Genetics of novelty seeking and propensity for drug abuse in outbred rats

近交系大鼠寻求新奇事物的遗传学和药物滥用倾向

• 批准号: 9234690
• 负责人: HUDA AKIL
• 金额: $ 69.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234690
• 关键词: Addictive Behavior; Address; Adult; Affect; Age; Alleles; American; Animal Model; Animals; Anxiety; Behavior; Behavioral; Biology; Brain region; Breeding; Catalogs; Chromosome Mapping; Chronic; Complex; Cues; DNA; Data; Development; Disease; Drug abuse; Emotional; Environment; Exhibits; Female; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genomics; Genotype; Goals; Hand; Healthcare Systems; Heritability; Hippocampus (Brain); Human; Impulsive Behavior; Impulsivity; In Situ Hybridization; Individual Differences; Intervention; Knowledge; Locomotion; Maps; Mediating; Methods; Modeling; Molecular; Motivation; Neurosciences; Novelty-Seeking Behaviors; Nucleus Accumbens; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Population; Psychosocial Stress; Quantitative Trait Loci; Rattus; Relapse; Research; Resolution; Resources; Rewards; Rotation; Signal Transduction; Sprague-Dawley Rats; Structure; Substance Addiction; Substance abuse problem; Techniques; Technology; Temperament; Tissues; Transcript; Translating; Validation; Variant; Weaning; addiction; analytical tool; anxious behavior; base; behavior test; behavioral study; brain tissue; clinical practice; clinically relevant; cohort; cost; depressive behavior; design; differential expression; drug of abuse; drug seeking behavior; effective therapy; emotional abuse; emotional behavior; experimental study; follow-up; functional genomics; gene environment interaction; genetic pedigree; genome sequencing; genome wide association study; genomic data; genomic signature; individual patient; insight; male; neuromechanism; novel; postnatal; psychostimulant; relating to nervous system; social stress; trait; transcriptome; transcriptome sequencing; translational neuroscience; whole genome

A long-standing challenge in basic and translational neuroscience and in clinical practice is to understand the vast inter-individual differences in vulnerability to substance abuse and addiction. To address this challenge we propose to study the genetic and functional basis of novelty-seeking behavior in two lines of rats that offer a uniquely powerful model for understanding the neural mechanisms of drug seeking, addiction and relapse. We developed these lines by selecting for high and low propensity to explore a mildly stressful novel environment, respectively. After 37 generations, the bred High Responders (bHRs) and bred Low Responders (bLRs) show contrasting spectra of behaviors, which are heritable in both lines. Compared to bLRs and outbred rats, bHRs exhibit higher novelty seeking and impulsive behaviors, lower anxiety, greater propensity to sensitize to psychostimulants, and lower thresholds for drug- and cue-induced relapse, reminiscent of human “externalizing disorders”. The bLRs are more prone to anxious and depressive behaviors, more responsive to psychosocial stress, which triggers drug-seeking behavior. Thus, the two lines exemplify two extremes of emotional reactivity that map onto human temperamental differences and underlie two paths to drug abuse—novelty seeking and reactivity to psychosocial stress. Our working hypothesis is that functional DNA variants in a limited number of genes, initially derived from outbred Sprague Dawley (SD) founders, account for the current molecular and behavioral divergence of the two lines. Our goal is to identify these causal genes through (1) mapping of quantitative trait loci (QTL) in both an F2 cohort already collected and in SD animals that represent the founders, and (2) further integration of functional genomic data. We propose to apply several sequencing-based technologies and analytical tools under the following specific aims (SAs): SA1: Conduct genome sequencing and quantitative trait loci (QTL) analyses in a bHR-bLR intercross population (n~636, males and females) using a low-cost Genotype by Sequencing method. SA2: Identify eQTLs, allele-specific expression, and transcripts/pathways associated with the traits by using RNAseq analysis of key neural structures-- the nucleus accumbens and hippocampus. As some genes may exert their primary influence during development, we will analyze both young F2 rats (age: 28 days) and adults. SA3: Perform genomewide association study of 1,000 outbred SD rats, followed by integration of all strands of data to identify putatively causal variants and provide initial validation using qPCR, in situ hybridization, and further behavioral tests. We expect to find functional alleles at multiple genes that existed in the SDs and have evolved further apart in the two lines. Many of these genes may be directly relevant to the corresponding human phenotypes or, at a minimum, provide clues to important pathways that could explain or predict the differential vulnerability to addiction and relapse in humans. Our ultimate goal is to gain a deeper mechanistic understanding of addiction, and translate this knowledge to more precise and effective treatment for patients.

在基础和转化神经科学以及临床实践中，一个长期存在的挑战是理解神经系统的功能。 对药物滥用和成瘾的脆弱性存在巨大的个体差异。为了应对这一挑战，我们 我建议研究两种大鼠求新行为的遗传和功能基础， 这是一个独特的强大模型，用于理解药物寻求，成瘾和复发的神经机制。我们 通过选择高倾向和低倾向来开发这些品系，以探索轻度压力的新环境， 分别在37代之后，繁殖的高应答者（bHR）和繁殖的低应答者（bLR）显示： 行为的对比谱，这是在两个线遗传。与bLR和远交系大鼠相比，bHR 表现出更高的新奇寻求和冲动行为，更低的焦虑，更倾向于敏感 精神兴奋剂，以及药物和线索诱导复发的较低阈值，让人想起人类的“外化 疾病”。bLR更容易出现焦虑和抑郁行为，对心理社会反应更敏感， 压力会引发寻求毒品的行为因此，这两条线是情感的两个极端。 反应性映射到人类的气质差异和基础的两个途径滥用药物-新奇 寻求和对社会心理压力的反应。我们的工作假设是， 有限数量的基因，最初来自远交的Sprague道利（SD）的创始人，占 目前两条线的分子和行为分歧。我们的目标是找出这些致病基因 通过（1）在已经收集的F2组群和SD动物中定位数量性状基因座（QTL 代表创始人，和（2）功能基因组数据的进一步整合。我们建议应用几个 基于测序的技术和分析工具，具体目标如下（SA）： SA 1：在bHR-bLR互交中进行基因组测序和数量性状基因座（QTL）分析 群体（n~636，男性和女性），使用低成本的基因型测序方法。 SA 2：通过使用以下方法鉴定与性状相关的eQTL、等位基因特异性表达和转录本/途径 关键神经结构--伏隔核和海马的RNA测序分析。就像某些基因 在发育过程中发挥其主要影响，我们将分析年轻的F2大鼠（年龄：28天）和成年大鼠。 SA 3：对1，000只远交SD大鼠进行全基因组关联研究，然后整合所有链的 数据，以确定pupestrin致病变异，并提供初步验证，使用qPCR，原位杂交，和 进一步的行为测试。我们希望在SD中存在的多个基因中找到功能等位基因， 在两条线上进化得更远。这些基因中的许多可能与相应的 人类的表型，或者至少提供线索的重要途径，可以解释或预测 人类对成瘾和复发的不同脆弱性。我们的最终目标是获得一个更深层次的机械 了解成瘾，并将这些知识转化为对患者更精确和有效的治疗。