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 nat...