Title: Rapid Control of Stress Coping by Opposing Sertongeric Subcircuits.

Abstract: Maladaptive stress-coping strategies are a core feature of mood disorders, yet most treatments operate on the timescale of weeks and the neural populations capable of rapidly modulating stress coping behavior remain poorly understood. The dorsal raphe nucleus (DRN) is a central node for stress regulation and the principal source of forebrain-projecting serotonin (5-HT), but its internal circuit organization and cell-type-specific roles in stress-coping remain unclear. Here, we dissect the molecular and functional architecture of DRN subcircuits by integrating spatial transcriptomics, with optogenetics, and whole-brain circuit mapping. We identify two transcriptionally distinct serotonergic subtypes—5-HT/Vglut3 and 5-HT/Gad2—that exhibit rapid opposing effects on stress-coping behavior: activation of 5-HT/Vglut3 neurons promotes active coping, while 5-HT/Gad2 neurons suppress it. These subtypes also differ in reinforcement properties, projection fields, local input connectivity, and expression of neuromodulatory receptors suggesting they represent molecularly distinct antagonistic 5HT subcircuits. Notably, we also find that 5-HT/Gad2 neurons provide dense local input to 5-HT/Vglut3 neurons, suggesting an antagonistic intra-DRN microcircuit. Our findings reveal a molecularly specified architecture that enables rapid bidirectional control of stress-coping responses within the DRN and suggest novel targets for rapid subtype-specific serotonergic modulation in the treatment of depression.

Please contact Leyre Caracuel for the zoom link.