REVIEW article
Front. Cell. Neurosci.
Sec. Cellular Neurophysiology
This article is part of the Research TopicThe Role of Cellular Subtypes in Striatal ActivityView all 7 articles
Regional heterogeneity of striatal cholinergic interneurons: setting the stage for diverse behavioral repertoires
Provisionally accepted
- 1University of Minnesota Twin Cities Department of Neuroscience, Minneapolis, United States
- 2Medical Discovery Team on Addiction, University of Minnesota Twin Cities, Minneapolis, United States
- 3Department of Neurology, University of California San Francisco, San Francisco, United States
- 4Department of Molecular Therapeutics, New York State Psychiatric Institute, New York, United States
- 5Department of Psychiatry, Columbia University, New York, United States
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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 late-breaking 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 that must be addressed experimentally to understand how ChIs contribute to regionally distinct behaviors in both healthy and pathological states.
Keywords: Acetylcholine, cholinergic interneuron, Dopamine, Nucleus accumbens (NAc), Striatum
Received: 05 Oct 2025; Accepted: 26 Jan 2026.
Copyright: © 2026 Lemos, Duhne and Chuhma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Julia C Lemos
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