Orexin/Hypocretin and Histamine: Distinct Roles in the Control of Wakefulness Demonstrated Using Knock-Out Mouse Models

被引:159
作者
Anaclet, Christelle [2 ]
Parmentier, Regis [2 ]
Ouk, Koliane [2 ]
Guidon, Gerard [2 ]
Buda, Colette [2 ]
Sastre, Jean-Pierre [2 ]
Akaoka, Hideo [3 ]
Sergeeva, Olga A. [4 ]
Yanagisawa, Masashi [5 ]
Ohtsu, Hiroshi [6 ]
Franco, Patricia [2 ]
Haas, Helmut L. [4 ]
Lin, Jian-Sheng [1 ,2 ]
机构
[1] Univ Lyon 1, Fac Med, INSERM, Dept Expt Med,UCBL U628, F-69373 Lyon 08, France
[2] Ctr Leon Berard, INSERM, U628, IFR19, F-69373 Lyon, France
[3] Fac Med Alexis Carrel, INSERM, U842, F-69372 Lyon, France
[4] Univ Dusseldorf, Dept Neurophysiol, D-40001 Dusseldorf, Germany
[5] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA
[6] Tohoku Univ, Dept Cellular Pharmacol, Sch Med, Sendai, Miyagi 9808575, Japan
关键词
FREELY MOVING CATS; SLEEP-WAKING CYCLE; POSTERIOR HYPOTHALAMUS; OREXIN-A; BRAIN HISTAMINE; H-3; RECEPTOR; CORTICAL ACTIVATION; THERAPEUTIC TARGET; NEURONAL-ACTIVITY; LOCUS-COERULEUS;
D O I
10.1523/JNEUROSCI.2604-09.2009
中图分类号
Q189 [神经科学];
学科分类号
071006 [神经生物学];
摘要
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.
引用
收藏
页码:14423 / 14438
页数:16
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