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.

项目概要/摘要 药物滥用造成无法估量的个人痛苦，并对社会造成毁灭性的损失。大多数广告- 言语障碍有重要的遗传基础。因此，对遗传途径有更深入的了解 参与成瘾的研究，加上基因组测序，可以产生个性化的治疗和预防 克是根据一个人的成瘾倾向基因型量身定制的。 不幸的是，药物滥用障碍（SUD）是一种极其广泛的诊断，可能包含多种因素 赤字程度。事实证明，很难将单个基因的变异与如此广泛的疾病联系起来，即使 使用强大的方法，例如人类全基因组关联（GWA）作图。作为回应，研究—— 研究者现在将注意力转向药物滥用的生物行为标志，包括几种形式的冲动行为。 敏感性，更容易识别，但与药物滥用密切相关，并且同样具有遗传性。 具有巨大影响的冲动基因的初始 GWA 映射虽然成功，但表明 下一步——找到许多具有微小但重要影响的基因——可能令人望而却步。更多的- 仍然存在功能分析的问题，将映射基因列表转化为预测模型 他们如何相互作用以产生疾病。如果生物行为标记物可以解决这两个问题 SUD 可以在遗传上易于处理的小动物模型中得到证明，这些模型适合廉价的 GWA 作图和功能遗传分析。该项目旨在建立一个与成瘾相关的模型 线虫秀丽隐杆线虫就是这样一个模型中的冲动。 这项研究的重点是一种被称为“努力折扣”的冲动，即选择低努力、低回报的倾向。 价值奖励胜于高努力、高价值的奖励。我们已经证明线虫对食物重新赋予价值 病房基于其内在质量和摄入它们的物理成本。充分利用这一点，我们将选择 采取多种方法在高通量测定中增加特定食物的物理成本。然后，我们将使用 这些测定是为了确定神经递质多巴胺的信号强度是否与 选择需要付出很大努力的选项，就像在哺乳动物模型中一样。最后，我们将估计努力的遗传力 通过量化一小部分野生捕获的、遗传多样性的线虫中的这种表型来折扣线虫 gent C. elegans 菌株。如果成功，该研究将建立一种快速、经济有效的方法来加速 与药物滥用疾病相关的基因发现。