Kernder Anna, De Luca Roberto, Yanovsky Yevgenij, Haas Helmut L, Sergeeva Olga A
Department of Neurophysiology, Molecular Neurophysiology, Medical Faculty, Heinrich-Heine University, 40225, Duesseldorf, Germany.
Cell Mol Neurobiol. 2014 Aug;34(6):777-89. doi: 10.1007/s10571-014-0065-6. Epub 2014 May 6.
Breathing and vigilance are regulated by pH and CO2 levels in the central nervous system. The hypocretin/orexin (Hcrt/Orx)- and histamine (HA)-containing hypothalamic neurons synergistically control different aspects of the waking state. Acidification inhibits firing of most neurons but these two groups in the caudal hypothalamus are excited by hypercapnia and protons, similar to the chemosensory neurons in the brain stem. Activation of hypothalamic wake-on neurons in response to hypercapnia, seen with the c-Fos assay, is supported by patch-clamp recordings in rodent brain slices: Hcrt/Orx and HA neurons are excited by acidification in the physiological range (pH from 7.4 to 7.0). Multiple molecular mechanisms mediate wake-promoting effects of protons in HA neurons in the tuberomamillary nucleus (TMN): among them are acid-sensing ion channels, Na(+),K(+)-ATPase, group I metabotropic glutamate receptors (mGluRI). HA neurons are remarkably sensitive to the mGluRI agonist DHPG (threshold concentration 0.5 µM) and mGluRI antagonists abolish proton-induced excitation of HA neurons. Hcrt/Orx neurons are excited through block of a potassium conductance and release glutamate with their peptides in TMN. The two hypothalamic nuclei and the serotonergic dorsal raphe cooperate toward CO2/acid-induced arousal. Their interactions and molecular mechanisms of H(+)/CO2-induced activation are relevant for the understanding and treatment of respiratory and metabolic disorders related to sleep-waking such as obstructive sleep apnea and sudden infant death syndrome.
呼吸和警觉性受中枢神经系统中pH值和二氧化碳水平的调节。含下丘脑泌素/食欲素（Hcrt/Orx）和组胺（HA）的下丘脑神经元协同控制清醒状态的不同方面。酸化会抑制大多数神经元的放电，但下丘脑尾部的这两组神经元会被高碳酸血症和质子兴奋，这与脑干中的化学感应神经元类似。用c-Fos检测法可观察到，响应高碳酸血症时下丘脑促醒神经元的激活，这一现象在啮齿动物脑片的膜片钳记录中得到了证实：Hcrt/Orx和HA神经元在生理范围内（pH值从7.4到7.0）会被酸化兴奋。多种分子机制介导了结节乳头体核（TMN）中质子对HA神经元的促醒作用：其中包括酸敏感离子通道、钠钾ATP酶、I组代谢型谷氨酸受体（mGluRI）。HA神经元对mGluRI激动剂二氢吡啶谷氨酸（DHPG）非常敏感（阈值浓度为0.5 μM），mGluRI拮抗剂可消除质子诱导的HA神经元兴奋。Hcrt/Orx神经元通过阻断钾离子电导而兴奋，并在TMN中与其肽类一起释放谷氨酸。这两个下丘脑核团与血清素能中缝背核共同作用，促成二氧化碳/酸诱导的觉醒。它们之间的相互作用以及H⁺/CO₂诱导激活的分子机制，对于理解和治疗与睡眠-觉醒相关的呼吸和代谢紊乱（如阻塞性睡眠呼吸暂停和婴儿猝死综合征）具有重要意义。
