title: The Regulation of Cytokine Networks in Hippocampal CA1 Differentiates Extinction from Those Required for the Maintenance of Contextual Fear Memory after Recall.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Birger
authors.initials: B
authors.lastname: Scholz
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Amie N
authors.initials: AN
authors.lastname: Doidge
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Barnes
authors.affiliation: Neuroscience & Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hall
authors.affiliation: Neuroscience & Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.|Schools of Psychology and Medicine, Behavioral Genetics Group, Cardiff University, Cardiff, United Kingdom.|MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Wilkinson
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom.|Neuroscience & Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D056547:CA1 Region, Hippocampal / Q000378:metabolism*; D003216:Conditioning, Operant; D016207:Cytokines / Q000378:metabolism*; D005108:Extinction, Psychological; D005239:Fear; D005786:Gene Expression Regulation; D008297:Male; D008568:Memory; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D051381:Rats; D059467:Transcriptome
chemical_list: D016207:Cytokines