Female microglia and neurogenesis respond differently to social defeat stress compared to males.

Abstract

Depression is a concerning public health threat highly associated with stress. Stress increases brain immune alterations, namely in microglia, which can affect neuron physiology, like neurogenesis, causing a depressive-like behavior. However, despite depression being twice as frequent in females, most studies have been done in males. This results in a gap in our current understanding of stress processing in both sexes, and consequently in our current therapeutical approach. Here, we used the social defeat stress (SDS) paradigm in 8-week-old male and female C57BL/6J mice for 10 consecutive days. Anhedonic and social behavior were assessed to evaluate depressive-like traits. Using immunohistochemical and computer image analysis, microglial distribution, morphology, and neuronal maturation were analyzed in the dentate gyrus of the hippocampus. Results show a different response to SDS in both sexes. Microglial morphological activation was enhanced in the subgranular cell layer of the male dentate gyrus, yet it was not affected in females. In turn, both sexes showed lower neurogenesis, especially in the supra cell layer. Strikingly, female mice neurogenesis was affected in earlier stages of maturation, whereas males showed greater alteration in later maturation steps. In male mice, this impairment was statistically mediated by the microglia, unlike in females where microglia seemed unrelated. Also, males showed a deeper social disability, whereas females had a greater anhedonic profile. As a conclusion, female and male mice responding differently to stress proved that our current approach to depression might need to change to adapt to differential alterations in both sexes.