Unraveling the Locus Coeruleus Circuitry in Opioidinduced Sleep Disturbances

解开阿片类药物引起的睡眠障碍中的蓝斑回路

• 批准号: 10187134
• 负责人: Li Li
• 金额: $ 17.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187134
• 关键词: Acute; Acute Pain; Anesthetics; Arousal; Behavior; Brain; Brain region; Cells; Chronic; Cognition; Data; Data Analyses; Disease; Doctor of Philosophy; Dose; Drug Targeting; Drug usage; Electroencephalography; Electromyography; Equilibrium; Fiber; Foundations; Future; Glutamates; Goals; Image; Injections; Machine Learning; Measures; Mediating; Mediator of activation protein; Mental Depression; Mentors; Mentorship; Morphine; Mus; Naloxone; Neurobiology; Neurons; Neuropharmacology; Norepinephrine; Operative Surgical Procedures; Opiate Addiction; Opioid; Opioid Receptor; Oxymorphone; Pain Threshold; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Photometry; Photons; Physicians; Postoperative Pain; Receptor Cell; Relapse; Research Personnel; Risk; Role; Saline; Sleep; Sleep disturbances; Source; Substance abuse problem; Technical Expertise; Techniques; Testing; Thalamic structure; Time; Training; United States; Universities; Virus; Washington; Withdrawal; Withdrawal Symptom; awake; base; behavior measurement; calcium indicator; career; cell type; conditional knockout; dependence relapse; economic cost; in vivo; insight; locus ceruleus structure; morphine administration; mouse model; mu opioid receptors; multidisciplinary; negative affect; neural circuit; neurobiological mechanism; novel strategies; novel therapeutics; opioid epidemic; opioid use; opioid use disorder; opioid withdrawal; optogenetics; overdose death; receptor expression; receptor function; response; sedative; sensor; side effect; skills; skills training; sleep pattern; tool

PROJECT SUMMARY The main goals of this training proposal is 1) to provide Li Li, MD, PhD, a practicing anesthesiologist at the University of Washington, with additional scientific and professional skills to facilitate his transition to become an independent investigator, and 2) to better understand how the locus coeruleus (LC), at the cellular and circuit levels, contributes to opioid-induced sleep disturbances. Studying sleep disturbances caused by opioids is important because opioids have enormous societal impact, causing over 46,000 overdose deaths in 2018 and almost $80 billion in economic cost annually in the United States; and because recent studies have implicated several aspects of sleep disturbances caused by opioids, including poorer cognition, decreased pain tolerance, and increased negative affect, in contributing to chronic opioid use and relapse. Interestingly, the LC and paraventricular thalamus (PVT) are two brain regions that modulate sleep-wake balance and mediate withdrawal behaviors from opioids, but their roles in opioid-induced sleep disturbances are relatively unknown. Thus, during his K99 phase, Dr. Li aims to 1) examine LC neuronal activity in relation to sleep patterns in a mouse model of acute and chronic opioid administration and 2) determine the role of local opioid receptors in the LC in opioid- induced sleep disturbances. Furthermore, he plans to receive training in 1-photon microendoscopic imaging, optogenetic manipulation of opioid receptors, and cell-specific drug targeting using drug acutely restricted by tethering (DART); and will be mentored by Prof. Michael Bruchas, a world-renowned expert in opioid neurobiology, and a committee of experts in neural circuitry analysis, sleep, and substance abuse disorders. Together, his training will help transition to his independent R00 phase, where he plans to use his trained skills 1) to examine PVT neuronal activity in relation to sleep patterns in acute and chronic opioid administration, and to determine role of local opioid receptors in PVT in opioid-induced sleep disturbances. Studies in the independent phase will prepare him for a future R01 submission to further examine arousal neural circuitry response to sedative and anesthetic drugs. Thus, this proposal aims to characterize the LC-PVT circuit in a mouse model of acute and chronic opioid administration using cutting-edge tools in neural circuit analysis and cell-specific pharmacology in order to better understand the cellular and circuit mechanism underlying opioid- induced sleep disturbances, and provides the essential training and mentorship for Dr. Li to help him achieve his career goal of starting his own lab and becoming an independent investigator.

项目概要 本培训计划的主要目标是 1) 提供 Li Li, MD, Ph.D, 执业麻醉师 华盛顿大学，拥有额外的科学和专业技能，以促进他过渡成为一名 独立研究者，2) 更好地了解蓝斑 (LC) 在细胞和电路中的作用 水平，导致阿片类药物引起的睡眠障碍。研究阿片类药物引起的睡眠障碍是 这很重要，因为阿片类药物具有巨大的社会影响，2018 年导致超过 46,000 人因服药过量死亡， 美国每年造成近 800 亿美元的经济损失；并且因为最近的研究表明 阿片类药物引起的睡眠障碍的几个方面，包括认知能力较差、疼痛耐受力下降、 并增加负面影响，导致慢性阿片类药物使用和复发。有趣的是，LC 和 室旁丘脑 (PVT) 是调节睡眠-觉醒平衡和介导戒断的两个大脑区域 阿片类药物的行为，但它们在阿片类药物引起的睡眠障碍中的作用相对未知。因此，期间 在 K99 阶段，李博士的目标是 1) 在小鼠模型中检查 LC 神经元活动与睡眠模式的关系 急性和慢性阿片类药物给药，2) 确定阿片类药物中局部阿片受体在 LC 中的作用 诱发睡眠障碍。此外，他计划接受 1 光子显微内窥镜成像培训， 阿片受体的光遗传学操作，以及使用严格限制的药物的细胞特异性药物靶向 网络共享（DART）；并将得到世界著名阿片类药物专家 Michael Bruchas 教授的指导 神经生物学，以及神经回路分析、睡眠和药物滥用障碍方面的专家委员会。 总之，他的训练将有助于过渡到他的独立 R00 阶段，他计划在此阶段运用他训练有素的技能 1) 检查急性和慢性阿片类药物给药中与睡眠模式相关的 PVT 神经元活动，以及 确定局部阿片受体在阿片类药物引起的睡眠障碍中 PVT 中的作用。研究领域 独立阶段将为他未来提交 R01 做好准备，以进一步检查唤醒神经回路 对镇静和麻醉药物的反应。因此，本提案旨在表征 LC-PVT 电路的特性 使用尖端工具进行神经回路分析和急性和慢性阿片类药物给药的小鼠模型 细胞特异性药理学，以便更好地了解阿片类药物的细胞和回路机制 引起的睡眠障碍，并为李医生提供必要的培训和指导，以帮助他实现他的目标 创办自己的实验室并成为一名独立研究者的职业目标。