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 patterns that are adopted when individuals perceive 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 how social stress shifts behavior from one stable state to another. My lab has developed an ethologically relevant model in hamsters termed 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 these changes might be prevented or reversed. This project will test the overarching hypothesis that brain derived neurotrophic factor (BDNF) systems within specific regions of the CD neural circuit mediate, at least in part, behavioral changes observed following social defeat stress. We propose that BDNF can both promote and prevent these changes depending on the brain area involved (Aim 1) and that these actions are mediated by BDNF actions on tyrosine kinase B (TrkB) receptors (Aim 2). We also propose that chromatin remodeling of the BDNF gene and promoters is a molecular mechanism underlying the behavioral changes that define CD (Aim 3). In this project, we will not only delineate the site specific behavioral effects of, and defeat-induced epigenetic changes in, the BDNF-TrkB system in the neural circuit for CD, but we will also assess the translational potential of this informatin with systemic manipulations. Advancing our understanding of the mechanisms involved in shifts among stable behavioral states will dramatically advance our ability to treat intractable mood and anxiety disorders such as depression and PTSD.
Exposure to social stress has pervasive deleterious effects on human health and is a major risk factor for the development of a variety of psychiatric disorders. Examination of ethologically relevant models of social stress in animals is critical for improving our understanding of how social stress produces these persistent deleterious effects, and advances in this area will result in improved strategies to treat and even prevent pathological responses to social stress in humans.
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