The Journal of Physiological Sciences

, Volume 68, Issue 3, pp 207–219 | Cite as

The mammalian circadian system: a hierarchical multi-oscillator structure for generating circadian rhythm

Review

Abstract

The circadian nature of physiology and behavior is regulated by a circadian clock that generates intrinsic rhythms with a periodicity of approximately 24 h. The mammalian circadian system is composed of a hierarchical multi-oscillator structure, with the central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus regulating the peripheral clocks found throughout the body. In the past two decades, key clock genes have been discovered in mammals and shown to be interlocked in transcriptional and translational feedback loops. At the cellular level, each cell is governed by its own independent clock; and yet, these cellular circadian clocks in the SCN form regional oscillators that are further coupled to one another to generate a single rhythm for the tissue. The oscillatory coupling within and between the regional oscillators appears to be critical for the extraordinary stability and the wide range of adaptability of the circadian clock, the mechanism of which is now being elucidated with newly advanced molecular tools.

Keywords

Circadian clock Suprachiasmatic nucleus Oscillatory coupling Clock gene Luciferase reporter 

Notes

Compliance with ethical standards

Conflict of interest

The author declares no conflicts of interest.

Research involving human participants and/or animals

All applicable international, national, and institutional guidelines for the care and use of animals were followed. This article did not contain any studies involving human participants.

Informed consent

Not applicable.

References

  1. 1.
    Zehring WA, Wheeler DA, Reddy P, Konopka RJ, Kyriacou CP, Rosbash M, Hall JC (1984) P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39:369–376PubMedCrossRefGoogle Scholar
  2. 2.
    Bargiello TA, Jackson FR, Young MW (1984) Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312:752–754PubMedCrossRefGoogle Scholar
  3. 3.
    Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ (1998) Role of the CLOCK protein in the mammalian circadian mechanism. Science 280:1564–1569PubMedCrossRefGoogle Scholar
  4. 4.
    Aschoff J (1981) Freerunning and entrained circadian rhythms. In: Aschoff J (ed) Handbook of behavioral neurobiology. 4. Biological rhythms. Plenum Press, New YorkGoogle Scholar
  5. 5.
    Daan S, Pittendrigh CS (1976) A functional analysis of circadian pacemakers in nocturnal rodents. II. The variability of phase response curves. J Comp Biol 106:253–266Google Scholar
  6. 6.
    Pittendrigh CS, Daan S (1976) A functional analysis of circadian pacemakers in nocturnal rodents. IV. Entrainment: pacemaker as clock. J Comp Biol 106:291–331Google Scholar
  7. 7.
    Johnson CH (1990) An atlas of phase responses curves for circadian and circatidal rhythm. Vanderbilt University, Nashville, NashvilleGoogle Scholar
  8. 8.
    Ma P, Woelfle MA, Johnson CH (2013) An evolutionary fitness enhancement conferred by the circadian system in cyanobacteria. Chaos, Solitons Fractals 50:65–74CrossRefGoogle Scholar
  9. 9.
    Narasimamurthy R, Virshup DM (2017) Molecular mechanisms regulating temperature compensation of the circadian clock. Front Neurol 8:161PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Abe J, Hiyama TB, Mukaiyama A, Son S, Mori T, Saito S, Osako M, Wolanin J, Yamashita E, Kondo T, Akiyama S (2015) Atomic-scale origins of slowness in the cyanobacterial circadian clock. Science 349:312–316PubMedCrossRefGoogle Scholar
  11. 11.
    Shinohara Y, Koyama YM, Ukai-Tadenuma M, Hirokawa T, Kikuchi M, Yamada RG, Ukai H, Fujishima H, Umehara T, Tainaka K, Ueda H (2017) Temperature-sensitive substrate and product binding underlie temperature-compensated phosphorylation in the clock. Mol Cell 67:783–798PubMedCrossRefGoogle Scholar
  12. 12.
    Weaver DR, Reppert SM (2002) Coordination of circadian timing in mammals. Nature 418:935–941PubMedCrossRefGoogle Scholar
  13. 13.
    Mohawk JA, Green CB, Takahashi JS (2012) Central and peripheral circadian clocks in mammals. Ann Rev Neurosci 35:445–462PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, Block GD, Sakaki Y, Menaker M, Tei H (2000) Resetting central and peripheral circadian oscillators in transgenic rats. Science 288:682–695PubMedCrossRefGoogle Scholar
  15. 15.
    Tei H, Okamura H, Shigeyoshi Y, Fukuhara C, Ozawa R, Hirose M, Sakaki Y (1997) Circadian oscillation of a mammalian homologue of the Drosophila period gene. Nature 389:512–516PubMedCrossRefGoogle Scholar
  16. 16.
    Ikeda M, Nomura M (1997) cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage. Biochem Biophys Res Commun 233:258–264PubMedCrossRefGoogle Scholar
  17. 17.
    Honma S, Ikeda M, Abe H, Tanahashi Y, Namihira M, Honma K, Nomura (1998) Circadian oscillation of BMAL1, a partner of a mammalian clock gene Clock, in rat suprachiasmatic nucleus. Biochem Biophys Res Commun 250:83–87PubMedCrossRefGoogle Scholar
  18. 18.
    Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM (1999) mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98:193–205PubMedCrossRefGoogle Scholar
  19. 19.
    Horwitz BA, Gressel J, Malkin S, Epel BL (1985) Modified cryptochrome in vivo absorption in dim photosporulation mutants of Trichoderma. Proc Natl Acad Sci U S A 82:2736–2740PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Sponga F, Deitzer GF, Mancinelli AL (1986) Cryptochrome, phytochrome, and the photoregulation of anthocyanin production under blue light. Plant Physiol 82:952–955PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Griffin EA Jr, Staknis D, Weitz CJ (1999) Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Science 286:768–771PubMedCrossRefGoogle Scholar
  22. 22.
    Alada R, White NE, So WV, Hall JC, Roshach MA (1998) A mutant Drosophila homolog of mammalian clock disrupts circadian rhythms and transcription of period and timeless. Cell 93:791–804CrossRefGoogle Scholar
  23. 23.
    Rutila JE, Suri V, Le M, So WV, Rosbash M, Hall JC (1998) CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93:805–814PubMedCrossRefGoogle Scholar
  24. 24.
    Takumi T, Taguchi K, Miyake S, Sakakida Y, Takashima N, Matsubara C, Maebayashi Y, Okumura K, Takekida S, Yamamoto S, Yagita K, Yan L, Young MW, Okamura HA (1998) Light-independent oscillatory gene mPer3 in mouse SCN and OVL. EMBO 17:4753–4759CrossRefGoogle Scholar
  25. 25.
    Unsal-Kaçmaz K, Mullen TE, Kaufmann WK, Sancar A (2005) Coupling of human circadian and cell cycles by the timeless protein. Mol Cell Biol 25:3109–3116PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B, Kume K, Lee CC, van der Horst GT, Hastings MH, Reppert SM (2000) Interacting molecular loops in the mammalian circadian clock. Science 288:1013–1019PubMedCrossRefGoogle Scholar
  27. 27.
    SatoTK Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik KA, FitzGerald GA, Kay SA, Hogenesch JB (2004) A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43:527–537CrossRefGoogle Scholar
  28. 28.
    Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (2002) The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110:251–260PubMedCrossRefGoogle Scholar
  29. 29.
    Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma K (2002) Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 419:841–844PubMedCrossRefGoogle Scholar
  30. 30.
    Ueda HR, Hayashi S, Chen W, Sano M, Machida M, Shigeyoshi Y, Iino M, Hashimoto S (2005) System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet 37:187–192PubMedCrossRefGoogle Scholar
  31. 31.
    Provencio I, Jiang G, De Grip WJ, Hayes WP, Rollag MD (1998) Melanopsin: an opsin in melanophores, brain, and eye. Proc Natl Acad Sci U S A 95:340–345PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Freedman MS, Lucas RJ, Soni B, von Schantz M, Munoz M, David-Gray Z et al (1999) Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284:502–504PubMedCrossRefGoogle Scholar
  33. 33.
    Berson DM, Dunn FA, Takao M (2002) Phototransduction by retinal ganglion cells that set the circadian clock. Science 295:1070–1073PubMedCrossRefGoogle Scholar
  34. 34.
    Moore RY, Eichler VB (1972) Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 42:201–206PubMedCrossRefGoogle Scholar
  35. 35.
    Schmidt TM, Do MT, Dacey D, Lucas R, Hattar S, Matynia A (2011) Melanopsin-positive intrinsically photosensitive retinal ganglion cells: from form to function. J Neurosci 31:16094–16101PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Lucas RJ, Freedman MS, Munoz M, Garcia-Fernandez JM, Foster RG (1999) Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284:505–507PubMedCrossRefGoogle Scholar
  37. 37.
    Lucas RJ, Douglas RH, Foster RG (2001) Characterization of an ocular photopigment capable of driving pupillary constriction in mice. Nat Neurosci 4:621–626PubMedCrossRefGoogle Scholar
  38. 38.
    Barnard AR, Hattar S, Hankins MW, Lucas RJ (2006) Melanopsin regulates visual processing in the mouse retina. Curr Biol 16:389–395PubMedCrossRefGoogle Scholar
  39. 39.
    Altimus CM, Guler AD, Villa KL, McNeill DS, Legates TA, Hattar S (2008) Rods-cones and melanopsin detect light and dark to modulate sleep independent of image formation. Proc Natl Acad Sci USA 105:19998–20003PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Shigeyoshi Y, Taguchi K, Yamamoto S, Takekida S, Yan L, Tei H, Moriya T, Shibata S, Loros JJ, Dunlap JC, Okamura H (1997) Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript. Cell 91:1043–1053PubMedCrossRefGoogle Scholar
  41. 41.
    Shearman LP, Zylka MJ, Weaver DR, Kolakowski LF Jr, Reppert SM (1997) Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron 19:1261–1269PubMedCrossRefGoogle Scholar
  42. 42.
    Yan L, Takekida S, Shigeyoshi Y, Okamura H (1999) Per1 and Per2 gene expression in the rat suprachiasmatic nucleus: circadian profile and the compartment-specific response to light. Neuroscience 94:141–150PubMedCrossRefGoogle Scholar
  43. 43.
    Koike N, Yoo SH, Huang HC, Kumar V, Lee C, Kim TK, Takahashi JS (2012) Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338:349–354PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Terajima H, Yoshitane H, Ozaki H, Suzuki Y, Shimba S, Kuroda S, Iwasaki W, Fukada Y (2017) ADARB1 catalyzes circadian A-to-I editing and regulates RNA rhythm. Nat Genet 49:146–151PubMedCrossRefGoogle Scholar
  45. 45.
    Ralph MR, Menaker M (1988) A mutation of the circadian system in golden hamsters. Science 241:1225–1227PubMedCrossRefGoogle Scholar
  46. 46.
    Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS (2000) Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288:483–492PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ, Fu YH (2001) An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291:1040–1043PubMedCrossRefGoogle Scholar
  48. 48.
    Gallego M, Virshup DM (2007) Post-translational modifications regulate the ticking of the circadian clock. Nat Rev Mol Cell Biol 8:139–148PubMedCrossRefGoogle Scholar
  49. 49.
    Hirota T, Lewis WG, Liu AC, Lee JW, Schultz PG, Kay SA (2008) A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3. Proc Natl Acad Sci USA 105:20746–20751PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Siepka SM, Yoo S-H, Park J, Song W, Kumar V, Hu Y, Lee C, Takahashi JS (2007) Circadian mutant overtime reveals F-box protein FBXL3 regulation of Cryptochrome and Period gene expression. Cell 129:1011–1023PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Godinho SI, Maywood ES, Shaw L, Tucci V, Barnard AR, Busino L, Pagano M, Kendall R, Quwailid MM, Romero MR, O’neill J, Chesham JE, Brooker D, Lalanne Z, Hastings MH, Nolan PM (2007) The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316:897–900PubMedCrossRefGoogle Scholar
  52. 52.
    Belden WJ, Dunlap JC (2008) SIRT1 is a circadian deacetylase for core clock components. Cell 134:212–214PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Cardone L, Hirayama J, Giordano F, Tamaru T, Palvimo JJ, Sassone-Corsi P (2005) Circadian clock control by SUMOylation of BMAL1. Science 309:1390–1394PubMedCrossRefGoogle Scholar
  54. 54.
    Yoo SH, Mohawk JA, Siepka SM, Shan Y, Huh SK, Hong HK, Kornblum I, Kumar V, Koike N, Xu M, Nussbaum J, Liu X, Chen Z, Chen ZJ, Green CB, Takahashi JS (2013) Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152:1091–1105PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Hirano A, Yumimoto K, Tsunematsu R, Matsumoto M, Oyama M, Kozuka-Hata H, Nakagawa T, Lanjakornsiripan D, Nakayama KI, Fukada Y (2013) FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell 152:1106–1118PubMedCrossRefGoogle Scholar
  56. 56.
    Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptácek LJ (2009) Fu YH (2005) Functional consequences of a CKI delta mutation causing familial advanced sleep phase syndrome. Nature 434:640–644CrossRefGoogle Scholar
  57. 57.
    He Y, Jones CR, Fujiki N, Xu Y, Guo B, Holder JL Jr, Rossner MJ, Nishino S, Fu YH (2009) The transcriptional repressor DEC2 regulates sleep length in mammals. Science 325:866–870PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Ebisawa T, Uchiyama M, Kajimura N, Mishima K, Kamei Y, Katoh M, Watanabe T, Sekimoto M, Shibui K, Kim K, Kudo Y, Ozeki Y, Sugishita M, Toyoshima R, Inoue Y, Yamada N, Nagase T, Ozaki N, Ohara O, Ishida N, Okawa M, Takahashi K, Yamauchi T (2001) Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep 2:342–346PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Partonen T (2012) Clock gene variants in mood and anxiety disorders. J Neural Transm 119:1133–1145PubMedCrossRefGoogle Scholar
  60. 60.
    Albrecht U (2017) Molecular mechanisms in mood regulation involving the circadian clock. Front Neurol 8:30PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    De Leersnyder H, Claustrat B, Munnich A, Verloes A (2006) Circadian rhythm disorder in a rare disease: smith-Magenis syndrome. Mol Cell Endocrinol 252:88–91PubMedCrossRefGoogle Scholar
  62. 62.
    Shi SQ, Bichell TJ, Ihrie RA, Johnson CH (2015) Ube3a imprinting impairs circadian robustness in Angelman syndrome models. Curr Biol 25:537–545PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Tsuchiya Y, Minami Y, Umemura Y, Watanabe H, Ono D, Nakamura W, Takahashi T, Honma S, Kondoh G, Matsuishi T, Yagita K (2015) Disruption of MeCP2 attenuates circadian rhythm in CRISPR/Cas9-based Rett syndrome model mouse. Genes Cells 20:992–1005PubMedCrossRefGoogle Scholar
  64. 64.
    Field MD, Maywood ES, O’Brien JA, Weaver DR, Reppert SM, Hastings MH (2000) Analysis of clock proteins in mouse SCN demonstrates phylogenetic divergence of the circadian clockwork and resetting mechanisms. Neuron 25:437–447PubMedCrossRefGoogle Scholar
  65. 65.
    Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong HK, Oh WJ, Yoo OJ, Menaker M, Takahashi JS (2004) PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA 101:5339–5346PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Nishide S, Honma S, Nakajima Y, Ikeda M, Baba K, Ohmiya Y, Honma K (2006) New reporter system for Per1 and Bmal1 expressions revealed self-sustained circadian rhythms in peripheral tissues. Genes Cells 11:1173–1182PubMedCrossRefGoogle Scholar
  67. 67.
    Yamaguchi S, Isejima H, Matsuo T, Okura R, Yagita K, Kobayashi M, Okamura H (2003) Synchronization of cellular clocks in the suprachiasmatic nucleus. Science 302:1408–1412PubMedCrossRefGoogle Scholar
  68. 68.
    Honma S (2016) Unveiling functions of the central circadian clock by imaging “clock time”. J Physiol Sci 66:S13Google Scholar
  69. 69.
    Stephan FK, Zucker I (1972) Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A 69:1583–1586PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Nagoshi E, Saini C, Bauer C, Laroche T, Naef F, Schibler U (2004) Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells. Cell 119:693–705PubMedCrossRefGoogle Scholar
  71. 71.
    Yamaguchi S, Kobayashi M, Mitsui S, Ishida Y, van der Horst GT, Suzuki M, Shibata S, Okamura H (2001) View of a mouse clock gene ticking. Nature 409:684PubMedCrossRefGoogle Scholar
  72. 72.
    Ono D, Honma K, Honma S (2015) Circadian and ultradian rhythms of clock gene expression in the suprachiasmatic nucleus of freely moving mice. Sci Rep 21:12310CrossRefGoogle Scholar
  73. 73.
    Hamada T, Sutherland K, Ishikawa M, Miyamoto N, Honma S, Shirato H, Honma K (2016) In vivo imaging of clock gene expression in multiple tissues of freely moving mice. Nat Commun 7:11705PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Van del Pol AN (1980) The hypothalamic suprachiasmatic nucleus of the rat: intrisic anatomy. J Comp Neurol 191:661–702CrossRefGoogle Scholar
  75. 75.
    Card JP, Brecha N, Karten HJ, Moore RY (1981) Immunocytochemical localization of vasoactive intestinal polypeptide-containing cells and processes in the suprachiasmatic nucleus of the rat: light and electron microscopic analysis. J Neurosci 1:1289–1303PubMedCrossRefGoogle Scholar
  76. 76.
    Moore RY (1996) Entrainment pathways and the functional organization of the circadian timing system. In: Buijs RM, Kalsbeek A, Romijn HJ, Pennartz CMA, Mirmiran M (eds) Hypothalamic integration of circadian rhythms. Elsevier, Amsterdam, pp 101–117Google Scholar
  77. 77.
    Mori K, Miyazato M, Ida T, Murakami N, Serino R, Ueta Y, Kojima M, Kangawa K (2005) Identification of neuromedin S and its possible role in the mammalian circadian oscillator system. EMBO J 24:325–335PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Lee IT, Chang AS, Manandhar M, Shan Y, Fan J, Izumo M, Ikeda Y, Motoike T, Dixon S, Seinfeld JE, Takahashi JS, Yanagisawa M (2015) Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms. Neuron 85:1086–1102PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Moore RY, Speh JC (1993) GABA is the principal neurotransmitter of the circadian system. Neurosci Lett 150:112–116PubMedCrossRefGoogle Scholar
  80. 80.
    Abrahamson EE, Moore RY (2001) Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res 916:172–191PubMedCrossRefGoogle Scholar
  81. 81.
    Welsh DK, Logothetis DE, Meister M, Reppert SM (1995) Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14:697–706PubMedCrossRefGoogle Scholar
  82. 82.
    Honma S, Shirakawa T, Katsuno Y, Namihira M, Honma K (1998) Circadian periods of single suprachiasmatic neurons in rats. Neurosci Lett 250:157–160PubMedCrossRefGoogle Scholar
  83. 83.
    Herzog ED, Kiss IZ, Mazusk C (2015) Measuring synchrony in the mammalian central circadian circuit. Methods Enzymol 552:3–22PubMedCrossRefGoogle Scholar
  84. 84.
    Honma S, Nakamura W, Shirakawa T, Honma K (2004) Diversity in the circadian periods of single neurons of the rat suprachiasmatic nucleus depends on nuclear structure and intrinsic period. Neurosci Lett 358:173–176PubMedCrossRefGoogle Scholar
  85. 85.
    Honma S, Ono D, Suzuki Y, Inagaki N, Yoshikawa T, Nakamura W, Honma K (2012) Suprachiasmatic nucleus: cellular clocks and networks. Prog Brain Res 199:129–141PubMedCrossRefGoogle Scholar
  86. 86.
    Nagano M, Adachi A, Nakahama K, Nakamura T, Tamada M, Meyer-Bernstein E, Sehgal A, Shigeyoshi Y (2003) An abrupt shift in the day/night cycle causes desynchrony in the mammalian circadian center. J Neurosci 23:6141–6651PubMedGoogle Scholar
  87. 87.
    Nakamura W, Yamazaki S, Takasu NN, Mishima K, Block GD (2005) Differential response of Period 1 expression within the suprachiasmatic nucleus. J Neurosci 25:5481–5487PubMedCrossRefGoogle Scholar
  88. 88.
    Shinohara K, Honma S, Katsuno Y, Abe H, Honma K (1995) Two distinct oscillators in the rat suprachiasmatic nucleus in vitro. Porc Natl Acad Sci USA 92:7396–7400CrossRefGoogle Scholar
  89. 89.
    de la Iglesia HO, Meyer J, Carpino A Jr, Schwartz WJ (2000) Antiphase oscillation of the left and right suprachiasmatic nuclei. Science 290:799–801PubMedCrossRefGoogle Scholar
  90. 90.
    de la Iglesia HO, Meyer J, Schwartz WJ (2003) Lateralization of circadian pacemaker output: activation of left- and right-sided luteinizing hormone-releasing hormone neurons involves a neural rather than a humoral pathway. J Neurosci 23(19):7412–7414PubMedGoogle Scholar
  91. 91.
    Pittendrigh CS, Daan S (1976) A functional analysis of circadian pacemakers in nocturnal rodents. V. Pacemaker structure: a clock for all seasons. J Comp Biol 106:333–355Google Scholar
  92. 92.
    Inagaki N, Honma S, Ono D, Tanahashi Y, Honma K (2007) Separate oscillating cell groups in mouse suprachiasmatic nucleus couple photoperiodically to the onset and end of daily activity. Proc Natl Acad Sci USA 104:7664–7669PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Yoshikawa T, Inagaki N, Takagi S, Kuroda S, Yamasaki M, Watanabe M, Honma S, Honma K (2017) Localization of photoperiod responsive circadian oscillators in the mouse suprachiasmatic nucleus. Sci Rep 7:820CrossRefGoogle Scholar
  94. 94.
    Nakamura W, Honma S, Shirakawa T, Honma K (2002) Clock mutation lengthens the circadian period without damping rhythms in individual SCN neurons. Nat Neurosci 5:399–400PubMedCrossRefGoogle Scholar
  95. 95.
    Liu AC, Welsh DK, Ko CH, Tran HG, Zhang EE, Priest AA, Buhr ED, Singer O, Meeker K, Verma IM, Doyle FJ 3rd, Takahashi JS, Kay SA (2007) Intercellular coupling confers robustness against mutations in the SCN circadian clock network. Cell 129:605–616PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Harmar AJ, Marston HM, Shen S, Spratt C, West KM, Sheward WJ, Morrison CF, Dorin JR, Piggins HD, Reubi JC, Kelly JS, Maywood ES, Hastings MH (2002) The VPAC2 receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109:497–508PubMedCrossRefGoogle Scholar
  97. 97.
    Aton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED (2005) Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci 8:476–483PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Ono D, Honma S, Honma K (2016) Differential roles of AVP and VIP signaling in the postnatal changes of neural networks for coherent circadian rhythms in the SCN. Sci Adv 2:e1600960PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, Takao M, de Wit J, Verkerk A, Eker AP, van Leenen D, Buijs R, Bootsma D, Hoeijmakers JH, Yasui A (1999) Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398:627–630PubMedCrossRefGoogle Scholar
  100. 100.
    Honma S, Ono D, Honma K (2014) Cellular oscillators in the suprachiasmatic nucleus for behavior rhythm expression in the mouse lacking CRYPTOCHROME. In: Honma K (ed) Dynamics of circadian oscillation in the SCN. Hokkaido University Press, Sapporo, pp 85–95Google Scholar
  101. 101.
    Ono D, Honma S, Honma K (2013) Cryptochromes are critical for the development of coherent circadian rhythms in the mouse suprachiasmatic nucleus. Nat Comm 4:1666CrossRefGoogle Scholar
  102. 102.
    Enoki R, Ono D, Hasan MT, Honma S (2012) Honma K (2012) Single-cell resolution fluorescence imaging of circadian rhythms detected with a Nipkow spinning disk confocal system. J Neurosci Methods 202:72–79CrossRefGoogle Scholar
  103. 103.
    Oda Y, Enoki R, Honma K, Honma S (2017) Simultaneous imaging of circadian Ca2 + rhythms and fast Ca2+ activities in the suprachiasmatic nucleus. J Physiol Sci 67:S165CrossRefGoogle Scholar
  104. 104.
    Enoki R, Kuroda S, Ono C, Hasan MT, Ueda T, Honma S, Honma K (2012) Topological specificity and hierarchical network of the circadian calcium rhythm in the suprachiasmatic nucleus. Proc Natl Acad Sci USA 109:21498–21503PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Enoki R, Oda Y, Mieda M, Ono D, Honma S, Honma K (2017) Optical detection of circadian voltage rhythms in the suprachiasmatic nucleus. J Physiol Sci 67:S73Google Scholar
  106. 106.
    Enoki R, Oda Y, Mieda M, Ono D, Honma S, Honma K (2017) Synchronous circadian voltage rhythms with asynchronous calcium rhythms in the suprachiasmatic nucleus. Proc Natl Acad Sci USA 114:E2476–E2485PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Mistlberger RE (1994) Circadian food-anticipatory activity: formal models and physiological mechanisms. Neurosci Biobehav Rev 18:171–195PubMedCrossRefGoogle Scholar
  108. 108.
    Stephan FK (2003) The “other” circadian system: food as a Zeitgeber. J Biol Rhythms 17:284–289CrossRefGoogle Scholar
  109. 109.
    Natsubori A, Honma K, Honma S (2014) Dual regulation of clock gene Per2 expression in discrete brain areas by the circadian pacemaker and methamphetamine-induced oscillator in rats. Eur J Neurosci 39:229–240PubMedCrossRefGoogle Scholar
  110. 110.
    Honma K, Honma S (2009) The SCN-independent clocks, methamphetamine and food restriction. Eur J Neurosci 30:1707–1717PubMedCrossRefGoogle Scholar
  111. 111.
    Pezuk P, Mohawk JA, Yoshikawa T, Sellix MT, Menaker M (2010) Circadian organization is governed by extra-SCN pacemakers. J Biol Rhythms 25:432–441PubMedCrossRefGoogle Scholar
  112. 112.
    Sassone-Corsi P, Christen Y (2016) A Time for metabolism and hormones. Springer Cham Heidelberg New York Dordrecht London, eBook. https://www.ncbi.nlm.nih.gov/books/NBK453176/pdf/Bookshelf_NBK453176.pdf
  113. 113.
    Takahashi JS (2017) Transcriptional architecture of the mammalian circadian clock. Nat Genet Review 18:164–179CrossRefGoogle Scholar
  114. 114.
    Honma A, Yamada Y, Nakamaru Y, Fukuda S (2015) Glucocorticoids reset the nasal circadian clock in mice. Endocrinology 156:4302–4311PubMedCrossRefGoogle Scholar
  115. 115.
    Nishide SY, Honma S, Nakajima Y, Ikeda M, Baba K, Ohmiya Y, Honma K (2006) New reporter system for Per1 and Bmal1 expressions revealed self-sustained circadian rhythms in peripheral tissues. Gene Cells 11:1173–1182CrossRefGoogle Scholar
  116. 116.
    Yoshikawa T, Honma S, K-i Honma (2012) Photoperiodic response of multiple circadian oscillators in mouse SCN. J Physiol Sci 62(S1):215Google Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Research and Education Center for Brain ScienceHokkaido UniversitySapporoJapan

Personalised recommendations