17β-estradiol regulates the behavioral, neuronal, and physiological responses to acute witness stress in female rats

Females are more than twice as likely as males to develop stress-related conditions such as depression, anxiety, and PTSD, but the neural mechanisms underlying this heightened stress sensitivity are unknown. Recent evidence demonstrates that cyclical ovarian hormones may contribute to the augmented stress responses observed in females. Thus, the current experiments were designed to determine the role of estrogen in the neuronal, behavioral, and physiological responses to social stress in female rats. Adult, female, Sprague-Dawley rats underwent ovariectomy or a sham procedure and were implanted with an intravenous catheter in the right jugular vein. One week later, rats were treated with 17β-Estradiol (10 μg) or vehicle prior to observing social defeat between two male rats (witness stress, WS) or undergoing control handling. Burying behavior was assessed during WS/control, blood samples were collected immediately following WS/control for analysis of circulating epinephrine, and brains were collected two hours after WS/control for quantification of cfos in the sexually dimorphic and stress sensitive locus coeruleus (LC). WS-exposed females exhibited a distinct burying phenotype that was attenuated by ovariectomy but reinstated with 17β-Estradiol pretreatment. Similarly, plasma epinephrine and LC cfos were elevated following WS selectively in females with intact circulating ovarian hormones. These physiological responses were blunted by ovariectomy and reinstated by 17β-Estradiol treatment prior to WS. Together, these data highlight a critical role for estrogen in the biobehavioral responses to acute psychosocial stress in females.