Genomic Analysis of Avoidance Learning in Addiction

成瘾中回避学习的基因组分析

• 批准号: 10379222
• 负责人: THOMAS C JHOU
• 金额: $ 38.92万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2023-06-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379222
• 关键词: Addictive Behavior; Address; Amygdaloid structure; Animal Model; Avoidance Learning; Behavior; Behavioral; Behavioral Genetics; Behavioral Model; Biology; Candidate Disease Gene; Cell Nucleus; Characteristics; Chromosome Mapping; Cocaine; Complex; Data; Data Set; Dependence; Disease; Drug Exposure; Drug usage; Exhibits; Exons; Exposure to; Family; Financial cost; Funding; Gene Expression; Genes; Genetic; Genetic study; Genomics; Genotype; Grant; Habenula; Haplotypes; Health Care Costs; Heritability; Human; Human Characteristics; Human Genetics; Individual; Knowledge; Lateral; Learning; Maps; Midbrain structure; Modeling; Molecular Target; National Institute of Drug Abuse; Pharmaceutical Preparations; Phenotype; Play; Population; Prefrontal Cortex; Procedures; Process; Property; Punishment; Quantitative Trait Loci; RNA; Rattus; Relapse; Research Personnel; Resistance; Rewards; Ribosomes; Running; Sampling; Screening Result; Series; Testing; Time; Tissues; Transcript; United States National Institutes of Health; Variant; addiction; adverse outcome; behavior influence; behavior test; cost; data sharing; dopaminergic neuron; drug of abuse; gene discovery; genome wide association study; genomic locus; human population genetics; individual variation; innovation; insight; neural circuit; neuropsychiatric disorder; novel; personalized medicine; primary outcome; rare variant; relational database; secondary analysis; societal costs; trait

Abstract: Addictions are among the most heritable of human neuropsychiatric disorders, but human genetic studies have been hampered by the extreme complexity of human genetics, as well as the sheer behavioral complexity of the addictive process, with multiple stages at which humans can exhibit addiction vulnerability – e.g. initial drug exposure, escalation, relapse, etc. We address these shortcomings by studying heterogeneous stock (HS) rats, which have extremely well characterized genetic profiles, and using behavioral models that examine multiple well-defined time periods in the progression of addictive behaviors. Our preliminary findings show that even though addiction is often viewed as aberrant reward learning, much individual variation in addiction propensity is actually due to differences in avoidance learning. For example, in addition to its well-known rewarding properties, cocaine has aversive effects that show greater individual variability than its rewarding effects, and are stronger predictors of cocaine-seeking. Furthermore, we found that rats differ greatly in “punishment resistance”, i.e. propensity to seek rewards despite adverse outcomes, which is one of the defining characteristics of addiction. Both cocaine avoidance and punishment resistance are highly heritable in HS rats (h2 = 0.58 and 0.48, respectively), and both are critically regulated by the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons that plays key roles in avoidance learning. Building on these findings, we seek to identify the genetic differences underlying these two distinct addiction vulnerability phenotypes using a genome-wide association screen (GWAS) to identify candidate genes in HS rats, followed by eQTL analysis on gene expression in the RMTg and afferent circuits that drive these behaviors. This project will identify candidate addiction-related genes using a highly innovative combination of powerful behavioral tests, extensive neural circuitry knowledge, and the Palmer lab's groundbreaking sequencing and analytical approaches.

摘要： 成瘾是人类神经精神障碍中最易遗传的，但人类遗传 人类遗传学的极端复杂性，以及人类基因组的绝对复杂性， 成瘾过程的行为复杂性，人类可以表现出多个阶段 成瘾脆弱性-例如，初始药物暴露，升级，复发等。 通过研究异质性股票（HS）大鼠的缺点，其中有非常好的特点， 遗传概况，并使用行为模型，检查多个明确的时间段，在 成瘾行为的发展。我们的初步研究结果表明，尽管成瘾通常 被视为异常的奖励学习，成瘾倾向的许多个体差异实际上是由于 回避学习的差异。例如，除了众所周知的奖励性质， 可卡因具有令人厌恶的效果，其个体差异性大于其奖励效果， 可卡因成瘾的预测指标此外，我们发现，大鼠在“惩罚”方面存在很大差异 抵抗”，即尽管有不利结果仍寻求奖励的倾向，这是定义之一 成瘾的特征。可卡因回避和惩罚抵抗都是高度遗传的， HS大鼠（分别为h2 = 0.58和0.48），两者均受吻内侧核的关键调节 被盖核（RMTg）是中脑多巴胺神经元的主要GABA能传入， 避免学习的作用。在这些发现的基础上，我们试图确定遗传差异， 这两种不同的成瘾脆弱性表型的基础是使用全基因组关联 筛选（GWAS），以确定HS大鼠的候选基因，然后进行基因的eQTL分析 RMTg和驱动这些行为的传入回路中的表达。该项目将确定 候选成瘾相关基因使用一个高度创新的组合强大的行为测试， 广泛的神经电路知识，以及帕尔默实验室开创性的测序和分析 接近。