Functional dissection of medullary respiratory microcircuits

描述（由申请人提供）：描述复杂行为背后的神经元是最基本的兴趣。我们将利用一种新的方法，使基因靶向神经元的兴奋性发生极快的变化，从而影响啮齿动物的一种强大而重要的持续调节行为，即呼吸。呼吸是一种调节气体交换以支持新陈代谢和调节ph值的重要行为。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状态下的呼吸，就必须揭示呼吸节律发生的机制。我们关注的是产生正常呼吸模式所必需的两个大脑部位，即前bvtzinger复合体和后梯形核/面旁呼吸群。利用病毒传递系统，我们将在这些关键区域的不同表型神经元中表达遗传编码的视蛋白。在麻醉、清醒或睡眠的大鼠中，通过光纤将光脉冲植入这些部位，这些神经元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。对这种扰动的分析将为理解呼吸节律和模式产生的机制提供一个非凡的窗口。

DESCRIPTION (provided by applicant): Delineating neurons that underlie complex behaviors is of fundamental interest. We will exploit a novel method for extremely rapid changes in excitability of genetically targeted neurons to affect a robust and vital ongoing regulatory behavior in rodents, i.e., breathing. 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 mechanisms for respiratory rhythmogenesis must be revealed. We focus on two brain sites essential for generation of the normal breathing pattern, the preBvtzinger Complex and the retrotrapezoid nucleus/parafacial respiratory group. Using a viral delivery system, we will express genetically encoded opsins in various phenotypes of neurons in these key regions. Rapid changes in excitability of these neurons by administration of light pulses delivered via an optical fiber implanted in these sites in anesthetized, awake or sleeping rats should produce noticeable, even profound perturbations in breathing. Analysis of such perturbations will provide an extraordinary window into understanding mechanisms of respiratory rhythm and pattern generation. PUBLIC HEALTH RELEVANCE: In humans, continuous breathing from birth is essential to life and requires that the nervous system generate a reliable and robust rhythm that drives inspiratory and expiratory muscles. The proposed studies will significantly advance our understanding of the neural mechanisms generating respiratory rhythm and shed light on human disorders of breathing.