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: 10385811
• 负责人: SUZANNE H MITCHELL
• 金额: $ 45.11万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385811
• 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; gene network; 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; 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; gene network; 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.

项目摘要 该应用对PAR-15-120的响应（鉴定下一代遗传和基因组变异 在非人类动物模型中进行测序）。 药物使用障碍通常的特征是对小的偏好增强，而不是较大， 延迟奖励（“延迟折扣”）。研究成功地将这种冲动的决策与 与病因学因素偏见，可预测药物使用，以及定期使用的进展以及 戒烟努力成功的可能性。研究还开始鉴定神经和遗传 延迟打折的关联。但是，研究确定与此相关的特定基因的研究 表型仍然模棱两可。彼此之间，拟议工作的主要目标是增加我们的 了解延迟打折的遗传基础，从而更好地理解 冲动。提出了四个目标来实现这一目标。 AIM 1将表型600异质 库存（HS）大鼠使用调整金额程序延迟打折（Richards等，1997； Wilhelm和 Mitchell 2009），以便逐个测试（GBS）可以检测行为定量性状基因座（BQTL）。 AIM 2将在这些HS大鼠的一部分上使用双向短期选择性育种，形成高（HD）和 低（LD）延迟折现选定的线，基于对小而立即奖励的相对偏好 更大的后来奖励。第四代选择中的大鼠将用于识别Alle的变化 频率是通过基因分型选择LD和HD选择线的频率，并使用GBS和基因下降。目标3 将在200个表型HS大鼠中对脑转录组进行测序以表征基因表达 延迟打折的签名在三个脑部的大脑区域：伏隔核核心，前提 皮质和脂质杏仁核。这些签名的充分性预测选择目标将是 通过分析第四代的HD和LD选定线的转录组（RNA-SEQ）评估 AIM 2收集的选择。AIM4将检查HD和LD大鼠在其他措施上的表现 冲动性，包括在会话内的表现延迟打折，停止信号任务和 5个选择的串行反应时间任务。这将使我们能够检查延迟打折的遗传相关性， 并为研究这些其他行为表型的共享遗传基础奠定了基础 冲动。 确定表达高或低延迟打折水平的基因型和功能遗传学将会 促进识别有可能发展物质使用障碍的人和其他风险的人 精神病理学。它将提供有关冲动选择的转录组学的信息，并鼓励 对这种决策偏见的神经遗传学的未来探索。