Functional dissection of preBotzinger Complex neuronal circuits

描述（由申请人提供）：描绘复杂行为背后的神经元具有根本意义。我们将探索一种新的方法，用于基因靶向神经元兴奋性的快速变化，以影响啮齿动物中稳健和重要的持续调节行为，即，呼吸了呼吸是介导气体交换以支持新陈代谢和调节pH的显著行为。可靠和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，必须揭示呼吸节律发生的机制。我们关注的是大脑中一个对正常呼吸模式的产生至关重要的部位，前B“tzinger复合体。使用病毒传递系统，我们将在preB“tzinger复合体中的各种神经元表型中表达遗传编码的视紫红质样分子。在麻醉、清醒或睡眠的大鼠中，通过植入前BtC中的光纤给予光脉冲，这些神经元的兴奋性发生快速变化，这将产生明显的，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。公共卫生相关性：在人类中，从出生开始的连续呼吸对生命至关重要，需要神经系统产生可靠和强大的节奏来驱动吸气和呼气肌肉。拟议的研究将显着推进我们对产生呼吸节律的神经机制的理解，并阐明人类呼吸障碍。

DESCRIPTION (provided by applicant): Delineating neurons that underlie complex behaviors is of fundamental interest. We will explore 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 a brain site essential for generation of the normal breathing pattern, the preB"tzinger Complex. Using a viral delivery system, we will express genetically encoded rhodopsin-like molecules in various phenotypes of neurons in the preB"tzinger Complex. Rapid changes in excitability of these neurons by administration of light pulses delivered via an optical fiber implanted in the preB"tC 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.