Role of an arousal circuit in respiration and opioid-induced respiratory depression

唤醒回路在呼吸和阿片类药物引起的呼吸抑制中的作用

• 批准号: 10833329
• 负责人: Adrienn Gabriella Varga
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10833329
• 关键词: Address; Animals; Arousal; Award; Brain; Brain Stem; Breathing; Career Choice; Cause of Death; Cell Nucleus; Cells; Coupled; Data; Depressed mood; Development; Electrophysiology (science); Fiber; Foundations; Frequencies; Glutamates; Goals; Image; Impairment; Individual; Knowledge; Mediator; Mentors; Mentorship; Methodology; Methods; Modeling; Monitor; Mus; Naloxone; Neurobiology; Neurons; Neurosciences; Norepinephrine; Opioid; Opioid Antagonist; Opsin; Outcome; Overdose; Pain; Pathway interactions; Pharmacology; Phase; Photometry; Play; Population; Research; Research Personnel; Respiration; Respiratory physiology; Role; Sedation procedure; Sensory; Slice; Solid; Source; Structure; Synapses; Technical Expertise; Techniques; Testing; Training; Ventilatory Depression; Wakefulness; Withdrawal; awake; career; career development; cell type; combat; design; experience; in vivo; insight; locus ceruleus structure; mind control; neural; neural circuit; neurochemistry; neuromechanism; neurophysiology; noradrenergic; novel; opioid mortality; opioid overdose; optogenetics; postsynaptic; presynaptic; professor; programs; research and development; respiratory; sedative; side effect; therapeutic target; virus genetics; voltage clamp

PROJECT SUMMARY This K99/R00 Pathway to Independence Award is designed to allow the candidate to achieve her long-term goal to establish an independent research career focused on how arousal circuits in the brain control breathing, and how these neural mechanisms are influenced by opioids. This proposal has been tailored to supplement the candidate’s background in neuroscience and respiratory neurophysiology with additional knowledge and technical skills to study respiratory control circuits in vivo and ex vivo, and will make her ideally suited to succeed on her career path. The primary cause of death from an opioid overdose is respiratory depression. The sedative effect of opioids further impairs respiratory drive through largely unexplored mechanisms. Although overdoses are routinely treated with the opioid antagonist, naloxone, naloxone reverses all opioid effects, causing pain and withdrawal. Our current understanding of opioid effects on the respiratory circuitry has not revealed an ideal therapeutic target to minimize respiratory depression without serious side effects. Therefore, it is essential to identify new strategies to alleviate respiratory depression and stimulate breathing. This proposal seeks to uncover important new insights whereby the locus coeruleus (LC), a brain structure widely known for its contributions to arousal, influences the Kӧlliker-Fuse (KF), a key respiratory region, which is highly sensitive to opioids and critical for opioid-induced respiratory depression. Preliminary data spanning cell-type specific neural tracing, ex vivo brain slice recordings, and in vivo optogenetics and fiber photometry, support a role for LC input to the KF in respiration, which has not been previously appreciated. Based on preliminary data, the overall hypothesis is that the LCKF circuit is a critical modulator of respiratory function, particularly during opioid-induced respiratory depression. The candidate’s prior training in brain slice recordings, in vivo electrophysiology in awake animals, and intersectional viral- genetic methods provides a solid foundation for the state-of-the-art ex vivo and in vivo optogenetics and fiber photometry techniques in the proposal. This multi-level approach will allow the candidate to test the hypothesis that KF neurons receive opioid-sensitive, monosynaptic excitatory input from LC neurons (Aim 1), that KF projecting LC neuron activity is coupled with respiration in vivo (Aim 2), and the LCKF circuit plays a key role in respiration and opioid-induced respiratory depression (Aim 3). Together, the aims of this proposal will yield novel information regarding the brain’s control of respiration and will also provide strong conceptual and methodological training, enabling development of an impactful and successful independent research program. Strong mentorship by Drs. Erica Levitt and David Fuller, as well as a Mentoring Committee comprised of established professors, who are experts in the proposed techniques and have extensive mentoring experience, will help the candidate achieve the research and career development goals of this proposal.

项目概要 K99/R00 独立之路奖旨在让候选人实现长期目标 目标是建立一个独立的研究事业，专注于大脑中的唤醒回路如何控制 呼吸，以及这些神经机制如何受到阿片类药物的影响。 补充候选人在神经科学和呼吸神经生理学方面的背景 研究体内和离体呼吸控制回路的知识和技术技能，将使她成为理想的人选 阿片类药物过量导致死亡的主要原因是呼吸系统。 阿片类药物的镇静作用进一步损害了呼吸动力，而这种作用在很大程度上尚未被探索。 尽管过量服用阿片类药物拮抗剂纳洛酮是常规治疗方法。 逆转所有阿片类药物的作用，导致疼痛和戒断。 呼吸回路尚未揭示出一种理想的治疗目标，可以在不发生呼吸抑制的情况下最大限度地减少呼吸抑制 因此，有必要寻找新的策略来缓解呼吸抑制和副作用。 该提案旨在揭示蓝斑（LC）的重要新见解， 因其对唤醒的贡献而广为人知的大脑结构，会影响 Kølliker-Fuse (KF)，这是一个关键的因素 呼吸区对阿片类药物高度敏感，对阿片类药物引起的呼吸抑制至关重要。 初步数据涵盖细胞类型特异性神经追踪、离体脑切片记录和体内 光遗传学和光纤光度测定法支持 LC 输入 KF 在呼吸中的作用，但这一点尚未得到证实 根据初步数据，总体假设是 LCKF 电路是一个关键电路。 呼吸功能调节剂，特别是在阿片类药物引起的呼吸抑制期间。 先前接受过脑切片记录、清醒动物体内电生理学和交叉病毒学方面的培训 遗传方法为最先进的离体和体内光遗传学和纤维提供了坚实的基础 提案中的光度测量技术将允许候选人检验假设。 KF 神经元从 LC 神经元接收阿片敏感的单突触兴奋性输入（目标 1），KF 投射 LC 神经元活动与体内呼吸耦合（目标 2），LCKF 电路起着关键作用 在呼吸和阿片类药物引起的呼吸抑制中的作用（目标 3），该提案的目标将共同实现。 产生有关大脑控制呼吸的新颖信息，并且还将提供强有力的概念和 方法培训，有助于制定有影响力且成功的独立研究计划。 Erica Levitt 博士和 David Fuller 博士的大力指导，以及由以下人员组成的指导委员会 知名教授，他们是所提议技术的专家，并拥有广泛的指导 经验，将帮助候选人实现本提案的研究和职业发展目标。