title: Changes in behaviour and cytokine expression upon a peripheral immune challenge.
abstract: Depression is frequently associated with inflammation. Animal studies have shown that peripheral inflammation induces depressive-like behaviour, but the underlying mechanisms remain unclear. A distinction between sickness- and depressive-like behaviour has been proposed. We hypothesize that the behavioural distinction is due to changes in the central production of immune mediators. As a model of peripheral inflammation, we administered lipopolysaccharide (LPS) intraperitoneally daily for 4 days in rats. The effect of LPS on sickness- and depressive-like behaviour was assessed. We examined protein levels and mRNA expression of cytokines and cyclooxygenase (COX) enzymes in serum, cerebrospinal fluid (CSF) and specific brain regions. Two hours post-LPS, the rats displayed sickness behaviour and cytokine levels were elevated in both serum and CSF. This was paralleled by specific alterations of mRNA transcription of IL-1β, IL-6 and TNF-α in frontal cortex, hippocampus and striatum. Twenty-four hours post-LPS the rats showed depressive-like behaviour and peripheral cytokine levels were back close to baseline. In contrast, the central transcription of IL-1β mRNA had increased even further, as well as IL-1β CSF levels. IL-6 and TNF-α transcription was unaltered compared to controls. COX enzymes were downregulated in the hippocampus during sickness behaviour and unaltered during depressive-like behaviour. Our results show for the first time that a peripheral immune challenge induces a region specific transcription of cytokines and COX-enzymes in the brain, at time-points corresponding to behavioural sickness and depression. When the peripheral inflammation and sickness behaviour had ceased, a production of proinflammatory cytokines remained within the brain parenchyma.
authors.affiliation: Psychoimmunology Unit, Division of Psychiatry, Department of Clinical Sciences, Lund University, Kioskgatan 19, 221 85 Lund, Sweden. Cecilie.Bay Richter@med.lu.se
authors.forename: Cecilie
authors.initials: C
authors.lastname: Bay-Richter
authors.forename: Shorena
authors.initials: S
authors.lastname: Janelidze
authors.forename: Ludvig
authors.initials: L
authors.lastname: Hallberg
authors.forename: Lena
authors.initials: L
authors.lastname: Brundin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001835:Body Weight / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013550:Swimming / Q000523:psychology; D013997:Time Factors
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011451:Prostaglandin-Endoperoxide Synthases