title: 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.
authors: Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
authors: Eric S
authors: ES
authors: Wohleb
authors: Nicole D
authors: ND
authors: Powell
authors: Jonathan P
authors: JP
authors: Godbout
authors: John F
authors: JF
authors: Sheridan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001008:Anxiety Disorders / Q000209:etiology* / Q000276:immunology / Q000473:pathology*; D001853:Bone Marrow / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005106:Exploratory Behavior; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000235:genetics; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000502:physiology; D009000:Monocytes / Q000502:physiology*; D009113:Muramidase / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000235:genetics; D013315:Stress, Psychological / Q000150:complications* / Q000276:immunology; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; C515335:Ccr2 protein, mouse; D016207:Cytokines; D008840:Microfilament Proteins; D054390:Receptors, CCR2; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D009113:Muramidase; C472450:lysozyme M, mouse
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