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PubMed1984

Influence of globus pallidus on arm movements in monkeys. II. Effects of stimulation.

The effect of changing basal ganglia activity with electrical stimulation in and around the globus pallidus (GP) was studied in monkeys trained to make rapid arm-reaching movements to a visual target in a reaction time task. As was the case following kainic acid (KA) lesions of the globus pallidus (30), stimulation changed movement times (MT) without affecting the pattern of sequential activation of muscles involved in the task or, in most cases, the reaction times (RT). Stimulation in the ventrolateral internal segment of the globus pallidus (GPi) or in the ansa lenticularis reduced movement times, whereas stimulation at many sites in the external pallidal segment (GPe), dorsal GPi, and putamen increased movement times for the contralateral arm. These results are consistent with the hypothesis that arm movements are speeded up when the critical output of GPi is increased and arm movements are slowed down when critical GPi output is reduced, either by an inhibitory process (via stimulation-induced activation of inhibitory elements presynaptic to GPi) or by destroying GPi neurons (via kainic acid). The influence of the basal ganglia on the scaling of electromyographic (EMG) amplitude, as opposed to the spatiotemporal organization of EMG activation, is discussed.

Animals↗

PubMed1991

The role of the subthalamic nucleus in the response of globus pallidus neurons to stimulation of the prelimbic and agranular frontal cortices in rats.

We investigated how the cerebral cortex can influence the globus pallidus by two routes: the larger, net inhibitory route through the neostriatum and the separate, smaller, net excitatory route through the subthalamic nucleus. Stimulation (0.3 and 0.7 mA) of two regions of frontal agranular (motor) cortex and of the medial orbitofrontal cortex centered in the prelimbic cortex typically elicited one or more of the following extracellularly recorded responses in over 50% of tested cells: an initial excitation (approximately 6 ms latency), a short inhibition (15 ms latency) and a late excitation (29 ms latency). Some other cells responded with an excitatory response only (18 ms latency). The excitatory responses largely arise from the subthalamic route. Kainic acid or electrolytic lesion of the subthalamic nucleus eliminated most excitatory responses and greatly prolonged the duration (16 vs 50 ms) of the inhibition. Subthalamic neurons typically showed one or more of the following responses to cortical stimulation: an early excitatory response (4 ms latency), an inhibitory period (9 ms) and a late excitatory response (16 ms). The early response was seen after motor cortex but not prelimbic stimulation. The timing of the globus pallidus and subthalamic responses suggest the operation of a reciprocal inhibitory/excitatory pathway. Two reciprocal interactions were indicated. First, pallidal inhibition may disinhibit the subthalamus and, via a feedback pathway onto the same pallidal cells, act to terminate the neostriatal-induced inhibition. Second, there may be a feedforward pathway from pallidal cells to subthalamic neurons to a different group of pallidal cells. This pathway could act to suppress competing responses. Thus the subthalamus may have three actions: 1) an early direct cortical and 2,3) later reciprocal feedforward and feedback excitatory antagonism of the neostriatal mediated inhibition of globus pallidus.

Animals↗

PubMed1998

Basal forebrain neurons adjacent to the globus pallidus co-express GABAergic and cholinergic marker mRNAs.

Semi-quantitative single cell RT-PCR techniques were used to determine the expression of mRNAs related to GABAergic and cholinergic neurotransmission in neurons of the rat globus pallidus and adjacent basal forebrain region. Neurons of the globus pallidus expressed relatively high levels of GAD67 and GABA vesicular transporter mRNA but undetectable levels of ChAT or ACh vesicular transporter mRNA. In contrast, nominally basal forebrain neurons co-expressed ChAT and GAD67 mRNAs and mRNAs for both ACh and GABA vesicular transporters. These results suggest that the neurons along the medial border of the globus pallidus may co-release GABA and ACh.

Animals↗

PubMed1984

Immunocytochemical demonstration of the GABA-ergic neurons in rat globus pallidus and nucleus entopeduncularis and their GABA-ergic innervation.

GAD (E.C. 4.1.1.15), the endogenous biosynthetic marker enzyme for GABA, was localized in rat globus pallidus and nucleus entopeduncularis (pallidum) by peroxidase-antiperoxidase immunocytochemistry. In the two nuclei we observed numerous GAD-like immunoreactive boutons containing large pleomorphic vesicles. These boutons formed axodendritic and axosomatic synaptic contacts mostly of the symmetric type. Following colchicine injection near the border of globus pallidus or nucleus entopeduncularis, the vast majority of both larger and smaller neurons exhibited GAD immunoreactivity and were contacted by numerous GAD-immunoreactive boutons. These data demonstrate that pallidal neurons are of predominately GABA-ergic nature and receive an extensive GABA-ergic input. Thus, the globus pallidus and the nucleus entopeduncularis major output stations of the basal ganglia may represent sites of extensive GABA-mediated inhibition of GABA-ergic inhibitory neurons.

Animals↗

PubMed1984

Effect of l-dopa or bromocriptine on feeding and motor behavior of rats with lesions in the globus pallidus.

Rats were lesioned bilaterally in the globus pallidus (GP) with anodal current or 6-OHDA, and were observed in various motor tests 10 min daily for 3 weeks. Body weight, home cage water and food intakes were recorded daily under two different food accessibility conditions. The lesions produced adipsia, aphagia, loss of body weight and motor impairments which could not be reversed by either l-dopa or bromocriptine. Animals could be made to recover, however, by making food easily accessible and palatable. The results do not support a "metabolic" role for the GP but support the idea that aphagia, adipsia and mortality is due to motoric impairments produced by the lesion.

Animals↗

PubMed2004

Bilateral globus pallidus stimulation for Huntington's disease.

Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) was performed in a patient with Huntington's disease (HD) with severe chorea. Stimulation at 40 and 130 Hz improved chorea. Stimulation at 130 Hz slightly worsened bradykinesia overall, whereas 40 Hz had little effect. A [15O] H2O positron emission tomography showed increased regional cerebral blood flow in motor decision making and execution areas more evident at 40 Hz. Adjustment of stimulation parameters in GPi DBS may have the potential to optimize the motor response in HD, improving chorea without aggravating bradykinesia.

Adult↗

PubMed1984

Fatty acid mobilization to 2-deoxyglucose is blocked by globus pallidus lesions.

Lesions of the lateral hypothalamus or discrete bilateral transections on the lateral border of the lateral hypothalamus disrupt the mobilization of metabolic fuels to intraperitoneal administration of the glucose analog 2-deoxyglucose. To better define the pathways involved in these responses, the effects of globus pallidus lesions on body fuel mobilization were investigated. Globus pallidus lesions blocked the increase in plasma free fatty acids normally caused by 2-deoxyglucose, but did not diminish the concomitant hyperglycemia. The data indicate that a pathway running through the globus pallidus, crossing the dorsoanterolateral hypothalamic border, and turning caudally in the dorsolateral hypothalamus is important in the immediate release of free fatty acids following 2-deoxyglucose administration.

Animals↗

PubMed2005

Striatal information signaling and integration in globus pallidus: timing matters.

Advances in research on globus pallidus (GP) suggest that this 'long thought to be' relay in the 'indirect pathway' plays a unique and critical role in basal ganglia function. The traditional idea of parallel processing within the basal ganglia is also challenged by recent findings. It is now clear that axons of GP neurons form large, perisomatic baskets around target neurons in all major basal ganglia nuclei, thereby exerting a profound influence on the output of the entire basal ganglia. GP neurons are autonomously active both in vivo and in vitro. It is believed that temporal information carried along the corticostriatopallidal pathway is critical for proper motor execution. The importance of appropriately controlled discharge of GP neurons is highlighted by psychomotor disorders such as Parkinson's disease, in which alterations in the pattern and synchrony of discharge in GP neurons are thought to contribute to motor symptoms. Several lines of evidence suggest that the aberrant activity of GP neurons following dopamine depletion is caused by alteration in the synaptic input from both striatum and subthalamic nucleus. In normal subjects, the capability of striatal input in translating cortical input into precisely timed responses in GP neurons is mediated by (1) the expression of postsynaptic GABA(A) receptor composed of subunits with fast kinetic properties; (2) an effective GABA reuptake system in terminating the action of synaptically released GABA, and (3) the existence of dendritic HCN channels that actively abbreviate the time course of the inhibitory postsynaptic potentials and reset rhythmic discharge. Despite the rapid pace in uncovering the elements that shape the activity along the striatopallidosubthalamic pathway, the origin of rhythmic, synchronized bursting of GP neurons seen in parkinsonism has not been fully established experimentally. Further elucidation of the factors that control the information transfer in the striatopallidal synapses is thus critical to our understanding of basal ganglia function and establishing treatment for Parkinson's disease and other basal ganglia disorders.

Animals↗

PubMed2000

Electrophysiological and morphological characteristics of three subtypes of rat globus pallidus neurone in vitro.

Neurones of the globus pallidus (GP) have been classified into three subgroups based on the visual inspection of current clamp electrophysiological properties and morphology of biocytin-filled neurones. Type A neurones (132/208; 63 %) were identified by the presence of the time- and voltage-dependent inward rectifier (Ih) and the low-threshold calcium current (It) giving rise to anodal break depolarisations. These cells were quiescent or fired regular spontaneous action potentials followed by biphasic AHPs. Current injection evoked regular activity up to maximum firing frequency of 350 Hz followed by moderate spike frequency adaptation. The somata of type A cells were variable in shape (20 x 12 micrometer) while their dendrites were highly varicose. Type B neurones (66/208; 32 %) exhibited neither Ih nor rebound depolarisations and only a fast monophasic AHP. These cells were spontaneously active while current injection induced irregular patterns of action potential firing up to a frequency of 440 Hz with weak spike frequency adaptation. Morphologically, these cells were the smallest encountered (15 x 10 micrometer), oval in shape with restricted varicose dendritic arborisations. Type C neurones were much rarer (10/208; 5 %). They were identified by the absence of Ih and rebound depolarisations, but did possess a prolonged biphasic AHP. They displayed large A-like potassium currents and ramp-like depolarisations in response to step current injections, which induced firing up to a maximum firing frequency of 310 Hz. These cells were the largest observed (27 x 15 micrometer) with extensive dendritic branching. These results confirm neuronal heterogeneity in the adult rodent GP. The driven activity and population percentage of the three subtypes correlates well with the in vivo studies (Kita & Kitai, 1991). Type A cells appear to correspond to type II neurones of Nambu & Llinas (1994, 1997) while the small diameter type B cells display morphological similarities with those described by Millhouse (1986). The rarely encountered type C cells may well be large cholinergic neurones. These findings provide a cellular basis for the study of intercellular communication and network interactions in the adult rat in vitro.

Action Potentials↗

PubMed2000

Ultrastructural localization of nitrotyrosine within the caudate-putamen nucleus and the globus pallidus of normal rat brain.

Nitration of protein tyrosine residues by nitric oxide (NO)-derived reactive species results in the production of stable nitrotyrosine (NT) moieties that are immunochemically detectable in many regions of normal brain and enriched in those areas containing constitutive nitric oxide synthase (cNOS). These include the caudate-putamen nucleus (CPN) and the globus pallidus, which receives major inhibitory input from the CPN. To determine the functional sites for NT production in these critical motor nuclei, we examined the electron microscopic immunocytochemical localization of NT and cNOS in rat brain. In the CPN, NT was localized to the somata and dendrites of cNOS-containing interneurons and spiny neurons, some of which received input from cNOS-labeled terminals. The NT immunoreactivity was most prevalent on outer mitochondrial membranes and nearby segments of the plasma membranes in dendrites and within asymmetric synapses on dendritic spines. In the CPN and globus pallidus, there was also a prominent labeling of NT in astrocytic processes, small axons, and tubulovesicles and/or synaptic vesicles in axon terminals. These terminals formed mainly asymmetric synapses in the CPN and inhibitory-type synapses in the globus pallidus where they often apposed cNOS-containing terminals that also formed asymmetric, excitatory-type synapses. Our results suggest that NT is generated by mechanisms requiring the dual actions of excitatory transmitters and NO derived either from interneurons in the CPN or from excitatory afferents in the globus pallidus. The findings also implicate NT in the physiological actions of NO within the striatal circuitry and, particularly, in striatopallidal neurons severely affected in Huntington's disease.

Animals↗

PubMed1999

Tyrosine hydroxylase-immunoreactive elements in the human globus pallidus and subthalamic nucleus.

In contrast to the well-established dopaminergic innervation of the neostriatum, the existence of dopaminergic innervation of the subthalamic nucleus and globus pallidus is controversial. In the present study, tyrosine hydroxylase (TH)-immunoreactive elements were observed by light microscopy after antigen retrieval in the subthalamic nucleus and in the internal and external segments of the globus pallidus in postmortem human brain. Small islands of apparent neostriatal tissue with abundant arborization of fine, TH-immunoreactive axons in the vicinity of calbindin-positive small neurons resembling neostriatal medium spiny neurons were present in the external segment of the globus pallidus. Large numbers of medium-large, TH-immunoreactive axons were observed passing above and through the subthalamic nucleus and through both pallidal segments; these are presumed to be axons of passage on their way to the neostriatum. In addition, fine, TH-immunoreactive axons with meandering courses, occasional branches, and irregular outlines, morphologically suggestive of terminal axon arborizations with varicosities, were seen in both pallidal segments, including the ventral pallidum, and the subthalamic nucleus, consistent with a catecholaminergic (probably dopaminergic) innervation of these nuclei. This finding suggests that, in Parkinson's disease and in animal models of this disorder, loss of dopaminergic innervation might contribute to abnormal neuronal activation in these three nuclei.

Adult↗

PubMed1993

[Methylmalonic acidemia with bilateral MRI high intensities of the globus pallidus].

We report a patient with methylmalonic acidemia who developed an acute extrapyramidal disorder after severe ketoacidosis. The neurologic findings resulted from bilateral destruction of the globus pallidus. A 10-year-old girl was the term product of an uncomplicated pregnancy and delivery. Poor feeding and vomiting were noted after one month. She was hospitalized at 6 months of age with vomiting, coma and tachypnea. Analysis of urinary organic acids revealed a massive amount methylmalonic acid. She was not vitamin B 12-responsive and was maintained on a low-protein diet. At 33 months of age, she was able to walk and speak, but she developed acute severe ketoacidosis. Involuntary movements and spastic paraplegia became evident two days after admission. Subsequently, the patient has had metabolic ketoacidosis once or twice a year. Her intelligence quotient was 47. Neurologic examination revealed spastic paraplegia and generalized hypotonicity with mild dystonia. Some relief from dystonic symptoms has been obtained through the use of L-dopa. A brain CT scan at 5 years of age disclosed bilaterally symmetric lucencies of the globus pallidus. T2-weighted brain MRI at 8 years of age showed bilateral symmetric high intensities of the globus pallidus.

Amino Acid Metabolism, Inborn Errors↗

PubMed1997

Electrophysiological and Fos immunohistochemical evidence for the excitatory nature of the parafascicular projection to the globus pallidus.

Extracellular recordings and immunohistological detection of c-Fos-like immunoreactive proteins were used to determine the synaptic effect of the parafascicular projection to the globus pallidus. Electrical stimulation of the parafascicular neurons induced a single-spike excitatory response with a stable latency of 2.3 ms, suggesting a monosynaptically driven effect. Pharmacological stimulation of the parafascicular nucleus with carbachol increased tonically the pallidal discharge rate by 142%. The discharge rate of the pallidal neurons was described by 37% in parafascicular-lesioned rats. These results demonstrate the excitatory nature and the tonic action of the parafasciculopallidal projection. Carbachol activation of parafascicular neurons also induced the synthesis of c-Fos-like immunoreactive proteins in the pallidal neurons. Control experiments in subthalamic-lesioned rats showed that the parafascicular excitation of the pallidal neurons remained, but both electrophysiological and expression of c-Fos-like immunoreactive proteins were attenuated. This suggests that the direct parafascicular excitation of the pallidal neurons is indirectly reinforced by the previously described parafascicular excitatory input to the subthalamic nucleus. Conversely, the effect of this last input to the subthalamic nucleus is dramatically enhanced in rats with pallidal lesion. Our results demonstrate the complex role of the parafascicular nucleus in activating both the globus pallidus and the subthalamic nucleus, two closely related structures. These results illustrate the integrative capacities of the globus pallidus, whose activity is modulated by multiple afferents.

Animals↗

PubMed1984

Characterization of benzodiazepine receptor changes in substantia nigra, globus pallidus and entopeduncular nucleus after striatal lesions.

This study explored the character and time course of benzodiazepine (BDZ) receptor changes in substantia nigra pars reticulata, globus pallidus and entopeduncular nucleus after striatal kainate lesions in the rat. Receptor levels at the lesion site and striatal projection areas were measured at 1 week, 1 month and 2 to 3 months after the lesion. One week after the lesion, no receptor changes in substantia nigra pars reticulata, globus pallidus, or entopeduncular nucleus were detected. There were small but insignificant increases in BDZ binding in striatal projection sites 1 month after the lesion. At the 2- to 3-month time point, BDZ binding increased in substantia nigra pars reticulata (44%, P less than .01), globus pallidus (43%, P less than .02) and entopeduncular nucleus (54%, P less than .05). At all time points, the binding affinities of BDZ receptors were unchanged in the denervated and corresponding intact structures. Likewise, BDZ binding was enhanced to a similar extent by gamma-aminobutyric acid on both sides of the brain. CL 218,872, a triazolopyridazine and ethyl beta-carboline-3-carboxylate were used to delineate BDZ receptor subtypes involved in the receptor increase. Deafferented areas were less sensitive to triazolopyridazine and ethyl beta-carboline-3-carboxylate when compared to the corresponding intact areas. This suggests that a proliferation of the triazolopyridazine-insensitive BDZ receptor subtype (BDZ2 receptors) has taken place.

Animals↗

PubMed1983

A biphasic influence of globus pallidus lesions: spontaneous catalepsy followed by anticataleptic effect.

The behavioural and histological effects of unilateral or bilateral lesions induced by kainic acid injections into the globus pallidus were investigated in rats. Both lesions provoked a behavioural syndrome similar to those seen in animals treated systemically with neuroleptics or opiates. Animals displayed akinesia, ptosis, catalepsy, hypothermia and muscular rigidity. Also a marked hypersensitivity to touch, and a sensory neglect to touch and pain limited to hindlegs, adipsia, aphagia and high mortality of lesioned rats were observed. These symptoms were much stronger and lasted longer (catalepsy lasted over 15 days) in bilaterally lesioned animals. Subcutaneous injections of apomorphine in bilaterally lesioned rats abolished akinesia and catalepsy while rigidity and ptosis were unaffected. In unilaterally lesioned rats in which the lesion-induced spontaneous catalepsy already disappeared the spiperone-induced catalepsy was suppressed while in bilaterally lesioned animals which showed still pronounced lesion-induced catalepsy the spiperone-induced catalepsy was unchanged when compared to the sham-operated rats. Our results and the literature data suggest that the lesions of the globus pallidus produce biphasic effects: spontaneous catalepsy and unchanged neuroleptic catalepsy in the first phase and suppression of the neuroleptic catalepsy in the second phase. The role of the globus pallidus as a distal link (for neostriatum and n. accumbens) in neuronal chain forming a matrix of central patterns of catalepsy, akinesia and rigidity is discussed.

Animals↗

PubMed1983

An experimental study of the pathogenesis of the selective lesion of the globus pallidus in acute carbon monoxide poisoning in cats. With special reference to the chronologic change in the cerebral local blood flow.

Twenty-eight mature cats were exposed to 0.3% carbon monoxide (CO) gas for 90-193 min using artificial ventilation. The systemic blood pressure (BP), venous pressure (VP), blood flow of the left common carotid artery (CF), and blood gas were monitored. The local blood flow (LBF) of the globus pallidus, putamen, or claustrum was measured by the hydrogen clearance method. Pallidal lesions were found histologically in 14 cats. The period of CO inhalation and the time thereafter were divided into the following four stages in the animals with pallidal lesions. Stage 1: Initial phase with rapid increase in the CF and LBF, and rapid decrease in the BP. Stage 2: Middle phase with slow decrease in the BP, CF, and LBF. Stage 3: Terminal phase with rapid decrease in the BP, CF, and LBF. Stage 4: Recovery phase. The changes in stage 3 were not so prominent in the animals without pallidal lesions. The LBF of the globus pallidus of the animals with lesions decreased to 67.3 +/- 20.7% of the initial value at the terminal stage of CO inhalation, while it was 188 +/- 46.7% in those without lesions. The difference was statistically significant (P less than 0.01). The LBF of the putamen or claustrum in the animals with lesions in the globus pallidus was 140 +/- 24.6% at this stage, and it was significantly higher than that of the globus pallidus (P less than 0.01). Other factors, such as CO inhalation time, degree of acidosis, and terminal CO-Hb concentration, did not correlate with the occurrence of the pallidal lesion.

Animals↗

PubMed2002

Global attentional-executive sequelae following surgical lesions to globus pallidus interna.

It has been demonstrated that selective unilateral surgical ablation of posteroventral globus pallidus interna relieves the movement disorders associated with advanced Parkinson's disease, without necessarily incurring the executive cognitive sequelae that have been observed following gross pathological lesions to this brain region. This finding is consistent with established theory that underlying neuronal circuitry is functionally segregated into parallel cortico-striatal-pallidal-thalamo-cortical 'loops'. We have studied a series of 12 patients with advanced Parkinson's disease at baseline, and then following bilateral pallidotomy, with a battery of neuropsychological tests including the Cambridge Neuro psychological Test Automated Battery. We identified a selective and universal loss of individual patients' ability to shift attention to novel dimensions in a test of abstract rule-learning following surgery, which was not reliably associated with any other change in cognition, personality, mood or medication. This finding is rare in its specificity and has implications for theoretical models of the functional architecture and pathophysiology of the globus pallidus, and the clinical practice of pallidotomy.

Adult↗

PubMed1994

Regulation of mu-opioid receptor mRNA in rat globus pallidus: effects of enkephalin increases induced by short- and long-term haloperidol administration.

The mRNA encoding mu-opioid receptors is expressed in neurons of the globus pallidus, a region of the basal ganglia that receives a dense enkephalinergic innervation from the striatum. The regulation of the mRNAs encoding the opioid peptide enkephalin in the striatum and the mu-opioid receptor in the globus pallidus was examined with in situ hybridization histochemistry following short- or long-term haloperidol treatments, which alter striatal enkephalin mRNA levels. Animals were administered haloperidol daily for 3 or 7 days (1 mg/kg, s.c.) or continuously for 8 months (1 mg/kg, depot followed by oral). Enkephalin and mu-opioid receptor mRNA levels were unchanged after 3 days of haloperidol treatment. In contrast, the enkephalin mRNA level was increased in the striatum, and mu-opioid receptor mRNA levels were markedly decreased in the globus pallidus after 7 days of haloperidol administration. Similar effects were observed in rats treated with haloperidol for 8 months. The results provide the first evidence of regulation of mu-opioid receptor mRNA in vivo.

Animals↗