title: Genetic divergence in the transcriptional engram of chronic alcohol abuse: A laser-capture RNA-seq study of the mouse mesocorticolimbic system.
abstract: Genetic factors that influence the transition from initial drinking to dependence remain enigmatic. Recent studies have leveraged chronic intermittent ethanol (CIE) paradigms to measure changes in brain gene expression in a single strain at 0, 8, 72 h, and even 7 days following CIE. We extend these findings using LCM RNA-seq to profile expression in 11 brain regions in two inbred strains - C57BL/6J (B6) and DBA/2J (D2) - 72 h following multiple cycles of ethanol self-administration and CIE. Linear models identified differential expression based on treatment, region, strain, or interactions with treatment. Nearly 40% of genes showed a robust effect (FDR < 0.01) of region, and hippocampus CA1, cortex, bed nucleus stria terminalis, and nucleus accumbens core had the highest number of differentially expressed genes after treatment. Another 8% of differentially expressed genes demonstrated a robust effect of strain. As expected, based on similar studies in B6, treatment had a much smaller impact on expression; only 72 genes (p < 0.01) are modulated by treatment (independent of region or strain). Strikingly, many more genes (415) show a strain-specific and largely opposite response to treatment and are enriched in processes related to RNA metabolism, transcription factor activity, and mitochondrial function. Over 3 times as many changes in gene expression were detected in D2 compared to B6, and weighted gene co-expression network analysis (WGCNA) module comparison identified more modules enriched for treatment effects in D2. Substantial strain differences exist in the temporal pattern of transcriptional neuroadaptation to CIE, and these may drive individual differences in risk of addiction following excessive alcohol consumption.
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, United States. Electronic address: mmulliga@uthsc.edu.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Mulligan
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, United States.
authors.forename: Khyobeni
authors.initials: K
authors.lastname: Mozhui
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, United States.
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Pandey
authors.affiliation: Department of Molecular Biology and Genetics, Virginia Commonwealth University, United States.
authors.forename: Maren L
authors.initials: ML
authors.lastname: Smith
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, United States.
authors.forename: Suzhen
authors.initials: S
authors.lastname: Gong
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, United States.
authors.forename: Jesse
authors.initials: J
authors.lastname: Ingels
authors.affiliation: Department of Molecular Biology and Genetics, Virginia Commonwealth University, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
authors.affiliation: Charleston Alcohol Research Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, United States.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Lopez
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, United States.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, United States.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
mesh_terms: D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage; D005786:Gene Expression Regulation; D061346:Laser Capture Microdissection / Q000379:methods*; D008032:Limbic System / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012646:Self Administration; D017423:Sequence Analysis, RNA / Q000379:methods*; D013045:Species Specificity; D014158:Transcription, Genetic
chemical_list: D000431:Ethanol
keywords: Addiction; Alcohol; C57BL/6J; CIE; DBA/2J; RNA-seq