Central cholinergic system and muscarinic subtype M4 : probabilistic decision-making deficits by inherent impulsivity

Deficits in decision making and response inhibition are core features of many neuropsychiatric disorders. While dopamine has a well-established role in these behaviors and is a common target for pharmacological treatments, these pharmacotherapies are often accompanied by adverse side effects and may fail to address cognitive symptoms such as impulsivity, reward sensitivity, and risky decision making. Acetylcholine modulates dopamine signaling and may treat a broader range of symptoms with fewer side effects. However, research on acetylcholine’s role in higher-order cognitive functions, such as probabilistic decision making, remains underexplored. Among the acetylcholine receptors, the muscarinic subgroup, particularly the M4 subtype, is expressed within mesolimbic and nigrostriatal circuits, uniquely situated to influence both goal-directed and habitual behaviors. Since impulsivity level may interact with treatment outcomes, investigating how trait-level impulsivity shapes decision making during cholinergic modulation can critically inform therapeutic development. The overarching hypothesis was that strategic, anatomically specific targeting of the cholinergic system would differentially affect decision making and impulsivity in a task phase- and trait impulsivity-dependent manner. To test this, pharmacological and chemogenetic challenges manipulated cholinergic and dopaminergic signaling within midbrain and striatal regions during acquisition or performance of the cued rat gambling task. Unique to the current work, behavioral outcomes were evaluated by high- and low-impulsivity phenotypes. The first experiment established that only muscarinic, not nicotinic, signaling mediated cue-induced impulsivity and risky decision making. Across all subsequent experiments, trait-level impulsivity consistently predicted the direction and magnitude of behavioral change following intervention. Chemogenetic modulation during task acquisition altered choice preference in opposite directions depending on region and trait, while impulsivity remained stable. Conversely, post-acquisition manipulations affected impulsivity without altering choice patterns. Lastly, M4-targeted pharmacological interventions partially mirrored those from chemogenetic modulation, consistent with M4’s regional expression. However, localized potentiation of SNc M4 receptors revealed trait-dependent differences, suggesting divergent circuit-level roles for M4 in modulating behavior. These findings demonstrate that the same intervention may have beneficial, ineffective, or detrimental effects depending on an individual’s phenotype. The specific manipulations used in the current work were hypothesis-informed, but future work should explore region and phase combinations not targeted here to fully delineate these interactions.