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A comprehensive dissection of cell types, circuits and molecular adaptations during opioid use

对阿片类药物使用过程中的细胞类型、回路和分子适应的全面剖析

基本信息

批准号：
10302852
负责人：
MARK J SCHNITZER
金额：
$ 143.73万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2021-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10302852
关键词：
Abstinence Adenylate Cyclase Amygdaloid structure Anatomy Architecture Arrestins BRAIN initiative Behavioral Binding Brain Brain imaging Brain region Catalogs Cell Nucleus Cells Censuses Chronic Complex Computer Analysis Crystallization Data Data Coordinating Center Data Set Databases Dependence Dissection Electrophysiology (science)Ensure Foundations Functional Imaging Funding G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Gene Expression Profile Gene Family Genes Habenula Hippocampus (Brain)Hypothalamic structure Immunohistochemistry In Situ Hybridization Institutes Ion Channel Knowledge Label Length Link Maps Mediating Modeling Molecular Molecular Target Morphine Mus National Institute of Drug Abuse Nerve Tissue Nervous system structure Neurobiology Neurons Nucleus Accumbens Nucleus solitarius ORL1 receptor Opiate Addiction Opioid Opioid Analgesics Opioid Peptide Opioid Receptor Optics Output Pain Pain management Phosphotransferases Postoperative Pain Prefrontal Cortex Protein Isoforms Protein Subunits Protocols documentation Reporter Research Research Personnel Resolution Resources Science Self Administration Sensitivity and Specificity Slice Surveys System Technology Thalamic structure Toxic effect Ventilatory Depression Ventral Tegmental Area Viral Withdrawal Work addiction brain cell cell type clinically relevant computer studies conditioned place preference cranium dorsal raphe nucleus endogenous opioids experimental group imaging modality imaging study improved in vivo innovation innovative technologies midbrain central gray substance molecular dynamics mouse model mu opioid receptors neural circuit nociceptin novel novel therapeutic intervention opioid exposure opioid use opioid use disorder parabrachial nucleus prevent radioligand receptor relating to nervous system response side effect single-cell RNA sequencing transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY A major barrier in the field of opioid research is our limited understanding of the organization of the opioid system in the brain: we still do not know which cell types express each opioid receptor (mu, delta, kappa, nociceptin) to mediate the effects of endogenous and exogenous opioids, nor what other molecules are present in these cells. Without this knowledge, understanding how opioids alter activity in circuits to produce behavioral effects remains elusive. This gap in knowledge prevents the identification of molecular targets to potentiate opioid analgesia and mitigate the deleterious effects of opioid use disorder (OUD), including addiction and respiratory depression. To fill this gap in knowledge, we propose to leverage the uniquely massive single-cell RNA sequencing (scRNA-seq) database generated by the Allen Institute for Brain Science (>3.4 million cells throughout the entire mouse brain) as part of the BRAIN Initiative Cell Census Network (BICCN) effort. Using this database, we will establish a comprehensive catalog of all the cell types that express each opioid receptor and peptide throughout the brain, as well as the co-expression of gene networks that mediate or regulate opioid actions, including other G protein-coupled receptors and cellular effectors of opioid receptors (Aim 1). Further, we will use our well- established high-throughput single-cell RNA-seq pipelines to characterize the cell-type-specific molecular adaptations that occur during chronic opioid exposure, withdrawal, and abstinence, using a clinically relevant model of post-surgical pain for which opioids are typically prescribed (Aim 2). Finally, we will leverage this novel knowledge to dissect the mechanisms of action of opioids by performing advanced circuit mapping and in vivo functional imaging studies of cell types expressing opioid receptors in the prefrontal cortex (PFC), a region critical to both opioid analgesia and addiction (Aim 3). Our transformative work will be the first to combine several highly innovative technologies at the molecular, circuit, and neural ensemble levels, including high-throughput scRNA-seq, new viral strains with improved transsynaptic transfer and decreased toxicity for circuit mapping, the crystal skull and miniscope- microprism optical approaches for in vivo wide-field imaging of brain state and for recording dynamics of molecularly defined neuron types in freely moving mice undergoing opioid analgesia and addiction paradigms. We have an extraordinary interdisciplinary team of investigators with highly complementary expertise in the neurobiology of opioids and the distribution and function of their receptors in pain and addiction circuits, the molecular and anatomical brain architecture, large-scale cell type characterization and circuit mapping, and highly innovative brain imaging methods as applied to the study of neural circuits. Overall, this research aims to generate an exceptional resource for the opioid field (to be made publicly available through the NIDA-funded SCORCH data coordination center) to explain how opioids change the brain, and discover novel therapeutic approaches to prevent and treat OUD.

项目总结