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

此申请是为艾米丽·卡斯特拉诺斯女士申请多样性补充资金，以启动她 在科罗拉多州立大学斯图尔特·托贝博士的实验室里攻读研究生课程。这个项目考察了 胎儿下丘脑-垂体-肾上腺(HPA)轴的程序设计是调节的重要系统 和协调肾上腺糖皮质激素(GC)的分泌，以允许适当地适应应激源和 保持生理动态平衡。作为监督这个项目的U54项目的一部分，卡斯特拉诺斯女士 将成为培训计划的一员，并将接受教育使命的分数 程序正在开发中。卡斯特拉诺斯女士还将与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Project 1的PI，以及Vitaly Napadow博士 罗纳德·加西亚是项目2的私人助理，塔本·黑尔博士是项目3的合作调查员。 在发育过程中，通过产前应激或炎症增加对GC的暴露可能会扰乱胎儿 大脑编程和增加长期健康后果的风险。这一假说的基础 是宫内环境对大脑进行编程，增加了发生长期复合体的风险 成年期的疾病。源于胎儿的疾病包括抑郁和焦虑样障碍，社交 精神障碍、精神分裂症和新陈代谢障碍。卡斯特拉诺斯女士项目的首要目标是 检查宫内过度暴露于GCs对下丘脑发育的影响，从而导致共病 焦虑和进食行为，新陈代谢和神经内分泌应激反应。初步数据显示 研究表明，啮齿动物在宫内暴露于铅后，会出现神经内分泌、行为和代谢的变化。 合成的GC，地塞米松(DEX)。也有研究表明，下丘脑室旁核 核团(PVN)是一个已知的体重调节区域，内含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神经元是馈入回路的一部分， 也会影响焦虑和抑郁等行为。因此，这一提议假设过剩的GC 子宫内暴露会组织代谢回路，从而巧合地改变喂养行为、焦虑和 抑郁样行为和神经内分泌应激反应。AIM 1将映射涉及的CRH电路 使用CRH-Ires-cre驱动小鼠品系进行代谢/喂养。目标2将确定CRH神经元的变化 这可能是使用新的转基因小鼠品系来识别一种 CRH神经元的常见亚群及其向脑干自主神经区的投射。目标3将 经皮迷走神经刺激逆转产前糖皮质激素暴露的长期效应 成人下丘脑功能。这些研究将对胎儿环境如何影响成人产生影响。 下丘脑功能及其对多种疾病易感性的影响

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