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

• Published in: The Journal of neuroscience Vol. 29; no. 46; pp. 14423 - 14438
• Main Authors: Anaclet, Christelle, Parmentier, Regis, Ouk, Koliane, Guidon, Gerard, Buda, Colette, Sastre, Jean-Pierre, Akaoka, Hideo, Sergeeva, Olga A, Yanagisawa, Masashi, Ohtsu, Hiroshi, Franco, Patricia, Haas, Helmut L, Lin, Jian-Sheng
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 18.11.2009; Society for Neuroscience
• Subjects: Animals; Circadian Rhythm - genetics; Electroencephalography - methods; Female; Histamine - physiology; Histidine Decarboxylase - deficiency; Histidine Decarboxylase - genetics; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Motor Activity - genetics; Neuropeptides - deficiency; Neuropeptides - genetics; Neuropeptides - physiology; Orexins; Sleep Deprivation - genetics; Sleep Deprivation - physiopathology; Sleep Stages - genetics; Wakefulness - genetics; Wakefulness - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2604-09.2009

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-synthesizing enzyme)-/- 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 W and 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.