Genetics of novelty seeking and propensity for drug abuse in outbred rats

在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 物质滥用障碍（SUD）是对个人和社会的重大挑战，是由形成药物成瘾脆弱性的遗传因素和可能引发和影响这些疾病过程的环境变量之间的相互作用引起的。该项目的目标是揭示寻求药物和药物成瘾倾向的遗传和基因组机制。有证据表明，对SUD的脆弱性的巨大个体间差异与气质特征密切相关。因此，我们建立了一个独特的动物模型的气质，是高度遗传和高度预测药物相关的行为。我们选择性地繁殖了两个品系的大鼠，根据它们在轻度压力的新环境中的探索性运动（EL）倾向的差异。繁殖的高反应者（bHR）和繁殖的低反应者（bLR）显示出可遗传行为的对比谱。与bLR相比，bHR表现出更高的感觉寻求和冲动性，对精神兴奋剂更敏感的倾向，以及药物和线索诱导的复发的阈值更低，这让人想起人类的“外化障碍”。bLR更容易出现焦虑和抑郁行为，对压力更敏感，从而引发寻求药物的行为。因此，这两条线将感觉寻求和对压力的高反应性建模为SUD的两条路径。我们的工作假设是，功能性DNA变异，来自远交的Sprague道利创始人，占目前的神经和行为分歧的两个线，并有关药物成瘾。在过去的资助期间，我们已经确定了EL和焦虑行为的数量性状位点（QTL），并发现了与气质差异相关的几个基因和遗传途径。我们目前的目标是增加我们对两个选择性繁殖系的遗传结构的理解，并专注于可能塑造可卡因寻求差异倾向的特定基因。我们的具体目标（SA）是： SA1：使用新技术来表征结构变异、染色质可及性和单核多组学，加深我们对bHR-bLR系的基因组和转录神经活性的理解。 SA2：描述可卡因获得对bHR与bLR大脑的不同影响，并将研究结果与它们之间的遗传和基因组差异联系起来。在单细胞水平和空间转录组学上使用染色质可及性/基因表达来定义可卡因对细胞粒度的神经影响。 SA3：使用严格的收敛标准确定在气质差异和/或对精神兴奋剂的反应中起关键作用的靶基因。我们将描述可卡因在特定细胞类型和与成瘾有关的大脑区域中的表达和调节。这将为建立其在成瘾中的因果作用的机制研究奠定基础，并将使未来的药物干预成为可能。 我们的发现将阐明人类感觉寻求和精神兴奋剂滥用之间的遗传和神经生物学联系，并为SUD的治疗和预防提供精确的方法。

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Substance abuse disorders (SUDs) are a major challenge to individuals and society and are caused by the interplay between genetic factors that shape vulnerability to drug addiction and environmental variables that can trigger and affect the course of these disorders. The goal of this project is to uncover the genetic and genomic mechanisms underlying the propensity for drug seeking and drug addiction. Evidence shows that the vast inter-individual differences in vulnerability to SUDs are strongly related to temperamental traits. We therefore established a unique animal model of temperament that is highly genetic and highly predictive of drug-related behaviors. We selectively bred two lines of rats based on differences in their propensity for exploratory locomotion (EL) in a mildly stressful novel environment. The bred High Responders (bHRs) and bred Low Responders (bLRs) show contrasting spectra of heritable behaviors. Compared to bLRs, bHRs exhibit higher sensation seeking and impulsivity, a 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 stress, which triggers drug-seeking behavior. Thus, the two lines model sensation seeking and high reactivity to stress as two paths to SUD. Our working hypothesis is that functional DNA variants, derived from outbred Sprague Dawley founders, account for the current neural and behavioral divergence of the two lines and are relevant to drug addiction. During the past funding period, we have identified quantitative trait loci (QTL) for EL and anxiety behaviors and have uncovered several genes and genetic pathways associated with differences in temperament. Our current goal is to increase our understanding of the genetic architecture of our two selectively bred lines and to focus on specific genes likely to shape the differential propensity for cocaine-seeking. Our Specific Aims (SA) are: SA1: Deepen our understanding of the genomic and transcriptional neural activity of the bHR-bLR lines using new technologies to characterize structural variations, chromatin accessibility and single nuclei multiomics. SA2: Characterize the differential impact of cocaine acquisition on the brains of bHRs vs. bLRs and relate the findings to genetic and genomic differences between them. Use chromatin accessibility/gene expression at the single cell level and spatial transcriptomics to define the neural impact of cocaine with cellular granularity. SA3: Identify target genes that play a key role in temperamental differences and/or the response to psychostimulants using stringent convergent criteria. We will characterize their expression and regulation by cocaine in specific cell types and brain areas implicated in addiction. This will lay the groundwork for mechanistic studies that establish their causal role in addiction and will enable future pharmacological interventions. Our discoveries will illuminate the genetic and neurobiological links between sensation seeking and psychostimulant abuse in humans and inform precision approaches to the treatment and prevention of SUDs.