CSF and the central chemical control of breathing.

CSF 和呼吸的中枢化学控制。

• 批准号: 8211022
• 负责人: EUGENE Edward NATTIE
• 金额: $ 39.11万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211022
• 关键词: Active Sites; Affect; Alveolar; Alveolar Process; Arousal; Back; Brain; Breathing; Carbon Dioxide; Cell Nucleus; Cells; Cerebrovascular Circulation; Chemicals; Chemoreceptors; Complex; Defect; Detection; Dialysis procedure; Environmental air flow; Equilibrium; Glutamates; Hypothalamic structure; Intercellular Fluid; Lateral; Lesion; Location; Measures; Metabolism; Monitor; Muscle; Neurons; Obstructive Sleep Apnea; Oral Administration; Physiological; Play; Pump; Ramp; Rattus; Reflex action; Regulation; Respiratory Diaphragm; Role; Serotonin; Site; Sleep; Structure; Substance P; Sudden infant death syndrome; System; Testing; Wakefulness; brain metabolism; brain tissue; congenital central hypoventilation syndrome; feeding; hindbrain; hypocretin; novel; public health relevance; receptor; respiratory; response; sleep regulation

DESCRIPTION (provided by applicant): Central chemoreception refers to the reflex regulation of breathing determined by the detection at many hindbrain sites of brain interstitial fluid (ISF) pH, which monitors the balance of three key processes, alveolar ventilation (via arterial PCO2), cerebral blood flow, and brain tissue metabolism. We hypothesize that three sites (and neurons), the retrotrapezoid nucleus (RTN: glutamatergic, Phox2b- expressing neurons), the medullary raphe (MR: serotonergic neurons), and the lateral hypothalamus (LH: orexinergic neurons) are of particular importance in sleep-related control of breathing, the upper airway and arousal. We propose that in wakefulness, the orexin neurons of the LH excite serotonergic neurons of the MR and both contribute to chemoreception via effects at the RTN. In sleep, orexinergic and medullary serotonergic neurons are less active and ventilatory chemosensitivity is reduced. In rats studied in wakefulness and sleep during both the active and quiet parts of their diurnal cycle, we manipulate these sites alone or in combination by cell specific lesions via orexin receptor-saporin conjugates, by focal dialysis of neuroactive agents, e.g., an OX1R antagonist, and by oral administration of a novel antagonist to both the OX1R and OX2R. We measure breathing as well as the electromyogram (EMG) of the major 'pump' muscle, the diaphragm, and a representative upper airway muscle, the genioglossus, in response to steady-state CO2 stimulation tests and to a newly applied dynamic CO2 test that evaluates the detection threshold at more physiological levels of CO2 elevation. We will also measure ISF pH at RTN and MR in these same conditions. This project continues our long-term focus on central chemoreception as a complex system function-not simply as a single site reflex-and focuses on chemoreceptor sites active in sleep vs wakefulness. PUBLIC HEALTH RELEVANCE: Central chemoreception, which involves detection of brain pH at many locations, provides critical chemical feed-back for the normal regulation of breathing in a breath-to-breath manner. Chemoreception is of particular importance in the stimulation of breathing and arousal during obstructive sleep apnea and in the breathing instability that may follow. We focus on the function in sleep and wakefulness of arousal neurons, orexin and serotonin, that sense pH and affect breathing via a third pH sensing structure, the retrotrapezoid nucleus. Abnormal central chemoreception is a key defect in the congenital central hypoventilation syndrome and is hypothesized to play a role in the Sudden Infant Death Syndrome.

描述（由申请人提供）：中枢化学感受是指通过在脑间质液（ISF）pH的许多后脑部位检测确定的呼吸反射调节，其监测三个关键过程的平衡，即肺泡通气（通过动脉PCO 2）、脑血流和脑组织代谢。我们假设，三个网站（和神经元），后斜方核（RTN：多巴胺能，Phox 2b表达神经元），延髓中缝（MR：多巴胺能神经元），和外侧下丘脑（LH：食欲素能神经元）在睡眠相关的控制呼吸，上气道和觉醒特别重要。我们认为，在清醒状态下，LH的食欲素神经元兴奋MR的食欲素能神经元，并通过RTN的作用促进化学感受。在睡眠中，食欲素能神经元和延髓多巴胺能神经元的活性降低，并降低了对化疗的敏感性。在大鼠昼夜周期的活跃和安静部分的清醒和睡眠中研究，我们通过食欲素受体-皂草素缀合物的细胞特异性损伤，通过神经活性剂的局部透析，例如，OX 1 R拮抗剂，以及口服给予OX 1 R和OX 2 R的新型拮抗剂。我们测量呼吸以及肌电图（EMG）的主要“泵”肌肉，隔膜，和一个代表性的上呼吸道肌肉，颏舌肌，在响应稳态CO2刺激测试和新应用的动态CO2测试，评估检测阈值在更多的生理水平的CO2海拔。我们还将在这些相同条件下在RTN和MR下测量ISF pH。这个项目延续了我们长期关注的中心化学感受作为一个复杂的系统功能，而不仅仅是作为一个单一的网站反射，并侧重于化学感受器网站活跃在睡眠与觉醒。 公共卫生关系：涉及在许多位置检测脑pH的中枢化学感受，以呼吸到呼吸的方式为呼吸的正常调节提供关键的化学反馈。化学感受在阻塞性睡眠呼吸暂停期间刺激呼吸和觉醒以及随后可能出现的呼吸不稳定中特别重要。我们专注于唤醒神经元，食欲素和5-羟色胺的睡眠和觉醒的功能，通过第三个pH传感结构，倒梯形核来感知pH值并影响呼吸。异常中枢化学感受是先天性中枢性换气不足综合征的一个关键缺陷，并被假设在婴儿猝死综合征中发挥作用。