Estrogen Regulation of the Hypothalamo-Pituitary-Adrenal Axis

 描述（由申请人提供）：本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）轴影响的神经生物学机制。哺乳动物中HPA轴激活是对威胁稳态的环境扰动的基本反应，并且这种反应虽然在短期内有益，但在慢性条件下具有有害后果。肾上腺糖皮质激素（GC）的长期升高会危及神经并改变行为。此外，HPA活性的失调伴随着神经精神障碍。在啮齿类动物中，女性比男性表现出更强大的HPA轴对压力的反应，部分原因是循环雌二醇（E2）水平的性别差异。因此， 这一应用是，成人应激反应的个体差异是由应激回路上的不同E作用引起的。我们的研究主要集中在雌激素受体β（ERβ）。啮齿类动物研究表明，ER α（ERα）可增加肾上腺皮质酮（CORT）和垂体促肾上腺皮质激素（ACTH）对应激的反应，而ERβ的激活可抑制HPA活性。重要的是，ERβ在雄性和雌性小鼠的PVN神经元中高度表达，允许性腺激素水平与应激相关输入整合。使用新型转基因小鼠模型，我们将鉴定小鼠下丘脑的应激反应性ERβ能神经回路，并确定PVN ERβ的激活是否通过OTergic通路减少HPA驱动。具体目标1将评估纳入小鼠大脑应激回路的ERβ和ERα神经元群体。目的2验证雌、雄PVN神经元ERβ激活通过1）ERβ与CRH神经元之间的突触联系或2）向Bed n的相互投射抑制HPA轴功能的假说。终纹（BST）或内侧杏仁核（mAmg）。目的3阐明室旁核ERβ神经元在应激或ER（α / β）激动剂作用下的分子变化和性别差异。目的4将直接检测ERβ对PVN功能的调节是否需要OT。这些研究的结果将为PVN ERβ神经元在控制垂体营养功能中所起的作用提供新的见解，希望为治疗应激和相关神经功能缺损的治疗方法确定新的靶点。

 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.