title: The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort.
abstract: The transition from acute to chronic ethanol exposure leads to lasting behavioral and physiological changes such as increased consumption, dependence, and withdrawal. Changes in brain gene expression are hypothesized to underlie these adaptive responses to ethanol. Previous studies on acute ethanol identified genetic variation in brain gene expression networks and behavioral responses to ethanol across the BXD panel of recombinant inbred mice. In this work, we have performed the first joint genetic and genomic analysis of transcriptome shifts in response to chronic intermittent ethanol (CIE) by vapor chamber exposure in a BXD cohort. CIE treatment is known to produce significant and sustained changes in ethanol consumption with repeated cycles of ethanol vapor. Using Affymetrix microarray analysis of prefrontal cortex (PFC) and nucleus accumbens (NAC) RNA, we compared CIE expression responses to those seen following acute ethanol treatment, and to voluntary ethanol consumption. Gene expression changes in PFC and NAC after CIE overlapped significantly across brain regions and with previously published expression following acute ethanol. Genes highly modulated by CIE were enriched for specific biological processes including synaptic transmission, neuron ensheathment, intracellular signaling, and neuronal projection development. Expression quantitative trait locus (eQTL) analyses identified genomic loci associated with ethanol-induced transcriptional changes with largely distinct loci identified between brain regions. Correlating CIE-regulated genes to ethanol consumption data identified specific genes highly associated with variation in the increase in drinking seen with repeated cycles of CIE. In particular, multiple myelin-related genes were identified. Furthermore, genetic variance in or near dynamin3 (Dnm3) on Chr1 at ∼164 Mb may have a major regulatory role in CIE-responsive gene expression. Dnm3 expression correlates significantly with ethanol consumption, is contained in a highly ranked functional group of CIE-regulated genes in the NAC, and has a cis-eQTL within a genomic region linked with multiple CIE-responsive genes.
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: van der Vaart
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: jennifer.wolstenholme@vcuhealth.org.
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Wolstenholme
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Maren L
authors.initials: ML
authors.lastname: Smith
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Guy M
authors.initials: GM
authors.lastname: Harris
authors.affiliation: Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, USA.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Lopez
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Wolen
authors.affiliation: Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Becker
authors.affiliation: Department of Genetics, Genomic and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism; D052636:Allostasis / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D015331:Cohort Studies; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000502:physiology; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D040081:Protein Array Analysis / Q000379:methods
chemical_list: D000431:Ethanol
keywords: Bioinformatics; Chronic intermittent ethanol; Genomics