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

项目摘要 本申请响应PAR-15-120（通过下一代生物技术鉴定遗传和基因组变异体） 非人类动物模型中的测序）。 物质使用障碍的特点往往是高度偏好小，立即超过大， 延迟折扣（Delay Discounting）研究已经成功地将这种冲动的决定- 使预测药物使用的病因学因素、定期使用的进展以及 成功戒烟的可能性。研究也已经开始确定神经和遗传 延迟折扣的相关性。然而，确定与此相关的特定基因的研究 表型仍不明确。因此，拟议工作的主要目标是增加我们的 理解延迟折扣的遗传基础，从而更好地理解 冲动为实现这一目标，提出了四个目标。目的1将表型600异质 使用调整量程序延迟贴现的普通（HS）大鼠（理查兹等人，1997年; Wilhelm和 Mitchell 2009），从而测序基因分型（GBS）可以检测行为数量性状基因座（bQTL）。 目标2将对这些HS大鼠的一个子集使用双向短期选择性繁殖，以形成高（HD）和 低（LD）延迟折扣选择线的基础上相对偏好的小，立即奖励超过 更大的奖励。第4代选择的大鼠将用于鉴定等位基因的变化 由于通过使用GBS和基因丢弃对LD和HD选择的品系进行基因分型而进行选择的频率。目标3 将对200只表现型HS大鼠的大脑转录组进行测序，以表征基因表达 在三个感兴趣的大脑区域中延迟折扣的签名： 大脑皮层和基底外侧杏仁核这些特征对预测选择目标的充分性将是 通过分析第4代HD和LD选择系的转录组（RNA-Seq）来评估， 目标2下收集的选择。目的4将检查HD和LD大鼠在其他测量方面的表现， 冲动性，包括延迟折扣，停止信号任务和 5-choice serial reaction time task五选择反应时间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基础。 冲动 鉴定高或低水平延迟折扣表达的基因型和功能遗传学将 促进识别有可能出现药物使用障碍和其他疾病的个人 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 未来对这类决策偏差的神经遗传学探索。

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.