Striatonigral Microcircuits in Motor Control and Parkinson's Disease

National Institute On Aging

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Abstract

We used the distinct molecular markers Kremen1 and Calb1 in the dorsal striatum to investigate the roles of direct-pathway striatal projection neuron (dSPN) subtypes in locomotor control. While Calb1+ dSPNs promoted locomotion—consistent with the canonical function of dSPNs—Kremen1+ dSPNs, including those forming patch-like clusters, suppressed locomotion. This regulation was state-dependent, with Calb1+ dSPNs activating early to initiate movement and Kremen1+ dSPNs activating later to terminate locomotion and facilitate transitions to immobility. Mechanistically, Calb1+ dSPNs enhanced dopamine release, likely by disinhibiting nigrostriatal dopaminergic neurons (DANs) via parvalbumin neuron inhibition in the substantia nigra pars reticulata (SNr). In contrast, Kremen1+ dSPNs suppressed dopamine release through GABBR1-mediated inhibition of Aldh1a1+ DANs, followed by a rebound release upon stimulation cessation. Genetic knockdown of GABBR1 in Aldh1a1+ DANs abolished both locomotor suppression and rebound dopamine release induced by Kremen1+ dSPN activation. These results reveal distinct, opposing roles for molecularly defined dSPN subpopulations in motor control, highlight the complex interplay between basal ganglia circuits and dopamine signaling, and underscore the importance of combining molecular markers with projection-specific approaches to dissect striatal circuit function.