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Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference

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 tha...

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Autores principales: Kozell, Laura B., Denmark, Deaunne L., Walter, Nicole A. R., Buck, Kari J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120100/
https://www.ncbi.nlm.nih.gov/pubmed/30210527
http://dx.doi.org/10.3389/fgene.2018.00323
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author Kozell, Laura B.
Denmark, Deaunne L.
Walter, Nicole A. R.
Buck, Kari J.
author_facet Kozell, Laura B.
Denmark, Deaunne L.
Walter, Nicole A. R.
Buck, Kari J.
author_sort Kozell, Laura B.
collection PubMed
description 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.
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spelling pubmed-61201002018-09-12 Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference Kozell, Laura B. Denmark, Deaunne L. Walter, Nicole A. R. Buck, Kari J. Front Genet Genetics 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. Frontiers Media S.A. 2018-08-27 /pmc/articles/PMC6120100/ /pubmed/30210527 http://dx.doi.org/10.3389/fgene.2018.00323 Text en Copyright © 2018 Kozell, Denmark, Walter and Buck. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Kozell, Laura B.
Denmark, Deaunne L.
Walter, Nicole A. R.
Buck, Kari J.
Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference
title Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference
title_full Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference
title_fullStr Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference
title_full_unstemmed Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference
title_short Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference
title_sort distinct roles for two chromosome 1 loci in ethanol withdrawal, consumption, and conditioned place preference
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120100/
https://www.ncbi.nlm.nih.gov/pubmed/30210527
http://dx.doi.org/10.3389/fgene.2018.00323
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