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

项目总结 创伤后应激障碍(PTSD)是一种适应不良和衰弱的精神障碍，由 暴露在创伤性事件中。患创伤后应激障碍的不同风险是多方面决定的，但部分是 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中的性别差异 在控制了环境因素后，患病率仍然存在，例如创伤暴露的类型，存在 迫切需要了解与女性创伤后应激障碍易感性相关的生物学因素。我们的长期目标是 在心理生理学中使用翻译工具，以更好地洞察促成因素的生物 增加女性创伤后应激障碍的风险。恐惧学习过程是导致和维持 创伤后应激障碍和恐惧消退过程是暴露疗法的典范--这是创伤后应激障碍的关键治疗方法。越来越多的证据 指出了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、学习和消亡的调节作用。然而，临床前研究历来匮乏。 检验性相关变量，如女性生殖周期和波动的雌激素水平， 实验室恐惧条件作用模型。此外，人们对另一种关键性激素的作用知之甚少， 黄体酮，在这些过程中。更少的研究考察了荷尔蒙避孕(HC)的影响，a 关键研究领域，有证据表明，美国85%的女性将在#年的某个时候使用HCS 他们的一生。因此，对现有的与恐惧学习相关的性别相关因素的研究进行临床翻译 记忆仍不明朗。对于我们的目标1，我们将通过检查调节角色来解决这些关键差距 雌激素和黄体酮对自然骑自行车女性恐惧学习和消退过程的影响 与使用HCS的女性相比。除了适应不良的恐惧学习和记忆外，创伤后应激障碍 以过度泛化与创伤相关的刺激或情况为特征的，这可能导致持续的焦虑 对非特定的威胁。虽然性别差异在对特定威胁的恐惧条件反射方面进行了探索，但 使用动物焦虑模型对非特定威胁进行性别差异的研究要少得多。另外，这种相互作用 在这些模型中，压力和性激素调节在创伤后应激障碍中的作用还不是很清楚。我们的目标2将解决 通过首次确定性激素与性激素之间的关系，这一巨大的文献差距 水平和黑暗增强的惊吓-对非特定威胁的焦虑的实验室模型-在不同的女性中 与使用荷尔蒙避孕药的女性和男性相比，他们的月经周期不同阶段。基于之前的 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(当水平较高时)或增加恐惧或脆弱性(当水平较低时) 在条件恐惧和焦虑中，这可能部分解释了女性中不成比例的风险。通过使用 创伤后应激障碍的翻译动物模型为了解决这些关键的科学空白，这项拟议的研究可能会产生 临床上有用的见解，为女性创伤后应激障碍提供更有效的干预和治疗结果。

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.