Project Summary Exposure to social stress has pervasive deleterious effects on health and is a primary risk factor for the development of depression and anxiety disorders. Despite the prevalence of these disorders, our current treatment strategies are woefully inadequate. One of the fundamental reasons that we have not developed better treatments is that these so-called pathological states likely stem from evolutionarily adaptive behavioral responses to perceived social stress or defeat. This would help explain not only their prevalence but also their persistence. In many non-human species, exposure to social stress also causes persistent physiological and behavioral responses that closely mimic the symptoms of depression and PTSD. What is desperately needed is an understanding of the neural factors underlying the ability of social stress to produce such persistent maladaptive behavioral and emotional outcomes. Our lab developed an ethologically relevant model in hamsters, conditioned defeat (CD), wherein even a single exposure to social defeat stress causes a striking behavioral shift from social engagement and aggression to social avoidance and submission. The ultimate goal of our work is to delineate the neural mechanisms of such stress-induced shifts in behavioral state and to discover how to prevent or reverse these changes. We have now expanded our model to demonstrate that mice, which have a very different social system than do hamsters, also respond to acute defeat with pronounced social avoidance. The currently funded parent R01 tests the overarching hypothesis that brain derived neurotrophic factor (BDNF) systems within specific regions of the CD neural circuit mediate, at least in part, social defeat stress- induced behavioral changes. We propose that BDNF can both promote and prevent these changes depending on the brain area involved (Aim 1) and that these effects are mediated by BDNF acting on tyrosine kinase B (TrkB) receptors (Aim 2). This competing revision leverages exciting data that we have generated using hamsters and proposes complementary experiments addressing these aims in mice where it will be possible to employ powerful genetic tools to conditionally and site-specifically manipulate the BDNF- TrkB system. Advancing our understanding of the mechanisms underlying the ability of social stress to induce persistent maladaptive outcomes will dramatically advance our ability to treat intractable stress-related disorders such as depression and PTSD. Our new comparative approach will allow us to use the most up-to-date genetic approaches to increase further the innovation of our work and will have important implications for the generalizability and translational value of our data.