Genomic mechanisms of decision-making and opioid use trajectories in the rat

大鼠决策和阿片类药物使用轨迹的基因组机制

• 批准号: 10266128
• 负责人: RALPH J DILEONE
• 金额: $ 64.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10266128
• 关键词: ATAC-seq; Affect; Amygdaloid structure; Animals; Behavior; Behavioral; Biological; Biological Assay; Biology; Chromatin; Chronic; Complex; Computer Models; Consequentialism; Data; Decision Making; Dependence; Dissociation; Drug Exposure; Drug abuse; Drug usage; Environmental Risk Factor; Female; Future; Genes; Genetic; Genetic Identity; Genetic study; Genomic approach; Genomics; Goals; Human; Individual; Individual Differences; Link; Mediating; Molecular; Neurobiology; Nucleus Accumbens; Opioid; Oral; Oxycodone; Pathology; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Predisposition; Process; Proteins; Proteomics; RNA Sequences; Rattus; Reporting; Risk; Sampling; Self Administration; Signal Pathway; Techniques; Therapeutic; Tissues; Transposase; Variant; Viral; Work; XCL1 gene; addiction; base; behavioral phenotyping; differential expression; drug development; experimental group; genetic variant; insight; male; neuromechanism; next generation; opioid use; opioid use disorder; psychostimulant; tool; transcriptome sequencing

PROJECT SUMMARY / ABSTRACT The transition from opioid use to abuse and, eventually, to dependence may be governed by distinct genetic mechanisms that alter the molecular pathways that mediate opioid use disorder (OUD). The identity of these genetic/genomic mechanisms is unknown, in part, because the majority of OUD studies have been done in substance-dependent individuals where the dissociation between susceptibility and consequence is ambiguous and genetic/environmental factors are equivocal. One potential strategy for investigating the genetic mechanisms underlying differences in opiate-use trajectories that we have been pursuing in rats is to examine the neurobiology of complex behavioral phenotypes that are associated with different phases of drug use. Our work has identified a decision-making phenotype (e.g., ¨+ parameter) that predicts opiate-taking behaviors in rats, which differs from the decision-making phenotype that is affected by opiate use (e.g., ¨0 parameter). We have found that these distinct phenotypes are controlled by different orbitofrontal circuits that involve the amygdala and nucleus accumbens, and our preliminary proteomic data indicates that these phenotypes are mediated by divergent signaling pathways. We posit, therefore, that these computationally-derived phenotypes could serve as a powerful tool for dissociating the genomic/genetic mechanisms of opioid use susceptibility from those that are consequential to drug use. Here, we propose to use state-of-the-art genomic approaches to identify genes that mediate susceptibility to opiate-taking behaviors and those that mediate drug-induced behavioral changes. In Aim 1, we will investigate the genomic mechanisms underlying susceptibility to oxycodone use. Decision making will be assessed in rats (N=300) to identify individuals who either have low or high ¨+ parameter (N=60/group) that predicts susceptibility to opiate-taking behaviors. RNA sequencing will be performed on tissue from the orbitofrontal cortex, nucleus accumbens and amygdala to identify genes whose expression differs between rats with a low or high ¨+ parameter. We will then perform ATAC sequencing to identify the open chromatin regions associated with the genes that differ between rats with a low or high ¨+ parameter. In Aim 2, we will investigate the genomic mechanisms underlying the decision-making consequences of oxycodone self- administration. Decision making will be assessed in rats (N=300) before and after they self-administer oxycodone to identify individuals who either have low or high ¨0 parameter (N=60/group) following drug exposure. Tissue collected from the orbitofrontal cortex, nucleus accumbens and amygdala will be sequenced using next- generation RNA sequence to identify genes whose expression differs between rats with a low or high ¨0 parameter. We will then perform ATAC sequencing to identify the open chromatin regions associated with the differentially expressed genes. Our results – integrating genomic approaches with human-based computational phenotypes in rats – will provide critical insights into the genomic mechanisms associated with distinct stages along the OUD trajectory and develop a translational platform for future studies of OUD in humans.

项目总结/摘要 从阿片类药物使用到滥用并最终依赖的转变可能受不同的遗传因素控制。 改变介导阿片类药物使用障碍（OUD）的分子途径的机制。这些人的身份 遗传/基因组机制尚不清楚，部分原因是大多数OUD研究都是在 易感性和后果之间的分离不明确的物质依赖个体 和遗传/环境因素是模棱两可的。研究遗传机制的一个潜在策略是 我们一直在大鼠中追踪的阿片类药物使用轨迹的潜在差异是检查 神经生物学的复杂行为表型与药物使用的不同阶段。我们的工作 已经鉴定了决策表型（例如，+参数）预测大鼠的阿片类药物服用行为， 其不同于受阿片剂使用影响的决策表型（例如，？0参数）。我们有 发现这些不同的表型是由涉及杏仁核的不同眶额神经回路控制的 我们初步的蛋白质组学数据表明，这些表型是由 不同的信号通路。因此，我们认为，这些计算衍生的表型可以服务于 作为一个强大的工具，分离阿片类药物使用易感性的基因组/遗传机制， 都与吸毒有关在这里，我们建议使用最先进的基因组方法来识别基因 介导对阿片类药物服用行为的易感性和介导药物诱导的行为变化的那些。 在目标1中，我们将研究羟考酮使用易感性的基因组机制。决定 将在大鼠（N=300）中进行评估，以确定具有低或高？+参数的个体 （N=60/组），预测对阿片类药物服用行为的易感性。将对组织进行RNA测序 从眶额皮质，杏仁核和杏仁核中提取基因，以确定其表达不同的基因， 具有低或高¨+参数的大鼠之间。然后我们将进行ATAC测序，以确定 与基因相关的染色质区域，这些基因在具有低或高？+参数的大鼠之间存在差异。在目标2中， 我们将研究羟考酮自我决策后果的基因组机制， 局将在大鼠（N=300）自我给予羟考酮之前和之后评估其决策能力 确定药物暴露后具有低或高？0参数的个体（N=60/组）。组织 从眶额皮质、杏仁核和杏仁核收集的DNA将使用next- 产生RNA序列，以确定基因的表达不同的大鼠之间的低或高 参数.然后，我们将进行ATAC测序，以确定开放的染色质区域相关的 差异表达基因我们的结果-整合基因组方法与基于人类的计算 表型-将提供关键的见解与不同阶段的基因组机制 沿着OUD的轨迹，并开发一个翻译平台，为未来的研究OUD在人类。