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

Abstract

Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2 ϩ neurons and ChAT ϩ neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of theremainingneurontypesarepoorlydefined.Inthisstudy,weleveragenewmouselines,viraltools,andmolecularmarkerstobetterdefineGPe neuron subtypes. We found that Sox6 represents a novel, defining marker for GPe neuron subtypes. Lhx6 ϩ 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 ϩ population. Neurons that arise from the Dbx1 ϩ lineage were similarly abundant in the GPe and displayed a heterogeneous makeup. Importantly, tracing experiments revealed that Npas1 ϩ-Nkx2.1 ϩ 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 ϩ neurons and Npas1 ϩ neurons.

A Disynaptic Circuit in the Globus Pallidus Controls Locomotion Inhibition

“…Interestingly, the collateral connections from arkypallidal to prototypic neurons are not reciprocal or only target a subset of prototypic neurons that were not sampled in our ex vivo recordings. Indeed, the population of prototypic neurons has been further divided into subclasses based on the differential expression of molecular markers, projection sites, and differential contribution to motor functions 24,30,33,34,58,59 . Another important aspect for future work is to determine whether specific inputs can directly control the activity of arkypallidal neurons 58,60,61 or whether their activity is always disynaptically controlled by prototypic axon collaterals.…”

Auditory Corticothalamic Neurons Are Recruited by Motor Preparatory Inputs

“…41,42 The external GP borders the ACtx-projecting regions of SIn and contains a sub-compartment that projects to neocortex, including targeting of deep layer neurons in primary somatosensory cortex. 43,44 In rats, neurons in the external GP and caudate/putamen project to ACtx, though the cell-typespecific targets and the balance of projections to A1 versus other cortical fields have not yet been resolved. 45 To identify long-range monosynaptic inputs onto A1 L6 CT neurons, we used RVdG-based trans-synaptic tracing.…”

Connectivity and Functionality of the Globus Pallidus Externa Under Normal Conditions and Parkinson's Disease

“…In addition to the direct and indirect pathways, multiple networks also participate in regulating BG function, such as the hyper-direct (Cortex-STN) pathway, pallidostriatal pathway, GPe-STN loop, and GPe-Cortex loop (Bevan et al, 2002 ; Nambu et al, 2002 ; Mallet et al, 2016 ; Abecassis et al, 2020 ). GPe exerts critical roles in all of these pathways, which provides the foundation for its central position in guiding the information flow through the BG networks.…”

“…The cellular heterogeneity of GPe neurons start from embryonic stages (Nóbrega-Pereira et al, 2010 ). Generally, prototypic neurons are primarily derived from the medial ganglionic eminence and arkypallidal neurons arise from the lateral ganglionic eminence or caudal ganglionic eminence (Nóbrega-Pereira et al, 2010 ; Dodson et al, 2015 ; Abecassis et al, 2020 ). However, to date, we still lack a comprehensive molecular description for both prototypic and arkypallidal neurons.…”