A Neural Control Circuit for Coughing

建议书摘要 咳嗽是一种重要的呼吸功能，可以保护呼吸道和肺部。咳嗽反射 可被吸入的颗粒物、病原体、刺激物或患有哮喘或COVID等肺部疾病激活- 19.大脑通过从呼吸系统排出空气来清除这些积聚的空气来控制咳嗽 分泌物。在病理情况下，咳嗽通常会变得过度，并产生严重的后果， 让人们寻求医疗救治。由于有限的原因，缺乏有效的止咳药物 对控制咳嗽的神经回路的认识。在我们的实验室里，我们最近开发了一个小鼠模型来研究 用小鼠身上可用的遗传和神经遗传学工具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 快速激动素1(Tac1)，在咳嗽挑战时被激活。这些神经元的光激活就足够了 在诱发咳嗽的过程中，这些神经元的遗传消融或化学沉默可以减少咳嗽 由止咳药引起的。这些结果揭示了大脑中第一个基因定义的神经元 由咳嗽药剂引起的咳嗽。根据这些初步结果，我们假设NTS Tac1 神经元是关键的咳嗽控制中心，由咳嗽刺激激活，并整合 大脑下游靶点通过SP-NK1R通路诱发咳嗽。两个目标是 建议：(1)研究NTS Tac1神经元的神经动力学和分子通路 咳嗽反应(2)识别NTS Tac1神经元下游咳嗽回路。这些研究将是 通过整合活动记录、药理学、电路追踪和光遗传学来追踪 咳嗽时NTS Tac1神经元的神经动力学、分子通路和下游回路。 为了了解这些神经元在病理条件下是如何调节的，我将研究它们的实时 在咳嗽挑战中的激活，并定义它们的分子途径。为了识别咳嗽回路，我会 确定NTS Tac1神经元的下游区域，并对这些投射进行功能研究。 该项目的成功完成将促进对内源性中枢神经回路的了解 和咳嗽的潜在途径。此外，这将导致潜在的毒品目标的确定 控制咳嗽，从而为新疗法的发展提供了新的机遇和更好的 治疗那些过度咳嗽的人。

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.