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

• 批准号: 10293782
• 负责人: Julie A Blendy
• 金额: $ 51.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10293782
• 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; Structure; System; Technology; Therapeutic; Time; Tissues; Visualization; Withdrawal; addiction; behavior measurement; cell type; combat; control theory; endogenous opioids; experimental study; 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

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.

项目摘要 阿片类药物成瘾是一种慢性，进行性疾病，可为当前美国阿片类药物过量死亡的流行促进。 多年来，大量的研究工作一直致力于理解生物学作用 卵虫类受体和开发新一代的合成烯酸药物来治疗疼痛和对抗卵虫类药物 瘾。但是，鉴于当代和新颖的神经科学技术的进步，我们有 超越MU-Apoid受体（MOR）的工具，以开发改进的OUD疗法。该提议的目的 研究内源表达大脑中内源性的神经回路的结构和功能 确定这些电路如何保持细胞依赖性并跨越大脑的不良适应可塑性 OUD周期的不同阶段。在四个完整的目标中，我们将首先绘制转移的结构和 Oioidergic网络的功能连通性使用病毒遗传和组织清除方法来识别 单突触的输入，以表达戒断激活的细胞和轴突输出投影，作为函数 opioet暴露和禁欲。然后，我们将将这些输入/输出图与单元类型信息整合在一起， 基因表达在依赖网络中使用超多形的3D原位杂交与 产生数百个依赖关系基因的解剖学定位，针对细胞类型和恢复 标记的连接。最后，揭示如何调制核心区域内的mor表达细胞。 实时暴露于Oopioer，我们将使用微型头部式头部显微镜来对种群活动进行图像 - 在细胞分辨率下 - 阿片类药物暴露和戒断的数周。我们的模型将提供正式 活动，连通性和基因表达的摘要随着重复的阿片类药物暴露而演变， 提取，我们的数据集将在生成时公开可用。桥接这些实验 测量并为我们的分析提供一个共同的框架，我们将采用网络控制理论 识别驱动阿片类药物依赖状态之间过渡以识别潜在候选者之间过渡的大脑节点 这不成比例地驱动每个状态。