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  • Review Article
  • Published:

Linking neural activity and molecular oscillations in the SCN

Nature Reviews Neuroscience volume 12, pages 553–569 (2011)Cite this article

Subjects

Key Points

  • Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. We have a good conceptual understanding of the cell-autonomous molecular clockwork that regulates the generation of circadian rhythms in gene expression, but there is a lack of a mechanistic understanding of how this molecular feedback loop interacts with the membrane to produce physiological circadian rhythms.

  • A hallmark feature of the SCN population is that these neurons are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Individual SCN neurons exhibit variability in their firing patterns and are best thought of as weakly coupled oscillators.

  • Sets of currents are responsible for this daily rhythm in spontaneous activity. During the day, SCN neurons are much more depolarized than neurons that do not show spontaneous activity. A set of currents (persistent sodium, hyperpolarization-activated, cyclic nucleotide-gated (HCN) and T- and L-type calcium currents) provide the excitatory drive that is necessary for any spontaneously active neurons. The excitatory drive in SCN neurons seems to be relatively constant throughout the daily cycle.

  • Another set of currents translate this excitatory drive into a regular pattern of action potentials. In the SCN, the fast delayed rectifier (FDR) current, subthreshold-operating A-type K+ current (IA current) and BK potassium current all seem to play a part in the regulation of spontaneous action potential firing in SCN neurons during the day. The biophysical properties of these currents suggest that these three currents will also be critically involved in determining how SCN neurons respond to synaptic stimulation from other regions. These currents are mostly active during the day.

  • There are currents that hyperpolarize the membrane and thereby underlie the nightly silencing of firing. We know the least about these night-active currents but two-pore domain potassium channels (K2P, TASK and TREK) are the most likely candidates.

  • There is evidence that membrane excitability and/or synaptic transmission may be required for the generation of molecular oscillations in SCN neurons. The hypothesis that dysregulated neural activity and synaptic transmission weakens basal Ca2+ and cyclic AMP-responsive element (CRE) activity to a level that is insufficient to drive the expression of period (PER) or cryptochrome (CRY) genes. This evidence is discussed but it is premature to form a conclusion. Certainly, many cell types without electrical activity can generate circadian oscillations.

  • There is strong evidence that membrane excitability can alter clock gene expression. The cellular and molecular mechanisms by which light regulates the expression of PER1 in the SCN have been the subject of much analysis and provide a clear example of how electrical activity can adaptively alter gene expression in this system.

  • Several studies that have explored the impact of mutations in the core clockwork on electrical activity rhythms that are recorded in the SCN have provided strong evidence that the molecular clockwork in the SCN can drive the rhythms in electrical activity. Unfortunately, we can only speculate about the likely mechanisms (rhythmic transcription and translation, ion channel trafficking, and post-translational modifications) by which the molecular clockwork alters membrane properties of SCN neurons.

  • Lastly, evidence is presented that raises the possibility that a decline in neural activity in the SCN may be a crucial mechanism by which ageing and disease may weaken the circadian output and contribute to a set of symptoms that impacts human health.

Abstract

Neurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behaviour and underlying physiology. A hallmark feature of SCN neuronal populations is that they are mostly electrically silent during the night, start to fire action potentials near dawn and then continue to generate action potentials with a slow and steady pace all day long. Sets of currents are responsible for this daily rhythm, with the strongest evidence for persistent Na+ currents, L-type Ca2+ currents, hyperpolarization-activated currents (IH), large-conductance Ca2+ activated K+ (BK) currents and fast delayed rectifier (FDR) K+ currents. These rhythms in electrical activity are crucial for the function of the circadian timing system, including the expression of clock genes, and decline with ageing and disease. This article reviews our current understanding of the ionic and molecular mechanisms that drive the rhythmic firing patterns in the SCN.

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Figure 1: The suprachiasmatic nucleus circuit.
Figure 2: How light regulates the molecular clockwork in SCN neurons.
Figure 3: Possible mechanisms by which the molecular clock can regulate spontaneous neural activity in SCN neurons.

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References

  1. Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Ko, C. H. & Takahashi, J. S. Molecular components of the mammalian circadian clock. Hum. Mol. Genet. 15, R271–R277 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Dibner, C., Schibler, U. & Albrecht, U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72, 517–549 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Herzog, E. D. Neurons and networks in daily rhythms. Nature Rev. Neurosci. 8, 790–802 (2007).

    Article  CAS  Google Scholar 

  5. Welsh, D., Takahashi, J. & Kay, S. Suprachiasmatic nucleus: cell autonomy and network properties. Annu. Rev. Physiol. 72, 551–577 (2010). This review focuses on what is known about how cell-autonomous oscillators are coupled within the SCN circuit.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mohawk, J. A. & Takahashi, J. S. Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators. Trends Neurosci. 34, 349–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Van den Pol, A. N. The hypothalamic suprachiasmatic nucleus of rat: intrinsic anatomy. J. Comp. Neurol. 191, 661–702 (1980).

    Article  CAS  PubMed  Google Scholar 

  8. Moore, R. Y. & Silver, R. Suprachiasmatic nucleus organization. Chronobiol. Int. 15, 475–487 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Antle, M. C., Smith, V. M., Sterniczuk, R., Yamakawa, G. R. & Rakai, B. D. Physiological responses of the circadian clock to acute light exposure at night. Rev. Endocr. Metab. Disord. 10, 279–291 (2009).

    Article  PubMed  Google Scholar 

  10. Golombek, D. A. & Rosenstein, R. E. Physiology of circadian entrainment. Physiol. Rev. 90, 1063–1102 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Morin, L. P. & Allen, C. N. The circadian visual system. Brain Res. Rev. 51, 1–60 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Lakin-Thomas, P. L., Brody, S. & Coté, G. G. Amplitude model for the effects of mutations and temperature on period and phase resetting of the Neurospora circadian oscillator. J. Biol. Rhythms 6, 281–297 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Pulivarthy, S. R. et al. Reciprocity between phase shifts and amplitude changes in the mammalian circadian clock. Proc. Natl Acad. Sci. USA. 104, 20356–20361 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hamada, T, Antle, M. C. & Silver, R. Temporal and spatial expression patterns of canonical clock genes and clock–controlled genes in the suprachiasmatic nucleus. Eur. J. Neurosci. 19, 1741–1748 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Nakamura, W., Yamazaki, S., Takasu, N. N., Mishima, K. & Block, G. D. Differential response of Period 1 expression within the suprachiasmatic nucleus. J. Neurosci. 25, 5481–5487 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yan, L. & Okamura, H. Gradients in the circadian expression of Per1 and Per2 genes in the rat suprachiasmatic nucleus. Eur. J. Neurosci. 15, 1153–1162 (2002).

    Article  PubMed  Google Scholar 

  17. Antle, M. C. & Silver, R. Orchestrating time: arrangements of the brain circadian clock. Trends Neurosci. 28, 145–151 (2005). This review provides a good introduction to the anatomy of the SCN.

    Article  CAS  PubMed  Google Scholar 

  18. Abrahamson, E. E. & Moore, R. Y. Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res. 916, 172–191 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Deurveilher, S. & Semba, K. Indirect projections from the suprachiasmatic nucleus to major arousal-promoting cell groups in rat: implications for the circadian control of behavioural state. Neuroscience 130, 165–183 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Kalsbeek, A. et al. SCN outputs and the hypothalamic balance of life. J. Biol. Rhythms 21, 458–469 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Schwartz, W., Gross, R. & Morton, M. The suprachiasmatic nuclei contain a tetrodotoxin-resistant circadian pacemaker. Proc. Natl Acad. Sci. USA 84, 1694–1698 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Albus, H. et al. Cryptochrome-deficient mice lack circadian electrical activity in the suprachiasmatic nuclei. Curr. Biol. 12, 1130–1133 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Yamaguchi, S. et al. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science 302, 1408–1412 (2003). An important study that used real-time analysis of gene expression to show synchronized, topographically patterned rhythms of clock gene transcription across hundreds of individual neurons within the SCN in organotypic slice culture. Application of TTX reduced the amplitude of single cell oscillations in SCN neurons.

    Article  CAS  PubMed  Google Scholar 

  24. Inouye, S. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Meijer, J., Watanabe, K., Schaap, J., Albus, H. & Détári, L. Light responsiveness of the suprachiasmatic nucleus: long-term multiunit and single-unit recordings in freely moving rats. J. Neurosci. 18, 9078–9087 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakamura, W. et al. In vivo monitoring of circadian timing in freely moving mice. Curr. Biol. 18, 381–385 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Shibata, S., Liou, S. Y. & Ueki, S. Development of the circadian rhythm of neuronal activity in suprachiasmatic nucleus of rat hypothalamic slices. Neurosci. Lett. 43, 231–234 (1983).

    Article  CAS  PubMed  Google Scholar 

  30. Schaap, J., Pennartz, C. & Meijer, J. Electrophysiology of the circadian pacemaker in mammals. Chronobiol. Int. 20, 171–188 (2003).

    Article  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. Herzog, E. D., Takahashi, J. S. & Block, G. D. Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nature Neurosci. 1, 708–713 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Honma, S., Shirakawa, T., Katsuno, Y., Namihira, M. & Honma, K. Circadian periods of single suprachiasmatic neurons in rats. Neurosci. Lett. 250, 157–160 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Kuhlman, S. & McMahon, D. Encoding the ins and outs of circadian pacemaking. J. Biol. Rhythms 21, 470–481 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Ko, G., Shi, L. & Ko, M. Circadian regulation of ion channels and their functions. J. Neurochem. 110, 1150–1169 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Aton, S. J., Colwell, C. S., Harmar, A. J., Waschek, J. & Herzog, E. D. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nature Neurosci. 8, 476–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Webb, A. B., Angelo, N., Huettner, J. E. & Herzog, E. D. Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons. Proc. Natl Acad. Sci. USA 106, 16493–16498 (2009). A very sophisticated combination of experimental and modelling work to explore the network properties of the SCN circuit. The firing rate and Per2 gene expression were measured in isolated and interconnected SCN neurons. The analysis suggests that individual SCN neurons can generate circadian oscillations but that network interactions are crucial for robust and stable oscillations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. VanderLeest, H. T. et al. Seasonal encoding by the circadian pacemaker of the SCN. Curr. Biol. 17, 468–473 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Brown, T. M. & Piggins, H. D. Spatiotemporal heterogeneity in the electrical activity of suprachiasmatic nuclei neurons and their response to photoperiod. J. Biol. Rhythms 24, 44–54 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Meijer, J. H., Michel, S., Vanderleest, H. T. & Rohling, J. H. Daily and seasonal adaptation of the circadian clock requires plasticity of the SCN neuronal network. Eur. J. Neurosci. 32, 2143–2151 (2010).

    Article  PubMed  Google Scholar 

  41. Llinás, R. R. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. Science 242, 1654–1664 (1988).

    Article  PubMed  Google Scholar 

  42. Bean, B. P. The action potential in mammalian central neurons. Nature Rev. Neurosci. 8, 451–465 (2007).

    Article  CAS  Google Scholar 

  43. Belle, M. D., Diekman, C. O., Forger, D. B. & Piggins, H. D. Daily electrical silencing in the mammalian circadian clock. Science 326, 281–284 (2009). During the day, SCN neurons are under strong depolarizing drive, which enables them to generate spontaneous action potentials. This intriguing study suggests that some SCN neurons are so depolarized that they cannot generate action potentials and are functionally silenced.

    Article  CAS  PubMed  Google Scholar 

  44. Pennartz, C. M., Bierlaagh, M. A., Geurtsen, A. M. Cellular mechanisms underlying spontaneous firing in rat suprachiasmatic nucleus: involvement of a slowly inactivating component of sodium current. J. Neurophysiol. 78, 1811–1825 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Jackson, A. C., Yao, G. L. & Bean, B. P. Mechanism of spontaneous firing in dorsomedial suprachiasmatic nucleus neurons. J. Neurosci. 24, 7985–7998 (2004). Careful analysis of the excitatory drive found in single SCN neurons in culture. The results highlight the importance of the persistent sodium influx that occurs at resting membrane potentials.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kononenko, N. I., Shao, L. R. & Dudek, F. E. Riluzole-sensitive slowly inactivating sodium current in rat suprachiasmatic nucleus neurons. J. Neurophysiol. 91, 710–718 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Lein, E. et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168–176 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Kononenko, N. I., Honma, S., Dudek, F. E. & Honma, K. On the role of calcium and potassium currents in circadian modulation of firing rate in rat suprachiasmatic nucleus neurons: multielectrode dish analysis. Neurosci. Res. 62, 51–57 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Biel, M., Wahl-Schott, C., Michalakis, S. & Zong, X. Hyperpolarization-activated cation channels: from genes to function. Physiol. Rev. 89, 847–885 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Akasu, T., Shoji, S. & Hasuo, H. Inward rectifier and low-threshold calcium currents contribute to the spontaneous firing mechanism in neurons of the rat suprachiasmatic nucleus. Pflugers Arch. 425, 109–116 (1993).

    Article  CAS  PubMed  Google Scholar 

  52. Jiang, Z. G., Nelson, C. S. & Allen, C. N. Melatonin activates an outward current and inhibits Ih in rat suprachiasmatic nucleus neurons. Brain Res. 687, 125–132 (1995).

    Article  CAS  PubMed  Google Scholar 

  53. de Jeu, M. T. & Pennartz, C. M. Functional characterization of the H-current in SCN neurons in subjective day and night: a whole-cell patch-clamp study in acutely prepared brain slices. Brain Res. 767, 72–80 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Atkinson, S. E. et al. Cyclic AMP signalling controls action potential firing rate and molecular circadian pacemaking in the suprachiasmatic nucleus. J. Biol. Rhythms 26, 210–220 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. O'Neill, J. S., Maywood, E. S., Chesham, J. E., Takahashi, J. S. & Hastings, M. H. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320, 949–953 (2008). An important study that explores the role of cAMP signalling in the SCN. Among other findings, the authors show that the transcriptional activity of the CRE is strongly rhythmic in the SCN. Importantly, pharmacological blockade of adenylyl cyclase activity reduced cAMP levels, suppressed CRE expression and greatly reduced PER2::LUC expression. The sustained pharmacological block of HCN channels also reduced circadian gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Notomi, T. & Shigemoto, R. Immunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain. J. Comp. Neurol. 471, 241–276 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Nahm, S. S., Farnell, Y. Z., Griffith, W. & Earnest, D. J. Circadian regulation and function of voltage-dependent calcium channels in the suprachiasmatic nucleus. J. Neurosci. 25, 9304–9308 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Vandael, D. H. et al. Ca(v)1.3 and BK channels for timing and regulating cell firing. Mol. Neurobiol. 42, 185–198 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Pennartz, C. M., de Jeu, M. T., Bos, N. P., Schaap, J. & Geurtsen, A. M. Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature 416, 286–290 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Huang, R. C. Sodium and calcium currents in acutely dissociated neurons from rat suprachiasmatic nucleus. J. Neurophysiol. 70, 1692–1703 (1993).

    Article  CAS  PubMed  Google Scholar 

  61. Kim, D. Y. et al. Voltage-gated calcium channels play crucial roles in the glutamate-induced phase shifts of the rat suprachiasmatic circadian clock. Eur. J. Neurosci. 21, 1215–1222 (2005).

    Article  PubMed  Google Scholar 

  62. Irwin, R. & Allen, C. Calcium response to retinohypothalamic tract synaptic transmission in suprachiasmatic nucleus neurons. J. Neurosci. 27, 11748–11757 (2007). The work shows careful simultaneous measurements of membrane events and intracellular calcium in SCN neurons. The data from this study show that driving the frequency of action potentials in the SCN neuron to 5–10 Hz (daytime levels) induces a rise in somatic calcium levels, and that this rise is mediated by L-type calcium channels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang, H. Y. & Huang, R. C. Diurnal modulation of the Na+/K+-ATPase and spontaneous firing in the rat retinorecipient clock neurons. J. Neurophysiol. 92, 2295–2301 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, Y. C. & Huang, R. C. Effects of sodium pump activity on spontaneous firing in neurons of the rat suprachiasmatic nucleus. J. Neurophysiol. 96, 109–118 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Newman, G. C., Hospod, F. E., Patlak, C. S. & Moore, R. Y. Analysis of in vitro glucose utilization in a circadian pacemaker model. J. Neurosci. 12, 2015–2021 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Baranauskas, G., Tkatch, T., Nagata, K., Yeh, J. & Surmeier, D. Kv3.4 subunits enhance the repolarizing efficiency of Kv3.1 channels in fast-spiking neurons. Nature Neurosci. 6, 258–266 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Rudy, B. & McBain, C. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci. 24, 517–526 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Itri, J., Michel, S., Vansteensel, M., Meijer, J. & Colwell, C. Fast delayed rectifier potassium current is required for circadian neural activity. Nature Neurosci. 8, 650–656 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Kudo, T., Loh, D. H., Kuljis, D., Constance, C. & Colwell, C. S. Fast delayed rectifier potassium current: critical for input and output of the circadian system. J. Neurosci. 31, 2746–2755 (2011). An analysis of transgenic mice lacking genes coding for the Kv3.1 and Kv3.2 channels. This provides clear evidence that the FDR current is important for both input and output of the SCN circuit.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bouskila, Y. & Dudek, F. E. A rapidly activating type of outward rectifier K+ current and A-current in rat suprachiasmatic nucleus neurones. J. Physiol. 488, 339–350 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Alvado, L. & Allen, C. N. Tetraethylammonium (TEA) increases the inactivation time constant of the transient K+ current in suprachiasmatic nucleus neurons. Brain Res. 1221, 24–29 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Itri, J., Vosko, A., Schroeder, A., Dragich, J., Michel, S. & Colwell, C. Circadian regulation of A-type potassium currents in the suprachiasmatic nucleus. J. Neurophysiol. 103, 632–640 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Cloues, R. K. & Sather, W. A. Afterhyperpolarization regulates firing rate in neurons of the suprachiasmatic nucleus. J. Neurosci. 23, 1593–1604 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Meredith, A. L. et al. BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output. Nature Neurosci. 9, 1041–1049 (2006). An analysis of transgenic mice lacking the gene that encodes the pore-forming subunit of the BK channel. Although the expression of clock genes in the SCN was relatively normal, the authors found clear deficits in circadian behaviour and altered spontaneous firing rates.

    Article  CAS  PubMed  Google Scholar 

  75. Pitts, G. R., Ohta, H. & McMahon, D. G. Daily rhythmicity of large-conductance Ca2+-activated K+ currents in suprachiasmatic nucleus neurons. Brain Res. 1071, 54–62 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Pennartz, C. M., De Jeu, M. T., Geurtsen, A. M., Sluiter, A. A. & Hermes, M. L. Electrophysiological and morphological heterogeneity of neurons in slices of rat suprachiasmatic nucleus. J. Physiol. 506, 775–793 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kuhlman, S. J. & McMahon, D. G. Rhythmic regulation of membrane potential and potassium current persists in SCN neurons in the absence of environmental input. Eur. J. Neurosci. 20, 1113–1117 (2004).

    Article  PubMed  Google Scholar 

  78. Mathie, A. Neural two-pore-domain potassium channels and their regulation by G protein-coupled receptors. J. Physiol. 578, 377–385 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Bayliss, D. A. & Barrett, P. Q. Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. Trends Pharmacol. Sci. 29, 566–575 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hille, B. Ion Channels of Excitable Membranes. (Sinauer, Sunderland, Massachusetts, 2001).

    Google Scholar 

  81. Kent, J. & Meredith, A. L. BK channels regulate spontaneous action potential rhythmicity in the suprachiasmatic nucleus. PLoS ONE 3, e3884 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Belenky, M. A., Yarom, Y. & Pickard, G. E. Heterogeneous expression of γ-aminobutyric acid and γ-aminobutyric acid-associated receptors and transporters in the rat suprachiasmatic nucleus. J. Comp. Neurol. 506, 708–732 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Choi, H. J. et al. Excitatory actions of GABA in the suprachiasmatic nucleus. J. Neurosci. 28, 5450–5459 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. vanderLeest, H. T., Rohling, J. H., Michel, S. & Meijer, J. H. Phase shifting capacity of the circadian pacemaker determined by the SCN neuronal network organization. PLoS ONE 4, e4976 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Itri, J., Michel, S., Waschek, J. A. & Colwell, C. S. Circadian rhythm in inhibitory synaptic transmission in the mouse suprachiasmatic nucleus. J. Neurophysiol. 92, 311–319 (2004).

    Article  PubMed  Google Scholar 

  86. Kim, S. M. et al. Deletion of the secretory vesicle proteins IA-2 and IA-2β disrupts circadian rhythms of cardiovascular and physical activity. FASEB J. 23, 3226–3232 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pakhotin, P., Harmar, A. J., Verkhratsky, A. & Piggins, H. VIP receptors control excitability of suprachiasmatic nuclei neurones. Pfluegers 452, 7–15 (2006).

    Article  CAS  Google Scholar 

  88. Nitabach, M., Blau, J. & Holmes, T. Electrical silencing of Drosophila pacemaker neurons stops the free-running circadian clock. Cell 109, 485–495 (2002). An elegant study in Drosophila in which the expression of a non-voltage sensitive potassium channel was manipulated to assess the impact of chronically hyperpolarizing circadian pacemaker neurons. As expected, this construct electrically silenced the neurons and blocked behavioural rhythms in Drosophila . The unexpected finding was that it also blocked the rhythm in expression of the PER and TIM proteins.

    Article  CAS  PubMed  Google Scholar 

  89. Shibata, S. & Moore, R. Y. Tetrodotoxin does not affect circadian rhythms in neuronal activity and metabolism in rodent suprachiasmatic nucleus in vitro. Brain Res. 606, 259–266 (1993).

    Article  CAS  PubMed  Google Scholar 

  90. Earnest, D. J., Digiorgio, S. M. & Sladek, C. D. Effects of tetrodotoxin on the circadian pacemaker mechanism in suprachiasmatic explants in vitro. Brain Res. Bull. 26, 677–682 (1991).

    Article  CAS  PubMed  Google Scholar 

  91. Maywood, E. S., O'Neill, J. S., Chesham, J. E. & Hastings, M. H. Minireview: the circadian clockwork of the suprachiasmatic nuclei-analysis of a cellular oscillator that drives endocrine rhythms. Endocrinology 148, 5624–5634 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Noda, M. et al. Expression of functional sodium channels from cloned cDNA. Nature 322, 826–828 (1986).

    Article  CAS  PubMed  Google Scholar 

  93. Baba, K., Ono, D., Honma, S. & Honma, K. A TTX-sensitive local circuit is involved in the expression of PK2 and BDNF circadian rhythms in the mouse suprachiasmatic nucleus. Eur. J. Neurosci. 27, 909–916 (2008).

    Article  PubMed  Google Scholar 

  94. Deery, M. J. et al. Proteomic analysis reveals the role of synaptic vesicle cycling in sustaining the suprachiasmatic circadian clock. Curr. Biol. 19. 2031–2036 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Aton, S. J., Huettner, J. E., Straume, M. & Herzog, E. D. GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons. Proc. Natl Acad. Sci. USA 103, 19188–19193 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vosko, A. M., Schroeder, A., Loh, D. H. & Colwell, C. S. Vasoactive intestinal peptide and the mammalian circadian system. Gen. Comp. Endocrinol. 152, 165–175 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Maywood, E. S., Chesham, J. E., O'Brien, J. A. & Hastings, M. H. A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits. Proc. Natl Acad. Sci. USA. 25 July 2011 (doi: 10.1073/pnas.1101767108).

    Article  CAS  Google Scholar 

  98. Maywood, E. S. et al. Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr. Biol. 16, 599–605 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Shearman, L. P., Zylka, M. J., Weaver, D. R., Kolakowski, L. F. Jr & Reppert, S. M. Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron 19, 1261–1269 (1997).

    Article  CAS  PubMed  Google Scholar 

  100. Shigeyoshi, Y. et al. Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript. Cell 91, 1043–1053 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Kuhlman, S. J., Silver, R., Le Sauter, J., Bult-Ito, A. & McMahon, D. G. Phase resetting light pulses induce Per1 and persistent spike activity in a subpopulation of biological clock neurons. J. Neurosci. 23, 1441–1450 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Quintero, J. E., Kuhlman, S. J. & McMahon, D. G. The biological clock nucleus: a multiphasic oscillator network regulated by light. J. Neurosci. 23, 8070–8076 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Vansteensel, M. J., Yamazaki, S., Albus, H., Deboer, T., Block, G. D. & Meijer, J. H. Dissociation between circadian Per1 and neuronal and behavioral rhythms following a shifted environmental cycle. Curr. Biol. 13, 1538–1542 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Lundkvist, G., Kwak, Y., Davis, E., Tei, H. & Block, G. A calcium flux is required for circadian rhythm generation in mammalian pacemaker neurons. J. Neurosci. 25, 7682–7686 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sheeba, V., Gu, H., Sharma, V. K., O'Dowd, D. K. & Holmes, T. C. Circadian- and light-dependent regulation of resting membrane potential and spontaneous action potential firing of Drosophila circadian pacemaker neurons. J. Neurophysiol. 99, 976–988 (2008).

    Article  PubMed  Google Scholar 

  106. Choi, C. et al. Cellular dissection of circadian peptide signals with genetically encoded membrane-tethered ligands. Curr. Biol. 19, 1167–1175 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Regehr, W. G. & Tank, D. W. Calcium dynamics in synaptically activated pyramidal cells. J. Neurosci. 12, 4202–4223 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Miyakawa, H. et al. Synaptically activated increases in Ca2+ concentration in hippocampal CA1 pyramidal cells are primarily due to voltage-gated Ca2+ channels. Neuron 9, 1163–1173 (1992).

    Article  CAS  PubMed  Google Scholar 

  109. Knopfel, T. & Gahwiler, B. H. Activity-induced elevations of intracellular calcium concentration in pyramidal and nonpyramidal cells of the CA3 region of rat hippocampal slice cultures. J. Neurophysiol. 68, 961–963 (1992).

    Article  CAS  PubMed  Google Scholar 

  110. Colwell, C. Circadian modulation of calcium levels in cells in the suprachiasmatic nucleus. Eur. J. Neurosci. 12, 571–576 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ikeda, M. et al. Circadian dynamics of cytosolic and nuclear Ca2+ in single suprachiasmatic nucleus neurons. Neuron 38, 253–263 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Aguilar-Roblero, R., Mercado, C., Alamilla, J., Laville, A. & Díaz-Muñoz, M. Ryanodine receptor Ca2+-release channels are an output pathway for the circadian clock in the rat suprachiasmatic nuclei. Eur. J. Neurosci. 26, 575–582 (2007).

    Article  PubMed  Google Scholar 

  113. Pologruto, T. A., Yasuda, R. & Svoboda, K. Monitoring neural activity and [Ca2+] with genetically encoded Ca2+ indicators. J. Neurosci. 24, 9572–9579 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Harrisingh, M. C., Wu, Y., Lnenicka, G. A. & Nitabach, M. N. Intracellular Ca2+ regulates free-running circadian clock oscillation in vivo. J. Neurosci. 27, 12489–12499 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. McMahon, D. G. & Block, G. D. The Bulla ocular circadian pacemaker. J. Comp. Physiol. 161, 335–346 (1987).

    Article  CAS  Google Scholar 

  116. Colwell, C. S., Whitmore, D., Michel, S. & Block, G. D. Calcium plays a central role in phase shifting the ocular circadian pacemaker of Aplysia. J. Comp. Physiol. A. 175, 415–423 (1994).

    Article  CAS  PubMed  Google Scholar 

  117. Johnson, C. H. et al. Circadian oscillation of cytosolic and chloroplastic free calcium in plants. Science 269, 1863–1865 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Wood, N. T. et al. The calcium rhythms of different cell types oscillate with different circadian phases, Plant Physiol. 125, 787–796 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Xu, X. et al. Distinct light and clock modulation of cytosolic free Ca2+ oscillations and rhythmic CHLOROPHYLL A/B BINDING PROTEIN2 promoter activity in Arabidopsis. Plant Cell 19, 3474–3490 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Prosser, R. A. & Gillette, M.U. Cyclic changes in cAMP concentration and phosphodiesterase activity in a mammalian circadian clock studied in vitro. Brain Res. 568, 185–192 (1991).

    Article  CAS  PubMed  Google Scholar 

  121. Ferreyra, G. A. & Golombek, D. A. Cyclic AMP and protein kinase A rhythmicity in the mammalian suprachiasmatic nuclei. Brain Res. 858, 33–39 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Fukuhara, C. et al. Gating of the cAMP signaling cascade and melatonin.synthesis by the circadian clock in mammalian retina. J. Neurosci. 24, 1803–1811 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hastings, M. H., Maywood, E. S. & O'Neill, J. S. Cellular circadian pacemaking and the role of cytosolic rhythms. Curr. Biol. 18, R805–R815 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Ferguson, G. D., & Storm, D. R. Why calcium-stimulated adenylyl cyclases? Physiology 19, 271–276 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Zhang, E. E. et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nature Med. 16, 1152–1156 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Robles, M. S., Boyault, C., Knutti, D., Padmanabhan, K. & Weitz, C. J. Identification of RACK1 and protein kinase Cα as integral components of the mammalian circadian clock. Science 327, 463–466 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Nakajima, M. et al. Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science 308, 414–415 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. O'Neill, J. S. & Reddy, A. B. Circadian clocks in human red blood cells. Nature 469, 498–503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hardin, P. E. Essential and expendable features of the circadian timekeeping mechanism. Curr. Opin. Neurobiol. 16, 686–692 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Panda, S. Multiple photopigments entrain the Mammalian circadian oscillator. Neuron 53, 619–621 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Ecker, J. L. et al. Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision. Neuron 67, 49–60 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lall, G. S. et al. Distinct contributions of rod, cone, and melanopsin photoreceptors to encoding irradiance. Neuron 66, 417–428 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Berson, D., Dunn, F. & Takao, M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Hannibal, J., Hindersson, P., Knudsen, S. M., Georg, B. & Fahrenkrug, J. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J. Neurosci. 22, RC191 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Hannibal, J., Brabet, P. & Fahrenkrug, J. Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R2050–R2058 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Cahill, G. M. & Menaker, M. Responses of the suprachiasmatic nucleus to retinohypothalamic tract volleys in a slice preparation of the mouse hypothalamus. Brain Res. 479, 65–75 (1989).

    Article  CAS  PubMed  Google Scholar 

  137. Kim, Y. I. & Dudek, F. E. Intracellular electrophysiological study of suprachiasmatic nucleus neurons in rodents: excitatory synaptic mechanisms. J. Physiol. 444, 269–287 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Jiang, Z. G., Yang, Y., Liu, Z. P. & Allen, C. N. Membrane properties and synaptic inputs of suprachiasmatic nucleus neurons in rat brain slices. J. Physiol. 499, 141–159 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Michel, S., Itri, J. & Colwell, C. S. Excitatory mechanisms in the suprachiasmatic nucleus: the role of AMPA/KA glutamate receptors. J. Neurophysiol. 88, 817–828 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Colwell, C. S. NMDA-evoked calcium transients and currents in the suprachiasmatic nucleus: gating by the circadian system. Eur. J. Neurosci. 13, 1420–1428 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Pennartz, C. M., Hamstra, R. & Geurtsen, A. M. Enhanced NMDA receptor activity in retinal inputs to the rat suprachiasmatic nucleus during the subjective night. J. Physiol. 532, 181–194 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Michel, S., Itri, J., Han, J. H., Gniotczynski, K. & Colwell, C. S. Regulation of glutamatergic signalling by PACAP in the mammalian suprachiasmatic nucleus. BMC Neurosci. 7, 15 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Haak, L. L. Metabotropic glutamate receptor modulation of glutamate responses in the suprachiasmatic nucleus. J. Neurophysiol. 81, 1308–1317 (1999).

    Article  CAS  PubMed  Google Scholar 

  144. Kim, Y. I. & Dudek, F. E. Intracellular electrophysiological study of suprachiasmatic nucleus neurons in rodents: inhibitory synaptic mechanisms. J. Physiol. 458, 247–260 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen, G. & van den Pol, A. N. Presynaptic GABAB autoreceptor modulation of P/Q-type calcium channels and GABA release in rat suprachiasmatic nucleus neurons. J. Neurosci. 18, 1913–1922 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Wagner, S., Castel, M., Gainer, H. & Yarom, Y. GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity. Nature 387, 598–603 (1997).

    Article  CAS  PubMed  Google Scholar 

  147. Irwin, R. P. & Allen, C. N. GABAergic signaling induces divergent neuronal Ca2+ responses in the suprachiasmatic nucleus network. Eur. J. Neurosci. 30, 1462–1475 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Berson, D. M., Dunn, F. A. & Takao, M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002).

    Article  CAS  PubMed  Google Scholar 

  149. Warren, E., Allen, C., Brown, R. & Robinson, D. Intrinsic light responses of retinal ganglion cells projecting to the circadian system. Eur. J. Neurosci. 17, 1727–1735 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Tu, D. et al. Physiologic diversity and development of intrinsically photosensitive retinal ganglion cells. Neuron 48, 987–999 (2005).

    Article  CAS  PubMed  Google Scholar 

  151. Gamble, K. L., Allen, G. C., Zhou, T. & McMahon, D. G. Gastrin-releasing peptide mediates light-like resetting of the suprachiasmatic nucleus circadian pacemaker through cAMP response element-binding protein and Per1 activation. J. Neurosci. 27, 12078–12087 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Gamble, K. L., Kudo, T., Colwell, C. S. & McMahon, D. G. Gastrin-releasing peptide modulates fast delayed rectifier potassium current in Per1-expressing SCN neurons. J. Biol. Rhythms 26, 99–106 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Itri, J. & Colwell, C. S. Regulation of inhibitory synaptic transmission by vasoactive intestinal peptide (VIP) in the mouse suprachiasmatic nucleus. J. Neurophysiol. 90, 1589–1597 (2003).

    Article  CAS  PubMed  Google Scholar 

  154. Wang, L. M. et al. Role for the NR2B subunit of the N-methyl-D-aspartate receptor in mediating light input to the circadian system. Eur. J. Neurosci. 27, 1771–1779 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Cermakian, N. & Sassone-Corsi, P. Environmental stimulus perception and control of circadian clocks. Curr. Opin. Neurobiol. 12, 359–365 (2002).

    Article  CAS  PubMed  Google Scholar 

  157. Gillette, M. U. & Mitchell, J. W. Signaling in the suprachiasmatic nucleus: selectively responsive and integrative. Cell Tissue Res. 309, 99–107 (2002).

    Article  CAS  PubMed  Google Scholar 

  158. Meijer, J. H. & Schwartz, W. J. In search of the pathways for light-induced pacemaker resetting in the suprachiasmatic nucleus. J. Biol. Rhythms 18, 235–249 (2003).

    Article  PubMed  Google Scholar 

  159. Obrietan, K., Impey, S. & Storm, D. R. Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nature Neurosci. 1, 693–700 (1998).

    Article  CAS  PubMed  Google Scholar 

  160. Dziema, H., Oatis, B., Butcher, G. Q., Yates, R., Hoyt, K. R. & Obrietan, K. The ERK/MAP kinase pathway couples light to immediate-early gene expression in the suprachiasmatic nucleus. Eur. J. Neurosci. 17, 1617–1627 (2003).

    Article  PubMed  Google Scholar 

  161. Butcher, G. Q., Lee, B., Cheng, H. Y. & Obrietan, K. Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/MAP kinase-dependent mechanism. J. Neurosci. 25, 5305–5313 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Yokota, S. et al. Involvement of calcium-calmodulin protein kinase but not mitogen-activated protein kinase in light-induced phase delays and Per gene expression in the suprachiasmatic nucleus of the hamster. J. Neurochem. 77, 618–627 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Ding, J. M. et al. Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. Science 266, 1713–1717 (1994).

    Article  CAS  PubMed  Google Scholar 

  164. Oster, H. et al. cGMP-dependent protein kinase II modulates mPer1 and mPer2 gene induction and influences phase shifts of the circadian clock. Curr. Biol. 13, 725–733 (2003).

    Article  CAS  PubMed  Google Scholar 

  165. Jakubcakova, V. et al. Light entrainment of the mammalian circadian clock by a PRKCA-dependent posttranslational mechanism. Neuron 54, 831–843 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Tischkau, S. A., Gallman, E. A., Buchanan, G. F. & Gillette, M. U. Differential cAMP gating of glutamatergic signaling regulates long-term state changes in the suprachiasmatic circadian clock. J. Neurosci. 20, 7830–7837 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kornhauser, J. M., Ginty, D. D., Greenberg, M. E., Mayo, K. E. & Takahashi, J. S. Light entrainment and activation of signal transduction pathways in the SCN. Prog. Brain Res. 111, 133–146 (1996).

    Article  CAS  PubMed  Google Scholar 

  168. Rieux, C. et al. Analysis of immunohistochemical label of Fos protein in the suprachiasmatic nucleus: comparison of different methods of quantification. J. Biol. Rhythms 17, 121–136 (2002).

    Article  CAS  PubMed  Google Scholar 

  169. Ginty, D. D. et al. Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science 260, 238–241 (1993).

    Article  CAS  PubMed  Google Scholar 

  170. Gau, D. et al. Phosphorylation of CREB Ser142 regulates light-induced phase shifts of the circadian clock. Neuron 34, 245–253 (2002).

    Article  CAS  PubMed  Google Scholar 

  171. Travnickova-Bendova, Z., Cermakian, N., Reppert, S. M. & Sassone-Corsi, P. Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc. Natl Acad. Sci. USA 99, 7728–7733 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Yan, L. & Silver, R. Resetting the brain clock: time course and localization of mPER1 and mPER2 protein expression in suprachiasmatic nuclei during phase shifts. Eur. J. Neurosci. 19, 1105–1109 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Lee, B. et al. CREB influences timing and entrainment of the SCN circadian clock. J. Biol. Rhythms 25, 410–420 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Tischkau, S. A., Mitchell, J. W., Tyan, S. H., Buchanan, G. F. & Gillette, M. U. Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. J. Biol. Chem. 278, 718–723 (2003).

    Article  CAS  PubMed  Google Scholar 

  175. Cao, R., Li, A., Cho, H. Y., Lee, B. & Obrietan, K. Mammalian target of rapamycin signaling modulates photic entrainment of the suprachiasmatic circadian clock. J. Neurosci. 30, 6302–6314 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Poo, M. M. Neurotrophins as synaptic modulators. Nature Rev. Neurosci. 2, 24–32 (2001).

    Article  CAS  Google Scholar 

  177. Greenberg, M. E., Xu, B., Lu, B. & Hempstead, B. L. New insights in the biology of BDNF synthesis and release: implications in CNS function. J. Neurosci. 29, 12764–12767 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zhou, Z. et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255–269 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Liang, F. Q., Sohrabji, F., Miranda, R., Earnest, B. & Earnest, D. Expression of brain-derived neurotrophic factor and its cognate receptor, TrkB, in the rat suprachiasmatic nucleus. Exp. Neurol. 151, 184–193 (1998).

    Article  CAS  PubMed  Google Scholar 

  180. Allen, G. C. & Earnest, D. J. Overlap in the distribution of TrkB immunoreactivity and retinohypothalamic tract innvervation of the rat suprachiasmatic nucleus. Neurosci. Lett. 376, 200–204 (2005).

    Article  CAS  PubMed  Google Scholar 

  181. Kim, Y. I., Choi, H. J. & Colwell, C. S. Brain-derived neurotrophic factor regulation of N-methyl-D-aspartate receptor-mediated synaptic currents in suprachiasmatic nucleus neurons. J. Neurosci. Res. 84, 1512–1520 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Michel, S., Clark, J. P., Ding, J. M. & Colwell, C. S. Brain-derived neurotrophic factor and neurotrophin receptors modulate glutamate-induced phase shifts of the suprachiasmatic nucleus. Eur. J. Neurosci. 24, 1109–1116 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Liang, F. Q., Allen, G. & Earnest, D. Role of brain-derived neurotrophic factor in the circadian regulation of the suprachiasmatic pacemaker by light. J. Neurosci. 20, 2978–2987 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Allen, G. C., Qu, X. & Earnest, D. J. TrkB-deficient mice show diminished phase shifts to the circadian activity rhythm in response to light. Neurosci. Lett. 378, 150–155 (2005).

    Article  CAS  PubMed  Google Scholar 

  185. Liu, C., Weaver, D. R., Strogatz, S. H. & Reppert, S. M. Cellular construction of a circadian clock: period determination in the suprachiasmatic nuclei. Cell 91, 855–860 (1997).

    Article  CAS  PubMed  Google Scholar 

  186. Nakamura, W., Honma, S., Shirakawa, T. & Honma, K. Clock mutation lengthens the circadian period without damping rhythms in individual SCN neurons. Nature Neurosci. 5, 399–400 (2002).

    Article  CAS  PubMed  Google Scholar 

  187. Fogle, K. J., Parson, K. G., Dahm, N. A. & Holmes, T. C. CRYPTOCHROME is a blue-light sensor that regulates neuronal firing rate. Science 331, 1409–1413 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. McDonald, M. J. & Rosbash, M. Microarray analysis and organization of circadian gene expression in Drosophila. Cell 107, 567–578 (2001).

    Article  CAS  PubMed  Google Scholar 

  189. Duffield, G. E. DNA microarray analyses of circadian timing: the genomic basis of biological time. J. Neuroendocrinol. 15, 991–1002 (2003).

    Article  CAS  PubMed  Google Scholar 

  190. Colley, B. S., Biju, K. C., Visegrady, A., Campbell, S. & Fadool, D. A. Neurotrophin B receptor kinase increases Kv subfamily member 1.3 (Kv1.3) ion channel half-life and surface expression. Neuroscience 144, 531–546 (2007).

    Article  CAS  PubMed  Google Scholar 

  191. Brussaard, A. B. Antisense oligonucleotides induce functional deletion of ligand gated ion channels in cultured neurons and brain explants. J. Neurosci. Methods 71, 55–64 (1997).

    Article  CAS  PubMed  Google Scholar 

  192. Palmer, M. L., Fahrenkrug, S. C. & O'Grady, S. M. RNA interference and ion channel physiology. Cell Biochem. Biophys. 46, 175–191 (2006).

    Article  CAS  PubMed  Google Scholar 

  193. Kessels, H. W. & Malinow, R. Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340–350 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Keifer, J. & Zheng, Z. AMPA receptor trafficking and learning. Eur. J. Neurosci. 32, 269–277 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Krugers, H. J., Hoogenraad, C. C. & Groc, L. Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory. Nature Rev. Neurosci. 11, 675–681 (2010).

    Article  CAS  Google Scholar 

  196. Strumbos, J. G., Polley, D. B. & Kaczmarek, L. K. Specific and rapid effects of acoustic stimulation on the tonotopic distribution of Kv3.1b potassium channels in the adult rat. Neuroscience 167, 567–572 (2010).

    Article  CAS  PubMed  Google Scholar 

  197. Strumbos, J. G., Brown, M. R., Kronengold, J., Polley, D. B. & Kaczmarek, L. K. Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b. J. Neurosci. 30, 10263–10271 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Xu, M., Gu, Y., Barry, J. & Gu, C. Kinesin I transports tetramerized Kv3 channels through the axon initial segment via direct binding. J. Neurosci. 30, 15987–16001 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Inoue, S. et al. A role for the Drosophila fragile X-related gene in circadian output. Curr. Biol. 12, 1331–1335 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Zhang, J. et al. Fragile X-related proteins regulate mammalian circadian behavioral rhythms. Am. J. Hum. Genet. 83, 43–52 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Levitan, I. B. Modulation of ion channels by protein phosphorylation and dephosphorylation. Annu. Rev. Physiol. 56, 193–212 (1994).

    Article  CAS  PubMed  Google Scholar 

  202. Park, K. S., Yang, J. W., Seikel, E. & Trimmer, J. S. Potassium channel phosphorylation in excitable cells: providing dynamic functional variability to a diverse family of ion channels. Physiology 23, 49–57 (2008).

    Article  CAS  PubMed  Google Scholar 

  203. Ko, G. Y., Ko, M. L. & Dryer, S. E. Circadian regulation of cGMP-gated channels of vertebrate cone photoreceptors: role of cAMP and Ras. J. Neurosci. 24, 1296–1304 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Bliwise, D. L. Sleep in normal aging and dementia. Sleep 16, 40–81 (1993).

    Article  CAS  PubMed  Google Scholar 

  205. Van Someren, E. J. Circadian rhythms and sleep in human aging. Chronobiol. Int. 17, 233–243 (2000).

    Article  CAS  PubMed  Google Scholar 

  206. Carrier, J. & Bliwise, D. L. in Sleep: Physiology Investigations, and Medicine (Eds Billiard, M. & Kent, A.) 297–333 (Kluwer Academic/Plenum. New York, 2003).

    Book  Google Scholar 

  207. Satinoff, E. et al. Do the suprachiasmatic nuclei oscillate in old rats as they do in young ones? Am. J. Physiol. 265, R1216–R1222 (1993).

    CAS  PubMed  Google Scholar 

  208. Turek, F. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Watanabe, A., Shibata, S. & Watanabe, S. Circadian rhythm of spontaneous neuronal activity in the suprachiasmatic nucleus of old hamster in vitro. Brain Res. 695, 237–239 (1995).

    Article  CAS  PubMed  Google Scholar 

  210. Aujard, F., Herzog, E. D. & Block, G. D. Circadian rhythms in firing rate of individual suprachiasmatic nucleus neurons from adult and middle-aged mice. Neuroscience 106, 255–261 (2001).

    Article  CAS  PubMed  Google Scholar 

  211. Biello, S. M. Circadian clock resetting in the mouse changes with age. Age 31, 293–303 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Nakamura, T. J. et al. Age-related decline in circadian output. J. Neurosci. 31, 10201–10205 (2011). Recent in vivo multiunit recordings from the SCN of freely moving young and middle-aged mice have shown that the day–night difference was substantially reduced in the SCN of middle-aged mice. Surprisingly, the molecular clockwork in the SCN, as measured by PER2 levels, was not disrupted in middle-aged mice, suggesting that the age-related disruption in the circadian output occurs before any disruption of the molecular clockwork.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Morton, A. et al. Disintegration of the sleep-wake cycle and circadian timing in Huntington's disease. J. Neurosci. 25, 157–163 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Pallier, P. et al. Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington's disease. J. Neurosci. 27, 7869–7878 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Sterniczuk, R., Dyck, R. H., Laferla, F. M. & Antle, M. C. Characterization of the 3xTg-AD mouse model of Alzheimer's disease: part 1. Circadian changes. Brain Res. 1348, 139–148 (2010).

    Article  CAS  PubMed  Google Scholar 

  216. Kudo, T. et al. Dysfunctions in circadian behavior and physiology in mouse models of Huntington's disease. Exp. Neurol. 228, 80–90 (2011).

    Article  CAS  PubMed  Google Scholar 

  217. Maywood, E. S. et al. Disruption of peripheral circadian timekeeping in a mouse model of Huntington's disease and its restoration by temporally scheduled feeding. J. Neurosci. 30, 10199–10204 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Kristensson, K., Nygård, M., Bertini, G. & Bentivoglio, M. African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions. Prog. Neurobiol. 91, 152–171 (2010).

    Article  CAS  PubMed  Google Scholar 

  219. Lundkvist, G. B. et al. Altered neuronal activity rhythm and glutamate receptor expression in the suprachiasmatic nuclei of Trypanosoma brucei-infected rats. J. Neuropathol. Exp. Neurol. 57, 21–29 (1998).

    Article  CAS  PubMed  Google Scholar 

  220. Lundkvist, G. B. et al. Clock gene expression during chronic inflammation induced by infection with Trypanosoma brucei brucei in rats. J. Biol. Rhythms 25, 92–102 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Kwak, Y. et al. Interferon-γ alters electrical activity and clock gene expression in suprachiasmatic nucleus neurons. J. Biol. Rhythms 23, 150–159 (2008).

    Article  CAS  PubMed  Google Scholar 

  222. Hastings, M., Reddy, A. & Maywood, E. A clockwork web: circadian timing in brain and periphery, in health and disease. Nature Rev. Neurosci. 4, 649–661 (2003).

    Article  CAS  Google Scholar 

  223. Takahashi, J., Hong, H., Ko, C. & McDearmon, E. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nature Rev. Genet. 9, 764–775 (2008).

    Article  CAS  PubMed  Google Scholar 

  224. Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Gale, J. E. et al. Disruption of circadian rhythms accelerates development of diabetes through pancreatic β-cell loss and dysfunction. J. Biol. Rhythms (in the press).

  226. Bray, M. et al. Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. Am. J. Physiol. Heart Circ. Physiol. 294, H1036–H1047 (2008).

    Article  CAS  PubMed  Google Scholar 

  227. Scheer, F. A., Hilton, M. F., Mantzoros, C. S. & Shea, S. A. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc. Natl Acad. Sci. USA. 106, 4453–4458 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Reid, K. J. & Zee, P. C. Circadian rhythm disorders. Semin. Neurol. 29, 393–405 (2009).

    Article  PubMed  Google Scholar 

  229. Wulff, K., Porcheret, K., Cussans, E. & Foster, R. G. Sleep and circadian rhythm disturbances: multiple genes and multiple phenotypes. Curr. Opin. Genet. Dev. 19, 237–246 (2009).

    Article  CAS  PubMed  Google Scholar 

  230. Gerstner, J. R. et al. Cycling behavior and memory formation. J. Neurosci. 29, 12824–12830 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Wang, L. et al. Expression of the circadian clock gene Period2 in the hippocampus: possible implications for synaptic plasticity and learned behaviour. ASN Neuro 1, e00012 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Loh, D. et al. Rapid changes in the light/dark cycle disrupt memory of conditioned fear in mice. PLoS ONE 5, e12546 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Flavell, S. W. & Greenberg, M. E. Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu. Rev. Neurosci. 31, 563–590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Block, G. D., Khalsa, S. B., McMahon, D. G., Michel, S. & Guesz, M. Block biological clocks in the retina: cellular mechanisms of biological timekeeping. Int. Rev. Cytol. 146, 83–144 (1993).

    Article  CAS  PubMed  Google Scholar 

  235. Cui, L. N. & Dyball, R. E. J. Synaptic input from the retina to the suprachiasmatic nucleus changes with the light-dark cycle in the Syrian hamster. J. Physiol. 497, 485–493 (1996).

    Article  Google Scholar 

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Acknowledgements

This work was supported by funding from the CHDI Foundation, the Stein–Oppenheimer Foundation and the American Heart Association. I would like to thank D. Crandall for assistance with the graphics.

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  1. Department of Psychiatry and Biobehavioral Sciences, Laboratory of Circadian and Sleep Medicine, David Geffen School of Medicine, University of California, Los Angeles, 90024, California, USA

    Christopher S. Colwell

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Glossary

Riluzole

Riluzole preferentially blocks tetrodotoxin-sensitive sodium channels but has been suggested to have other effects, including activating glutamate uptake and increasing potassium currents.

BMAL1

A protein that dimerizes with CLOCK to form a complex. Inside the nucleus, the protein complex binds to a site in the DNA known as the Ebox, to drive transcription. The period and cryptochrome genes contain Eboxes and thus are transcriptionally activated by the complex formed of a brain and muscle ARNT-like (BMAL) protein and CLOCK, in the beginning of the daily cycle.

Period

The time that it takes for the biological oscillator to complete one cycle. In the case of circadian oscillators, the period (tau) is close to, but not equal to, 24 hours.

Phase shift

A shift in the phase of the biological oscillation. Phase (Φ) is one of the most important parameters that describe any oscillation, as it refers to the time points within the cycle. To measure the phase of the rhythm, a reliable reference point must be chosen. In the case of circadian oscillations, the onset of activity or the peak expression of a biochemical parameter are commonly used.

Entrainment

In the context of the circadian system, entrainment refers to the process by which a biological oscillator with a free-running period that is close to 24 hours is adjusted to the exact 24-hour period of the environment. When entrained, the period of the biological rhythm equals the period of the entraining stimuli and the two oscillations exhibit a stable phase relationship.

CRE decoy oligodeoxynucleotide

A synthetic DNA molecule that contains a cyclic AMP-responsive element (CRE). When expressed in a cell, the CRE decoys compete with native CRE sites in gene promoters for binding of phosphorylated CRE-binding protein (CREB). Thus, these oligodeoxynucleotides can function as competitive inhibitors of CREB binding.

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Colwell, C. Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci 12, 553–569 (2011). https://doi.org/10.1038/nrn3086

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