The distribution and some morphological features of substantia nigra neurons that project to the thalamus,superior colliculus and pedunculopontine nucleus in the monkey

Neurons of the substantia nigra's pars reticulata that send axons to the thalamus, superior colliculus and midbrain reticular formation (including the pedunculopontine nucleus) have been revealed in monkeys by the technique of retrograde transport of horseradish peroxidase. The populations of nigrothalamic, nigrotectal and nigroreticular neurons differ from one another in their number, intranigral distribution and somatodendritic size and shape. Nigrothalamic cells are the most abundant and, although scattered throughout the mediolateral expanse of the pars reticulata, their numbers progressively diminish from rostral to caudal levels. Nigrotectal cells are least numerous and are restricted almost exclusively to the lateral margin of the rostral one-half of the pars reticulata. Nigroreticular cells, like nigrothalamic, are scattered throughout the mediolateral dimension of the nucleus, but are more commonly located at middle to caudal levels. In addition to their restricted intranigral location, the nigrotectal cells are larger, polygonal and have more major dendritic processes than the smaller nigrothalamic and nigroreticular cells which are usually triangular or fusiform. A small proportion of cells of all three types appears to project contralaterally.These findings indicate that the efferent organization of the primate pars reticulata differs markedly from that of the rodent¹⁸ and the monkey's nigrotectal cells constitute a spatially and morphologically distinct subpopulation within the pars reticulata. These data should be useful in understanding the functional organization of topographic inputs to the pars reticulata such as that from the neostriatum.     

Ensemble neural activity of the frontal cortical basal ganglia system predicts reaction time task performance in rats

The question pursued in this study was when neural activity appears in the cortico-basal ganglia system that could predict alternate behavioral responses in a reaction time (RT) task. In this protocol, rats first performed a nose poke to initiate a trial, depressed a lever when presented, and then released the lever after a tone cue. Multiple-channel, single-unit recordings (up to 62 units) were obtained simultaneously from the prefrontal cortex, the dorsal medial striatum, the globus pallidus, and the substantia nigra pars reticulata in a single rat during a session. Results indicated that (1) global alterations of neural activity appeared in clusters, which was associated with different behavioral components and observed in each of the targeted areas; (2) small independent subsets of neurons responded differently between error (lever was released before tone presentation) and correct trials (lever was released within 0.5 s after tone onset) during these behavioral episodes; (3) significant correlations between RTs and single units activities were found in the early preparation phases of the task. The results reveal that complex early preparatory activity exists several seconds before the final movements in a RT task, which may determine executive functions leading to rapid decoding of alternate behavioral performances.     

Differential role of GABAA and GABAB receptors in two distinct output stations of the rat striatum: studies on the substantia nigra pars reticulata and the globus pallidus

The role of GABA_A and GABA_B receptors in the substantia nigra pars reticulata and the globus pallidus in turning behaviour of rats was studied. Unilateral injection of the GABA_A receptor agonist muscimol (25 and 50 ng) into the substantia nigra pars reticulata elicited contralateral pivoting, namely tight head-to-tail turning marked by abnormal hindlimb backward stepping. This effect was GABA_A receptor specific, since it was dose-dependent and prevented by co-administration of the GABA_A receptor antagonist bicuculline (100 and 200 ng) which alone did not elicit turning behaviour. Unilateral injection of the GABA_B receptor agonist baclofen (100 and 200 ng) into the substantia nigra pars reticulata also produced contralateral pivoting. This effect was GABA_B receptor specific, since it was dose-dependent and inhibited by the GABA_B receptor antagonist CGP 55845 (200 ng) which alone did not elicit turning behaviour. In contrast, unilateral injection of bicuculline (100 and 200 ng) into the globus pallidus produced contralateral circling, namely turning marked by normal stepping. This effect was GABA_A receptor specific, since it was dose-dependent and prevented by muscimol (50 ng), which alone did not elicit turning behaviour. Unilateral injection of baclofen (100 and 200 ng) into the globus pallidus dose-dependently produced ipsilateral pivoting; this effect was inhibited by CGP 55845 (200 ng), which alone did not elicit turning behaviour. The present study demonstrates that GABA_A and GABA_B receptors in the globus pallidus and the substantina nigra pars reticulata play differential roles in the production of turning behaviour. This study underlines the notion that the two types of turning, namely pivoting and circling, are valid tools to map out the information flow across the basal ganglia.     

An anatomical and electrophysiological investigation of the serotonergic projection from the dorsal raphe nucleus to the substantia nigra in the rat

Evidence for a projection from the dorsal raphe nucleus to the substantia nigra was obtained by the demonstration of reactive perikarya in the dorsal raphe nucleus after injections of horseradish peroxidase into the substantia nigra of the rat. No labelled cells were observed in the median raphe nucleus. Stereotaxic injections of [³H]leucine into the dorsal raphe nucleus resulted in the appearance of autoradiographic grains over both the zona compacta and zona reticulate of the substantia nigra, although the concentration of grains was higher over the zona compacta. Electrolytic lesions of the dorsal raphe nucleus reduced nigral and striatal 5-hydroxytryptamine content by 61.5 and 70% respectively. Stimulation of the dorsal raphe nucleus was found to inhibit the unit activity of cells in both the zona compacta and zona reticulate of the substantia nigra and this inhibition could be blocked by 60–72 h pretreatment with p-chlorophenylalanine. Stimulation of the median raphe nucleus produced no consistent effects upon nigral unit activity. para-Chlorophenylalanine pretreatment did not significantly affect the rate of striatal dopamine depletion produced by injections of α-methyl-para-tyrosine, suggesting that the serotonergic raphe-nigral projection exerts a phasic rather than a tonic inhibitory influence over the dopaminergic neurons of the nigro-striatal projection.The results are discussed with reference to the possibility that the projections of the dorsal raphe nucleus to the substantia nigra and the striatum may mediate some of the interactions between central serotonergic and dopaminergic mechanisms.     

The influence of group III metabotropic glutamate receptor stimulation by (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid on the parkinsonian-like akinesia and striatal proenkephalin and prodynorphin mRNA expression in rats

Group III metabotropic glutamate receptors (mGluRs) are widely distributed in the basal ganglia, especially on the terminals of pathways which seem to be overactive in Parkinson's disease. The aim of the present study was to determine whether (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-1), an agonist of group III mGluRs, injected bilaterally into the globus pallidus (GP), striatum or substantia nigra pars reticulata (SNr), can attenuate the haloperidol-induced catalepsy in rats, and whether that effect was related to modulation of proenkephalin (PENK) or prodynorphin (PDYN) mRNA expression in the striatum. Administration of ACPT-1 (0.05-1.6 microg/0.5 microl/side) caused a dose-and-structure-dependent decrease in the haloperidol (0.5 mg/kg i.p. or 1.5 mg/kg s.c.)-induced catalepsy whose order was as follows: GP>striatum>SNr. ACPT-1, given alone to any of those structures, induced no catalepsy in rats. Haloperidol (3 x 1.5 mg/kg s.c.) significantly increased PENK mRNA expression in the striatum, while PDYN mRNA levels were not affected by that treatment. ACPT-1 (3 x 1.6 microg/0.5 microl/side) injected into the striatum significantly attenuated the haloperidol-increased PENK mRNA expression, whereas administration of that compound into the GP or SNr did not influence the haloperidol-increased striatal PENK mRNA levels. Our results demonstrate that stimulation of group III mGluRs in the striatum, GP or SNr exerts antiparkinsonian-like effects in rats. The anticataleptic effect of intrastriatally injected ACPT-1 seems to correlate with diminished striatal PENK mRNA expression. However, since the anticataleptic effect produced by intrapallidal and intranigral injection of ACPT-1 is not related to a simultaneous decrease in striatal PENK mRNA levels, it is likely that a decrease in enkephalin biosynthesis is not a necessary condition to obtain an antiparkinsonian effect.     

电刺激大鼠黑质网状部对脚桥核神经元自发放电的影响

目的:观察电刺激大鼠黑质网状部(substantia nigra pars reticulata,SNr)对脚桥核(pedunculopontine nucleus,PPN)神经元自发放电活动的影响,进一步探讨脑内电刺激治疗帕金森病(Parkinson's disease,PD)的机制.方法:应用细胞外记录方法观察不同...     

Role of the ventromedial nucleus of the thalamus in motor behaviour—II. Effects of lesions

Rotational behaviour was initiated in naive rats by injecting muscimol into one substantia nigra pars reticulata, or in unilaterally 6-hydroxydopamine-treated rats with systemic or intracaudate apomorphine. Electrolytic or kainic acid lesions were made in one or both ventromedial nuclei of the thalamus and their effects on the components of circling studied. A unilateral ventromedial electrolesion imposed a weak ipsilateral posture and occasionally elicited weak ipsiversive circling acutely, but not chronically. Challenging these rats with a large subcutaneous dose of apomorphine invariably provoked ipsiversive circling, however old was the lesion. Bilateral electrolesions caused slight hypoactivity. Kainic acid treatments of one or both ventromedial thalami produced uncontrolled hypermotility initially, with subsequent loss of ventromedial neurones and recovery of normal motor behaviour. No form of ventromedial lesion affected the incidence of stereotypy. Acute (but not chronic) contralateral or ipsilateral ventromedial electrolesions, or both, slowed muscimol and apomorphine-induced circling (often in different ways) through complex changes in posture and/or locomotor drive. Animals lesioned during the course of a circling episode often showed the biggest changes in circling to begin with, only to recover minutes later. Rapidly circling rats were sometimes more readily inhibited than slowly circling rats. Toxin injury of the ventromedial nucleus appeared to suppress muscimol and not apomorphine circling. Any ventromedial lesion (electrical or chemical, acute or chronic), if positioned opposite a contraversive circling stimulus, intensified the associated posture. Ipsilateral lesions tended to abolish posture altogether or, like bilateral treatments, to suppress locomotion. Sham operations had none of these effects. Acute electrical lesions and drug-induced inhibition of one or both ventromedial thalami were more or less identical in their effects on rat circling behaviour, save that bilateral muscimol injection caused profound catalepsy while lesions did not.

It is suggested that the ventromedial thalamus is more concerned with the registration of striatal dopamine-mediated behaviours in drug-stimulated than in spontaneously behaving rats, and that other output pathways may rapidly compensate for any impairment of function in the ventromedial nuclei.     

The ventral basal ganglia,a selection mechanism at the crossroads of space,strategy, and reward.

The basal ganglia are often conceptualised as three parallel domains that include all the constituent nuclei. The ‘ventral domain’ appears to be critical for learning flexible behaviours for exploration and foraging, as it is the recipient of converging inputs from amygdala, hippocampal formation and prefrontal cortex, putatively centres for stimulus evaluation, spatial navigation, and planning/contingency, respectively. However, compared to work on the dorsal domains, the rich potential for quantitative theories and models of the ventral domain remains largely untapped, and the purpose of this review is to provide the stimulus for this work. We systematically review the ventral domain’s structures and internal organisation, and propose a functional architecture as the basis for computational models. Using a full schematic of the structure of inputs to the ventral striatum (nucleus accumbens core and shell), we argue for the existence of many identifiable processing channels on the basis of unique combinations of afferent inputs. We then identify the potential information represented in these channels by reconciling a broad range of studies from the hippocampal, amygdala and prefrontal cortex literatures with known properties of the ventral striatum from lesion, pharmacological, and electrophysiological studies. Dopamine’s key role in learning is reviewed within the three current major computational frameworks; we also show that the shell-based basal ganglia sub-circuits are well placed to generate the phasic burst and dip responses of dopaminergic neurons. We detail dopamine’s modulation of ventral basal ganglia’s inputs by its actions on pre-synaptic terminals and post-synaptic membranes in the striatum, arguing that the complexity of these effects hint at computational roles for dopamine beyond current ideas. The ventral basal ganglia are revealed as a constellation of multiple functional systems for the learning and selection of flexible behaviours and of behavioural strategies, sharing the common operations of selection-by-disinhibition and of dopaminergic modulation.     

Primate models of dystonia

Several models of dystonia have emerged from clinical studies providing a comprehensive explanation for the pathophysiology of this movement disorder. However, several points remain unclear notably concerning the specific role of brainstem, basal ganglia nuclei and premotor cortex. We review data collected in sub-human primate to see whether they might provide new insights into the pathophysiology of dystonia. As in human patients, lesions of the putamen induce dystonia, as well as pharmacological manipulations of the dopaminergic system. In addition, primate studies revealed that lesions in brain stem areas involved in the control of muscular tone and GABAergic manipulations in various basal ganglia nuclei or thalamus also lead to dystonia. Moreover, there is a dramatic disruption in the processing of proprioceptive information with abnormal large receptive fields in the basal ganglia, thalamus, primary somesthetic cortex and premotor cortex of dystonic monkeys. These data highlight the idea that dystonia is associated with aberrant sensory representations interfering with motor control. Considering that the supplementary motor area (SMAp) is the target of basal ganglia projections within the motor loop, we propose a model of dystonia in which abnormal excitability, associated with alteration in sensory receptive fields within the SMAp, leads to an abnormal synchronization between primary motor cortex columns. Such a phenomenon might account for the co-contractions of antagonist muscles favored by action and the abnormal postures observed in dystonia.     

Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans

A comparative and integrated account is provided of the evidence that implicates frontostriatal systems in neurodegenerative and neuropsychiatric disorders. Specifically, we have made detailed comparisons of performance following basal ganglia disease such as Parkinson's disease, with other informative groups, including Alzheimer's disease, schizophrenia and attention deficit/hyperactivity disorder and structural damage to the frontal lobes themselves. We have reviewed several behavioural paradigms including spatial attention and set-shifting, working memory and decision-making tasks in which optimal performance requires the operation of several cognitive processes that can be successfully dissociated with suitable precision in experimental animals. The role of ascending neurotransmitter systems are analysed from the perspective of different interactions with the prefrontal cortex. In particular, the role of dopamine in attentional control and spatial working memory is surveyed with reference to its deleterious as well as facilitatory effects. Parallels are identified in humans receiving dopaminergic medication, and with monkeys and rats with frontal dopamine manipulations. The effects of serotonergic manipulations are also contrasted with frontal lobe deficits observed in both humans and animals. The main findings are that certain tests of frontal lobe function are very sensitive to several neurocognitive and neuropsychiatric disorders. However, the nature of some of these deficits often differs qualitatively from those produced by frontal lobe lesions, and animal models have been useful in defining various candidate neural systems thus enabling us to translate basic laboratory science to the clinic, as well as in the reverse direction.     

Comparison of caudate nucleus and substantia nigra control of medial thalamic cell activities in the rat

Systematic mapping of the intralaminar thalamic cells was performed in rats. We studied the characteristics of extracellular spontaneous activity and how the stimulation of caudate nucleus and substania nigra changes firing rate.The majority of cells exhibited a decrease in their activity after the caudate nucleus and substania nigra stimulation; the duration of the decrease was significantly different for each structures stimulated. We propose the participation of a relay structure mediating the decrease of thalamic activity. The responses to caudate nucleus and substantia nigra stimulation could be due to a cortical disfacilitation on the thalemic cells.     

The effects of the mediodorsal nucleus of the thalamus on respiratory neurons of the medulla oblongata and respiration in rats in conditions of hypoxia

The effects of the associated mediodorsal nucleus of the thalamus on spike activity of respiratory neurons in the medulla oblongata and on respiration were studied in normal conditions and in oxygen insufficiency. At normal atmospheric pressure, before animals were elevated to low pressures, electrical stimulation of the mediodorsal nucleus of the thalamus had predominantly inhibitory effects. At the initial phase of hypoxia, at a “height” of 4000–5000 m, hypoxic activation of neuron discharge frequency occurred, with an increase in the frequency of respiration. In these conditions, the inhibitory effect of stimulation of the mediodorsal nucleus of the thalamus was less marked than in normoxic conditions. The opposite effect occurred at the second phase of hypoxia (7500–8000 m)— inhibition of activity in the medulla oblongata and thalamic center. In severe hypoxia, there was inhibition of neuron spike activity and a decrease in the frequency of respiration, which became superficial; in these conditions, the inhibitory effect of the thalamus was insignificant. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 85, No. 2, pp. 283–289, February, 1999.     

Analysis of the Morphological Substrate for Information Processing in the Pallidal Nuclear Complex of the Dog Brain in Terms of the Organizational Characteristics of Its Afferent Projections

Axonal transport of retrograde markers was used to study the distribution of the afferent projections of the nuclei of the pallidal complex (the globus pallidus, the entopeduncular nucleus, and the ventral pallidum) from functionally diverse cortical and subcortical structures (cortical fields, substantia nigra, ventral tegmental field, and thalamus) in the dog brain. The results were used to analyze the morphological aspects both of the functional heterogeneity of the pallidum and integrative information processing, which underlie the mechanisms of adaptive behavior.     

Cerebellar nuclei are activated by high-frequency stimulation of the subthalamic nucleus

The cerebellum, primarily considered a pure motor structure, is increasingly considered to play a role in behaviour and cognition. In a similar manner, there is increasing evidence that the basal ganglia are involved in non-motor processes. Recently a direct connection between the cerebellum and the basal ganglia has been shown to exist. High-frequency stimulation (HFS) of the subthalamic nucleus (STN) has become an accepted treatment in advanced Parkinson's disease (PD). We performed HFS of the STN in rats to evaluate the neuronal activation in the deep cerebellar nuclei (DCbN) using c-Fos immunohistochemistry. We found an increased c-Fos expression in the DCbN. Previously, we have shown that STN HFS in rats leads to decreased impulsive behaviour and our findings now suggest a link with increased DCbN activity. This is in line with our previous work showing that decreased DCbN activity is accompanied by disruptive behaviour. We suggest that the DCbN play a role in the selection of relevant information on which a behavioural response is based. The connection between the cerebellum and the basal ganglia may imply a role for the cerebellum in behavioural aspects of disorders of the basal ganglia.     

The presence and absence of prosencephalic cell groups relaying striatal information to the medial and lateral thalamus in tenrec

Although there are remarkable differences regarding the output organization of basal ganglia between mammals and non-mammals, mammalian species with poorly differentiated brain have scarcely been investigated in this respect. The aim of the present study was to identify the pallidal neurons giving rise to thalamic projections in the Madagascar lesser hedgehog tenrec (Afrotheria). Following tracer injections into the thalamus, retrogradely labelled neurons were found in the depth of the olfactory tubercle (particularly the hilus of the Callejal islands and the insula magna), in subdivisions of the diagonal band complex, the peripeduncular region and the thalamic reticular nucleus. No labelled cells were seen in the globus pallidus. Pallidal neurons were tentatively identified on the basis of their striatal afferents revealed hodologically using anterograde axonal tracer substances and immunohistochemically with antibodies against enkephalin and substance P. The data showed that the tenrec's medial thalamus received prominent projections from ventral pallidal cells as well as from a few neurons within and ventral to the cerebral peduncle. The only regions projecting to the lateral thalamus appeared to be the thalamic reticular nucleus (RTh) and the dorsal peripeduncular nucleus (PpD). On the basis of immunohistochemical data and the topography of its thalamic projections, the PpD was considered to be an equivalent to the pregeniculate nucleus in other mammals. There was no evidence of entopeduncular (internal pallidal) neurons being present within the RTh/PpD complex, neuropils of which did not stain for enkephalin and substance P. The ventrolateral portion of RTh, the only region eventually receiving a striatal input, projected to the caudolateral rather than the rostrolateral thalamus. Thus, the striatopallidal output organization in the tenrec appeared similar, in many respects, to the output organization in non-mammals. This paper considers the failure to identify entopeduncular neurons projecting to the rostrolateral thalamus in a mammal with a little differentiated cerebral cortex, and also stresses the discrepancy between this absence and the presence of a distinct external pallidal segment (globus pallidus).     

The anatomical substrate of the turning behaviour seen after lesions in the nigrostriatal dopamine system

Studies of the fibre connections of the substantia nigra suggest that the behavioural results of changes in the activity in the striatal dopamine-containing system are mediated by a pathway from the striatum to the substantia nigra and thence to the thalamus. Small discrete electrolytic lesions in the appropriate part of the crus cerebri interrupt the striatonigral axons without damage to the nigrostriatal system. Such lesions inhibit turning induced by activation of striatal dopamine receptors.Similarly, turning induced by apomorphine in rats lesioned with 6-hydroxydopamine is inhibited by damage to the ipsilateral ventromedial area of thalamus which receives fibres from the substantia nigra.     

Projections from the central nucleus of the amygdala to the nucleus pontis oralis in the rat: An anterograde labeling study

The present study was designed to elucidate the neuronal projections from the amygdala to the nucleus pontis oralis (NPO). We propose that glutamatergic cells in the central nucleus of the amygdala (CNA) activate neurons in the NPO, which is the critical brainstem site that is responsible for the generation and maintenance of active (REM) sleep. Phaseolus vulgaris-leucoagglutinin (PHA-L), an anterograde transported neuronal tracer, was iontophoresed into the CNA of adult male Sprague-Dawley rats. After a survival time of 7-8 days, the animals were perfused with a fixative and brain tissue was prepared for histological analysis. Sections of the NPO and CNA, which were immunostained with an antibody against PHA-L, were examined with light microscopy. In addition, in order to identify the phenotype of PHA-L-labeled fibers and terminals in the NPO, a double immunohistochemical technique was employed with antibodies against PHA-L and the vesicular glutamate transporter type 2 (VGluT2). Numerous PHA-L-labeled axons and terminals were found in the NPO ipsilateral to the injection site in the CNA. Within the NPO, the majority of labeled fibers were located in the dorsolateral portion of the caudal part of the nucleus. Double-labeling immunostaining studies revealed that PHA-L-labeled axons and terminals in the NPO were glutamatergic. The present demonstration of direct, excitatory (glutamatergic) projections from the CNA to the NPO provide an anatomical basis for the amygdalar control of active sleep.     

Analysis of the Morphological Substrate for Information Processing in the Striatum Based on the Organizational Characteristics of Its Afferent Projections

Retrograde axonal transport of markers was used to study the afferent projections arising from functionally diverse cortical and subcortical structures and running to various segments of the caudate nucleus, nucleus accumbens, and putamen of the dog brain. The characteristics of the spatial organization of these projections were used to analyze the morphological aspects of the segregated and convergent conduction and processing of information in the striatum which underlie striatal function.