Genetic analysis of effort discounting in C. elegans

项目总结/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- 言语障碍具有重要的遗传基础。因此，更深入地了解遗传途径- 参与成瘾，加上基因组测序，可以产生个性化的治疗和预防， 根据一个人的成瘾倾向基因型量身定制的克数。 不幸的是，物质滥用障碍（SUD）是一个非常广泛的诊断，可能包括多种疾病， 的赤字。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，如人类全基因组关联（GWA）映射。作为回应，研究- 现在，急救人员正将注意力转移到药物滥用的生物行为标志上，包括几种形式的冲动， 性，这是更容易识别，但很好地与药物滥用相关，同样遗传。 冲动性基因的初始GWA映射具有较大的影响，虽然成功，但表明 下一步--寻找许多具有微小但重要作用的基因--可能是令人望而却步的。更多- 除此之外，还有功能分析的问题，即把一系列已定位的基因转化为预测模型 它们是如何相互作用产生紊乱的。这两个问题都可以得到解决，如果生物行为标志物的 SUD可以在遗传上易于处理的小动物模型中得到证明，这些模型适合于廉价的 GWA作图和功能遗传分析。该项目旨在建立一个与成瘾有关的模型， 在一个这样的模型中，线虫C.优雅 这项研究的重点是一种被称为努力折扣的冲动形式，即选择低努力、低回报的倾向。 价值回报高于高努力、高价值回报。我们证明了C. elegans赋予食物价值， 基于其内在质量和获取它们的物理成本。利用这一点，我们将选择- 米泽的方法，增加特定食品的物理成本，在高通量测定。然后，我们将使用 这些测定以确定神经递质多巴胺的信号强度是否与 选择高努力的选择，因为它是在哺乳动物模型。最后，我们将估计努力的遗传力 在C中折现。通过量化这种表型在一个小的收集野生捕获，遗传潜水员， 根特角elegans菌株。如果成功，该研究将建立一种快速，具有成本效益的方法， 与物质滥用障碍有关的基因发现。

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.