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Hypothalamic integration of central and peripheral clocks

Abstract

During sleep, our biological clock prepares us for the forthcoming period of activity by controlling the release of hormones and the activity of the autonomic nervous system. Here, we review the history of the study of circadian rhythms and highlight recent observations indicating that the same mechanisms that govern our central clock might be at work in the cells of peripheral organs. Peripheral clocks are proposed to synchronize the activity of the organ, enhancing the functional message of the central clock. We speculate that peripheral visceral information is then fed back to the same brain areas that are directly controlled by the central clock. Both clock mechanisms are proposed to have a complementary function in the organization of behaviour and hormone secretion.

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Figure 1: Light–dark cycles and the clock.
Figure 2: Targets of the SCN.
Figure 3: Interaction between peripheral and central clocks.

References

  1. Whitmore, D., Foulkes, N. S., Strahle, U. & Sassone-Corsi, P. Zebrafish Clock rhythmic expression reveals independent peripheral circadian oscillators. Nature Neurosci. 1, 701–707 (1998).

    CAS  Article  PubMed  Google Scholar 

  2. Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).

    CAS  Article  PubMed  Google Scholar 

  3. Yamazaki, S. et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 288, 682–685 (2000).

    CAS  Article  PubMed  Google Scholar 

  4. Whitmore, D., Foulkes, N. S. & Sassone-Corsi, P. Light acts directly on organs and cells in culture to set the vertebrate circadian clock. Nature 404, 87–91 (2000).

    CAS  Article  PubMed  Google Scholar 

  5. Tresher, R. J. et al. Role of the mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282, 1490–1494 (1998).

    Article  Google Scholar 

  6. Van der Horst, G. T. J. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999).

    CAS  Article  PubMed  Google Scholar 

  7. Shearman, L. P. et al. Interacting molecular loops in the mammalian circadian clock. Science 288, 1013–1019 (2000).

    CAS  Article  PubMed  Google Scholar 

  8. Dunlap, J. C. Molecular bases for circadian clocks. Cell 96, 271–290 (1999).

    CAS  Article  PubMed  Google Scholar 

  9. Menaker, M. Rhythms, reproduction, and photoreception. Biol. Reprod. 4, 295–308 (1971).

    CAS  Article  PubMed  Google Scholar 

  10. Ding, J. M., Faiman, L. E., Hurst, W. J., Kuriashkina, L. R. & Gillette, M. U. Resetting the biological clock: mediation of nocturnal CREB phosphorylation via light, glutamate, and nitric oxide. J. Neurosci. 17, 667–675 (1997).

    CAS  Article  PubMed  Google Scholar 

  11. Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Miyamoto, Y. & Sancar, A. Circadian regulation of cryptochrome genes in the mouse. Brain Res. Mol. Brain Res. 71, 238–243 (1999).

    CAS  Article  PubMed  Google Scholar 

  13. Zylka, M. J., Shearman, L. P., Weaver, D. R. & Reppert, S. M. Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 20, 1103–1110 (1998).

    CAS  Article  PubMed  Google Scholar 

  14. Bünning, E. Das weiterlaufen der 'physiologischen uhr' im saugerdarm ohne zentrale steuerung. Naturwissenschaften 45, 68 (1958).

    Article  Google Scholar 

  15. Andrews, R. V. & Folk, J. E. Circadian metabolic patterns in cultured hamster adrenal glands. Comp. Biochem. Physiol. 11, 393–409 (1964).

    CAS  Article  PubMed  Google Scholar 

  16. Langner, R. & Rensing, L. Circadian rhythms of oxygen consumption in rat liver suspension culture: changes of pattern. Z. Naturforsch. 27, 1117–1118 (1972).

    CAS  Article  Google Scholar 

  17. De Mairan, J. Observation botanique. Histoire de L'Academie Royale des Sciences 35–36 (1729).

  18. Simpson, S. & Galbraith, J. J. Observations on the normal temperature of the monkey and its diurnal variation, and on the effect of changes in the daily routine on this variation. Trans. R. Soc. Edinb. 45, 65–106 (1906).

    Article  Google Scholar 

  19. Richter, C. P. Biological Clocks in Medicine and Psychiatry (Springfield, Illinois, 1965).

    Google Scholar 

  20. Richter, C. P. Sleep and activity: their relation to the 24-hour clock. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 45, 8–27 (1967).

    CAS  PubMed  Google Scholar 

  21. Hendrickson, A. E., Wagoner, N. & Cowan, W. M. An autoradiographic and electron microscopic study of retino-hypothalamic connections. Z. Zellforsch. Mikrosk. Anat. 135, 1–26 (1972).

    CAS  Article  PubMed  Google Scholar 

  22. Moore, R. Y. & Eichler, V. B. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res. 42, 201–206 (1972).

    CAS  Article  PubMed  Google Scholar 

  23. Stephan, F. K. & Zucker, I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc. Natl Acad. Sci. USA 69, 1583–1586 (1972).

    CAS  Article  PubMed  Google Scholar 

  24. Inouye, S. I. T. & Kawamura, H. Persistence of circadian rhythmicity in a mammalian hypothalamic 'island' containing the suprachiasmatic nucleus. Proc. Natl Acad. Sci. USA 76, 5962–5966 (1979).

    CAS  Article  PubMed  Google Scholar 

  25. Green, D. J. & Gillette, R. Circadian rhythm of firing rate recorded from single cells in the rat suprachiasmatic brain slice. Brain Res. 245, 198–200 (1982).

    CAS  Article  PubMed  Google Scholar 

  26. Groos, G. A. & Hendriks, J. Circadian rhythms in electrical discharge of rat suprachiasmatic neurones recorded in vitro. Neurosci. Lett. 34, 283–288 (1982).

    CAS  Article  PubMed  Google Scholar 

  27. Shibata, S., Oomura, Y., Kita, H. & Hattori, K. Circadian rhythmic changes of neuronal activity in the suprachiasmatic nucleus of the rat hypothalamic slice. Brain Res. 247, 154–158 (1982).

    CAS  Article  PubMed  Google Scholar 

  28. Bos, N. P. A. & Mirmiran, M. Circadian rhythms in spontaneous neuronal discharges of the cultured suprachiasmatic nucleus. Brain Res. 511, 158–162 (1990).

    CAS  Article  PubMed  Google Scholar 

  29. Schwartz, W. J. & Gainer, H. Suprachiasmatic nucleus: use of 14C-labeled deoxyglucose uptake as a functional marker. Science 197, 1089–1091 (1977).

    CAS  Article  PubMed  Google Scholar 

  30. Flood, D. G. & Gibbs, F. P. Species difference in circadian [14C]2-deoxyglucose uptake by suprachiasmatic nuclei. Brain Res. 232, 200–205 (1982).

    CAS  Article  PubMed  Google Scholar 

  31. Gillette, M. U. & Reppert, S. M. The hypothalamic suprachiasmatic nuclei: circadian patterns of vasopressin secretion and neuronal activity in vitro. Brain Res. Bull. 19, 135–139 (1987).

    CAS  Article  PubMed  Google Scholar 

  32. Perlow, M. J. et al. Oxytocin, vasopressin, and estrogen-stimulated neurophysin: daily patterns of concentration in cerebrospinal fluid. Science 216, 1416–1418 (1982).

    CAS  Article  PubMed  Google Scholar 

  33. Ralph, M. R., Foster, R. G., Davis, F. C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990).

    CAS  Article  PubMed  Google Scholar 

  34. Wager-Smith, K. & Kay, S. A. Circadian rhythm genetics: from flies to mice to humans. Nature Genet. 26, 23–27 (2000).

    CAS  Article  PubMed  Google Scholar 

  35. Whitmore, D. & Sassone-Corsi, P. Cryptic clues to clock function. Nature 398, 557–558 (1999).

    CAS  Article  PubMed  Google Scholar 

  36. Silver, R., Lesauter, J., Tresco, P. A. & Lehman, M. A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382, 810–813 (1996).

    CAS  Article  PubMed  Google Scholar 

  37. Hermes, M. L. H. J., Coderre, E. M., Buijs, R. M. & Renaud, L. P. GABA and glutamate mediate rapid neurotransmission from suprachiasmatic nucleus to hypothalamic paraventricular nucleus in rat. J. Physiol. 496, 749–757 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Lehman, M. N. et al. Circadian rhythmicity restored by neural transplant. Immunocytochemcical characterization of the graft and its integration with the host brain. J. Neurosci. 7, 1626–1638 (1987).

    CAS  Article  PubMed  Google Scholar 

  39. Meyer-Bernstein, E. L. et al. Effects of suprachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters. Endocrinology 140, 207–218 (1999).

    CAS  Article  PubMed  Google Scholar 

  40. Sherin, J. E., Shiromani, P. J., McCarley, R. W. & Saper, C. B. Activation of ventrolateral preoptic neurons during sleep. Science 271, 216–219 (1996).

    CAS  Article  PubMed  Google Scholar 

  41. McGinty, D. & Szymusiak, R. The sleep–wake switch: a neuronal alarm clock. Nature Med. 6, 510–511 (2000).

    CAS  Article  PubMed  Google Scholar 

  42. Buijs, R. M., Wortel, J. & Hou, Y. X. Colocalization of γ-aminobutyric acid with vasopressin, vasoactive intestinal peptide, and somatostatin in the rat suprachiasmatic nucleus. J. Comp. Neurol. 358, 343–352 (1995).

    CAS  Article  PubMed  Google Scholar 

  43. Castel, M. & Morris, J. F. Morphological heterogeneity of the GABAergic network in the suprachiasmatic nucleus, the brain's circadian pacemaker. J. Anat. 196, 1–13 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Kalsbeek, A., Van Heerikhuize, J. J., Wortel, J. & Buijs, R. M. A diurnal rhythm of stimulatory input to the hypothalamo–pituitary–adrenal system as revealed by timed intrahypothalamic administration of the vasopressin V1 antagonist. J. Neurosci. 16, 5555–5565 (1996).

    CAS  Article  PubMed  Google Scholar 

  45. Kalsbeek, A. et al. Melatonin sees the light: blocking GABA-ergic transmission in the paraventricular nucleus induces daytime secretion of melatonin. Eur. J. Neurosci. 12, 3146–3154 (2000).

    CAS  Article  PubMed  Google Scholar 

  46. Jagota, A., De la Iglesia, H. O. & Schwartz, W. J. Morning and evening circadian oscillations in the suprachiasmatic nucleus in vitro. Nature Neurosci. 3, 372–376 (2000).

    CAS  Article  PubMed  Google Scholar 

  47. Kalsbeek, A., Buijs, R. M., Van Heerikhuize, J. J., Arts, M. & Van der Woude, T. P. Vasopressin-containing neurons of the suprachiasmatic nuclei inhibit corticosterone release. Brain Res. 580, 62–67 (1992).

    CAS  Article  PubMed  Google Scholar 

  48. Buijs, R. M., Kalsbeek, A., Van der Woude, T. P., Van Heerikhuize, J. J. & Shinn, S. Suprachiasmatic nucleus lesion increases corticosterone secretion. Am. J. Physiol. 264, R1186–1192 (1993).

    Google Scholar 

  49. Kalsbeek, A., Van der Vliet, J. & Buijs, R. M. Decrease of endogenous vasopressin release necessary for expression of the circadian rise in plasma corticosterone: a reverse microdialysis study. J. Neuroendocrinol. 8, 299–307 (1996).

    CAS  Article  PubMed  Google Scholar 

  50. Buijs, R. M. et al. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur. J. Neurosci. 11, 1535–1544 (1999).

    CAS  Article  PubMed  Google Scholar 

  51. Buijs, R. M., Wortel, J., Van Heerikhuize, J. J. & Kalsbeek, A. Novel environment induced inhibition of corticosterone secretion: physiological evidence for a suprachiasmatic nucleus mediated neuronal hypothalamo–adrenal cortex pathway. Brain Res. 758, 229–236 (1997).

    CAS  Article  PubMed  Google Scholar 

  52. Watson, R. E., Langub, M. C., Engle, M. G. & Maley, B. E. Estrogen-receptive neurons in the anteroventral periventricular nucleus are synaptic targets of the suprachiasmatic nucleus and peri-suprachiasmatic region. Brain Res. 689, 254–264 (1995).

    CAS  Article  PubMed  Google Scholar 

  53. Van der Beek, E. M., Horvath, T. L., Wiegant, V. M., Van den Hurk, R. & Buijs, R. M. Evidence for a direct neuronal pathway from the suprachiasmatic nucleus to the gonadotropin-releasing hormone system: combined tracing and light and electron microscopic immunocytochemical studies. J. Comp. Neurol. 384, 569–579 (1997).

    CAS  Article  PubMed  Google Scholar 

  54. Palm, I. F., Van der Beek, E. M., Wiegant, V. M., Buijs, R. M. & Kalsbeek, A. Vasopressin induces an LH surge in ovariectomized, estradiol-treated rats with lesion of the suprachiasmatic nucleus. Neuroscience 93, 659–666 (1999).

    CAS  Article  PubMed  Google Scholar 

  55. Kalsbeek, A. et al. GABA receptors in the region of the dorsomedial hypothalamus of rats are implicated in the control of melatonin. Neuroendocrinology 63, 69–78 (1996).

    CAS  Article  PubMed  Google Scholar 

  56. Kalsbeek, A., Cutrera, R. A., Van Heerikhuize, J. J., Van der Vliet, J. & Buijs, R. M. GABA release from SCN terminals is necessary for the light-induced inhibition of nocturnal melatonin release in the rat. Neuroscience 91, 453–461 (1999).

    CAS  Article  PubMed  Google Scholar 

  57. Ottenweller, J. E. & Meier, A. H. Adrenal innervation may be an extrapituitary mechanism able to regulate adrenocortical rhythmicity in rats. Endocrinology 111, 1334–1338 (1982).

    CAS  Article  PubMed  Google Scholar 

  58. Kaneko, M., Kaneko, K., Shinsako, J. & Dallman, M. F. Adrenal sensitivity to adrenocorticotropin varies diurnally. Endocrinology 109, 70–75 (1981).

    CAS  Article  PubMed  Google Scholar 

  59. Jasper, M. S. & Engeland, W. C. Splanchnic neural activity modulates ultradian and circadian rhythms in adrenocortical secretion in awake rats. Neuroendocrinology 59, 97–109 (1994).

    CAS  Article  PubMed  Google Scholar 

  60. Kalsbeek, A., Fliers, E., Franke, A. N., Wortel, J. & Buijs, R. M. Functional connections between the suprachiasmatic nucleus and the thyroid gland as revealed by lesioning and viral tracing techniques in the rat. Endocrinology 141, 3832–3841 (2000).

    CAS  Article  PubMed  Google Scholar 

  61. La Fleur, S. E., Kalsbeek, A., Wortel, J. & Buijs, R. M. An SCN generated rhythm in basal glucose levels. J. Neuroendocrinol. 11, 643–652 (1999).

    Article  PubMed  Google Scholar 

  62. La Fleur, S. E., Kalsbeek, A., Wortel, J., Fekkes, M. L. & Buijs, R. M. A daily rhythm in glucose tolerance. A role for the suprachiasmatic nucleus in insulin-independent glucose uptake? Diabetes 50, 1237–1243 (2001).

    Article  PubMed  Google Scholar 

  63. Dai, J. P., Swaab, D. F. & Buijs, R. M. Recovery of axonal transport in “dead neurons”. Lancet 351, 499–500 (1998). | PubMed |

    CAS  Article  PubMed  Google Scholar 

  64. Dai, J. P., Swaab, D. F., Van der Vliet, J. & Buijs, R. M. Postmortem tracing reveals the organization of hypothalamic projections of the suprachiasmatic nucleus in the human brain. J. Comp. Neurol. 400, 87–102 (1998).

    CAS  Article  PubMed  Google Scholar 

  65. Kurumiya, S. & Kawamura, H. Circadian oscillation of the multiple unit activity in the guinea pig suprachiasmatic nucleus. J Comp Physiol [A] 162, 301–308 (1988).

    CAS  Article  Google Scholar 

  66. Buijs, R. M., Chun, S. J., Niijima, A., Romijn, H. J. & Nagai, K. Parasympathetic and sympathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake. J. Comp. Neurol. 431, 405–423 (2001).

    CAS  Article  PubMed  Google Scholar 

  67. Ueyama, T. et al. Suprachiasmatic nucleus: a central autonomic clock. Nature Neurosci. 2, 1051–1053 (1999).

    CAS  Article  PubMed  Google Scholar 

  68. Sato, T. & Kawamura, H. Circadian rhythms in multiple unit activity inside and outside the suprachiasmatic nucleus in the chipmunk (Eutamias sibiricus). Neurosci. Res. 1, 45–52 (1984).

    CAS  Article  PubMed  Google Scholar 

  69. Krieger, D. T., Hauser, H. & Krey, L. C. Suprachiasmatic nuclear lesions do not abolish food-shifted circadian adrenal and temperature rhythmicity. Science 197, 398–399 (1977).

    CAS  Article  PubMed  Google Scholar 

  70. Stephan, F. K., Swann, J. M. & Sisk, C. L. Anticipation of 24-hr feeding schedules in rats with lesions of the suprachiasmatic nucleus. Behav. Neural Biol. 25, 346–363 (1979).

    CAS  Article  PubMed  Google Scholar 

  71. Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001).

    CAS  Article  PubMed  Google Scholar 

  72. Balsalobre, A. et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000).

    CAS  Article  PubMed  Google Scholar 

  73. Tribukait, B. Die aktivitatsperiodik der wissen maus im kunsttag von 16 bis 29 stunden lange. Z. Vergl. Physiol. 38, 479–490 (1956).

    Google Scholar 

  74. Aschoff, J. in Environmental Endocrinology (eds Assenmacher, I. & Farner, D. S.) 172–181 (Springer, New York, 1978).

    Book  Google Scholar 

  75. Stephan, F. K. Limits of entrainment to periodic feeding in rats with suprachiasmatic lesions. J. Comp. Physiol. 143, 401–410 (1981).

    Article  Google Scholar 

  76. Davidson, A. J., Cappendijk, S. L. T. & Stephan, F. K. Feeding-entrained circadian rhythms are attenuated by lesions of the parabrachial region in rats. Am. J. Physiol. 278, R1296–1304 (2000). PubMed

    Google Scholar 

  77. Comperatore, C. A. & Stephan, F. K. Effects of vagotomy on entrainment of activity rhythms to food access. Physiol. Behav. 47, 671–678 (1990).

    CAS  Article  PubMed  Google Scholar 

  78. Norgren, R. Projections from the nucleus of the solitary tract in the rat. Neuroscience 3, 207–218 (1978).

    CAS  Article  PubMed  Google Scholar 

  79. Miura, M. & Reis, D. J. Termination and secondary projections of carotid sinus nerve in the cat brainstem. Am. J. Physiol. 217, 142–153 (1969).

    CAS  Article  PubMed  Google Scholar 

  80. Sawchenko, P. E., Arias, C. & Bittencourt, J. C. Inhibin B, somatostatin, and enkephalin immunoreactivities coexist in caudal medullary neurons that project to the paraventricular nucleus of the hypothalamus. J. Comp. Neurol. 291, 269–280 (1990).

    CAS  Article  PubMed  Google Scholar 

  81. Ter Horst, G. J., De Boer, P., Luiten, P. G. M. & Van Willigen, J. D. Ascending projections from the solitary tract nucleus to the hypothalamus. A Phaseolus vulgaris lectin tracing study in the rat. Neuroscience 31, 785–797 (1989).

    Article  PubMed  Google Scholar 

  82. Hall, J. C. Tripping along the trail to the molecular mechanisms of biological clocks. Trends Neurosci. 18, 230–240 (1995).

    CAS  Article  PubMed  Google Scholar 

  83. Yamamoto, M. et al. Impaired diurnal cardiac autonomic function in subjects with type 2 diabetes. Diabetes Care 22, 2072–2077 (1999).

    CAS  Article  PubMed  Google Scholar 

  84. De Faire, U., Lindvall, K. & Nilsson, B. Noninvasive ambulatory 24h blood pressures and basal blood pressures predict development of sustained hypertension from a borderline state. Am. J. Hypertens. 6, 149–155 (1993).

    CAS  Article  PubMed  Google Scholar 

  85. Zipes, D. P. Warning: the short days of winter may be hazardous to your health. Circulation 100, 1590–1592 (1999).

    CAS  Article  PubMed  Google Scholar 

  86. Stopa, E. G. et al. Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J. Neuropathol. Exp. Neurol. 58, 29–39 (1999).

    CAS  Article  PubMed  Google Scholar 

  87. Liu, R. Y. et al. Decreased vasopressin gene expression in the biological clock of Alzheimer disease patients with and without depression. J. Neuropathol. Exp. Neurol. 59, 314–322 (2000).

    CAS  Article  PubMed  Google Scholar 

  88. Goncharuk, V. D., Van Heerikhuize, J. J., Dai, J. P., Swaab, D. F. & Buijs, R. M. Neuropeptide changes in the suprachiasmatic nucleus in primary hypertension indicate functional impairment of the biological clock. J. Comp. Neurol. 431, 320–330 (2001).

    CAS  Article  PubMed  Google Scholar 

  89. Richter, C. P. A behavioristic study of the activity of the rat. Comp. Psych. Monogr. 1, 1–55 (1922).

    Google Scholar 

  90. Beling, I. Uber das zeitgedachtnis der bienen. Z. Vergl. Physiol. 9, 259–338 (1929).

    Article  Google Scholar 

  91. Pincus, G. A diurnal rhythm in the excretion of urinary ketosteroids by young men. J. Clin. Endocrinol. Metab. 3, 195–199 (1943).

    CAS  Article  Google Scholar 

  92. Aschoff, J. & Wever, R. Spontanperiodik des menschen bei ausschluss aller zeitgeber. Naturwissenschaften 49, 337–342 (1962).

    Article  Google Scholar 

  93. Konopka, R. J. & Benzer, S. Clock mutants of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 68, 2112–2116 (1971).

    CAS  Article  PubMed  Google Scholar 

  94. Bargiello, T. A., Jackson, F. R. & Young, M. W. Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752–754 (1984).

    CAS  Article  PubMed  Google Scholar 

  95. Reddy, P. et al. Molecular analysis of the period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms. Cell 38, 701–710 (1984).

    CAS  Article  PubMed  Google Scholar 

  96. Ralph, M. R. & Menaker, M. A mutation of the circadian system in golden hamsters. Science 241, 1225–1227 (1988).

    CAS  Article  PubMed  Google Scholar 

  97. Vitaterna, M. H. et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264, 719–725 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Welsh, D. K., Logothetis, D. E., Meister, M. & Reppert, S. M. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14, 697–706 (1995).

    CAS  Article  PubMed  Google Scholar 

  99. Tosini, G. & Menaker, M. Circadian rhythms in cultured mammalian retina. Science 272, 419–421 (1996).

    CAS  Article  Google Scholar 

  100. Sun, Z. S. et al. RIGUI, a putative mammalian ortholog of the Drosophila period gene. Cell 90, 1003–1011 (1997).

    CAS  Article  PubMed  Google Scholar 

  101. Tei, H. et al. Circadian oscillation of a mammalian homologue of the Drosophila period gene. Nature 389, 512–516 (1997).

    CAS  Article  PubMed  Google Scholar 

  102. Giebultowicz, J. M. & Hege, D. M. Circadian clock in Malpighian tubules. Nature 386, 664 (1997).

    CAS  Article  PubMed  Google Scholar 

  103. Lowrey, P. L. et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–491 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank all the members of our group at the Netherlands Institute for Brain Research for their contributions, and H. Stoffels for his artwork.

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Buijs, R., Kalsbeek, A. Hypothalamic integration of central and peripheral clocks. Nat Rev Neurosci 2, 521–526 (2001). https://doi.org/10.1038/35081582

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