COORDINATED NEURAL DYNAMICS IN THE DORSAL RAPHE NUCLEUS AND ORBITOFRONTAL CORTEX DURING A COGNITIVE FLEXIBILITY PARADIGM

Cognitive flexibility, the ability to adapt behavior to changing environmental conditions, is strongly associated with the function of the orbitofrontal cortex (OFC). The dorsal raphe nucleus (DRN), the primary source of serotonergic input to the OFC, is thought to modulate this ability, yet its specific contribution and the underlying neural mechanisms remain unclear. Here, we investigated the behavioral and neuronal correlates of cognitive flexibility and the temporal dynamics between the OFC and DRN during rule switching. We developed a visual rule-switching task for head-restrained mice and recorded extracellular neuronal activity simultaneously in the OFC and DRN using Neuropixels. Behavioral performance assessed cognitive flexibility, while single-neuron and population activity were analyzed across task epochs, rule transitions, and rule states. Neurons in both regions exhibited heterogeneous but selective modulation by task epochs, rule switches, and rule states. However, the DRN exhibited a higher proportion of task-epoch–modulated neurons, and more frequent modulation across multiple epochs, whereas OFC neurons displayed greater epoch specificity. Neurons modulated by rule transitions were present in comparable proportions in both regions, and both areas showed similar temporal specificity around rule switches, suggesting coordinated involvement in cognitive flexibility. Surprisingly, while DRN neurons showed more stable task-epoch activity within a rule, they exhibited stronger modulation across rules compared to OFC neurons. Population-level analyses further revealed more robust rule representation in the DRN than in the OFC. Together, these results suggest that the DRN dynamically modulates task-relevant information across rules, complementing OFC function for cognitive flexibility. Grant: WWTF CS18-039.