title: NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors.
abstract: The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent "orphan" nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function.
authors.affiliation: Neuroscience Graduate Group and Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hawk
authors.forename: Angie L
authors.initials: AL
authors.lastname: Bookout
authors.forename: Shane G
authors.initials: SG
authors.lastname: Poplawski
authors.forename: Morgan
authors.initials: M
authors.lastname: Bridi
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Rao
authors.forename: Michael E
authors.initials: ME
authors.lastname: Sulewski
authors.forename: Brian T
authors.initials: BT
authors.lastname: Kroener
authors.forename: David J
authors.initials: DJ
authors.lastname: Manglesdorf
authors.forename: Ted
authors.initials: T
authors.lastname: Abel
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004597:Electroshock; D005239:Fear / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005799:Genes, Dominant; D006624:Hippocampus / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008569:Memory Disorders / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology*; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018697:Nootropic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D056572:Histone Deacetylase Inhibitors; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D057093:Orphan Nuclear Receptors; D014157:Transcription Factors