Essential Role of Ovarian Hormones in Susceptibility to the Consequences of Witnessing Social Defeat in Female Rats

BACKGROUND: Women are at greater risk than men of developing depression and comorbid disorders such as cardiovascular disease. This enhanced risk begins at puberty and ends following menopause, suggesting a role for ovarian hormones in this sensitivity. Here we used a model of psychosocial witness stress in female rats to determine the stress-induced neurobiological adaptations that underlie stress susceptibility in an ovarian hormone-dependent manner. METHODS: Intact or ovariectomized (OVX) female rats were exposed to five daily 15-minute witness-stress exposures. Witness-stress-evoked burying, behavioral despair, and anhedonia were measured. Cardiovascular telemetry was combined with plasma measurements of inflammation, epinephrine, and corticosterone as indices of cardiovascular dysfunction. Finally, levels of interleukin-1b and corticotropin-releasing factor were assessed in the central amygdala. RESULTS: Witness stress produced anxiety-like burying, depressive-like anhedonia, and behavioral despair selectively in intact female rats, which was associated with enhanced sympathetic responses during stress, including increased blood pressure, heart rate, and arrhythmias. Moreover, intact female rats exhibited increases in 12-hour resting systolic pressure and heart rate and reductions in heart rate variability. Notably, OVX female rats remained resilient. Moreover, intact, but not OVX, female rats exposed to witness stress exhibited a sensitized cytokine and epinephrine response to stress and distinct increases in levels of corticotropin-releasing factor and interleukin-1b in the central amygdala. CONCLUSIONS: Together these data suggest that ovarian hormones play a critical role in the behavioral, inflammatory, and cardiovascular susceptibility to social stress in female rats and reveal putative systems that are sensitized to stress in an ovarian hormone-dependent manner.