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: 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=740501
• 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.

心肺控制对所有脊椎动物的生存都至关重要，但我们对其中涉及的神经回路的理解还很初级，部分原因是除了哺乳动物之外，几乎没有数据可以指导我们。我的nserc资助的研究项目通过研究低等脊椎动物的心肺节律产生来解决这一重要的知识差距。我们的大部分工作都集中在利用分离的脑干制备牛蛙的呼吸节律产生上。这种准备可以产生至少24小时类似于完整动物的呼吸运动模式。蝌蚪的这种弹性和发育性使青蛙成为教授神经科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控制呼吸的神经回路有着惊人的相似之处，尽管它们的呼吸机制存在根本差异。我们发现三个离散的位点对节律发生至关重要（即振荡器）；一个用于口腔通气，另外两个用于肺部膨胀。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必需的。在哺乳动物中也发现了三种耦合的呼吸振荡器，两种用于吸气，另一种用于呼气。此外，哺乳动物和牛蛙脑干中的振荡器是双向迭代的，占据相似的后脑菱形球位置，并且似乎共享一些功能特性。最近，我的研究生发现(a)网络兴奋的轻微增加导致颊振子转变为分布式节奏产生网络（即颊振子部位的神经元活动不再对节奏产生至关重要）和(b)蛙神经系统中脊髓神经（SN） III水平的第四个双边迭代振荡器，可能是交感神经系统的一部分。提出的研究的总体目标是通过批判性地评估网络激励将离散呼吸和交感振荡转变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)将交感振荡精确定位到脊髓中的特定神经元群；(b)测试网络兴奋是否将肺和交感振荡转变为分布式网络，就像它在颊部一样；(c)测试哪种架构（振荡器还是分布式）最有可能在更完整的准备中使用。这项研究将(a)提供细胞神经科学和比较神经科学的优秀培训机会；(b)对青蛙的心肺节律产生网络有了新的认识；(c)有可能确定哺乳动物交感振荡的身份——这是对我们如何呼吸和调节组织灌注的更深入的机制理解的重要新知识。