title: Circadian factor BMAL1 in histaminergic neurons regulates sleep architecture.
abstract: Circadian clocks allow anticipation of daily environmental changes. The suprachiasmatic nucleus (SCN) houses the master clock, but clocks are also widely expressed elsewhere in the body. Although some peripheral clocks have established roles, it is unclear what local brain clocks do. We tested the contribution of one putative local clock in mouse histaminergic neurons in the tuberomamillary nucleus to the regulation of the sleep-wake cycle. Histaminergic neurons are silent during sleep, and start firing after wake onset; the released histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness. We found that hdc gene expression varies with time of day. Selectively deleting the Bmal1 (also known as Arntl or Mop3) clock gene from histaminergic cells removes this variation, producing higher HDC expression and brain histamine levels during the day. The consequences include more fragmented sleep, prolonged wake at night, shallower sleep depth (lower nonrapid eye movement [NREM] δ power), increased NREM-to-REM transitions, hindered recovery sleep after sleep deprivation, and impaired memory. Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms. We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN.
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Zecharia
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Qianzi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Raquel
authors.initials: R
authors.lastname: Yustos
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Polona
authors.initials: P
authors.lastname: Jager
authors.affiliation: Institute of Neuroinformatics, University of Zurich and ETH Zurich, Winterhurerstrasse 190, Zurich 8057, Switzerland.
authors.forename: Alexei L
authors.initials: AL
authors.lastname: Vyssotski
authors.affiliation: Neurobiology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Maywood
authors.affiliation: Neurobiology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Chesham
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Brickley
authors.affiliation: Neurobiology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hastings
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK. Electronic address: n.franks@imperial.ac.uk.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Franks
authors.affiliation: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, Exhibition Road, London SW7 2AZ, UK. Electronic address: w.wisden@imperial.ac.uk.
authors.forename: William
authors.initials: W
authors.lastname: Wisden
mesh_terms: D056930:ARNTL Transcription Factors / Q000502:physiology*; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology; D005786:Gene Expression Regulation; D006632:Histamine / Q000378:metabolism; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D012890:Sleep / Q000502:physiology*; D012892:Sleep Deprivation; D013493:Suprachiasmatic Nucleus / Q000502:physiology
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D006632:Histamine; D006640:Histidine Decarboxylase