Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions

The dorsal striatum is critically involved in a variety of motor behaviours, including regulation of motor activity, motor skill learning and motor response to psychostimulant and neuroleptic drugs, but contribution of D 2 R‐striatopallidal and D 1 R‐striatonigral neurons in the dorsomedial (DMS, associative) and dorsolateral (DLS, sensorimotor) striatum to distinct functions remains elusive. To delineate cell type‐specific motor functions of the DMS or the DLS, we selectively ablated D 2 R‐ and D 1 R‐expressing striatal neurons with spatial resolution. We found that associative striatum exerts a population‐selective control over locomotion and reactivity to novelty, striatopallidal and striatonigral neurons inhibiting and stimulating exploration, respectively. Further, DMS‐striatopallidal neurons are involved only in early motor learning whereas gradual motor skill acquisition depends on striatonigral neurons in the sensorimotor striatum. Finally, associative striatum D 2 R neurons are required for the cataleptic effect of the typical neuroleptic drug haloperidol and for amphetamine motor response sensitization. Altogether, these data provide direct experimental evidence for cell‐specific topographic functional organization of the dorsal striatum. A diphtheria toxin receptor‐mediated cell ablation strategy reveals cell type‐selective involvement of dorsal striatum subregions in motor control and skill learning.