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

• 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
• 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

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 在压力/情绪相关疾病方面存在显著的性别差异，例如焦虑和抑郁， 妇女的患病率比男子高2-3倍。这些差异被认为是由性别调节的- 性激素暴露的特定模式及其对大脑回路的后续影响。特别是， 雄激素通过同源雄激素受体（AR）的作用已经被我们的实验室和其他人证明， 抑制压力荷尔蒙的释放，减少与焦虑有关的压力相关行为， 萧条然而，雄激素产生这些作用的具体神经机制 但基本上仍不为人所知。我们实验室和其他实验室最近的研究表明，表达 促肾上腺皮质激素释放因子受体1（CRFR 1）可能对雄激素调节应激反应至关重要。 众所周知，通过CRFR 1的CRF信号传导调节焦虑和抑郁样行为， 控制应激激素（如糖皮质激素）的下丘脑垂体肾上腺（HPA）轴的激活 分泌物。我们的实验室已经证明了CRFR 1神经元内高水平的AR在关键的应激调节中的作用。 小鼠的脑区，以前被认为是雄激素调节应激的部位 功能（室旁下丘脑（PVN）和终纹腹侧床核（BSTv））。我们 建议确定AR的作用，特别是在PVN和BSTv的CRFR 1神经元内， 压力相关行为和HPA轴。这将使用Cre小鼠系和病毒来完成 其被设计为在表达Cre的神经元内敲低或过表达AR。总的来说，我们预计这些研究将 确定调节压力相关功能的关键细胞群，从而帮助我们理解 相关人类疾病的神经生物学根源，包括抑郁和焦虑。