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PubMed1993

Noradrenergic innervation of the hypothalamus of rhesus monkeys: distribution of dopamine-beta-hydroxylase immunoreactive fibers and quantitative analysis of varicosities in the paraventricular nucleus.

The distribution of noradrenergic processes within the hypothalamus of rhesus monkeys (Macaca mulatta) was examined by immunohistochemistry with an antibody against dopamine-beta-hydroxylase. The results revealed that the pattern of dopamine-beta-hydroxylase immunoreactivity varied systematically throughout the rhesus monkey hypothalamus. Extremely high densities of dopamine-beta-hydroxylase-immunoreactive processes were observed in the paraventricular and supraoptic nuclei, while relatively lower levels were found in the arcuate and dorsomedial nuclei and in the medial preoptic, perifornical, and suprachiasmatic areas. Moderate levels of dopamine-beta-hydroxylase immunoreactivity were found throughout the lateral hypothalamic area and in the internal lamina of the median eminence. Very few immunoreactive processes were found in the ventromedial nucleus or in the mammillary complex. Other midline diencephalic structures were found to have high densities of dopamine-beta-hydroxylase immunoreactivity, including the paraventricular nucleus of the thalamus and a discrete subregion of nucleus reuniens, the magnocellular subfascicular nucleus. A moderate density of dopamine-beta-hydroxylase immunoreactive processes were found in the rhomboid nucleus and zona incerta whereas little dopamine-beta-hydroxylase immunoreactivity was found in the fields of Forel, nucleus reuniens, or subthalamic nucleus. The differential distribution of dopamine-beta-hydroxylase-immunoreactive processes may reflect a potential role of norepinephrine as a regulator of a variety of functions associated with the nuclei that are most heavily innervated, e.g., neuroendocrine release from the paraventricular and supraoptic nuclei, and gonadotropin release from the medial preoptic area and mediobasal hypothalamus. Additionally, quantitative analysis of dopamine-beta-hydroxylase-immunoreactive varicosities was performed on a laser scanning microscope in both magnocellular and parvicellular regions of the paraventricular nucleus of the hypothalamus. The methodology employed in this study allowed for the high resolution of immunoreactive profiles through the volume of tissue being analyzed, and was more accurate than conventional light microscopy in terms of varicosity quantification. Quantitatively, a significant difference in the density of dopamine-beta-hydroxylase-immunoreactive varicosities was found between magnocellular and parvicellular regions, suggesting that parvicellular neurons received a denser noradrenergic input. These differential patterns may reflect an important functional role for norepinephrine in the regulation of anterior pituitary secretion through the hypothalamic-pituitary-adrenal stress axis.

Animals↗
PubMed1995

Cloning of a human kappa opioid receptor from the brain.

By using a rat kappa opioid receptor cDNA as a probe to screen a human brain cDNA library, we isolated a 4.0-kb clone (z115) which encompasses a major portion of a human kappa opioid receptor (hkor), extending from the amino acid residue #6 to the 3'-untranslated region. The extreme 5'-region 232-bp fragment of z115 was used as a probe to screen a human genomic DNA library. A 1.6-kb fragment (d2) of one positive clone was found to extend from 5'-untranslated region to beyond the exon/intron junction at residue Arg86. The genomic DNA fragment d2 and the cDNA clone z115 were assembled to generate a clone (d2-z115) containing the entire coding sequence of hkor. Clone d2-z115 has an open reading frame of 1140 bp, which encodes for a 380-amino acid protein. The deduced amino acid sequence has 93.9% and 93.2% identity to rat and mouse kappa receptors, respectively. It also displays approximately 60% identity to both human mu and delta receptors. Northern blot analysis showed that in the human brain there was a single hkor mRNA transcript of 6.0 kb. Among brain regions examined, the amygdala, caudate nucleus, hypothalamus and subthalamic nucleus contained high levels of hkor mRNA. Hkor was cloned into the expression vector pBK-CMV and transiently expressed in COS-1 cells. Hkor had high affinity for [3H] diprenorphine, a nonselective opioid antagonist, and displayed stereospecific binding to naloxone. kappa selective ligands (U50,488H and nor-BNI) had high affinities, whereas mu and delta selective ligands bound with much lower affinities. Dynorphin A (1-17) and alpha-neoendorphin, both endogenous kappa peptides, bound with high affinities. These binding characteristics confirmed that hkor is a kappa receptor, most likely kappa 1 type. Cloning of the human kappa receptor allows investigation of interactions of compounds with the human receptor, instead of rodent receptors, for development of better therapeutic agents.

Amino Acid Sequence↗
PubMed1983

Methylphenidate decreases local glucose metabolism in the motor cortex.

The local cerebral metabolism on glucose (l-CMRg) was evaluated in animals given methylphenidate (15 mg/kg) in order to investigate possible mechanisms of action of the drug. Significant increases in l-CMRg (p greater than 0.05) were found in the globus pallidus, entopeduncular nucleus, substantia nigra, subthalamic nucleus, inferior olive, red nucleus, lateral cerebellar cortex, ventral lateral nucleus of the thalamus and the midbrain reticular formation. Significant decreases (p greater than 0.05) in l-CMRg were found in the motor cortex. These results suggest possible mechanisms for methylphenidate's action in attention deficit disorders.

Animals↗
PubMed1994

Autoradiographic localization and quantitative determination of specific binding sites of anxiolytic homophthalazines (formerly called 2,3-benzodiazepines) in the striato-pallido-nigral system of rats.

Homophthalazines (2,3-benzodiazepin-derivates, such as tofisopam, nerisopam, girisopam) constitute a drug family with strong anxiolytic and antipsychotic potencies. By autoradiography, all of these drugs showed a specific distribution pattern of binding sites exclusively in brain areas which relate to the striato-pallido-nigral system, while no specific label was found in any other brain areas in the rat. Quantitative analyses of the autoradiograms by computerized densitometry, as well as by a receptor binding assay on 32 microdissected brain areas showed very high concentrations of tritiated homophthalazines in the glubus pallidus, caudate nucleus, putamen and the substantia nigra. Relatively high density of binding sites was measured in the nucleus accumbens, the olfactory tubercle, the entopeduncular nucleus and the subthalamic nucleus. Concentrations measured in the cerebral cortical areas, cerebellum or brainstem nuclei did not differ from the background. No significant differences were found between the homophthalazines investigated in terms of the distribution patterns or density of binding sites.

Animals↗
PubMed2005

Immunohistochemical localization of toluene-induced c-Fos protein expression in the rat brain.

Although toluene is a widely abused substance, the neuronal populations and pathways mediating its effects are not well understood. Using c-Fos protein as a marker for neuronal activation, the present study investigated the pattern of c-Fos induction at 1h after various doses (0, 300, 750, and 1000 mg/kg, i.p.) of toluene injection in adult male rats. Quantitative analysis of Fos-immunoreactive neurons indicated toluene dose-related induced c-Fos immunoreactivity in the majority of structures examined. The structures included several cortex subareas (primary motor cortex, secondary motor cortex, somatosensory cortex, frontal association cortex, cigulate cortex area 1, cigulate cortex area 2, prelimbic cortex, infralimbic cortex, retrosplenial agranular cortex, ventral orbital cortex, lateral orbital cortex, and piriform cortex), ventral tegmental area, nucleus accumbens shell, thalamic nuclei (mediodorsal, lateral posterior, and laterodorsal ventrolateral) and pontine nuclei. However, the substantia nigra, caudate putamen, nucleus accumbens core, subthalamic nucleus, hippocampus and cerebellum were almost unaffected. The data demonstrate that toluene dose-related induced a unique pattern of c-Fos immunoreactivity. The widespread distribution of toluene-induced c-Fos expression seen in this study can be linked to the profound alterations in physiological function and behavior produced by this solvent.

Animals↗
PubMed2003

The basal ganglia: a neural network with more than motor function.

The basal ganglia is a group of subcortical nuclei involved in motor control, cognition, and emotion. Basal ganglia disorders are manifested by abnormal movement and a number of neuropsychiatric disorders. Basal ganglia nuclei are organized into sensorimotor, associative, and limbic territories based on their connectivity and function. The caudate nucleus, putamen, and subthalamic nucleus comprise the input nuclei of the basal ganglia. The internal segment of globus pallidus and substantia nigra reticulata are the output nuclei. The input and output nuclei are interconnected by direct and indirect pathways. The cerebral cortex, basal ganglia, and thalamus communicate with each other via closed (segregated) parallel as well as open (split) loops. Recent anatomic, functional, and clinical data have necessitated modifications in the classical models of local connectivity between input and output nuclei of the basal ganglia as well as in the corticobasal ganglia-thalamus-cortical loops.

Animals↗
PubMed1996

A single-cell study of the axonal projections arising from the posterior intralaminar thalamic nuclei in the rat.

Thalamostriatal projections arising from the posterior intralaminar nuclei (P1; the parafascicular nucleus and the adjacent caudalmost part of the posterior thalamic group) were studied in rats by tracing the axons of small pools of neurons labelled anterogradely with biocytin. Thirteen P1 cells were also stained by juxta cellular application of the tracer. Relay cells of P1 nuclei have a morphology that differs radically from the classical descriptions of the bushy cells which represent the main neuronal type of the sensory thalamic relay nuclei. P1 cells have ovoid or polygonal somata of approximately 20-25 microm, from which emerge four or five thick, long and poorly branched dendrites bearing spines and filamentous appendages; their dendritic domains extend for up to 1.5 mm. Before leaving the nucleus 20% of axons give off collaterals that ramify locally. All axons course through the thalamic reticular nucleus, where they also distribute collaterals, and arborize massively in the striatum and sparsely in the cerebral cortex. At the striatal level four or five collaterals leave the main axon and terminate in patches scattered dorsoventrally within a rostrocaudally oriented slab. As revealed by calbindin D-28k immunohistochemistry, only the matrix compartment receives terminations from P1 axons. The cortical branch form small terminal puffs centred upon layer VI of the motor cortex. Before entering the striatum some axons of the parafascicular nucleus give rise to descending collaterals that arborize in the entopeduncular nucleus, in the subthalamic nucleus and in the vicinity of the red nucleus. Other axons arising from the caudal part of the posterior group send descending branches only to the entopeduncular nucleus. These findings show that P1 cells belong to a distinct category of thalamic relay neurons which, beside their massive projection to the striatum, also distribute collaterals to other components of the basal ganglia. Moreover, these results provide the first direct evidence that virtually all P1 cells project to both striatum and cerebral cortex. Finally, it is proposed on the basis of morphological, histochemical and hodological criteria that the caudal part of the posterior thalamic group in the rat is homologous to the suprageniculate-limitans nuclei of cats and primates.

Afferent Pathways↗
PubMed2005

A preliminary study of transient confusional states following bilateral subthalamic stimulation for Parkinson's disease.

Transient postoperative confusion (POC) occurs in 5-25% of patients following bilateral subthalamic nucleus stimulation. We retrospectively reviewed data on 96 patients who underwent bilateral subthalamic nucleus deep brain stimulation for Parkinson's disease. Nine percent of patients developed POC. There was no significant correlation between age/perioperative factors and POC. The POC group had a significantly higher incidence of depression and frontal-subcortical dysfunction on preoperative evaluation than patients without POC. Postoperative neuropsychological evaluations revealed declines on measures of general cognitive function and memory in the POC group. We provide preliminary evidence that patients with depression and frontal-subcortical dysfunction are more likely to develop POC, and that POC is more often associated with cognitive decline following surgery.

Aged↗
PubMed1987

[An autopsy case of myoclonus epilepsy associated with ragged-red fibers (Fukuhara disease)].

In 1980, Fukuhara et al. have reported two patients with "myoclonus epilepsy associated with ragged-red fibers" (MERRF), which is at present accepted as a distinctive clinical entity among the mitochondrial encephalomyopathies. We describe here postmortem findings of the case whose clinical findings were reported in detail by Fukuhara et al. (1980) as Case 1. The neuropathological findings were summarized as follows: 1) degeneration of dentate nucleus, red nucleus, globus pallidus, subthalamic nucleus and pontine tegmentum, 2) degeneration of the Clarke's column, spinocerebellar tract, posterior column and corticospinal tract, as well as of the posterior spinal nerve root and sural nerve, and 3) degeneration of substantia nigra, locus ceruleus, cerebellar cortex and inferior olivary nucleus. The lesions were degenerative in nature, and their distribution was different from those of dentato-rubropallidoluysian atrophy, Joseph's disease or Friedreich's ataxia. It was concluded that MERRF is a single disease entity also from pathological point of view.

Adult↗
PubMed1987

[Afferent connections of the dorsal sections of the pars magnocellularis in the red nucleus of the cat].

Location of retrogradely labelled neurons in various structures of the central nervous system was studied by microiontophoretic injection of horseradish peroxidase into dorsal sections of the magnocellular part of the cat red nucleus. Projections were revealed from some hypothalamic nuclei, centrum medianum, as well as from nucleus parafascicularis and subthalamic nucleus; from zone incerta, field of Forel, nucleus medialis habenulae; from reticular formation of the pons, medulla oblongata and midbrain, central gray matter, colliculus superior, nucleus interstitialis Cajal; from contralateral red nucleus, nucleus fastigii and facial nucleus; from nucleus vestibularis lateralis (pars dorsalis) and nucleus vestibularis medialis as well as from ventral horn of the spinal cord cervical segments. Connections between substantia nigra and the red nucleus have been studied more accurately. Bilateral trajectories of retrogradely labelled fibre systems are described.

Afferent Pathways↗
PubMed2005

Subthalamic stimulation for Parkinson's disease.

Subthalamic nucleus stimulation by means of permanently implanted brain electrodes is a very effective therapy for all the cardinal features of Parkinson's disease. In appropriate patients, motor improvement is accompanied by a significantly improved quality of life and a reduced necessity for medication. This article briefly reviews the indications, technique and postoperative management of patients undergoing subthalamic nucleus stimulation.

Contraindications↗
PubMed2003

Noradrenaline increases the firing rate of a subpopulation of rat subthalamic neurones through the activation of alpha 1-adrenoceptors.

In the rat subthalamic nucleus, which plays a critical role in the control of motor behaviour, specific binding of [3H]-prazosin was detected by radioligand binding to homogenates and by autoradiography in slices. [3H]-Prazosin binding to homogenates (Bmax 71 +/- 5 fmol/mg protein; Kd 0.27 +/- 0.05 nM) was competed for by alpha1-antagonists. In subthalamic nucleus slices and in the presence of 10 mM LiCl, noradrenaline (100 microM) produced a modest, but consistent, stimulation of [3H]-inositol phosphate accumulation (146 +/- 6% of basal), reversed by the alpha1-antagonist prazosin (1 microM). Extracellular single-unit recordings in slices showed that in a subpopulation (61 out of 94 cells) of rat subthalamic neurones with regular, single-spike firing pattern, noradrenaline induced a concentration-dependent increase in the firing rate (EC50 2.5 +/- 0.2 microM, maximum effect 272 +/- 33% of basal). The action of noradrenaline was mimicked by the selective alpha1-agonist phenylephrine but not by selective alpha2- or beta-agonists, and was blocked by the alpha1-antagonist prazosin but not by alpha2- or beta-antagonists. The excitatory effect of noradrenaline was not prevented by perfusion with low Ca2+/high Mg2+ solution. In four out of 11 neurones perfusion with 3 microM noradrenaline resulted in a shift from bursting to regular firing. Taken together, our results indicate that rat subthalamic neurones express alpha1-adrenoceptors responsible for noradrenaline-induced stimulation of the firing rate of a subpopulation of neurones. By modulating the spontaneous activity of STN neurones, noradrenergic pathways might have a significant role in regulating basal ganglia function and thus motor activity.

Action Potentials↗
PubMed1989

Neural mechanisms in disorders of movement.

1. Experimental models of ballism, chorea and Parkinson's disease have been developed in the primate, and the underlying neural mechanisms which mediate these disorders of movement have been investigated using the 2-deoxyglucose uptake technique. 2. In ballism, the subthalamic nucleus is either lesioned or underactive. Because of the excitatory nature of subthalamic efferent fibres, this leads to abnormal underactivity of neurons in the medical segment of the globus pallidus which project to the ventral anterior and ventral lateral nuclei of the thalamus, and to the pedunculopontine nucleus of the caudal midbrain. 3. In chorea, there is underactivity of GABAergic striatal (putaminal) neurons which project to the lateral segment of the globus pallidus. This leads to overacting of lateral pallidal neurons and, thus, physiological inhibition of the subthalamic nucleus. Common neural mechanisms, therefore, underlie the appearance of dyskinesia in ballism and chorea. 4. In parkinsonism, there is overactivity of putaminal neurons projecting to the lateral pallidal segment. This results in excessive inhibition of lateral pallidal neurons and, as a consequence, disinhibition of the subthalamic nucleus. Overactivity of the subthalamic nucleus provides excessive drive upon medial pallidal neurons projecting to thalamic and pedunculopontine nuclei.

Animals↗
PubMed2000

Dopaminergic innervation of human basal ganglia.

This paper summarises the results of some of our recent tyrosine hydroxylase (TH) immunohistochemical studies of the dopaminergic innervation of the human basal ganglia. It also reports new findings on the presence of TH-immunoreactive (ir) neurons in the striatum. Our data show the existence of nigrostriatal TH-ir axons that provide collaterals arborizing in the globus pallidus and subthalamic nucleus. These thin and varicose collaterals emerge from thick and smooth axons that course along the main output pathways of the basal ganglia, including the ansa lenticularis, the lenticular fasciculus and Wilson's pencils. We postulate that this extrastriatal innervation, which allows nigral dopaminergic neurons to directly affect the pallidum and subthalamic nucleus, plays a critical role in the functional organisation of human basal ganglia. The TH-ir fibres that reach the striatum arborize according to a highly heterogeneous pattern. At rostral striatal levels, numerous small TH-poor zones embedded in a TH-rich matrix correspond to calbindin-poor striosomes and calbindin-rich extrastriosomal matrix, respectively. At caudal striatal levels, in contrast, striosomes display a TH immunostaining that is more intense than that of the matrix. A significant number of small, oval, aspiny TH-ir neurons scattered throughout the rostrocaudal extent of the caudate nucleus and putamen, together with a few larger, multipolar, spiny TH-ir neurons lying principally within the ventral portion of the putamen, were disclosed in human. This potential source of intrinsic striatal dopamine might play an important role in the functional organisation of the human striatum, particularly in case of Parkinson's disease.

Adult↗
PubMed2001

Metabolic changes following subthalamotomy for advanced Parkinson's disease.

We studied 6 advanced-stage Parkinson's disease patients with [18F] fluorodeoxyglucose/positron emission tomography before and 3 months after unilateral ablation of the subthalamic nucleus performed with microelectrode mapping. Operative changes in glucose metabolism were assessed by comparing baseline and postoperative scans. We also quantified operative changes in the activity of an abnormal Parkinson's disease-related metabolic network that we had identified in previous [18F] fluorodeoxyglucose/positron emission tomography studies. Following unilateral subthalamic nucleus ablation, a highly significant reduction in glucose utilization was present in the midbrain ipsilateral to the lesion site, most pronounced in the vicinity of the substantia nigra pars reticularis. Significant metabolic reductions were also present in the ipsilateral internal globus pallidus, ventral thalamus, and pons. Operative changes in Parkinson's disease network activity differed significantly for the lesioned and unlesioned hemispheres. In the lesioned hemisphere, network activity declined significantly following surgery, but was unaltered in the contralateral, unlesioned hemisphere. These results suggest that subthalamotomy reduces basal ganglia output through internal globus pallidus/substantia nigra pars reticularis and also influences downstream neural activity in the pons and ventral thalamus. This procedure also reduces the activity of abnormal Parkinson's disease-related metabolic brain networks, suggesting a widespread modulation of motor circuitry.

Adult↗
PubMed1983

Local cerebral glucose consumption in the rat. II. Effects of unilateral substantia nigra stimulation in conscious and in halothane-anesthetized animals.

The energy metabolism of 74 anatomically discrete central nervous structures was investigated by means of the autoradiographic 2-deoxy-D-(1-14C)glucose method (14C-DG) in conscious awake, as well as in halothane-anesthetized rats, following unilateral substantia nigra (SN) electrical stimulation. All the basal ganglia structures displayed bilateral metabolic activation in conscious animals, with only the contralateral subthalamic nucleus being unaffected. In anesthetized rats only the SN reticulata, globus pallidus, and subthalamic nucleus were affected ipsilaterally whereas anesthesia masked the effects of SN stimulation in SN compacta and striatum ipsilaterally, as well as within all the above structures contralaterally. The entopeduncular nucleus was bilaterally activated no matter the state of consciousness. Unilateral SN stimulation also increased glucose utilization within several thalamic regions (ventromedial, ventrolateral, ventroanterior, intralaminar, ventrobasal, and mediodorsal nuclei), the habenular complex, a few mesencephalic, brainstem (locus coeruleus and dorsal raphe) and cerebellar structures, mostly bilaterally and independently of the state of consciousness. Some of the factors suggested to be responsible for the masking effects of halothane-anesthesia on the metabolic activations elicited by unilateral SN stimulation are the following: (1) absence of movements in anesthetized rats, (2) halothane-induced depression of polysynaptic pathways mostly mediated through the thalamus, and (3) the stimulatory effect of halothane-anesthesia itself on metabolic activity in both parts of the SN.

Anesthesia, General↗
PubMed2005

Thalamic innervation of the direct and indirect basal ganglia pathways in the rat: Ipsi- and contralateral projections.

The present study describes the thalamic innervation coming from the rat parafascicular nucleus (PF) onto striatal and subthalamic efferent neurons projecting either to the globus pallidus (GP) or to the substantia nigra pars reticulata (SNr) by using a protocol for multiple neuroanatomical tracing. Both striatofugal neurons targeting the ipsilateral SNr (direct pathway) as well as striatal efferent neurons projecting to the ipsilateral GP (indirect pathway) were located within the terminal fields of the thalamostriatal afferents. In the subthalamic nucleus (STN), both neurons projecting to ipsilateral GP as well as neurons projecting to ipsilateral SNr also appear to receive thalamic afferents. Although the projections linking the caudal intralaminar nuclei with the ipsilateral striatum and STN are far more prominent, we also noticed that thalamic axons could gain access to the contralateral STN. Furthermore, a small number of STN neurons were seen to project to both the contralateral GP and PF nuclei. These ipsi- and contralateral projections enable the caudal intralaminar nuclei to modulate the activity of both the direct and the indirect pathway.

Animals↗
PubMed2000

GluR1 glutamate receptor subunit is regulated differentially in the primate basal ganglia following nigrostriatal dopamine denervation.

Nigrostriatal dopaminergic denervation is associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. The excitatory neurotransmitter glutamate mediates neural signaling at crucial points of this circuitry, and glutamate receptors are differentially distributed in the basal ganglia. Available evidence suggests that the glutamatergic corticostriatal and subthalamofugal pathways become overactive after nigrostriatal dopamine depletion. In this study, we have analyzed the regulation of the GluR1 subunit of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in the basal ganglia of primates following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine denervation. The dopamine denervation resulted in distinct alterations in GluR1 distribution: (1) GluR1 protein expression was markedly increased in caudate and putamen, and this was most pronounced in the striosomes; (2) GluR1 protein was altered minimally in subthalamic nucleus; (3) expression of GluR1 was down-regulated in the globus pallidus by 63% and in the substantia nigra by 57%. The down-regulation of GluR1 expression in the output nuclei of the basal ganglia, the internal segment of the globus pallidus and the substantia nigra pars reticulata, may be a compensation for the overactive glutamatergic input from subthalamic nucleus, which arises after striatal dopamine denervation. Our results indicate that the glutamatergic system undergoes regulatory changes in response to altered basal ganglia activity in a primate model of Parkinson's disease. Targeted manipulation of the glutamatergic system may be a viable approach to the symptomatic treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗