Locus coeruleus norepinephrine neurons facilitate orbitofrontal cortex remapping and behavioral flexibility

To guide behavior, orbitofrontal cortex (OFC) maintains cellular representations of task-related information and expected outcomes. When actions produce undesirable results, these representations must be updated to promote behavioral change. Here, we show that OFC remapping is facilitated by the locus coeruleus (LC). In a reward-based behavioral flexibility task, LC activity evolves across days and with task proficiency to reflect task outcome on a trial-by-trial basis. Microendoscopic calcium imaging within the OFC reveals the emergence of task-related information with training, which is initially disrupted during reversal but soon reappears to reflect the new task contingencies. Silencing LC neurons during reversal impedes OFC state remapping and causes perseverative behavior, while enhancing LC activity hinders stabilization of new task-relevant state maps and reversal task proficiency. Collectively, this work reveals a novel role for bidirectional LC-norepinephrine (NE) signaling in the regulation of behavioral flexibility via modulation of OFC state map stability.