Gonadal Steroid Receptors and the Hypothalamo-Pituitary-Adrenal Axis

性腺类固醇受体和下丘脑-垂体-肾上腺轴

• 批准号: 7760577
• 负责人: Robert J Handa
• 金额: $ 40.94万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760577
• 关键词: Address; Adrenal Glands; Adult; Agonist; Androgens; Androstanes; Animal Model; Animals; Anterior Pituitary Gland; Area; Binding; Biological Assay; Brain; Brain Stem; Brain region; Cell Line; Cell Nucleus; Cells; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Data; Enzymes; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Exhibits; FOS gene; Feedback; Female; Future; Genes; Genetic Transcription; Glean; Glucocorticoid Receptor; Glucocorticoids; Glycols; Goals; Gonadal Steroid Hormones; Histone Acetylation; Homeostasis; Hormonal; Hormones; Human; Hydroxysteroid Dehydrogenases; Hypothalamic structure; In Situ Hybridization; Infusion procedures; Knock-out; Knockout Mice; Ligand Binding; Ligands; Location; Messenger RNA; Metabolism; Mus; NCOA2 gene; Nature; Neurons; Neuropeptides; Neurosecretory Systems; Output; Oxidoreductase; Oxytocin; Oxytocin Receptor; Pathway interactions; Pituitary Gland; Pituitary-Adrenal System; Publishing; Rattus; Recruitment Activity; Regulation; Regulatory Element; Reporter; Reporter Genes; Role; Sex Characteristics; Site; Site-Directed Mutagenesis; Son; Stanolone; Steroid Receptors; Steroids; Stress; Testing; Testosterone; Transgenic Mice; Vasopressins; biological adaptation to stress; chromatin immunoprecipitation; chromatin modification; interest; mRNA Expression; male; mouse model; neural circuit; neurobiological mechanism; novel; nuclear receptor coactivator 1; oxysterol 7-alpha-hydroxylase; paraventricular nucleus; prevent; promoter; psychological stressor; public health relevance; recombinase; reproductive; reproductive hormone; response; sex

DESCRIPTION (provided by applicant): The long-term goals of this project are to determine the neurobiological mechanisms that underlie the sex differences in the function of the adult hypothalamo-pituitary-adrenal (HPA) axis. In humans and animals, sex differences in HPA reactivity are well established; females exhibit a more robust activation of the HPA axis following stress than do males. Our hypothesis is that sex differences in adult hormonal stress responses are primarily the result of the opposing actions of testosterone (T) and estrogen (E) on HPA function. Activation of the HPA axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are regulated by neurons residing in the paraventricular nucleus of the hypothalamus (PVN) that synthesize and secrete corticotropin-releasing hormone (CRH). Other PVN neuropeptides, such as vasopressin (AVP) and oxytocin (OT), modulate activity of CRH neurons at the level of the PVN as well as enhancing CRH secretogogue activity at the anterior pituitary gland. The reproductive steroids, E and T can also modulate stress responses. Circulating E enhances stress activated ACTH and CORT secretion. In contrast, T decreases the gain of the HPA axis. Published and preliminary data show that androgens can act directly on PVN neurons in the male rat through a novel pathway that involves estrogen receptor beta (ERbeta), whereas E acts predominantly through ERalpha. Thus, we hypothesize that in males, T suppresses HPA function by androgen metabolites that bind ERbeta. Clues to the neurobiological mechanisms underlying such a novel action can be gleaned from studies showing extensive colocalization of ERbeta in OT-containing cells of the PVN. Hence, in this application we address the possibility that testosterone inhibits HPA reactivity by metabolizing to a compound that binds ERbeta and regulates OT containing neurons of the PVN. Furthermore, we hypothesize that this action is distinct from that found in females where estradiol is the ligand acting through ERalpha. Five specific aims are proposed. Aim 1 will identify the location and regulation of steroid metabolizing enzymes in neurons of the PVN that allow synthesis of 32-Diol. Aim 2 will use mouse models to test the hypothesis that locally synthesized 32-Diol acts upon ERbeta neurons in the PVN to inhibit HPA reactivity. Aim 3 will determine if ERbeta containing neurons regulate HPA axis function through local release of OT or extra-PVN oxytocinergic connections with limbic nuclei. Aim 4 will test the hypothesis that 32 Diol and ERbeta functionally interact with the oxytocin promoter in a ligand dependent fashion. Aim 5 will test the hypothesis that the nature of the ligand bound to ERbeta determines the assembly of co-regulatory factors recruited to target sites on the OT promoter. PUBLIC HEALTH RELEVANCE: Sex differences exist in the hormonal response of animals to physical and psychological stressors. These sex differences arise as a result of the actions of estrogen and androgen acting upon neural circuits within the hypothalamus. In this application we will test the hypothesis that the actions of testosterone act to inhibit neuroendocrine responses to stress through metabolism to 32-Diol and subsequent binding to estrogen receptor beta found in oxytocin neurons of the hypothalamus.

描述（由申请人提供）：该项目的长期目标是确定成人下丘脑-垂体-肾上腺（HPA）轴功能性别差异背后的神经生物学机制。在人类和动物中，HPA 反应性的性别差异已得到证实。与男性相比，女性在压力后表现出更强烈的 HPA 轴激活。我们的假设是，成人荷尔蒙应激反应的性别差异主要是睾酮 (T) 和雌激素 (E) 对 HPA 功能相反作用的结果。 HPA 轴的激活是动物对威胁体内平衡的环境扰动的基本反应。这些反应受到下丘脑室旁核 (PVN) 中合成和分泌促肾上腺皮质激素释放激素 (CRH) 的神经元的调节。其他 PVN 神经肽，例如加压素 (AVP) 和催产素 (OT)，在 PVN 水平调节 CRH 神经元的活性，并增强垂体前叶的 CRH 促分泌素活性。生殖类固醇 E 和 T 也可以调节应激反应。循环 E 增强应激激活的 ACTH 和 CORT 分泌。相反，T 会降低 HPA 轴的增益。已发表的初步数据表明，雄激素可以通过涉及雌激素受体β (ERbeta) 的新途径直接作用于雄性大鼠的PVN 神经元，而E 主要通过ERα 发挥作用。因此，我们假设在男性中，T 通过结合 ERbeta 的雄激素代谢物抑制 HPA 功能。这种新作用背后的神经生物学机制的线索可以从研究中获得，这些研究表明 ERbeta 在含有 OT 的 PVN 细胞中广泛共定位。因此，在本申请中，我们解决了睾酮通过代谢为结合 ERbeta 并调节含有 OT 的 PVN 神经元的化合物来抑制 HPA 反应性的可能性。此外，我们假设这种作用与女性中发现的作用不同，女性中雌二醇是通过 ERα 发挥作用的配体。提出了五个具体目标。目标 1 将确定 PVN 神经元中类固醇代谢酶的位置和调节，从而合成 32-二醇。目标 2 将使用小鼠模型来测试局部合成的 32-二醇作用于 PVN 中的 ERbeta 神经元以抑制 HPA 反应性的假设。目标 3 将确定含有 ERbeta 的神经元是否通过局部释放 OT 或与边缘核的 PVN 催产素连接来调节 HPA 轴功能。目标 4 将检验 32 Diol 和 ERbeta 以配体依赖性方式与催产素启动子功能性相互作用的假设。目标 5 将检验以下假设：与 ERbeta 结合的配体的性质决定了招募到 OT 启动子上靶位点的共调节因子的组装。公共卫生相关性：动物对身体和心理压力源的激素反应存在性别差异。这些性别差异是雌激素和雄激素作用于下丘脑内神经回路的结果。在本申请中，我们将测试以下假设：睾酮的作用是通过代谢为 32-二醇并随后与下丘脑催产素神经元中发现的雌激素受体β结合来抑制神经内分泌对压力的反应。