CSF and the central chemical control of breathing.

描述(申请人提供)：中枢化学感受是指通过检测脑间质液(ISF)的许多后脑部位的pH值来确定对呼吸的反射调节，它监测三个关键过程的平衡：肺泡通气量(通过动脉二氧化碳分压)、脑血流量和脑组织新陈代谢。我们假设有三个部位(和神经元)，即斜方后核(RTN：谷氨酸能、PHOX2B阳性神经元)、延髓中缝(MR：5-羟色胺能神经元)和下丘脑外侧核(LH：食欲素能神经元)在与睡眠有关的呼吸、上呼吸道和觉醒控制中起着特别重要的作用。我们认为在清醒状态下，LH区的增食欲素神经元兴奋MR的5-羟色胺能神经元，两者都通过对RTN的影响参与化学感受。在睡眠中，食欲素能神经元和延髓5-羟色胺能神经元不那么活跃，通气性化疗敏感性降低。在被研究的大鼠的白天活跃和安静部分的觉醒和睡眠中，我们通过食欲素受体-皂苷结合物、神经活性物质的局部透析(例如，OX1R拮抗剂)以及口服OX1R和OX2R的新型拮抗剂，通过细胞特异性损伤单独或联合操作这些位置。我们测量呼吸以及主要的“泵”肌、横隔肌和具有代表性的上呼吸道肌肉-颧舌肌的肌电(EMG)，以响应稳态二氧化碳刺激测试和新应用的动态二氧化碳测试，该测试评估在更生理水平的二氧化碳升高的检测阈值。我们还将在相同的条件下测量RTN和MR下的ISF pH。这个项目延续了我们长期以来对中枢化学接收作为一种复杂的系统功能的关注--而不仅仅是作为一个单一的部位反射--并专注于睡眠和清醒中活跃的化学感受器部位。

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.