Role of gonadal steroids in stress-sensitive neural circuits

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Project Summary Social stress is a risk factor for several stress-related psychopathologies, including post-traumatic stress disorder (PTSD). However, most individuals exposed to trauma do not develop stress-related psychopathologies and previous social experience has the potential to improve coping strategies and enable stress resilience. One social experience that contributes to the development of stress resilience is a dominant position in a social hierarchy. In this proposal, we use a Syrian hamster model in which dominant animals show less stress-related behavior than their subordinate counterparts. Our preliminary data indicate that male dominants show increased c-Fos immunoreactivity in androgen receptor (AR)-positive cells in dorsal aspects of the posterior medial amygdala (MePD) compared to their subordinate counterparts. In addition, they show increased c-Fos immunoreactivity in MePD cells projecting to posterior regions of the bed nucleus of the stria terminalis (BNSTp) compared to subordinates. Unlike males, dominant female hamsters have a greater number of estrogen receptor alpha (ERα)-positive cells in the MePD compared to subordinates. However, dominant females do not show elevated c-Fos immunoreactivity in BNSTp-projecting MePD cells compared to subordinates. Altogether, these findings suggest that while AR expression in a MePD-BNSTp pathway may be critical for status-dependent differences in stress vulnerability in male hamsters, ERα expression in MePD- BNSTp pathway may not contribute to status-dependent differences in stress vulnerability in female hamsters. Because of these sex differences, we have two separate hypotheses in this proposal. We hypothesize that AR+ neurons in a MePD-BNSTp pathway are essential for status-dependent differences in stress-related behavior in male hamsters. Also, we hypothesize that ERα+ cells in the MePD are necessary for status- dependent differences in stress-related behavior in female hamsters. We will use a Cre-dependent AAV vector that expresses a short hairpin RNA (shRNA) for AR to selectively knockdown AR receptors in a MePD-BNSTp pathway. In addition, we will use an AAV-shRNA to knockdown ERα receptors in the MePD in a non-Cre- dependent manner in both females and males. Overall, this project will investigate the cellular mechanisms and neural circuits by which gonadal steroid hormone receptors contribute to status-dependent changes in stress vulnerability. This line of research will determine how social experience generates neural plasticity in select neural ensembles and thereby changes stress vulnerability in a sex-dependent manner.