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Alcohol and fear conditioning produce strain-specific changes in the dorsal hippocampal transcriptome of adolescent C57BL/6J and DBA/2J mice

ABSTRACT: Adolescent sensitivity to alcohol is predictive of later alcohol use and is influenced by genetic background. Data from our laboratory suggested that adolescent C57BL/6J and DBA/2J inbred mice differed in susceptibility to dorsal hippocampus-dependent contextual fear learning deficits after acute alcohol exposure. To investigate the biological underpinnings of this strain difference, we examined dorsal hippocampus gene expression via RNA-sequencing after alcohol and/or fear conditioning across male and female C57BL/6J and DBA/2J adolescents. Strains exhibited dramatic differences in dorsal hippocampal gene expression. Specifically, C57BL/6J and DBA/2J strains differed in 3526 transcripts in males and 2675 transcripts in females. We identified pathways likely to be involved in mediating alcohol’s effects on learning, including networks associated with Chrna7 and Fmr1. These findings provide insight into the mechanisms underlying strain differences in alcohol’s effects on learning and suggest that different biological networks are recruited for learning based on genetics, sex, and alcohol exposure.

ORGANISM(S): Mus musculus

PROVIDER: GSE269129 | GEO | 2024/08/21

REPOSITORIES: GEO

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Project description:Differential gene expression between mouse distal chromsome 1 congenic and background and reciprocal congenic and background Genetic factors significantly affect vulnerability to alcohol dependence (alcoholism). We previously identified a quantitative trait locus on chromosome 1 (Adw1) with a large effect on predisposition to alcohol physiological dependence and associated withdrawal following both chronic and acute alcohol exposure in mice. We fine-mapped these loci to a 1.1-1.7 Mb interval syntenic with human 1q23.2-23.3. Adw1 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 Adw1 congenic model (R2) in which the Adw1 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 Adw1 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 and 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. 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 alcohol use disorders.

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Alcohol and fear conditioning produce strain-specific changes in the dorsal hippocampal transcriptome of adolescent C57BL/6J and DBA/2J mice

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