Neuroendocrine Mechanisms of Risk for Trauma-Related Psychopathology in Women

项目摘要 大多数美国人在一生中都会经历创伤性事件，但女性的比例是男性的两倍。 在创伤后，如创伤后应激反应， 创伤后应激障碍（PTSD）和抑郁症。女性患病率增加的原因尚不清楚，部分原因是 因为历史上在人类和临床前动物研究中缺乏对女性的研究。在 在这项研究中，我们将调查性激素在女性患创伤后应激障碍风险中的作用。的 性腺激素雌二醇（E2）以前与情绪调节和恐惧消退有关， 啮齿动物和健康人的研究，通过杏仁核和调节神经元之间的通路的可塑性介导， 前额叶皮层和海马体的输入。患有PTSD的女性在调节 情绪唤起和恐惧消退学习。我们将测试低E2有助于这些的假设 通过实验操作E2，并研究其对威胁反应性的fMRI测量的影响， 恐惧消失，在PTSD女性，没有PTSD的创伤暴露女性和健康对照组中。我们将使用 一项随机、双盲、安慰剂对照、受试者内交叉设计，给予E2/安慰剂， 自然周期的妇女在周期的早期卵泡阶段，当内源性E2最低。 参与者将在第一次MRI扫描时随机分配至E2或安慰剂组，并将交叉至另一种情况 在随后的月经周期的同一时间点进行第二次扫描。其次，鉴于现有 观察证据表明PTSD风险/症状在黄体期升高，我们将测试E2 在黄体期给药以观察E2-孕酮比率的增加是否减少PTSD 症状和损伤的威胁反应和恐惧灭绝在这个时候的高度风险。研究 埃默里大学医学院的环境将为成功的 完成拟议的研究，特别是最先进的神经成像设施，一个发达的 通过格雷迪创伤项目识别有创伤和创伤后应激障碍风险的参与者的基础设施，以及 强大的创伤、神经内分泌、神经成像和妇女健康研究专家社区。结果 这项研究可能有助于开发新的治疗和干预措施，以增加妇女的心理健康。 创伤后的健康状况。

Project Summary The majority of Americans will experience a traumatic event during their lifetimes, but women are twice as likely as men to experience negative psychiatric outcomes following trauma such as post-traumatic stress disorder (PTSD) and depression. The reason for the increased prevalence in women is unclear, partially because of the historical lack of investigation of females in both human and pre-clinical animal research. In the proposed research, we will investigate the role of sex hormones in contributing to women's risk for PTSD. The gonadal hormone estradiol (E2) has previously been associated with emotion regulation and fear extinction in rodent and healthy human studies, mediated by plasticity in pathways between the amygdala and regulatory inputs from the prefrontal cortex and hippocampus. Women with PTSD show clear deficits in regulating emotional arousal, and in fear extinction learning. We will test the hypothesis that low E2 contributes to these deficits by experimentally manipulating E2, and studying its effects on fMRI measures of threat reactivity and fear extinction, in women with PTSD, trauma-exposed women without PTSD, and healthy controls. We will use a randomized double-blind, placebo-controlled, within-subjects crossover design, with E2/placebo given to naturally-cycling women during the early follicular phase of the cycle when endogenous E2 is lowest. Participants will be randomized to E2 or placebo at the first MRI scan, and will cross over to the other condition for a second scan conducted at the same point in the subsequent menstrual cycle. Secondly, given existing observational evidence that PTSD risk/symptoms are heightened during the luteal phase, we will test this E2 administration in the luteal phase to observe whether an increase in the E2-progesterone ratio reduces PTSD symptoms and impairments in threat reactivity and fear extinction in this time of heightened risk. The research environment at Emory University School of Medicine will provide excellent support for the successful completion of the proposed research, particularly with state of the art neuroimaging facilities, a well-developed infrastructure for identifying participants at risk for trauma and PTSD through the Grady Trauma Project, and a strong community of experts in trauma, neuroendocrine, neuroimaging, and women's health research. Findings from this study may aid in the development of new treatments and interventions to increase women's mental health outcomes following trauma.