A Neural Control Circuit for Coughing

咳嗽的神经控制电路

• 批准号: 10678004
• 负责人: Noam Gannot
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-08 至 2024-10-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10678004
• 关键词: Ablation; Air; Animals; Antitussive Agents; Asthma; Brain; Brain Stem; COVID-19; Cavia; Cell Nucleus; Chronic; Complex; Coughing; Defense Mechanisms; Development; Drug Targeting; Dust; Event; Fiber; Foundations; Genetic; Germ; Goals; Inhalation; Irritants; Knowledge; Life; Lung; Lung diseases; Maps; Mediating; Medical; Modeling; Molecular; Molecular Target; Motor Neurons; Motor output; Mucous body substance; Mus; Nerve; Neural Pathways; Neurons; Neuropeptide Gene; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pharyngeal structure; Phase; Photometry; Physiological; Placebos; Play; Population; Prevalence; Reflex action; Resort; Respiration; Respiratory Disease; Respiratory System; Respiratory physiology; Role; Signal Transduction; System; TACR1 gene; Tachykinin; Testing; Therapeutic; Time; antagonist; calcium indicator; central pattern generator; common symptom; design; guinea pig model; in vivo; medical attention; mind control; mouse model; neural; neural circuit; neurogenetics; neuroregulation; novel therapeutics; optogenetics; particle; pathogen; pharmacologic; photoactivation; postsynaptic; response; success; tool

PROPOSAL SUMMARY Coughing is an important respiratory function that protects the airways and the lungs. The cough reflex can be activated by inhaled particles, pathogens, irritants, or having a lung disease such as asthma or COVID- 19. The brain controls coughing by expelling air from the respiratory system to clear these accumulated secretions. Coughing often becomes excessive with severe consequences under pathological conditions, resorting people to seek medical attention. Effective anti-tussive medications are lacking due to the limited knowledge on the neural circuit controlling cough. In our lab, we recently developed a mouse model to study the neural pathways for coughing with the genetic and neurogenetic tools available in mice. We identified a sub-population of neurons within the nucleus tractus solitarius (NTS) that express the neuropeptide gene tachykinin 1 (Tac1) that are activated during tussive challenges. Photoactivation of these neurons is sufficient in inducing coughing, while genetic ablation or chemogenetic silencing of these neurons diminishes the coughs induced by tussive agents. These results reveal the first genetically defined neurons in the brain that mediate coughing induced by tussive agents. Based on these preliminary results, we hypothesize that the NTS Tac1 neurons are the key cough control center that are activated by the tussive challenge and integrate the downstream targets in the brain to induce coughing through the SP-NK1R pathway. Two aims are proposed: (1) investigate the neural dynamics and molecular pathway underlying how NTS Tac1 neurons respond to coughing (2) identify the downstream cough circuit of the NTS Tac1 neurons. These studies will be accomplished by integrating activity recording, pharmacology, circuit tracing, and optogenetics to trace the neural dynamics, the molecular pathways, and the downstream circuits of the NTS Tac1 neurons in coughing. To understand how these neurons are modulated in pathological conditions, I will examine their real-time activation during a tussive challenge and define their molecular pathway. To identify the cough circuit, I will identify the downstream regions of NTS Tac1 neurons and conduct a functional study on these projections. The successful completion of this project will advance the knowledge of the endogenous central neural circuit and pathway underlying cough. Furthermore, it will lead to the potential identification of drug targets for manipulating cough, thereby providing new opportunities for the development of novel therapeutics and better treatments for those suffering from excessive coughing.

提案摘要 咳嗽是保护气道和肺部的重要呼吸功能。咳嗽反射 可以通过吸入的颗粒，病原体，刺激性或患有肺部疾病（例如哮喘或共同）激活 19。大脑通过从呼吸系统中排出空气来清除这些积累来控制咳嗽 分泌物。在病理条件下，咳嗽通常会变得过度，严重后果， 求助于人们寻求医疗护理。由于有限 关于控制咳嗽的神经回路的知识。在我们的实验室中，我们最近开发了一个鼠标模型来研究 小鼠可用的遗传和神经遗传学工具咳嗽的神经途径。我们确定了一个 表达神经肽基因的神经元（NTS）内神经元的亚群 在打击挑战期间激活的速度蛋白1（TAC1）。这些神经元的光活化就足够了 在咳嗽时，这些神经元的遗传消融或化学遗传沉默会减少咳嗽 由打击剂诱导。这些结果揭示了大脑中第一个遗传定义的神经元介导的 咳嗽是由打击剂引起的。基于这些初步结果，我们假设NTS TAC1 神经元是被打击挑战激活并整合的关键咳嗽控制中心 大脑中的下游靶标诱导通过SP-NK1R途径咳嗽。两个目标是 提议：（1）研究NTS TAC1神经元的神经动力学和分子途径 应对咳嗽（2）识别NTS TAC1神经元的下游咳嗽电路。这些研究将是 通过整合活动记录，药理学，电路跟踪和光遗传学来实现 咳嗽中NTS TAC1神经元的神经动力学，分子途径和下游电路。 要了解这些神经元如何在病理状况下调节，我将检查它们的实时 在打击挑战期间的激活并定义了它们的分子途径。要识别咳嗽电路，我将 确定NTS TAC1神经元的下游区域，并就这些预测进行功能研究。 该项目的成功完成将促进内源性中心神经回路的知识 和咳嗽的途径。此外，它将导致对药物靶标的潜在识别 操纵咳嗽，从而为开发新型治疗和更好 为患有过度咳嗽的人的治疗。