%0 Journal Article %A Rand S. Eid %A Stephanie E. Lieblich %A Sarah J. Wong %A Liisa A.M. Galea %T Ovarian hormone status dictates the neuroinflammatory and behavioural consequences of sub-chronic stress exposure in middle-aged female mice %D 2019 %R 10.1101/706887 %J bioRxiv %P 706887 %X Ovarian hormones influence the outcomes of stress exposure and are implicated in stress-related disorders including depression, yet their roles are often complex and seemingly contradictory. Importantly, depression and stress exposure are associated with immune dysregulation, and ovarian hormones have immunomodulatory properties. However, how ovarian hormones can influence the inflammatory outcomes of stress exposure is poorly understood. Here, we examined the effects of long-term ovariectomy on the behavioural and neuroinflammatory outcomes of sub-chronic stress exposure in middle-aged mice. Briefly, sham-operated and ovariectomized mice were assigned to non-stress groups or exposed to 6 days of variable stress. Mice were assessed on a battery of behavioural tests, and cytokine concentrations were quantified in the frontal cortex and hippocampus. Postsynaptic density protein-95 and phosphorylated mitogen-activated protein kinases (MAPKs) were also measured in the frontal cortex. Long-term ovariectomy modified the central cytokine profile by robustly reducing cytokine concentrations in the frontal cortex and modestly increasing concentrations in the hippocampus. Under non-stress conditions, long-term ovariectomy also reduced extracellular signal-regulated kinase (ERK) phosphoprotein expression in the frontal cortex and increased some measures of depressive-like behaviour. The effects of sub-chronic stress exposure were however more pronounced in sham-operated mice. Notably, in sham-operated mice only, sub-chronic stress exposure increased IL-1β and IL-6:IL-10 ratio in the frontal cortex and hippocampus and reduced pERK1/2 expression in the frontal cortex. Further, although sub-chronic stress exposure increased anhedonia-like behaviour regardless of ovarian status, it increased passive-coping behaviour in sham-operated mice only. These data indicate that long-term ovariectomy has potent effects on the central cytokine milieu and mitigates the neuroinflammatory and behavioural effects of sub-chronic stress exposure in middle-aged mice. These findings therefore suggest that the immunomodulatory properties of ovarian hormones are of relevance in the context of stress and possibly depression. %U https://www.biorxiv.org/content/biorxiv/early/2019/07/18/706887.full.pdf