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Genetic analysis of effort discounting in C. elegans

线虫努力折扣的遗传分析

基本信息

批准号：
10363756
负责人：
SHAWN R LOCKERY
金额：
$ 18.44万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
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/10363756
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 addiction liability 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

项目摘要

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.

项目总结/文摘