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（由适用提供）：呼吸是由沿着腹侧髓质的Rostro-caudal轴分布的神经元网络（“腹侧呼吸柱”，VRC）。该网络产生了三个不同的阶段：灵感（I），灵感后（I）和主动到期（AE）。许多疾病与不同形式的呼吸和对缺氧的反应有关。理解这些呼吸的这些阶段是如何在多种疾病（例如缺氧）下产生和动态调节的。在这个项目中，我们介绍了两种新颖的节奏和主动的脑干切片制剂，使我们能够研究宽髓网络中突触，内在和调节性能的整合，这是不可能的。基于我们的初步数据，我们提出了以下假设：I和灵感是由一个令人兴奋的柱子产生的，该柱从前 - 贝辛格综合体延伸到Bötzinger综合体。该分布式令人兴奋的网络与GABA能和甘体能机制以及内在的膜特性相互作用，这些特性将在水平切片制备中使用多种电生理学，药物和光遗传学方法进行探索（AIM 1）。将在此水平切片制剂中获得的见解与从分离此兴奋柱的尾尾和鼻瓣部分获得的两个横向切片制剂获得的数据（AIM 2）。这种方法将使我们能够区分该列的尾端和延髓端发生的节奏机制。然后，这些体外发现中揭示的概念将在体内制备中的赞助呼吸中进行测试（AIM 3）。我们预计，这些新颖的体外制剂引入，结合现代光学遗传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奏产生模型。这可能会使人们更好地理解各种问题，这些问题仍无法解决且无法解释的呼吸神经控制领域的知识状态。