External Segment Of Globus Pallidus Research Articles

Behavioral and Movement Disorders Induced by Local Inhibitory Dysfunction in Primate Striatum

The current model of basal ganglia organization postulates their functional division into sensorimotor, associative, and limbic territories, implicated, respectively, in motor, cognitive, and motivational aspects of behavior. Based on this model, we previously demonstrated, in the external segment of globus pallidus of monkeys, that the same neuronal dysfunction induced dyskinesia or abnormal behavior depending on the functional territory. To extend these findings, we performed bicuculline microinjections into the different functional territories of the striatum in 6 monkeys. Abnormal movements were observed after microinjections into the posterior putamen, corresponding to the sensorimotor territory, and into the dorsal part of the anterior striatum, corresponding to the associative functional territory. Within the ventral striatum, referred to as the limbic functional territory, we identified 3 subregions corresponding to different types of abnormal behaviors. Simultaneous neuronal recordings performed close to the microinjection sites confirmed that bicuculline produced a focal increase of neuronal activity surrounded by a zone with neuronal hypoactivity. This study provides new evidence for the involvement of specific striatal regions in movement as well as in a large spectrum of behavioral disorders and suggests that local inhibitory dysfunction could be a pathological mechanism of various neurological and psychiatric disorders.

Encoding of Probabilistic Rewarding and Aversive Events by Pallidal and Nigral Neurons

Previous studies have rarely tested whether the activity of high-frequency discharge (HFD) neurons of the basal ganglia (BG) is modulated by expectation, delivery, and omission of aversive events. Therefore the full value domain encoded by the BG network is still unknown. We studied the activity of HFD neurons of the globus pallidus external segment (GPe, n=310), internal segment (GPi, n=149), and substantia nigra pars reticulata (SNr, n=145) in two monkeys during a classical conditioning task with cues predicting the probability of food, neutral, or airpuff outcomes. The responses of BG HFD neurons were long-lasting and diverse with coincident increases and decreases in discharge rate. The population responses to reward-related events were larger than the responses to aversive and neutral-related events. The latter responses were similar, except for the responses to actual airpuff delivery. The fraction of responding cells was larger for reward-related events, with better discrimination between rewarding and aversive trials in the responses with an increase rather than a decrease in discharge rate. GPe and GPi single units were more strongly modulated and better reflected the probability of reward- than aversive-related events. SNr neurons were less biased toward the encoding of the rewarding events, especially during the outcome epoch. Finally, the latency of SNr responses to all predictive cues was shorter than the latency of pallidal responses. These results suggest preferential activation of the BG HFD neurons by rewarding compared with aversive events.

Oxidative stress in neurodegeneration in dentatorubral-pallidoluysian atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is one of the CAG-repeat diseases, and is classified into juvenile and early adult types showing progressive myoclonus epilepsy (PME) in addition to late adult type. We immunohistochemically examined accumulation of oxidative products and expression of superoxide dismutase (SOD) in autopsy cases of DRPLA. Oxidative products to nucleosides, 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine, were accumulated in the lenticulate nucleus predominantly in DRPLA cases having PME. Neuronal accumulation of 4-hydroxy nonenal, a reactive lipid aldehyde, was found in the hippocampus, globus pallidus and cerebellar dentate nucleus in adult DRPLA cases and controls. Cytoplasmic immunoreactivity for Cu/ZnSOD was reduced in the external segment of globus pallidus, dentate nucleus and cerebellar cortex in DRPLA cases. Mitochondrial immunoreactivity for MnSOD was reduced in the lenticulate nucleus and cerebellum in DRPLA cases having PME. Some DRPLA cases showed reduced immunoreactivity for MnSOD in the cerebral cortex. Coexistence of reduced SOD expression and polyglutamine was observed in a few cases. It has been discussed in Huntington's disease that expanded polyglutamine can lead to oxidative neurodegeneration. It is likely that oxidative stress can be involved in DRPLA, although relationship with expanded polyglutamine remains to be elusive.

Familial pediatric rapidly progressive extrapyramidal syndrome: is it Hallervorden-Spatz disease?

The clinical features of two children of a family with rapidly progressive extrapyramidal-pyramidal-dementia complex have been described. Inheritance seems most likely to be autosomal recessive. Magnetic resonance imaging results of brain were negative. Even so, the authors argued in favor of a diagnosis of Hallervorden-Spatz disease because the cases fulfilled the clinical criteria for diagnosis of this disease. Apart from the negative magnetic resonance findings, the other unusual feature was the early development of levodopa-induced dyskinesia. Few conditions need to be considered in the differential diagnosis of a childhood-onset rapidly progressive extrapyramidal syndrome. Such conditions include Wilson’s disease, Hallervorden-Spatz disease (HSD), juvenile form of Huntington’s disease, juvenile neuronal ceroid lipofuscinosis, early-onset Machado-Joseph disease neuroacanthocytosis, storage disorders, and variant form of dopa-response dystonias (DRD). Rarer conditions are Leigh’s disease, Lafora body disease, and dentato-rubro-pallido-luysian atrophy. HSD is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Onset is most commonly in late childhood or early adolescence. The disease can be familial or sporadic. When familial, it is inherited recessively and has been linked to chromosome 20 [1]. Recently, a mutation in the pantothenate kinase ( PANK2) gene on band 20pl3 has been described in patients with typical HSD [2]. HSD produces typical magnetic resonance imaging (MRI) changes in brain, [3,4] aiding in antemortem diagnosis. The typical finding is of bilaterally symmetrical hyperintense signal changes in the external segment of globus pallidus, with surrounding hypointensity on T 2-weighted image. These imaging features are fairly diagnostic and have been termed the “eye-of-the tiger sign” [5]. The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling, and the surrounding hypointensity is caused by loss of signal secondary to iron deposition [5]. Described herein are the clinical aspects of a family with autosomal recessive inheritance with rapidly progressive extrapyramidal-pyramidal-dementia complex but with negative brain MRI results. The diagnosis should be considered a variant form of HSD.

D2 antagonist-induced c- fos in an identified subpopulation of globus pallidus neurons by a direct intrapallidal action

Much research now supports the view that the dopaminergic innervation of the globus pallidus external segment (GP) influences basal ganglia information processing via pallidal dopamine (DA) D2, D3, and possibly D1 receptors. Systemic DA agonists, or systemic or intrapallidal dopamine D2-class antagonist administration, can induce immediate early gene expression (IEG) in the rat GP. In view of the distinct chemical phenotypes and axonal projections of the GP neurons, it is important to characterize the population(s) of pallidal neurons responding to local DA manipulations. Parvalbumin (PV) immunostaining was used to identify one of the two principal GP neuron populations. Awake, behaving rats received intrapallidal infusions of the dopamine D2 antagonist sulpiride (50 or 100 ng), the D1-class antagonist SCH-23390 (100 ng), the D2-class agonist quinpirole (500 ng), the GABA A antagonist picrotoxin (0.25, 0.5 or 1 μg) or bicuculline (20 ng), the GABA A agonist muscimol (15 ng) or vehicle. Intrapallidal GABA manipulations were used to assess the likelihood that the effects of the DAergic drugs on Fos induction occurred secondarily to altering intrapallidal GABA release. Using Fos and PV double immunolabeling procedures, we found that several treatments induced GP Fos, but that intrapallidal sulpiride induced Fos almost exclusively in PV-lacking pallidal neurons. No other intrapallidal drug-induced Fos showed similar population specificity. These results support evidence suggesting that GP DA can play a unique and critical role in modulating pallidal neuron function, and that the cessation of pallidal dopamine transmission can activate gene expression within the pallidal neuron subpopulation that maintains extensive axonal projections to caudate-putamen.

A computational model of action selection in the basal ganglia. II. Analysis and simulation of behaviour.

In a companion paper a new functional architecture was proposed for the basal ganglia based on the premise that these brain structures play a central role in behavioural action selection. The current paper quantitatively describes the properties of the model using analysis and simulation. The decomposition of the basal ganglia into selection and control pathways is supported in several ways. First, several elegant features are exposed--capacity scaling, enhanced selectivity and synergistic dopamine modulation--which might be expected to exist in a well designed action selection mechanism. The discovery of these features also lends support to the computational premise of selection that underpins our model. Second, good matches between model globus pallidus external segment output and globus pallidus internal segment and substantia nigra reticulata area output, and neurophysiological data, have been found which are indicative of common architectural features in the model and biological basal ganglia. Third, the behaviour of the model as a signal selection mechanism has parallels with some kinds of action selection observed in animals under various levels of dopaminergic modulation.

Chronic D1 and D2 dopaminomimetic treatment of MPTP-denervated monkeys: effects on basal ganglia GABA A/benzodiazepine receptor complex and GABA content

The effect of various chronic dopaminergic treatments in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys on the brain γ-aminobutyric acid type A (GABA A) /benzodiazepine receptor complex and GABA content was investigated in order to assess the GABAergic involvement in dopaminomimetic-induced dyskinesia. Three MPTP monkeys received for one month pulsatile administrations of the D1 dopamine (DA) receptor agonist SKF 82958 whereas three others received the same dose of SKF 82958 by continuous infusion. A long acting D2 DA receptor agonist, cabergoline, was given to another three animals. Untreated MPTP as well as naive control animals were also included. Pulsatile SKF 82958 relieved parkinsonian symptoms but was also associated with dyskinesia in two of the three animals whereas animals treated continuously with SKF 82958 remained as untreated MPTP monkeys. Chronic cabergoline administration improved motor response with no persistent dyskinesia. MPTP treatment induced a decrease of 3H-flunitrazepam binding in the medial anterior part of caudate-putamen and an increase in the internal segment of globus pallidus (GPi) which was in general unchanged by pulsatile or continuous SKF 82958 administration. Throughout the striatum, binding of 3H-flunitrazepam remained reduced in MPTP monkeys treated with cabergoline but was not significantly lower than untreated MPTP monkeys. Moreover, cabergoline treatment reversed the MPTP-induced increase in 3H-flunitrazepam binding in the GPi. GABA concentrations remained unchanged in the striatum, external segment of globus pallidus and GPi following MPTP denervation. Pulsatile but not continuous SKF 82958 administration decreased putamen GABA content whereas cabergoline treatment decreased caudate GABA. No alteration in GABA levels were observed in the GPe and GPi following the experimental treatments. These results suggest that: (1) D2-like receptor stimulation with cabergoline modulates GABA A receptor density in striatal subregions anatomically related to associative cortical afferent and (2) the absence of dyskinesia in dopaminomimetic-treated monkeys might be associated with the reversal of the MPTP-induced upregulation of the GABA A/benzodiazepine receptor complex in the Gpi.

Monkey globus pallidus external segment neurons projecting to the neostriatum.

Experiments were performed to assess the number and parvalbumin (PV) immunoreactivity of neurons participating in the pallidostriatal projection in macaque monkeys. Injection of WGA-HRP into the right caudate nucleus and the left putamen of a Macaca mulatta and a M. fuscata labeled a large number of the globus pallidus external segment (GPe) neurons. Counting neurons labeled with WGA-HRP and those stained with neuronal markers indicated that approximately 30% of GPe neurons project to neostriatum. Approximately 2/3 of the pallidostriatal neurons are PV-immunoreactive. This study revealed that a significant number of primate GPe PV immunoreactive neurons project to the neostriatum, and suggest that the pallidostriatal projection should be taken into account in the analysis of functional roles of the basal ganglia circuitry.

Effects of SCH 32615, an enkephalinase inhibitor, on D-1 and D-2 dopamine receptor-mediated behaviors

Striatal enkephalin-containing neurons receive dopaminergic inputs from the substantia nigra and project to the external segment of globus pallidus. These neurons express primarily dopamine (DA) D-2 receptors. Accordingly, stimulation of enkephalinergic transmission might be expected to influence mainly D-2 receptor agonist or antagonist effects on motor function. To test this hypothesis, the effects of SCH 32615, an enkephalinase inhibitor, on DA antagonist-induced catalepsy, DA D-1 agonist-induced non-stereotyped grooming, and DA D-2 agonist-induced stereotyped behavior were studied. The administration of SCH 32615 (3 mg/kg) decreased both D-1 and D-2 antagonist-induced catalepsy. In contrast, SCH 32615 (0.3 mg/kg) increased D-1 agonist-induced non-stereotyped grooming and D-2 agonist-induced stereotypies. These results suggest that a DA agonist-like, mostly D-2 activity may be involved in enkephalinergic-mediated functions.

Outward potassium currents activated by depolarization in rat globus pallidus

Voltage-dependent potassium currents play a key role in shaping the firing pattern of central neurons. Their pharmacological and physiological identification is rather important in the structures which are involved in the filtering of input/output messages. In this regard, globus pallidus external segment (GPe) is indicated as a crucial station in the well-known indirect pathway of the basal ganglia. Among the potassium conductances which have been indicated to condition the firing behavior and the neuronal integrative properties in many central neurons, we analysed the depolarization-activated ones by means of patch-clamp recordings in the whole-cell configuration. Two main families of calcium-independent outward potassium currents are activated by depolarization in GPe neurons acutely isolated from the adult rat. From depolarized holding potentials (-50/-45 mV), a slowly-activating, sustained current is evoked; it manifests very little inactivation and it is available at rather depolarized potentials (-30 mV/-20 mV). This current is relatively resistant to 4-aminopyridine (4-AP) but it is blocked by tetraethilammonium ions (TEA) and consequently it resembles delayed rectifier current (Ik). From negative holding potentials (-80/-100 mV), on the other hand, A-like conductances are activated. Together with a fast-inactivating transient current, another component is observed in a significant proportion of recordings (45%). This current shows half-inactivation voltage around -90 mV, peculiar sensitivity to micromolar doses of 4-AP and a slow rate of recovery from inactivation. The presence and the modulation of these A-like currents may be a very critical aspect in the membrane physiology of pallidal neurons.

Neurochemical compartmentalization of the globus pallidus in the rat: An immunocytochemical study of calcium‐binding proteins

The globus pallidus external segment forms a major target center of the mammalian striatum which is characterized by neurochemically distinct compartments. The present study was undertaken to determine if a corresponding compartmentalization exists within the globus pallidus external segment in the rat. Immunocytochemical examination of the calcium-binding proteins parvalbumin and calbindin D28kDa, which are present in neurons of the striatal matrix compartment, was employed. The results indicate three neurochemically distinct compartments within the globus pallidus external segment: 1) an area in the medial aspect of the entire length of the globus pallidus that contains dense immunoreactivity for calbindin D28kDa; 2) a narrow rim at the striatopallidal junction in the rostral two-thirds of the globus palidus that contains calbindin D28kDa immunoreactivity designated as the "border zone" of the globus pallidus; and 3) an area between these two zones showing very poor immunoreactivity for calbindin D28kDa but containing parvalbumin immunoreactive neurons. The calbindin D28kDa immunoreactive border zone corresponds to the area of the globus pallidus where striatal inputs converge extensively, whereas the rest of the nucleus is involved in segregated, topographically organized pathways. Parvalbumin-containing neurons are involved in the propagation of striatal output related to striosomal and sensorimotor aspects of basal ganglia function. The present results also indicate that calbindin D28kDa immunoreactivity is completely absent from striosomal neurons and is therefore a useful marker for striatal compartments.

The pallidostriatal projection in the rat: a recurrent inhibitory loop?

The pallidostriatal projection in the rat was investigated employing the PHA-L tracing technique. Following iontophoretic injections into the lateral aspect of the globus pallidus external segment, the ipsilateral striatum showed patches of dense anterograde labeling separated by areas containing sparse anterograde labeling and isolated retrogradely labeled neurons. The densely labeled patches did not correspond to any known compartments of the striatum. The retrogradely labeled neurons consistenly showed similar distribution of morphological features reminiscent of striatal type II projection neurons. As all projection neurons of the striatum and all pallidal neurons are GABAergic, the complementary pattern of anterogradely and retrogradely labeled profiles from the globus pallidus suggest a possible mechanism whereby a horizontal inhibition may be exerted on groups of striatal neurons via the striato-pallido-striatal pathway.

Activity of identified wrist-related pallidal neurons during step and ramp wrist movements in the monkey

1. The activity of globus pallidus (GP) neurons (n = 1,117) was studied in two monkeys to reexamine the relation of neuronal activity to movement type (slow vs. fast) while they performed both a visually guided step and ramp wrist tracking task. To select neurons specifically related to wrist movements, we employed both a somatosensory examination of individual body parts and a statistical analysis of the strength of temporal coupling of neuronal discharges to active wrist movement. 2. Neuronal responses to somatosensory stimulation were studied in 1,000 high-frequency GP neurons, of which 686 exhibited clear responses to manipulation of body parts. Of the latter, 336 responded to passive manipulation of forelimb joints and 58 selectively to passive flexion or extension of the wrist. 3. In the external segment of GP (GPe), most neurons responding to passive wrist movement were found to be clustered in four to five adjacent, closely positioned (separated by 200 microns) tracks in single coronal planes. The clusters were irregular in shape with a maximal width of 800-1,000 microns. Separate clusters of neurons responsive to passive wrist movement were identified in planes 3 mm apart in one monkey and in planes 500 microns apart in the other. Multiple clusters of neurons were also found for neurons responsive to joints other than the wrist. These findings suggest a more discrete and complex representation of individual joints in the primate GP than previously conceived. 4. During the performance of the wrist flexion and extension task, 92 neurons showed clear and consistent changes in activity. For these neurons we measured, with a statistical method on a trial-by-trial basis, the strength of temporal coupling between the onset of active wrist movement and the onset of change in neuronal discharge rate. Fifteen neurons showed changes in activity time-locked to the onset of active wrist movement. 5. Twelve pallidal neurons were classified as "wrist-related" based on their movement-locked changes in discharge during task performance and their clear responses to passive wrist joint rotation on examination. All of these neurons exhibited statistically significant modulation of their discharge rate during both fast (peak velocity 97-205 degrees/s) and slow (peak velocity 20-62 degrees/s) wrist movements in the task. The amplitudes of modulation were larger during fast wrist movement than slow movement. These results suggest that the basal ganglia motor circuit plays a similar, rather than an exclusive, role in the control of slow and fast limb movements.

A comparative immunohistochemical study on striatal Met-enkephalin expression in Alzheimer's disease and in progressive supranuclear palsy

Using a sensitive immunoperoxidase technique we examined Met-enkephalin (MEnk) expression in the striatum and globus pallidus external segment (GPe) from patients with Alzheimer's disease (AD) and with progressive supranuclear palsy (PSP). In AD patients strong MEnk-like immunoreactivity was persistent in the striatum showing so-called "striosomes". In addition, a number of typical "woolly fibers" were observed in the GPe. MEnk-positive striosomes were also visible in the striatum of PSP patients and were similar to those of normal controls and of AD patients. However, the MEnk-positive "woolly fibers" appearance was less well recognizable in the GPe from all the PSP patients examined.