A broad goal of this Center is to combine the use of Quantitative Trait Loci (QTL) linkage mapping techniques with several different animal genetic models to identify and localize genes affecting behavioral and pharmacological responses to ethanol. Our previous studies have revealed substantial genetic variability within the BXD recombinant inbred strains in three different ethanol phenotypes believed to be relevant to understanding the rewarding and aversive effects of ethanol: ethanol drinking, conditioned place preference, and conditioned taste aversion. Moreover, our studies suggest partial overlap in the genetic mechanisms influencing these behaviors and QTL analyses have identified several chromosomal regions of potential interest. However, because of limitations imposed by the statistical strategy used for QTL mapping, these loci must be considered provisional until they are confirmed by additional studies. Thus, the goal of this Component Project is to verify several of the strongest QTL identified for each of these ethanol reward phenotypes (e.g., withdrawal, hypothermia, ataxia). Our primary strategy for QTL verification involves testing of F2 mice derived from the BXD progenitor strains, C57BL/6 (B6 and DBA/2 (D2), and genotyping high responders and low responders at markers flanking the provisional QTL. The importance of QTL verified in this population will be evaluated further in studies in which F2 mice are selectively bred on the basis of their genotype at markers flanking a verified QTL (Genotypic Selection). These mice will then be tested for differences in the behavioral phenotypes to determine the role of allelic status at the QTL of interest. Genotypic selection will also sere as the starting point for the development of Congenic Strains in which either the B6 or D2 allele at a target QTL is transferred to the background of the opposite progenitor strain by repeated backcrossing. These oncogenic strains will facilitate future research aimed at identifying specific genes influencing each behavioral phenotype. Finally, to evaluate the genetic interrelatedness of these behavioral phenotypes, we will examine correlated responses to selection in mouse lines that have been selectively bred for differences in sensitivity to ethanol' behavioral effects in each of these tasks (Phenotypic Selection). These selected liens will also be genotyped at appropriate markers to determine whether divergence in the behavioral phenotype is accompanied by divergence in gene frequency. Once candidate genes have been identified in the mouse, homologous genes or regions of the human chromosome can be studied in detail to determine whether they are linked to alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
1P50AA010760-01
Application #
5204293
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1996
Total Cost
Indirect Cost
Iancu, Ovidiu D; Colville, Alexander; Walter, Nicole A R et al. (2018) On the relationships in rhesus macaques between chronic ethanol consumption and the brain transcriptome. Addict Biol 23:196-205
Purohit, Kush; Parekh, Puja K; Kern, Joseph et al. (2018) Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge-Like Alcohol Drinking in Mice. Alcohol Clin Exp Res 42:879-888
Iancu, Ovidiu Dan; Colville, Alex M; Wilmot, Beth et al. (2018) Gender-Specific Effects of Selection for Drinking in the Dark on the Network Roles of Coding and Noncoding RNAs. Alcohol Clin Exp Res :
Aoun, E G; Jimenez, V A; Vendruscolo, L F et al. (2018) A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans. Mol Psychiatry 23:1466-1473
Buck, Kari J; Chen, Gang; Kozell, Laura B (2017) Limbic circuitry activation in ethanol withdrawal is regulated by a chromosome 1 locus. Alcohol 58:153-160
Crabbe, John C; Ozburn, Angela R; Metten, Pamela et al. (2017) High Drinking in the Dark (HDID) mice are sensitive to the effects of some clinically relevant drugs to reduce binge-like drinking. Pharmacol Biochem Behav 160:55-62
Colville, A M; Iancu, O D; Oberbeck, D L et al. (2017) Effects of selection for ethanol preference on gene expression in the nucleus accumbens of HS-CC mice. Genes Brain Behav 16:462-471
Hitzemann, Robert; Oberbeck, Denesa; Iancu, Ovidiu et al. (2017) Alignment of the transcriptome with individual variation in animals selectively bred for High Drinking-In-the-Dark (HDID). Alcohol 60:115-120
Chesler, Elissa J; Gatti, Daniel M; Morgan, Andrew P et al. (2016) Diversity Outbred Mice at 21: Maintaining Allelic Variation in the Face of Selection. G3 (Bethesda) 6:3893-3902
Crabbe, John C; Schlumbohm, Jason P; Hack, Wyatt et al. (2016) Fear conditioning in mouse lines genetically selected for binge-like ethanol drinking. Alcohol 52:25-32

Showing the most recent 10 out of 162 publications