Stress-Induced Recruitment of Bone Marrow-Derived Monocytes to the Brain Promotes Anxiety-Like Behavior

Abstract

Social stress is associated with altered immunity and higher incidence of anxiety-related disorders. Repeated social defeat (RSD) is a murine stressor that primes peripheral myeloid cells, activates microglia, and induces anxiety-like behavior. Here we show that RSD-induced anxiety-like behavior corresponded with an exposure-dependent increase in circulating monocytes (CD11b⁺/SSC^lo/Ly6C^hi) and brain macrophages (CD11b⁺/SSC^lo/CD45^hi). Moreover, RSD-induced anxiety-like behavior corresponded with brain region-dependent cytokine and chemokine responses involved with myeloid cell recruitment. Next, LysM-GFP⁺ and GFP⁺ bone marrow (BM)-chimeric mice were used to determine the neuroanatomical distribution of peripheral myeloid cells recruited to the brain during RSD. LysM-GFP⁺ mice showed that RSD increased recruitment of GFP⁺ macrophages to the brain and increased their presence within the perivascular space (PVS). In addition, RSD promoted recruitment of GFP⁺ macrophages into the PVS and parenchyma of the prefrontal cortex, amygdala, and hippocampus of GFP⁺ BM-chimeric mice. Furthermore, mice deficient in chemokine receptors associated with monocyte trafficking [chemokine receptor-2 knockout (CCR2^KO) or fractalkine receptor knockout (CX₃CR1^KO)] failed to recruit macrophages to the brain and did not develop anxiety-like behavior following RSD. Last, RSD-induced macrophage trafficking was prevented in BM-chimeric mice generated with CCR2^KO or CX₃CR1^KO donor cells. These findings indicate that monocyte recruitment to the brain in response to social stress represents a novel cellular mechanism that contributes to the development of anxiety.