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）：中央化学感受是指通过在许多脑间纹液（ISF）pH值检测确定的呼吸的反射调节，该呼吸是指导三个关键过程的平衡，肺泡通气的平衡（通过动脉PCO2），脑血液流动和大脑血流和大脑组织组织。 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.我们建议，在清醒状态下，LH的Orexin神经元激发了MR的血清素能神经元，并且两者都通过RTN的效应有助于化学感受。在睡眠中，甲状腺素能和髓质血清素能神经元的活性较小，通气化学敏感性降低。在昼夜周期的活跃和安静的部分中，我们单独或通过细胞特异性病变组合通过Orexin受体 - 索糖蛋白结合物，通过神经活性剂的焦点透析，例如神经活性剂，例如，OX1R拮抗剂和新颖的Atagonist of Antagogons的大鼠，通过Orexin受体受体 - 舒张蛋白结合物来操纵这些部位，或通过神经活性剂的焦点透析来操纵这些部位。我们测量主要“泵”肌肉，隔膜和代表性的上呼吸道肌肉（Genioglossus）的呼吸以及肌动图（EMG），以响应于稳态的CO2刺激测试以及对新应用的动态CO2测试的响应，从而评估了CO2高度生理学水平的检测阈值。在这些相同条件下，我们还将测量RTN和MR的ISF pH。该项目延续了我们长期关注中央化学感受，这是一个复杂的系统功能，不仅仅是单个站点反射，而是专注于活跃于睡眠与清醒的化学感受器位点。 公共卫生相关性：中央化学感受，涉及在许多位置检测脑pH值，为以呼吸呼吸方式进行正常调节呼吸提供了关键的化学饲料。在阻塞性睡眠呼吸暂停期间刺激呼吸和唤醒以及可能随后的呼吸不稳定中，化学感受至关重要。我们专注于唤醒神经元，甲状腺素和5-羟色胺的睡眠和清醒的功能，这些功能通过第三个pH感应结构，即逆转录了核核。异常中央化学感受是先天性中央中枢性不足综合征的关键缺陷，并假设在猝死综合征中发挥作用。