GENETIC BASIS FOR ETHANOL'S HEDONIC EFFECTS

乙醇的享乐效果的遗传基础

• 批准号: 6200896
• 负责人: CHRISTOPHER L CUNNINGHAM
• 金额: $ 18.89万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6200896
• 关键词: alcoholic beverage consumption; animal breeding; animal genetic material tag; avoidance behavior; behavior test; behavioral /social science research tag; behavioral genetics; conditioning; ethanol; gene frequency; genetic markers; genetic models; genetic strain; genotype; laboratory mouse; linkage mapping; model design /development; motivation; paired stimuli; pharmacogenetics; phenotype; preference; quantitative trait loci; reinforcer; taste

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.

该中心的一个广泛目标是将数量性状的使用结合起来 几种不同动物遗传基因座（QTL）连锁作图技术 识别和定位影响行为和行为的基因的模型 对乙醇的药理反应。 我们之前的研究表明 BXD 重组近交系内存在显着的遗传变异 在三种不同的乙醇表型中被认为与 了解乙醇的奖励和厌恶效果：乙醇 饮酒、条件性地点偏好和条件性味觉厌恶。 此外，我们的研究表明遗传机制部分重叠 影响这些行为的因素和 QTL 分析已经确定了一些 潜在感兴趣的染色体区域。 但由于限制 由于用于 QTL 作图的统计策略的影响，这些位点必须 被认为是临时的，直到得到进一步的研究证实。 因此，该组件项目的目标是验证其中的几个 为每个乙醇奖励表型鉴定出最强的 QTL（例如， 戒断、体温过低、共济失调）。 我们的 QTL 主要策略 验证涉及对源自 BXD 祖细胞的 F2 小鼠进行测试 菌株、C57BL/6（B6 和 DBA/2 (D2)），并对高反应者和低反应者进行基因分型 临时 QTL 侧翼标记处的响应者。 QTL的重要性 将在研究中进一步评估该人群的验证，其中 F2 小鼠根据其标记基因型进行选择性繁殖 侧翼经过验证的 QTL（基因型选择）。 这些老鼠将被 测试行为表型的差异以确定作用 感兴趣的 QTL 的等位基因状态。 基因型选择也将 作为同源菌株开发的起点，其中 目标 QTL 处的 B6 或 D2 等位基因转移到背景 通过重复回交产生相反的祖细胞株。 这些 致癌菌株将有助于未来的研究，旨在确定 影响每种行为表型的特定基因。 最后来评价一下 这些行为表型的遗传相互关联性，我们将 检查小鼠品系中选择的相关反应 针对乙醇行为敏感性差异进行选择性培育 对每项任务的影响（表型选择）。 这些选定的 留置权还将在适当的标记处进行基因分型，以确定是否 行为表型的差异伴随着基因的差异 频率。 一旦在小鼠体内鉴定出候选基因， 可以研究人类染色体的同源基因或区域 详细确定它们是否与酗酒有关。