The role of estradiol on social stress induced depressive‐like behavior and neuroinflammation in females

Abstract

It has long been established that repeated exposure to social stress can lead to the development of psychosocial disorders, such as depression. Strikingly, women are more sensitive to stress‐related disorders, such as depression compared to men. This enhanced stress sensitivity in females begins at the onset of puberty and ends during menopause, suggesting that ovarian hormones could be a large contributing factor to this phenomenon. However, the mechanism by which ovarian hormones could be driving this enhanced stress sensitivity is unknown. Using a modified social defeat paradigm which consists of a rat bearing witness to an aggressive social defeat encounter, we have previously shown that witness stress produces depressive‐like anhedonia and enhanced pressor and tachycardic responses selectively in intact cycling females while females that are ovariectomized (OVX) are resistant, making this an ideal model to study mechanisms of stress susceptibility in females. We recently demonstrated that neuroinflammation is crucial in the development of depressive‐like anhedonia in socially stressed males. The purpose of this study was to determine the effects of estradiol on social stress‐induced neuroinflammation within the central amygdala (CeA) and locus coeruleus (LC) of witness stressed females. Study 1 determined the differential neuroinflammatory consequences of witness stress in intact cycling vs. OVX females. Much like our behavioral data suggests, intact cycling females show enhanced neuroinflammation in the CeA compared to OVX females. Interestingly, neuroinflammation was not elevated in the LC in response to witness stress, but rather OVX females demonstrated stress‐induced reductions of IL‐1β within the LC vs. controls. In order to determine the discrete role of estradiol in these neuroinflammatory responses to stress, study 2 determined cytokine levels in OVX females that received estradiol or placebo replacement. While estradiol replacement did not result in the emergence of stress‐induced depressive‐like anhedonia, it did promote anxiety‐like behavior as evidenced by increased burying during witness stress exposure. Based on this enhanced anxiety‐like response, we predict concomitant increases in neuroinflammation within the CeA, a brain region known to contribute to behavioral stress responses. Therefore, the current study suggests that ovarian hormones, potentially estrogen, may mediate enhanced stress sensitivity in females by promoting stress‐induced inflammation in critical brain regions involved in the behavioral stress response, providing novel therapeutic targets to study female stress resiliency and susceptibility.Support or Funding InformationASPIRE18080‐16‐41861, 15SDG22430017, and P20GM103641