Microglial recruitment of monocytes to the brain underlies reoccurring anxiety in stress-sensitized mice

Abstract

Repeated social defeat (RSD) is a murine stress model that promotes long-term “stress-sensitization”, in which exposure to sub-threshold stress causes re-establishment of anxiety. We previously reported that RSD-induced anxiety depends on trafficking of monocytes to fear and threat appraisal brain regions. We hypothesize that RSD drives the production of inflammatory monocytes that are recruited to the brain by microglia, and these monocytes augment pro-inflammatory signaling that reinforces activation of threat circuitry. To address this, we used the CSF-1R inhibitor, PLX5622, to deplete microglia. Subsequent removal of the inhibitor allows microglia to rapidly repopulate. Here, we show that elimination of microglia after RSD prevented the recruitment of monocytes to the brain and recall of anxiety in stress-sensitized mice. Furthermore, microglia were depleted prior to RSD and allowed to repopulate. The phenotype of microglia was assessed by measuring behavioral and cytokine reactivity to peripheral LPS administered 24 days after RSD. We report that mice exposed to RSD displayed a prolonged reduction in social interaction to peripheral LPS and exaggerated pro-inflammatory cytokine expression from microglia. Importantly, repopulating microglia in mice exposed to RSD normalized social interaction and reduced microglial pro- inflammatory cytokine expression to levels similar to non-stressed mice. These data demonstrate that microglia depletion/repopulation can be used to prevent microglial priming. Collectively, microglial priming may underlie monocyte recruitment to the brain and re-establishment of anxiety in stress-sensitized mice.