The Genetics of Impulsivity and Motivation

-项目摘要/摘要-冲动和动力的遗传学 分离导致成瘾的新基因的一种方法是专注于内表型，更有局限性 生物和行为标记物与物质使用障碍(SUD)有很好的相关性。冲动，使 鲁莽的决定和“糟糕的”/代价高昂的选择，以及动机，目标导向型行为的动力和 为达到所述目标而招致努力或成本意愿，是所有SUD共同的关键行为领域， 但人们对它们的基因基础知之甚少。醋蝇，果蝇黑腹果蝇，一直是 遗传模式生物已经有一百多年的历史了。在过去的15年里，我们取得了很大的进步 研究果蝇对酒精和其他滥用药物的行为反应，这两项研究都是在描述新的 保守的基因和途径，但也在发展类似于内表型的新的检测方法 更接近于上瘾。这项提议的目标是分离、验证和功能表征 影响一种新的冲动和动力模式。在我们新开发的液体食品电击分析中 (跳蚤)，果蝇在两口液体食物之间进行选择，这两口井配上两种不同的电击， 这让我们不禁要问，果蝇更喜欢高休克/高蔗糖还是低休克/低蔗糖。重要的是，当 苍蝇被剥夺了食物，它们改变了休克/蔗糖的相对估值，更喜欢高休克/高 蔗糖。常用的冲动动物模型，例如延迟折扣任务，对 剥夺。相反，当被剥夺权利时，人类的行为确实更冲动，例如转向较小的药物 现在就给药，而不是以后再打更大的一针。因此，我们的新的跳蚤检测模型的一些重要方面 人类的冲动与SUD高度相关。我们将把果蝇的规模经济与 我们创新的跳蚤测试的独特表面有效性，以阐明导致冲动的基因和变种 以及动机：1)决定M6在冲动和动机中扮演的角色。M6是人类的苍蝇直系同源物 候选冲动基因GPM6B。2)我们将对约200个完全测序的果蝇品系进行GWA， 这让我们对影响冲动和动机的变异和基因有了前所未有的洞察。这将有助于 为研究调节冲动和动机的功能和回路提供新的研究途径。我们 也将在我们刚刚开发的测量经验依赖的测试中测试来自这些目标的候选基因 偏爱安非他明或可卡因。因此，我们的建议与尖端的Basic 研究奖(CEBRA)，不适用于增量研究或正在进行的扩展研究 计划“，而不是”此公告鼓励具有SUD经验的调查人员申请- 希望探索和开发新的研究方法、技术或概念框架的相关研究 这一研究领域的基本问题“(PAR-21-208)。

––– PROJECT SUMMARY/ABSTRACT ––––––––––––––––– The Genetics of Impulsivity and Motivation ––– One way to isolate novel genes contributing to addiction is to focus on endophenotypes, more circumscribed biological and behavioral markers well-correlated with the substance use disorder (SUD). Impulsivity, making rash decisions and ‘bad’/costly choices, and motivation, the impetus for goal-directed behavior and the willingness to incur effort or cost to reach said goal, are key behavioral domains that are common to all SUDs, but their genetic underpinnings are poorly understood. The vinegar fly, Drosophila melanogaster, has been a genetic model organism for more than a hundred years. Major strides have been made in the last 15 years studying the behavioral responses to alcohol and other drugs of abuse in flies, both in characterizing novel conserved genes and pathways, but also in the development of new assays that resemble endophenotypes of addiction more closely. The goal of this proposal is to isolate, validate, and functionally characterize genes that affect a novel model of impulsivity and motivation. In our newly developed Fly Liquid-food Electroshock Assay (FLEA), Drosophila choose between two wells of liquid food that are paired with two distinct electroshocks, allowing us to ask whether flies prefer high shock/high sucrose, or low shock/low sucrose. Importantly, when flies are food deprived, they change their relative valuation of shock/sucrose and prefer the high shock/high sucrose. Commonly used animal models for impulsivity, e.g. the delay discounting task, are insensitive to deprivation. Conversely, humans do act more impulsively when deprived, e.g. shifting towards a smaller drug dose now, rather than a larger ‘hit’ later. Therefore, our novel FLEA assay models some important aspects of human impulsivity that are highly relevant for SUD. We will combine the economy of scale of Drosophila with the unique face validity of our innovative FLEA assay to illuminate the genes and variants that underlie impulsivity and motivation to 1) determine the role M6 plays in impulsivity and motivation. M6 is the fly ortholog of the human candidate impulsivity gene GPM6B. 2) We will perform a GWAS with ~200 fully sequenced Drosophila lines, giving us unprecedented insight into variants and genes that affect impulsivity and motivation. This will serve to seed new avenues of research to investigate the function and circuitry regulating impulsivity and motivation. We will also test candidate genes from these Aims in our just developed assays measuring experience-dependent amphetamine or cocaine preference. Our proposal is therefore fully compatible with the Cutting-Edge Basic Research Award (CEBRA) which is “not intended for incremental research or research extending ongoing programs”, but rather “this announcement encourages applications from investigators with experience in SUD- relevant research who wish to explore and develop new methods, techniques or conceptual frameworks to study basic questions in this research area” (PAR-21-208).