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

项目摘要 对于本F31提案，申请人将利用其现有技能确定雌二醇（E2）的影响 在月经周期的早期黄体期， 没有创伤后应激障碍（PTSD）。女性被诊断为PTSD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出现恐惧消退障碍。E2的自然波动 与黄体早期妇女焦虑、抑郁和创伤后应激障碍症状的增加有关， 当E2急剧下降时，已经表明患有PTSD的女性有更大的恐惧消退， 与卵泡早期相比，在黄体早期至中期出现缺陷。恐惧消失是强烈的 怀疑是由腹内侧前额叶皮层（vmPFC）调节，恐惧条件反射由 杏仁核低E2水平和创伤后应激障碍都与vmPFC血氧减少相关- 水平依赖性（BOLD）活动和较低的功能连接之间的vmPFC和杏仁核。然而，在这方面， 我们还不知道E2管理如何影响恐惧消退和BOLD活动的妇女和没有 早期黄体期的创伤后应激障碍。鉴于先前的发现，我们假设在早期给予E2， 与安慰剂相比，黄体期将增加恐惧消退。为了验证这个核心假设，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E2 在黄体早期影响健康女性的恐惧消退（目标1）。然后我们将确定 与对照组相比，外源性E2对PTSD女性黄体期恐惧消退的影响（目的2）。 vmPFC感兴趣区域（ROI）分析和功能连接性分析将用于目标1和2， 其中皮肤电导用作心理生理恐惧条件反射的量度。去探索物种灭绝- 相关的可塑性在vmPFC和杏仁核，我们将进行多变量模式分析，收集 来自对照组和PTSD参与者的fMRI数据（探索性目标3）。先前的文献显示了 VMPFC内的激活区分PTSD患者和对照组。这将提供一个因果关系的测试 E2对女性在黄体早期E2急剧下降时恐惧消退的影响，提供了 支持从E2中退出会产生恐惧消退缺陷，并对PTSD产生负面影响的观点 症状这些发现可能为那些经历过癌症的女性提供一种未来可能的治疗途径。 创伤性事件为了获得神经影像学，神经内分泌学，心理生理学和临床 研究，申请人的培训将包括来自这些领域的专家团队的指导研究的组合 领域和访问另一个实验室研究创伤和创伤后应激障碍，以及课程，研讨会，并出席 国家和国际会议。该提案旨在提供一个指导性的研究经验 申请人将不会以其他方式获得和促进独立的研究生涯的发展， 神经影像学和神经科学。

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.