Striatal Direct Pathway Targets Npas1⁺Pallidal Neurons

Abstract

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum ( DMS dSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum ( DLS dSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1 1 neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson's disease, the dSPN-Npas1 1 projection was dramatically strengthened. As DLS dSPN-Npas1 1 projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson's disease that has not been previously considered. In sum, our results suggest that dSPN input to the GPe is a critical circuit component that is involved in the regulation of movement in both healthy and parkinsonian states.

Synaptic pathology in Huntington's disease: Beyond the corticostriatal pathway

“…Notably, the hypoactivity of STN and arkypallidal GPe neurons was partially alleviated by optogenetic inhibition of prototypic GPe neurons ( Callahan et al, 2021 ). Another recent study identified a subnetwork of direct pathway MSNs specifically targeting arkypallidal Npas-positive neurons in the GPe ( Cui et al, 2021 ). Its role in HD pathogenesis remains to be determined.…”

Population-specific neuromodulation prolongs therapeutic benefits of deep brain stimulation

“…3C), electrical stimulation was unlikely to engage all striatal cell types equally. Instead, electrical stimulation was likely biased toward antidromic activation of D1-type dopamine receptor SPNs (D1-SPNs), which are not a canonical source of inhibitory input to the GPe, although they do make some synaptic contacts (12,(15)(16)(17)(18). To test the hypothesis that striatal afferents from D1-SPNs preferentially inhibit Lhx6-GPe neurons, Chronos expression was restricted to D1-SPNs (Fig.…”

Dendritic involvement in inhibition and disinhibition of vulnerable dopaminergic neurons in healthy and pathological conditions

“…One alternative pathway is through the external globus pallidus (GPe). Striatal direct pathway neurons selectively inhibit the Lhx6-positive ( Spix et al, 2021 ) and Npas1-positive ( Cui et al, 2021 ) population of GPe neurons. While there is some overlap between these GPe subtypes ( Abecassis et al, 2020 ), the Lhx6-positive neurons have been shown to inhibit both the dorsal and ventral tier SNc neurons selectively activating GABAA receptors and undergoing strong short-term synaptic depression ( Evans et al, 2020 ).…”