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

• 批准号: 10089495
• 负责人: Robert J Handa
• 金额: $ 46.35万
• 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/10089495
• 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; 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

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.

项目摘要 /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 因此，发育过度暴露于糖皮质激素会引起长期的成人性选择性编程 焦虑和抑郁样行为，神经内分泌功能以及自主神经系统对 压力。发展节目，胎儿对母亲环境信号的永久改编 可以提升胎儿糖皮质激素来编程神经发育。小鼠和大鼠的初步数据显示性别 - 妊娠晚期暴露于合成糖皮质激素，地塞米松后的偏见变化。这些 包括增加焦虑和类似抑郁的行为，以及过度反应性神经内分泌和自主神经 神经系统对下丘脑中压力和基因表达的变化的反应。在所有情况下，成人 女性显示出比男性更大的变化。我们假设这些成年功能障碍有一个常见 与下丘脑室室内n的编程变化有关的机制。 （PVN），一个大脑区域 已显示影响所有这些生理终点。我们的研究表明两者都有相似的反应 大鼠和小鼠允许这些研究利用大鼠的描述良好的生理学以及 小鼠遗传方法。描述了3个具体目标。 AIM 1将确定长期的因果因素 焦虑和抑郁症行为的术语改变，神经内分泌对压力的反应和不平衡 自主神经系统。此外，此目标将研究中央肾素 - 血管紧张素系统 产前糖皮质激素过度暴露后观察到的脑功能变化的中心介体。 AIM 2将确定产前糖皮质激素暴露对下丘脑之间连通性的影响 术语和脑干自主核，并使用小鼠遗传方法和病毒向量 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并逆转产前糖皮质激素对 成人行为，神经内分泌和对压力的自主性反应。这些研究的结果将确定， 不仅是行为，内分泌和 成年后的自主反应，但也揭示了潜在的治疗机制 可以在成年后逆转。