Neural circuit control of sighing

叹气的神经回路控制

• 批准号: 10545167
• 负责人: Peng Li
• 金额: $ 38.2万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545167
• 关键词: Ablation; Affect; Alveolar; American; Apnea; Arousal; Atelectasis; Biological Assay; Brain; Brain Stem; Breathing; Calcium; Carbon Dioxide; Cause of Death; Clinical; Dedications; Diagnosis; Disease; Failure; Foundations; Frequencies; Functional Imaging; Functional disorder; Gases; Gastrin releasing peptide; Generations; Genetic; Goals; Homeostasis; Hypothalamic structure; Hypoxia; Knowledge; Laboratories; Leigh Disease; Life; Lung; Modality; Monitor; Mus; Neurologic; Neurons; Neuropeptides; Outcome; Oxygen; Pathologic; Pathway interactions; Patients; Pattern; Persons; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Physiological; Process; Respiration Disorders; Respiratory distress; Rett Syndrome; Role; Sleep; Sleep Apnea Syndromes; Stimulus; Sudden infant death syndrome; Testing; Work; experimental study; hypocretin; imaging modality; improved; in vivo; in vivo imaging; insight; mouse genetics; neural; neural circuit; neuromechanism; neuromedin B; neuroregulation; novel; novel therapeutic intervention; opioid mortality; optogenetics; pharmacologic; prevent; pulmonary function; receptor; respiratory; response; transmission process

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.

提案摘要 呼吸是维持氧气和二氧化碳稳态的重要过程，其失调会导致 各种且往往是毁灭性的情况。呼吸系统疾病患者的有效药物治疗 由于我们缺乏对控制神经机制的了解，异常现象受到严重限制。 呼吸以及它们在病理条件下如何可能出错。叹息是长而深的呼吸，带有一种 双峰吸气每隔几分钟自发发生一次，以逆转肺泡塌陷 （肺不张）并维持正常的肺功能。叹息也与多种病理有关 情况，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，包括叹气，以及它在病理条件下如何失效。在这个项目中， 我们建议了解叹息的中枢控制机制是如何受生理叹息调节的 诱导刺激，包括缺氧和睡眠-觉醒状态。我们最近发现小鼠脑干 表达神经调节素 B (Nmb) 或胃泌素释放肽 (Grp) 的神经元包含 专用叹气控制电路。利用这种叹息的内源性通路和回路，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 成像和生理测定，从基因和功能上剖析小鼠的神经控制回路 体内实验。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网络 电路是缺氧引起的叹息的基础。在目标 2 中，我们将检查输入神经元对叹气电路的作用 调节叹息作为睡眠-觉醒状态的功能。在目标 3 中，我们将监测叹息的钙活性 在基础叹息和诱导叹息期间控制神经元，以了解叹息背后的神经元基础 在生理条件下产生叹息和其他呼吸模式。预期结果是 更好地理解叹气控制电路的功能，并提供更好的基础 了解如何控制不同的呼吸模式以及生理状态如何决定 改变呼吸模式。这些结果将通过揭示机制产生重要影响 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 各种临床情况下的新治疗方式。