Orexin/hypocretin and histamine: distinct roles in the control of wakefulness demonstrated using knock-out mouse models.
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.
Anaclet
Christelle
C
Inserm-U628, Integrated Physiology of Brain Arousal Systems, IFR19, 69373 Lyon, France.
Parmentier
Régis
R
Ouk
Koliane
K
Guidon
Gérard
G
Buda
Colette
C
Sastre
Jean-Pierre
JP
Akaoka
Hidéo
H
Sergeeva
Olga A
OA
Yanagisawa
Masashi
M
Ohtsu
Hiroshi
H
Franco
Patricia
P
Haas
Helmut L
HL
Lin
Jian-Sheng
JS
D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics; D004569:Electroencephalography / Q000379:methods; D005260:Female; D006632:Histamine / Q000502:physiology*; D006640:Histidine Decarboxylase / Q000172:deficiency / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009043:Motor Activity / Q000235:genetics; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000068797:Orexins; D012892:Sleep Deprivation / Q000235:genetics / Q000503:physiopathology; D012894:Sleep Stages / Q000235:genetics; D014851:Wakefulness / Q000235:genetics / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D006632:Histamine; D006640:Histidine Decarboxylase