Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior

• Published in: The Journal of neuroscience Vol. 33; no. 34; pp. 13820 - 13833
• Main Authors: Wohleb, Eric S, Powell, Nicole D, Godbout, Jonathan P, Sheridan, John F
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 21.08.2013
• Subjects: Animals; Antigens, CD - metabolism; Anxiety Disorders - etiology; Anxiety Disorders - immunology; Anxiety Disorders - pathology; Bone Marrow - pathology; Brain - pathology; Calcium-Binding Proteins - metabolism; Cell Movement - genetics; Cell Movement - immunology; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Green Fluorescent Proteins - genetics; Macrophages - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins - metabolism; Microglia - physiology; Monocytes - physiology; Muramidase - genetics; Muramidase - metabolism; Receptors, CCR2 - deficiency; Receptors, CCR2 - genetics; Receptors, Interleukin-8A - genetics; Receptors, Interleukin-8B - deficiency; Receptors, Interleukin-8B - genetics; Stress, Psychological - complications; Stress, Psychological - immunology; Time Factors
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.1671-13.2013

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.