Neural circuit control of sighing

建议书摘要 呼吸是维持氧气和二氧化碳动态平衡的重要过程，其失调导致 到各种通常是毁灭性的条件。呼吸系统疾病患者的有效药物治疗 由于我们缺乏对神经控制机制的了解，异常情况非常有限。 呼吸，以及它们在病理条件下可能会出现的错误。叹息是长长的深呼吸，带着 每隔几分钟自发产生的双峰吸气，以逆转肺泡塌陷 (肺不张)和维持正常的肺功能。叹息也牵涉到各种病理变化 情况，包括婴儿猝死综合症。我的实验室的长期目标是了解 呼吸模式的神经控制，包括叹息，以及在病理条件下它是如何失败的。在这个项目中， 我们建议理解叹息的中枢控制机制是如何受到生理叹息的调节的。 诱导刺激，包括缺氧和睡眠-觉醒状态。我们最近发现小鼠的脑干 表达神经梅毒素B(NMB)或胃泌素释放肽(GRP)的神经元是 一个专用的叹息控制电路。利用这种内生的途径和感叹背后的电路，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，以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 低氧引起的叹息是电路的基础。在目标2中，我们将研究输入神经元对SIGH回路的作用 在调节叹息作为睡眠-觉醒状态的函数。在目标3中，我们将监测叹息的钙活动 控制神经元在基础和诱导叹息，以了解神经基础的基础 在生理条件下产生叹息和其他呼吸模式。预期结果是 有助于更好地了解SIGH控制电路的功能，并提供改进的基础 为了了解不同的呼吸模式是如何控制的，以及生理状态是如何决定的 在呼吸模式中切换。这些结果将通过揭示机制而产生重要影响 呼吸障碍的病理生理学基础和确定治疗呼吸障碍的靶向药理学方法 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.