Optogenetic activation of mesencephalic projections to the nucleus accumbens shell impairs probabilistic reversal learning by disrupting learning from negative reinforcement.

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including schizophrenia and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesized to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning. Here, rats acquired a two-choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%|20% basis (correct|incorrect responses) that assessed the flexibility of behaviour to repeated reversals of response-outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). VTA → NAcS stimulation during other phases of the behavioural task was without significant effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or prior to making a choice, had no significant effect on reversal learning. These findings are consistent with the notion that increased activity in the VTA → NAcS pathway disrupts behavioural flexibility by impairing learning from negative reinforcement.