Generation of Respiratory Rhythm

描述（由申请人提供）：呼吸是一种重要的行为，通过调节气体交换来支持新陈代谢和调节ph。一个可靠而强健的节奏对哺乳动物的呼吸至关重要。患有睡眠呼吸暂停、早产呼吸暂停、先天性中枢性低通气综合征、过度通气综合征、Rett综合征以及婴儿猝死综合征的人不能维持正常的呼吸节奏，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，我们假设这是由控制呼吸的大脑区域的神经元丧失造成的。如果要理解正常和病理条件下的呼吸，就必须揭示每一种神经元亚型对呼吸节律发生的潜在回路和功能贡献。我们专注于两个对产生正常呼吸模式至关重要的大脑部位，前青inger复合体和后梯形核/面旁呼吸群。我们将开发：i)一种新的方法来快速改变基因靶向神经元的兴奋性，从而影响呼吸；Ii)神经元投射研究的新发展技术。利用病毒传递系统，我们将在这些关键区域的目标神经元亚群中表达遗传编码的荧光蛋白或抑抑素受体。在麻醉或行为正常的啮齿动物中施用抑化抑素，这些神经元亚群的兴奋性会发生快速变化，这应该会产生明显的、甚至是深刻的呼吸扰动，从而阐明它们的功能作用。定义呼吸中枢模式产生器的详细解剖组织对于促进我们对呼吸神经控制的理解至关重要，并且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。

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.