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: 9391010
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391010
• 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）：呼吸是由沿腹外侧延髓（“腹侧呼吸柱”，VRC）的头尾轴分布的神经元网络产生的。该网络产生三个不同的阶段：吸气 (I)、吸气后 (Post-I) 和主动呼气 (AE)。许多疾病与不同形式的呼吸紊乱和缺氧反应有关。因此，了解这些呼吸阶段如何在缺氧等各种条件下产生和动态调节具有重要的基础科学和临床意义。在这个项目中，我们介绍了两种新颖的有节奏的活跃脑干切片制剂，使我们能够研究更广泛的髓质网络中突触、内在和调节特性的整合，达到以前不可能的程度。根据我们的初步数据，我们提出这样的假设：后 I 和灵感是由兴奋柱产生的，该兴奋柱从前 Bötzinger 复合体延伸到 Bötzinger 复合体。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，这些特性将在水平切片制备中使用各种电生理学、药理学和光遗传学方法进行探索（目标 1）。在此水平切片制备中获得的见解将与从分离该兴奋柱尾部和喙部的两个横向切片制备获得的数据进行比较（目标 2）。这种方法将使我们能够区分发生在该柱尾端和头端的节律发生机制。这些体外研究结果揭示的概念随后将在自主呼吸的体内制剂中进行测试（目标 3）。我们期望引入这些新颖的体外制剂，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生成模型。这可能会导致更好地理解在呼吸神经控制领域的当前知识状态下仍未解决和无法解释的各种问题。