Light entrains the master circadian clock in the suprachiasmatic nucleus (SCN) predominantly through glutamatergic signaling via NMDA receptors. The magnitude and the direction of resulting phase shifts depend on timing of the photic stimulus. Previous reports based on behavioral and electrophysiological data suggested that endocannabinoids (EC) might reduce the ability of the SCN clock to respond to light. However, there is little direct evidence for the involvement of EC in entrainment of the rhythmic clock gene expression in the SCN. We have used luminescence recording of cultured SCN slices from mPer2 Luc mice to construct a complete phase response curve (PRC) for NMDA receptor activation. The results demonstrated that NMDA administration phase-shifts the PER2 rhythm in a time-specific manner. A stable "singularity," in the course of which the clock seemingly stops while the overall phase is caught between delays and advances, can occur in response to NMDA at a narrow interval during the PER2 level decrease. NMDA-induced phase delays were affected neither by the agonist (WIN 55,212-2 mesylate) nor by the antagonist (rimonabant hydrochloride) of EC receptors. However, the agonist significantly reduced the NMDA-induced phase advance of the clock, while the antagonist enhanced the phase advance, causing a shift in the sensitivity window of the SCN to NMDA. The modulation of EC signaling in the SCN had no effect by itself on the phase of the PER2 rhythm. The results provide evidence for a modulatory role of EC in photic entrainment of the circadian clock in the SCN.

Institute of Physiology Academy of Sciences of the Czech Republic Prague Czechia

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Abraham U., Granada A. E., Westermark P. O., Heine M., Kramer A., Herzel H. (2010). Coupling governs entrainment range of circadian clocks. Mol. Syst. Biol. 6:438. 10.1038/msb.2010.92 PubMed DOI PMC

Acuna-Goycolea C., Obrietan K., Van Den Pol A. N. (2010). Cannabinoids excite circadian clock neurons. J. Neurosci. 30 10061–10066. 10.1523/JNEUROSCI.5838-09.2010 PubMed DOI PMC

Albers H. E., Walton J. C., Gamble K. L., Mcneill J. K., Hummer D. L. (2017). The dynamics of GABA signaling: revelations from the circadian pacemaker in the suprachiasmatic nucleus. Front. Neuroendocrinol. 44 35–82. 10.1016/j.yfrne.2016.11.003 PubMed DOI PMC

An S., Harang R., Meeker K., Granados-Fuentes D., Tsai C. A., Mazuski C., et al. (2013). A neuropeptide speeds circadian entrainment by reducing intercellular synchrony. Proc. Natl. Acad. Sci. U.S.A. 110 E4355–E4361. 10.1073/pnas.1307088110 PubMed DOI PMC

Asai M., Yamaguchi S., Isejima H., Jonouchi M., Moriya T., Shibata S., et al. (2001). Visualization of mPer1 transcription in vitro. NMDA induces a rapid phase shift of mPer1 gene in cultured SCN. Curr. Biol. 11 1524–1527. 10.1016/S0960-9822(01)00445-6 PubMed DOI

Bazwinsky-Wutschke I., Zipprich A., Dehghani F. (2017). Daytime-dependent changes of cannabinoid receptor type 1 and type 2 expression in rat liver. Int. J. Mol. Sci. 18:e1844. 10.3390/ijms18091844 PubMed DOI PMC

Brancaccio M., Patton A. P., Chesham J. E., Maywood E. S., Hastings M. H. (2017). Astrocytes control circadian timekeeping in the suprachiasmatic nucleus via glutamatergic signaling. Neuron 93 1420.E5–1435.E5. 10.1016/j.neuron.2017.02.030 PubMed DOI PMC

Challet E., Caldelas I., Graff C., Pevet P. (2003). Synchronization of the molecular clockwork by light- and food-related cues in mammals. Biol. Chem. 384 711–719. 10.1515/BC.2003.079 PubMed DOI

Challet E., Denis I., Rochet V., Aioun J., Gourmelen S., Lacroix H., et al. (2013). The role of PPARbeta/delta in the regulation of glutamatergic signaling in the hamster suprachiasmatic nucleus. Cell Mol. Life Sci. 70 2003–2014. 10.1007/s00018-012-1241-9 PubMed DOI PMC

Chen L., Yang G. (2014). PPARs integrate the mammalian clock and energy metabolism. PPAR Res. 2014:653017. 10.1155/2014/653017 PubMed DOI PMC

Choi H. J., Lee C. J., Schroeder A., Kim Y. S., Jung S. H., Kim J. S., et al. (2008). Excitatory actions of GABA in the suprachiasmatic nucleus. J. Neurosci. 28 5450–5459. 10.1523/JNEUROSCI.5750-07.2008 PubMed DOI PMC

Colwell C. S., Menaker M. (1992). NMDA as well as non-NMDA receptor antagonists can prevent the phase-shifting effects of light on the circadian system of the golden hamster. J. Biol. Rhythms 7 125–136. 10.1177/074873049200700204 PubMed DOI

Daan S., Pittendrigh C. S. (1976). Functional-analysis of circadian pacemakers in nocturnal rodents.2. variability of phase response curves. J. Comp. Physiol. 106 253–266. 10.1007/BF01417857 DOI

DeWoskin D., Myung J., Belle M. D., Piggins H. D., Takumi T., Forger D. B. (2015). Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping. Proc. Natl. Acad. Sci. U.S.A. 112 E3911–E3919. 10.1073/pnas.1420753112 PubMed DOI PMC

Ding J. M., Buchanan G. F., Tischkau S. A., Chen D., Kuriashkina L., Faiman L. E., et al. (1998). A neuronal ryanodine receptor mediates light-induced phase delays of the circadian clock. Nature 394 381–384. 10.1038/28639 PubMed DOI

Ding J. M., Chen D., Weber E. T., Faiman L. E., Rea M. A., Gillette M. U. (1994). Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. Science 266 1713–1717. 10.1126/science.7527589 PubMed DOI

Field M. D., Maywood E. S., O′Brien J. A., Weaver D. R., Reppert S. M., Hastings M. (2000). Analysis of clock proteins in mouse SCN demonstrates phylogenetic divergence of the circadian clockwork and resetting mechanism. Neuron 25 437–447. 10.1016/S0896-6273(00)80906-X PubMed DOI

Gannon R. L., Rea M. A. (1994). In situ hybridization of antisense mRNA oligonucleotides for AMPA, NMDA and metabotropic glutamate receptor subtypes in the rat suprachiasmatic nucleus at different phases of the circadian cycle. Brain Res. Mol. Brain Res. 23 338–344. 10.1016/0169-328X(94)90244-5 PubMed DOI

Gau D., Lemberger T., Von Gall C., Kretz O., Le Minh N., Gass P., et al. (2002). Phosphorylation of CREB Ser142 regulates light-induced phase shifts of the circadian clock. Neuron 34 245–253. 10.1016/S0896-6273(02)00656-6 PubMed DOI

Hastings M. H., Brancaccio M., Maywood E. S. (2014). Circadian pacemaking in cells and circuits of the suprachiasmatic nucleus. J. Neuroendocrinol. 26 2–10. 10.1111/jne.12125 PubMed DOI PMC

Honma S., Honma K. (1999). Light-induced uncoupling of multioscillatory circadian system in a diurnal rodent, asian chipmunk. Am. J. Physiol. 276 R1390–R1396. 10.1152/ajpregu.1999.276.5.R1390 PubMed DOI

Jewett M. E., Kronauer R. E., Czeisler C. A. (1991). Light-induced suppression of endogenous circadian amplitude in humans. Nature 350 59–62. 10.1038/350059a0 PubMed DOI

Johnson C. H. (1992). “Phase response curves: What can they tell us about circadian clocks?,” in Circadian Clocks from Cell to Human, eds Hiroshige T., Honma K. (Sapporo: Hokkaido University Press; ),209–249.

Lee C. M., Neighbors C., Woods B. A. (2007). Marijuana motives: young adults’ reasons for using marijuana. Addict. Behav. 32 1384–1394. 10.1016/j.addbeh.2006.09.010 PubMed DOI PMC

Liu C., Reppert S. M. (2000). GABA synchronizes clock cells within the suprachiasmatic circadian clock. Neuron 25 123–128. 10.1016/S0896-6273(00)80876-4 PubMed DOI

Lu H. C., Mackie K. (2016). An introduction to the endogenous cannabinoid system. Biol. Psychiatry 79 516–525. 10.1016/j.biopsych.2015.07.028 PubMed DOI PMC

Marichal-Cancino B. A., Fajardo-Valdez A., Ruiz-Contreras A. E., Mendez-Diaz M., Prospero-Garcia O. (2017). Advances in the physiology of gpr55 in the central nervous system. Curr. Neuropharmacol. 15 771–778. 10.2174/1570159X14666160729155441 PubMed DOI PMC

McNeill J. K. T., Walton J. C., Albers H. E. (2018). Functional significance of the excitatory effects of gaba in the suprachiasmatic nucleus. J. Biol. Rhythms 33 376–387. 10.1177/0748730418782820 PubMed DOI PMC

Meijer J. H., Schwartz W. J. (2003). In search of the pathways for light-induced pacemaker resetting in the suprachiasmatic nucleus. J. Biol. Rhythms 18 235–249. 10.1177/0748730403018003006 PubMed DOI

Mintz E. M., Marvel C. L., Gillespie C. F., Price K. M., Albers H. E. (1999). Activation of NMDA receptors in the suprachiasmatic nucleus produces light-like phase shifts of the circadian clock in vivo. J. Neurosci. 19 5124–5130. 10.1523/JNEUROSCI.19-12-05124.1999 PubMed DOI PMC

Mizoro Y., Yamaguchi Y., Kitazawa R., Yamada H., Matsuo M., Fustin J. M., et al. (2010). Activation of AMPA receptors in the suprachiasmatic nucleus phase-shifts the mouse circadian clock in vivo and in vitro. PLoS One 5:e10951. 10.1371/journal.pone.0010951 PubMed DOI PMC

Mohawk J. A., Takahashi J. S. (2011). Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators. Trends Neurosci. 34 349–358. 10.1016/j.tins.2011.05.003 PubMed DOI PMC

Moore R. Y., Lenn N. J. (1972). A retinohypothalamic projection in the rat. J. Comp. Neurol. 146 1–14. 10.1002/cne.901460102 PubMed DOI

Olde Engberink A. H. O., Meijer J. H., Michel S. (2018). Chloride cotransporter KCC2 is essential for GABAergic inhibition in the SCN. Neuropharmacology 138 80–86. 10.1016/j.neuropharm.2018.05.023 PubMed DOI

O’Sullivan S. E. (2016). An update on PPAR activation by cannabinoids. Br. J. Pharmacol. 173 1899–1910. 10.1111/bph.13497 PubMed DOI PMC

Pembroke W. G., Babbs A., Davies K. E., Ponting C. P., Oliver P. L. (2015). Temporal transcriptomics suggest that twin-peaking genes reset the clock. eLife 4:e10518. 10.7554/eLife.10518 PubMed DOI PMC

Pennartz C. M., Hamstra R., Geurtsen A. M. (2001). Enhanced NMDA receptor activity in retinal inputs to the rat suprachiasmatic nucleus during the subjective night. J. Physiol. 532 181–194. 10.1111/j.1469-7793.2001.0181g.x PubMed DOI PMC

Polidarova L., Olejnikova L., Pauslyova L., Sladek M., Sotak M., Pacha J., et al. (2014). Development and entrainment of the colonic circadian clock during ontogenesis. Am. J. Physiol. Gastrointest. Liver Physiol. 306 G346–G356. 10.1152/ajpgi.00340.2013 PubMed DOI

Pulivarthy S. R., Tanaka N., Welsh D. K., De Haro L., Verma I. M., Panda S. (2007). Reciprocity between phase shifts and amplitude changes in the mammalian circadian clock. Proc. Natl. Acad. Sci. U.S.A. 104 20356–20361. 10.1073/pnas.0708877104 PubMed DOI PMC

Ralph M. R., Foster R. G., Davis F. C., Menaker M. (1990). Transplanted suprachiasmatic nucleus determines circadian period. Science 247 975–978. 10.1126/science.2305266 PubMed DOI

Ryberg E., Larsson N., Sjogren S., Hjorth S., Hermansson N. O., Leonova J., et al. (2007). The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 152 1092–1101. 10.1038/sj.bjp.0707460 PubMed DOI PMC

Sanford A. E., Castillo E., Gannon R. L. (2008). Cannabinoids and hamster circadian activity rhythms. Brain Res. 1222 141–148. 10.1016/j.brainres.2008.05.048 PubMed DOI

Shibata S., Watanabe A., Hamada T., Ono M., Watanabe S. (1994). N-methyl-D-aspartate induces phase shifts in circadian rhythm of neuronal activity of rat SCN in vitro. Am. J. Physiol. 267 R360–R364. 10.1152/ajpregu.1994.267.2.R360 PubMed DOI

Soethoudt M., Grether U., Fingerle J., Grim T. W., Fezza F., De Petrocellis L., et al. (2017). Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity. Nat. Commun. 8:13958. 10.1038/ncomms13958 PubMed DOI PMC

Sun Y., Alexander S. P., Kendall D. A., Bennett A. J. (2006). Cannabinoids and PPARalpha signalling. Biochem. Soc. Trans. 34 1095–1097. 10.1042/BST0341095 PubMed DOI

Tahara Y., Aoyama S., Shibata S. (2017). The mammalian circadian clock and its entrainment by stress and exercise. J. Physiol. Sci. 67 1–10. 10.1007/s12576-016-0450-7 PubMed DOI PMC

Ukai H., Kobayashi T. J., Nagano M., Masumoto K. H., Sujino M., Kondo T., et al. (2007). Melanopsin-dependent photo-perturbation reveals desynchronization underlying the singularity of mammalian circadian clocks. Nat. Cell Biol. 9 1327–1334. 10.1038/ncb1653 PubMed DOI

Van den Pol A. N. (1991). Glutamate and aspartate immunoreactivity in hypothalamic presynaptic axons. J. Neurosci. 11 2087–2101. 10.1523/JNEUROSCI.11-07-02087.1991 PubMed DOI PMC

VanderLeest H. T., Rohling J. H., Michel S., Meijer J. H. (2009). Phase shifting capacity of the circadian pacemaker determined by the SCN neuronal network organization. PLoS One 4:e4976. 10.1371/journal.pone.0004976 PubMed DOI PMC

Wagner S., Castel M., Gainer H., Yarom Y. (1997). GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity. Nature 387 598–603. 10.1038/42468 PubMed DOI

Welsh D. K., Reppert S. M. (1996). Gap junctions couple astrocytes but not neurons in dissociated cultures of rat suprachiasmatic nucleus. Brain Res. 706 30–36. 10.1016/0006-8993(95)01172-2 PubMed DOI

Welsh D. K., Takahashi J. S., Kay S. A. (2010). Suprachiasmatic nucleus: cell autonomy and network properties. Annu. Rev. Physiol. 72 551–577. 10.1146/annurev-physiol-021909-135919 PubMed DOI PMC

Whitehurst L. N., Fogler K., Hall K., Hartmann M., Dyche J. (2015). The effects of chronic marijuana use on circadian entrainment. Chronobiol. Int. 32 561–567. 10.3109/07420528.2015.1004078 PubMed DOI

Winfree A. T. (1970). Integrated view of resetting a circadian clock. J. Theor. Biol. 28 327–374. 10.1016/0022-5193(70)90075-5 PubMed DOI

Wittmann G., Deli L., Kallo I., Hrabovszky E., Watanabe M., Liposits Z., et al. (2007). Distribution of type 1 cannabinoid receptor (CB1)-immunoreactive axons in the mouse hypothalamus. J. Comp. Neurol. 503 270–279. 10.1002/cne.21383 PubMed DOI

Yamazaki S., Takahashi J. S. (2005). Real-time luminescence reporting of circadian gene expression in mammals. Methods Enzymol. 393 288–301. 10.1016/S0076-6879(05)93012-7 PubMed DOI PMC

Yang X., Downes M., Yu R. T., Bookout A. L., He W., Straume M., et al. (2006). Nuclear receptor expression links the circadian clock to metabolism. Cell 126 801–810. 10.1016/j.cell.2006.06.050 PubMed DOI

Yoo S. H., Yamazaki S., Lowrey P. L., Shimomura K., Ko C. H., Buhr E. D., et al. (2004). PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl. Acad. Sci. U.S.A. 101 5339–5346. 10.1073/pnas.0308709101 PubMed DOI PMC

Zhang R., Lahens N. F., Ballance H. I., Hughes M. E., Hogenesch J. B. (2014). A circadian gene expression atlas in mammals: implications for biology and medicine. Proc. Natl. Acad. Sci. U.S.A. 111 16219–16224. 10.1073/pnas.1408886111 PubMed DOI PMC

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