Generation of Respiratory Rhythm

呼吸节律的产生

• 批准号: 8680302
• 负责人: JACK L FELDMAN
• 金额: $ 36.61万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680302
• 关键词: Acute; Adolescent; Adult; Affect; Allatostatin; Amyotrophic Lateral Sclerosis; Anesthesia procedures; Apnea; Area; Asphyxia; Automobile Driving; Behavior; Birth; Brain; Brain Stem; Breathing; Cell Nucleus; Cessation of life; Complex; Depressed mood; Disease; Disinhibition; Facial nerve nucleus; Failure; Figs - dietary; Gases; Generations; Glutamates; Goals; Health; Human; Hypercapnia; Hyperventilation; Hypoxia; Left; Life; Light; Mammals; Maps; Measures; Mediating; Metabolism; Multiple System Atrophy; Muscle; Neonatal; Nervous system structure; Neuroanatomy; Neurodegenerative Disorders; Neurons; Opiates; Parkinson Disease; Pattern; Play; Pontine structure; Population; Preparation; Proteins; Rattus; Respiration; Respiratory Muscles; Rett Syndrome; Rodent; Role; Side; Site; Sleep; Sleep Apnea Syndromes; Slice; Spinal Cord; Structure; Sudden infant death syndrome; Surface; Syndrome; System; TACR1 gene; Techniques; Technology; Viral; Wakefulness; awake; central pattern generator; congenital central hypoventilation syndrome; design; expiration; forgetting; neuromechanism; neuron loss; neuronal excitability; neuroregulation; novel; premature; raphe nuclei; rapid technique; receptor; relating to nervous system; respiratory

DESCRIPTION (provided by applicant): Breathing is a remarkable behavior that mediates gas exchange to support metabolism and regulate pH. A reliable and robust rhythm is essential for breathing in mammals. Failure to maintain a normal breathing rhythm in humans suffering from sleep apnea, apnea of prematurity, congenital central hypoventilation syndrome, hyperventilation syndrome, Rett syndrome, and perhaps sudden infant death syndrome, leads to serious adverse health consequences, even death. Various neurodegenerative diseases, such as Parkinson's disease, multiple systems atrophy and amyotrophic lateral sclerosis, are associated with sleep disordered breathing that we hypothesize results from the loss of neurons in brain areas controlling respiration. If breathing is to be understood in normal and in pathological conditions, the underlying circuits and the functional contribution of each neuronal subtype to respiratory rhythmogenesis must be revealed. We focus on two brain sites essential for generation of the normal breathing pattern, the preB¿tzinger Complex and the retrotrapezoid nucleus/parafacial respiratory group. We will exploit: i) a novel method for rapid changes in excitability of genetically targeted neurons to affect respiration, and; ii) newly developed techniques for the study of neuronal projections. Using a viral delivery system, we will express genetically encoded fluorescent proteins or the allatostatin receptor in targeted subpopulations of neurons in these key regions. Rapid changes in the excitability of these neuronal subpopulations by administration of allatostatin in anesthetized or behaving rodents should produce noticeable, even profound perturbations in breathing that will illuminate their functional roles. Defining the detailed anatomical organization of the respiratory central pattern generator is essential to advance our understanding of the neural control of breathing and determining the perturbations that arise from selectively suppressing neuronal subtypes will provide a unique and extraordinary window into understanding mechanisms of central respiratory rhythm and pattern generation.

描述(申请人提供)：呼吸是一种调节气体交换以支持新陈代谢和调节pH值的非凡行为。一个可靠而有力的节奏对于哺乳动物的呼吸是必不可少的。睡眠呼吸暂停、早产儿呼吸暂停、先天性中枢低通气综合征、过度换气综合征、Rett综合征，甚至可能是婴儿猝死综合征的人类无法保持正常的呼吸节律，会导致严重的不良健康后果，甚至死亡。各种神经退行性疾病，如帕金森氏病、多系统萎缩和肌萎缩侧索硬化症，都与睡眠呼吸障碍有关，我们推测是由于控制呼吸的大脑区域神经元丢失所致。如果要在正常和病理条件下理解呼吸，就必须揭示每种神经元亚型对呼吸节律发生的潜在回路和功能贡献。我们专注于两个对正常呼吸模式的产生至关重要的大脑部位，Preb？tzinger复合体和后梯形核/面旁呼吸群。我们将开发一种新的方法来快速改变遗传靶标神经元的兴奋性以影响呼吸，以及；ii)新开发的研究神经元投射的技术。利用病毒传递系统，我们将在这些关键区域的靶向神经元亚群中表达基因编码的荧光蛋白或Alatostatin受体。在麻醉或行为正常的啮齿动物中，这些神经元亚群的兴奋性的快速变化应该会在呼吸中产生明显的、甚至是深刻的扰动，从而阐明它们的功能作用。定义呼吸中枢模式发生器的详细解剖结构对于促进我们对呼吸的神经控制的理解至关重要，确定选择性抑制神经元亚型所产生的扰动将为理解中枢呼吸节律和模式产生的机制提供一个独特而非凡的窗口。