Central and Peripheral Elements of Respiratory Pattern Formation

呼吸模式形成的中枢和外周要素

• 批准号: 7372839
• 负责人: DONALD R. MC CRIMMON
• 金额: $ 37.75万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372839
• 关键词: Address; Afferent Pathways; Airway Resistance; Amino Acid Neurotransmitters; Amyotrophic Lateral Sclerosis; Axon; Behavior; Brain Stem; Breathing; Cell Nucleus; Cells; Cephalic; Characteristics; Chemoreceptors; Chest; Chest wall structure; Class; Cranial Nerves; Data; Drug Formulations; Dyes; Economic Inflation; Electrodes; Electron Microscopy; Electrons; Elements; Goals; Human; Hypoglossal nerve structure; Individual; Infant; Injection of therapeutic agent; Interneurons; Knowledge; Label; Light; Link; Lung; Lung diseases; MSMB gene; Mammals; Maps; Mechanoreceptors; Mediating; Microscopic; Motor; Motor Activity; Motor Neurons; Motor output; Muscle; Neural Pathways; Neuraxis; Neurons; Nucleus solitarius; Output; Pathway Analysis; Pathway interactions; Patients; Pattern; Pattern Formation; Peripheral; Phenotype; Physiological; Pliability; Population; Presynaptic Terminals; Property; Pump; Range; Rattus; Reflex action; Regulation; Relative (related person); Research; Respiration Disorders; Role; Secure; Spinal; Spinal Cord; Stretch Receptors; Structure of phrenic nerve; Structure of superior laryngeal nerve; Subgroup; Sudden infant death syndrome; Surveys; Synapses; Synaptic Potentials; System; Techniques; Tidal Volume; Time; Tracer; Training; base; extracellular; human disease; immunocytochemistry; indexing; motor disorder; neural circuit; neurochemistry; neuronal circuitry; neurophysiology; receptor; research study; respiratory; respiratory reflex; response

DESCRIPTION (provided by applicant): Breathing is a vital, multifaceted behavior in which a centrally generated rhythm must be transformed into coordinated patterns of motor activity on spinal and cranial nerves that produce the pumping action of the chestwall and regulate airway tone. Mechanosensory input from the airways is essential for this coordination. Especially in mammals that have highly compliant chest walls - including human infants - antagonistic sets of airway receptors regulate end-inspiratory volume (ie, tidal volume) and end-expiratory volume. However, little is known about how these differential respiratory motor responses are coordinated within the central nervous system. In this application we will define (in rats) the central pathways by which two antagonistic reflexes are elicited in response to lung inflation (slowly adapting receptors; SARs) and lung deflation (deflation activated receptors; DARs). Three Specific Aims will be addressed. In Aim 1 the axonal projections of the different types of SAR and DAR NTS relay neurons will be comprehensively surveyed using anterograde labeling of small groups of NTS cells combined with retrograde labeling of their synaptic targets. Complementary studies using cross-correlation of simultaneously recorded spike trains will assess these functional interactions. In Aim 2, juxtacellular dye filling of single, uniquely defined SAR and DAR interneurons along with retrograde labeling of their targets will permit combined light- and electron-microscopic analysis of the synaptic connections of NTS relay neurons with multiple targets. In Aim 3 the electrophysiologically defined phenotypes of neurons post- synaptic to SAR and DAR NTS interneurons will be defined using juxtacellular labeling of both NTS neurons and their potential targets. Spike-triggered averaging will permit characterization of the synaptic connectivity, and its relative strength, between the NTS relay neurons and specific post-synaptic cells. Taken together, these experiments will identify, for the first time, the post-synaptic targets of SAR and DAR afferent relay neurons and provide a polysynaptic circuit diagram of the pathways producing coordinated respiratory reflex responses to activation of lung mechanoreceptors. Knowledge of these circuits may elucidate treatment strategies for patients with compromised airway control characteristic of a range of respiratory disorders and degenerative motor diseases. PROJECT NARRATIVE: This research will examine the brainstem circuits related to central reflexes modulating breathing. By following in detail the interconnections of neurons receiving information from the airways and lungs we will describe the control system for the force and temporal pattern of breathing in a way that has not previously been possible. This type of information will be important for analyzing the role of these circuits in a variety of human diseases ranging from amyotrophic lateral sclerosis to sudden infant death syndrome.

描述（由申请人提供）：呼吸是一种至关重要的，多方面的行为，其中必须将中心产生的节奏转化为脊柱和颅神经上的运动活动的协调模式，从而产生胸壁的抽水作用并调节气道音调。来自气道的机械增强输入对于这种协调至关重要。尤其是在具有高度符合胸壁的哺乳动物（包括人类婴儿）中，气道受体的拮抗剂集调节最终启发性量（即潮汐体积）和呼吸量。然而，对于如何在中枢神经系统中协调这些差异呼吸运动反应，知之甚少。在此应用中，我们将（在大鼠中）定义中心途径，通过这些途径，通过响应肺膨胀（缓慢适应受体； SARS）和肺部缩气（放气激活受体； DARS），从而引起了两种拮抗反射。将解决三个具体目标。在AIM 1中，将使用小组的NTS细胞的顺行标记，结合其突触靶标的逆行标记，对不同类型的SAR和DAR NTS继电器神经元的轴突投影进行全面调查。使用同时记录的尖峰列车的互相关的互补研究将评估这些功能相互作用。在AIM 2中，单个，独特定义的SAR和DAR中间神经元的并置染料以及其目标的逆行标记将允许将NTS中继神经元突触连接的光和电子显微镜分析与多个靶标组合。在AIM 3中，使用NTS神经元的并置标记及其潜在靶标，在SAR和DAR NTS中间神经元的神经元的电论表型定义。尖峰触发的平均将允许在NTS继电器神经元和特定的突触后细胞之间表征突触连通性及其相对强度。综上所述，这些实验将首次识别SAR和DAR传入中继神经元的突触后靶标，并提供产生对肺机械疗法激活的呼吸反射反应的途径的多突触电路图。这些电路的知识可能会阐明一系列呼吸道疾病和退化性运动疾病的气道控制特征受损特征的患者的治疗策略。项目叙述：这项研究将检查与调节呼吸的中央反射有关的脑干电路。通过详细介绍从气道和肺部接收信息的神经元的互连，我们将以以前无法实现的方式描述呼吸的力和时间模式的控制系统。这种类型的信息对于分析这些电路在各种人类疾病中的作用至关重要，从肌萎缩性侧向硬化症到猝死综合征。