Sex differences and metabolic responses to chronic stress

Project Summary This proposal aims to train a dual-degree, DVM-PhD, student in preparation for a successful career as a clinician-scientist. The applicant will earn a PhD in Biomedical Sciences while simultaneously earning a DVM. Given that cardiovascular disease and metabolic disorders are an increasingly prevalent global epidemic and these disorders significantly contribute to both increased mortality and increased years lived with disability, it is vital to understand the pathogenesis of these disorders. Epidemiologically, chronic stress has a prominent role in cardiometabolic risk. Neural processes are known to influence physiologic responses to stress. However, the specific mechanisms that underlie sex-dependent changes in endocrine and metabolic physiology after chronic stress are not well understood. Therefore, the research outlined in this proposal aims to determine how specific neural circuitry influences stress reactivity and, consequently, metabolic health in male and female rats. Specifically, testing the hypothesis that signaling from the infralimbic cortex (IL) to the rostral ventrolateral medulla (RVLM) mitigates endocrine stress reactivity after chronic stress in a sex-specific manner. The following specific aims will be addressed: 1) determines if activation of the IL-RVLM circuit mitigates endocrine responses to glycemic challenge and psychological stress in male and female rats. 2) Determines if activation of the IL-RVLM circuit following exposure to chronic stress reduces female susceptibility to endocrine hyper- reactivity. Activation of the IL-RVLM circuit will be achieved using optogenetic stimulation. Acute restraint will be used as a psychological stressor to measure activation of stress hormones, namely glucocorticoids, glucose, glucagon, angiotensin II, and insulin. Glycemic challenge in the form of a glucose tolerance test will be used a metabolic stressor. In aim 2, chronic variable stress (CVS) exposure will consist of 14 days of twice- daily randomized stressors. Following exposure to CVS, animals will undergo acute restraint and glycemic challenge. In addition to stress hormones, glucose, glucagon, angiotensin II and insulin, non-invasive measures of metabolism and autonomic activation such as heart rate, blood pressure, and body temperature will be taken during acute stress in both aims. Corticotropin Releasing Hormone mRNA will be quantified in the hypothalamus. Additionally, basal metabolic measures will be taken in the form of bodyweight and food intake. Taken together, these studies will provide novel insight into how cortical and brainstem processes integrate to influence metabolic health in a sex-specific manner. This will further our understanding of how stress contributes to metabolic and cardiovascular diseases.