INIA:Complex Trait Analysis--Alcohol /Stress Interaction

描述（由申请人提供）： 许多非遗传变量与基因变异相互作用， 酒精使用、依赖和复发。一个关键的影响是一个复杂的组合， 压力源与此INIA应用程序的其他组件一样， 项目探索酒精的遗传，分子和细胞基质 消费是为了应对压力。我们的重点是使用新的高分辨率 基因作图资源和方法，以剖析遗传相互作用之间 酒精压力和前脑-中脑解剖学我们使用特征良好的 首次与复杂的行为范式相结合 杏仁核和钥匙的体视学和免疫组织化学分析 神经调节输入到前脑。来自分子和 结构分析将与EtOH-应力相互作用措施相结合， 共同的和独特的遗传决定因素。第一个目标是 系统地应用新数量性状基因座（QTL）作图方法， 在老鼠体内绘制酒精和压力相关基因的精细图谱。超过10个位点是 以高精度绘制和重新绘制（1-2 cM的关键区域） 使用一组约100种新型重组近交（RI）菌株， 互交（RIX）方法和间隔特异同源系。并行 通过这些遗传学研究，我们将探索遗传学和表观遗传学， 压力和饮酒的相互作用和共同决定因素。我们打算 为了系统地绘制基因图谱， 调节基底前脑生理学的三种主要神经递质系统 中缝背核有肾上腺素能细胞， 蓝核和中脑的多巴胺能细胞。这一目标将我们的分析 与INIA的其他发射机相关组件密切相关。我们将使用 无偏体视学方法我们预计， 结构和功能分析将使我们能够更有效地 产生影响酒精中毒发展的候选基因， 人类

DESCRIPTION (provided by applicant): Numerous non-genetic variables interact with gene variants to influence alcohol use, dependence, and relapse. One key influence is a complex mix of stressors. In common with other components of this INIA application, this project explores genetic, molecular, and cellular substrates of alcohol consumption in response to stress. Our focus is on using new high-resolution gene mapping resources and methods to dissect genetic interactions between alcohol, stress, and forebrain-midbrain anatomy. We use well characterized behavioral paradigm that are combined for the first time with sophisticated stereology and immunohistochemical analysis of the amygdala and key neuromodulatory inputs to the forebrain. Data from the molecular and structural analyses will be combined with EtOH-stress interaction measures to define shared and unique genetic determinants. The first aim is to systematically apply new quantitative trait locus (QTL) mapping methods to fine map alcohol and stress-related genes in mice. More than ten loci are being mapped and remapped with high precision (a critical region of 1-2 cM) using a set of -100 new types of recombinant inbred (RI) strains, an novel RI intercross (RIX) method, and interval-specific congenic lines. In parallel with these genetic studies, we will explore genetic and epigenetic interactions and codeterrninants of stress and alcohol consumption. We intend to systematically map genes that influence the number and distribution of three major neurotransmitter systems that modulate basal forebrain physiology serotoninergic cells in the dorsal raphe, noradrenergic neurons in the locus coeruleus, and dopaminergic cells in the midbrain. This aim links our analysis closely to the other transmitter-related components of the INIA. We will use unbiased stereological methods. We anticipate that the synergy between the structural and functional analysis will allow us to far more efficiently generate candidate genes that influence the development of alcoholism in humans.