Regional heterogeneity of striatal cholinergic interneurons: setting the stage for diverse behavioral repertoires

Cholinergic interneurons (ChIs) constitute only a small fraction of striatal neurons, yet their dense axonal arborizations and widespread acetylcholine release make them powerful regulators of basal ganglia output. While the striatum is often described as cytoarchitecturally uniform, accumulating evidence reveals significant regional heterogeneity in ChI properties that shape striatal computation and behavior. Recent observations suggest that ChI heterogeneity occurs at multiple levels, extending beyond simple dorsal-ventral differences. This includes morphological, electrophysiological, and molecular heterogeneity among ChIs, as well as ChI-driven behaviors in the dorsolateral striatum, dorsomedial striatum, and nucleus accumbens (core and shell). Despite these accumulating observations, most studies and reviews of ChIs focus narrowly on one or two functional levels. As a result, a systematic and comprehensive comparison of ChI activity and its modulation across finer striatal subregions and multiple levels of analysis has not been undertaken. Here, we integrate findings across cellular, circuit, and behavioral levels to frame how regional ChI heterogeneity may set the stage for diverse behavioral repertoires. In light of recent studies, we highlight ChI activity and dopamine neuron-ChI interactions and compare mechanisms of cholinergic modulation across striatal subregions. This integrative perspective reveals critical discrepancies in the current literature, which should be addressed experimentally to understand how ChIs contribute to regionally distinct behaviors in both healthy and pathological states.