Differential effects of homotypic vs. heterotypic chronic stress regimens on microglial activation in the prefrontal cortex

•Chronic restraint stress produces microglial activation in the prefrontal cortex.•Chronic variable stress does not produce microglial activation.•Chronic restraint stress, but not variable stress, produces HPA axis habituation.•Microglial activation may be an adaptive process.

Stress pathology is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and aberrant glucocorticoid responses. Recent studies indicate increases in prefrontal cortical ionized calcium-binding adapter molecule 1 (Iba-1) staining following repeated restraint, reflecting increased microglial densities. Our experiments tested expression of Iba-1 staining in the prelimbic cortex (PL), infralimbic cortex (IL) and the hypothalamic paraventricular nucleus (PVN) following two-week exposure to repeated restraint (RR) and chronic variable stress (CVS), representing homotypic and heterotypic regimens, respectively. Unstressed animals served as controls. We specifically examined Iba-1 immunofluorescence in layers 2 and 3 versus layers 5 and 6 of the PL and IL, using both cell number and field staining density. Iba-1 field staining density was increased in both the PL and IL following RR in comparison to controls. This effect was not observed following CVS. Furthermore, PVN Iba-1 immunoreactivity was not affected by either stress regimen. Cell number did not vary within any brain areas or across stress exposures. Changes in microglial field density did not reflect changes in vascular density. Increases in PL and IL microglial density indicate selective microglial activation during RR, perhaps due to mild stress in the context of limited elevations in anti-inflammatory glucocorticoid actions. This research was supported by NIH grants [MH049698 and MH069860].