Alteration of neuronal responses in the subthalamic nucleus following globus pallidus and neostriatal lesions in rats

Kainic acid (2-4 days) or ibotenic acid (7-9 days) lesions of the globus pallidus or neostriatum altered the responsiveness of subthalamic nucleus neurons to electrical stimulation of the agranular frontal cortex. Three changes in responsiveness were seen following pallidal lesion: a) An increase in the proportion of responding cells as compared to controls (approximately 90% vs. 60%); b) an increase in the total duration of the evoked response (62.5 ms vs. 28.6 ms); 3) an increase in magnitude of response (9.76 spikes per stimulus vs. 3.24). Both an increase in firing rate (17.94 spikes/s vs. 8.23) and a change to a bursty spontaneous firing pattern were seen. Lesion of the neostriatum had fewer but opposite effects including decreased firing rate (7.21 spikes/s) and decreased total response duration (18.9 ms). These results suggest that the normal tonic inhibition of the subthalamic nucleus by the globus pallidus may play an important role in controlling subthalamic neuronal spontaneous activity and responsiveness. The neostriatum may influence the subthalamic nucleus via the globus pallidus. Globus pallidus lesions may have important consequences on the specificity of cortical control of the subthalamic nucleus and may alter subthalamic influence on basal ganglia output.     

Changes in the firing pattern of globus pallidus neurons after the degeneration of nigrostriatal pathway are mediated by the subthalamic nucleus in the rat

Changes in the neuronal activity of globus pallidus (GP) have been shown in animal models of parkinsonism. In order to study the implication of the subthalamic nucleus (STN) in these changes, the effects of STN lesions alone or in combination with 6-hydroxydopamine (6-OHDA) -induced damage to the substantia nigra compacta (SNc) were examined in rats using electrophysiological recordings of GP cells. In normal rats, the firing rate was 22.1+/-1.4 spikes/s. The pattern was regular in 45%, irregular in 49% and bursty in 6% of the cases. In rats with STN lesions, the firing rate of GP units (20.15+/-1.25 spikes/s) did not differ from that of normal rats and only regular (46%) and irregular (54%) cells were found; a bursty pattern was not observed. 6-OHDA lesions of the SNc induced no change in the firing rate of GP neurons (21.5+/-1.4 spikes/s, P>0.05) but a significant decrease in the percentage of regular cells (27%, P<0.001), a significant increase in burst cells (21%, P<0.001) with no change in the percentage of irregular units (52%) were observed. In rats with combined SNc and STN lesions, the firing pattern did not change from that of normal rats. The present results show that STN lesions induced the disappearance of bursts in normal rats and normalization of firing pattern in the GP units of rats with 6-OHDA lesions suggesting that the STN plays an important role in the modulation of the pattern of activity of GP neurons which may account for the therapeutic effect of STN lesions in Parkinson's disease.     

Information processing from the motor cortices to the subthalamic nucleus and globus pallidus and their somatotopic organizations revealed electrophysiologically in monkeys

To understand how the information derived from different motor cortical areas representing different body parts is organized in the basal ganglia, we examined the neuronal responses in the subthalamic nucleus (STN), and the external (GPe) and internal (GPi) segments of the globus pallidus (input, relay and output nuclei, respectively) to stimulation of the orofacial, forelimb and hindlimb regions of the primary motor cortex (MI) and supplementary motor area (SMA) in macaque monkeys under the awake state. Most STN and GPe/GPi neurons responded exclusively to stimulation of either the MI or SMA, and one‐fourth to one‐third of neurons responded to both. STN neurons responding to the hindlimb, forelimb and orofacial regions of the MI were located along the medial–lateral axis in the posterolateral STN, while neurons responding to the orofacial region of the SMA were located more medially than the others in the anteromedial STN. GPe/GPi neurons responding to the hindlimb, forelimb and orofacial regions of the MI were found along the dorsal–ventral axis in the posterolateral GPe/GPi, and neurons responding to the corresponding regions of the SMA were similarly but less clearly distributed in more anteromedial regions. Moreover, neurons responding to the distal and proximal forelimb MI regions were found along the lateral–medial axis in the STN and the ventral–dorsal axis in the GPe/GPi. Most STN and GPe/GPi neurons showed kinaesthetic responses with similar somatotopic maps. These observations suggest that the somatotopically organized inputs from the MI and SMA are well preserved in the STN and GPe/GPi with partial convergence.     

Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat

High frequency stimulation (130 Hz) of the subthalamic nucleus has dramatic beneficial motor effects in severe parkinsonian patients. However, the mechanisms underlying these clinical results remain obscure. The objective of the present work was to study the neurochemical changes induced in rats by high frequency stimulation of the subthalamic nucleus by using intracerebral microdialysis within its target structures. Our results show that high frequency stimulation of the subthalamic nucleus induces a significant increase of extracellular glutamate levels in the ipsilateral globus pallidus and substantia nigra while GABA was augmented only in the substantia nigra. These data suggest that functional effects induced by high frequency stimulation of the subthalamic nucleus might imply distal mechanisms involving the synaptic relationships with the subthalamic efferences. They question the current view that the direct inhibition of the subthalamic neurons is induced by high frequency stimulation.     

Differential effects of prolonged high frequency stimulation and of excitotoxic lesion of the subthalamic nucleus on dopamine denervation-induced cellular defects in the rat striatum and globus pallidus

This study examined the effects of prolonged (4 days) high frequency stimulation (HFS) of the subthalamic nucleus (STN), in comparison with those of STN lesion, on the dopamine denervation-mediated cellular changes in the basal ganglia in a Wistar rat model of Parkinson's disease. STN HFS counteracted the dopamine lesion-induced increase in GAD67 mRNA expression in the output structures of the basal ganglia, as shown previously after STN lesion, providing cellular support for the similar antiparkinsonian benefits produced by the two surgical procedures. The dopamine denervation-induced increase in GAD67 mRNA levels in the globus pallidus was partially antagonized after HFS and totally reversed after ibotenate-induced STN lesion. The overexpression of striatal enkephalin mRNA tended to be further increased by HFS but was antagonized by STN lesion. The decrease in striatal substance P mRNA levels was affected neither by STN HFS nor lesion. As STN HFS for two hours was previously found not to interfere with the effects of dopamine lesion in the globus pallidus and striatum, the present data provide strong evidence that the effects of STN surgery in these structures involve long-term adaptive processes and that the rearrangements mediated by HFS and lesion are, at least in part, different.     

Pallidotomy suppresses beta power in the subthalamic nucleus of Parkinson's disease patients

Parkinsonian patients, who have had a unilateral pallidotomy, may require bilateral deep brain stimulation of the subthalamic nucleus (STN), due to disease progression. The current model of the basal ganglia circuitry does not predict a direct effect of pallidotomy on the neuronal activity of the ipsilateral STN. To date, only three studies have investigated the effect of pallidotomy on overall activity of the STN or neuronal firing rate, but not on the spectral content of the neuronal oscillatory activity. Moreover, none of these studies attempted to differentiate the effects on the dorsal (sensory-motor) and ventral (associative-limbic) parts of the STN. We studied the effect of pallidotomy on spectral power in six frequency bands in the STN ipsilateral and contralateral to pallidotomy from seven patients and in 60 control nuclei of patients without prior functional neurosurgery, and investigated whether this effect is different on the dorsal and ventral STN. The data show that pallidotomy suppresses beta power (13-30 Hz) in the ipsilateral STN. This effect tends predominantly to be present in the dorsal part of the STN. In addition, spectral power in the frequency range 3-30 Hz is significantly higher in the dorsal part than in the ventral part. The effect of pallidotomy on STN neural activity is difficult to explain with the current model of basal ganglia circuitry and should be envisaged in the context of complex modulatory interactions in the basal ganglia.     

Electrophysiological alterations in subthalamic neurons after unilateral dopamine depletion in the rat

The present study examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) on electrophysiological properties of subthalamic neurons (STN) in adult rats. Most neurons displayed regular spontaneous tonic firing patterns in both control and lesioned animals; however, the percentage of neurons with spontaneous burst firing at hyperpolarized membrane potentials was increased significantly in lesioned animals compared with controls (45% vs. 14% respectively). In the presence of bicuculline, a gamma-aminobutyric acid type A (GABAA) receptor antagonist, electrical stimulation of the internal capsule produced monosynaptic excitatory postsynaptic potentials (EPSPs) in almost all recorded neurons. DA (50 microM) increased the amplitude and/or duration of the EPSPs in neurons from both groups, whereas the DA D1 receptor agonist SKF 81297 (10 microM) produced a significant increase in amplitude and/or duration of EPSPs in neurons from the lesioned group only. This latter increase was blocked by pretreatment with the DA D1 antagonist SCH 23390 (10 microM). These data suggest that unilateral degeneration of DA neurons in the SNc changes firing properties and enhances electrophysiological responsiveness of STN neurons to activation of DA D1 receptors.     

Modulation of neuronal activity by reward identity in the monkey subthalamic nucleus

The subthalamic nucleus (STN) has been argued to be an important component of reward‐sensitive basal ganglia circuitry. This view is especially supported by the behavioral changes observed after STN inactivation, which could reflect impairments in the motivational control of action. However, it is still unclear how the STN integrates reward information and to what extent such integration correlates with behavior. In this study, the response properties of STN neurons in monkeys performing reaching movements with a cue predicting the identity of an upcoming liquid reward (juice or water) were investigated. Although the timing of movements reliably indicated that monkeys had greater motivation for juice than water, rarely did task‐related changes in neuronal activity depend on the nature of the expected reward. Conversely, when presented with a choice of selecting a response that leads to juice or water delivery, animals showed a clear preference for juice and more than half of the neurons were differentially modulated dependent on the reward obtained, mostly after the monkeys's overt choice of action. Under such circumstances, an increase in activity specifically followed the action outcomes across the population of neurons when monkeys failed to choose the juice reward. These results indicate that STN neurons encode whether or not a preferred reward had been received when a choice between response alternatives is required. This differential neuronal activity might reflect the participation of the STN in evaluating the reward value of chosen actions, thus highlighting its contribution to decision‐making processes.     

Functional characterization of GABAergic pallidopallidal and striatopallidal synapses in the rat globus pallidus in vitro

As a central integrator of basal ganglia function, the external segment of the globus pallidus (GP) plays a critical role in the control of voluntary movement. Driven by intrinsic mechanisms and excitatory glutamatergic inputs from the subthalamic nucleus, GP neurons receive GABAergic inhibitory input from the striatum (Str–GP) and from local collaterals of neighbouring pallidal neurons (GP–GP). Here we provide electrophysiological evidence for functional differences between these two inhibitory inputs. The basic synaptic characteristics of GP–GP and Str–GP GABAergic synapses were studied using whole-cell recordings with paired-pulse and train stimulation protocols and variance–mean (VM) analysis. We found (i) IPSC kinetics are consistent with local collaterals innervating the soma and proximal dendrites of GP neurons whereas striatal inputs innervate more distal regions. (ii) Compared to GP–GP synapses Str–GP synapses have a greater paired-pulse ratio, indicative of a lower probability of release. This was confirmed using VM analysis. (iii) In response to 20 and 50 Hz train stimulation, GP–GP synapses are weakly facilitatory in 1 mm external calcium and depressant in 2.4 mm calcium. This is in contrast to Str–GP synapses which display facilitation under both conditions. This is the first quantitative study comparing the properties of GP–GP and Str–GP synapses. The results are consistent with the differential location of these inhibitory synapses and subtle differences in their release probability which underpin stable GP–GP responses and robust short-term facilitation of Str–GP responses. These fundamental differences may provide the physiological basis for functional specialization.     

The output neurones and the dopaminergic neurones of the substantia nigra receive a GABA-containing input from the globus pallidus in the rat.

One of the major pathways of information flow through the basal ganglia is the pallidonigrofugal system. In order to better understand this system in the rat, experiments have been performed to study the topography, synaptic organization, and neurotransmitter content of the pallidonigral projection and to determine whether the pallidonigral neurones make direct synaptic contacts with nigrofugal cells. This was achieved by combining the anterograde transport of the lectin Phaseolus vulgaris-leucoagglutinin (PHA-L) with the retrograde transport of lectin-conjugated horseradish peroxidase (WGA-HRP), postembedding immunocytochemistry for gamma-aminobutyric acid (GABA), and pre-embedding immunocytochemistry for tyrosine hydroxylase (TH). Following injections of PHA-L in different regions of the lateral part of the globus pallidus, a substantial number of immunoreactive fibres and terminals occurred in the ipsilateral substantia nigra reticulata (SNr). The immunoreactive elements were distributed according to a rostral to medial and caudal to lateral topography. Injections that were restricted to the medial tip of the globus pallidus led to the anterograde labeling of a small number of fibres that were sparsely distributed in the SNr. The most characteristic feature of the pallidonigral fibres was the presence of large varicosities that were often grouped to form pericellular baskets. Injections of WGA-HRP in the ventromedial thalamic nucleus, superior colliculus, or midbrain tegmentum, including the pedunculopontine nucleus, showed that the perikarya and primary dendrites of the output cells of the SNr were often surrounded by the large pallidonigral varicosities. The number of varicosities surrounding a single cell varied from 2-12. Electron microscopic analysis showed that the varicosities contained round or slightly pleomorphic vesicles and numerous mitochondria and that they established symmetrical synaptic contacts. Quantitative measurements revealed that the varicosities had a maximum diameter varying from 0.5 to 2.5 microns and a mean cross-sectional area of 0.76 +/- 0.25 microns 2 (N = 237, mean +/- S.D.). The postsynaptic structures of the pallidonigral varicosities included perikarya (48%), large dendrites (38%), and small dendrites (14%). A large proportion of these postsynaptic targets were retrogradely labeled after injection of WGA-HRP in the ventromedial thalamic nucleus, superior colliculus, or midbrain tegmentum. Postembedding immunocytochemistry was used to show that the pallidonigral axons and terminals in contact with nigrofugal neurones displayed GABA immunoreactivity. The use of a double immunocytochemical method revealed, that in addition to the nondopaminergic SNr output neurones, the dendrites and perikarya of the substantia nigra pars compacta (SNc) receive an input from the globus pallidus.(ABSTRACT TRUNCATED AT 400 WORDS)     

Efferent connections of the caudal part of the globus pallidus in the rat

The efferent connections of the caudal pole of the globus pallidus (GP) were examined in the rat by employing the anterograde axonal transport of Phaseolus vulgaris leucoagglutinin (PHA-L), and the retrograde transport of fluorescent tracers combined with choline acetyltransferase (ChAT) or parvalbumin (PV) immunofluorescence histochemistry. Labeled fibers from the caudal GP distribute to the caudate-putamen, nucleus of the ansa lenticularis, reuniens, reticular thalamic nucleus (mainly its posterior extent), and along a thin strip of the zona incerta adjacent to the cerebral peduncle. The entopeduncular and subthalamic nuclei do not appear to receive input from the caudal GP. Descending fibers from the caudal GP course in the cerebral peduncle and project to posterior thalamic nuclei (the subparafascicular and suprageniculate nuclei, medial division of the medial geniculate nucleus, and posterior intralaminar nucleus/peripeduncular area) and to extensive brainstem territories, including the pars lateralis of the substantia nigra, lateral terminal nucleus of the accessory optic system, nucleus of the brachium of the inferior colliculus, nucleus sagulum, external cortical nucleus of the inferior colliculus, cuneiform nucleus, and periaqueductal gray. In cases with deposits of PHA-L in the ventral part of the caudal GP, labeled fibers in addition distribute to the lateral amygdaloid nucleus, amygdalostriatal transition area, cerebral cortex (mainly perirhinal, temporal, and somatosensory areas) and rostroventral part of the lateral hypothalamus. Following injections of fluorescent tracer centered in the lateral hypothalamus, posterior intralaminar nucleus, substantia nigra, pars lateralis, or lateral terminal nucleus, a substantial number of retrogradely labeled cells is observed in the caudal GP. None of these cells express ChAT immunoreactivity, but, except for the ones projecting to the lateral hypothalamus, a significant proportion is immunoreactive to PV. Our results indicate that caudal GP efferents differ from those of the rostral GP in that they project to extensive brainstem territories and appear to be less intimately related to intrinsic basal ganglia circuits. Moreover, our data suggest a possible participation of the caudal GP in feedback loops involving posterior cortical areas, posterior striatopallidal districts, and posterior thalamic nuclei. Taken as a whole, the projections of the caudal GP suggest a potential role of this pallidal district in visuomotor and auditory processes. © 1996 Wiley-Liss, Inc.     

Expression of N-Methyl-D-Aspartate receptor subunit mRNAs in the human brain: Striatum and globus pallidus

N-methyl-D-aspartate receptors (NRs) play an important role in basal ganglia function. By using in situ hybridization with ribonucleotide probes, we investigated the regional and cellular distribution of NR subunit mRNA expression in the human basal ganglia: caudate nucleus, putamen, lateral globus pallidus (LGP), and medial globus pallidus (MGP). Analysis of both film autoradiograms and emulsion-dipped slides revealed distinct distribution patterns for each subunit. On film autoradiograms, the signal for NR1, NR2B, and NR2C in the striatum (STR) was higher than in globus pallidus (GP). The NR2D probe gave a stronger signal in GP than in STR. For NR2A we found a signal in all regions. Analysis of emulsion-dipped sections demonstrated that in striatal neurons, the NR2B signal was higher than in GP neurons. In GP neurons, NR2D was more abundant than in striatal neurons. Despite the relatively low signal on film for NR2C in GP, we found a slightly higher signal in GP per neuron than in STR since in the pallidal areas neurons were sparse but intensely labeled. NR1 and NR2A were more evenly distributed over neurons of STR and GP. Between the different parts of STR and GP, we observed only minor differences in the expression of NRs. In MGP a subpopulation of neurons exhibiting low NR2D signals could be separated from the majority of neurons showing an intense NR2D signal. Since the physiological properties of NRs are dependent on subunit composition, these data suggest a high degree of regional specialization of NR properties in the human basal ganglia. J. Comp. Neurol. 390:63–74, 1998. © 1998 Wiley-Liss, Inc.     

Involvement of the subthalamic nucleus in engagement with behaviourally relevant stimuli

In this study we investigate how the basal ganglia (BG) may process the behavioural relevance of environmental cues by recording local field potentials (LFPs) in the subthalamic nucleus of patients with Parkinson's disease who had undergone implantation of electrodes for deep brain stimulation. Fourteen patients were recorded as they performed a paradigm dissociating warning cue presentation from programming related to execution of specific tasks. Target and non-target warning cues of differing behavioural relevance were contrasted, and we evaluated if warning cue-evoked activities varied according to whether the eventual task to be performed was motor or cognitive and whether patients were receiving or withdrawn from dopaminergic therapy. Warning cues evoked a complex temporal sequence of activities with three epochs over the 760 ms following the onset of the warning cue. In contrast to the initial evoked LFP, evoked activities over two later periods were significantly influenced by behavioural relevance and by treatment state. The early activity was likely related to the initial orientating of attention induced by a novel target, while the delayed responses in our paradigm may reflect processing related to the non-motor resource implications of cues. The results suggest that the BG are intimately involved in the evaluation of changes in the environment and of their behavioural significance. The latter process is partly modulated by dopamine. Weakness in this function might contribute to the behavioural impairment that can follow BG lesions and surgery.     

Distribution of glutamate receptor subunits at neurochemically characterized synapses in the entopeduncular nucleus and subthalamic nucleus of the rat

Glutamatergic neurotransmission in the subthalamic nucleus (STN) and in the output nuclei of the basal ganglia is critical in the expression of basal ganglia function, and increased glutamate transmission in these nuclei has been implicated in the pathology of Parkinson's disease. In order to determine the precise spatial relationship of subunits of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors to nerve terminals enriched in glutamate or γ-aminobutyric acid (GABA) in one of the output nuclei, the entopeduncular nucleus (EP), and the STN, postembedding immunolabelling for glutamate receptor subunits and for glutamate and GABA was carried out in the rat. Immunolabelling for the AMPA glutamate receptor subunits 1, 2/3, and 4 (GluR1, GluR2/3, and GluR4) and the NMDA receptor subunit 1 (NR1) was localized predominantly within asymmetrical synapses in both the EP and STN. Quantitative analysis revealed that, on average for the whole population, each of the receptor subunits was evenly distributed along the synaptic specialization. Multiple AMPA receptor subunits and the GluR2/3 and NMDA (NR1) subunits were co-localized within individual synapses. The combination of immunolabelling for glutamate and GABA with the receptor immunolabelling revealed that the majority of axon terminals presynaptic to the receptor-immunoreactive synapses were enriched in glutamate immunoreactivity and were GABA-immunonegative. However, at some NR1- and GluR2/3-positive synapses, the level of glutamate immunoreactivity was low in the presynaptic terminal and, in the STN, some of them were GABA-immunopositive. It is concluded that glutamatergic transmission at individual synapses of different origins in the EP and STN is mediated by a combination of AMPA and NMDA glutamate receptors. J. Comp. Neurol. 397:403–420, 1998. © 1998 Wiley-Liss, Inc.     

Subthalamic nucleus and globus pallidus interna influence firing of tonically active neurons in the primate striatum through different mechanisms

Both the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) are major targets for neuromodulation therapy for movement disorders. An example of such a therapy is deep brain stimulation (DBS). The striatum is the primary target for pharmacological treatment of these disorders. To further our understanding of both the functional relationships among motor nuclei and the mechanisms of therapies for movement disorders, it is important to clarify how changing the neuronal activity of one target, either by medication or by artificial electrical stimulation, affects the other connected nuclei. To investigate this point, we recorded single‐unit activity from tonically active neurons (TANs), which are putative cholinergic interneurons in the striatum, of healthy monkeys (Macaca fuscata) during electrical stimulation of the STN or GPi. Both STN stimulation and GPi stimulation reduced the TAN spike rate. Local infusion of a D2 receptor antagonist in the striatum blocked the reduction in spike rate induced by STN stimulation but not that induced by GPi stimulation. Further, STN stimulation induced phasic dopamine release in the striatum as revealed by in vivo fast‐scan cyclic voltammetry. These results suggest the presence of multiple, strong functional relationships among the STN, GPi, and striatum that have different pathways and imply distinct therapeutic mechanisms for STN‐ and GPi‐DBS.     

Premovement activities in the subthalamic area of patients with Parkinson's disease and their dependence on task

Movement preparation and execution are associated with a reduction in oscillatory synchrony over 6-35 Hz (event-related desynchronization; ERD) and increases in oscillatory synchrony at higher frequencies (event-related synchronization; ERS) in the human parkinsonian subthalamic nucleus (STN). The timing of the ERD < 35 Hz in STN correlates with, but precedes, the timing of voluntary movement, in line with a role in motor processing. Here, we explore how directly the synchrony manifest in local field potential (LFP) activities depends on the details of motor processing. To this end, we recorded local field potentials from the STN area of parkinsonian subjects while they performed internally paced single movements or double movements with one hand. Analysis was limited to time periods that were unequivocally premovement, so as to avoid the confounding effects of sensory afferance during movement. LFP power differed from baseline activity as early as 2.1-1.1 s prior to movement over 6-18 Hz and 56-70 Hz. However, only the early changes in LFP power in the 56-70 Hz band depended on task type. Later on, within 0.5 s of the forthcoming movement, the behaviour of both the 6-18 and 56-70 Hz bands differed according to movement type. In addition, a change was seen in LFP activity over 23-35 Hz, although the ERD in this band remained similar across movement types. The findings further implicate the human STN in the feedforward organization of movement in premotor circuits. Different aspects of this organization may be preferentially reflected in changes in synchrony at different frequencies.     

Unilateral lesion of the pedunculopontine nucleus induces hyperactivity in the subthalamic nucleus and substantia nigra in the rat

Recent data suggest a role for the pedunculopontine nucleus (PPN) in the pathophysiology of Parkinson's disease. Although there is anatomical evidence that the PPN and the basal ganglia are reciprocally connected, the functional importance of these connections is poorly understood. Lesioning of the PPN was shown to induce akinesia in primates, whereas in the 6-hydroxydopamine rat model the PPN was found to be hyperactive. As both nigrostriatal dopamine depletion and lesioning of the PPN were shown to induce akinesia and parkinsonism, the present study was performed in order to investigate the changes in neuronal activity of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) after unilateral ibotenic acid lesioning of the PPN and after unilateral 6-hydroxydopamine lesioning of the substantia nigra pars compacta (SNc). The firing rate of STN neurones significantly increased from 10.2 +/- 6.2 (mean +/- SD) to 14.6 +/- 11.7 spikes/s after lesion of the PPN and to 18.6 +/- 14.5 spikes/s after lesion of the SNc. The activity of the SNr significantly increased from 19.6 +/- 10.5 to 28.7 +/- 13.4 spikes/s after PPN lesioning and to 23.5 +/- 10.8 spikes/s after SNc lesioning. Furthermore, PPN lesion decreased the number of spontaneously firing dopaminergic SNc cells, while having no effect on their firing rate. The results of our study show that lesion of the PPN leads to hyperactivity of the STN and SNr, similar to the changes induced by lesion of the SNc. Moreover, the decreased activity of SNc cells observed after PPN lesion might be at the origin of activity changes in the STN and SNr.     

Distribution and ultrastructural features of the serotonin innervation in rat and squirrel monkey subthalamic nucleus

The main purpose of this light and electron microscopic immunocytochemical study was to characterize and compare the serotonin (5‐HT) innervation of the subthalamic nucleus (STN) in rats and squirrel monkeys (Saimiri sciureus) following labeling with an antibody against the 5‐HT transporter (SERT). Unbiased counts of SERT+ axon varicosities revealed an average density of 5‐HT innervation higher in monkeys (1.52 × 10⁶ varicosities/mm³) than rats (1.17 × 10⁶), particularly in the anterior half of the nucleus (1.70 × 10⁶). As measured by electron microscopy, SERT+ axon varicosity profiles in the STN of both species were smaller than unlabeled profiles. The number of SERT+ profiles displaying a synaptic junction indicated that, in both rat and monkey STN, approximately half of 5‐HT axon varicosities were asynaptic. In monkeys, all synaptic junctions made by SERT+ varicosities were asymmetrical, as opposed to only 77% in rats. Despite the higher density of 5‐HT innervation in the anterior half of monkey STN, the ultrastructural features of its SERT+ varicosities, including synaptic incidence, did not significantly differ from those in its posterior half. These findings suggest that, throughout the rat and monkey STN, 5‐HT afferents may exert their influence via both synaptic delivery and diffusion of 5‐HT, and that an ambient level of 5‐HT maintained in STN by these two modes of transmission might also modulate neuronal activity and influence motor behavior. A better understanding of the factors governing the complex interplay between these signaling processes would greatly improve our knowledge of the physiopathology of the STN.     

Prior pallidotomy reduces and modifies neuronal activity in the subthalamic nucleus of Parkinson's disease patients

Parkinson's disease (PD) patients with prior radio-frequency lesions in the internal segment of the globus pallidus (GPi, pallidotomy), whose symptoms have deteriorated, may be candidates for further invasive treatment such as subthalamic deep brain stimulation (STN DBS). Six patients with prior pallidotomy (five unilaterally; one bilaterally) underwent bilateral STN DBS. The microelectrode recordings (MERs, used intraoperatively for STN verification), ipsilateral and contralateral to pallidotomy, and MERs from 11 matched PD patients who underwent bilateral STN DBS without prior pallidotomy were compared. For each trajectory, average, variance and mean successive difference (MSD, a measure of irregularity) of the root mean square (RMS) of the STN MER were calculated. The RMS in trajectories ipsilateral to pallidotomy showed significant reduction of the mean average and MSD of STN activity when compared with trajectories from patients without prior pallidotomy. The RMS parameters contralateral to pallidotomy tend to lie between those ipsilateral to pallidotomy and those without prior pallidotomy. The average STN power spectral density of oscillatory activity was notably lower ipsilateral to pallidotomy than contralateral, or without prior pallidotomy. The finding that pallidotomy reduces STN activity and changes firing characteristics, in conjunction with the effectiveness of STN DBS despite prior pallidotomy, calls for reappraisal and modification of the current model of the basal ganglia (BG) cortical network. It highlights the critical role of direct projections from the BG to brain-stem structures and suggests a possible GPi–STN reciprocal positive-feedback mechanism.