Genetic analysis of effort discounting in C. elegans

线虫努力折扣的遗传分析

• 批准号: 10244629
• 负责人: SHAWN R LOCKERY
• 金额: $ 21.62万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244629
• 关键词: Address; Animal Model; Award; Bacteria; Behavior; Biological Assay; Biological Markers; Caenorhabditis elegans; Candidate Disease Gene; Characteristics; Collection; Consumption; Costs and Benefits; Coupled; Decision Making; Diagnosis; Diagnostic; Disease; Dopamine; Etiology; Exhibits; Failure; Felis catus; Food; Food Preferences; Fostering; Fruit; Future; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Genotype; Heritability; Hour; Human; Human Genome; Impulsivity; Individual; Ingestion; Laws; Learning; Link; Liquid substance; Logic; Mammals; Maps; Measures; Methods; Microfluidics; Modeling; Nature; Nematoda; Neurotransmitters; Organism; Orthologous Gene; Outcome; Pathway interactions; Persons; Pharmacology; Phenotype; Prevention program; Quantitative Genetics; Research; Research Personnel; Resources; Rewards; Sample Size; Serotonin; Signal Transduction; Site; Societies; Source; Stream; Substance abuse problem; Suspensions; System; Testing; Time; Translating; Validation; Variant; Viscosity; addiction; base; behavioral economics; behavioral study; biobehavior; comparative; compare effectiveness; cost; cost effective; density; discounting; endophenotype; experimental study; feeding; gene discovery; genetic analysis; genetic association; genetic variant; genome sequencing; genome wide association study; high risk; high throughput screening; individualized medicine; individualized prevention; innovation; learning ability; optogenetics; physical property; predictive modeling; response; screening; trait; treatment program; ward

PROJECT SUMMARY/ABSTRACT Substance abuse causes immeasurable personal suffering and exacts a devastating toll on society. Most ad- dictive disorders have a significant genetic basis. Thus, a deeper understanding of the genetic pathways in- volved in addiction, coupled with genome sequencing, could yield individualized treatment and prevention pro- grams tailored to a person's addiction liability genotype. Unfortunately, substance abuse disorder (SUD) is an extremely broad diagnosis that likely subsumes a multi- tude of deficits. It has proved difficult to link variants of individual genes to such a broad disorder, even when using powerful approaches such as human genome-wide association (GWA) mapping. In response, research- ers are now shifting their focus to bio-behavioral markers of substance abuse, including several forms of impul- sivity, which are simpler to identify, yet well correlated with substance abuse, and likewise heritable. Initial GWA mappings of impulsivity genes with large effects, though successful, indicate that the cost of the next step – of finding the many genes with small but nevertheless essential effects – may be prohibitive. More- over, there remains the problem of functional analysis, translating lists of mapped genes into predictive models of how they interact to produce the disorder. Both concerns could be addressed if bio-behavioral markers of SUD could be demonstrated in genetically tractable, small-animal models, which are amenable to inexpensive GWA mappings and functional genetic analysis. This project seeks to establish a model of addiction related impulsivity in one such a model, the nematode worm C. elegans. The research focuses on a form of impulsivity called effort discounting, the tendency to choose low-effort, low- value rewards over high-effort, high-value rewards. We have shown that C. elegans assigns values to food re- wards based on their inherent quality and the physical costs of ingesting them. Capitalizing on this, we will opti- mize methods of increasing the physical costs of specific foods in high-throughput assays. Then, we will use these assays to ascertain whether the strength of signaling by the neurotransmitter dopamine is correlated with selection of high-effort options, as it is in mammalian models. Finally, we will estimate the heritability of effort discounting in C. elegans by quantifying this phenotype in a small collection of wild-caught, genetically diver- gent C. elegans strains. If successful, the research will establish a rapid, cost-effective method for accelerating gene discovery related to substance abuse disorders.

项目摘要/摘要 滥用药物会造成不可估量的个人苦难，并严重对社会造成毁灭性的损失。最广告 命令障碍具有明显的遗传基础。这是对遗传途径的更深入的理解 成瘾，再加上基因组测序，可以产生个性化的治疗和预防 根据一个人的成瘾责任基因型量身定制的克。 不幸的是，药物滥用障碍（SUD）是一种极为广泛的诊断，可能归因于多种 缺陷的tude。事实证明，即使 使用强大的方法，例如人类全基因组关联（GWA）映射。作为回应，研究 - 现在，ERS正在将重点转移到滥用毒品的生物行为标记上，其中包括几种形式的冲动 更简单的识别，但与滥用毒品相关，同样可以遗传。 最初的GWA映射具有巨大影响的冲动基因，尽管成功，这表明 可能会禁止下一步 - 找到许多具有小但基本影响的基因。更多的- 结束时，仍然存在功能分析的问题，将映射基因的列表转化为预测模型 它们如何相互作用以产生疾病。如果生物行为标记 SUD可以在一般可拖动的小动物模型中证明，这些模型适合便宜 GWA映射和功能遗传分析。该项目旨在建立与成瘾相关的模型 在这样一个模型中，冲动性是线虫蠕虫秀丽隐杆线虫。 该研究重点是一种冲动性的形式，称为努力打折，选择低及低 - 低 - 价值奖励高高，高价值奖励。我们已经表明，秀丽隐杆线虫将价值分配给食物重新 - 病房基于其继承的质量和摄取其的物理成本。利用这一点，我们将选择 在高通量测定中增加特定食物的物理成本的方法。然后，我们将使用 这些测定法确定神经递质多巴胺的信号强度是否与 在哺乳动物模型中，选择高贵的选项。最后，我们将估计努力的遗传力 通过在一小部分野生捕获的，基因脱位的量子中量化这种表型，在秀丽隐杆线虫中打折 - 绅士秀丽隐杆线虫菌株。如果成功，该研究将建立一种加速的快速，成本效益的方法 基因发现与药物滥用障碍有关。