| Autor: |
Kozell LB; Department of Behavioral Neuroscience, Portland Veterans Affairs Medical Center and School of Medicine, Oregon Health and Science University, Portland, OR, United States., Denmark DL; Department of Behavioral Neuroscience, Portland Veterans Affairs Medical Center and School of Medicine, Oregon Health and Science University, Portland, OR, United States., Walter NAR; Department of Behavioral Neuroscience, Portland Veterans Affairs Medical Center and School of Medicine, Oregon Health and Science University, Portland, OR, United States., Buck KJ; Department of Behavioral Neuroscience, Portland Veterans Affairs Medical Center and School of Medicine, Oregon Health and Science University, Portland, OR, United States. |
| Jazyk: |
angličtina |
| Zdroj: |
Frontiers in genetics [Front Genet] 2018 Aug 27; Vol. 9, pp. 323. Date of Electronic Publication: 2018 Aug 27 (Print Publication: 2018). |
| DOI: |
10.3389/fgene.2018.00323 |
| Abstrakt: |
We previously identified a region on chromosome 1 that harbor quantitative trait loci (QTLs) with large effects on alcohol withdrawal risk using both chronic and acute models in mice. Here, using newly created and existing QTL interval-specific congenic (ISC) models, we report the first evidence that this region harbors two distinct alcohol withdrawal QTLs ( Alcw1 1 and Alcw1 2 ), which underlie 13% and 3-6%, respectively, of the genetic variance in alcohol withdrawal severity measured using the handling-induced convulsion. Our results also precisely localize Alcw1 1 and Alcw1 2 to discreet chromosome regions (syntenic with human 1q23.1-23.3) that encompass a limited number of genes with validated genotype-dependent transcript expression and/or non-synonymous sequence variation that may underlie QTL phenotypic effects. ISC analyses also implicate Alcw1 1 and Alcw1 2 in withdrawal-induced anxiety-like behavior, representing the first evidence for their broader roles in alcohol withdrawal beyond convulsions; but detect no evidence for Alcw1 2 involvement in ethanol conditioned place preference (CPP) or consumption. Our data point to high-quality candidates for Alcw1 2 , including genes involved in mitochondrial respiration, spatial buffering, and neural plasticity, and to Kcnj9 as a high-quality candidate for Alcw1 1 . Our studies are the first to show, using two null mutant models on different genetic backgrounds, that Kcnj9 -/- mice demonstrate significantly less severe alcohol withdrawal than wildtype littermates using acute and repeated exposure paradigms. We also demonstrate that Kcnj9 -/- voluntarily consume significantly more alcohol (20%, two-bottle choice) than wildtype littermates. Taken together with evidence implicating Kcnj9 in ethanol CPP, our results support a broad role for this locus in ethanol reward and withdrawal phenotypes. In summary, our results demonstrate two distinct chromosome 1 QTLs that significantly affect risk for ethanol withdrawal, and point to their distinct unique roles in alcohol reward phenotypes. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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