Using Tools in Translational Neuroscience to Study Sex-linked Factors Related to PTSD Risk - PROJECT SUMMARY Posttraumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder precipitated by exposure to a traumatic event. The differential risk for developing PTSD is multi-determined, but in part depends on sex, with women having approximately twice the risk as men. Since sex disparities in PTSD prevalence remain after controlling for environmental factors, such as the type of trauma exposure, there is a critical need to understand biological factors associated with female PTSD vulnerability. Our long-term goal is to use translational tools in psychophysiology to gain better insight into biological factors contributing to heightened PTSD risk in women. Fear learning processes underlie the pathogenesis and maintenance of PTSD, and fear extinction processes model exposure therapy – a key treatment for PTSD. Growing evidence points to an important role of the sex hormone, estrogen, in women's heightened PTSD risk through its modulatory effects on fear learning and extinction. Yet, there is a historical dearth of preclinical research examining sex-related variables, such as the female reproductive cycle and fluctuating estrogen levels, in laboratory fear conditioning models. Also, little is known about the role of another key sex hormone, progesterone, on these processes. Even fewer studies examined hormonal contraceptive (HC) effects, a critical area of study, given evidence that 85% of women in the United States will use HCs at some point in their lifetime. Hence, the clinical translation of existing research on sex-linked factors related to fear learning and memory remain unclear. For our Aim 1, we will address these critical gaps by examining modulating roles of estradiol and progesterone on fear learning and extinction processes among naturally cycling women compared to women using HCs. In addition to maladaptive fear learning and memory, PTSD has been characterized by overgeneralization of trauma-related stimuli or situations, which may lead to sustained anxiety to nonspecific threats. While sex differences have been explored in fear conditioning to a specific threat, there is far less research on sex differences using animal models of anxiety to nonspecific threat. Also, the interplay of stress and sex hormone modulation in PTSD is not well understood in these models. Our Aim 2 will address this enormous gap in the literature by determining for the first time the relationship between sex hormone levels and dark-enhanced startle – a laboratory model of anxiety to a nonspecific threat – in women at varying stages of their menstrual cycle compared to women using hormonal contraceptives and men. Based on prior research and our own preliminary data, our central hypothesis is that gonadal hormone levels will confer either reduced fear or resiliency (when levels are high) or heightened fear or vulnerability (when levels are low) in conditioned fear and anxiety, which may partially explain disproportionate risk among women. By using translational animal models of PTSD to address these critical scientific gaps, this proposed study could yield clinically useful insights that inform more effective intervention and treatment outcomes for PTSD in women.
