Neural circuit control of sighing

提案摘要 呼吸是维持氧气和二氧化碳稳态的重要过程，其失调导致 各种各样的，往往是毁灭性的条件。呼吸道疾病患者的有效药物治疗 由于我们缺乏对神经机制的了解， 呼吸以及在病理条件下它们如何出错。深呼吸是长时间的深呼吸， 每隔几分钟自发发生的双峰吸气，以逆转肺泡萎陷 （肺不张）并维持正常的肺功能。叹息也被牵连在各种病理 包括婴儿猝死综合症。我实验室的长期目标是了解 呼吸模式的神经控制，包括叹息，以及它在病理条件下如何失败。在这个项目中， 我们建议了解叹息的中枢控制机制是如何被生理叹息调节的- 诱导刺激，包括缺氧和睡眠-觉醒状态。我们最近发现老鼠的脑干 表达神经介肽B（Nmb）或胃泌素释放肽（Grp）的神经元包含以下核心组分： 专用信号控制电路。利用这种内源性途径和电路的基础叹息，我们将 整合小鼠遗传学、光遗传学和化学遗传学、基因消融、神经回路追踪、功能 成像和生理分析，从基因和功能上剖析小鼠的神经控制回路， 活体实验在目标1中，我们将使用光遗传学，基因消融和电路追踪来定义神经元。 缺氧引起的叹息的基础。在目标2中，我们将研究输入神经元对sigh回路的作用 在调节作为睡眠-觉醒状态的函数的叹气方面。在目标3中，我们将监测叹息的钙活性 控制神经元在基础和诱导的叹息，以了解神经元的基础上， 在生理条件下产生叹息和其他呼吸模式。预期的结果是 使人们更好地了解叹息控制电路的功能，并提供改进的基础 了解不同的呼吸模式是如何控制的，以及生理状态如何反过来决定 呼吸模式的转换这些结果将通过揭示机械的 呼吸障碍的病理生理学基础，并确定有针对性的药理学方法， 在各种临床情况下的新治疗模式。

Proposal Summary Breathing is a vital process that maintains oxygen and carbon dioxide homeostasis, and its dysregulation leads to various and often devastating conditions. Effective pharmaceutical treatments for patients in respiratory abnormalities are severely limited due to our lack of knowledge on the neurological mechanisms controlling breathing and how they may go awry under pathological conditions. Sighs are long, deep breaths with a bimodal inspiration that occur spontaneously every several minutes to reverse the alveolar collapse (atelectasis) and maintain normal lung function. Sighing has also been implicated in various pathological conditions, including sudden infant death syndrome. The long-term goal of my laboratory is to understand the neural control of breathing patterns, including sighing, and how it fails in pathological conditions. In this project, we propose to understand how the central control mechanism of sighing is regulated by physiological sigh- inducing stimuli, including hypoxia and sleep-wake states. We recently identified that the mouse brainstem neurons expressing neuromedin B (Nmb) or gastrin releasing peptide (Grp) comprise the core components of a dedicated sigh control circuit. Leveraging this endogenous pathway and circuit underlying sighing, we will integrate mouse genetics, optogenetics and chemogenetics, genetic ablation, neural circuit tracing, functional imaging, and physiological assays, to genetically and functionally dissect the neural control circuits in mouse in vivo experiments. In Aim 1, we will use optogenetics, genetic ablation, and circuit tracing to define the neural circuit underlies hypoxia-induced sighing. In Aim 2, we will examine the role of input neurons to the sigh circuit in regulating sighing as a function of sleep-wake state. In Aim 3, we will monitor the calcium activity of the sigh control neurons during basal and induced sighs in order to understand the neuronal basis underlying the generation of sighing and other breathing patterns in physiological conditions. The expected outcomes are to lead to a better understanding of the function of the sigh control circuits, and provide an improved foundation for understanding how different breathing patterns are controlled and how physiological states in turn dictate switches in the breathing patterns. These outcomes will have an important impact by revealing the mechanistic basis for the pathophysiology of breathing disorders and identifying targeted pharmacological approaches for new treatment modalities in a variety of clinical scenarios.