Vulnerability and Resilience to Social Defeat: The Role of Neuroplasticity Within the Mesolimbic Dopamine Circuit

The pathophysiology of major depression and post-traumatic stress disorder are poorly understood. In particular, while stressful life events are an important cause of psychopathology, most individuals exposed to adversity maintain normal psychological functioning. The molecular mechanisms underlying this “resilience” are poorly understood. Here, we demonstrate that an inbred population of mice subjected to social defeat can be separated into susceptible and unsusceptible subpopulations which differ along several behavioral and physiological domains. Through a series of molecular and electrophysiological techniques, we identify signature adaptations within the mesolimbic dopamine circuit that are uniquely associated with vulnerability and, by a combination of viral-mediated gene transfer and genetic mouse models, we demonstrate how these adaptations are causally linked to a vulnerable phenotype. We also show that molecular recapitulations of adaptations associated with the unsusceptible phenotype are sufficient to promote resilient behavior. Our results validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance, and illustrate the importance of plasticity within the brain’s reward circuits in actively maintaining an emotional homeostasis.