Sex Differences in Hypothalamo-Pituitary-Adrenal Axis

下丘脑-垂体-肾上腺轴的性别差异

基本信息

批准号：
7664679
负责人：
Robert J Handa
金额：
$ 11.38万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7664679
关键词：
3-Hydroxysteroid Dehydrogenase Inhibitor Address Adrenal Glands Adult Androgen Receptor Androgens Androstanes Animals Anterior Hypothalamus Antibodies Aromatase Binding Biological Assay Cells Corticosterone Corticotropin Corticotropin-Releasing Hormone Coupled Data Enzymes Estrogen Receptor beta Estrogens Exhibits Female Finasteride Future Glucocorticoid Receptor Glucocorticoids Glycol Goals Homeostasis Hormonal Human Hydroxysteroid Dehydrogenases Hypothalamic structure In Situ Hybridization Ligand Binding Ligands Messenger RNA Metabolism Neurons Neuropeptide Gene Neuropeptides Neurosecretory Systems Neurotransmitter Receptor Oligonucleotides Operative Surgical Procedures Output Oxytocin Pathway interactions Pituitary Gland Pituitary-Adrenal System Population Proteins RNA Splicing Rattus Regulation Reporter Reporter Genes Reverse Transcriptase Polymerase Chain Reaction Sex Characteristics Stanolone Steroids Stress Testing Testosterone Testosterone 5-alpha-Reductase Trilostane Variant Vasopressins androstane biological adaptation to stress cholestenone 5 alpha-reductase chromatin immunoprecipitation hormone regulation inhibitor/antagonist male neural circuit neurobiological mechanism novel paraventricular nucleus prevent promoter receptor expression receptor function reproductive response sex

项目摘要

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to determine the neurobiological mechanisms that underlie sex differences in the function of the 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 these sex differences in adult hormonal stress responses are largely 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. Neuroendocrine stress responses are controlled by neurons residing in the paraventricular n. of the hypothalamus (PVN). These neurons synthesize and secrete corticotropin-releasing hormone (CRH). Other neuropeptides, such as vasopressin (AVP) and oxytocin (OXY) are also synthesized by PVN neurons and act to modulate the actions of CRH. Thus, neurons in the PVN function as an integratory node, coordinating both excitatory and inhibitory inputs to produce a tightly controlled output. E and T have also been shown to modulate stress responses. In females, E enhances stress activated ACTH and CORT secretion, in part through direct action on neuropeptide neurons in the PVN. In males, T decreases the gain of the HPA axis. Although androgen receptors are NOT found in neuroendocrine neurons of the PVN, our data show that androgens can inhibit PVN neuron function through a novel pathway. Accordingly, within the male PVN, T may be metabolized to 5alpha-androstane-3beta, 17beta-diol (3beta-diol) which can bind ERbeta and potently inhibit the activity of PVN neurons. In this application we will address the possibility that ER-beta is a dual function receptor which can act to both activate and inhibit neuropeptide components of the HPA depending on the available ligand. This switch also depends on the splice variant of ERbeta expressed. To address this, we will determine 1) the splice variant population and their hormone regulation in neuropeptide neurons of the PVN. 2) The interactions of ERbeta variants with E and 3beta-diol in the regulation of the CRH promoter. 3) We will determine if appropriate androgen metabolizing enzymes are found in PVN neurons and 4) we will determine if this pathway acts through ERbeta to regulate HPA function. Studies described in this application will focus on the function of ER-beta in PVN neurons, however, they will also provide information necessary for directing future studies examining the neural circuitry regulating HPA reactivity.

描述（由申请人提供）：该提案的长期目标是确定下丘脑-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中的这些性别差异很大程度上是睾酮 (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。神经内分泌应激反应由位于室旁神经元控制。下丘脑 (PVN)。这些神经元合成并分泌促肾上腺皮质激素释放激素（CRH）。其他神经肽，如加压素 (AVP) 和催产素 (OXY) 也由 PVN 神经元合成，并起到调节 CRH 作用的作用。因此，PVN 中的神经元充当整合节点，协调兴奋性和抑制性输入以产生严格控制的输出。 E 和 T 也被证明可以调节应激反应。在女性中，E 可以部分通过直接作用于 PVN 中的神经肽神经元来增强应激激活的 ACTH 和 CORT 分泌。在男性中，T 会降低 HPA 轴的增益。尽管在 PVN 的神经内分泌神经元中未发现雄激素受体，但我们的数据表明雄激素可以通过一种新的途径抑制 PVN 神经元功能。因此，在雄性PVN内，T可代谢为5α-雄甾烷-3β、17β-二醇(3β-二醇)，其可结合ERbeta并有效抑制PVN神经元的活性。在本申请中，我们将解决 ER-β 是一种双重功能受体的可能性，它可以根据可用的配体激活和抑制 HPA 的神经肽成分。该开关还取决于表达的 ERbeta 剪接变体。为了解决这个问题，我们将确定 1) PVN 神经肽神经元中的剪接变体群体及其激素调节。 2) ERbeta 变体与 E 和 3beta-二醇在 CRH 启动子调节中的相互作用。 3) 我们将确定在 PVN 神经元中是否发现适当的雄激素代谢酶，4) 我们将确定该途径是否通过 ERbeta 发挥作用来调节 HPA 功能。本申请中描述的研究将重点关注 PVN 神经元中 ER-β 的功能，然而，它们还将提供指导未来检查调节 HPA 反应性的神经回路的研究所需的信息。