The GPCR Smoothened on cholinergic interneurons modulates dopamine-associated acetylcholine dynamics, learning, and effort management.

The striatum is a hub for associative learning where fluctuations in dopamine (DA) and acetylcholine (ACh) regulate behavior. ACh is released by cholinergic interneurons (CIN), which integrate diverse inputs that contextualize DA signals and shape behavior. We previously observed that the GPCR Smoothened (Smo) on CINs suppresses L-DOPA-induced dyskinesias, a motor side effect resulting from medication elevated DA in the Parkinsonian brain. Here, we examine whether Smo signaling modulates ACh dynamics, its coordination with DA, and motor learning in the healthy brain. We find that cholinergic neuron-specific Smo activity bidirectionally modulates ACh inhibition following dopaminergic or cholinergic neuron activity. These effects alter the temporal organization of ACh and its coupling to DA in the dorsolateral striatum. Behaviorally, Smo ablation from cholinergic neurons promotes motor learning and alters adjustments in the effort or time to obtain reward. These findings identify Smo as a modulator of striatal DA-ACh coordination, striatal learning, and effort-management.