Androgen Regulation of CRF Receptor 1 as a mediator of stress responses

雄激素对 CRF 受体 1 的调节作为应激反应的调节剂

基本信息

批准号：
10724308
负责人：
Damian Gabriel Zuloaga
金额：
$ 15.65万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-08-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10724308
关键词：
Adrenal Glands Affect Aging Androgen Receptor Androgens Anhedonia Anxiety Anxiety Disorders Behavior Behavioral Brain region CRF receptor type 1 Cells Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Data Development Disease Experimental Designs Functional disorder Future Glucocorticoids Goals Gonadal Hormones Hormones Human Hypothalamic structure Individual Injections Knowledge Laboratories Mediator Mental Depression Moods Motivation Mus Neurobiology Neurons Neurosecretory Systems Pattern Phenotype Pituitary Gland Play Population Prevalence Regulation Reporting Research Rodent Role Self Care Sex Differences Signal Transduction Site Stress Structure of terminal stria nuclei of preoptic region Testing Virus Woman Work anxiety treatment behavioral response biological adaptation to stress brain cell brain circuitry cell type combat depressive symptoms design experimental study hypothalamic-pituitary-adrenal axis knock-down men neural circuit neuromechanism nonhuman primate overexpression response sex

项目摘要

Project Summary There are striking sex differences in stress/mood associated disorders, such as anxiety and depression with women showing 2-3 fold greater prevalence than men. These differences are believed to be regulated by sex- specific patterns of gonadal hormone exposure and their subsequent effects on brain circuitry. In particular, androgen actions through the cognate androgen receptor (AR) have been shown by our lab and others to suppress the release of stress hormones and decrease stress-related behaviors associated with anxiety and depression. However, the specific neural mechanisms through which androgens act to produce these effects remain largely unknown. Recent studies in our laboratory and others have demonstrated that cells expressing corticotropin releasing factor receptor 1 (CRFR1) are likely critical for androgen regulation of stress responses. CRF signaling through CRFR1 is widely known to regulate anxiety- and depressive-like behaviors as well as activation of the hypothalamic pituitary adrenal (HPA) axis which controls stress hormone (e.g. glucocorticoid) secretion. Our laboratory has demonstrated high levels of AR within CRFR1 neurons in key stress regulating brain regions in the mouse that have previously been implicated as sites for androgen regulation of stress functions ((paraventricular hypothalamus (PVN) and ventral bed nucleus of the stria terminalis (BSTv)). We propose to determine the role of AR, specifically within CRFR1 neurons of the PVN and BSTv, in regulating stress-associated behaviors and the HPA axis. This will be accomplished using a Cre mouse line and viruses designed to knockdown or overexpress AR within Cre-expressing neurons. Overall, we expect these studies will identify critical cell groups that regulate stress-related functions, thus aiding in our understanding of the neurobiological roots of related human disorders, including depression and anxiety.

项目摘要压力/情绪相关的疾病存在明显的性别差异，例如焦虑和抑郁症妇女表现出比男性高2-3倍的患病率。这些差异被认为受性别调节 - 性腺激素暴露的特定模式及其随后对脑电路的影响。尤其，我们的实验室已经显示了通过同源雄激素受体（AR）的雄激素作用抑制压力激素的释放，并减少与焦虑相关的压力相关行为沮丧。但是，雄激素作用产生这些作用的特定神经机制在很大程度上未知。在我们的实验室和其他研究中的最新研究表明，表达的细胞皮质激素释放因子受体1（CRFR1）可能对雄激素调节胁迫反应至关重要。 CRF通过CRFR1的信号传导众所周知，可以调节焦虑和抑郁样行为以及控制应激激素（例如糖皮质激素）的下丘脑垂体肾上腺（HPA）轴的激活分泌。我们的实验室在CRFR1神经元中显示了高水平的AR，在调节关键应力下小鼠中的大脑区域以前被认为是应激的雄激素调节位点函数（（（旁丘脑下丘脑（PVN）和腹膜末端的腹床核（BSTV））。我们建议确定AR的作用，特别是在PVN和BSTV的CRFR1神经元中的作用，在调节中应力相关行为和HPA轴。这将使用CRE鼠标线和病毒来完成旨在在表达CRE的神经元内敲低或过表达AR。总的来说，我们希望这些研究将确定调节压力相关功能的关键细胞组，从而有助于我们对相关人类疾病的神经生物学根源，包括抑郁和焦虑。