Exploring the connectome of the respiratory network

探索呼吸网络的连接组

• 批准号: RGPIN-2021-02551
• 负责人: Pagliardini, Silvia
• 金额: $ 2.4万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742048
• 关键词: Exploring; connectome; respiratory; network

Breathing requires the synchronization of a complex motor program to control gas exchange and adequately respond to various physiological and environmental conditions. The central pattern generator that orchestrates the respiratory rhythm lies in the medulla and is hypothesized to be composed by at least two coupled oscillators. The preBötzinger complex is essential for inspiratory rhythmogenesis through contraction of inspiratory muscles and the paraFacial Respiratory Group, silent in resting conditions, is recruited during periods of increased respiratory demand and generates active expiration through contraction of abdominal muscles. Recently, the existence of a third generator, the Post-Inspiratory Complex, has been proposed to regulate respiratory braking during post-inspiration. It is essential that these oscillatory networks interact with each other on a breath by breath basis when they are all active, and that they receive an appropriately timed balance of excitatory and inhibitory inputs that support their rhythmic activity and allow for the coordination of respiratory motor activity with more complex orofacial behaviours, such as swallowing or vocalization. Research conducted in my laboratory aims to gain an understanding of the neural mechanisms that control breathing and affect its function during sleep, with a particular interest to the dissection of rhythmogenic, pharmacological and state-dependent properties of respiratory networks in the paraFacial Respiratory group and in the preBötzinger Complex. In the next five years of my NSERC research program we will focus on investigating the role of excitatory, inhibitory and neuromodulatory inputs on the main inspiratory oscillator, the preBötzinger Complex. Using state-of the-art technologies and transgenic mice lines in which specific neuronal population can be identified and controlled we will illuminate not only the connectivity of the network, but more importantly, the functional dynamics, the state dependence of these connections and their effect on ongoing breathing. The program will provide an outstanding opportunity for trainees to get involved in a cutting edge research program that is at the intersection of neuroscience, respiratory physiology and molecular pharmacology. The results from this work will increase our mechanistic understanding of the indispensable motor behavior of breathing in mammals and will serve as an example and the foundation for future work addressing other state-dependent neuromodulatory processes occurring in the brain.

呼吸需要一个复杂的运动程序的同步，以控制气体交换，并充分响应各种生理和环境条件。协调呼吸节律的中央模式发生器位于延髓，并被假设为由至少两个耦合振荡器组成。前Bötzinger复合体通过吸气肌的收缩对吸气节律的发生至关重要，而在静息状态下沉默的面旁呼吸群在呼吸需求增加期间被招募，并通过腹肌的收缩产生主动呼气。最近，已经提出了第三种发生器，即吸气后复合体的存在，以调节吸气后期间的呼吸制动。当这些振荡网络都处于活动状态时，它们必须在呼吸的基础上相互作用，并且它们接收到适当定时的兴奋性和抑制性输入的平衡，这些平衡支持它们的节律活动，并允许呼吸运动活动与更复杂的口面行为（如吞咽或发声）的协调。在我的实验室进行的研究旨在了解控制呼吸和影响其功能的神经机制在睡眠中，特别感兴趣的是解剖的节奏，药理学和状态依赖性的呼吸网络在paraFacial呼吸组和preBötzinger复合体。在接下来的五年里，我的NSERC研究计划将集中于研究兴奋性、抑制性和神经调节性输入对主要吸气振荡器（preBötzinger Complex）的作用。使用最先进的技术和转基因小鼠品系，其中特定的神经元群体可以被识别和控制，我们将不仅阐明网络的连接性，更重要的是，功能动力学，这些连接的状态依赖性及其对持续呼吸的影响。该计划将为学员提供一个绝佳的机会，参与神经科学，呼吸生理学和分子药理学交叉的前沿研究计划。这项工作的结果将增加我们对哺乳动物呼吸的不可或缺的运动行为的机械理解，并将作为一个例子和未来工作的基础，解决大脑中发生的其他状态依赖性神经调节过程。