A Neural Control Circuit for Coughing

提案摘要 咳嗽是一种重要的呼吸功能，可以保护气道和肺部。咳嗽反射 可被吸入颗粒、病原体、刺激物或患有哮喘或COVID等肺部疾病激活。 19.大脑通过排出呼吸系统中的空气来控制咳嗽，以清除这些积聚的空气 分泌物在病理条件下，咳嗽常常变得过度并具有严重后果， 让人们去寻求医疗救助有效的止咳药物缺乏，由于有限的 关于控制咳嗽的神经回路的知识。在我们的实验室里，我们最近开发了一种小鼠模型来研究 用老鼠身上的遗传和神经遗传学工具来研究咳嗽的神经通路。我们确定了一个 孤束核（NTS）内表达神经肽基因的神经元亚群 速激肽1（Tac 1）在咳嗽挑战期间被激活。光激活这些神经元就足够了 而基因切除或化学沉默这些神经元则会减少咳嗽 由咳嗽药引起的。这些结果揭示了大脑中第一个遗传定义的神经元， 由咳嗽剂引起的咳嗽。基于这些初步结果，我们假设NTS Tac 1 神经元是关键的咳嗽控制中心，它们被咳嗽激发激活，并整合 在脑中的下游靶点通过SP-NK 1 R途径诱导咳嗽。两个目标是 研究内容如下：（1）研究NTS Tac 1神经元在不同时间点的神经动力学和分子通路 （2）识别NTS Tac 1神经元的下游咳嗽回路。这些研究报告将 通过整合活动记录，药理学，电路跟踪和光遗传学来跟踪 神经动力学、分子通路和NTS Tac 1神经元在咳嗽中的下游回路。 为了了解这些神经元在病理条件下是如何调节的，我将检查它们的实时 在咳嗽挑战期间激活并定义其分子途径。为了识别咳嗽回路，我会 确定NTS Tac 1神经元的下游区域，并对这些投射进行功能研究。 本课题的成功完成将进一步加深对内源性中枢神经回路的认识 和咳嗽的潜在途径。此外，它将导致潜在的药物靶点识别， 控制咳嗽，从而为开发新的治疗方法提供新的机会， 治疗那些患有过度咳嗽。

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.