The goal of this project is to characterize sex differences in mechanisms of fear extinction learning and retention that may account for differences in vulnerability for Posttraumatic Stress Disorder (PTSD) in women versus men. A mechanism proposed to account for recovery from traumatic stress is variability in the extinction of conditioned fear. While several studies have examined sex differences in fear conditioning and extinction in healthy individuals, it is notable that few studies have systematically examined sex differences in these measures in individuals with PTSD, which may represent a more vulnerable group. Our pilot data of individuals with PTSD suggest that women have increased fear conditioning and decreased extinction learning and recall, which may provide a mechanism that could explain the epidemiological findings. Another promising discovery that may explain differential vulnerability in some women is related to the peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), which is a regulator of the stress response. Higher levels of PACAP have been associated with greater fear conditioning and PTSD presence and severity in women, but not men. Furthermore, estrogen modulates PACAP and has also been associated with enhanced extinction retention. However, PACAP has not been studied for potential effects on extinction. We propose to conduct a laboratory study of fear conditioning in male and female veterans with and without PTSD to establish whether there are sex differences in fear extinction learning and retention in PTSD. This study will also examine the role of PACAP in explaining PTSD group and sex differences in extinction ability. We will recruit medically healthy trauma-exposed PTSD+ and PTSD- male and pre-menopausal female veterans for participation in this study (n=108). Four age-matched groups (n=27 per group) will consist of: 1) PTSD+ female veterans;2) PTSD- female veterans;3) PTSD+ male veterans;4) PTSD- male veterans. Participants will be trained in a 10-day fear conditioning task. On Day 1, they will be presented with computer- generated neutral images that are paired (CS+) or unpaired (CS-) with a mild electrical shock (US) and skin conductance responses will be assessed throughout. On Day 4, participants will undergo extinction training, in which they will be shown the images but will not receive shock. Participants will return on Day 11 for an evaluation of the durability of extinction. Blood samples will be drawn prior to each session to assess for levels of PACAP and estrogen. We predict that PTSD participants will have decreased fear extinction learning and retention compared to participants without PTSD. We also predict that men will have greater fear extinction learning and retention compared to women. Women with PTSD will have decreased extinction learning and retention compared to women without PTSD and men. We also predict that PACAP will be associated with decreased extinction learning and retention in women, but not in men. Among women, PACAP levels will be higher in PTSD+ participants compared to PTSD- participants. We will also explore whether lower PACAP accompanied by higher estrogen will be associated with greater extinction learning and retention. The ultimate goal of this research is to characterize sex differences in fear extinction processes in order to advance the identification of the pathophysiology of PTSD that may vary by sex and may be influenced by PACAP and sex hormones.

Public Health Relevance

Women comprise the fastest growing group of Veterans and are deployed to conflicts around the world more than ever before. Data suggests that women are twice as likely to develop Posttraumatic Stress Disorder (PTSD) than men, despite greater trauma exposure in men. Given the rapidly expanding cohort of women veterans who will require treatment for PTSD, it is critical that research be expanded to include women veterans and to identify underlying mechanisms of risk and resilience for PTSD that may differ by sex. The proposed study will characterize sex differences in fear extinction, a core mechanism of PTSD, which may account for the higher prevalence of PTSD in women. Additional aims include examining candidate biomarkers that have a sex-specific association with fear extinction and PTSD that may explain the differential risk. This research will advance our understanding of the pathophysiology of PTSD, ultimately leading to better-targeted, more efficient and effective treatments that can improve the lives of men and women veterans with PTSD.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Mental Health and Behavioral Science A (MHBA)
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Veterans Affairs Medical Center San Francisco
San Francisco
United States
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Inslicht, Sabra S; Rao, Madhu N; Richards, Anne et al. (2018) Sleep and hypothalamic pituitary adrenal axis responses to metyrapone in posttraumatic stress disorder. Psychoneuroendocrinology 88:136-143
Alexandra Kredlow, M; Pineles, Suzanne L; Inslicht, Sabra S et al. (2017) Assessment of skin conductance in African American and Non-African American participants in studies of conditioned fear. Psychophysiology 54:1741-1754
Gibson, Carolyn J; Richards, Anne; Villanueva, Cynthia et al. (2017) Subjective Sleep Related to Post Traumatic Stress Disorder Symptoms among Trauma-Exposed Men and Women. Behav Sleep Med :1-10