Cellular Adaptations of Dorsal Raphe Serotonin Neurons Associated with the Development of Active Coping in Response to Social Stress

Background: Social stress is a risk factor for affective disorders for certain vulnerable individuals. Stress and depression are linked in part through regulation of the dorsal raphe (DR)-serotonin (5-HT) system by the stress-related neuropeptide, corticotropin-releasing factor (CRF). We used a rat social stress model that shows individual differences in coping strategies to determine whether differences in CRF-5-HT interactions underlie individual differences in the vulnerability to social stress. Methods: Rats were exposed to the resident-intruder model of social stress for 5 days. In vivo single-unit recordings assessed DR-5-HT neuronal responses to CRF and immunoelectron microscopy assessed CRF1 and CRF2 cellular localization 24 hours after the last stress. Results: Rats responded to social stress passively, assuming defeat with short latencies (48%), or actively, with proactive behaviors and longer defeat latencies (LL, 52%). Whereas CRF (30 ng, intra-DR) inhibited 5-HT neuronal activity of control and SL rats, it activated 5-HT neurons of LL rats, an effect that was CRF2-mediated. Consistent with this, social stress promoted CRF1 internalization together with CRF2 recruitment to the plasma membrane of DR neurons selectively in LL rats. Conclusions: These data suggest that a proactive coping strategy toward social stress is associated with a redistribution of CRF1 and CRF2 in DR-5-HT neurons that primes the system to be activated by subsequent stress. The lack of this adaptation in passive coping rats may contribute to their depressive-like phenotype. These studies provide a cellular mechanism for individual differences in stress responses and consequences.