title: A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co-expression Network in Genetic Vulnerability to Alcohol Withdrawal.
abstract: Genetic factors significantly affect vulnerability to alcohol dependence (alcoholism). We previously identified quantitative trait loci on distal mouse chromosome 1 with large effects on predisposition to alcohol physiological dependence and associated withdrawal following both chronic and acute alcohol exposure in mice (Alcdp1 and Alcw1, respectively). We fine-mapped these loci to a 1.1-1.7 Mb interval syntenic with human 1q23.2-23.3.Alcw1/Alcdp1interval genes show remarkable genetic variation among mice derived from the C57BL/6J and DBA/2J strains, the two most widely studied genetic animal models for alcohol-related traits. Here, we report the creation of a novel recombinantAlcw1/Alcdp1congenic model (R2) in which theAlcw1/Alcdp1interval from a donor C57BL/6J strain is introgressed onto a uniform, inbred DBA/2J genetic background. As expected, R2 mice demonstrate significantly less severe alcohol withdrawal compared to wild-type littermates. Additionally, comparing R2 and background strain animals, as well as reciprocal congenic (R8) and appropriate background strain animals, we assessedAlcw1/Alcdp1dependent brain gene expression using microarray and quantitative PCR analyses. To our knowledge this includes the first Weighted Gene Co-expression Network Analysis using reciprocal congenic models. Importantly, this allows detection of co-expression patterns limited to one or common to both genetic backgrounds with high or low predisposition to alcohol withdrawal severity. The gene expression patterns (modules) in common contain genes related to oxidative phosphorylation, building upon human and animal model studies that implicate involvement of oxidative phosphorylation in alcohol use disorders (AUDs). Finally, we demonstrate that administration of N-acetylcysteine, an FDA-approved antioxidant, significantly reduces symptoms of alcohol withdrawal (convulsions) in mice, thus validating a phenotypic role for this network. Taken together, these studies support the importance of mitochondrial oxidative homeostasis in alcohol withdrawal and identify this network as a valuable therapeutic target in human AUDs.
authors.affiliation: Research and Development, Portland Veterans Affairs Medical Center, PortlandOR, USA; Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, PortlandOR, USA.
authors.forename: Nicole A R
authors.initials: NA
authors.lastname: Walter
authors.affiliation: Research and Development, Portland Veterans Affairs Medical Center, PortlandOR, USA; Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, PortlandOR, USA.
authors.forename: DeAunne L
authors.initials: DL
authors.lastname: Denmark
authors.affiliation: Research and Development, Portland Veterans Affairs Medical Center, PortlandOR, USA; Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, PortlandOR, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Kozell
authors.affiliation: Research and Development, Portland Veterans Affairs Medical Center, PortlandOR, USA; Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, PortlandOR, USA.
authors.forename: Kari J
authors.initials: KJ
authors.lastname: Buck
keywords: N-acetylcysteine; alcoholism; congenic; mouse models; oxidative stress; withdrawal