ACTIVATION OF PROTEIN KINASE CΑ IN STRIATAL CHOLINERGIC INTERNEURONS DURING EARLY PHASES OF REVERSAL LEARNING

Instrumental reversal learning is a form of cognitive flexibility where behaviours are adjusted according to changes in response-outcome contingencies, allowing efficient decision-making in dynamic environments. Cholinergic interneurons (CINs) of the posterior dorsomedial striatum (pDMS) are shown to help integrate old and new goal-directed learning, but its molecular mechanisms remain elusive. We investigated this with a focus on the role of protein kinase Cα (PKCα), which has been implicated in increasing CIN excitability.
Mice and rats were trained to press one of two levers to obtain distinct outcomes (Action 1 → Outcome 1, Action 2 → Outcome 2), then either continued training on the same contingencies or were trained on reversed contingencies (Action 1 → Outcome 2, Action 2 → Outcome 1). Animals were culled after either 1 day (early phase of learning) or 5 days (late phase of learning) of reversal/continued initial training. We observed that striatal PKCα and phospho-PKCα expression were primarily restricted to CINs in both mice and rats. Notably, animals in the early phase of reversal learning showed increased PKCα localization to the cytoplasmic membrane, indicating its activation, compared to animals that continued initial training. This effect was absent in the late learning phase. These findings suggest PKCα activation in the pDMS is specifically associated with early phases of reversal learning, implying a role for PKCα in modulating CIN activity to support the flexible updating of action–outcome associations.