Chronic stress has been associated with an increased inflammatory profile in the brain, linking inflammation to the development of stress-related disorders. Although the detailed mechanism connecting chronic stress to inflammation remains unclear, as primary mediators of the immune response, it has been established that microglia play a role. We further investigated the effect of chronic stress on microglia reactivity by incorporating sex and multiple brain regions as variables in our analysis. We utilized the unpredictable chronic mild stress (UCMS) paradigm and then quantified the number of microglia, process arborization, process length, and the number of processes of microglia in the prefrontal cortex (PFC), nucleus accumbens (NAC), hypothalamus (HYPO), amygdala (AMY), and hippocampal CA1 and CA3. We did not observe a stress-induced change in the number of microglia in each region; however, chronic stress reduced microglia arborization, length, and number of processes in a brain region and sex-specific manner. Independent of stress, microglia exhibited a region-dependent reactive phenotype. Together, chronic stress affects microglia reactivity uniquely based on sex and brain region, while the different reactivity profile of microglia in males and females might underlie the sex-specific mechanism of the diseases.
Zhang et al. (2025) studied this question.