Uncovering links between neuronal transcriptomic and functional profiles in opioid addiction

揭示阿片类药物成瘾中神经元转录组和功能谱之间的联系

基本信息

批准号：
10663262
负责人：
Lucas L Sjulson
金额：
$ 50.4万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2020-09-01 至 2025-07-31
项目状态：
未结题

项目摘要

Project Summary Recent advances in single-cell transcriptomic methods have revealed an incredible diversity of neuronal subtypes. This presents a challenge for understanding substance use disorders because these subtypes can only be identified in post mortem brain tissue, but substance use disorders occur only in living humans. One of the key unsolved problems is how to link these numerous transcriptomically-defined neuronal subtypes to their functional roles in drug addiction in the intact brain. In this proposal, we take first steps toward bridging this gap. First, we will use innovative optogenetic and electrophysiological techniques to record neuronal activity from genetically identified cell types in the nucleus accumbens during oral opioid self-administration in mice. We will also take the converse approach, using innovative optical methods to label neuronal subpopulations that are active during different phases of opioid self-administration, then identifying their transcriptomic profiles post mortem using a novel in situ sequencing method. We also describe plans to extend these techniques for compatibility with advanced in vivo multiphoton imaging and single-cell transcriptomic and epigenomic studies. We expect this project will open new lines of exploration in substance use disorders and contribute broadly to understanding the relationship between neuronal gene regulation and functional roles in opioid addiction, which may identify new therapeutic targets.

项目摘要单细胞转录组方法的最新进展揭示了令人难以置信的多样性神经元亚型。这给理解物质使用障碍带来了挑战因为这些亚型只能在验尸后脑组织中识别，但使用物质疾病仅发生在活人中。关键的未解决问题之一是如何链接这些问题许多转录定义的神经元亚型在药物成瘾中的功能作用在完整的大脑中。在此提案中，我们迈出了弥合这一差距的第一步。首先，我们将使用创新的光遗传学和电生理技术记录来自口服阿片类药物自我给药期间伏隔核中遗传鉴定的细胞类型在老鼠中。我们还将使用创新的光学方法采用相反的方法来标记在阿片类药物自我管理的不同阶段活跃的神经元亚群，然后使用小说的原位测序识别验尸后的转录组轮廓方法。我们还描述了扩展这些技术以与Advanced In相兼容的计划体内多光子成像以及单细胞转录组和表观基因组学研究。我们期望这一点项目将在物质使用障碍中开放新的探索线，并为了解神经元基因调节与阿片类药物的功能作用之间的关系成瘾，可以识别新的治疗靶标。