Characterizing 17‐β Estradiol as a Precipitating Factor in Heightened Stress Susceptibility in Female Rats

Abstract

Social stress is a common risk factor for anxiety and women are twice as likely as men to develop stress‐related disorders. Mechanisms behind this increased risk remains unclear, thereby limiting targeted therapeutic options. Because females are only at increased risk following puberty until the end of menopause, this suggests that estrogen, the predominant female hormone, might be responsible for sensitizing neural targets involved in stress‐related psychopathology. The current study aimed to characterize the role that estrogen may play in sensitizing behavioral dysfunction produced by social stress exposure in females. First, timecourse studies were conducted to determine the appropriate dose and estradiol formulation to accurately mimic the estrous cycle. These findings led to the following study design: Female rats were either intact or ovariectomized (OVX) and treatment consisted of an injection of 17‐β Estradiol (17βE, 10ug/rat, subcutaneous) or vehicle (sesame oil) administered every 4 days to mimic the rat estrus cycle. Female rats (Intact + vehicle, OVX+vehicle, and OVX+17βE were then subjected to witnessing an aggressive social defeat encounter between a male intruder and a novel male resident for 15 min on 5 consecutive days, or a non‐stress control environment. Stress and anxiety‐like behaviors were quantified on days 1 and 5 including stress‐evoked burying, rearing and freezing. Despite witnessing a comparable number of attacks, intact females were highly sensitive to witness stress as demonstrated by increased anxiety‐like burying compared with OVX rats treated with vehicle. Importantly, cyclic administration of 17βE reinstated burying behavior in OVX females. Rearing and freezing behavior analysis is ongoing. These studies provide evidence of estrogen’s primary role in enhancing stress susceptibility, evidenced by increased anxiety‐like responses to social stress. Moreover, this study lays the foundation for future work to identify the specific neural systems that are sensitized by estradiol to identify neurotherapeutic targets to treat the increased stress susceptibility in females.Support or Funding InformationSupport provided by MH113892‐01A1 (SKW), NARSAD Young Investigator Award 26809 (SKW), South Carolina Honors College Exploration Scholars Research Program (BMC)