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Sex differences in fetal programming by glucocorticoids: Adult hypothalamus and Autonomic Nervous System

糖皮质激素对胎儿编程的性别差异：成人下丘脑和自主神经系统

基本信息

批准号：
10349465
负责人：
Robert J Handa
金额：
$ 45.27万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10349465
关键词：
Address Adult Adult Children Agonist Angiotensin II Animals Anxiety Area Autonomic nervous system Behavior Behavioral Brain Brain Stem Brain region CRH gene Cell Nucleus Cells Coupled Data Development Dexamethasone Disease Endocrine Environment Equilibrium Exposure to Female Fetus Functional disorder Gene Expression Genetic Models Glucocorticoids Goals Heart Rate Hormonal Hormone Responsive Hormone secretion Hormones Hypothalamic structure Immune In Situ Hybridization Inflammation Insulin-Like-Growth Factor I Receptor Lateral Major Depressive Disorder Malnutrition Measures Mediator of activation protein Messenger RNA Mus Nerve Nervous System Physiology Nervous System control Neural Pathways Neurons Neuropeptides Neurophysiology - biologic function Neurosecretory Systems Neurotransmitters Oxytocin Receptor Pathway interactions Physiological Physiology Population Pregnancy Rattus Recombinant adeno-associated virus (rAAV)Renin-Angiotensin System Reporter Genes Role Sex Bias Sex Differences Signal Transduction Stress TNF gene Technology Testing Therapeutic Tissues Transgenic Mice Viral Vector Virion antagonist brain circuitry cell type depressive symptoms designer receptors exclusively activated by designer drugs environmental change fetal fetal programming genetic approach heart rate variability in utero male mind control mouse genetics mouse model nano-string neonate neurodevelopment offspring pregnant prenatal prenatal exposure prenatal stress pressure programs receptor response restraint sex stress reactivity

项目摘要

PROJECT SUMMARY / ABSTRACT The overarching goal, and ultimate impact, of this project is to identify the cellular and physiological pathways whereby developmental overexposure to glucocorticoids cause long-term, sex-selective programming of adult anxiety- and depressive-like behaviors, neuroendocrine function and autonomic nervous system responses to stress. Developmental programming, the permanent adaptation of the fetus to maternal environmental signals can elevate fetal glucocorticoids to program neurodevelopment. Preliminary data in mice and rats show sex- biased changes following late-gestation exposure to the synthetic glucocorticoid, dexamethasone. These include increased anxiety- and depressive-like behaviors, and hyperreactive neuroendocrine and autonomic nervous system responses to stress and changes in gene expression in the hypothalamus. In all cases, adult females showing a greater change than males. We hypothesize that these adult dysfunctions have a common mechanism related to programmed changes in the hypothalamic paraventricular n. (PVN), a brain region that has been shown to influence all of these physiological endpoints. Our studies show similar responses in both rats and mice allowing these studies to exploit the well-described physiology of the rat as well as the power of mouse genetic approaches. 3 specific aims are described. Aim 1 will determine the causal factors for long- term alterations in anxiety-and depressive-like behaviors, neuroendocrine response to stress and an imbalance of the autonomic nervous system. Moreover, this aim will examine the central renin-angiotensin system as a central mediator of the observed changes in brain function following prenatal glucocorticoid overexposure. Aim 2 will determine the impact of prenatal glucocorticoid exposure on connectivity between hypothalamic preautonomic and brainstem autonomic nuclei and use mouse genetic approaches and viral vectors to specifically activate neuron populations in the PVN. Aim 3 will use transcutaneous vagal nerve stimulation to modulate autonomic nervous system balance and reverse the effects of prenatal glucocorticoid exposure on adult behaviors, neuroendocrine, and autonomic responses to stress. The results of these studies will identify, not only the brain circuitry underlying the sex-biased developmental programming of behavioral, endocrine and autonomic responses in adulthood, but also reveal potential therapeutic mechanisms whereby these changes can be reversed in adulthood.

项目概要/摘要该项目的总体目标和最终影响是确定细胞和生理途径发育过程中过度接触糖皮质激素会导致成人的长期、性别选择性编程焦虑和抑郁样行为、神经内分泌功能和自主神经系统反应压力。发育规划，胎儿对母亲环境信号的永久适应可以提高胎儿糖皮质激素水平以编程神经发育。小鼠和大鼠的初步数据显示，妊娠晚期接触合成糖皮质激素地塞米松后发生的偏差。这些包括焦虑和抑郁样行为增加，以及神经内分泌和自主神经反应过度神经系统对压力的反应和下丘脑基因表达的变化。在所有情况下，成人女性比男性表现出更大的变化。我们假设这些成人功能障碍有一个共同点与下丘脑室旁神经程序性变化相关的机制。（PVN），一个大脑区域已被证明会影响所有这些生理终点。我们的研究表明，两者的反应相似大鼠和小鼠允许这些研究利用大鼠的良好描述的生理学以及小鼠遗传方法。描述了3个具体目标。目标 1 将确定长期的因果因素焦虑和抑郁样行为的术语改变、对压力的神经内分泌反应和不平衡自主神经系统。此外，该目标将检查中枢肾素-血管紧张素系统作为产前糖皮质激素过度暴露后观察到的脑功能变化的中心调节因素。目标 2 将确定产前糖皮质激素暴露对下丘脑之间连接的影响前自主神经和脑干自主神经核，并使用小鼠遗传方法和病毒载体特异性激活 PVN 中的神经元群。目标 3 将使用经皮迷走神经刺激调节自主神经系统平衡并逆转产前糖皮质激素暴露对胎儿的影响成人行为、神经内分泌和对压力的自主反应。这些研究的结果将确定，不仅是行为、内分泌和性别偏见发展规划背后的大脑回路成年期的自主反应，但也揭示了这些变化的潜在治疗机制成年后可以逆转。