title: Hypocretin/orexin prevents recovery from sickness.
abstract: Sickness behavior is defined as states of lethargy, depression, anxiety, loss of appetite, hypersomnia, hyperalgesia, reduction of grooming and failure to concentrate that can be induced by inflammatory diseases, such as infections and cancer. Recent findings revealed that the lipopolysaccharide (LPS) injection causes lethargy as a consequence of the inhibition of hypocretin signaling. The hypocretin system maintains the vigilance state in various physiological processes. In order to investigate the sleep arousal system against sickness behavior, LPS-induced sickness behavior was examined in hypocretin-ataxin-3 transgenic mice, whose hypocretin neurons were postnatally ablated. Sleep-wake activity was determined following the administration of LPS at Zeitgeber time (ZT) 8.0 in ataxin-3 transgenic mice, and the age-, gender-matched wild-type littermates. LPS injection induced increases in non-rapid eye movement (REM) sleep in the matched wild-type littermates. In addition, a further increase in periods of sleep according to the loss of hypocretin neurons was identified in the ataxin-3 transgenic mice. A marked reduction of awakening during ZT12-ZT18 was observed as expected following LPS injection in the mouse lines. The increase in the period of non-REM sleep was not observed on the next day following LPS administration in either of the mouse lines. Complete recovery of physical activity was not observed in the matched wild-type littermates. Ataxin-3 transgenic mice recovered their physical activity to the same level as that on the first day before LPS administration. These results suggest the possibility that a faster recovery is the result of deeper resting according to the absence of hypocretin neurons, as ataxin-3 transgenic mice demonstrated more non-REM sleep.
authors.affiliation: Sleep Disorders Project, Department of Psychiatry and Behavioral Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan ; Department of Anatomy and Cell Science, Kansai Medical University, Hirakata, Osaka 573-1010, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Sleep Disorders Project, Department of Psychiatry and Behavioral Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan ; Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Toyoda
authors.affiliation: Sleep Disorders Project, Department of Psychiatry and Behavioral Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Sleep Disorders Project, Department of Psychiatry and Behavioral Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Seki
authors.affiliation: Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan ; International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Sleep Disorders Project, Department of Psychiatry and Behavioral Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Honda
authors.affiliation: Sleep Disorders Project, Department of Psychiatry and Behavioral Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kodama
keywords: hypocretin; orexin; sickness behaviour; sleep; wakefulness