Modeling the role of the NTS in the neurogenesis of airway defensive behaviors

项目总结 各种神经肌肉疾病会导致严重咳嗽(肌无力)。这些呼吸道保护性疾病 行为增加了吸入引起的肺部感染，这是神经肌肉疾病死亡的主要原因 疾病。吸入性肺炎的死亡率-存在于超过一半的长期护理居民-可以 接近40%。对呼吸道的防御是通过协调多种保护行为来实现的， 仍未完全了解的大脑回路。当代数据驱动的计算模型 结合呼吸的脑干网络可以迅速重组，产生咳嗽的三个阶段 运动模式：吸气、压缩和排气。然而，呼吸道保护的关键要素不能 被解释清楚。在激励初步数据和网络模拟的基础上，我们提出了 孤束核(NTS)和延髓背侧调节相位计时和呼吸肌驱动 在阵发性咳嗽期间，并对脑干呼吸控制系统施加命令功能，以 协调咳嗽和呼吸。该项目有三个具体目标：(1)确定动态行为- 在呼吸道保护行为表达过程中NTS环路的依赖组织。(二)确定 咳嗽时NTS和VRC神经元之间的功能连接。(3)重建我们的 呼吸系统模型结合了对呼吸道保护性反射和呼吸的调节。我们独一无二的 在对NTS地区进行试验性审讯的基础上，采用了多阵列记录 在动物模型系统中产生对生理反应的防御行为的技术 相关的呼吸道紊乱。我们预计该项目将导致：a)一种新的、可预测的呼吸道模型 将产生保护，b)我们将了解条件活动细胞之间的功能关系 和t-E NTS神经元在咳嗽中的作用，以及c)我们将确定NTS对面旁/VRC功能的关键作用 调节咳嗽和呼吸的关系。这一新知识将提供关键的一步 了解咳嗽的神经发生机制以及如何控制这一行为以保护呼吸道。

PROJECT SUMMARY Various neuromuscular diseases result in impaired cough (dystussia). Disorders of these airway protective behaviors increase pulmonary infection due to aspiration, the leading cause of death in neuromuscular disease. Mortality rates of aspiration pneumonia - present in over half of long-term care residents - can approach 40%. Defense of the airway is achieved through coordination of multiple protective behaviors by brain circuits that remain incompletely understood. A contemporary data-driven computational model incorporating the brainstem network for breathing can rapidly reconfigure to produce the three phases a cough motor pattern: inspiration, compression, and expulsion. However, critical elements of airway protection cannot be explained. Based on motivating preliminary data and network simulations, we propose that a circuit in the nucleus of the solitary tract (NTS) and dorsal medulla regulates phase timing and respiratory muscle drive during paroxysmal coughs and exerts a command function over the brainstem respiratory control system to coordinate coughing and breathing. The project has 3 Specific Aims: (1) Determine dynamic behavior- dependent organization of NTS circuits during the expression of airway protective behaviors. (2) Determine functional connectivity between NTS and VRC neurons during expression of coughing. (3) Reconstruct our respiratory system model to incorporate regulation of both airway protective reflexes and breathing. Our unique approach, building upon experimental interrogation of the NTS region, incorporates multi-array recording technologies in an animal model system that generates defensive behaviors in response to physiologically relevant airway perturbations. We anticipate that the project will lead to: a) a new, predictive model of airway protection will be produced, b) we will understand functional relationships between conditionally active cells and t-E NTS neurons in producing cough, and c) we will identify critical NTS to parafacial/VRC functional relationships that regulate cough and breathing. This new knowledge will provide a critical step in understanding the neurogenesis of cough and how this behavior is controlled to protect the airway.