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

这份申请是为艾米丽·卡斯特拉诺斯女士申请多元化补充资金 在科罗拉多州立大学斯图尔特·托贝特博士的实验室进行研究生学习。本项目研究 下丘脑-垂体-肾上腺（HPA）轴的胎儿编程，这是一个重要的调节系统 和协调肾上腺糖皮质激素（GC）分泌，以允许适当适应压力， 维持生理平衡作为监督该项目的U 54计划的一部分，卡斯特拉诺斯女士 将成为培训计划的一员，并接触到SCORE的教育使命， 方案正在开发中。Castellanos女士还将与SCORE计划中的其他PI密切合作。 这包括Jill Goldstein博士，他是该计划的PI和项目1的PI，以及Vitaly Napadow博士 和项目2的PI罗纳德加西亚以及项目3的共同研究者Taben黑尔博士。 在发育过程中，通过产前应激或炎症增加对GC的暴露会破坏胎儿的发育。 大脑编程并增加长期健康后果的风险。这个假设的基础 子宫内的环境会对大脑进行编程，增加了患长期复杂性痴呆症的风险。 成年期的疾病与胎儿起源的疾病包括抑郁症和焦虑样障碍，社会 损伤、精神分裂症和代谢紊乱。卡斯特拉诺斯女士项目的首要目标是 检查子宫内过度暴露于GC对下丘脑发育的影响， 焦虑和进食行为，代谢和神经内分泌应激反应。初步数据显示， 显示啮齿类动物在子宫内暴露于 合成的GC，地塞米松（DEX）。还表明下丘脑室旁核 核（PVN）是一个已知的体重调节区域，容纳了一组关键的应激反应神经元 表达促肾上腺皮质激素释放激素（CRH）。这些CRH神经元是进食回路的一部分， 也会影响焦虑和抑郁的行为。因此，该提案假设， 子宫内的暴露组织代谢回路，从而同时改变进食行为、焦虑和 抑郁样行为和神经内分泌应激反应。目标1将绘制CRH电路， 使用CRH-Ires-cre驱动小鼠系进行代谢/喂养。目标2将确定CRH神经元的变化 这可能是喂养和压力共病变化的基础，使用新的转基因小鼠品系来鉴定一种 CRH神经元的常见亚群及其向脑干自主区的投射。目标3将 利用经皮迷走神经刺激来逆转产前GC暴露的长期影响， 成人下丘脑功能这些研究将对胎儿环境如何影响成人 下丘脑功能及其如何有助于增加多种疾病风险的易感性

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