title: Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction.
abstract: BACKGROUND
  A key finding from recent studies of epigenetic mechanisms of memory is that increasing histone acetylation after a learning experience enhances memory consolidation. This has been demonstrated in several preparations, but little is known about whether excitatory and inhibitory memories are equally sensitive to drugs that promote histone acetylation and how transcriptional changes in the hippocampal-medial prefrontal cortex network contribute to these drug effects.
  
  
  METHODS
  We compare the long-term behavioral consequences of systemic, intrahippocampal and intra-medial prefrontal cortex administration of the histone deacetylase inhibitor sodium butyrate (NaB) after contextual fear conditioning and extinction 1 and/or 14 days later in male c57BL/6J mice (n = 302). Levels of histone acetylation and expression of the product of the immediate-early gene c-Fos were assessed by immunohistochemistry following infusion of NaB into the hippocampus (n = 26).
  
  
  RESULTS
  Across a variety of conditions, the effects of NaB on extinction were larger and more persistent compared to the effects on initial memory formation. NaB administered following weak extinction induced behavioral extinction, infralimbic histone acetylation and c-Fos expression consistent with strong extinction. No similar effect was seen in the prelimbic cortex. The involvement of the infralimbic cortex was confirmed as infusions of NaB into the infralimbic, but not prelimbic cortex, induced extinction enhancements.
  
  
  CONCLUSIONS
  These studies show that the memory modulating ability of drugs that enhance acetylation is sensitive to a variety of behavioral and molecular conditions. We further identify transcriptional changes in the hippocampal-infralimbic circuit associated with extinction enhancements induced by the histone deacetylase inhibitor NaB.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, 97239-3098, USA. stafforj@ohsu.edu
authors.forename: James M
authors.initials: JM
authors.lastname: Stafford
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Raybuck
authors.forename: Andrey E
authors.initials: AE
authors.lastname: Ryabinin
authors.forename: K Matthew
authors.initials: KM
authors.lastname: Lattal
mesh_terms: D000107:Acetylation; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D003213:Conditioning, Psychological; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000187:drug effects / Q000378:metabolism*; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D016760:Proto-Oncogene Proteins c-fos