Phytoestrogen genistein modulates neuron–microglia signaling in a mouse model of chronic social defeat stress

Microglia, resident immune cells in the brain, are shown to mediate the crosstalk between psychological stress and depression. Interestingly, increasing evidence indicates that sex hormones, particularly estrogen, are involved in the regulation of immune system. In this study, we aimed to understand the potential effects of chronic social defeat stress (CSDS) and genistein (GEN), an estrogenic compound of the plant origin, on neuron–microglia interactions in the mouse hippocampus. The time spent in the avoidance zone in the social interaction test was increased by CSDS 1 day after the exposure, while the avoidance behavior returned to control levels 14 days after the CSDS exposure. Similar results were obtained from the elevated plus-maze test. However, the immobility time in the forced swim test was increased by CSDS 14 days after the exposure, and the depression-related behavior was in part alleviated by GEN. The numerical densities of microglia in the hippocampus were increased by CSDS, and they were decreased by GEN. The voxel densities of synaptic structures and synaptic puncta colocalized with microglia were decreased by CSDS, and they were increased by GEN. Neither CSDS nor GEN affected the gene expressions of major pro-inflammatory cytokines. Conversely, the expression levels of genes related to neurotrophic factors were decreased by CSDS, and they were partially reversed by GEN. These findings show that GEN may in part alleviate stress-related symptoms, and the effects of GEN may be associated with the modulation of neuron–microglia signaling via chemokines and neurotrophic factors in the hippocampus.