Serotonin in the orbitofrontal cortex enhances cognitive flexibility

Cognitive flexibility is a brain’s ability to switch between different rules or action plans depending on the context. However, cellular level understanding of cognitive flexibility have been largely unexplored. We probed a specific serotonergic pathway from dorsal raphe nuclei (DRN) to the orbitofrontal cortex (OFC) while animals are performing reversal learning task. We found that serotonin release from DRN to the OFC promotes reversal learning. A long-range connection between these two brain regions was confirmed anatomically and functionally. We further show that spatiotemporally precise serotonergic action directly enhances the excitability of OFC neurons and offers enhanced spike probability of OFC network. Serotonergic action facilitated the induction of synaptic plasticity by enhancing Ca 2+ influx at dendritic spines in the OFC. Thus, our findings suggest that a key signature of flexibility is the formation of choice specific ensembles via serotonin-dependent synaptic plasticity.