Neuronal basis of cardiorespiratory control in vertebrates

脊椎动物心肺控制的神经元基础

• 批准号: RGPIN-2020-05312
• 负责人: Wilson, Richard
• 金额: $ 4.74万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717281
• 关键词: Neuronal; basis; cardiorespiratory; control; vertebrates

Cardiorespiratory control is essential for survival of all vertebrates, yet our understanding of the neuronal circuits involved is rudimentary, in part because there is little data beyond mammals to guide us. My NSERC-funded research program addresses this important knowledge gap by investigating cardiorespiratory rhythm generation in lower vertebrates. Most of our efforts have focused on respiratory rhythm generation in the bullfrog by using an isolated brainstem preparation. This preparation produces breathing motor patterns resembling those of intact animals for at least 24 hours. This resilience and the developmental accessibility of tadpoles makes frogs ideal for teaching neuroscience and for studying neuronal development and function in vertebrates. We discovered striking similarities in the neuronal circuits controlling breathing between bullfrogs and mammals, despite fundamental differences in their breathing mechanics. We found three discrete sites essential for rhythmogenesis (i.e., oscillators); one is for buccal ventilation, the other two are for lung inflation. Interactions between these oscillators (i.e.., their coupling) is required for the normal breathing motor patterns. Three coupled respiratory oscillators in mammals have also been identified, two for inspiration, the other for expiration. Moreover, the oscillators in the mammal and bullfrog brainstems are bilaterally iterated, occupy similar hindbrain rhombomere locations, and appear to share several functional properties. Recently, my graduate students discovered (a) that a mild increase in network excitation causes the buccal oscillator to transform into a distributed rhythm generating network (i.e. neuronal activity at the site of the buccal oscillator is no longer critical for rhythm generation) and (b) a fourth bilaterally-iterated oscillator in the frog nervous system at the level of Spinal Nerve (SN) III that is likely part of the sympathetic nervous system. The overall objective of the proposed research is to increase our understanding of cardiorespiratory circuits by critically evaluating the hypothesis that network excitation transforms discrete respiratory and sympathetic oscillators into distributed networks. In the next 5 years, my trainees and I will (a) pinpoint sympathetic oscillators to specific neuronal populations in the spinal cord; (b) test if network excitation transforms lung and sympathetic oscillators into distributed networks, as it does the buccal; and (c) test which architecture oscillator vs distributed is most likely in more intact preparations. This research will (a) provide excellent training opportunities in cellular and comparative neuroscience; (b) shed new light on cardiorespiratory rhythm generating networks in frogs; and (c) have the potential to determine the identity of the sympathetic oscillator in mammals important new knowledge for a deeper mechanistic understanding of how we breathe and regulate tissue perfusion.

呼吸控制对所有脊椎动物的生存都是必不可少的，但我们对所涉及的神经回路的理解是初步的，部分原因是除了哺乳动物之外，几乎没有什么数据可以指导我们。我的NSERC资助的研究项目通过调查低等脊椎动物的心肺节律产生来解决这一重要的知识缺口。 我们的大部分努力都集中在牛蛙呼吸节律的产生，通过使用一个孤立的脑干准备。该制剂产生类似于完整动物的呼吸运动模式至少24小时。这种弹性和蝌蚪的发育可及性使青蛙成为神经科学教学和研究脊椎动物神经元发育和功能的理想选择。 我们发现牛蛙和哺乳动物之间控制呼吸的神经回路有惊人的相似之处，尽管它们的呼吸机制有根本的不同。我们发现了三个对节律发生至关重要的离散位点（即，振荡器）;一个用于口腔通气，另外两个用于肺充气。这些振荡器之间的相互作用（即，它们的耦合）是正常呼吸运动模式所需要的。在哺乳动物中也发现了三个耦合的呼吸振荡器，两个用于吸气，另一个用于呼气。此外，振荡器在哺乳动物和牛蛙脑干是双边迭代，占据类似的后脑菱形位置，并出现共享几个功能特性。 最近，我的研究生发现（a）网络激励的轻微增加会导致颊振荡器转变为分布式节律生成网络（即颊侧振荡器部位的神经元活动对于节律产生不再是关键的）和（B）蛙神经系统中脊神经（SN）水平的第四个双侧迭代振荡器可能是交感神经系统的一部分。 拟议的研究的总体目标是通过严格评估网络激励将离散的呼吸和交感神经振荡器转换为分布式网络的假设来增加我们对心肺回路的理解。 在接下来的5年里，我和我的学员将（a）将交感神经振荡器精确定位到脊髓中的特定神经元群体;（B）测试网络激励是否将肺和交感神经振荡器转化为分布式网络，就像它在口腔中所做的那样;（c）测试哪种架构振荡器与分布式振荡器最有可能在更完整的准备中。 这项研究将（a）提供细胞和比较神经科学的极好培训机会;（B）阐明青蛙心肺节律生成网络的新观点;以及（c）有可能确定哺乳动物交感神经振荡器的身份，这是对我们如何呼吸和调节组织灌注的更深入机械理解的重要新知识。