The impact of exogenous estradiol on fear extinction in healthy young women and those with PTSD

项目总结 对于这项F31计划，申请者将根据他们目前的技能来确定雌二醇(E2)的影响 在月经周期的早期黄体期对患有女性和女性恐惧消退的神经相关性的影响 没有创伤后应激障碍(PTSD)。女性被诊断为创伤后应激障碍的可能性是男性的两倍， 而那些患有创伤后应激障碍的人更有可能有恐惧消退障碍。雌二醇的自然波动一直是 与女性黄体早期焦虑、抑郁和创伤后应激障碍症状的增加有关， 当雌激素水平急剧下降时，研究表明患有创伤后应激障碍的女性的恐惧消退程度更大 与早期卵泡期相比，黄体早期至中期的营养不良。恐惧的消退是强有力的 怀疑受腹侧前额叶皮质(VmPFC)调节，恐惧条件反射受 杏仁核。低雌二醇水平和创伤后应激障碍分别与vmPFC血氧减少相关。 水平依赖的(BOLD)活动和vmPFC和杏仁核之间较低的功能连接。然而， 我们还不知道雌二醇管理如何影响患有和不患有雌激素症的女性的恐惧消退和大胆活动。 黄体早期的PTSD。根据先前的发现，我们假设在早期服用雌二醇 与安慰剂相比，黄体期会增加恐惧消退。为了验证这一中心假设，我们将利用 功能磁共振成像(FMRI)的vmPFC和杏仁核，以确定如何外源性的E2 在黄体早期影响健康妇女的恐惧消退(目标1)。然后我们将确定影响 与对照组相比，外源性E2对PTSD妇女黄体期恐惧消退的影响(目标2)。 VMPFC感兴趣区域(ROI)分析和功能连通性分析将用于目标1和2， 皮肤电导被用作心理生理恐惧条件反射的衡量标准。为了探索物种灭绝- 在vmPFC和杏仁核内的相关可塑性，我们将对收集到的 来自对照组和创伤后应激障碍参与者的fMRI数据(探索性目标3)。先前的文献已经显示出 VmPFC内的激活可以区分创伤后应激障碍和对照组。这将提供一个因果关系的检验 雌二醇对黄体早期女性恐惧消退的影响 支持退出E2会产生恐惧消退缺陷并可能对创伤后应激障碍产生负面影响的观点 症状。这些发现可能为经历过这种情况的女性提供未来可能的治疗途径 创伤性事件。为了获得神经影像、神经内分泌学、心理生理学和临床方面的专业知识 研究，申请者的培训将包括来自以下专家团队的指导研究的组合 菲尔德和参观另一个研究创伤和创伤后应激障碍的实验室，以及课程作业、研讨会和参加 国内和国际会议。本提案旨在提供一种有指导的研究体验 申请人将不会以其他方式接受和促进独立研究事业的发展 神经成像和神经科学。

PROJECT SUMMARY For this F31 proposal, the applicant will build upon their current skills to determine the influence of estradiol (E2) during the early luteal phase of the menstrual cycle on neural correlates of fear extinction in women with and without Post Traumatic Stress Disorder (PTSD). Women are twice as likely as men to be diagnosed with PTSD, and those with PTSD are more likely to have fear extinction impairments. Natural fluctuations of E2 have been associated with an increase in anxiety, depression, and PTSD symptoms in women during the early luteal phase, when there is a sharp decrease in E2, and it has been shown women with PTSD have the greater fear extinction deficits during the early- to mid-luteal phase, compared to the early follicular phase. Fear extinction is strongly suspected to be regulated by the ventral medial prefrontal cortex (vmPFC), with fear conditioning regulated by the amygdala. Both low E2 levels and PTSD are individually correlated with reduced vmPFC blood-oxygenation- level-dependent (BOLD) activity and lower functional connectivity between the vmPFC and amygdala. However, we do not yet know how E2 administration impacts fear extinction and BOLD activity in women with and without PTSD during the early luteal phase. Given prior findings, we hypothesize that E2 administration during the early luteal phase will increase fear extinction compared to placebo. To test this central hypothesis, we will utilize functional magnetic resonance imaging (fMRI) of the vmPFC and amygdala to determine how exogenous E2 during the early luteal phase impacts fear extinction in healthy women (Aim 1). We will then determine the effects of exogenous E2 on fear extinction during the luteal phase in women with PTSD compared to controls (Aim 2). vmPFC Region of Interest (ROI) analysis and functional connectivity analysis will be utilized for Aim 1 and 2, with skin conductance utilized as a measure of psychophysiological fear conditioning. To explore extinction- related plasticity within the vmPFC and amygdala, we will perform multivariate pattern analysis on the collected fMRI data from control and PTSD participants (Exploratory Aim 3). Prior literature has shown patterns of activation within the vmPFC differentiate those with PTSD and controls. This will provide a test of the causal influence of E2 on fear extinction in women during the early luteal phase when E2 sharply declines, providing support for the idea that withdrawal from E2 produces fear extinction deficits and can negatively impact PTSD symptoms. Such findings may provide an avenue of future possible treatment for women who have experienced traumatic events. In order to gain expertise in neuroimaging, neuroendocrinology, psychophysiology, and clinical research, the applicant’s training will include a combination of mentored research from a team of experts in these fields and a visit to another lab studying trauma and PTSD, as well as coursework, seminars, and attendance at national and international conferences. This proposal is designed to provide a mentored research experience the applicant would not otherwise receive and facilitate the development of an independent research career in neuroimaging and neuroscience.