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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要从阿片类药物使用到滥用并最终到依赖的转变可能受不同遗传因素的影响改变介导阿片类药物使用障碍（OUD）的分子途径的机制。遗传/基因组机制尚不清楚，部分原因是大多数 OUD 研究都是在物质依赖个体，其易感性和后果之间的分离是模糊的遗传/环境因素是研究遗传机制的一种潜在策略。我们一直在老鼠身上研究的阿片类药物使用轨迹的根本差异是为了检查与药物使用的不同阶段相关的复杂行为表型的神经生物学。已经确定了预测大鼠阿片类药物服用行为的决策表型（例如，“+参数”），这与受阿片类药物使用影响的决策表型不同（例如，我们有“0 参数”）。发现这些不同的表型是由涉及杏仁核的不同眶额回路控制的和伏核，我们的初步蛋白质组数据表明这些表型是由因此，我们假设这些计算得出的表型可以发挥作用。作为将阿片类药物使用敏感性的基因组/遗传机制与那些在这里，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引起的行为改变。在目标 1 中，我们将研究对羟考酮使用决策敏感的基因组机制。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）将在组织上进行 RNA 测序，预测对阿片类药物服用行为的敏感性。从眶额皮质、伏隔核和杏仁核中识别表达不同的基因然后，我们将进行 ATAC 测序来识别开放性。在目标 2 中，与具有低或高 ¡+ 参数的大鼠之间存在差异的基因相关的染色质区域。我们将研究羟考酮自我决策后果背后的基因组机制将在大鼠（N=300）自行施用羟考酮之前和之后评估决策制定。识别组织暴露后具有低或高 ¡0 参数（N=60/组）的个体。从眶额皮层、伏隔核和杏仁核收集的数据将使用下一步进行测序生成 RNA 序列，以识别具有低或高 ¡0 的大鼠之间不同表达的基因然后我们将执行 ATAC 测序来识别与该参数相关的开放染色质区域。我们的结果——将基因组方法与基于人类的计算相结合。大鼠的表型——将为与不同阶段相关的基因组机制提供重要的见解沿着 OUD 轨迹发展并为未来人类 OUD 研究开发一个转化平台。