Neural control of breathing

项目摘要 呼吸是一种对生命至关重要的显著行为，它介导气体交换以支持新陈代谢， 调节pH值。呼吸肌活动的可靠、不间断、稳健的节律模式对于 哺乳动物的呼吸无法维持患有睡眠呼吸暂停的人的正常呼吸模式， 早产儿呼吸暂停，先天性中枢性低通气综合征，过度通气综合征，Rett综合征， 可能还有婴儿猝死综合症，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，如帕金森病、多系统萎缩和肌萎缩 脊髓侧索硬化症，与睡眠呼吸障碍有关，我们假设这是由于失去了 控制呼吸的大脑区域的神经元。如果要理解呼吸在正常和病理 在这种条件下，必须揭示呼吸中枢模式产生的机制。我们专注于两个大脑 对于正常呼吸模式的产生至关重要的部位，前Bötzinger复合体和后梯形 核/面旁呼吸组。我们提出了一系列广泛的实验，包括体内和体外实验， 啮齿类动物使用先进的技术，包括：病毒传递表达基因编码的视蛋白， 在这些区域的神经元的关键亚群中的DREADDs;先进的光学技术来确定 前Bötzinger复合体微电路对节律产生的贡献;最先进的神经解剖学 技术，以建立适当和必要的细节，脑干呼吸系统的相互连接， 模式发生器这些实验的数据将提供一个非凡的窗口， 潜在的呼吸节律和模式生成。

PROJECT SUMMARY Breathing is a remarkable behavior fundamental to life that mediates gas exchange to support metabolism and regulate pH. A reliable, non-stop, 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 retrotrapezoid nucleus/parafacial respiratory group. We propose a broad series of experiments both in vivo and in vitro in rodents using advanced techniques including: viral delivery to express genetically encoded opsins or DREADDs in key subpopulations of neurons in these regions; advanced optical techniques to determine the contributions of the preBötzinger Complex microcircuit to rhythm generation; state-of-the-art neuroanatomical techniques to establish, in appropriate and necessary detail, the interconnectivity of the brainstem respiratory pattern generator. The data from these experiments will provide an extraordinary window into the mechanisms underlying respiratory rhythm and pattern generation.