Estrogen Regulation of the Hypothalamo-Pituitary-Adrenal Axis

雌激素对下丘脑-垂体-肾上腺轴的调节

基本信息

批准号：
9043875
负责人：
Robert J Handa
金额：
$ 33.02万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-05 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9043875
关键词：
Acute Adrenal Glands Adult Agonist Amygdaloid structure Androgens Androstanes Beds Behavior Binding Brain Cell Nucleus Chronic Corticosterone Corticotropin Corticotropin-Releasing Hormone Data Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens FOS gene Female Gap Junctions Gene Expression Glucocorticoids Glycols Goals Gonadal Hormones Gonadal Steroid Hormones Health Hemagglutinin Homeostasis Hormonal Hormone Receptor Hormones Hypothalamic structure Immediate-Early Genes Immune Sera Immunoprecipitation Individual Differences Injection of therapeutic agent Knock-out Knockout Mice Ligands Location Mammals Measures Medial Messenger RNA Molecular Monitor Mus Neurobiology Neurologic Neurons Neuropeptides Neurotransmitters Output Oxytocin Pathway interactions Phenotype Pituitary Gland Pituitary-Adrenal System Play Polyribosomes Population Preparation Recovery Regulation Reporter Ribosomal Proteins Rodent Role Sex Characteristics Shapes Slice Stress Suid Herpesvirus 1 Synapses Testing Testosterone Three-Dimensional Image Tissues Tracer Transgenic Mice Transgenic Organisms Translating Vasopressins Wild Type Mouse anxiety-related behavior base biological adaptation to stress gamma-Aminobutyric Acid insight male mouse Cre recombinase mouse model neural circuit neurobiological mechanism neurobiotin neuropsychiatric disorder new therapeutic target novel paraventricular nucleus reproductive response restraint stress reactivity stressor stria terminalis

项目摘要

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.

描述（由申请人提供）：该项目的长期目标是确定雌激素对哺乳动物下丘脑-垂体-肾上腺 (HPA) 轴影响的神经生物学机制，HPA 轴激活是对环境的基本反应。威胁体内平衡和此类反应的扰动虽然在短期内有益，但在慢性条件下会产生有害后果。此外，在啮齿类动物中，HPA 活性的失调会比雄性表现出更强烈的 HPA 轴反应，部分原因是循环雌二醇 (E2) 水平的性别差异。的总体假设该应用表明，成人应激反应的个体差异源于 E 对应激回路的不同作用。我们的研究主要集中在雌激素受体 β (ERβ) 上，啮齿动物研究表明 ER (ERα) 的 α 形式会增加肾上腺皮质酮。 CORT）和垂体促肾上腺皮质激素（ACTH）对应激源的反应，而 ERβ 的激活会抑制 HPA 活性。重要的是，ERβ 在 PVN 神经元中高度表达。雄性和雌性小鼠，允许将性腺激素水平与压力相关的输入整合使用新型减少转基因小鼠模型，我们将识别小鼠下丘脑的压力反应性 ERβ 能神经回路，并确定 PVN ERβ HPA 的激活是否通过。 OTergic 途径。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，目标 2 将测试雄性和雌性中 ERβ 激活的假设。雌性 PVN 神经元通过 1) ERβ 和 CRH 神经元之间的突触连接或 2) 通过向终纹 (BST) 或内侧杏仁核 (mAmg) 的相互投射来抑制 HPA 轴功能。目标 3 将阐明分子变化和性别。目的 4 将直接测试 PVN ERβ 神经元对应激或 ER (α/β) 激动剂治疗的反应是否存在差异。 OT 是 ERβ 调节 PVN 功能所必需的。这些研究的结果将为了解 PVN ERβ 神经元在控制生理营养功能减退中的作用提供新的见解，并希望为治疗压力和神经相关缺陷的治疗方法确定新的靶点。