Estrogen Regulation of the Hypothalamo-Pituitary-Adrenal Axis

 描述(申请人提供)：这个项目的长期目标是确定雌激素对成人下丘脑-垂体-肾上腺(HPA)轴的影响的神经生物学机制。哺乳动物HPA轴的激活是对威胁动态平衡的环境扰动的基本反应，这种反应虽然在短期内是有益的，但在慢性条件下会产生有害的后果。肾上腺糖皮质激素(GC)的长期升高是神经危害和改变的行为。此外，HPA活性的失调伴随着神经精神障碍。在啮齿动物中，雌性比雄性表现出更强大的HPA轴对压力的反应，部分原因是循环中雌二醇(E2)水平的性别差异。因此，最重要的假设是 这一应用是，成人应激反应的个体差异是由于应激回路上不同的E动作引起的。我们的研究主要集中在雌激素受体β(ERβ)。啮齿动物研究表明，α形式的ER(ERα)可增加肾上腺皮质酮(CORT)和垂体促肾上腺皮质激素(ACTH)对应激源的反应，而激活ERβ则抑制HPA的活性。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高度表达，使性腺激素水平与应激相关的输入整合在一起。利用新的转基因小鼠模型，我们将鉴定小鼠下丘脑的应激反应ER-β能神经回路，并确定PVN ERβ的激活是否通过OT能途径减少HPA驱动。具体目标1将评估并入小鼠大脑应激回路的ERβ和ERα神经元群体。目的2通过1)ERβ和CRH神经元之间的突触联系或2)通过向终纹N床或杏仁内侧核的相互投射抑制下丘脑室旁核神经元的功能这一假说进行验证。目的3阐明下丘脑室旁核ERβ神经元在应激或ER(α/β)激动剂处理后的分子变化和性别差异。Aim 4将直接测试内质网β对室旁核功能的调节是否需要OT。这些研究的结果将为了解下丘脑室旁核β神经元在控制垂体营养功能中所起的作用提供新的见解，并希望为治疗应激和相关的神经功能障碍寻找新的靶点。

 DESCRIPTION (provided by applicant): The long-term goal of this project is to determine the neurobiological mechanisms that underlie effects of estrogen 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 behaviors. Moreover, a dysregulation of the HPA activity accompanies neuropsychiatric 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 E 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 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, allows 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 if activation of PVN ERβ reduces HPA drive through OTergic pathways. Specific aim 1 will assess populations of ERβ and ERα neurons that are incorporated into the stress circuitry of the mouse brain. Aim 2 will test the hypothesis that activation of ERβ in male and female PVN neurons inhibits HPA axis function through 1) synaptic connections between ERβ and CRH neurons or 2) through reciprocal projections to the Bed n. of the Stria Terminalis (BST) or medial Amygdala (mAmg). Aim 3 will elucidate molecular changes and sex differences that occur in PVN ERβ neurons in response to stress or ER (α / β) agonist treatment. Aim 4 will directly test whether OT is requird for ERβ regulation of PVN function. The results of these studies will provide novel insight into the role played by PVN ERβ neurons in controlling hypophysiotrophic function with hopes of identifying novel targets for therapeutic approaches to treating stress and associated neurological deficits.