Genetic analysis of effort discounting in C. elegans

项目摘要/摘要 药物滥用造成了无法估量的个人痛苦，给社会造成了毁灭性的损失。大多数广告- 辨证障碍有重要的遗传基础。因此，对遗传途径的更深入了解-- 成瘾的人，加上基因组测序，可以产生个体化的治疗和预防 克是为一个人的成瘾倾向基因量身定做的。 不幸的是，物质滥用障碍(SUD)是一种非常广泛的诊断，可能包括多个 大量的赤字。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，即使在 使用强大的方法，如人类基因组范围关联(GWA)作图。作为回应，研究- ERS现在正将他们的重点转移到药物滥用的生物行为标志上，包括几种形式的脉冲- 敏感度更容易识别，但与药物滥用有很好的相关性，而且同样是可遗传的。 具有大效应的冲动基因的初始GWA图谱虽然成功，但表明 下一步--寻找许多具有微小但本质影响的基因--可能是令人望而却步的。更多- 此外，仍然存在功能分析的问题，即将映射的基因列表转换为预测模型 它们是如何相互作用而产生这种紊乱的。这两个问题都可以得到解决，如果生物行为标志物 可以在遗传上易驯化的小动物模型中证明sud，这些模型易于廉价。 GWA作图和功能遗传分析。本项目旨在建立一种与成瘾相关的模型 在一个这样的模型中，线虫线虫具有冲动性。 这项研究的重点是一种称为努力折扣的冲动形式，这种倾向选择低努力，低努力，低成本 价值奖励胜过高努力、高价值的奖励。我们已经证明线虫对食物的再利用具有价值。 根据它们的内在质量和摄取它们的实际成本来决定病房。利用这一点，我们将优化- 在高通量分析中增加特定食品物理成本的小方法。然后，我们将使用 这些试验旨在确定神经递质多巴胺的信号强度是否与 选择高强度选项，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 通过量化野生捕获的遗传潜水员的小集合中的这种表型来对线虫进行折扣- 雅致线虫品系。如果成功，这项研究将建立一种快速、经济有效的方法来加速 与物质滥用障碍相关的基因发现。

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.