Ventral Striatal Cholinergic Interneurons Regulate Decision-Making or Motor Impulsivity Differentially across Learning and Biological Sex

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 behaviors concurrently. While the resulting indices of risky choice and impulsivity correlate at the population level, dopaminergic manipulations rarely impact both behaviors 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 (DA) 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 (DA) release and gating periods of DA-facilitated neuroplasticity. We therefore hypothesized 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 (<i>Rattus norvegicus</i>), we found support for this hypothesis: activation and inhibition of vsCINs once behavior 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-DA interactions that may explain sex differences.