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）：美国成年人中有很大一部分（2-4%，可能更多）患有睡眠呼吸障碍，这是一种以频繁呼吸中断（呼吸暂停）和睡眠不佳为特征的疾病。呼吸暂停，无论其原因是什么，都会降低体内的氧气水平（缺氧）并增加二氧化碳（二氧化碳，高碳酸血症）。这些血气的变化反过来又会扰乱睡眠，影响记忆，并对健康产生不利影响，如血压和心率升高、慢性高血压和糖尿病加重。这项研究的主要目的是了解维持呼吸自动性的机制，特别是在睡眠期间，以及这种自我平衡机制的失败如何反过来扰乱睡眠。不自主呼吸在很大程度上是由血液中的氧气和二氧化碳水平驱动的，这一观点长期以来一直是常识，但其机制仍远未明确。我们最近发现了一小群大脑神经元，称为后梯形核（RTN），它们编码血液中二氧化碳的浓度。有多种理由假设这些神经元在睡眠中维持呼吸方面起着关键作用。一个特别有说服力的论点是，RTN神经元在患有人类遗传疾病的小鼠模型中无法发育，这种疾病的特征是夜间无法呼吸，对二氧化碳不敏感（先天性中枢低通气综合征）。因此，我们设计了实验来测试RTN神经元在完全意识的啮齿动物中的功能，以便结果可能与人类尽可能相关。我们还将探索RTN神经元对缺氧的反应，试图解释由海拔引起的呼吸功能不全，我们认为这是由RTN神经元活性降低引起的。最后，将进行神经解剖学实验，找出RTN神经元刺激呼吸的脑回路。该项目将使用先进的光遗传学和交叉遗传学方法，以及设计用于在突触间逆行或逆行传播的病毒载体进行。这项研究有望阐明睡眠时呼吸自动性是如何维持的，以及呼吸功能不全或衰竭是如何反过来扰乱睡眠的。如果RTN神经元像我们假设的那样重要，并且可以找到一种从药物上激活它们的方法，那么这项研究可能会产生有利于睡眠呼吸障碍的新型治疗干预措施。