Striatal Direct Pathway Targets Npas1⁺ Pallidal Neurons

Area of Science:

• Neuroscience
• Motor Control
• Basal Ganglia Function

Background:

• The classic basal ganglia model posits segregated striatal output pathways.
• Empirical evidence suggests direct-pathway striatal projection neurons (dSPNs) also project to the external globus pallidus (GPe).
• The functional role of this dSPN-GPe projection has remained largely unknown.

Purpose of the Study:

• To investigate the organization of striatopallidal projections.
• To determine the role of dSPN input to the GPe in regulating full-body movement.
• To examine changes in this circuit in a Parkinson's disease model.

Main Methods:

• Optogenetic stimulation of dSPNs in specific striatal subregions (dorsomedial striatum - DMS, dorsolateral striatum - DLS) in mice.
• Circuit tracing and neuronal activity analysis.
• Assessment in a 6-hydroxydopamine lesion model of Parkinson's disease.

Main Results:

• Optogenetic stimulation of DLS dSPNs suppressed locomotion, unlike DMS dSPNs.
• dSPNs selectively target Npas1+ neurons within the GPe.
• The dSPN-Npas1+ projection was significantly strengthened in the Parkinson's disease model.

Conclusions:

• dSPN input to the GPe is a critical, previously overlooked component in motor regulation.
• The motor-suppressing DLS dSPN-Npas1+ pathway is implicated in Parkinson's disease hypokinesia.
• This pathway represents a novel circuit mechanism contributing to movement deficits in Parkinson's disease.