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

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.

项目概要 该应用程序响应 PAR-15-120（下一代遗传和基因组变异的识别） 非人类动物模型中的测序）。 物质使用障碍通常的特点是肉质偏好较小的、直接的而不是较大的、 研究已成功地将这种类型的冲动决策与延迟奖励（“延迟折扣”）联系起来。 对预测药物使用的病因学因素、常规使用的进展以及药物使用的进展产生偏差 研究也开始确定戒烟成功的神经和遗传因素。 然而，研究确定了与此相关的特定基因。 因此，拟议工作的主要目标是增加我们的研究成果。 了解延迟贴现的遗传基础，从而更好地理解 提出了四个目标来实现这一目标，目标 1 将表型 600 异质性。 使用调整金额程序延迟贴现的库存（HS）大鼠（Richards 等人，1997 年；Wilhelm 和 Mitchell 2009）以便测序基因分型（GBS）可以检测行为数量性状位点（bQTL）。 目标 2 将在这些 HS 大鼠的子集上使用双向短期选择性育种，以形成高 (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 来自第四代选择的较大的后续奖励将用于识别等位基因的变化。 频率归因于使用 GBS 和基因删除对 LD 和 HD 所选品系进行基因分型的选择。 将对 200 只表型 HS 大鼠的大脑转录组进行测序，以表征基因表达 三个感兴趣的大脑区域的延迟贴现特征：伏隔核核心、前边缘 这些特征足以预测选择目标。 通过分析第 4 代 HD 和 LD 选定品系的转录组 (RNA-Seq) 进行评估 在目标 2 下收集的选择。目标 4 将检查 HD 和 LD 大鼠在其他指标上的表现 冲动性，包括延迟折扣、停止信号任务和会话内衡量指标的表现 5 选择串行反应时间任务这将使我们能够检查延迟贴现的遗传相关性， 并为检查这些其他行为表型的共享遗传基础的研究奠定基础 冲动。 识别高水平或低水平延迟折扣表达的基因型和功能遗传学将 促进识别有患药物滥用障碍和其他疾病风险的个人 它将提供有关冲动选择的转录组学的信息，并鼓励 未来对此类决策偏差的神经遗传学的探索。

项目成果

Reward Maximization Assessed Using a Sequential Patch Depletion Task in a Large Sample of Heterogeneous Stock Rats.

在大量异质大鼠样本中使用顺序补丁消耗任务评估奖励最大化。

• DOI: 10.21203/rs.3.rs-2525080/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Gancarz,AmyM;Mitchell,SuzanneH;George,AnthonyM;Martin,ConnorD;Turk,MarisaC;Bool,HeatherM;Aktar,Fahmida;Kwarteng,Francis;Palmer,AbrahamA;Meyer,PaulJ;Richards,JerryB;Dietz,DavidM;Isiwari,Keita
• 通讯作者: Isiwari,Keita

Environmental enrichment promotes adaptive responding during tests of behavioral regulation in male heterogeneous stock rats.

环境富集促进雄性异种大鼠行为调节测试过程中的适应性反应。

• DOI: 10.1101/2023.06.30.547228
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Ishiwari,Keita;King,ChristopherP;Martin,ConnorD;Tripi,JordanA;George,AnthonyM;Lamparelli,AlexanderC;Chitre,Apurva;Polesskaya,Oksana;Richards,JerryB;Woods,LeahCSolberg;Gancarz,Amy;Palmer,AbrahamA;Dietz,DavidM;Mitchell,S
• 通讯作者: Mitchell,S