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

项目摘要 在压力/情绪相关的障碍方面，如焦虑和抑郁，存在显著的性别差异 女性的患病率是男性的2-3倍。这些差异被认为是由性别决定的-- 性腺激素暴露的特定模式及其对大脑回路的后续影响。特别是， 我们的实验室和其他实验室已经证明，雄激素通过同源雄激素受体(AR)发挥作用 抑制应激激素的释放，减少与焦虑和焦虑有关的应激相关行为 抑郁症。然而，雄激素产生这些效应的具体神经机制 在很大程度上仍然不为人知。我们实验室和其他实验室最近的研究表明，细胞表达 促肾上腺皮质激素释放因子受体1(CRFR1)可能是雄激素调节应激反应的关键。 众所周知，CRF通过CRFR1信号调节焦虑和抑郁样行为以及 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CRFR1神经元中高水平的AR参与关键的应激调节 小鼠大脑中先前被认为是雄激素调节应激部位的区域 功能(下丘脑室旁核(PVN)和终纹腹床核(BSTv))。我们 建议确定AR，特别是在PVN和BSTv的CRFR1神经元中的调节作用 应激相关行为和HPA轴。这将使用CRE鼠系和病毒来完成 被设计为在表达CRE的神经元中抑制或过度表达AR。总体而言，我们预计这些研究将 识别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。

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.