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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.

项目总结/摘要该项目的首要目标和最终影响是确定细胞和生理途径由此对糖皮质激素的发育过度引起成年人的长期、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对应力发育编程，胎儿对母体环境信号的永久适应可以提高胎儿糖皮质激素水平以促进神经发育。在小鼠和大鼠中的初步数据显示性别- 妊娠晚期暴露于合成糖皮质激素地塞米松后的偏倚变化。这些包括焦虑和抑郁样行为增加，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，成人女性的变化比男性大。我们假设这些成人功能障碍有一个共同的与下丘脑室旁核的程序性变化有关的机制。(PVN)大脑中的一个区域，已经被证明会影响所有这些生理终点。我们的研究显示，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学方法。三个具体的目标被描述。目标1将确定长期的因果因素- 焦虑和抑郁样行为的长期改变，对压力的神经内分泌反应和失衡自主神经系统。此外，这一目标将检查中央肾素-血管紧张素系统，在产前糖皮质激素过量后观察到的脑功能变化的中枢介质。目的2将确定产前糖皮质激素暴露对下丘脑-小脑连接的影响。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中的神经元群体。Aim 3将使用经皮迷走神经刺激，调节自主神经系统平衡，逆转产前糖皮质激素暴露对成年人的行为，神经内分泌，以及对压力的自主反应。这些研究的结果将确定，不仅是行为、内分泌和行为的性别偏见发展程序背后的大脑回路，自主反应，但也揭示了潜在的治疗机制，使这些变化可以在成年后逆转。