Genetic pathways for impulsivity and drug reinforcement: DNA and transcriptome variation in mice

项目描述 该项目将以高分辨率绘制导致确定的临床表型的遗传途径 与可卡因成瘾有关。我们将利用杂交小鼠多样性小组（HMDP）的力量， 通过高质量的行为表型分析和大规模的RNA测序， 从DNA到RNA再到临床特征，并提供可卡因滥用机制的分层信息。的 HMDP由100个近交系和重组近交系组成，具有广泛的减数分裂断点。的 面板已密集基因分型超过200，000单核苷酸多态性（SNP），允许 数量性状基因座（QTL）的精细定位。此外，HMDP是遗传稳定的和可再生的， 可以分析多种表型，产生累积的生物学信息。我们将扩大我们 通过添加双尺度RNA测序，先前基于HMDP的可卡因滥用相关性状研究 （RNA-Seq），以详细说明成瘾途径的遗传控制。我们的方法提供了独特的 这是已知途径以及涉及变异和外来RNA种类的途径的基因座作图的优势。的 （1）对HMDP小鼠自身静脉注射可卡因进行定量研究。 这种表型被认为是动物中可卡因滥用的最可靠模型之一， 评估调节成瘾相关表型的QTL。(2)我们将在两个关键领域进行RNA-Seq 在控制药物滥用方面发挥作用的大脑内侧前额叶皮层（mPFC）和核团 壳区。(3)我们将使用强大的统计工具分析组合数据集， 了解药物滥用相关表型的遗传调控。这些研究将绘制基因网络图 以及可卡因成瘾的组织间调节途径，并提出了新的，高度特异性的治疗方法。 战略布局

PROJECT DESCRIPTION This project will chart with high-resolution the genetic pathways that give rise to defined clinical phenotypes related to cocaine addiction. We will utilize the power of the hybrid mouse diversity panel (HMDP), combined with high quality behavioral phenotyping and massive-scale RNA sequencing, to trace the interconnections from DNA to RNA to clinical trait and provide layered information on the mechanisms of cocaine abuse. The HMDP consists of 100 inbred and recombinant inbred strains and has a wide array of meiotic breakpoints. The panel has been densely genotyped with more than 200,000 single nucleotide polymorphisms (SNPs), allowing very fine mapping of quantitative trait loci (QTLs). Further, the HMDP is genetically stable and renewable and can be assayed for multiple phenotypes, yielding cumulative biological information. We will expand our previous HMDP-based studies of cocaine abuse-related traits by adding massive-scale RNA sequencing (RNA-Seq), in order to detail the genetic control of the pathways to addiction. Our approach offers the distinct advantage of mapping loci for known pathways as well as those involving variant and exotic RNA species. The following aims are proposed: (1) We will quantitate intravenous self-administration of cocaine in HMDP mice. This phenotype is regarded as being one of the most faithful models of cocaine abuse in animals and will allow evaluation of QTLs that regulate addiction-related phenotypes. (2) We will perform RNA-Seq on two key areas of the brain that play a role in the control of drug abuse, the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) shell region. (3) We will analyze the combined datasets with powerful statistical tools to understand the genetic regulation of drug abuse-related phenotypes. These studies will map genetic networks and inter-tissue regulatory pathways for cocaine addiction and suggest new, highly specific therapeutic strategies.