Unraveling respiratory rhythm generation in the medullary network

解开髓质网络中呼吸节律的产生

• 批准号: 9180721
• 负责人: Jan M. Ramirez
• 金额: $ 69.9万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180721
• 关键词: Acute; Affect; Area; Attention; Brain Stem; Breathing; Cell Nucleus; Clinical; Complement; Complex; Data; Disease; Electrophysiology (science); Embryo; Generations; Grant; Hypoxia; In Vitro; Knowledge; Lead; Lesion; Membrane; Modeling; Modernization; Mus; Neurons; Opioid; Periodicity; Pharmacology; Phase; Physiological; Pontine structure; Preparation; Property; Respiration Disorders; Slice; Synapses; Techniques; Testing; base; excitatory neuron; experimental study; expiration; fictional works; gabazine; in vivo; inhibitory neuron; insight; interest; nervous system disorder; neuroregulation; novel; optogenetics; preBotzinger complex; presynaptic; public health relevance; respiratory; response; synaptic inhibition

DESCRIPTION (provided by applicant): Breathing is generated by a neuronal network that is distributed along the rostro-caudal axis of the ventrolateral medulla ("ventral respiratory column", VRC). This network gives rise to three distinct phases: inspiration (I), post-inspiration (Post-I), and active expiration (AE). Many disorders are associated with disturbances in different forms of breathing and the response to hypoxia. Thus understanding how these phases of breathing are generated and dynamically regulated under various conditions such as hypoxia is of great basic scientific and clinical interest. In this project we introduce two novel rhythmicall active brainstem slice preparations that allow us to study the integration of synaptic, intrinsic and modulatory properties in the wider medullary network to an extent that was not possible before. Based on our preliminary data we propose the hypothesis that post-I and inspiration are generated by an excitatory column that extends rostrally from the pre-Bötzinger complex into the Bötzinger complex. This distributed excitatory network interacts with GABAergic and glycinergic mechanisms as well as intrinsic membrane properties that will be explored in the horizontal slice preparation using a variety of electrophysiological, pharmacological, and optogenetic approaches (Aim 1). Insights gained in this horizontal slice preparation will be compared with data obtained from two transverse slice preparations that isolate the caudal and rostral portion of this excitatory column (Aim 2). This approach will allow us to differentiate rhythmogenic mechanisms occurring at the caudal and rostral end of this column. Concepts revealed in these in vitro findings will then be tested in a spontaneously breathing in vivo preparation (Aim 3). We expect that the introduction of these novel in vitro preparations, combined with modern optogenetic techniques and a rigorous integration with in vivo approaches will allow us to revisit existing models of respiratory rhythm generation. This may lead to a better understanding of various issues that remain unresolved and unexplained at the current state of knowledge in the field of neural control of breathing.

描述（由申请人提供）：呼吸是由沿腹外侧髓质（“腹侧呼吸柱”，VRC）的前尾轴分布的神经网络产生的。这个网络产生了三个不同的阶段：灵感(I)，灵感后（Post-I）和主动呼气（AE）。许多疾病与不同形式的呼吸紊乱和对缺氧的反应有关。因此，了解这些阶段的呼吸是如何在各种条件下产生和动态调节的，如缺氧，具有重要的基础科学和临床意义。在这个项目中，我们引入了两种新颖的节律性活动脑干切片制备，使我们能够在更广泛的髓质网络中研究突触、内在和调节特性的整合，这在以前是不可能的。根据我们的初步数据，我们提出了一个假设，即后i和灵感是由一个从pre-Bötzinger复合体向Bötzinger复合体纵向延伸的兴奋柱产生的。这种分布式兴奋网络与gaba能和甘氨酸能机制以及内在膜特性相互作用，将在使用各种电生理、药理学和光遗传学方法的水平切片制备中进行探索（目的1）。在这种水平切片制备中获得的见解将与从分离该兴奋柱的尾侧和吻侧部分的两种横向切片制备中获得的数据进行比较（目的2）。这种方法将使我们能够区分发生在这一柱的尾端和吻端的节律机制。在这些体外发现中揭示的概念将在自发呼吸的体内制剂中进行测试（目的3）。我们期望这些新型体外制剂的引入，结合现代光遗传学技术以及与体内方法的严格整合，将使我们能够重新审视现有的呼吸节律产生模型。这可能会导致更好地理解在呼吸神经控制领域的知识的当前状态下仍未解决和无法解释的各种问题。