CSF and the central chemical control of breathing.

描述（由申请人提供）：中枢化学感受是指通过检测后脑许多部位的脑间质液（ISF） pH值来确定呼吸的反射性调节，它监测三个关键过程的平衡，肺泡通气（通过动脉PCO2），脑血流量和脑组织代谢。我们假设三个部位（和神经元），后梯形核（RTN：谷氨酸能，Phox2b-表达神经元），中脑髓质（MR：血清素能神经元）和外侧下丘脑（LH：食欲能神经元）在睡眠相关的呼吸控制，上呼吸道和觉醒中特别重要。我们认为，在清醒状态下，LH的食欲素神经元激发MR的血清素能神经元，两者都通过RTN的作用参与化学接受。睡眠时，食欲能神经元和髓质血清素能神经元活性降低，通气化学敏感性降低。在昼夜周期的活跃和安静部分，在清醒和睡眠状态下研究的大鼠中，我们通过食欲素受体-皂素偶联物单独或联合操作这些部位，通过神经活性药物的局部透析，例如OX1R拮抗剂，以及口服OX1R和OX2R的新型拮抗剂。我们测量呼吸和肌电图（EMG）的主要“泵”肌，隔膜，和代表性的上呼吸道肌肉，颏舌肌，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，评估检测阈值在更多的生理水平的二氧化碳升高。我们还将在相同的条件下测量RTN和MR处的ISF pH。这个项目继续了我们对中枢化学接受作为一个复杂系统功能的长期关注，而不仅仅是作为一个单一的部位反射，并专注于在睡眠和清醒状态下活跃的化学受体部位。

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.