GENETIC BASIS FOR ETHANOL'S HEDONIC EFFECTS

该中心的一个广泛的目标是将数量性状的使用联合收割机 几种不同动物遗传特性的QTL连锁作图技术 模型来识别和定位影响行为和 对乙醇的药理学反应。 我们之前的研究表明 BXD重组近交系内的大量遗传变异性 在三种不同的乙醇表型中， 了解乙醇的有益和有害影响：乙醇 饮酒、条件性位置偏好和条件性味觉厌恶。 此外，我们的研究表明，部分重叠的遗传机制， 影响这些行为和QTL分析已经确定了几个 潜在感兴趣的染色体区域。 然而，由于局限性 由于QTL作图的统计策略，这些位点必须 在其他研究确认之前，这些数据应被视为临时性的。 因此，本组件项目的目标是验证 为这些乙醇奖励表型中的每一种鉴定的最强QTL（例如， 戒断、体温过低、共济失调）。 QTL的主要策略 验证涉及测试来自BXD祖细胞的F2小鼠 菌株C57 BL/6（B6）和DBA/2（D2），以及基因分型高反应者和低反应者 在临时QTL侧翼的标记处的应答者。 QTL的重要性 将在以下研究中进一步评价在该人群中验证的结果， F2小鼠基于它们在标记物处的基因型选择性地繁殖 侧接经验证的QTL（基因型选择）。 然后这些老鼠 测试行为表型的差异，以确定 在感兴趣的QTL的等位基因状态。 基因型选择也将 作为同类菌株开发的起点， 靶QTL处的B6或D2等位基因被转移到背景中 通过反复的回交， 这些 致癌菌株将促进未来的研究，旨在确定 影响每个行为表型的特定基因。 最后，为了评估 我们将研究这些行为表型的遗传相关性， 研究小鼠品系对选择的相关反应， 选择性地培育对乙醇敏感性不同的 这些任务中的每一个的影响（表型选择）。 这些选定 留置权也将在适当的标记基因分型，以确定是否 行为表型的分歧伴随着基因的分歧， 频率. 一旦候选基因在小鼠中被鉴定出来， 人类染色体的同源基因或区域可以在 以确定它们是否与酗酒有关。

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.