Cholinergic-dependent dopamine signals in mouse dorsomedial striatum are regulated by frontal but not sensory cortices

Abstract

Abstract Everyday decisions depend on associations between sensory stimuli, actions, and outcomes. The striatum supports these sensorimotor associations through dopamine-dependent plasticity. Recent work has characterized a local striatal microcircuit in which cholinergic interneurons (CINs) modulate dopamine release via activation of nicotinic receptors on dopamine axons. Here, we show that visual stimuli evoke dopamine in the dorsomedial striatum partly through this cholinergic mechanism. Using anatomical and functional methods to identify the pathways involved, we found that visual and auditory cortices lack connectivity with CINs and were unable to drive cholinergic-dependent dopamine release. Frontal regions, which were activated by visual stimuli, strongly recruited CINs, producing robust dopamine release both ex vivo and in vivo. These findings reveal a fundamental distinction between sensory and frontal corticostriatal inputs, demonstrating that only the latter can evoke cholinergic-dependent dopamine signals. This work establishes a framework for understanding how cortical circuits shape striatal dopamine to support reinforcement learning.