Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms

Donal T. Skelly, Éadaoin W. Griffin, Carol L. Murray, Sarah Harney, Conor O’Boyle, Edel Hennessy, J Nicholas Rawlins, David M. Bannerman, View ORCID ProfileColm Cunningham
doi: https://doi.org/10.1101/127084
Donal T. Skelly
1School of Biochemistry and Immunology & Trinity College Institute of Neuroscience
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Éadaoin W. Griffin
1School of Biochemistry and Immunology & Trinity College Institute of Neuroscience
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carol L. Murray
1School of Biochemistry and Immunology & Trinity College Institute of Neuroscience
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sarah Harney
2Department of Physiology, Trinity College Dublin, Dublin 2, Republic of Ireland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Conor O’Boyle
1School of Biochemistry and Immunology & Trinity College Institute of Neuroscience
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Edel Hennessy
1School of Biochemistry and Immunology & Trinity College Institute of Neuroscience
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J Nicholas Rawlins
3Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David M. Bannerman
3Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, UK.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Colm Cunningham
1School of Biochemistry and Immunology & Trinity College Institute of Neuroscience
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Colm Cunningham
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Acute episodes of delirium also contribute significantly to rates of long-term cognitive decline, implying that de novo pathology occurs during these acute episodes. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms has not been investigated. 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 (100μg/kg) did not affect working memory but robustly impaired contextual fear conditioning (CFC). 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. Although LPS-induced deficits still occured in IL-1RI-/- mice, systemic TNF-α was sufficient to induce similar deficits, indicating redundancy among these cytokines. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits despite failing to block brain IL-1β synthesis. Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irrevesible 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 dysfunction leading to neuronal death is mediated by hippocampal IL-1β. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury that may lead to long-term cognitive impairment but that these events are mechanistically dissociable. This would have significant implications for management of cognitive dysfunction and decline during acute illness.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted April 12, 2017.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms
Donal T. Skelly, Éadaoin W. Griffin, Carol L. Murray, Sarah Harney, Conor O’Boyle, Edel Hennessy, J Nicholas Rawlins, David M. Bannerman, Colm Cunningham
bioRxiv 127084; doi: https://doi.org/10.1101/127084
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms
Donal T. Skelly, Éadaoin W. Griffin, Carol L. Murray, Sarah Harney, Conor O’Boyle, Edel Hennessy, J Nicholas Rawlins, David M. Bannerman, Colm Cunningham
bioRxiv 127084; doi: https://doi.org/10.1101/127084

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (4663)
  • Biochemistry (10320)
  • Bioengineering (7647)
  • Bioinformatics (26266)
  • Biophysics (13486)
  • Cancer Biology (10655)
  • Cell Biology (15372)
  • Clinical Trials (138)
  • Developmental Biology (8473)
  • Ecology (12787)
  • Epidemiology (2067)
  • Evolutionary Biology (16806)
  • Genetics (11374)
  • Genomics (15438)
  • Immunology (10586)
  • Microbiology (25099)
  • Molecular Biology (10176)
  • Neuroscience (54271)
  • Paleontology (399)
  • Pathology (1663)
  • Pharmacology and Toxicology (2884)
  • Physiology (4329)
  • Plant Biology (9216)
  • Scientific Communication and Education (1583)
  • Synthetic Biology (2547)
  • Systems Biology (6765)
  • Zoology (1459)