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基本兴趣所在。我们将利用一种强大的方法，光遗传学，来诱导遗传靶标神经元兴奋性的极快速变化，以影响小鼠强大而活跃的持续调节行为，即呼吸。呼吸是一种非凡的行为，它通过调节气体交换来支持新陈代谢和调节pH。一种可靠而强健的呼吸肌活动节奏模式对哺乳动物的呼吸是必不可少的。没有保持 人类患有睡眠呼吸暂停、早产儿呼吸暂停、先天性中枢低通气综合征、过度换气综合征、Rett综合征，甚至可能是婴儿猝死综合征，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，我们推测是由于控制呼吸的大脑区域神经元丢失所致。如果要在正常和病理条件下理解呼吸，就必须揭示呼吸中枢模式产生的机制。我们专注于两个对正常呼吸模式的产生至关重要的大脑部位，Prebötzinger复合体和反向梯形核/面旁呼吸群。利用病毒传递系统，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。呼吸中枢模式生成器组织的一个完全未知的方面是这些关键人群在轴突靶点的行动。通过植入这些部位的光纤发出的光脉冲，这些神经元兴奋性的快速变化I小鼠应该会在呼吸中产生明显的甚至深刻的扰动。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特别的窗口。

 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.