Sex Differences in Major Depression: Impact of Prenatal Stress-Immune and Autonomic Dysregulation

这份申请是为艾米丽·卡斯特利亚诺斯女士申请多元化补充资金以启动她

This application is a request for diversity supplemental funding for Ms. Emily Castellanos to initiate her graduate studies in the laboratory of Dr. Stuart Tobet at Colorado State University. This project examines the fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, an important system for regulating and coordinating adrenal glucocorticoid (GC) secretion to allow for proper adaptation to stressors and maintain physiological homeostasis. As part of the U54 program that oversees this project, Ms. Castellanos will be a member of the training program and be exposed to the educational mission that the SCORE program is developing. Ms. Castellanos will also work closely with the other PIs in the SCORE program. This includes Dr. Jill Goldstein who is PI of the Program and the PI of Project 1, and Drs. Vitaly Napadow and Ronald Garcia who are PIs of Project 2 and Dr. Taben Hale who is a co-investigator in project 3. During development, increased exposure to GCs through prenatal stress or inflammation can disrupt fetal brain programming and increase risk for long-term health consequences. The foundation for this hypothesis is that the in utero environment programs the brain and increases the risk developing long-term complex diseases in adulthood. Diseases with fetal origins include depression and anxiety-like disorders, social impairments, schizophrenia, and metabolic disorders. The overarching goal of Ms Castellanos’ project is to examine the effects of in utero overexposure to GCs on hypothalamic development resulting in co-morbid anxiety and feeding behaviors, metabolism and neuroendocrine stress responses. Preliminary data has shown that rodents display neuroendocrine, behavioral and metabolic changes after in utero exposure to the synthetic GC, dexamethasone (DEX). It has also been shown that the hypothalamic paraventricular nucleus (PVN), a known body weight-regulating region, houses a key group of stress-responsive neurons expressing corticotropin-releasing hormone (CRH). These CRH neurons are part of the feeding circuitry and also impact anxiety and depressive like behaviors. Therefore, this proposal hypothesizes that excess GC exposure in utero organizes metabolic circuitry to coincidently alter feeding behavior, anxiety and depressive like behaviors and neuroendocrine stress responses. Aim 1 will map CRH circuitry involved in metabolism / feeding using a CRH-Ires-cre driver mouse line. Aim 2 will identify changes in CRH neurons that may underlie comorbid changes in feeding and stress using novel transgenic mouse lines to identify a common subpopulation of CRH neurons and their projections to brainstem autonomic areas. Aim 3 will utilize transcutaneous Vagal Nerve Stimulation to reverse the long-term effects of prenatal GC exposure on adult hypothalamic function. These studies will have implications for how the fetal environment affects adult hypothalamic function and how it contributes to susceptibility for increased risk for multiple diseases