Identification of genetic features of delay discounting using a heterogeneous stock rat model

使用异质大鼠模型鉴定延迟贴现的遗传特征

• 批准号: 9926858
• 负责人: ROBERT J. HITZEMANN
• 金额: $ 49.68万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926858
• 关键词: Address; Alcoholism; Amygdaloid structure; Animal Model; Behavior; Behavioral; Brain; Brain region; Breeding; Clinical Data; Cocaine Abuse; Data; Decision Making; Drops; Drug usage; Etiology; Family; Female; Foundations; Future; Gene Expression Profile; Gene Frequency; Generations; Genes; Genetic; Genetic Drift; Genetic Predisposition to Disease; Genotype; Haplotypes; Heritability; Heroin Abuse; Human; Impulsive Behavior; Impulsivity; Inbred Strains Rats; Individual; Life; Measures; Meta-Analysis; Methods; Modeling; Mus; Nucleus Accumbens; Performance; Phenotype; Predictive Factor; Procedures; Process; Psychopathology; Quantitative Trait Loci; Rattus; Reaction Time; Research; Rewards; Risk; SNP genotyping; Sample Size; Signal Transduction; Substance Use Disorder; Substance abuse problem; Testing; Work; base; behavioral phenotyping; cohort; discounting; experience; genetic variant; genome wide association study; interest; male; neurogenetics; next generation sequencing; novel; pre-clinical; preference; pressure; prevent; relating to nervous system; response; trait; transcriptome; transcriptome sequencing; transcriptomics; treatment strategy

PROJECT SUMMARY This application is responsive to PAR-15-120 (Identification of Genetic and Genomic Variants by Next-Gen Sequencing in Non-Human Animal Models). Substance use disorders are often characterized by heightened preference for small, immediate over larger, delayed rewards (“delay discounting”). Research has successfully related this type of impulsive decision- making bias with etiological factors predictive of drug use, with the progression to regular use, and with the likelihood of succeeding in cessation efforts. Research has also begun to identify the neural and genetic correlates of delay discounting. However, research identifying the specific genes associated with this phenotype remains ambiguous. Accordingly, the primary objective of the proposed work is to increase our understanding of the genetic basis of delay discounting, thereby providing a better understanding of impulsivity. Four aims are proposed to accomplish this objective. Aim 1 will phenotype 600 heterogeneous stock (HS) rats for delay discounting using the adjusting amount procedure (Richards et al. 1997; Wilhelm and Mitchell 2009) so that Genotyping-By-Sequencing (GBS) can detect behavioral quantitative trait loci (bQTLs). Aim 2 will use bi-directional short-term selective breeding on a subset of these HS rats to form high (HD) and low (LD) delay discounting selected lines based on relative preference for the small, immediate reward over the larger later reward. Rats from the 4th generation of selection will be used to identify changes in allele frequency due to selection by genotyping the LD and HD selected lines using GBS and gene dropping. Aim 3 will sequence the brain transcriptome in 200 phenotyped HS rats to characterize the gene expression signatures for delay discounting in three brain regions of interest: nucleus accumbens core, the prelimbic cortex and the basolateral amygdala. The sufficiency of these signatures to predict selection targets will be evaluated by analyzing the transcriptomes (RNA-Seq) from HD and LD selected lines at the 4th generation of selection collected under Aim 2. Aim 4 will examine HD and LD rats' performance on other measures of impulsivity, including performance on a within sessions measure of delay discounting, the stop signal task and the 5-choice serial reaction time task. This will permit us to examine genetic correlates of delay discounting, and lay a foundation for research examining the shared genetic bases of these other behavioral phenotypes of impulsivity. Identifying the genotype and functional genetics for expression of high or low levels of delay discounting will facilitate identification of individuals at risk for developing substance use disorders and other psychopathologies. It will provide information about the transcriptomics of impulsive choice, and encourage future explorations of the neurogenetics of this type of decision-making bias.

项目总结 此应用程序响应PAR-15-120(由下一代识别遗传和基因组变体 非人类动物模型中的测序)。 物质使用障碍的特征通常是对小的，直接的，而不是大的， 延迟奖励(“延迟折扣”)。研究已经成功地将这种类型的冲动决定联系起来-- 与病因学因素预测药物使用、进展为常规使用、与 戒烟努力取得成功的可能性。研究也已经开始识别神经和基因 延迟贴现的相关性。然而，识别与此相关的特定基因的研究 表型仍然不明确。因此，拟议工作的主要目标是增加我们的 了解延迟折扣的遗传基础，从而更好地了解 冲动。为实现这一目标，提出了四个目标。AIM 1将表现出600种异质性 使用调整量程序对(HS)大鼠进行延迟贴现(Richards等人1997年；威廉和 Mitchell 2009)，以便通过测序进行基因分型(GBS)可以检测行为数量性状基因座(BQTL)。 AIM 2将对这些HS大鼠的一部分进行双向短期选择性育种，以形成高密度(HD)和 低(LD)延迟，根据对小额、即时奖励的相对偏好，对选定的线路进行折扣 以后的奖励就越大。来自第四代选择的大鼠将被用来识别等位基因的变化 通过GBS和基因滴定对LD和HD所选品系进行基因分型所产生的选择频率。目标3 将对200只表型HS大鼠的脑转录组进行测序，以确定基因表达的特征 三个感兴趣的大脑区域延迟折扣的信号：伏核核心、前庭 皮质和基底外侧杏仁核。这些签名对预测选择目标的充分性将是 通过分析HD和LD选育的品系在第4代的转录本(RNA-Seq)进行了评估 根据目标2收集的选择。目标4将检查HD和LD大鼠在其他指标上的表现 冲动性，包括在会话内测量延迟折扣的性能，停止信号任务和 5项连续反应时任务。这将使我们能够检查延迟折扣的遗传相关性， 并为研究这些其他行为表型的共同遗传基础奠定了基础 冲动。 确定表达高或低水平延迟折扣Will的基因和功能遗传学 促进识别有患药物使用障碍和其他疾病风险的个人 精神变态。它将提供有关冲动选择的转录信息，并鼓励 未来对这种决策偏差的神经遗传学的探索。