GPe Neuron Research Articles

Phase Delays between Mouse Globus Pallidus Neurons Entrained by Common Oscillatory Drive Arise from Their Intrinsic Properties, Not Their Coupling.

A hallmark of Parkinson's disease is the appearance of correlated oscillatory discharge throughout the cortico-basal ganglia (BG) circuits. In the primate globus pallidus (GP), where the discharge of GP neurons is normally uncorrelated, pairs of GP neurons exhibit oscillatory spike correlations with a broad distribution of pairwise phase delays in experimental parkinsonism. The transition to oscillatory correlations is thought to indicate the collapse of the normally segregated information channels traversing the BG. The large phase delays are thought to reflect pathological changes in synaptic connectivity in the BG. Here we study the structure and phase delays of spike correlations measured from neurons in the mouse external GP (GPe) subjected to identical 1-100 Hz sinusoidal drive but recorded in separate experiments. First, we found that spectral modes of a GPe neuron's empirical instantaneous phase response curve (iPRC) elucidate at what phases of the oscillatory drive the GPe neuron locks when it is entrained and the distribution of phases at which it spikes when it is not. Then, we show that in this case the pairwise spike cross-correlation equals the cross-correlation function of these spike phase distributions. Finally, we show that the distribution of GPe phase delays arises from the diversity of iPRCs and is broadened when the neurons become entrained. Modeling GPe networks with realistic intranuclear connectivity demonstrates that the connectivity decorrelates GPe neurons without affecting phase delays. Thus, common oscillatory input gives rise to GPe correlations whose structure and pairwise phase delays reflect their intrinsic properties captured by their iPRCs.

Propagation of Oscillations in the Indirect Pathway of the Basal Ganglia.

Oscillatory signals propagate in the basal ganglia from prototypic neurons in the external globus pallidus (GPe) to their target neurons in the substantia nigra pars reticulata (SNr), internal pallidal segment, and subthalamic nucleus. Neurons in the GPe fire spontaneously, so oscillatory input signals can be encoded as changes in timing of action potentials within an ongoing spike train. When GPe neurons were driven by an oscillatory current in male and female mice, these spike-timing changes produced spike-oscillation coherence over a range of frequencies extending at least to 100 Hz. Using the known kinetics of the GPe→SNr synapse, we calculated the postsynaptic currents that would be generated in SNr neurons from the recorded GPe spike trains. The ongoing synaptic barrage from spontaneous firing, frequency-dependent short-term depression, and stochastic fluctuations at the synapse embed the input oscillation into a noisy sequence of synaptic currents in the SNr. The oscillatory component of the resulting synaptic current must compete with the noisy spontaneous synaptic barrage for control of postsynaptic SNr neurons, which have their own frequency-dependent sensitivities. Despite this, SNr neurons subjected to synaptic conductance changes generated from recorded GPe neuron firing patterns also became coherent with oscillations over a broad range of frequencies. The presynaptic, synaptic, and postsynaptic frequency sensitivities were all dependent on the firing rates of presynaptic and postsynaptic neurons. Firing rate changes, often assumed to be the propagating signal in these circuits, do not encode most oscillation frequencies, but instead determine which signal frequencies propagate effectively and which are suppressed.SIGNIFICANCE STATEMENT Oscillations are present in all the basal ganglia nuclei, include a range of frequencies, and change over the course of learning and behavior. Exaggerated oscillations are a hallmark of basal ganglia pathologies, and each has a specific frequency range. Because of its position as a hub in the basal ganglia circuitry, the globus pallidus is a candidate origin for oscillations propagating between nuclei. We imposed low-amplitude oscillations on individual globus pallidus neurons at specific frequencies and measured the coherence between the oscillation and firing as a function of frequency. We then used these responses to measure the effectiveness of oscillatory propagation to other basal ganglia nuclei. Propagation was effective for oscillation frequencies as high as 100 Hz.

Cell type-specific processing of non-motor signals in the external pallidum

The external globus pallidus (GPe) regulates motor control. However, whether the GPe encodes non-motor information remains unclear. Two recent studies, by Johansson and Ketzef, and Katabi et al., provide in vivo evidence for GPe neuron processing of sensory stimulation and reward cues via a division of labor among its cell types.

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.

Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns.

We have previously established that PV+ neurons and Npas1+ neurons are distinct neuron classes in the external globus pallidus (GPe): they have different topographical, electrophysiological, circuit, and functional properties. Aside from Foxp2+ neurons, which are a unique subclass within the Npas1+ class, we lack driver lines that effectively capture other GPe neuron subclasses. In this study, we examined the utility of Kcng4-Cre, Npr3-Cre, and Npy2r-Cre mouse lines (both males and females) for the delineation of GPe neuron subtypes. By using these novel driver lines, we have provided the most exhaustive investigation of electrophysiological studies of GPe neuron subtypes to date. Corroborating our prior studies, GPe neurons can be divided into two statistically distinct clusters that map onto PV+ and Npas1+ classes. By combining optogenetics and machine learning-based tracking, we showed that optogenetic perturbation of GPe neuron subtypes generated unique behavioral structures. Our findings further highlighted the dissociable roles of GPe neurons in regulating movement and anxiety-like behavior. We concluded that Npr3+ neurons and Kcng4+ neurons are distinct subclasses of Npas1+ neurons and PV+ neurons, respectively. Finally, by examining local collateral connectivity, we inferred the circuit mechanisms involved in the motor patterns observed with optogenetic perturbations. In summary, by identifying mouse lines that allow for manipulations of GPe neuron subtypes, we created new opportunities for interrogations of cellular and circuit substrates that can be important for motor function and dysfunction.SIGNIFICANCE STATEMENT Within the basal ganglia, the external globus pallidus (GPe) has long been recognized for its involvement in motor control. However, we lacked an understanding of precisely how movement is controlled at the GPe level as a result of its cellular complexity. In this study, by using transgenic and cell-specific approaches, we showed that genetically-defined GPe neuron subtypes have distinct roles in regulating motor patterns. In addition, the in vivo contributions of these neuron subtypes are in part shaped by the local, inhibitory connections within the GPe. In sum, we have established the foundation for future investigations of motor function and disease pathophysiology.

Parvalbumin+ and Npas1+ Pallidal Neurons Have Distinct Circuit Topology and Function.

The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. Phasic changes in the activity of GPe neurons during movement and their alterations in Parkinson's disease (PD) argue that the GPe is important in motor control. Parvalbumin-positive (PV+) neurons and Npas1+ neurons are the two principal neuron classes in the GPe. The distinct electrophysiological properties and axonal projection patterns argue that these two neuron classes serve different roles in regulating motor output. However, the causal relationship between GPe neuron classes and movement remains to be established. Here, by using optogenetic approaches in mice (both males and females), we showed that PV+ neurons and Npas1+ neurons promoted and suppressed locomotion, respectively. Moreover, PV+ neurons and Npas1+ neurons are under different synaptic influences from the subthalamic nucleus (STN). Additionally, we found a selective weakening of STN inputs to PV+ neurons in the chronic 6-hydroxydopamine lesion model of PD. This finding reinforces the idea that the reciprocally connected GPe-STN network plays a key role in disease symptomatology and thus provides the basis for future circuit-based therapies.SIGNIFICANCE STATEMENT The external pallidum is a key, yet an understudied component of the basal ganglia. Neural activity in the pallidum goes awry in neurologic diseases, such as Parkinson's disease. While this strongly argues that the pallidum plays a critical role in motor control, it has been difficult to establish the causal relationship between pallidal activity and motor function/dysfunction. This was in part because of the cellular complexity of the pallidum. Here, we showed that the two principal neuron types in the pallidum have opposing roles in motor control. In addition, we described the differences in their synaptic influence. Importantly, our research provides new insights into the cellular and circuit mechanisms that explain the hypokinetic features of Parkinson's disease.

Activity pattern analysis of the subthalamopallidal network under ChannelRhodopsin-2 and Halorhodopsin photocurrent control

This paper incorporates the neural photostimulation to model firing activities of the subthalamopallidal network from basal ganglia, and the emphasis is to explore the possible effects of light-gated cation membrane channel on neural system, especially to estimate the probability of therapeutic strategy in neurological disorders. Under excitatory and inhibitory photosensitive protein, we mainly study the firing rhythms of subthalamic nucleus (STN) and also external segment of globus pallidus (GPe) in different coupling modes, which is closely related with somatic movement. Firstly, the applicability of earlier proposed three-state and four-state models of ChannelRhodopsin-2 (ChR2) has been tested and verified through the reaction of single GPe neuron, together with the response of neurons to Halorhodopsin (NpHR). Then we analyze the firing patterns of neural population under two prototype network architectures respectively, being considered as different types and degrees of morbidity. The sparsely coupled network can produce six general classes of sustained firing patterns with little regularity, while the tightly coupled network can provide five different general waveforms with high correlation, including cluster synchronization of in-phase and anti-phase. Most noteworthy, with the concern of ultrafast optogenetic control, we find the pathological firing patterns can be destroyed and even eliminated under appropriate conditions, which can give some enlightenment for the treatment and regulation of Parkinson’s disease and other motor neurone disease related to basal ganglia.

Dysregulation of external globus pallidus-subthalamic nucleus network dynamics in parkinsonian mice during cortical slow-wave activity and activation.

Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key network within the basal ganglia. In Parkinson's disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Using cell class-specific optogenetic identification and inhibition during cortical slow-wave activity and activation, we report that, in dopamine-depleted mice, (1) D2 dopamine receptor expressing striatal projection neurons (D2-SPNs) discharge at higher rates, especially during cortical activation, (2) prototypic parvalbumin-expressing GPe neurons are excessively patterned by D2-SPNs even though their autonomous activity is upregulated, (3) despite being disinhibited, STN neurons are not hyperactive, and (4) STN activity opposes striatopallidal patterning. These data argue that in parkinsonian mice abnormal, temporally offset prototypic GPe and STN neuron firing results in part from increased striatopallidal transmission and that compensatory plasticity limits STN hyperactivity and cortical entrainment. Reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) neurons form a key, centrally positioned network within the basal ganglia. In Parkinson's disease and its models, abnormal rates and patterns of GPe-STN network activity are linked to motor dysfunction. Following the loss of dopamine, the activities of GPe and STN neurons become more temporally offset and strongly correlated with cortical oscillations below 40Hz. Previous studies utilized cortical slow-wave activity and/or cortical activation (ACT) under anaesthesia to probe the mechanisms underlying the normal and pathological patterning of basal ganglia activity. Here, we combined this approach with in vivo optogenetic inhibition to identify and interrupt the activity of D2 dopamine receptor-expressing striatal projection neurons (D2-SPNs), parvalbumin-expressing prototypic GPe (PV GPe) neurons, and STN neurons. We found that, in dopamine-depleted mice, (1) the firing rate of D2-SPNs was elevated, especially during cortical ACT, (2) abnormal phasic suppression of PV GPe neuron activity was ameliorated by optogenetic inhibition of coincident D2-SPN activity, (3) autonomous PV GPe neuron firing ex vivo was upregulated, presumably through homeostatic mechanisms, (4) STN neurons were not hyperactive, despite being disinhibited, (5) optogenetic inhibition of the STN exacerbated abnormal GPe activity, and (6) exaggerated beta band activity was not present in the cortex or GPe-STN network. Together with recent studies, these data suggest that in dopamine-depleted mice abnormally correlated and temporally offset PV GPe and STN neuron activity is generated in part by elevated striatopallidal transmission, while compensatory plasticity prevents STN hyperactivity and limits cortical entrainment.

Npas1+-Nkx2.1+ Neurons Are an Integral Part of the Cortico-pallido-cortical Loop.

Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2+ neurons and ChAT+ neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly defined. In this study, we leverage new mouse lines, viral tools, and molecular markers to better define GPe neuron subtypes. We found that Sox6 represents a novel, defining marker for GPe neuron subtypes. Lhx6+ neurons that lack the expression of Sox6 were devoid of both parvalbumin and Npas1. This result confirms previous assertions of the existence of a unique Lhx6+ population. Neurons that arise from the Dbx1+ lineage were similarly abundant in the GPe and displayed a heterogeneous makeup. Importantly, tracing experiments revealed that Npas1+-Nkx2.1+ neurons represent the principal noncholinergic, cortically-projecting neurons. In other words, they form the pallido-cortical arm of the cortico-pallido-cortical loop. Our data further show that pyramidal-tract neurons in the cortex collateralized within the GPe, forming a closed-loop system between the two brain structures. Overall, our findings reconcile some of the discrepancies that arose from differences in techniques or the reliance on preexisting tools. Although spatial distribution and electrophysiological properties of GPe neurons reaffirm the diversification of GPe subtypes, statistical analyses strongly support the notion that these neuron subtypes can be categorized under the two principal neuron classes: PV+ neurons and Npas1+ neurons.SIGNIFICANCE STATEMENT The poor understanding of the neuronal composition in the external globus pallidus (GPe) undermines our ability to interrogate its precise behavioral and disease involvements. In this study, 12 different genetic crosses were used, hundreds of neurons were electrophysiologically characterized, and >100,000 neurons were histologically- and/or anatomically-profiled. Our current study further establishes the segregation of GPe neuron classes and illustrates the complexity of GPe neurons in adult mice. Our results support the idea that Npas1+-Nkx2.1+ neurons are a distinct GPe neuron subclass. By providing a detailed analysis of the organization of the cortico-pallidal-cortical projection, our findings establish the cellular and circuit substrates that can be important for motor function and dysfunction.

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.

Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus.

Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping expression of the markers parvalbumin and Npas1. Our study provides evidence that parvalbumin and Npas1 neurons have different topologies within the basal ganglia.

Dichotomous Organization of the External Globus Pallidus

SummaryDifferent striatal projection neurons are the origin of a dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in vivo are underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of a dichotomous organization as fundamental as that in striatum. Thus, two populations of GPe neuron together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.