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dc.contributor.authorCunningham, Colm
dc.contributor.authorSkelly, Donal T.
dc.contributor.authorGriffin, Éadaoin W.
dc.contributor.authorMurray, Carol L.
dc.contributor.authorHarney, Sarah
dc.contributor.authorO'Boyle, Conor
dc.contributor.authorHennessy, Edel
dc.contributor.authorDansereau, Marc-Andre
dc.contributor.authorNazmi, Arshed
dc.contributor.authorTortorelli, Lucas
dc.contributor.authorRawlins, J. Nicholas
dc.contributor.authorBannerman, David M.
dc.date.accessioned2019-10-25T13:59:31Z
dc.date.available2019-10-25T13:59:31Z
dc.date.issued2018
dc.date.submitted2018en
dc.identifier.citationSkelly, D.T., Griffin, É.W., Murray, C.L., Harney, S., O'Boyle, C., Hennessy, E., Dansereau, M., Nazmi, A., Tortorelli, L. Rawlins, J.N., Bannerman, D.M. & Cunningham, C., Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms, Molecular Psychiatry, 2018, 1-en
dc.identifier.otherY
dc.identifier.urihttps://www.nature.com/articles/s41380-018-0075-8
dc.identifier.urihttp://hdl.handle.net/2262/89898
dc.descriptionPUBLISHEDen
dc.description.abstractSystemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consolidation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1β replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1β synthesis. Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1β but direct hippocampal action of IL-1β causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.en
dc.format.extent1-en
dc.language.isoenen
dc.relation.ispartofseriesMolecular Psychiatry;
dc.rightsYen
dc.subjectSystemic inflammationen
dc.subjectAcute brain injuryen
dc.subjectDeliriumen
dc.titleAcute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanismsen
dc.typeJournal Articleen
dc.contributor.sponsorWellcome Trusten
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/cunninco
dc.identifier.rssinternalid204313
dc.identifier.doihttps://doi.org/10.1038/s41380-018-0075-8
dc.rights.ecaccessrightsopenAccess
dc.identifier.orcid_id0000-0003-1423-5209


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