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

<jats:p>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<jats:sup>+</jats:sup>/SSC<jats:sup>lo</jats:sup>/Ly6C<jats:sup>hi</jats:sup>) and brain macrophages (CD11b<jats:sup>+</jats:sup>/SSC<jats:sup>lo</jats:sup>/CD45<jats:sup>hi</jats:sup>). Moreover, RSD-induced anxiety-like behavior corresponded with brain region-dependent cytokine and chemokine responses involved with myeloid cell recruitment. Next, LysM-GFP<jats:sup>+</jats:sup>and GFP<jats:sup>+</jats:sup>bone marrow (BM)-chimeric mice were used to determine the neuroanatomical distribution of peripheral myeloid cells recruited to the brain during RSD. LysM-GFP<jats:sup>+</jats:sup>mice showed that RSD increased recruitment of GFP<jats:sup>+</jats:sup>macrophages to the brain and increased their presence within the perivascular space (PVS). In addition, RSD promoted recruitment of GFP<jats:sup>+</jats:sup>macrophages into the PVS and parenchyma of the prefrontal cortex, amygdala, and hippocampus of GFP<jats:sup>+</jats:sup>BM-chimeric mice. Furthermore, mice deficient in chemokine receptors associated with monocyte trafficking [chemokine receptor-2 knockout (CCR2<jats:sup>KO</jats:sup>) or fractalkine receptor knockout (CX<jats:sub>3</jats:sub>CR1<jats:sup>KO</jats:sup>)] 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<jats:sup>KO</jats:sup>or CX<jats:sub>3</jats:sub>CR1<jats:sup>KO</jats:sup>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.</jats:p>