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.

项目摘要 这项K99/R00独立奖项旨在使候选人能够长期实现她的长期 建立独立研究职业的目标，重点介绍了大脑控制中的唤醒电路 呼吸，以及这些神经机制如何受阿片类药物的影响。该提议已量身定制 补充候选人在神经科学和呼吸神经生理学方面的背景 在体内和体内研究呼吸控制电路的知识和技术技能，并将使她理想地 适合在她的职业道路上取得成功。阿片类药物过量导致死亡的主要原因是呼吸道 沮丧。阿片类药物的镇静作用进一步损害了呼吸驱动 机制 逆转所有阿片类药物作用，引起疼痛和戒断。我们目前对阿片类药物对阿片类药物的影响 呼吸回路尚未揭示一个理想的治疗靶标，可以最大程度地减少呼吸抑郁症 严重的副作用。因此，必须确定缓解呼吸抑郁症和 刺激呼吸。该建议旨在揭示重要的新见解，该见解层coeruleus（LC）， 大脑结构以其对唤醒的贡献而闻名，影响了Knamelliker-Fuse（KF），钥匙 呼吸区，对卵毒素高度敏感，对卵巢诱导的呼吸道抑郁症至关重要。 跨越细胞类型特异性神经跟踪的初步数据，离体脑切片记录和体内 光遗传学和光纤光度法，支持在呼吸中对KF输入的作用，这还不是 以前受到赞赏。基于初步数据，总体假设是LCKF电路是关键 呼吸功能的调节剂，特别是在阿片类药物诱导的呼吸抑制期间。候选人的 事先在脑切片记录中训练，体内电生理学中的动物和病毒术相交 遗传学方法为最先进的离体和体内光遗传学和光纤提供了坚实的基础 该提案中的光度法技术。这种多层次方法将使候选人能够检验假设 KF神经元从LC神经元（AIM 1）中接受阿片类药物敏感的单突触兴奋性输入（AIM 1） 投射LC神经元活性与体内呼吸相结合（AIM 2），LCKF电路弹奏钥匙 在呼吸和阿片类药物诱导的呼吸抑郁症中的作用（AIM 3）。该提议的目的在一起将 产生有关大脑控制呼吸控制的新信息，还将提供强大的概念和 方法论培训，使有影响力和成功的独立研究计划的发展。 博士的强烈精神训练。埃里卡·莱维特（Erica Levitt）和戴维·富勒（David Fuller）以及一个指导委员会完成 成熟的教授，他们是拟议技术的专家，并且具有广泛的心理 经验，将帮助候选人实现该提案的研究和职业发展目标。