Functional Dissection of Medullary Respiratory Microcircuits

 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。我们将开发一种强大的方法，光遗传学，用于诱导遗传靶向神经元的兴奋性的极其快速的变化，以影响小鼠中稳健和持续的调节行为，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。呼吸肌活动的可靠和稳健的节律模式对于哺乳动物的呼吸是必不可少的。没有维持 在患有睡眠呼吸暂停、早产儿呼吸暂停、先天性中枢换气不足综合征、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，正常的呼吸模式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，必须揭示呼吸中枢模式产生的机制。我们专注于两个大脑网站必不可少的生成正常的呼吸模式，preBötzinger复杂和后斜方核/parasfacial呼吸组。使用病毒递送系统，我们将在这些区域的几个关键神经元亚群中表达遗传编码的视蛋白。呼吸中枢模式发生器组织的一个完全未探索的方面是这些关键群体在其轴突靶位点的作用。这些神经元的兴奋性的快速变化，通过管理的光脉冲通过光纤植入这些网站i小鼠应产生明显的，甚至深刻的呼吸扰动。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 powerful method, optogenetics, for inducing extremely rapid changes in excitability of genetically targeted neurons to affect a robust and vita ongoing regulatory behavior in mice, i.e., breathing. Breathing is a remarkable behavior that mediates gas exchange to support metabolism and regulate pH. A reliable and robust rhythmic pattern of respiratory muscle activity is essential for breathing in mammals. Failure to maintain a normal breathing pattern 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 central pattern generation must be revealed. We focus on two brain sites essential for generation of the normal breathing pattern, the preBötzinger Complex and the retro trapezoid nucleus/parafacial respiratory group. Using a viral delivery system, we will express genetically encoded opsins in several key subpopulations of neurons in these regions. A totally unexplored aspect of the organization of the respiratory central pattern generator is the actions of these critical populations at their axonal target sites. Rapid changes in excitability of these neurons by administration of light pulses delivered via an optical fiber implanted in these sites i mice 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.