Dynamic Responses of Striatal Cholinergic Interneurons Control Behavioral Flexibility

Striatal cholinergic interneurons (CINs) are key to regulating behavioral flexibility, involving both extinguishing learned actions and adopting new ones. However, the mechanisms driving these processes remain elusive. In this study, we initially demonstrate that chronic alcohol consumption disrupts the burst-pause dynamics of CINs and impairs behavioral flexibility. We next aimed to elucidate the mechanisms by which CIN dynamics control behavioral flexibility. We found that extinction learning enhances acetylcholine (ACh) release and that mimicking this enhancement through optogenetic induction of CIN burst firing accelerates the extinction process. In addition, we demonstrate that disrupting CIN pauses via continuous optogenetic stimulation reversibly impairs the updating of goal-directed behaviors. Overall, we demonstrate that CIN burst firing, which increases ACh release, promotes extinction learning, aiding the extinguishment of learned behaviors. Conversely, CIN firing pauses, which lead to ACh dips, are crucial for reversal learning, facilitating the adaptation of new actions. These findings shed light on how CIN dynamics regulate behavioral flexibility.