The Genetics of Impulsivity and Motivation

- 项目概要/摘要--冲动和动机的遗传学- 分离出导致成瘾的新基因的一种方法是集中于内表型， 生物和行为标记物与物质使用障碍（SUD）密切相关。冲动，使 鲁莽的决定和“糟糕”/昂贵的选择，以及动机、目标导向行为的动力和 愿意付出努力或成本来实现所述目标，是所有SUD共有的关键行为领域， 但人们对它们的基因基础知之甚少。醋蝇，黑腹果蝇， 遗传模式生物超过一百年。在过去的15年里， 研究果蝇对酒精和其他滥用药物的行为反应， 保守的基因和途径，但也在开发类似的内源性表型的新的检测方法， 更紧密地上瘾。该提案的目标是分离、验证和功能性表征基因， 影响了一种新的冲动和动机模型。在我们新开发的苍蝇液体食物电休克分析中， （FLEA），果蝇在两个威尔斯井的液体食物中选择，这两个井与两个不同的电击配对， 这让我们可以问苍蝇是喜欢高冲击/高蔗糖，还是低冲击/低蔗糖。重要的是 果蝇被剥夺食物后，它们改变了它们对休克/蔗糖的相对估价，并更喜欢高休克/高蔗糖。 蔗糖。常用的冲动性动物模型，例如延迟折扣任务，对 剥夺相反，当被剥夺时，人类确实会更冲动，例如转向较小的药物 现在剂量，而不是一个更大的'击中'后。因此，我们的新型FLEA测定模型的一些重要方面 与SUD高度相关人类冲动。我们将联合收割机与果蝇的规模经济相结合， 我们创新的FLEA检测的独特表面有效性，以阐明冲动性背后的基因和变异 和动机来确定M6在冲动和动机中的作用。M6是人类的果蝇直系同源物， 候选冲动基因GPM 6 B。2)我们将对约200个完全测序的果蝇品系进行GWAS， 让我们对影响冲动和动机的变异和基因有了前所未有的了解。这将有助于 为研究调节冲动和动机的功能和电路开辟了新的途径。我们 我们还将在我们刚刚开发的测量经验依赖性的测定中测试来自这些目标的候选基因。 安非他明或可卡因的偏好。因此，我们的建议完全兼容最先进的基本 研究奖（CEBRA）“不用于增量研究或正在进行的研究” 计划”，而是“这一宣布鼓励申请调查人员与经验，在南- 希望探索和开发新方法，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).