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.

基础神经科学、转化神经科学以及临床实践中的一个长期挑战是了解 个体之间在药物滥用和成瘾方面存在巨大差异。为了应对这一挑战，我们 提议研究两个品系老鼠寻求新奇行为的遗传和功能基础，这两个品系提供了 用于理解药物寻求、成瘾和复发的神经机制的独特强大模型。 通过选择探索轻度压力新环境的高倾向和低倾向来开发这些线路， 分别在 37 代后，培育出的高反应者 (bHR) 和低反应者 (bLR) 分别表现出来。 与 bLR 和远交大鼠相比，bHR 的行为谱在两个品系中都是可遗传的。 表现出更高的寻求新奇和冲动行为、更低的焦虑、更强的敏感倾向 精神兴奋剂，以及药物和线索诱发的复发的较低阈值，提醒人类“外化” bLR 更容易出现焦虑和抑郁行为，对心理社会反应更敏感。 因此，这两条线体现了两种极端的情绪。 反映人类气质差异的反应性是导致药物滥用的两条途径——新奇 我们的工作假设是，功能性 DNA 变异存在于心理社会压力中。 有限数量的基因最初源自远交的斯普拉格道利 (SD) 创始人，解释了 目前这两个系的分子和行为差异是我们的目标是识别这些因果基因。 通过 (1) 在已收集的 F2 队列和 SD 动物中绘制数量性状位点 (QTL) 代表创始人，以及（2）进一步整合功能基因组数据。 基于测序的技术和分析工具遵循以下具体目标（SA）： SA1：在 bHR-bLR 杂交中进行基因组测序和数量性状位点 (QTL) 分析 使用低成本基因型测序方法对人群（n~636，男性和女性）进行分析。 SA2：使用以下方法识别 eQTL、等位基因特异性表达以及与性状相关的转录本/途径 对关键神经结构——伏隔核和海马体进行 RNAseq 分析。 为了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。 SA3：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 数据来识别推定的因果变异并使用 qPCR、原位杂交和提供初步验证 我们期望找到 SD 中存在的多个基因的功能等位基因。 这些基因中的许多可能与相应的基因直接相关。 人类表型，或者至少提供可以解释或预测的重要途径的线索 我们的最终目标是获得更深入的机制。 了解成瘾，并将这些知识转化为对患者更精确、更有效的治疗。