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The regulation of cytokine networks in hippocampal CA1 differentiates extinction from those required for the maintenance of contextual fear memory after recall

Scholz, Birger, Doidge, Amie N., Barnes, Philip, Hall, Jeremy ORCID:, Wilkinson, Lawrence S. ORCID: and Thomas, Kerrie L. ORCID: 2016. The regulation of cytokine networks in hippocampal CA1 differentiates extinction from those required for the maintenance of contextual fear memory after recall. PLoS ONE 11 (5) , e0153102. 10.1371/journal.pone.0153102

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We investigated the distinctiveness of gene regulatory networks in CA1 associated with the extinction of contextual fear memory (CFM) after recall using Affymetrix GeneChip Rat Genome 230 2.0 Arrays. These data were compared to previously published retrieval and reconsolidation-attributed, and consolidation datasets. A stringent dual normalization and pareto-scaled orthogonal partial least-square discriminant multivariate analysis together with a jack-knifing-based cross-validation approach was used on all datasets to reduce false positives. Consolidation, retrieval and extinction were correlated with distinct patterns of gene expression 2 hours later. Extinction-related gene expression was most distinct from the profile accompanying consolidation. A highly specific feature was the discrete regulation of neuroimmunological gene expression associated with retrieval and extinction. Immunity–associated genes of the tyrosine kinase receptor TGFβ and PDGF, and TNF families’ characterized extinction. Cytokines and proinflammatory interleukins of the IL-1 and IL-6 families were enriched with the no-extinction retrieval condition. We used comparative genomics to predict transcription factor binding sites in proximal promoter regions of the retrieval-regulated genes. Retrieval that does not lead to extinction was associated with NF-κB-mediated gene expression. We confirmed differential NF-κBp65 expression, and activity in all of a representative sample of our candidate genes in the no-extinction condition. The differential regulation of cytokine networks after the acquisition and retrieval of CFM identifies the important contribution that neuroimmune signalling plays in normal hippocampal function. Further, targeting cytokine signalling upon retrieval offers a therapeutic strategy to promote extinction mechanisms in human disorders characterised by dysregulation of associative memory.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Additional Information: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Publisher: Public Library of Science
ISSN: 1932-6203
Date of First Compliant Deposit: 22 June 2016
Date of Acceptance: 23 March 2016
Last Modified: 11 May 2023 05:26

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