Key roles of the histaminergic system in sleep-wake regulation
Key roles of the histaminergic system in sleep-wake regulation
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DOI：
10.1111/j.1479-8425.2010.00471.x
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发表时间：
2011-02
影响因子：
1.1
通讯作者：
Zhi-Li Huang;Y. Urade;O. Hayaishi
中科院分区：
文献类型：
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作者：
Zhi-Li Huang;Y. Urade;O. Hayaishi
组胺在调节哺乳动物的觉醒中起着重要作用。基于基因操作小鼠的研究结果，我们提供了几条证据，表明组胺能系统在前列腺素（PG）D2和腺苷的促眠作用中的作用，以及在PGE 2和食欲素的唤醒作用中的作用。PGD 2激活DP 1受体（R），通过刺激它们释放腺苷来促进睡眠。释放的腺苷激活腺苷A2 AR，随后兴奋腹外侧视前区（VLPO），下丘脑前部的睡眠中心之一。VLPO神经元然后发送抑制信号以下调组胺能结节乳头核（TMN），这有助于唤醒。A1 R在大鼠TMN的组胺能神经元中表达。TMN中的腺苷通过A1 R抑制组胺能系统，促进非快速眼动睡眠。相反，内源性PGE 2和食欲素分别通过EP 4 R和OX-2 R激活组胺能系统，通过组胺H1 R促进觉醒。此外，H3 R拮抗剂环丙昔芬的唤醒作用依赖于组胺能系统的激活。这些发现表明，VLPO和TMN调节睡眠和觉醒的“触发器”的机制，在一个反一致的方式在睡眠-觉醒状态转换。
Histamine plays an important role in mediating wakefulness in mammals. Based on the findings from gene-manipulated mice, we provide several lines of evidence showing the roles of the histaminergic system in the somnogenic effects of prostaglandin (PG) D2 and adenosine, and in the arousal effects of PGE2 and orexin. PGD2 activates DP1 receptors (R) to promote sleep by stimulating them to release adenosine. The released adenosine activates adenosine A2AR and subsequently excites the ventrolateral preoptic area (VLPO), one of the sleep centers in the anterior hypothalamus. VLPO neurons then send inhibitory signals to downregulate the histaminergic tuberomammillary nucleus (TMN), which contributes to arousal. A1R is expressed in histaminergic neurons of the rat TMN. Adenosine in the TMN inhibits the histaminergic system via A1R and promotes non–rapid eye movement sleep. Conversely, both endogenous PGE2 and orexin activate the histaminergic system through EP4R and OX-2R, respectively, to promote wakefulness via histamine H1R. Furthermore, the arousal effect of ciproxifan, H3R antagonist, depends on the activation of histaminergic systems. These findings indicate that VLPO and TMN regulate sleep and wakefulness by means of a “flip-flop” mechanism operating in an anti-coincident manner during sleep–wake state transitions.