title: H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice.
abstract: An increased incidence in the sleep-disorder narcolepsy has been associated with the 2009-2010 pandemic of H1N1 influenza virus in China and with mass vaccination campaigns against influenza during the pandemic in Finland and Sweden. Pathogenetic mechanisms of narcolepsy have so far mainly focused on autoimmunity. We here tested an alternative working hypothesis involving a direct role of influenza virus infection in the pathogenesis of narcolepsy in susceptible subjects. We show that infection with H1N1 influenza virus in mice that lack B and T cells (Recombinant activating gene 1-deficient mice) can lead to narcoleptic-like sleep-wake fragmentation and sleep structure alterations. Interestingly, the infection targeted brainstem and hypothalamic neurons, including orexin/hypocretin-producing neurons that regulate sleep-wake stability and are affected in narcolepsy. Because changes occurred in the absence of adaptive autoimmune responses, the findings show that brain infections with H1N1 virus have the potential to cause per se narcoleptic-like sleep disruption.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden; Department of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
authors.forename: Chiara
authors.initials: C
authors.lastname: Tesoriero
authors.affiliation: Section of Neurogeriatrics, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Huddinge 14157, Sweden;
authors.forename: Alina
authors.initials: A
authors.lastname: Codita
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden; Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden;
authors.forename: Ming-Dong
authors.initials: MD
authors.lastname: Zhang
authors.affiliation: Department of Brain Physiology, Institute of Biology of Taras Shevchenko National University, Kiev 01601, Ukraine;
authors.forename: Andrij
authors.initials: A
authors.lastname: Cherninsky
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden;
authors.forename: Håkan
authors.initials: H
authors.lastname: Karlsson
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
authors.forename: Gigliola
authors.initials: G
authors.lastname: Grassi-Zucconi
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bertini
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden; Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna A-1090, Austria;
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.affiliation: Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Ljungberg
authors.affiliation: Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm SE-17177, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Liljeström
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden; tomas.hokfelt@ki.se krister.kristensson@ki.se.
authors.forename: Tomas G M
authors.initials: TG
authors.lastname: Hökfelt
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Verona 37134, Italy;
authors.forename: Marina
authors.initials: M
authors.lastname: Bentivoglio
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden; tomas.hokfelt@ki.se krister.kristensson@ki.se.
authors.forename: Krister
authors.initials: K
authors.lastname: Kristensson
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D004569:Electroencephalography; D018398:Homeodomain Proteins / Q000378:metabolism; D007031:Hypothalamus / Q000503:physiopathology / Q000821:virology; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009290:Narcolepsy / Q000503:physiopathology* / Q000821:virology*; D009474:Neurons / Q000502:physiology*; D009830:Olfactory Bulb / Q000503:physiopathology / Q000821:virology; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D012890:Sleep; D014851:Wakefulness
chemical_list: D000956:Antigens, Viral; D018398:Homeodomain Proteins; C064658:RAG-1 protein
keywords: influenza A virus; lateral hypothalamus; locus coeruleus; noradrenaline; orexin