title: A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood.
abstract: Binge drinking during adolescence is a risk factor for neuropsychiatric disorders that can develop later in life. Histone acetylation is an important epigenetic mechanism that contributes to neurodevelopment. We investigated the effects of adolescent intermittent ethanol (AIE) exposure, as opposed to normal saline (AIS) exposure, on histone acetylation-mediated regulation of brain-derived neurotrophic factor (BDNF) expression and developmental stages of neurogenesis (proliferating and immature neurons) in the hippocampus in adulthood. AIE exposure increased whole hippocampal histone deacetylase (HDAC) activity and decreased binding protein of cyclic adenosine monophosphate response element binding protein (CBP) and histone H3-K9 acetylation levels in the CA1, CA2, and CA3 regions of the hippocampus. BDNF protein and exon IV mRNA levels in the CA1 and CA3 regions of the hippocampus of AIE-exposed adult rats were decreased as compared to AIS-exposed adult rats. AIE-induced anxiety-like behaviors and deficits in histone H3 acetylation at BDNF exon IV promoter in the hippocampus during adulthood, which were reversed by treatment with the HDAC inhibitor, trichostatin A (TSA). Similarly, neurogenesis was inhibited by AIE in adulthood as demonstrated by the decrease in Ki-67 and doublecortin (DCX)-positive cells in the dentate gyrus, which was normalized by TSA treatment. These results indicate that AIE exposure increases HDACs and decreases CBP levels that may be associated with a decrease in histone H3 acetylation in the hippocampus. These epigenetic changes potentially decrease BDNF expression and inhibit neurogenesis in the hippocampus that may be involved in AIE-induced behavioral abnormalities, including anxiety, in adulthood.
authors.affiliation: Department of Psychiatry, Center for Alcohol Research in Epigenetics (CARE), University of Illinois at Chicago, 1601 West Taylor Street (m/c 912), Chicago, IL, 60612, USA.|Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA.
authors.forename: Amul J
authors.initials: AJ
authors.lastname: Sakharkar
authors.affiliation: Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Vetreno
authors.affiliation: Department of Psychiatry, Center for Alcohol Research in Epigenetics (CARE), University of Illinois at Chicago, 1601 West Taylor Street (m/c 912), Chicago, IL, 60612, USA.|Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA.
authors.forename: Huaibo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, Center for Alcohol Research in Epigenetics (CARE), University of Illinois at Chicago, 1601 West Taylor Street (m/c 912), Chicago, IL, 60612, USA.
authors.forename: Dadasaheb M
authors.initials: DM
authors.lastname: Kokare
authors.affiliation: Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Fulton T
authors.initials: FT
authors.lastname: Crews
authors.affiliation: Department of Psychiatry, Center for Alcohol Research in Epigenetics (CARE), University of Illinois at Chicago, 1601 West Taylor Street (m/c 912), Chicago, IL, 60612, USA. spandey@psych.uic.edu.|Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA. spandey@psych.uic.edu.|Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA. spandey@psych.uic.edu.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Pandey
mesh_terms: D000107:Acetylation; D000818:Animals; D001007:Anxiety / Q000139:chemically induced; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism; D000089662:Doublecortin Protein; D044127:Epigenesis, Genetic; D000431:Ethanol / Q000008:administration & dosage*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008297:Male; D055495:Neurogenesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C000714847:Dcx protein, mouse; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D000431:Ethanol; C012589:trichostatin A; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse
keywords: Adolescent alcohol; Anxiety; Brain-derived neurotrophic factor; Hippocampus; Histone H3 acetylation; Neurogenesis