title: The contribution of hypothalamic neuroendocrine, neuroplastic and neuroinflammatory processes to lipopolysaccharide-induced depressive-like behaviour in female and male rats: Involvement of glucocorticoid receptor and C/EBP-β.
abstract: Peripheral inflammation induced by lipopolysaccharide (LPS) causes behavioural changes indicative for depression. The possible mechanisms involve the interference with neuroinflammatory, neuroendocrine, and neurotrophic processes. Apart from heterogeneity in the molecular background, sexual context may be another factor relevant to the manifestation of mood disturbances upon an immune challenge. We investigated sex-dependent effects of a 7-day LPS treatment of adult Wistar rats on depressive-like behaviour and their relation with hypothalamic neuroendocrine factor, corticotrophin-releasing hormone (CRH), proplastic brain-derived neurotropic factor (BDNF), pro-inflammatory cyclooxygenase-2 (COX-2) and nuclear factor kappa beta (NFkB). Also, their regulators, the glucocorticoid receptor (GR) and CCAAT enhancer-binding protein (C/EBP) β were followed. LPS induced depressive-like behaviour in females was associated with the increased hypothalamic CRH and decreased BDNF, but not with COX-2. These changes were paralleled by an increase in nuclear GR, NFkB and 20 kDa C/EBPβ. LPS also altered behaviour in males and increased CRH expression, but in contrast to females, this was accompanied with the elevated COX-2, accumulation of cytosolic GR and elevated nuclear 38 kDa C/EBPβ and NFkB. In conclusion, depressive-like phenotype induced by LPS in both sexes emerges from similar HPA axis activation and sex-specific alterations of hypothalamic molecular signalling: in males it is related to compromised control of neuroinflamation connected with cytoplasmic GR retention, while in females it is related to diminished proplastic capacity of BDNF. Sex-dependent mechanisms by which inflammation alters hypothalamic processes and cause pathological behaviour in animals, could be operative in the treatment of depression-related brain inflammation.
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia. Electronic address: miraz@vinca.rs.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Adzic
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Djordjevic
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia.
authors.forename: Milos
authors.initials: M
authors.lastname: Mitic
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia.
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Brkic
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia.
authors.forename: Iva
authors.initials: I
authors.lastname: Lukic
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Radojcic
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003866:Depressive Disorder / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012727:Sex Characteristics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D022782:CCAAT-Enhancer-Binding Protein-beta; C545014:Cebpb protein, rat; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D003346:Corticotropin-Releasing Hormone; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat
keywords: C/EBPβ; Depressive-like behaviour; Glucocorticoid receptor; Hypothalamus; Lypopolysaccharide (LPS); Sex