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

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。

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.