Circuit Mechanisms of the Cholinergic System Across Behavioral Domains
GAO Shibin1, MA Xiaoyu1,2*
Research on acetylcholine is shifting from the traditional narrative that treats it as a diffuse background modulator to a circuit-mechanistic framework organized around cell subtypes, projection pathways, andreceptor subtypes. This article summarizes the role patterns of cholinergic signaling in different brain regions andcircuits in the contexts of learning and attention, reward and addiction, as well as emotional stress and chronic pain.In light of advances in circuit tracing, genetic manipulation, and in vivo neurotransmitter recording, this reviewfurther proposes that integrating the true kinetics of acetylcholine release, receptor-subtype-mediated cellular andsynaptic effects, and network-level functional changes within a unified circuit framework is a key route to improveexplanatory power and testability. Major bottlenecks currently include the lack of comparable metrics for dynamicsacross brain regions and tasks, and the continued reliance on nucleus-level manipulations that average over the contributions of distinct cell subpopulations, thereby limiting closure of the pathway-receptor-phenotype chain. Futurestudies should perform causal tests using more physiologically realistic release patterns and, through projectionand receptor-subtype-specific manipulations combined with parallel multi-neurotransmitter recordings, establish atransferable and predictive framework for cholinergic circuit mechanisms.
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