A systems approach implicates a brain mitochondrial oxidative homeostasis co-expression network in genetic vulnerability to alcohol withdrawal

Nicole A R Walter, De Aunne L Denmark, Laura B. Kozell, Kari Buck

Research output: Contribution to journalArticle

2 Citations (Scopus)

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/Alcdp1 interval 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 recombinant Alcw1/Alcdp1 congenic model (R2) in which the Alcw1/Alcdp1 interval 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 assessed Alcw1/Alcdp1 dependent 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.

Original languageEnglish (US)
Article number218
JournalFrontiers in Genetics
Volume7
Issue numberJAN
DOIs
StatePublished - Jan 3 2017

Fingerprint

Systems Analysis
Homeostasis
Alcohols
Brain
Alcoholism
Oxidative Phosphorylation
Gene Expression
Animal Models
Substance Withdrawal Syndrome
Chromosomes, Human, Pair 1
Quantitative Trait Loci
Genetic Models
Acetylcysteine
Inbred C57BL Mouse
Genes
Seizures
Antioxidants
Polymerase Chain Reaction

Keywords

  • Alcoholism
  • Congenic
  • Mouse models
  • N-acetylcysteine
  • Oxidative stress
  • Withdrawal

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

Cite this

A systems approach implicates a brain mitochondrial oxidative homeostasis co-expression network in genetic vulnerability to alcohol withdrawal. / Walter, Nicole A R; Denmark, De Aunne L; Kozell, Laura B.; Buck, Kari.

In: Frontiers in Genetics, Vol. 7, No. JAN, 218, 03.01.2017.

Research output: Contribution to journalArticle

@article{6fb2639824014d5e9f552042c5aad3d1,
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/Alcdp1 interval 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 recombinant Alcw1/Alcdp1 congenic model (R2) in which the Alcw1/Alcdp1 interval 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 assessed Alcw1/Alcdp1 dependent 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.",
keywords = "Alcoholism, Congenic, Mouse models, N-acetylcysteine, Oxidative stress, Withdrawal",
author = "Walter, {Nicole A R} and Denmark, {De Aunne L} and Kozell, {Laura B.} and Kari Buck",
year = "2017",
month = "1",
day = "3",
doi = "10.3389/fgene.2016.00218",
language = "English (US)",
volume = "7",
journal = "Frontiers in Genetics",
issn = "1664-8021",
publisher = "Frontiers Media S. A.",
number = "JAN",

}

TY - JOUR

T1 - A systems approach implicates a brain mitochondrial oxidative homeostasis co-expression network in genetic vulnerability to alcohol withdrawal

AU - Walter, Nicole A R

AU - Denmark, De Aunne L

AU - Kozell, Laura B.

AU - Buck, Kari

PY - 2017/1/3

Y1 - 2017/1/3

N2 - 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/Alcdp1 interval 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 recombinant Alcw1/Alcdp1 congenic model (R2) in which the Alcw1/Alcdp1 interval 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 assessed Alcw1/Alcdp1 dependent 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.

AB - 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/Alcdp1 interval 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 recombinant Alcw1/Alcdp1 congenic model (R2) in which the Alcw1/Alcdp1 interval 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 assessed Alcw1/Alcdp1 dependent 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.

KW - Alcoholism

KW - Congenic

KW - Mouse models

KW - N-acetylcysteine

KW - Oxidative stress

KW - Withdrawal

UR - http://www.scopus.com/inward/record.url?scp=85012118551&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85012118551&partnerID=8YFLogxK

U2 - 10.3389/fgene.2016.00218

DO - 10.3389/fgene.2016.00218

M3 - Article

AN - SCOPUS:85012118551

VL - 7

JO - Frontiers in Genetics

JF - Frontiers in Genetics

SN - 1664-8021

IS - JAN

M1 - 218

ER -