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，影响 酗酒、依赖和旧病复发。一个关键的影响是复杂的 压力源。与此INIA应用程序的其他组件一样，这 该项目探索酒精的遗传、分子和细胞底物 应对压力的消费。我们的重点是使用新的高分辨率 基因作图资源和分析遗传互作的方法 酒精、压力和前脑--中脑解剖。我们用很好的特色化 第一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 前脑的神经调节性输入。来自分子和分子的数据 结构分析将与乙醇-应力相互作用措施相结合，以 定义共享和独特的遗传决定因素。第一个目标是 系统应用新的数量性状基因座(QTL)定位方法 对小鼠的酒精和压力相关基因进行精细定位。有十多个基因座是 高精度测绘和重新测绘(1-2厘米的临界区) 利用一组-100个新型重组自交系，建立了一种新的重组自交系 杂交(Rix)方法和区间专化同源系。并行的 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 为了系统地定位影响病毒数量和分布的基因 调节基底前脑生理的三个主要神经递质系统 中缝背侧5-羟色胺能细胞，去甲肾上腺素能神经元 蓝斑和中脑中的多巴胺能细胞。这个目标将我们的分析联系在一起 与INIA与发射机相关的其他部分密切相关。我们将使用 无偏见的体视学方法。我们预计两国之间的协同效应 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.