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Ventral striatal cholinergic interneurons regulate decision making or motor impulsivity differentially across learning and biological sex.

2025-11-03, The Journal of neuroscience : the official journal of the Society for Neuroscience (10.1523/JNEUROSCI.0764-25.2025) (online)
Tristan J Hynes, Chloe S Chernoff, Kelly Hrelja, Andrew Li, Graeme D Betts, Lucas S Calderhead, and Catharine A Winstanley (?)
Dopaminergic transmission within the ventral striatum is broadly implicated in risk/reward decision making and impulse control, and the rat gambling task (rGT) measures both behaviours concurrently. While the resulting indices of risky choice and impulsivity correlate at the population level, dopaminergic manipulations rarely impact both behaviours uniformly, with changes in choice more likely when dopaminergic transmission is altered during task acquisition. Although the task structure of the rGT remains constant, the relative importance of ventral striatal dopamine signals relevant for reward prediction versus impulse control may vary as learning progresses; the former should dominate while rats learn the probabilistic contingencies of the task, whereas suppression of premature responses becomes more valuable once a decision-making strategy is established and exploited. Striatal cholinergic interneurons (CINs) critically influence reinforcement learning by modulating dopamine release and gating periods of dopamine-facilitated neuroplasticity. We therefore hypothesised that ventral striatal CINs (vsCINs) could influence reward learning or impulse control during task acquisition or stable performance, respectively. Using chemogenetics in Sprague Dawley rats (Rattus norvegicus), we found support for this hypothesis: activation and inhibition of vsCINs once behaviour was stable increased and decreased motor impulsivity in both sexes but had no effect on choice patterns. In contrast, activating and inhibiting vsCINs during task acquisition did not alter motor impulsivity but instead decreased and increased risky choice, respectively. Notably, the former effect was only observed in males, and the latter in females. We conclude by proposing testable predictions regarding acetylcholine-dopamine interactions that may explain sex differences. Impairments in decision making and impulsivity are central to psychiatric conditions such as addiction, ADHD, and impulse control disorders. Understanding how these behaviours are regulated in the brain, and why they differ across individuals and sexes, is critical for developing targeted treatments. This study identifies ventral striatal cholinergic interneurons as important modulators of both impulsivity and risk-based decision making, with their influence depending on learning stage and biological sex. These results show how acetylcholine and dopamine systems interact to shape behaviour in flexible and individualized ways. By revealing circuit-level mechanisms that may underlie sex-specific vulnerabilities and stage-specific treatment outcomes, this work lays the groundwork for more personalized approaches to treating disorders involving poor impulse control and risky decision making.
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Basal Ganglia Advances
 
 
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