Estrogen Regulation of the Hypothalamic-Pituitary-Adrenal Axis

摘要： 这一项目的长期目标是确定作为基础的神经生物学机制。 雌激素对成人下丘脑-垂体-肾上腺(HPA)轴的影响。哺乳动物HPA轴的激活是一种基本的 对威胁动态平衡的环境扰动的反应以及这种反应，尽管在 短期而言，在慢性条件下会产生有害的后果。肾上腺延长升高症 糖皮质激素(GC)危害神经，改变摄食和自主神经功能。此外，一个 HPA活性的失调伴随着这些紊乱。在啮齿动物中，雌性表现出更强健的HPA AXIS对压力的反应比男性更大，部分原因是循环中雌二醇(E2)水平的性别差异。 因此，这一应用的首要假设是成人应激反应的个体差异产生。 来自不同的E2对压力回路的作用。我们的研究主要集中在雌激素受体β。 (呃β)。啮齿动物研究表明，α形式ER(ERα)增加肾上腺皮质酮(CORT)和 垂体促肾上腺皮质激素对应激源的反应而激活ERβ则抑制 HPA活动。重要的是，ERβ在雄性和雌性小鼠的下丘脑室旁核神经元中都有高表达 允许性腺激素水平与压力相关的输入相结合。利用新的转基因小鼠模型， 我们将识别小鼠下丘脑的应激反应ER-β能神经回路，并确定如何 PVN ERβ的激活降低了HPA的驱动力和能量平衡。具体目标1将确定是否需要加班 使用新的催产素：Cre重组酶小鼠系和ERβ-Cre小鼠对下丘脑室旁核功能的ERβ调节 基因操作OT和ERβ神经元的品系。目标2将评估ERβ神经元的功能 在多模式应激和慢性不可预测的应激后结合到小鼠大脑的应激回路中 轻度压力源。目的3阐明下丘脑室旁核ERβ神经元的分子变化和性别差异。 对彩信和糖皮质激素的反应。在所有情况下，我们都高度认知性的存在 在这些生理途径上的差异，并将探索雌二醇或5α-雄激素3β，17β二醇的作用 (3β二醇)是雄激素的代谢物，双氢睾酮，结合并激活ERβ，在HPA轴上 激活和取食行为。这些研究的结果将为我们提供新的视角，了解 下丘脑室旁核ER-β神经元对垂体营养功能和代谢的调控作用 治疗压力和相关神经缺陷的治疗方法的目标。

ABSTRACT: The long-term goal of this project is to determine the neurobiological mechanisms that underlie the effects of estrogens on the adult hypothalamo-pituitary-adrenal (HPA) axis. HPA axis activation in mammals is a basic response to environmental perturbations that threaten homeostasis and such responses, although beneficial in the short-term, have deleterious consequences under chronic conditions. Prolonged elevations of adrenal glucocorticoids (GCs) are neuroendangering and alter feeding and autonomic functions. Moreover, a dysregulation of the HPA activity accompanies these disorders. In rodents, females show a more robust HPA axis response to stress than do males, partly because of sex-differences in circulating estradiol (E2) levels. Thus, the overarching postulate of this application is that individual differences in adult stress-responses arise from differential E2 actions on the stress-circuitry. Our studies focus predominantly on estrogen receptor beta (ERβ). Rodent studies show that the alpha form of ER (ERα) increases adrenal corticosterone (CORT) and the pituitary adrenocorticotropic hormone (ACTH) response to stressors whereas activation of ERβ inhibits HPA activity. Importantly, ERβ is highly expressed in neurons of the PVN of both male and female mice to allow integration of gonadal hormone levels with stress-related inputs. Using novel transgenic mouse models, we will identify stress responsive ERβ-ergic neural circuitry of the mouse hypothalamus and determine how activation of PVN ERβ reduces HPA drive and energy balance. Specific aim 1 will determine if OT is required for ERβ regulation of PVN function using a novel Oxytocin:cre recombinase mouse line and an ERβ-cre mouse line to genetically manipulate OT and ERβ neurons. Aim 2 will assess the function of ERβ neurons that are incorporated into the stress circuitry of the mouse brain following multimodal stress and chronic unpredictable mild stressors. Aim 3 will elucidate molecular changes and sex differences that occur in PVN ERβ neurons in response to MMS and to glucocorticoids. In all cases we are highly cognizant of the presence of sex differences in these physiological pathways and will explore the role that estradiol or 5α-androstan 3β,17β diol (3β diol), a metabolite of the androgen, dihydrotestosterone that binds and activates ERβ, have on HPA axis activation and feeding behaviors. The results of these studies will provide novel insight into the role played by PVN ERβ neurons in controlling hypophysiotrophic function and metabolism with hopes of identifying novel targets for therapeutic approaches to treating stress and associated neurological deficits.