Estrogen Regulation of the Hypothalamo-Pituitary-Adrenal Axis

雌激素对下丘脑-垂体-肾上腺轴的调节

• 批准号: 9040279
• 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
• 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/9040279
• 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; Disease; 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; 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; neuropsychiatry; new therapeutic target; novel; paraventricular nucleus; public health relevance; reproductive; response; restraint; stress reactivity; stressor; stria terminalis

 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（由应用提供）：该项目的长期目标是确定雌激素对成人下丘脑 - 垂体 - 肾上腺肾上腺（HPA）轴的影响的神经生物学机制。哺乳动物中的HPA轴激活是对威胁稳态和这种反应的环境扰动的基本反应，尽管在短期内有益，但在慢性条件下已删除了后果。肾上腺糖皮质激素（GC）的长时间升高是神经内成为的和改变行为。此外，HPA活性患有神经精神疾病的失调。在啮齿动物中，女性比男性表现出更强的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。那是总体假设 该应用是，成人应力响应的个体差异是由对应激环路的差异作用引起的。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形式增加了肾上腺皮质酮（CORT）和垂体肾上腺皮质激素激素（ACTH）对应激源的反应，而ERβ激活抑制了HPA活性。重要的是，ERβ在雄性和雌性小鼠的PVN的神经元中高度表达，从而使性腺激素水平与应激相关输入的分解。使用新型的转基因小鼠模型，我们将鉴定小鼠下丘脑的应力反应性ERβ-凝神经元回路，并确定PVNERβ的激活是否会降低HPA通过耳能途径的动力。具体目标1将评估掺入小鼠大脑应力回路中的ERβ和ERα神经元的种群。 AIM 2将检验以下假设：雄性和雌性PVN神经元中ERβ的激活通过1）ERβ和CRH神经元之间的突触连接抑制HPA轴的功能，或者2）通过对床n的相互性项目进行。 Stria末端（BST）或内侧杏仁核（MAMG） AIM 3将对应激或ER（α /β）激动剂治疗响应PVNERβ神经元中发生的分子变化和性别差异。 AIM 4将直接测试ERβ调控PVN功能是否需要OT。这些研究的结果将为PVNERβ神经元在控制下生理功能方面所起的作用提供新的见解，并希望鉴定出用于治疗应激和相关神经系统缺陷的治疗方法的新靶标。