Mapping opioid-dependence state transitions across structural, functional, and transcriptomic topologies

绘制结构、功能和转录组拓扑中阿片类药物依赖性状态转变的图谱

基本信息

批准号：
10493185
负责人：
Julie A Blendy
金额：
$ 48.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10493185
关键词：
3-Dimensional Abstinence Acute Address Adopted Anatomy Architecture Atlases Axon Behavior Biological Brain Brain region Cell Nucleus Cells Characteristics Chronic Classification Coupled Data Set Databases Dependence Development Disease Drug usage Epidemic Evolution Future Gene Expression Gene Targeting Generations Genes Genetic Genetic Transcription Genomics Graph Head Image In Situ Hybridization Incidence Label Lifestyle-related condition Machine Learning Maps Measurement Mediating Methods Microscope Modeling Neurons Neurophysiology - biologic function Neurosciences Opiate Addiction Opioid Opioid Peptide Opioid Receptor Output Pain Pathologic Pharmaceutical Preparations Population Relapse Research Research Personnel Resolution Rodent Role Sampling Site System Technology Therapeutic Time Tissues Visualization Withdrawal addiction behavior measurement cell type combat control theory endogenous opioids experimental study gene network high throughput screening improved innovation mathematical model mu opioid receptors neural circuit neural network neuroadaptation next generation novel opioid epidemic opioid exposure opioid mortality opioid use disorder opioid withdrawal relating to nervous system searchable database synthetic opioid theories tool transcriptome sequencing transcriptomics virus genetics

项目摘要

PROJECT SUMMARY Opioid addiction is a chronic, progressive disorder that fuels the current US epidemic of opioid overdose deaths. Over the years, a tremendous amount of research effort has been devoted to understanding the biological roles of opioid receptors and developing newer generations of synthetic opioids to treat pain and combat opioid addiction. However, given the advancement of contemporary and novel neuroscience technologies, we have the tools to think beyond mu-opioid receptors (MORs) to develop improved OUD therapeutics. This proposal aims to investigate the architecture and function of endogenous MOR-expressing neural circuits in the brain and to determine how these circuits maintain cellular dependence and drive brain-wide maladaptive plasticity across different stages of the OUD cycle. In four complementary aims, we will first map the shifting structural and functional connectivity of opioidergic networks using viral-genetic and tissue clearing methods to identify monosynaptic inputs to withdrawal-active MOR-expressing cells and axonal output projections, as a function of opioid exposure and abstinence. We will then integrate these input/output maps with cell-type information and gene expression changes within dependence networks using hyper-multiplexed 3D in situ hybridizations to generate the anatomic localization of hundreds of dependence-related genes, targeted to cell types and retro- labeled connections. Finally, to reveal how MOR-expressing cells within core regions are modulated during opioid exposure in real-time, we will use miniature head-mounted microscopes to image the population activity— at cellular resolution—across weeks of opioid exposure and withdrawal. Our models will provide formal summaries of activity, connectivity, and gene expression as they evolve with repetitive opioid exposure and withdrawal, and our datasets will be made publicly available as they are generated. To bridge these experimental measurements and provide a common framework for our analyses, we will adopt Network Control Theory to identify brain nodes that drive the transition between opioid dependence states to identify potential candidates that disproportionately drive each state.

项目概要阿片类药物成瘾是一种慢性进行性疾病，加剧了美国目前阿片类药物过量死亡的流行。多年来，大量的研究工作致力于了解其生物学作用阿片受体并开发新一代合成阿片类药物来治疗疼痛和对抗阿片类药物然而，鉴于当代和新颖的神经科学技术的进步，我们已经有了。超越 mu-阿片受体 (MOR) 的工具来开发改进的 OUD 疗法。研究大脑中内源性 MOR 表达神经回路的结构和功能确定这些回路如何维持细胞依赖性并驱动整个大脑的适应不良可塑性在 OUD 周期的不同阶段，我们将首先绘制结构和结构转变的四个互补目标。使用病毒遗传和组织清除方法识别阿片能网络的功能连接撤回活性 MOR 表达细胞的单突触输入和轴突输出投影，作为函数然后，我们将这些输入/输出图与细胞类型信息结合起来。使用超多重 3D 原位杂交在依赖网络中改变基因表达生成数百个依赖性相关基因的解剖定位，针对细胞类型和逆转录最后，揭示核心区域内的 MOR 表达细胞在过程中是如何受到调节的。实时阿片类药物暴露，我们将使用微型头戴式显微镜对人群活动进行成像—— 在细胞分辨率上——在阿片类药物暴露和戒断的几周内，我们的模型将提供正式的结果。活动、连接性和基因表达随着重复阿片类药物暴露而演变的总结退出，我们的数据集将在生成后公开，以桥接这些实验。测量并为我们的分析提供一个通用框架，我们将采用网络控制理论来识别驱动阿片类药物依赖状态之间转变的大脑节点，以识别潜在的候选人这不成比例地推动了每个州。