title: β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat.
abstract: Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b(+)/CD45(high)/Ly6C(high) macrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.
authors.affiliation: Division of Oral Biology, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wohleb
authors.forename: Mark L
authors.initials: ML
authors.lastname: Hanke
authors.forename: Angela W
authors.initials: AW
authors.lastname: Corona
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Powell
authors.forename: La'Tonia M
authors.initials: LM
authors.lastname: Stiner
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bailey
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Nelson
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Godbout
authors.forename: John F
authors.initials: JF
authors.lastname: Sheridan
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001008:Anxiety Disorders / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000473:pathology; D011433:Propranolol / Q000008:administration & dosage*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000172:deficiency; D012919:Social Behavior; D013315:Stress, Psychological / Q000150:complications*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000319:Adrenergic beta-Antagonists; D015703:Antigens, CD; D016207:Cytokines; D008070:Lipopolysaccharides; D011433:Propranolol; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D022021:Tacrolimus Binding Proteins; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D000099159:Tacrolimus Binding Protein 5; C498608:Dsip1 protein, mouse; C493487:Tlr4 protein, mouse