Hormonal Regulation of Extinction: Implications for Gender Differences in the Mechanisms of PTSD

摘要

This project investigates the role of gonadal hormones in the regulation of Pavlovian fear conditioning and its extinction. Pavlovian fear conditioning and its extinction serve as an animal model for the development of pathological fear in humans that suffer posttraumatic stress disorders and other anxiety disorders. Despite the increased incidence of PTSD and depressive disorders in women, the specific neurobiological mechanisms of gender differences of PTSD are poorly understood and very little basic research currently investigates this dichotomy. One possible hypothesis is that female hormones also play a role in predisposition to PTSD through epigenetic mechanisms. This concept is currently being tested in this proposal by investigation of the role of gonadal hormones in fear learning and extinction. Contrary to our original hypothesis, we saw no overall effect of gonadal hormones in any of our treatment groups (young female, young male, adult female, adult male). We did, however, observe interesting developmental differences. Young males and adult females exhibited enhanced contextual fear memory relative to young females. Furthermore, young males exhibited enhanced rate of extinction training relative to all groups tested. Investigation of epigenetic regulation in the hippocampus revealed that young males that were extinguished exhibited reduced acetylated H4 relative to young females and adult male and female groups. This is consistent with the behavioral data and provides a target to investigate the role of this modification and genes involved in modulation of extinction rate.