title: Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior.
abstract: Regulation of neuroinflammation by glial cells plays a major role in the pathophysiology of major depression. While astrocyte involvement has been well described, the role of microglia is still elusive. Recently, we have shown that Adiponectin (ApN) plays a crucial role in the anxiolytic/antidepressant neurogenesis-independent effects of enriched environment (EE) in mice; however its mechanisms of action within the brain remain unknown. Here, we show that in a murine model of depression induced by chronic corticosterone administration, the hippocampus and the hypothalamus display increased levels of inflammatory cytokines mRNA, which is reversed by EE housing. By combining flow cytometry, cell sorting and q-PCR, we show that microglia from depressive-like mice adopt a pro-inflammatory phenotype characterized by higher expression levels of IL-1β, IL-6, TNF-α and IκB-α mRNAs. EE housing blocks pro-inflammatory cytokine gene induction and promotes arginase 1 mRNA expression in brain-sorted microglia, indicating that EE favors an anti-inflammatory activation state. We show that microglia and brain-macrophages from corticosterone-treated mice adopt differential expression profiles for CCR2, MHC class II and IL-4recα surface markers depending on whether the mice are kept in standard environment or EE. Interestingly, the effects of EE were abolished when cells are isolated from ApN knock-out mouse brains. When injected intra-cerebroventricularly, ApN, whose level is specifically increased in cerebrospinal fluid of depressive mice raised in EE, rescues microglia phenotype, reduces pro-inflammatory cytokine production by microglia and blocks depressive-like behavior in corticosterone-treated mice. Our data suggest that EE-induced ApN increase within the brain regulates microglia and brain macrophages phenotype and activation state, thus reducing neuroinflammation and depressive-like behaviors in mice.
authors.affiliation: Université de Nice Sophia Antipolis, 06103 Nice, France; Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 06560 Valbonne, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Chabry
authors.affiliation: Université de Nice Sophia Antipolis, 06103 Nice, France; Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 06560 Valbonne, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nicolas
authors.affiliation: Université de Nice Sophia Antipolis, 06103 Nice, France; Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 06560 Valbonne, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Cazareth
authors.affiliation: Université de Nice Sophia Antipolis, 06103 Nice, France; Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 06560 Valbonne, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Murris
authors.affiliation: Université de Nice Sophia Antipolis, 06103 Nice, France; Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 06560 Valbonne, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Guyon
authors.affiliation: Université de Nice Sophia Antipolis, 06103 Nice, France; Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 06560 Valbonne, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Glaichenhaus
authors.affiliation: Université de Nice Sophia Antipolis, 06103 Nice, France; Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 06560 Valbonne, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Heurteaux
authors.affiliation: Université de Nice Sophia Antipolis, 06103 Nice, France; Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 06560 Valbonne, France. Electronic address: paitel@ipmc.cnrs.fr.
authors.forename: Agnès
authors.initials: A
authors.lastname: Petit-Paitel
mesh_terms: D052242:Adiponectin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003345:Corticosterone / Q000008:administration & dosage; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D004660:Encephalitis / Q000150:complications / Q000378:metabolism*; D004777:Environment; D006624:Hippocampus / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D007276:Injections, Intraventricular; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D052242:Adiponectin; D016207:Cytokines; D012333:RNA, Messenger; D003345:Corticosterone
keywords: Adiponectin; Antidepressant; Brain macrophages; Cytokines; Depression; Enriched environment; Microglia; Neuroinflammation