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Time-dependent deficits of rat's memory consolidation induced by tetrodotoxin injections into the caudate-putamen, nucleus accumbens, and globus pallidus.

In order to better define corpus striatum involvement in memory processing, tetrodotoxin functional ablation was employed to assess the respective roles of the caudate-putamen as a whole and of its anterior, median, and posterior regions, of the nucleus accumbens, and of the globus pallidus during early passive avoidance response consolidation of the rat. Under general ketamine anesthesia (100 mg/kg) by means of microinjections, tetrodotoxin (10 ng/microliter) was bilaterally administered at the appropriate stereotaxic locations of the chosen sites and subsites at different postacquisition delays (0.25, 1.5, and 6 h). Saline solution was administered to control subjects in the same sites. Rats always underwent retrieval testing 48 h after treatment, i.e., when tetrodotoxin blockade had completely disappeared. The results show that both total caudate-putamen and median caudate-putamen blockades caused passive avoidance responding impairment when performed at 0.25- and 1.5-h postacquisition delays, that caudate-putamen anterior and caudate-putamen posterior blockades were never followed by passive avoidance impairment, and that both nucleus accumbens and globus pallidus blockades were followed by passive avoidance impairment when performed at 0.25- and 1.5-h postacquisition delays. In all structures, tetrodotoxin administration caused no impairment at the 6-h delay. The results are discussed with reference both to previous results obtained after reversible or irreversible lesions of the same structures and to the functional mnemonic relationships of the corpus striatum and its components with other subcortical structures, particularly the substantia nigra.

Animals↗

Neuronal depletion in the globus pallidus of heroin addicts.

Decreased neuronal population densities are described in the globus pallidus of narcotic addicts. Toxicologic studies indicate mixed addiction to be frequent, but exposure to parenteral heroin is the only common factor. This permanent brain damage seems more likely to be caused by recurrent episodes of hypoxia during severe reactions to narcotics than to be related to direct neurotoxic effects of heroin. The lesion may account for some of the long term changes observed in addicts.

Adolescent↗

Synaptic and extrasynaptic GABA-A and GABA-B receptors in the globus pallidus: an electron microscopic immunogold analysis in monkeys.

GABA-A and GABA-B receptors mediate differential effects in the CNS. To better understand the role of these receptors in regulating pallidal functions, we compared their subcellular and subsynaptic localization in the external and internal segments of the globus pallidus (GPe and GPi) in monkeys, using pre- and post-embedding immunocytochemistry with antibodies against GABA-A (alpha1, beta2/3 subunits) and GABA-BR1 receptor subtype. Our results demonstrate that GABA-A and GABA-B receptors display a differential pattern of subcellular and subsynaptic localization in both segments of the globus pallidus. The majority of GABA-BR1 immunolabeling is intracellular, whereas immunoreactivity for GABA-A receptor subunits is mostly bound to the plasma membrane. A significant proportion of both GABA-BR1 and GABA-A receptor immunolabeling is extrasynaptic, but GABA-A receptor subunits also aggregate in the main body of putative GABAergic symmetric synapses established by striatal- and pallidal-like terminals. GABA-BR1 immunoreactivity is expressed presynaptically in putative glutamatergic terminals, while GABA-A alpha1 and beta2/3 receptor subunits are exclusively post-synaptic and often coexist at individual symmetric synapses in both GPe and GPi. In conclusion, our findings corroborate the concept that ionotropic and metabotropic GABA receptors are located to subserve different effects in pallidal neurons. Although the aggregation of GABA-A receptors at symmetric synapses is consistent with their role in fast inhibitory synaptic transmission, the extrasynaptic distribution of both GABA-A and GABA-B receptors provides a substrate for complex modulatory functions that rely predominantly on the spillover of GABA.

Animals↗

Globus pallidus deep brain stimulation for generalized dystonia: clinical and PET investigation.

Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) in a patient with severe idiopathic generalized dystonia resulted in immediate improvement of all aspects of dystonia. During joystick movement, GPi DBS reduced PET activation bilaterally in the primary motor, lateral premotor, supplementary motor, anterior cingulate, and prefrontal areas and ipsilaterally in the lentiform nucleus. Altering basal ganglia function with GPi DBS reverses the overactivity of certain motor cortical areas present in dystonia.

Brain↗

Lack of correlation between cortical levels of choline acetyltransferase and learning scores in rats with globus pallidus lesions.

Previous work has shown that rats with lesions of the globus pallidus (GP) exhibit a generalized learning impairment. Data are presented suggesting that this impairment is not due to inadvertent damage to the nucleus basalis magnocellularis. Rats with GP lesions evidenced a significant visual discrimination learning loss and a significant reduction in cortical choline acetyltransferase (ChAT) activity. However, there was no significant correlation between the severity of the learning loss and the amount of reduction of cortical ChAT activity.

Animals↗

Deep brain stimulation of the internal segment of the globus pallidus in delayed runaway dyskinesia.

BACKGROUND: Dyskinesias that occur during a period without medication after embryonic cell transplantation have been commonly reported in double-blind trials; however, to date, they have not been reported in the few patients who participated in open-label pilot studies. DESIGN: Single case observation with preoperative and postoperative data, and intraoperative single-cell physiology. PATIENT: A patient who underwent embryonic cell transplantation in 1993 as part of the University of South Florida open-label study was referred for evaluation of intractable dyskinesia of the right arm. The dyskinesia was present during evaluation of the patient after a 12-hour period without medication and was clinically disabling. It was manifested as a severe groping movement of the hand. Intraoperative physiologic evaluation revealed decreased firing rates in the internal segment of the globus pallidus. RESULTS: Deep brain stimulation of the internal segment of the globus pallidus resulted in resolution of the dyskinesia. CONCLUSION: This case highlights the delayed development of runaway dyskinesia after a period without medication as an important potential long-term adverse effect of embryonic cell transplantation in patients with Parkinson disease.

Deep Brain Stimulation↗

Caffeine mimics the effect of a dopamine D2/3 receptor agonist on the expression of immediate early genes in globus pallidus.

In order to evaluate the effect of caffeine on striatopallidal neurons we used in situ hybridization to examine the mRNA expression of the immediate early genes (IEGs), c-fos, fos B, c-jun, jun B, NGFI-A and NGFI-B in globus pallidus in rats given single or repeated administration of caffeine. A significant induction of c-fos mRNA, but not of any of the other IEGs, was found 2, 4 and 8 hr after a single injection of 50 mg/kg caffeine. Following repeated injections of caffeine for 2 weeks a single challenge with caffeine did not induce the expression of any of the studied genes. The ability of caffeine to increase pallidal c-fos mRNA expression was mimicked by the dopamine D2/3 receptor agonist quinpirole (1 or 3 mg/kg), whereas the dopamine D2/3 receptor antagonist raclopride (2 mg/kg) was ineffective. Caffeine and quinpirole did not have synergistic effects when given together. The caffeine-induced c-fos mRNA expression was not counteracted by concomitant treatment with raclopride. The present data provide evidence that acute treatment with caffeine reduces the activity of the striatopallidal neuron, and since this neuron is inhibitory the result is an increased activity in globus pallidus. The effect of blocking the striatal A2A receptors with caffeine is essentially identical to that observed after activation of dopamine D2 receptors, but is independent of these receptors. The fact that pallidal c-fos mRNA expression decreased upon repeated administration of caffeine may be related to the development of tolerance to locomotion stimulation that occurs following chronic caffeine ingestion.

Animals↗

A-current in rat globus pallidus: a whole-cell voltage clamp study on acutely dissociated neurons.

Globus pallidus neurons were dissociated from adult rats and recorded in whole-cell voltage-clamp mode. In tetrodotoxin- and cadmium-added bath, outward potassium conductances were evaluated. Depolarization activated large and predominantly sustained currents, with little inactivation. The transient outward current was isolated through its voltage-dependency, kinetics and pharmacology. A-like current activated around -45 mV and decayed exponentially with a time-constant of about 50 ms at 0 mV. Steady-state half-inactivation voltage was about -60 mV, suggesting that A-current was not fully inactivated at rest. 4-Aminopyridine sensitivity of the transient outward current was in the low millimolar range. A-current might play a relevant role in shaping firing properties of pallidal neurons.

4-Aminopyridine↗

The neuronal structure of globus pallidus in bison bonasus: Nissl and Golgi study.

The two subnuclei of globus pallidus have been investigated in the telencephalon of bison bonasus. The Nissl and Golgi procedures have been used to reveal their cellular organization. The Golgi preparation suggests the existence of two fairly divergent cellular subpopulations. The first class comprising the bulk of pallidal neurons consists of large efferent cells with long thick infrequently branching dendrites. The morphology of their dendritic processes is very complex and variable even in the one neuron (complex terminal endings, thin dendritic appendages, spiny segments, aspiny segments). Some of these structures (i.e. terminal endings, thin appendages) seem to be of presynaptic nature and allow one efferent neuron to influence on the functions of other large pallidal cells (interneuronal functions). The second one is composed of small interneurons with short highly arborized axons and thin varicose dendritic processes. Their distribution is very sparse and irregular in both segments of investigated nucleus.

Animals↗

Projections of the globus pallidus and adjacent structures: an autoradiographic study in the monkey.

Because the globus pallidus gives rise to the principal efferent system of the corpus striatum and is traversed by several fibers systems, attempts were made to study the projections of its cells by autoradiographic technics. Tritiated amino acids (L-leucine, L-proline and L-lysine) were injected into: (1) the medial pallidal segment (MPS), (2) the MPS and the substantia innominata (SI), (3) portions of the MPS and the lateral pallidal segment (LPS) and (4) parts of the putamen. Cells labeled by injections of the MPS transported isotope to thalamic nuclei (ventral anterior, VApc, ventral lateral, VLo and VLm, and the centromedian, CM), the pedunculopontine nucleus (PPN), and the lateral habenular nucleus (Hbl). Labeled cells of the MPS and SI transported isotope to: (1) thalamic nuclei (VLo, VLm and CM), (2) PPN, (3) Hbl, (4) lateral and posterior regions of the hypothalamus, and (5) extensive dorsal regions of the substantia migra (SN). Comparisons of label transported from uptake of isotope by cells of the MPS, and cells of both pallidal segments, suggest that the LPS projects fibers only to the subthalamic nucleus (STN). Not all regions of the STN appear to receive fibers from the LPS. Selectively labeled neurons of the putamen transport isotope to broad regions of both pallidal segments and to the pars reticulata of the SN. This study suggests that cells of the MPS project profusely and topographically to: (1) the rostral ventral tier thalamic nuclei (VApc, VLo and VLm), (2) lateral portions of CM, and (3) the PPN. Fibers of the lenticular fasciculus appear to terminate preferentially in VLo. Cells in sublenticular portions of SI, and those extending into the medullary laminae of the pallidum, appear to project to: (1) HB1 via the stria medullaris, (2) the pars compacta of SN, (3) lateral and posterior regions of the hypothalamus, and (4) the so-called nucleus of the ansa lenticularis. Some fibers from cells of SI appear to join the dorsal stria terminalis, but none enter the inferior thalamic peduncle and none project to any part of the dorsomedial nucleus of the thalamus.

Amygdala↗

Selective injury of the globus pallidus in children with post-cardiac surgery choreic syndrome.

Occasionally children undergoing cardiac surgery using cardiopulmonary bypass with deep hypothermia and cardiac arrest develop a postoperative syndrome of acute chorea. The authors report the neuropathological findings in two such children surgically treated for congenital heart disease. Examination of the brain showed neuronal loss, reactive astrocytosis and degeneration of myelinated fibers (without frank necrosis) in the globus pallidus, primarily the outer segment, with sparing of other regions commonly susceptible to hypoxic-ischemic necrosis. The localization and relative mildness of the brain damage suggest a susceptibility of the globus pallidus to injury in this setting and implicate disruption of pallidal pathways in the pathogenesis of post-cardiac surgery choreic syndrome.

Acute Disease↗

Behavioural disorders induced by external globus pallidus dysfunction in primates II. Anatomical study.

The anatomical organization of the basal ganglia supports their involvement in movement and behavioural disorders. Thus dyskinesia, attention deficit with or without hyperactivity, and stereotyped behaviour can be induced by microinjections of bicuculline, a GABAergic antagonist, into different parts of the external globus pallidus (GPe) in monkeys. The aim of the present study was to determine the anatomo-functional circuits inside the basal ganglia which are specifically related to each of these behavioural changes. For that, axonal tracers were injected in the same pallidal sites where abnormal behaviours have previously been obtained by bicuculline microinjections. The labelling was mapped in the different basal ganglia and matched with the topography of the cortico-striato-pallidal projections already reported in the literature and with the distribution of calbindin immunoreactivity. Our results first show that the pallidal sites related to dyskinesia, attention deficit with or without hyperactivity, and stereotyped behaviour, were respectively in motor, associative and limbic territories, defined as weak, moderate and intensive calbindin immunoreactivity. The same relationship was observed between the distribution of the labelling in the different basal ganglia after tracer injections performed in these different pallidal sites and the anatomo-functional territories. Thus regarding the origin of the circuits within the striatum, tracer injections performed in the dyskinesia site labelled neurons located in the posterior sensorimotor putamen, those performed in the hyperactivity and/or attention deficit labelled neurons in the laterodorsal putamen and caudate nucleus, regions corresponding to associative and anterior motor territories, while those performed in the stereotyped behaviour site labelled neurons in the ventral limbic striatum. Regarding the GPe output on the basal ganglia, the different circuits also appeared underlined by different anatomo-functional territories, even if a partial overlap exists. Each of these anatomical circuits systematically involves both the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr) but, whereas movement circuit is mainly related to the GPi, stereotyped behaviour is mainly related to the SNr. Additionally, subregions of the subthalamic nucleus were also systematically involved, depending on the movement or behavioural disorder produced. These results demonstrate that distinct circuits involving different anatomo-functional territories of the basal ganglia, with partial overlap, participate in different behavioural disorders in monkeys. It seems likely that these neuronal circuits are involved in pathologies like Tourette's syndrome, attention deficit/hyperactivity disorders and obsessional compulsive troubles. This study provides the basis for further researches with a therapeutical viewpoint.

Animals↗

Neuronal activity in globus pallidus interna can be synchronized to local field potential activity over 3-12 Hz in patients with dystonia.

Pallidal recordings of local field potentials (LFPs) in patients with dystonia have demonstrated semi-oscillatory activity over 3-12 Hz. Although this activity has been hypothesized to contribute to dystonia, it is unclear to what extent these LFP oscillations arise in the globus pallidus interna (GPi) and are synchronous with local neuronal discharge. We therefore recorded LFPs and neuronal activity from microelectrodes inserted into the pallidum on nine sides in six awake patients with primary dystonia during functional neurosurgery. Mean normalized LFP power over 3-12 Hz was higher in GPi than globus pallidus externa. Spike triggered averages were computed, and 11 exhibited significant features in the 3-12 Hz band, indicating that the discharges of local neurons were locked to 3-12 Hz oscillations in the LFP. All but two of these STAs were in GPi. We conclude that pallidal oscillations at 3-12 Hz are maximal in GPi, the surgical target, in patients with dystonia and that they can be synchronized to activity in local neurons. This lends support to a pathophysiological relationship between LFP activity at 3-12 Hz and dystonia.

Adult↗

Motor effects of GABA(A) antagonism in globus pallidus: studies of locomotion and tremulous jaw movements in rats.

RATIONALE: Although most rodent studies related to parkinsonian symptoms have focused on locomotion, tremulous jaw movements also have been used as a rodent model of tremor for investigating the circuitry of the basal ganglia. OBJECTIVE: There are multiple pathways involved in the generation of parkinsonian symptoms. The globus pallidus is a basal ganglia relay nucleus, and the present study was conducted to investigate the effect of pallidal GABA antagonism on locomotion and tremulous jaw movements. METHODS: Suppression of locomotion and induction of tremulous jaw movements were produced by repeated (i.e., 14 day) systemic administration of the dopamine D2 antagonist haloperidol, and by acute systemic injection of the muscarinic agonist pilocarpine. The GABA(A) antagonist bicuculline was injected into the globus pallidus, and its effects on locomotion in haloperidol- and pilocarpine-treated rats were assessed in the first group of experiments. In the second group of experiments, the effects of intrapallidal infusions of bicuculline on haloperidol- and pilocarpine-induced jaw movements were observed. RESULTS: Pallidal GABA antagonism stimulated locomotion when no other treatment was present, and also when animals were coadministered haloperidol or pilocarpine. Bicuculline suppressed haloperidol-induced jaw movements in a dose-related manner, and had no effect on pilocarpine-induced jaw movements. CONCLUSIONS: These results support the notion that there are distinct pathways conveying basal ganglia outflow and demonstrate that the striatopallidal pathway is involved in the generation of the haloperidol-induced tremulous jaw movements. These findings are consistent with some features of current models of basal ganglia function and may lead to an understanding of the specific mechanisms that generate parkinsonian symptoms.

Animals↗

[Chronic high frequency deep brain stimulation of the globus pallidus internus for torsion dystonia].

Deep Brain Stimulation (DBS, chronic high frequency stimulation) is well established for Parkinson's disease and tremordominant movement disorders. Generalized dystonia is known as a type of movement disorder in which therapeutic options are very limited. A case of generalized dystonia is reported which was successfully treated by DBS in the Globus pallidus internus (GPI). A 26 years old male suffered from severe torsion dystonia of the lower limbs. The onset of symptoms was at age 7. It started with dystonia of the left foot. He very fast developed severe dystonia of the lower limbs. These complaints were initially treated by diazepam, later by baclofen (Lioresal ((R))) p.o em leader There was no L-DOPA response. Because of the rapid progression of the disease a cervical spinal cord stimulator was implanted with a transient success. Due to further progression of the disease the patient became wheelchair bounded and resistant for oral medication. Limited improvement of symptoms was achieved using continuous intrathecal administration of baclofen. Finally the patient was treated with 980 microgram intrathecal Baclofen (Lioresal ((R))) daily and up to 100 mg diazepam. Under these conditions the patient remained wheelchair bounded with severe lower limb dystonia. As an ultima ratio it was decided to treat the patient with stereotactic implantation of two electrodes (Medtronic 3387) and two neurostimulators (Medtronic ITREL ((R))II). The GPI was the bilateral target point. Intraoperative computerized tomography and ventriculography were used for target setting. Furthermore microrecordings were helpful to ensure the exact electrode positioning. Surgery was performed under sedation. Two weeks after surgery first improvement of symptoms was observed. Patient was able to stand with assistance. At the three months follow-up he could walk without assistance. Slight dystonic movement of the left ankle was the only remaining symptom under stimulation. The oral medication has been continuously reduced. After 6 months it was stopped. The intrathecal administered baclofen was diminished to 250 microgram daily. At the 24 months follow-up the effect of stimulation remained unchanged. However high stimulation parameters are required to maintain an optimal effect (3,5 V, 400 microseconds 145 Hz for both sides). Deep Brain Stimulation of the Globus Pallidus internus is an alternative approach for severe cases of generalized dystonia.

Adult↗

Manganese poisoning reduces strychnine-insensitive glycine binding sites in the globus pallidus of the mouse brain.

Manganese (Mn) poisoning is characterized by central nervous system manifestations, including psychiatric disturbances and extrapyramidal disorders. This metal is thought to produce neuronal degeneration due to cytotoxic products originated by oxidative stress and through an indirect excitotoxic process. In previous studies, we have found a reduction in the density of N-methyl-D-aspartate (NMDA) recognition sites in some brain areas of Mn-treated mice. Due to the close relationship between NMDA sites and strychnine-insensitive glycine (Gly) modulatory sites in the NMDA receptor complex, the [3H]-glycine ([3H]-Gly) binding was analyzed by autoradiographic methods in the brain of mice treated with manganese chloride for 8 weeks. Among all analyzed areas, only the globus pallidus showed a significant reduction in [3H]-Gly binding (27-28%). The Gly binding decrease, focalized in the globus pallidus, could reflect a degeneration of structures containing strychnine-insensitive Gly receptors, since this area is the most frequently reported damaged brain region in Mn intoxication. However, it might also be due to a Gly receptor down-regulation to control NMDA complex activation during Mn poisoning.

Animals↗

Neuronal activity in the putamen and the globus pallidus of rabbit during mastication.

The pattern of jaw movements is changed during a masticatory sequence from ingestion of food to its deglutition. The masticatory sequence is divided into three distinct stages in the rabbit. However, the neural mechanism involved in the alteration of the masticatory stages is still unknown. This study was designed to determine whether neuronal activity in the putamen and globus pallidus is related to the alteration of the masticatory stages. Fifty-three percent of the recorded neurons showed significant alterations of activity during mastication. Of these neurons, 16% changed their firing frequency throughout the masticatory sequence (sequence-related neurons) and 84% changed their firing frequency with the transition of the masticatory stages (stage-related neurons). The stage-related neurons were classified into two groups based on their neuronal activity patterns observed during mastication, i.e. simple type and complex type. The former are the neurons that were either facilitated or inhibited once during mastication, and the latter are those showing the facilitation or inhibition twice or more during mastication. Complex-type neurons were observed more frequently in the globus pallidus than in the putamen. These results suggest that the basal ganglia is involved in mastication and may related to the transition between the masticatory stages.

Animals↗

Electrophysiological characteristics of limbic and motor globus pallidus internus (GPI) neurons in two cases of Lesch-Nyhan syndrome.

OBJECTIVE: Lesch-Nyhan syndrome is a rare and debilitating condition characterized by dystonia and self-mutilating behavior. In order to shed light on the pathophysiology of dystonia, we report the pallidal electrophysiological activity recorded in two patients during deep brain stimulation surgery (DBS). METHODS: Microrecordings were performed on 162 neurons along four tracks aimed at the right and left anterior (limbic) and posterior (motor) globus pallidus internus (GPI). RESULTS: Regardless of the anesthetic agent used (propofol or sevoflurane), both patients showed similar neurons firing rates in the four regions studied, namely the limbic and motor portions of the globus pallidus externus (GPE) or GPI. In both patients, firing rates were similar in the GPE (12.2+/-1.8 Hz, N=38) and GPI (13.2+/-1.0 Hz, N=83) portions of the limbic track, while the motor GPE fired at a higher frequency (23.8+/-2.7 Hz, N=18) than the motor GPI (12.5+/-1.4 Hz, N=23). CONCLUSIONS: These results demonstrate that light propofol or sevoflurane anesthesia influences pallidal activity in a similar way. Electrophysiological recordings suggest that Lesch-Nyhan syndrome might be characterized by analogous firing frequencies in the limbic GPE and GPI while motor GPE would tend to fire at higher rate than the motor GPI. It is therefore tempting to suggest that the symptoms that are observed in Lesch-Nyhan syndrome might result from motor GPI inhibition. SIGNIFICANCE: This observation may confirm the Albin and Delong's model of the basal nuclei in hypokinetic and hyperkinetic disorders.

Child↗