Retrotrapezoid nucleus and central chemoreception

梯形后核和中枢化学感受

• 批准号: 8658136
• 负责人: Patrice G. Guyenet
• 金额: $ 41.41万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658136
• 关键词: Acute; Address; Adult; Affect; Anesthesia procedures; Animals; Apnea; Arousal; Biochemical; Birth; Blood Pressure; Blood gas; Brain Part; Brain Stem; Breathing; Carbon Dioxide; Carotid Body; Cell Nucleus; Cells; Chemicals; Chemoreceptors; Clinical; Code; Collection; Conscious; Defect; Development; Dorsal; Fatigue; Frequencies; Genes; Grant; Halorhodopsins; Health; Hereditary Disease; Homeostasis; Human; Hypercapnic respiratory failure; Hypertension; Intervention; Label; Lentivirus Vector; Life; Mammals; Membrane; Metabolic; Methods; Mus; Muscle; Mutate; Neurons; Neurotransmitters; Obstructive Sleep Apnea; Opiates; Output; Oxygen; Pain; Pattern; Phenotype; Play; Pontine structure; Population; Property; Rattus; Regulation; Research; Rodent; Role; Serotonin; Sleep; Sleep Apnea Syndromes; Subfamily lentivirinae; Sudden infant death syndrome; System; Testing; Therapeutic; Time; Transfection; Ventilatory Depression; Work; base; clinically relevant; congenital central hypoventilation syndrome; fascinate; in vivo; mouse model; neuromechanism; neuron loss; neurophysiology; neuroregulation; noradrenergic; novel; optogenetics; prevent; research study; respiratory; response; selective expression; tissue oxygenation; tool; vigilance

DESCRIPTION (provided by applicant): The central neural mechanisms that maintain breathing and achieve blood gas homeostasis during sleep have considerable clinical relevance for congenital central hypoventilation syndrome (CCHS), central and obstructive sleep apnea (OSA), sudden infant death syndrome (SIDS) and the treatment of pain with opiates. Under the auspices of this grant, we have identified and extensively characterized a population of lower brainstem neurons (ccRTN neurons) that could be playing a pivotal role in the CO2-mediatedregulation of breathing. The activity of these neurons is exquisitely sensitive to CO2 in vivo due to the fact that they respond directly to changes in the surrounding pH and receive powerful input from the oxygen and CO2- sensing carotid bodies. Furthermore, we have shown that the ccRTN neurons provide a strong excitatory drive to the respiratory pattern generator (RPG) and that their absence eliminates RPG activity under anesthesia regardless of the level of CO2. Recent findings of major significance to CCHS suggest that the ccRTN neurons may be even more important for CO2 homeostasis in conscious mammals than anticipated. Without input from these neurons, breathing may not be possible during sleep. In 2006, we demonstrated that, in rodents, the ccRTN neurons express Phox2b, the defining mutated gene in CCHS identified in 2003. The cardinal signs of CCHS are day time hypoventilation, total sleep apnea and loss of breathing stimulation by CO2. In 2008/9, geneticists found that the ccRTN neurons are selectively absent at birth in a mouse model of CCHS. In other words, the input-output properties of the ccRTN neurons, as we understand them currently, seem precisely appropriate for these cells to contribute to CO2 homeostasis via breathing. The genetic disease, CCHS, suggests that these neurons are critical in this regard, especially during sleep. These possibilities are fascinating and deserve to be thoroughly tested, not merely for their importance in CCHS but for their control of breathing during sleep in normal animals. Accordingly, the main objectives of this renewal application are: a) to assess the importance of the ccRTN neurons for involuntary breathing during various states of vigilance, b) to determine how the ccRTN neurons control breathing, specifically which respiratory neurons they target, and c) to further examine how the activity of the ccRTN neurons is regulated with special focus on their control by serotonin, another major neurotransmitter involved in breathing. The results from the proposed experiments will help to determine whether selective stimulation of these neurons could offer a therapeutic opportunity when hypoventilation is detrimental to health, e.g. OSA. To address these issues we will continue using the large repertoire of neurophysiological and neuroanatomical methods that we have developed in prior years and we will make heavy use of a new lentiviral vector approach to manipulate ccRTN neurons selectively in vivo, a method that has allowed us to unleash the power of optogenetics for the study of cardiorespiratory control.

描述（由申请人提供）：在睡眠期间保持呼吸并实现血液稳态的中央神经机制与先天性中央中央中性不足衰减综合征（CCHS），中枢和阻塞性睡眠呼吸暂停（OSA），猝死综合征（SIDS）以及阿片剂疼痛的治疗具有相当大的临床相关性。在这笔赠款的主持下，我们已经确定并广泛地表征了脑干神经元（CCRTN神经元）的人群，这些脑干神经元（CCRTN神经元）可能在CO2介导的呼吸调节中起关键作用。这些神经元的活性对体内的CO2非常敏感，因为它们直接响应周围pH的变化并从氧气和二氧化碳感应颈动脉体中接收强大的输入。此外，我们已经表明，CCRTN神经元为呼吸模式发生器（RPG）提供了强烈的兴奋性动力，并且无论CO2水平如何，它们的缺失都消除了麻醉下的RPG活性。最近对CCH的主要意义的发现表明，对于有意识的哺乳动物中的二氧化碳稳态而言，CCRTN神经元可能比预期更重要。没有这些神经元的输入，睡眠期间可能无法呼吸。在2006年，我们证明，在啮齿动物中，CCRTN神经元表达PHOX2B，在2003年确定的CCH中定义的突变基因。CCH的基本符号是白天的时间不足，总睡眠呼吸暂停，总睡眠呼吸暂停和CO2呼吸刺激的损失。在2008/9年度，遗传学家发现CCRTN神经元在CCH的小鼠模型中出生时缺乏。换句话说，众所周知，CCRTN神经元的输入输出特性似乎完全适合这些细胞通过呼吸对CO2稳态促进。遗传病CCHS表明，这些神经元在这方面至关重要，尤其是在睡眠期间。这些可能性令人着迷，应该得到彻底的测试，这不仅是因为它们在CCH中的重要性，而且是因为它们在正常动物的睡眠中控制呼吸。因此，此续签应用的主要目标是：a）评估CCRTN神经元在各种警惕状态下的非自愿呼吸的重要性，b）确定CCRTN神经元控制呼吸的呼吸，具体是如何靶向哪些呼吸神经元，以及ccrtn神经元的另一个呼吸神经元，以进一步研究CCRTN神经元的活动。神经递质参与呼吸。提出的实验的结果将有助于确定当不利于健康有害时，对这些神经元的选择性刺激是否可以提供治疗机会，例如OSA。为了解决这些问题，我们将继续使用前几年开发的神经生理学和神经植物学方法的大量曲目，我们将大量使用一种新的慢病毒矢量方法来选择性地在体内操纵CCRTN神经元，这种方法使我们能够对CardioreSprieres of Cardioresprioresspiorespriorespriorespriorespriorespriorespriorespriorespriorespriorespriorespriorespriorespiorespiorespiorespiorespiorespioresspioresspiorespriores进行控制。