Retrotrapezoid nucleus and central chemoreception

梯形后核和中枢化学感受

• 批准号: 9196369
• 负责人: Patrice G. Guyenet
• 金额: $ 43.76万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196369
• 关键词: Acetazolamide; Address; Adult; Affect; Altitude; Altitude Sickness; Animals; Apnea; Behavioral; Bilateral; Blood; Blood Pressure; Blood gas; Bradycardia; Brain; Brain Stem; Breathing; Bypass; Carbon Dioxide; Carotid Body; Cell Nucleus; Central Sleep Apnea; Chemoreceptors; Chronic; Congestive Heart Failure; Conscious; Diabetes Mellitus; Failure; Gases; Genetic; Glutamates; Goals; Grant; Health; Heart Rate; Hereditary Disease; Human; Human Genetics; Hypercapnia; Hypertension; Hypocapnia; Hypoxia; In Vitro; Interruption; Knowledge; Life; Measures; Mediating; Memory; Methods; Mus; Muscle; Neurons; Obstructive Sleep Apnea; Opiates; Output; Oxygen; Pain; Pathology; Pathway interactions; Pattern; Periodicity; Peripheral; Pharmacology; Play; Population; Premature Infant; REM Sleep; Rabies virus; Rattus; Regulation; Research; Respiratory Failure; Respiratory Insufficiency; Respiratory System; Rest; Rodent; Role; Sleep; Sleep Apnea Syndromes; Slice; Sudden infant death syndrome; Sum; Synapses; Syndrome; Techniques; Testing; Time; Viral Vector; Virus; Work; base; brain circuitry; congenital central hypoventilation syndrome; connectome; design; experimental study; in vivo; intersectionality; loss of function; mouse model; mutant; neuroregulation; non rapid eye movement; novel; novel therapeutic intervention; optogenetics; public health relevance; receptor; respiratory; theories; tissue oxygenation; transmission process; vector; vigilance

DESCRIPTION (provided by applicant): A notable portion of the adult US population (2-4%, possibly more) suffers from sleep-disordered breathing, a condition characterized by frequent interruptions of breathing (apneas) and poor sleep. Apneas, whatever their cause, reduce the body's oxygen level (hypoxia) and increase carbon dioxide (CO2, hypercapnia). These changes in blood gases in turn disrupt sleep, affect memory and have adverse health consequences such as increased blood pressure and heart rate, chronic hypertension and exacerbation of diabetes. The main objective of the research is to understand the mechanisms that sustain breathing automaticity, especially during sleep and how failure of this homeostatic mechanism, in turn, disrupts sleep. That involuntary breathing is driven to a large extent by the level of oxygen and carbon dioxide in the blood has been common knowledge for a long time but the mechanisms are still far from clear. We have recently identified a small group of brain neurons, called retrotrapezoid nucleus (RTN), that encode the blood concentration of carbon dioxide. There are multiple reasons to hypothesize that these neurons play a critical role in sustaining breathing during sleep. One especially convincing argument is that RTN neurons fail to develop in a mouse model of a human genetic disease characterized both by the inability to breathe at night and by an insensitivity to carbon dioxide (congenital central hypoventilation syndrome). We have therefore designed experiments to test the function of RTN neurons in fully conscious rodents so that the results might be as relevant as possible to humans. We will also be exploring how RTN neurons respond to hypoxia in an attempt to explain the respiratory insufficiency caused by altitude, which we believe to be caused by a reduced activity of RTN neurons. Finally, neuroanatomical experiments will be conducted to find out the brain circuitry through which RTN neurons stimulate breathing. This project will be carried out using advanced optogenetic and intersectional genetic method and viral vectors designed to propagate in the anterograde or retrograde direction across synapses. This research is expected to clarify how breathing automaticity is maintained during sleep and how respiratory insufficiency or failure in turn disrupts sleep. Novel therapeutic interventions benefiting sleep disordered breathing could result from this research if RTN neurons prove to be as important as we postulate and a way can be found to activate them pharmacologically.

描述（由申请人提供）：美国成年人口中有一个显着的部分（2-4％，可能更多）遭受睡眠呼吸的呼吸，其特征是呼吸频繁中断（apneas）和睡眠不佳。无论其原因如何，呼吸暂停都会降低人体的氧气水平（缺氧）并增加二氧化碳（CO2，高碳酸盐）。血液气体的这些变化反过来破坏了睡眠，影响记忆力并产生不利的健康后果，例如血压升高和心率，慢性高血压和加剧糖尿病。该研究的主要目的是了解维持呼吸自动化的机制，尤其是在睡眠期间以及这种体内稳态机制的失败又如何破坏睡眠。长期以来，由于血液中的氧气和二氧化碳的水平，这种非自愿呼吸在很大程度上被驱动了很长一段时间，但机制仍然远非清晰。我们最近确定了一小组脑神经元，称为逆转肌核（RTN），该核编码二氧化碳的血液浓度。有多种原因可以假设这些神经元在维持睡眠期间的呼吸中起着关键作用。一个特别令人信服的论点是，RTN神经元无法在人类遗传疾病的小鼠模型中发展，其特征是无法在夜间呼吸和对二氧化碳（先天性中央中央低衰减综合征）的不敏感。因此，我们设计了实验来测试RTN神经元在完全有意识的啮齿动物中的功能，以使结果可能与人类尽可能重要。我们还将探索RTN神经元如何对缺氧的反应，以解释由高度引起的呼吸不足，我们认为这是由RTN神经元的活性降低引起的。最后，将进行神经解剖学实验，以找出RTN神经元刺激呼吸的脑电路。该项目将使用高级光遗传学和交叉遗传学方法以及旨在在突触跨星形或逆行方向传播的病毒载体进行。预计这项研究将阐明睡眠期间如何保持呼吸自动化，以及呼吸不足或失败又如何破坏睡眠。如果RTN神经元被证明与我们假设一样重要，并且可以找到一种可以在药理上激活它们的方法，则该研究的新型治疗干预措施使这项研究受益于睡眠障碍。