92. Repeated social defeat causes infiltration of bone marrow-derived macrophages into the brain parenchyma that are pivotal to the development of anxiety-like behavior

Abstract

Stress is associated with impaired immune regulation and a higher incidence of mental health disorders including anxiety. Repeated social defeat (RSD) is a stressor in mice that recapitulates physiological, immunological, and behavioral alterations that are observed in humans. Recent evidence indicates that RSD enhanced the inflammatory profile of microglia and increased the number of macrophages in the brain. Therefore, the objective of this study was to determine the contribution of trafficking macrophages in the brain to stress-induced neuroinflammation and anxiety-like behavior. Here we show that RSD caused anxiety-like behavior that corresponded with accumulation of macrophages in the brain and increased expression of interleukin-1β and chemokine ligand-2 mRNA. Next, to assess trafficking chimeric mice were developed with bone marrow (BM)-derived cells that express green fluorescent protein (GFP+). Indeed, RSD caused a significant increase of GFP+ macrophages in the brain. Moreover, histology revealed that trafficking macrophages infiltrated the parenchyma of specific brain regions that are implicated in anxiety-like behavior. Because chemokine receptor-2 (CCR2) and fractalkine receptor (CX3CR1) are integral to recruitment of macrophages, CCR2−/− or CX3CR1−/− mice were subjected to RSD. CCR2−/− and CX3CR1−/− mice exhibited physiological changes associated with RSD, however macrophage trafficking in the brain and development of anxiety were absent. Together, these findings demonstrate that RSD causes infiltration of macrophages into specific brain regions and these cells are pivotal in the development of anxiety.