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一次创伤性事件，但女性的比例是女性的两倍 男性在创伤后可能会经历负面的精神后果，如创伤后应激障碍 精神障碍(PTSD)和抑郁。女性患病率增加的部分原因尚不清楚 因为在人类和临床前的动物研究中，历来缺乏对女性的调查。在 在拟议的研究中，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。这个 性腺激素雌二醇(E2)以前被认为与情绪调节和恐惧消退有关 啮齿动物和健康人的研究，由杏仁核和调节性通路之间的可塑性介导 来自前额叶皮质和海马体的输入。患有创伤后应激障碍的女性表现出明显的调节缺陷 情绪唤醒，并在恐惧中消亡学习。我们将检验这样的假设，即低雌二醇对这些 通过实验操作E2，并研究其对威胁反应性和功能磁共振测量的影响 在患有创伤后应激障碍的女性、没有创伤后应激障碍的创伤暴露女性和健康对照组中，恐惧消退。我们将使用 这是一项随机双盲、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，此时内源性雌二醇水平最低。 参与者将在第一次MRI扫描时被随机分为E2组或安慰剂组，并将交叉进入另一种情况 在随后的月经周期的同一时间点进行第二次扫描。其次，鉴于现有的 观察证据表明，PTSD风险/症状在黄体期升高，我们将测试这个E2 黄体期给药观察雌二醇孕酮比率增加是否可降低PTSD 在这种高风险时期，威胁、反应和恐惧消退方面的症状和损害。这项研究 埃默里大学医学院的环境将为成功的 完成拟议的研究，特别是拥有最先进的神经成像设施，一个完善的 通过格雷迪创伤项目确定有创伤和创伤后应激障碍风险的参与者的基础设施，以及 创伤、神经内分泌、神经成像和妇女健康研究方面的专家组成的强大社区。发现 这项研究可能有助于开发新的治疗方法和干预措施，以提高妇女的智力 创伤后的健康后果。

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.