High mobility group box‐1 as a putative ovarian hormone dependent mechanism mediating stress susceptibility in females

Abstract

Women are more than twice as likely to suffer from depression and anxiety compared with men. This enhanced susceptibility begins at puberty and ends at menopause suggesting that cycling ovarian hormones are likely a contributing factor to this phenomenon. However, the mechanism by which ovarian hormones contribute to this enhanced susceptibility to stress remains unknown. Using a modified social defeat model in which a female repeatedly bears witness to an aggressive social defeat encounter, we have previously shown that cycling females exhibit anxiety‐like burying and depressive‐like anhedonia that was associated with enhanced peripheral inflammatory sensitivity. Furthermore, witness stress in intact females produced enhanced expression of high mobility group box 1 (HMGB‐1), a marker of neuroinflammatory priming, within the central amygdala (CeA). Increased HMGB‐1 expression suggests that exposure to a subsequent stressor would result in a faster and greater neuroinflammatory response and likely a sensitized behavioral response. Importantly, these behavioral and inflammatory consequences were attenuated or absent in ovariectomized (OVX) females, suggesting that the presence of ovarian hormones are critical in these stress‐induced effects. The current studies build upon these initial findings to further implicate neuroinflammatory priming, and HMGB‐1 as a putative target to reduce susceptibility.METHODSStudy 1 evaluated the effect of a history of witness stress on the behavioral and neuroinflammatory response to the Porsolt forced swim test (FST) in intact and OVX females. Study 2 evaluated whether treatment with an HMGB‐1 antagonist could inhibit the emergence of anxiety‐ and depressive‐like behaviors and neuroinflammation induced by witness stress in intact females. Finally, study 3 determined the involvement of estrogen in these processes by comparing anxiety‐like burying, depressive‐like anhedonia, cytokine and HMGB‐1 levels in OVX females that received 17β‐estradiol (17β‐E) or placebo replacement.RESULTSFindings from these studies indicated that 1) a previous history of witness stress produced behavioral sensitization in intact females as evidence by enhanced behavioral despair in the FST, 2) administration of the HMGB‐1 antagonist was unable to block the emergence of anxiety‐ and depressive‐like behaviors, and 3) constant levels of 17β‐E selectively contributed to the anxiety‐like behaviors evoked by witness stress. Findings from study 3 further indicated that witness stress evoked HMGB‐1 was directly dependent upon the presence of 17β‐E. Cytokine data are still being evaluated; however, it is expected that exposure to a novel stressor will produce sensitization of CeA inflammation and that this priming can be blocked by the HMGB‐1 antagonist. While the current studies suggest that CeA neuroinflammatory priming may be a putative ovarian hormone dependent mechanism associated with stress susceptibility in intact females, targeting this neuroinflammation globally using an HMBG‐1 inhibitor does not provide therapeutic benefit for the behavioral effects of psychosocial stress.Support or Funding Information17PRE33670106 NARSAD26809 15SDG22430017 I21BX002085 1101BX001374This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.