Neuronal basis of bimodal ventilation in lower vertebrates

呼吸可能是哺乳动物中最重要、最强健、最有节奏的行为，但有关产生呼吸节奏的节律性神经元回路的本质的关键问题，在很大程度上仍未得到解决。这些包括：(a)节律性回路的范围有多广？(b)它能否被简化为若干离散但相互作用的神经元振荡器？(c)电路是如何进化的？由于(a)呼吸对人类健康和福祉至关重要，(b)需要对非哺乳动物物种呼吸的中枢控制有更多的了解，以及(c)比较方法有助于阐明其他系统生理学基础的神经元机制，拟议的实验将重点放在低等脊椎动物呼吸的神经元控制上，并解决节律性回路的进化问题。最近的数据表明，鱼类、青蛙和哺乳动物的呼吸节奏是由脑干内的一对神经元时钟或振荡器产生的。这就提出了一种可能性，即哺乳动物的一种或两种呼吸振荡器首先出现在4亿年前的一种古老的呼吸空气的鱼类身上。本研究的总体目标是测试这种可能性，并通过以下方法扩大我们对低等脊椎动物呼吸节律发生的理解：(1)使用一种新的“羊浸”技术快速识别和确定青蛙和其他低等脊椎动物分离脑干中功能重要的节律发生区域的药理学特性；投射到这些区域的神经元的电特性和分子指纹与其他脊椎动物的呼吸神经元群。

Breathing is perhaps the most vital, robust and rhythmic behavior in mammals yet key questions regarding the nature of the rhythmogenic neuronal circuit that generates the breathing rhythm remain largely unresolved. These include: (a) How extensive is the rhythmogenic circuit? (b) Can it be reduced to a number of discrete, but interacting neuronal oscillators?  And (c) how did the circuit evolve?  Motivated by (a) the fact that breathing is quintessential to human health and well-being, (b) the need for greater knowledge about central control of breathing in non-mammalian species and (c) the fact that a comparative approach has been instrumental in illuminating neuronal mechanisms underlying the physiology of other systems, the proposed experiments focus on neuronal control of breathing in lower vertebrates and address the evolution of the rhythmogenic circuit.Recent data suggest that the breathing rhythms in fish, frog and mammals is generated by pairs of neuronal clocks, or oscillators, located within the brainstem. This raises the possibility that one or both of the breathing oscillators in mammals first arose in an ancient air-breathing fish, 400 million years ago.The overall aim of this proposal is to test this possibility and expand our understanding of respiratory rhythmogenesis in lower vertebrates by:(1) Using a novel "sheep-dip" technique to quickly identify and determine the pharmacological properties of functionally important rhythmogenic regions within the isolated brainstems of frogs and other lower vertebrates, and(2) Comparing the location, electrical properties and molecular fingerprint of the neurons that project to these regions with populations of respiratory neurons in other vertebrates.