Neural control of respiration

呼吸是一种基本的有节奏的运动，贯穿一生。在脊椎动物中，它是脑干神经元节律活动的结果，统称为呼吸节律产生器。突触的连通性和膜的特性在呼吸的产生中都起着至关重要的作用。在利用哺乳动物脑干组织的体外制备来理解呼吸作用的基本机制方面取得了进展。由于这些体外制剂大多由神经组织切片组成，它们不包括负责呼吸及其调节的整个神经回路。这些限制阻碍了对相关神经元之间突触相互作用的详细识别。我们正在使用七鳃鳗，一种基本的脊椎动物，作为一个强大的模型来洞察这些问题。在七鳃鳗中，呼吸活动在体外条件下可以在分离的完整脑干中保持数小时，甚至可以在包括外围呼吸器在内的半完整准备中保持。我们研究计划的长期目标是详细描述呼吸产生和调节的神经机制。七鳃鳗有两种截然不同的呼吸节律：快节奏(1.5赫兹)和慢节奏(≈0.02赫兹)。在下一个授予任期内，我们将专注于三个具体的研究主题：主题1将专注于快呼吸节奏。使用解剖学技术，我们将定义参与产生快节奏的神经元的突触连接。整个细胞的斑片记录将被用来检查兴奋性和抑制性输入的贡献以及神经元的膜特性。主题2将集中在产生慢节奏的机制上。我们将使用全细胞贴片记录来定义生成性神经元的连通性和属性。由于它们在七鳃鳗脑干中的解剖位置，产生慢节奏的神经元组是哺乳动物产生呼吸的神经元的进化祖先的极佳候选者。主题3将侧重于运动期间呼吸活动增加的机制。我们在七鳃鳗中发现了一种中枢神经底物，负责使呼吸输出适应运动过程中的能量需求。它由一个从运动控制中心到快速呼吸节律发生器的前馈机构组成。七鳃鳗模型是研究这种与行为相关的呼吸节律调节的理想模型。我们现在将确定涉及的神经机制，重点是乙酰胆碱和P物质的作用。总之，我们正在提出一个全面的长期研究计划，以确定在基础脊椎动物中负责产生和调节呼吸的机制。

Respiration is a basic rhythmic motor activity maintained throughout life. In vertebrates, it results from rhythmic activity of brainstem neurons, collectively known as “respiratory rhythm generator”. Both synaptic connectivity and membrane properties play a crucial role in generating respiration. Advances have been made in understanding the basic mechanisms underlying respiration using in vitro preparations of mammalian brainstem tissue. Because most of these in vitro preparations consist of slices of neural tissue, they do not include the entire neural circuitry responsible for respiration and its modulation. These limitations have prevented the detailed identification of the synaptic interactions between the neurons involved. We are using the lamprey, a basal vertebrate, as a powerful model to gain insight into these questions. In lampreys, respiratory activity is maintained for hours under in vitro conditions in the isolated intact brainstem and can even be maintained in semi-intact preparations that include the peripheral respiratory apparatus. The long-term objective of our research program is to characterize in detail the neural mechanisms underlying the generation and modulation of respiration. There are two distinct respiratory rhythms in lampreys: a fast (1.5 Hz) and a slow rhythm (≈0.02 Hz). During this next granting term, we will focus on 3 specific research themes: Theme 1 will focus on the fast respiratory rhythm. Using anatomical techniques we will define the synaptic connectivity of neurons involved in generating the fast rhythm. Whole cell patch recordings will be used to examine the contribution of excitatory and inhibitory inputs as well as the membrane properties of the neurons. Theme 2 will focus on the mechanisms responsible for generating the slow rhythm. We will use whole cell patch recordings to define the connectivity and properties of generator neurons. Because of their anatomical location in the lamprey brainstem, the groups of neurons generating the slow rhythm are excellent candidates for being the evolutionary ancestors of the neurons generating breathing in mammals. Theme 3 will focus on the mechanisms underlying the increase in respiratory activity during movement. We have discovered in lampreys a central neural substrate responsible for adapting the respiratory output to energy demands during locomotion. It consists of a feed forward mechanism from a locomotor control center to the fast respiratory rhythm generator. The lamprey model is ideal to examine such a behaviourally relevant modulation of the respiratory rhythm. We will now identify the neural mechanisms involved, focusing on the role of acetylcholine and Substance P. Altogether, we are proposing a comprehensive long-term research program to identify the mechanisms responsible for generating and modulating respiration in a basal vertebrate.