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

重度抑郁症的性别差异：产前压力免疫和自主神经失调的影响

• 批准号: 10527864
• 负责人: JILL M GOLDSTEIN
• 金额: $ 7.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527864
• 关键词: Adrenal Glands; Adult; Affect; Anxiety; Area; Behavior; Behavioral; Body Weight; Brain; Brain Stem; Colorado; Complex; Corticotropin-Releasing Hormone; Cre driver; Data; Development; Dexamethasone; Disease; Environment; Exposure to; Feeding behaviors; Foundations; Funding; Glucocorticoids; Goals; Health; Homeostasis; Hypothalamic structure; Immune; Impairment; Inflammation; Knowledge; Laboratories; Long-Term Effects; Major Depressive Disorder; Maps; Mental Depression; Metabolic; Metabolic Diseases; Metabolism; Minority Graduate Student; Mission; Mus; Nerve; Neurons; Neurosecretory Systems; Predisposition; Request for Proposals; Research; Research Personnel; Risk; Rodent; Schizophrenia; Sex Differences; Stress; System; Training Programs; Transgenic Mice; Universities; Work; anxiety-like behavior; biological adaptation to stress; comorbidity; depressive symptoms; feeding; fetal; fetal programming; hypothalamic-pituitary-adrenal axis; in utero; maternal stress; member; multimodality; neuropsychiatric disorder; novel; paraventricular nucleus; prenatal; prenatal exposure; prenatal stress; programs; social; stressor

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

该申请是为Emily Castellanos女士启动她的多样性补充资金的要求 科罗拉多州立大学Stuart Tobet博士实验室的研究生研究。该项目考试 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 和协调的肾上腺糖皮质激素（GC）分泌，以适当适应压力源和 保持身体稳态。作为监督该项目的U54计划的一部分，Castellanos女士 将是培训计划的成员，并接触到得分的教育任务 程序正在开发。 Castelanos女士还将与分数计划中的其他PI紧密合作。 这包括该计划的PI和Project 1的PI和Drs博士。 Vitaly Napadow Ronald Garcia是Project 2的PI和Project 3中的共同评估者Taben Hale博士。 在开发过程中，通过产前压力或注射增加对GC的暴露会破坏胎儿 大脑编程并增加长期健康后果的风险。这个假设的基础 是子宫内环境计划大脑并增加了发展长期复杂的风险 成年疾病。胎儿起源的疾病包括抑郁症和类似焦虑的疾病，社会 障碍，精神分裂症和代谢障碍。 Castellanos项目的总体目标是 检查子宫内过度暴露于GC对下丘脑发育的影响，导致合并症 焦虑和喂养行为，代谢和神经内分泌压力反应。初步数据具有 表明啮齿动物在子宫暴露后显示神经内分泌，行为和代谢变化 合成GC，地塞米松（DEX）。还显示下丘脑旁腔室 核（PVN）是一种已知的体重调节区域，容纳了一组应力反应性神经元 表达皮质激素释放激素（CRH）。这些CRH神经元是进食电路的一部分， 还影响焦虑和抑郁症行为。因此，该提议假设超过GC 子宫内的暴露会组织代谢电路，以巧妙地改变喂养行为，动画和 抑郁症的行为和神经内分泌压力反应。 AIM 1将绘制涉及的CRH电路 使用CRH-IRES-CRE驱动器鼠标系列代谢 /进食。 AIM 2将确定CRH神经元的变化 这可能是使用新型的转基因小鼠系的合并症喂养和压力变化的基础 CRH神经元的常见亚群及其对脑干自主区域的项目。目标3意志 利用经皮迷走神经刺激来扭转产前GC暴露对 成人下丘脑功能。这些研究将对胎儿环境如何影响成人有影响 下丘脑功能及其如何促进多种疾病风险的易感性