Vulnerability To Chronic Social Stress Is Mediated By Serotonergic Input From The Dorsal Raphe To The Ventral Tegmental Area

The serotonin system has been hypothesized to control a highly diverse range of behavioral and physiological processes,including feeding,aggression,reward,anxiety and depression.Multiple lines of evidence show that dysregulated serotonergic neurotransmission and exposure to social stress have both been implicated in the etiology of psychiatric disorders.The dorsal raphe nucleus(DRN)harbors the vast majority of serotonergic neurons that provide?70%of serotonin in the forebrain.The ventral tegmental area(VTA)in the reward-related circuit plays a critical role in mediating maladaptive behaviors in response to emotional stress.Serotonergic neurons in the DRN projecting to VTA neurons are key to shape reward responses.However,whether VTA-projecting DRN serotonin neurons influence vulnerability to social stress and how they adapt in response to stress have not been determined.Moreover,despite the clear clinical efficacy of selective serotonin reuptake inhibitors(SSRIs)administration in depressive and anxiety-related disorders,but the exact mechanisms to explain this remain highly controversial.In this study,we identified a distinct,anatomically defined serotonin subpopulation in the DRN that projects to the VTA.We found that this subpopulation demonstrates electrophysiological adaptaions in response to social defeat stress.Specifically,we reported that susceptibility to social defeat stress decreased neuronal activation and intrinsic excitability of VTA-projecting DRN serotonin neurons.Furthermore,we found that inhibition of the DRN serotonin neuronal activity or VTA-projecting DRN serotonin neurons following subthreshold social defeat stress promoted stress vulnerability.Moreover,bidirectional manipulation of VTA-projecting DRN serotonin neurons can modulate susceptibility to social defeat stress.Chronic,but not acute,silencing of VTA-projecting DRN serotonin neurons induced stress vulnerability in mice resilient to chronic social defeat,while both acute and chronic activation of this pathway were sufficient to confer stress resilience.Our findings reveal that the activity of serotonin neurons may be an essential factor in determining individual levels of susceptibility to social stress,and suggest that targeting serotonergic circuits may aid development of novel therapies for the treatment of stress-related disorders.