Sex Differences in Stress Receptors Underlie Female Vulnerability to Stress

与压力有关的精神障碍，如抑郁症和创伤后应激障碍， 女性患精神疾病的人数是男性的两倍。尽管这种差异的病因仍然存在 未知，这被认为是由于压力反应的性别差异。促肾上腺皮质激素释放因子 协调应激反应，部分是通过调节去甲肾上腺素（NE）和5-羟色胺（5-HT）的传递， CRF在应激相关疾病中失调。我目前研究的目标是 CRF（CRF 1亚型）受体的差异可能解释了应激反应的性别差异。 到目前为止，我发现CRF 1在雌性大鼠中以不同的方式发出信号和被贩运，这种方式可以解释 对急性压力的反应增强，对慢性压力的适应减弱。在女性中，CRF 1 免疫沉淀揭示了更大的耦合到Gs，GTP结合蛋白，介导大多数细胞 应答此外，应激诱导的CRF 1与<$-arrestin 2相关，这是受体表达的一个组成步骤。 内化，在男性中很明显，但在女性中不明显。免疫电镜证实了应激诱导的 CRF 1的内化只在雄性大鼠，这表明这种适应性过程，以弥补大量的 在抑郁症中可能释放的CRF在女性中受到损害。重要的是，CRF 1的性别差异 功能使雌性大鼠蓝斑中的NE神经元对低水平的CRF更敏感， 对高水平的通用报告格式适应性较差。然而，因为这是第一份关于压力性别差异的报告- 与神经肽受体相关，许多问题仍然没有答案。本提案的目标1将是 在指导阶段（K99）完成，调查为什么CRF 1在男性与女性中结合蛋白质的方式不同。 女性CRF 1结构没有性别差异，所以我将学习蛋白质组学方法来鉴定 CRF 1翻译后修饰的性别差异是否是这些效应的原因。目标2和3将 在独立阶段完成。目标2将确定有助于性的激素 CRF 1的差异。为此，我将联合收割机以前获得的内分泌技术与所学的技能相结合 在K99阶段，以确定是否卵巢或睾丸激素建立性别差异。目标3 将评估性别差异是否延伸到中缝背核中的其他受体亚型CRF 2。 由于CRF 1和CRF 2具有高度的序列同一性，因此蛋白质组学方法有望 显示CRF 2中的性别差异。中缝背核-5-HT系统的CRF 2激活促进了被动的 对压力的行为反应策略是抑郁症的危险因素。因此，CRF 2的性别差异可能 导致女性更容易患上这种疾病。通过解决这些问题，本提案 将有助于阐明压力相关疾病的性别差异的病因。此外，由于CRF 考虑到CRF受体的性别差异可能 增加这些化合物在女性中的功效。

Stress-related psychiatric disorders, like depression and post-traumatic stress disorder, are debilitating mental illnesses that affect twice as many women as men. Although the etiology of this disparity remains unknown, it is thought to be due to sex differences in stress responses. Corticotropin-releasing factor (CRF) orchestrates stress responses, in part, by regulating norepinephrine (NE) and serotonin (5-HT) transmission, and CRF is dysregulated in stress-related disorders. The goal of my current research is to identify sex differences in a receptor for CRF (CRF1 subtype) that may account for sex differences in stress responsivity. To date, I found that CRF1 signals and is trafficked differently in female rats in a manner that can account for elevated responses to acute stress and decreased adaptation to chronic stress. In females, CRF1 immunoprecipitation revealed a greater coupling to Gs, the GTP-binding protein that mediates most cellular responses. Additionally, stress-induced CRF1 association with ¿-arrestin2, an integral step in receptor internalization, was apparent in males but not females. Immunoelectron microscopy confirmed stress-induced CRF1 internalization in male rats only, suggesting that this adaptive process to compensate for large amounts of CRF, as may be released in depression, is compromised in females. Importantly, sex differences in CRF1 function rendered NE neurons in the locus coeruleus of female rats more sensitive to low levels of CRF and less adaptable to high levels of CRF. However, because this is the first report of sex differences in stress- related neuropeptide receptor, many questions remain unanswered. Aim 1 of this proposal, which will be completed during the mentored phase (K99), investigates why CRF1 binds proteins differently in males vs. females. There are no sex differences in CRF1 structure, so I will learn proteomic approaches to identify whether sex differences in post-translational modifications of CRF1 account for these effects. Aims 2 and 3 will be completed during the independent phase. Aim 2 will identify the hormones that contribute to the sex difference in CRF1. To this end, I will combine previously acquired endocrine techniques with the skills learned during the K99 phase to determine whether ovarian or testicular hormones establish the sex differences. Aim 3 will evaluate whether sex differences extend to the other receptor subtype, CRF2, in the dorsal raphe nucleus. Because CRF1 and CRF2 share a high degree of sequence identity, proteomic approaches are expected to reveal sex differences in the CRF2. CRF2 activation of the dorsal raphe-5-HT system promotes a passive behavioral response strategy to stress that is a risk factor for depression. Thus, sex differences in CRF2 may contribute to the increased vulnerability of females this disorder. By addressing these questions, this proposal will help elucidate the etiology of sex differences in stress-related disorders. Moreover, because CRF antagonists are being developed to treat these illnesses, considering sex differences in CRF receptors may increase the efficacy of these compounds in women.