific marker for γ-aminobutyrate-containing neurons, has been analysed in microdissected samples from rat mesencephalon following unilateral electrocoagulations of the nucleus accumbens. This lesion resulted in a consistent decrease of 50% in the enzyme activity in the rostromedial substantia nigra, and a slight, but insignificant decrease (?15%) in the medial parts of the caudal pars compacta of the substantia nigra. No change was found in the lateral pars compacta or the central pars reticulata. In the ventral tegmental area, the highest activity was found in the rostromedial part, adjacent to the mammillary body. At this level, a significant decrease of 20% was found in the ventral tegmental area on the lesioned side. In contrast, the activities in the medial accessory optic nucleus and the caudal ventral tegmental area adjacent to the interpenduncular nucleus were unchanged.The results indicate that the nucleus accumbens sends γ-aminobutyrate-containing fibres to the rostromedial substantia nigra and to the rostral ventral tegmental area. The caudal ventral tegmental area, the lateral pars compacta and the central pars reticulata do not receive measurable amounts of such fibres.     

大鼠眶皮质的间脑和脑干的传入投射

目的：研究间脑和脑干对眶皮质的传入投射。方法：ＨＲＰ逆行示踪法。结果：将ＨＲＰ分别导入１８只大鼠的内侧及腹侧眶区、腹外侧内和外侧区后，在同侧丘脑背内侧核中可见密集的标记细胞，并有一定的局部定位，其次在内丘脑的胶状核、前内侧核、菱形核、腹我侧和腹内侧核中可见大量标记细胞。在同侧下丘脑餐侧区、背侧区、未定带和背内侧核中可见少量标记细胞。在脑干的黑质致密部、腹侧被盖区、中缝背核、导水管周灰质中也可见标记     

The role of the ventromedial thalamic nucleus in the catalepsy evoked from the substantia nigra pars reticulata in rats

Picrotoxin (25, 50 and 100 ng), injected unilaterally into the posterior part of the substantia nigra pars reticulata (SNR) of rats, evoked a dose-dependent catalepsy. The catalepsy evoked by 100 ng of picrotoxin injected into the SNR was abolished by a subsequent bilateral injection of the same drug (200 ng) into the ventromedial thalamic nuclei. It is suggested that impulses pertinent to the catalepsy evoked from the SNR are transmitted via a GABAergic pathway to the ventromedial thalamic nucleus, wherefrom they reach the striatum, as had been shown previously.     

Distribution of γ-aminobutyrate in the rat thalamus: Specific decreases in thalamic γ-aminobutyrate following lesion or electrical stimulation of the substantia nigra

Various subnuclei of the rat's thalamus were punched out or finely microdissected from frozen coronal sections of brain and assayed for γ-aminobutyrate by microdansylation. Highest levels were recorded in the ventromedial and parafascicular regions, corresponding to the sites of termination of nigrothalamic neurones. One week after placing a unilateral electrolytic lesion in the zona reticulata of the substantia nigra there were significant decreases in γ-aminobutyrate levels in the ipsilateral ventromedial (?14%) and parafascicular (?11%) nuclei, but not in other nuclei tested. Falls in the level of γ-aminobutyrate of 19–26% were found to be confined to the ventromedial region in microdissections of brain slices containing this nucleus, two weeks after injecting 1 μg kainic acid into the substantia nigra. The concentrations of glutamate, aspartate, glutamine, glycine and alanine were not altered in the deafferented ventromedial thalamus. Pathological effects of kainate were registered as a complete loss of neuronal perikarya at the injection site coupled with intense gliosis. Mild gliosis, but no postsynaptic neuronal damage, was visible in the corresponding ventromedial and parafascicular nuclei in the thalamus, although degenerating electron-dense terminal boutons were occasionally seen in electron micrographs of this tissue.In rats in which thalamic glutamate decar?ylase activity was inhibited by systemic injection of 3-mercaptopropionic acid, trains of biphasic electrical pulses delivered to the nigra (100 Hz, 0.1 mA, width 0.6 ms for 15 min) evoked a stimulus-dependent decrease in ventromedial (?17%) and parafascicular (?10%) γ-aminobutyrate content, but not in that of other thalamic nuclei. Similar post-stimulus falls in the level of γ-aminobutyrate in the ventromedial nucleus were noted after direct stereotaxic injection of this nucleus with the enzyme inhibitor.These findings are consistent with the existence of γ-aminobutyrate-containing nigrothalamic fibres whose cell bodies lie in the medial part of the substantia nigra zona reticulata and which terminate in the ventromedial and parafascicular nuclear regions of the thalamus.