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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales.;Cardiff Univ, Sch Psychol, Cardiff CF10 3AX, S Glam, Wales..
Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales..
Cardiff Univ, Neurosci & Mental Hlth Res Inst, Cardiff CF10 3AX, S Glam, Wales..
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, e0153102Article in journal (Refereed) PublishedText
Abstract [en]

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 TGF beta 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-kappa B-mediated gene expression. We confirmed differential NF-kappa Bp65 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.

Place, publisher, year, edition, pages
2016. Vol. 11, no 5, e0153102
National Category
Pharmacology and Toxicology Pharmaceutical Sciences Neurology
URN: urn:nbn:se:uu:diva-298898DOI: 10.1371/journal.pone.0153102ISI: 000376881700003PubMedID: 27224427OAI: diva2:948520
Swedish Research CouncilWellcome trust, 503147
Available from: 2016-07-12 Created: 2016-07-12 Last updated: 2016-07-12Bibliographically approved

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