Orexin/Hypocretin and Histamine: Distinct Roles in the Control of Wakefulness Demonstrated Using Knock-Out Mouse Models
Orexin/Hypocretin and Histamine: Distinct Roles in the Control of Wakefulness Demonstrated Using Knock-Out Mouse Models
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DOI：
10.1523/jneurosci.2604-09.2009
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发表时间：
2009-11-18
影响因子：
5.3
通讯作者：
Lin, Jian-Sheng
中科院分区：
文献类型：
--
作者：
Anaclet, Christelle;Parmentier, Regis;Lin, Jian-Sheng
为了确定食欲素/下丘脑泌素和组胺（HA）神经元在维持觉醒（W）中各自的作用，我们描述了食欲素（Ox）基因敲除（-/-）小鼠的行为和睡眠-觉醒表型，并将其与组氨酸脱羧酶（HDC，HA合成酶）基因敲除（-/-）小鼠的行为和睡眠-觉醒表型进行比较。虽然两种小鼠都表现出睡眠片段化和异相睡眠（PS）增加，但它们呈现出一些显著的差异：（1）HDC-/-小鼠的PS增加出现在明亮时，而Ox（-/-）小鼠的PS增加出现在黑暗时;（2）与HDC-/-小鼠相反，Ox（-/-）小鼠在熄灯前后没有W缺乏，也没有异常EEG，对新环境的反应是W增加;（3）只有Ox（-/-）小鼠在运动负荷下表现出发作性睡病和W缺乏，而HDC（-/-）小鼠则没有。因此，当被放置在轮子上时，野生型（WT）而不是同窝出生的Ox（-/-）小鼠自愿花费时间转动轮子，因此保持高度清醒;这伴随着它们大脑许多区域中密集的c-fos表达，包括背外侧下丘脑中的Ox神经元。Ox（-/-）小鼠的W和运动缺陷是由于缺乏Ox，因为脑室内给药食欲素-A恢复了它们的W量和运动性能，而SB-334867（Ox 1-受体拮抗剂，i. p.）在测试期间WT小鼠的Wand运动受损。这些数据表明，牛，但不是HA，促进W通过增强运动，并表明HA和牛神经元发挥不同的，但互补和协同控制W：神经肽更多地参与其行为方面，而胺主要是负责其定性认知方面和皮层脑电图激活。
To determine the respective role played by orexin/hypocretin and histamine (HA) neurons in maintaining wakefulness (W), we characterized the behavioral and sleep-wake phenotypes of orexin (Ox) knock-out (-/-) mice and compared them with those of histidine-decarboxylase (HDC, HA-synthesizingenzyme) -/- mice. While both mouse strains displayed sleep fragmentation and increased paradoxical sleep (PS), they presented a number of marked differences: (1) the PS increase in HDC-/- mice was seen during lightness, whereas that in Ox(-/-) mice occurred during darkness; (2) contrary to HDC-/-, Ox(-/-) mice had no W deficiency around lights-off, nor an abnormal EEG and responded to a new environment with increased W; (3) only Ox (-/-), but not HDC (-/-) mice, displayed narcolepsy and deficient W when faced with motor challenge. Thus, when placed on a wheel, wild-type (WT), but not littermate Ox(-/-) mice, voluntarily spent their time in turning it and as a result, remained highly awake; this was accompanied by dense c-fos expression in many areas of their brains, including Ox neurons in the dorsolateral hypothalamus. The W and motor deficiency of Ox (-/-) mice was due to the absence of Ox because intraventricular dosing of orexin-A restored their W amount and motor performance whereas SB-334867 (Ox1-receptor antagonist, i.p.) impaired Wand locomotion of WT mice during the test. These data indicate that Ox, but not HA, promotes W through enhanced locomotion and suggest that HA and Ox neurons exert a distinct, but complementary and synergistic control of W: the neuropeptide being more involved in its behavioral aspects, whereas the amine is mainly responsible for its qualitative cognitive aspects and cortical EEG activation.