External Globus Pallidus Neurons Research Articles

Transmission of delta band (0.5-4 Hz) oscillations from the globus pallidus to the substantia nigra pars reticulata in dopamine depletion.

Parkinson's disease (PD) and animal models of PD feature enhanced oscillations in several frequency bands in the basal ganglia (BG). Past research has emphasized the enhancement of 13-30 Hz beta oscillations. Recently, however, oscillations in the delta band (0.5-4 Hz) have been identified as a robust predictor of dopamine loss and motor dysfunction in several BG regions in mouse models of PD. In particular, delta oscillations in the substantia nigra pars reticulata (SNr) were shown to lead oscillations in motor cortex (M1) and persist under M1 lesion, but it is not clear where these oscillations are initially generated. In this paper, we use a computational model to study how delta oscillations may arise in the SNr due to projections from the globus pallidus externa (GPe). We propose a network architecture that incorporates inhibition in SNr from oscillating GPe neurons and other SNr neurons. In our simulations, this configuration yields firing patterns in model SNr neurons that match those measured in vivo. In particular, we see the spontaneous emergence of near-antiphase active-predicting and inactive-predicting neural populations in the SNr, which persist under the inclusion of STN inputs based on experimental recordings. These results demonstrate how delta oscillations can propagate through BG nuclei despite imperfect oscillatory synchrony in the source site, narrowing down potential targets for the source of delta oscillations in PD models and giving new insight into the dynamics of SNr oscillations.

The Dynamics of Dopamine D2 Receptor-Expressing Striatal Neurons and the Downstream Circuit Underlying L-Dopa-Induced Dyskinesia in Rats.

L-dopa (l-3,4-dihydroxyphenylalanine)-induced dyskinesia (LID) is a debilitating complication of dopamine replacement therapy for Parkinson's disease. The potential contribution of striatal D2 receptor (D2R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear. In this study, we investigated the role of striatal D2R+ neurons and downstream globus pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a D2R antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D2-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry revealed the overinhibition of striatal D2R+ neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats. In contrast, the striatal D2R+ neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia. Consistent with the above findings, optogenetic activation of striatal D2R+ neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats. Our data demonstrate that the aberrant activity of striatal D2R+ neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.

Dysregulation of the Basal Ganglia Indirect Pathway in Early Symptomatic Q175 Huntington's Disease Mice.

The debilitating psychomotor symptoms of Huntington's disease (HD) are linked partly to degeneration of the basal ganglia indirect pathway. At early symptomatic stages, before major cell loss, indirect pathway neurons exhibit numerous cellular and synaptic changes in HD and its models. However, the impact of these alterations on circuit activity remains poorly understood. To address this gap, optogenetic- and reporter-guided electrophysiological interrogation was used in early symptomatic male and female Q175 HD mice. D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs) were hypoactive during synchronous cortical slow-wave activity, consistent with known reductions in dendritic excitability and cortical input strength. Downstream prototypic parvalbumin-expressing external globus pallidus (PV+ GPe) neurons discharged at 2-3 times their normal rate, even during periods of D2-SPN inactivity, arguing that defective striatopallidal inhibition was not the only cause of their hyperactivity. Indeed, PV+ GPe neurons also exhibited abnormally elevated autonomous firing ex vivo Optogenetic inhibition of PV+ GPe neurons in vivo partially and fully ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative PV- GPe neurons, respectively. In contrast to STN neurons whose autonomous firing is impaired in HD mice, putative PV- GPe neuron activity was unaffected ex vivo, implying that excessive inhibition was responsible for their hypoactivity in vivo Together with previous studies, these data demonstrate that (1) indirect pathway nuclei are dysregulated in Q175 mice through changes in presynaptic activity and/or intrinsic cellular and synaptic properties; and (2) prototypic PV+ GPe neuron hyperactivity and excessive target inhibition are prominent features of early HD pathophysiology.SIGNIFICANCE STATEMENT The early symptoms of Huntington's disease (HD) are linked to degenerative changes in the action-suppressing indirect pathway of the basal ganglia. Consistent with this linkage, the intrinsic properties of cells in this pathway exhibit complex alterations in HD and its models. However, the impact of these changes on activity is poorly understood. Using electrophysiological and optogenetic approaches, we demonstrate that the indirect pathway is highly dysregulated in early symptomatic HD mice through changes in upstream activity and/or intrinsic properties. Furthermore, we reveal that hyperactivity of external globus pallidus neurons and excessive inhibition of their targets are key features of early HD pathophysiology. Together, these findings could help to inform the development and targeting of viral-based, gene therapeutic approaches for HD.

Roles for globus pallidus externa revealed in a computational model of action selection in the basal ganglia

The basal ganglia are considered vital to action selection - a hypothesis supported by several biologically plausible computational models. Of the several subnuclei of the basal ganglia, the globus pallidus externa (GPe) has been thought of largely as a relay nucleus, and its intrinsic connectivity has not been incorporated in significant detail, in any model thus far. Here, we incorporate newly revealed subgroups of neurons within the GPe into an existing computational model of the basal ganglia, and investigate their role in action selection. Three main results ensued. First, using previously used metrics for selection, the new extended connectivity improved the action selection performance of the model. Second, low frequency theta oscillations were observed in the subpopulation of the GPe (the TA or ‘arkypallidal’ neurons) which project exclusively to the striatum. These oscillations were suppressed by increased dopamine activity — revealing a possible link with symptoms of Parkinson’s disease. Third, a new phenomenon was observed in which the usual monotonic relationship between input to the basal ganglia and its output within an action ‘channel’ was, under some circumstances, reversed. Thus, at high levels of input, further increase of this input to the channel could cause an increase of the corresponding output rather than the more usually observed decrease. Moreover, this phenomenon was associated with the prevention of multiple channel selection, thereby assisting in optimal action selection. Examination of the mechanistic origin of our results showed the so-called ‘prototypical’ GPe neurons to be the principal subpopulation influencing action selection. They control the striatum via the arkypallidal neurons and are also able to regulate the output nuclei directly. Taken together, our results highlight the role of the GPe as a major control hub of the basal ganglia, and provide a mechanistic account for its control function.

PO-147 Effect of Exercise-induced Fatigue on the Electrical Activity of the External Globus Pallidus Neurons in rats

Objective The motor cortex (MC) stimulation-induced unitary responses of globus pallidus external segment (GPe) neurons in control and exercise induced-fatigue rats were recorded in vivo to examine the role of cortical-striatum-external globus pallidal pathway in the mechanism of central fatigue.
 Methods 32 Clean healthy male Wistar rats (260~300g), were randomly divided into 4 groups: control group (Control), 1-day fatigue group (1FG), 3-day fatigue group (3FG) and 7-day fatigue group (7FG). Rats were subjected to a 5-day adaptive treadmill training. Modified Bedford treadmill exercise with progressively increasing load was used to creat the exercise fatigue model. （3 levels:8.2 m/min, 15 min; 15m/min, 15 min; 20 m/min, lasting till exhaustion） The spontaneous unit activity and responses to MC stimulation of GPe neurons were recorded by the electrophysiological technique of extracellular recording of glass microelectrodes.
 Results The results showed that the firing frequency of high-frequency firing with pause (HFP) and low frequency firing with burst (LFB) in the GPe of 1FG was comparable with that of control group (P>0.05). However in 3FG and 7FG , the percentage of HFP neuron was significantly decreased (P<0.05), while the proportion of LFB was significantly increased (P<0.05), and the average firing rate of LFB was higher and inter spike intervals (ISI) was significantly lower than that of the control group. With 200μA electrical stimulation, the explosive discharge of GPe neurons was attenuated after fatigue in rats. The response of GPe neurons to variable frequency stimulation in exhausted model groups was stronger than that of the control group.MC-stimulation typically induced a triphasic response composed of early excitation, inhibition, and late excitation in GPe neurons. The population of neurons showing a short inhibition slightly increased in 3FG and 7FG.
 Conclusions 1. The results confirmed that GPe is an important nucleus of basal ganglia involved in the regulation of exercise-induced fatigue by the change of spontaneous activity.
 
 Electrical stimulation on the cortex can alter response patterns of GPe neurons in exercise-induced fatigue rats, the results confirmed that the Ctx-Str-GPe neural pathway is involved in the regulation of exercise fatigue, and the indirect pathway is over-activated.

Dynamic Encoding of Effort and Reward throughout the Execution of Action by External Globus Pallidus Neurons in Monkeys.

Humans and animals must evaluate the costs and expected benefits of their actions to make adaptive choices. Prior studies have demonstrated the involvement of the basal ganglia in this evaluation. However, little is known about the role of the external part of the globus pallidus (GPe), which is well positioned to integrate motor and reward-related information, in this process. To investigate this role, the activity of 126 neurons was recorded in the associative and limbic parts of the GPe of two monkeys performing a behavioral task in which different levels of force were required to obtain different amounts of liquid reward. The results first revealed that the activity of associative and limbic GPe neurons could be modulated not only by cognitive and limbic but also motor information at the same time, both during a single period or during different periods throughout the trial, mainly in an independent way. Moreover, as a population, GPe neurons encoded these types of information dynamically throughout the trial, when each piece of information was the most relevant for the achievement of the action. Taken together, these results suggest that GPe neurons could be dedicated to the parallel monitoring of task parameters essential to adjusting and maintaining goal-directed behavior.

Homologous Basal Ganglia Network Models in Physiological and Parkinsonian Conditions.

The classical model of basal ganglia has been refined in recent years with discoveries of subpopulations within a nucleus and previously unknown projections. One such discovery is the presence of subpopulations of arkypallidal and prototypical neurons in external globus pallidus, which was previously considered to be a primarily homogeneous nucleus. Developing a computational model of these multiple interconnected nuclei is challenging, because the strengths of the connections are largely unknown. We therefore use a genetic algorithm to search for the unknown connectivity parameters in a firing rate model. We apply a binary cost function derived from empirical firing rate and phase relationship data for the physiological and Parkinsonian conditions. Our approach generates ensembles of over 1,000 configurations, or homologies, for each condition, with broad distributions for many of the parameter values and overlap between the two conditions. However, the resulting effective weights of connections from or to prototypical and arkypallidal neurons are consistent with the experimental data. We investigate the significance of the weight variability by manipulating the parameters individually and cumulatively, and conclude that the correlation observed between the parameters is necessary for generating the dynamics of the two conditions. We then investigate the response of the networks to a transient cortical stimulus, and demonstrate that networks classified as physiological effectively suppress activity in the internal globus pallidus, and are not susceptible to oscillations, whereas parkinsonian networks show the opposite tendency. Thus, we conclude that the rates and phase relationships observed in the globus pallidus are predictive of experimentally observed higher level dynamical features of the physiological and parkinsonian basal ganglia, and that the multiplicity of solutions generated by our method may well be indicative of a natural diversity in basal ganglia networks. We propose that our approach of generating and analyzing an ensemble of multiple solutions to an underdetermined network model provides greater confidence in its predictions than those derived from a unique solution, and that projecting such homologous networks on a lower dimensional space of sensibly chosen dynamical features gives a better chance than a purely structural analysis at understanding complex pathologies such as Parkinson's disease.

A cell-type-specific jolt for motor disorders.

Manipulating the activity of a subpopulation of external globus pallidus neurons with optogenetic deep brain stimulation ameliorates motor deficits in a mouse model of Parkinson's disease.

Parkinsonism and dystonia are differentially induced by modulation of different territories in the basal ganglia

Numerous clinical and experimental observations suggest that deficient neuronal signaling in the globus pallidus externa (GPe) is integral to both Parkinson’s disease (PD) and dystonia. In our previous studies in jaundiced dystonic rats, widespread silencing of neurons in GP (rodent equivalent to GPe) preceded and persisted during dystonic motor activity. We therefore hypothesized that on a background of slow and highly irregular and bursty neuronal activity in GP, cortical motor drive produces profound inhibition of GP as the basis for action-induced dystonia in Gunn rats. Presently, the neurotoxin ibotenate was injected locally into the motor territory of GP at one to four sites, over one to two tracts, in 19 normal rats. We found that highly circumscribed dorsal motor territory lesions reproducibly induced parkinsonism, while ventral lesions consistently produced dystonia. Post-lesioning, slow neuronal burst oscillations in the entopeduncular nucleus distinguished parkinsonian from dystonic rats. Next, we compared the deep brain stimulation contact sites in the GP internus used to treat patients with PD (n=21 implants in 12 successive patients) versus dystonia (n=16 implants in nine patients) and found the efficacious territory for ameliorating PD to be located chiefly dorsal to that for dystonia. The comparative distribution for treating PD versus dystonia was therefore anatomically consistent with that for inducing these features via GP lesions in rodents. Our collective findings thus suggest that dystonia and parkinsonism are differentially produced by pathological silencing of GPe neurons along distinct motor sub-circuits, resulting in disparate pathological basal ganglia output signaling.

Frequency-dependent, transient effects of subthalamic nucleus deep brain stimulation on methamphetamine-induced circling and neuronal activity in the hemiparkinsonian rat

Methamphetamine-induced circling is used to quantify the behavioral effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in hemiparkinsonian rats. We observed a frequency-dependent transient effect of DBS on circling, and quantified this effect to determine its neuronal basis. High frequency STN DBS (75–260Hz) resulted in transient circling contralateral to the lesion at the onset of stimulation, which was not sustained after the first several seconds of stimulation. Following the transient behavioral change, DBS resulted in a frequency-dependent steady-state reduction in pathological ipsilateral circling, but no change in overall movement. Recordings from single neurons in globus pallidus externa (GPe) and substantia nigra pars reticulata (SNr) revealed that high frequency, but not low frequency, STN DBS elicited transient changes in both firing rate and neuronal oscillatory power at the stimulation frequency in a subpopulation of GPe and SNr neurons. These transient changes were not sustained, and most neurons exhibited a different response during the steady-state phase of DBS. During the steady-state, DBS produced elevated neuronal oscillatory power at the stimulus frequency in a majority of GPe and SNr neurons, and the increase was more pronounced during high frequency DBS than during low frequency DBS. Changes in oscillatory power during both transient and steady-state DBS were highly correlated with changes in firing rates. These results suggest that distinct neural mechanisms were responsible for transient and sustained behavioral responses to STN DBS. The transient contralateral turning behavior following the onset of high frequency DBS was paralleled by transient changes in firing rate and oscillatory power in the GPe and SNr, while steady-state suppression of ipsilateral turning was paralleled by sustained increased synchronization of basal ganglia neurons to the stimulus pulses. Our analysis of distinct frequency-dependent transient and steady-state responses to DBS lays the foundation for future mechanistic studies of the immediate and persistent effects of DBS.

Altered membrane properties and firing patterns of external globus pallidus neurons in the R6/2 mouse model of Huntington's disease.

In mouse models of Huntington's disease (HD), striatal neuron properties are significantly altered. These alterations predict changes in striatal output regions. However, little is known about alterations in those regions. The present study examines changes in passive and active membrane properties of neurons in the external globus pallidus (GPe), the first relay station of the indirect pathway, in the R6/2 mouse model of juvenile HD at presymptomatic (1 month) and symptomatic (2 month) stages. In GPe, two principal types of neurons can be distinguished based on firing properties and the presence (type A) or absence (type B) of Ih currents. In symptomatic animals (2 month), cell membrane capacitance and input resistance of type A neurons were increased compared with controls. In addition, action potential afterhyperpolarization amplitude was reduced. Although the spontaneous firing rate of GPe neurons was not different between control and R6/2 mice, the number of spikes evoked by depolarizing current pulses was significantly reduced in symptomatic R6/2 animals. In addition, these changes were accompanied by altered firing patterns evidenced by increased interspike interval variation and increased number of bursts. Blockade of GABAA receptors facilitated bursting activity in R6/2 mice but not in control littermates. Thus, alterations in firing patterns could be caused by changes in intrinsic membrane conductances and modulated by synaptic inputs. © 2016 Wiley Periodicals, Inc.

Critical Roles of the Direct GABAergic Pallido-cortical Pathway in Controlling Absence Seizures.

The basal ganglia (BG), serving as an intermediate bridge between the cerebral cortex and thalamus, are believed to play crucial roles in controlling absence seizure activities generated by the pathological corticothalamic system. Inspired by recent experiments, here we systematically investigate the contribution of a novel identified GABAergic pallido-cortical pathway, projecting from the globus pallidus externa (GPe) in the BG to the cerebral cortex, to the control of absence seizures. By computational modelling, we find that both increasing the activation of GPe neurons and enhancing the coupling strength of the inhibitory pallido-cortical pathway can suppress the bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) during absence seizures. Appropriate tuning of several GPe-related pathways may also trigger the SWD suppression, through modulating the activation level of GPe neurons. Furthermore, we show that the previously discovered bidirectional control of absence seizures due to the competition between other two BG output pathways also exists in our established model. Importantly, such bidirectional control is shaped by the coupling strength of this direct GABAergic pallido-cortical pathway. Our work suggests that the novel identified pallido-cortical pathway has a functional role in controlling absence seizures and the presented results might provide testable hypotheses for future experimental studies.

Hold your pauses: external globus pallidus neurons respond to behavioural events by decreasing pause activity.

Awareness of its rich structural pathways has earned the external segment of the globus pallidus (GPe) recognition as a central figure within the basal ganglia circuitry. Interestingly, GPe neurons are uniquely identified by the presence of prominent pauses interspersed among a high-frequency discharge rate of 50-80spikes/s. These pauses have an average pause duration of 620ms with a frequency of 13/min, yielding an average pause activity (probability of a GPe neuron being in a pause) of (620×13)/(60×1000)=0.13. Spontaneous pause activity has been found to be inversely related to arousal state. The relationship of pause activity with behavioural events remains to be elucidated. In the present study, we analysed the electrophysiological activity of 200 well-isolated GPe pauser cells recorded from four non-human primates (Macaque fascicularis) while they were engaged in similar classical conditioning tasks. The isolation quality of the recorded activity and the pauses were determined with objective automatic methods. The results showed that the pause probability decreased by 9.09 and 10.0%, and the discharge rate increased by 2.96 and 1.95%, around cue and outcome presentation, respectively. Analysis of the linear relationship between the changes in pause activity and discharge rate showed r(2) =0.46 and r(2) =0.66 upon cue onset and outcome presentation, respectively. Thus, pause activity is a pertinent element in short-term encoding of relevant behavioural events, and has a significant, but not exclusive, role in the modulation of GPe discharge rate around these events.

Identification of a direct GABAergic pallidocortical pathway in rodents.

Interaction between the basal ganglia and the cortex plays a critical role in a range of behaviors. Output from the basal ganglia to the cortex is thought to be relayed through the thalamus, but an intriguing alternative is that the basal ganglia may directly project to and communicate with the cortex. We explored an efferent projection from the globus pallidus externa (GPe), a key hub in the basal ganglia system, to the cortex of rats and mice. Anterograde and retrograde tracing revealed projections to the frontal premotor cortex, especially the deep projecting layers, originating from GPe neurons that receive axonal inputs from the dorsal striatum. Cre-dependent anterograde tracing in Vgat-ires-cre mice confirmed that the pallidocortical projection is GABAergic, and in vitro optogenetic stimulation in the cortex of these projections produced a fast inhibitory postsynaptic current in targeted cells that was abolished by bicuculline. The pallidocortical projections targeted GABAergic interneurons and, to a lesser extent, pyramidal neurons. This GABAergic pallidocortical pathway directly links the basal ganglia and cortex, and may play a key role in behavior and cognition in normal and disease states.

Nigrostriatal Dopamine Acting on Globus Pallidus Regulates Sleep.

Lesions of the globus pallidus externa (GPe) produce a profound sleep loss (∼45%) in rats, suggesting that GPe neurons promote sleep. As GPe neuronal activity is enhanced by dopamine (DA) from the substantia nigra pars compacta (SNc), we hypothesized that SNc DA via the GPe promotes sleep. To test this hypothesis, we selectively destroyed the DA afferents to the caudoputamen (CPu) using 6-hydroxydopamine and examined changes in sleep-wake profiles in rats. Rats with 80-90% loss of SNc neurons displayed a significant 33.7% increase in wakefulness (or sleep reduction). This increase significantly correlated with the extent of SNc DA neuron loss. Furthermore, these animals exhibited sleep-wake fragmentation and reduced diurnal variability of sleep. We then optogenetic-stimulated SNc DA terminals in the CPu and found that 20-Hz stimulation from 9 to 10 PM increased total sleep by 69% with high electroencephalograph (EEG) delta power. We finally directly optogenetic-stimulated GPe neurons and found that 20-Hz stimulation of the GPe from 9 to 10 PM increased total sleep by 66% and significantly increased EEG delta power. These findings elucidate a novel circuit for DA control of sleep and the mechanisms of abnormal sleep in BG disorders such as Parkinson's disease and Huntington's disease.

HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by a profound motor disability that is traceable to the emergence of synchronous, rhythmic spiking in neurons of the external segment of the globus pallidus (GPe). The origins of this pathophysiology are poorly defined. Following the induction of a parkinsonian state in mice, there was a progressive decline in autonomous GPe pacemaking that normally serves to desynchronize activity. The loss was attributable to the downregulation of an ion channel that plays an essential role in its generation – the HCN channel. Viral delivery of HCN2 subunits restored pacemaking and reduced burst spiking in GPe neurons. However, the motor disability induced by dopamine (DA) depletion was not reversed, suggesting that the loss of pacemaking was a consequence, not a cause, of key network pathophysiology – a conclusion consistent with the ability of L-type channel antagonists to attenuate silencing following DA depletion.

Activity of Neurons in Monkey Globus Pallidus During Oculomotor Behavior Compared With That in Substantia Nigra Pars Reticulata

The basal ganglia are a subcortical assembly of nuclei involved in many aspects of behavior. Three of the nuclei have high firing rates and inhibitory influences: the substantia nigra pars reticulata (SNr), globus pallidus interna (GPi), and globus pallidus externa (GPe). The SNr contains a wide range of visual, cognitive, and motor signals that have been shown to contribute to saccadic eye movements. Our hypothesis was that GPe and GPi neurons carry similarly diverse signals during saccadic behavior. We recorded from GPe, GPi, and SNr neurons in monkeys that made memory-guided saccades and found that neurons in all three structures had increases or decreases in activity synchronized with saccade generation, visual stimulation, or reward. Comparing GPe neurons with GPi neurons, we found relatively more visual-related activity in GPe and more reward-related activity in GPi. Comparing both pallidal samples with the SNr, we found a greater resemblance between GPe and SNr neurons than that between GPi and SNr neurons. As expected from a known inhibitory projection from GPe to SNr, there was a general reversal of sign in activity modulations between the structures: bursts of activity were relatively more common in GPe and pauses more common in SNr. We analyzed the response fields of neurons in all three structures and found relatively narrow and lateralized fields early in trials (during visual and saccadic events) followed by a broadening later in trials (during reward). Our data reinforce an emerging, new consensus that the GPe and GPi, in addition to the SNr, contribute to oculomotor behavior.

Total number of neurons in the neostriatal, pallidal, subthalamic, and substantia nigral nuclei of the rat basal ganglia: a stereological study using the cavalieri and optical disector methods.

The total number of neurons within six subdivisions of the rat basal ganglia was estimated using unbiased stereological counting methods and systematic random sampling techniques. Six young adult rats were perfuse-fixed, their right cerebral hemispheres were embedded in glycolmethacrylate, and a complete set of serial 40-mu m sections was cut through each hemisphere. After a random start, a systematic subset (e.g., every tenth) of these sections was used to estimate the total volume of each subdivision using Cavalieri's method. The same set of sampled sections was used to estimate the number of neurons in a known subvolume (i.e., the Nv) by the optical disector method. The product of the total volume and the Nv by these methods yields an unbiased estimate of the total number of neurons. It was found that the right basal ganglia consisted, on average, of 2.79 million neostriatal or caudate-putamen neurons (with a coefficient of variation of 0.07), 46,000 external globus pallidus neurons (0.11), 3,200 entopeduncular/internal globus pallidus neurons (0.10), 13,600 subthalamic neurons (0.10), 7,200 substantial nigra pars compacta neurons (0.15), and 26,300 substantia nigra pars reticulata neurons (0.07).