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A Neural Control Circuit for Coughing

咳嗽的神经控制电路

基本信息

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
项目类别：
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

项目摘要

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.

建议总结