title: Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse.
abstract: Post-septic encephalopathy is a poorly understood condition in survivors of sepsis that is characterised by cognitive and affective impairments. In this study we have sought to better understand this condition by undertaking a comprehensive behavioural and cognitive assessment of mice who had previously survived sepsis. Mice were treated with lipopolysaccharide (LPS; 5mg/kg) and one month after this assessed on a battery of tests. Post-septic animals were found to display significantly more immobility in the tail suspension test and show a significantly decreased sucrose preference. Acute fluoxetine treatment reversed the increase in immobility in the tail suspension test in post-septic animals. Post-septic animals also showed less overall exploratory behaviour in the novel object recognition task and also showed increased anxiety-like behaviour in the elevated plus maze. Post-septic mice did not show signs of cognitive impairment, as assessed in the Morris watermaze, the 8-arm radial maze or on preference for the novel object in the novel object recognition task. Immunohistochemical analysis revealed significant upregulation of the microglial marker CD-11b, F4/80 and IBA-1 in the hippocampus of post-septic animals, as well as significant downregulation of the plasticity-related immediate early gene products ARC and EGR1. We also observed a decrease in neural stem cell proliferation in the dentate gyrus of post-septic animals as judged by BrdU incorporation. Co-treatment with the NF-κB pathway inhibitor PDTC attenuated the long-lasting effects of LPS on most of the affected parameters, but not on neural stem cell proliferation. These results show that LPS-induced sepsis in the mouse is followed by long-lasting increases in depressive- and anxiety-like behaviours, as well as by changes in neuroinflammatory- and neural plasticity-associated factors, and that attenuation of the severity of sepsis by PDTC attenuates many of these effects.
authors: Department of Psychology, National University of Ireland Maynooth, County Kildare, Ireland.
authors: Seán T
authors: ST
authors: Anderson
authors: Department of Psychology, National University of Ireland Maynooth, County Kildare, Ireland.
authors: Seán
authors: S
authors: Commins
authors: Institute of Immunology, National University of Ireland Maynooth, County Kildare, Ireland.
authors: Paul N
authors: PN
authors: Moynagh
authors: Department of Psychology, National University of Ireland Maynooth, County Kildare, Ireland. Electronic address: andrew.coogan@nuim.ie.
authors: Andrew N
authors: AN
authors: Coogan
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000378:metabolism; D008070:Lipopolysaccharides; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D003598:Cytoskeletal Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D005473:Fluoxetine
keywords: Behaviour; Cognition; Depression; Hippocampus; LPS; Neuroinflammation; Sepsis