Using Tools in Translational Neuroscience to Study Sex-linked Factors Related to PTSD Risk

项目摘要 创伤后应激障碍（PTSD）是一种适应不良和衰弱的精神障碍， 暴露在创伤事件中发展PTSD的不同风险是多因素决定的，但部分 这取决于性别，女性的风险大约是男性的两倍。由于创伤后应激障碍的性别差异 在控制了环境因素（如创伤暴露类型）后， 迫切需要了解与女性创伤后应激障碍脆弱性相关的生物因素。我们的长期目标是 使用心理生理学中的翻译工具，以更好地了解生物因素， 女性患创伤后应激障碍的风险恐惧学习过程的发病机制和维护的基础， 创伤后应激障碍和恐惧消退过程模型暴露疗法-创伤后应激障碍的关键治疗。越来越多的证据 指出性激素，雌激素，在女性创伤后应激障碍风险增加中的重要作用， 对恐惧学习和消退的调节作用。然而，临床前研究一直缺乏 检查与性别有关的变量，如女性生殖周期和波动的雌激素水平， 实验室恐惧条件反射模型此外，人们对另一种关键性激素的作用知之甚少， 孕酮，在这些过程中。甚至更少的研究检查激素避孕（HC）的影响， 这是一个关键的研究领域，因为有证据表明，美国85%的女性将在2020年的某个时候使用HC。 他们的一生。因此，现有的关于与恐惧学习相关的性连锁因素的研究的临床翻译 记忆仍然不清楚。对于我们的目标1，我们将通过检查调节作用来解决这些关键差距 雌二醇和孕酮对自然骑自行车的女性的恐惧学习和消退过程的影响 与使用HC的女性相比。除了适应不良的恐惧学习和记忆，创伤后应激障碍一直是 以过度概括创伤相关刺激或情况为特征，这可能导致持续的焦虑 非特定的威胁。虽然性别差异已被探索在恐惧条件反射到一个特定的威胁， 利用动物模型对非特异性威胁的焦虑进行性别差异的研究则少之又少。同时， 在这些模型中，PTSD中压力和性激素调节的作用还没有得到很好的理解。我们的目标2将解决 通过首次确定性激素与 水平和黑暗增强惊吓-一个实验室模型的焦虑，以一个非特异性的威胁-在妇女在不同的 与使用激素避孕药的女性和男性相比，女性在月经周期的各个阶段。基于先验 研究和我们自己的初步数据，我们的中心假设是，性腺激素水平将赋予 减少恐惧或恢复能力（当水平高时）或增加恐惧或脆弱性（当水平低时） 在条件性恐惧和焦虑中，这可能部分解释了妇女风险不成比例的原因。通过使用 PTSD的转化动物模型来解决这些关键的科学空白，这项拟议的研究可以产生 临床上有用的见解，为女性PTSD的更有效干预和治疗结果提供信息。

PROJECT SUMMARY Posttraumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder precipitated by exposure to a traumatic event. The differential risk for developing PTSD is multi-determined, but in part depends on sex, with women having approximately twice the risk as men. Since sex disparities in PTSD prevalence remain after controlling for environmental factors, such as the type of trauma exposure, there is a critical need to understand biological factors associated with female PTSD vulnerability. Our long-term goal is to use translational tools in psychophysiology to gain better insight into biological factors contributing to heightened PTSD risk in women. Fear learning processes underlie the pathogenesis and maintenance of PTSD, and fear extinction processes model exposure therapy – a key treatment for PTSD. Growing evidence points to an important role of the sex hormone, estrogen, in women's heightened PTSD risk through its modulatory effects on fear learning and extinction. Yet, there is a historical dearth of preclinical research examining sex-related variables, such as the female reproductive cycle and fluctuating estrogen levels, in laboratory fear conditioning models. Also, little is known about the role of another key sex hormone, progesterone, on these processes. Even fewer studies examined hormonal contraceptive (HC) effects, a critical area of study, given evidence that 85% of women in the United States will use HCs at some point in their lifetime. Hence, the clinical translation of existing research on sex-linked factors related to fear learning and memory remain unclear. For our Aim 1, we will address these critical gaps by examining modulating roles of estradiol and progesterone on fear learning and extinction processes among naturally cycling women compared to women using HCs. In addition to maladaptive fear learning and memory, PTSD has been characterized by overgeneralization of trauma-related stimuli or situations, which may lead to sustained anxiety to nonspecific threats. While sex differences have been explored in fear conditioning to a specific threat, there is far less research on sex differences using animal models of anxiety to nonspecific threat. Also, the interplay of stress and sex hormone modulation in PTSD is not well understood in these models. Our Aim 2 will address this enormous gap in the literature by determining for the first time the relationship between sex hormone levels and dark-enhanced startle – a laboratory model of anxiety to a nonspecific threat – in women at varying stages of their menstrual cycle compared to women using hormonal contraceptives and men. Based on prior research and our own preliminary data, our central hypothesis is that gonadal hormone levels will confer either reduced fear or resiliency (when levels are high) or heightened fear or vulnerability (when levels are low) in conditioned fear and anxiety, which may partially explain disproportionate risk among women. By using translational animal models of PTSD to address these critical scientific gaps, this proposed study could yield clinically useful insights that inform more effective intervention and treatment outcomes for PTSD in women.