Striatal acetylcholine enables latent-state creation during reversal learning.

Like dopamine, acetylcholine is modulated in the striatum by reward-predicting cues and outcomes, yet its computational role remains unclear. Here, we manipulated dorsomedial striatal acetylcholine in mice performing a reversal learning task using genetic and physiologically guided optogenetic approaches. Inhibiting phasic acetylcholine modulation impaired reversal learning, while enhancing modulation during non-rewarded trials facilitated reversal learning. Trial-by-trial acetylcholine dynamics were best explained by a reinforcement learning model in which new latent states are created when experience is poorly explained by existing states. A circuit-constrained model further suggested that acetylcholine promotes plasticity when reward-omission is ambiguous, leading to a surprising prediction: making reward omission explicit should reduce the need for acetylcholine. We confirmed this in a new experiment in which an auditory omission cue substantially reduced the reversal-learning deficit caused by genetic acetylcholine knockdown. These findings suggest that striatal acetylcholine supports reversal learning by promoting state construction in reinforcement learning.