Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex

Abstract

Susceptibility to stress-linked psychological disorders, including post-traumatic stress disorder and depression, differs between men and women. Dysfunction of medial prefrontal cortex (mPFC) has been implicated in many of these disorders. Chronic stress affects mPFC in a sex-dependent manner, differentially remodeling dendritic morphology and disrupting prefrontally mediated behaviors in males and females. Chronic restraint stress induces microglial activation, reflected in altered microglial morphology and immune factor expression, in mPFC in male rats. Unstressed females exhibit increased microglial ramification in several brain regions compared to males, suggesting both heightened basal activation and a potential for sex-dependent effects of stress on microglial activation. Therefore, we assessed microglial density and ramification in the prelimbic region of mPFC, and immune-associated genes in dorsal mPFC in male and female rats following acute or chronic restraint stress. Control rats were left unstressed. On the final day of restraint, brains were collected for either qPCR or visualization of microglia using Iba-1 immunohistochemistry. Microglia in mPFC were classified as ramified, primed, reactive, or amoeboid, and counted stereologically. Expression of microglia-associated genes (MHCII, CD40, IL6, CX3CL1, and CX3CR1) was also assessed using qPCR. Unstressed females showed a greater proportion of primed to ramified microglia relative to males, alongside heightened CX3CL1-CX3CR1 expression. Acute and chronic restraint stress reduced the proportion of primed to ramified microglia and microglial CD40 expression in females, but did not significantly alter microglial activation in males. This sex difference in microglial activation could contribute to the differential effects of stress on mPFC structure and function in males versus females.

Microglia shape presynaptic properties at developing glutamatergic synapses

“…Finally, it has to be considered that discrepancies in the literature could also arise from the age, sex or environmental conditions, including health/housing status of the animals used. Microglia react to stress stimuli (Bollinger, Bergeon Burns, & Wellman, ; Tian et al, ) and may undergo genotype‐specific changes following different types of environmental challenges (Hellwig et al, ; Maggi et al, ; Milior et al, ; Reshef et al, ; Winkler et al, ). Collectively, the described heterogeneities could explain some area‐ and context‐dependent microglia properties.…”

Impact of sleep, fatigue, and systemic inflammation on neurocognitive and behavioral outcomes in long‐term survivors of childhood acute lymphoblastic leukemia

“…There is mounting evidence in the literature that supports inflammatory mediators and immune cells as principle regulators of brain sexual differentiation, other than just neurotransmitters and sex hormones 26 . Acute and chronic stress can induce microglial cell mediated immune activation and inflammation in the brain, and recent studies have demonstrated sex differences in microglial density, function, and morphology in several brain regions 27 . Sex-specific association of oxidative stress and inflammation is also observed in other vascular-related diseases 10 .…”

Social defeat induces depressive-like states and microglial activation without involvement of peripheral macrophages

“…For instance, stress has been reported to both de-ramify and hyper-ramify microglia, to increase and decrease cell size, and to increase and decrease Iba1 levels [33, 45, 50, 73, 74]. Differences may be due to the method used to detect microglia morphology.…”