Project Summary In the coming decades, cardiometabolic and affective disorders will become an epidemic in the U.S. These disorders disproportionately afflict racial and ethnic minorities. While wealth and geography contribute to health disparities, emerging evidence indicates that rank within a social hierarchy is a potent predictor of pathogenesis. Consistent with this notion, we’ve determined that mice rendered subordinate in the chronic social defeat stress (CSDS) paradigm become hypertensive, exhibit marked weight gain and increased anxiety-like behavior. Insight on causal mechanisms comes from our prior studies on cardiometabolic interoception. We discovered that neurons within the nodose ganglia that express oxytocin receptors (hereafter referred to as NDGOxtr) serve as mechanoreceptors that relay stretch exerted on the heart and gut to brain circuits orchestrating cardiovascular and gastrointestinal function. Fascinatingly, chemogenetic activation of NDGOxtr imitates the sensation of vascular and gastrointestinal stretch, thereby producing compensatory reductions in blood pressure and food intake. Impaired interoception is implicated in the etiology of cardiometabolic and affective disorders and our preliminary studies suggest that CSDS blunts mechanosensation of the heart and gut. That is, subordinate mice have impaired baroreflex sensitivity, consume large meals, and neurons within the nodose ganglia (NDG) have reduced expression of Piezo2 mRNA (i.e., molecular mechanoreceptor). These observations have led to the overall hypothesis that blunted mechanosensation of the heart and gut by NDGOxtr contributes to the development of cardiometabolic and affective disorders that accompany social adversity. We propose the following three aims to test this hypothesis. Aim 1 uses intravital imaging to investigate the impact of CSDS on NDGOxtr activity in response to mechanical stretch of the vasculature and gut. Aim 2 uses a genetically engineered mouse model to determine whether deleting Piezo2 from NDGOxtr recapitulates and/or exacerbates the effects of CSDS. Aim 3 uses chronic chemogenetics to determine whether stimulating NDGOxtr during CSDS restores cardiometabolic mechanosensation and alleviates the deleterious effects of CSDS. Collectively, our experiments will reveal, at a detailed and mechanistic level, whether 1.) chronic social stress impairs mechanosensation of the heart and gut, 2.) downregulation of Piezo2 within NDGOxtr contributes to the hypertension, hyperphagia, and anxiety-like behavior that comes with chronic social stress, 3.) restoring mechanosensation of the heart and gut by activating specific vagal sensory afferents is a viable therapeutic strategy. By elucidating the mechanisms by which social stress disrupts body-to-brain communication this research has the potential to identify novel therapeutic targets for improving health outcomes in populations experiencing social adversity.

Project Narrative This proposal investigates how chronic social stress disrupts communication between the body and brain to cause high blood pressure, weight gain, and mental health disorders. We propose that the mental stress that comes with low social status impairs how the brain senses the heart and the gut. Completion of this work may identify new therapeutic strategies to restore body-to-brain communication to improve health in disadvantaged populations.