Generation of Respiratory Rhythm

描述（申请人提供）：呼吸是一种显着的行为，它介导气体交换以支持新陈代谢并调节pH值。可靠且稳健的节律对于哺乳动物的呼吸至关重要。在患有睡眠呼吸暂停、早产儿呼吸暂停、先天性中枢性换气不足综合征、换气过度综合征、Rett综合征以及可能的婴儿猝死综合征的人中，不能维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性侧索硬化症，与睡眠呼吸障碍有关，我们假设这是由于控制呼吸的大脑区域神经元的丢失。如果要了解正常和病理条件下的呼吸，必须揭示每个神经元亚型对呼吸节律发生的潜在回路和功能贡献。我们专注于两个大脑网站必不可少的正常呼吸模式的产生，前B？tzinger复合体和后斜方核/面旁呼吸组。我们将利用：i）一种新的方法，用于快速改变遗传靶向神经元的兴奋性以影响呼吸，以及; ii）新开发的用于研究神经元投射的技术。使用病毒递送系统，我们将在这些关键区域的靶向神经元亚群中表达遗传编码的荧光蛋白或allatostatin受体。在麻醉或行为啮齿动物中给予allatostatin，这些神经元亚群的兴奋性迅速变化，应产生明显的，甚至是深刻的呼吸扰动，这将阐明其功能作用。定义呼吸中枢模式发生器的详细解剖组织对于促进我们对呼吸的神经控制的理解至关重要，并且确定由选择性抑制神经元亚型引起的扰动将为理解中枢呼吸节律和模式生成机制提供独特且非凡的窗口。

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.