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Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice


An Erratum to this article was published on 17 February 2015


Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

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  1. McClung CA . Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther 2007; 114: 222–232.

    CAS  Article  Google Scholar 

  2. Plante DT, Winkelman JW . Sleep disturbance in bipolar disorder: therapeutic implications. Am J Psychiatry 2008; 165: 830–843.

    Article  Google Scholar 

  3. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V et al. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci USA 2007; 104: 6406–6411.

    CAS  Article  Google Scholar 

  4. Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 1998; 280: 1564–1569.

    CAS  Article  Google Scholar 

  5. King DP, Vitaterna MH, Chang AM, Dove WF, Pinto LH, Turek FW et al. The mouse Clock mutation behaves as an antimorph and maps within the W(19H) deletion, distal of Kit. Genetics 1997; 146: 1049–1060.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. McClung CA, Sidiropoulou K, Vitaterna M, Takahashi JS, White FJ, Cooper DC et al. Regulation of dopaminergic transmission and cocaine reward by the Clock gene. Proc Natl Acad Sci USA 2005; 102: 9377–9381.

    CAS  Article  Google Scholar 

  7. Coque L, Mukherjee S, Cao J-L, Spencer S, Marvin M, Falcon E et al. Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the Clock[Delta]19 mouse model of mania. Neuropsychopharmacology 2011; 36: 1478–1488.

    CAS  Article  Google Scholar 

  8. Cousins DA, Butts K, Young AH . The role of dopamine in bipolar disorder. Bipolar Disord 2009; 11: 787–806.

    CAS  Article  Google Scholar 

  9. Mukherjee S, Coque L, Cao J-L, Kumar J, Chakravarty S, Asaithamby A et al. Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. Biol Psychiatry 2010; 68: 503–511.

    CAS  Article  Google Scholar 

  10. Tsai H-C, Zhang F, Adamantidis A, Stuber GD, Bonci A, de Lecea L et al. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 2009; 324: 1080–1084.

    CAS  Article  Google Scholar 

  11. Grace AA, Bunney BS . Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—3. Evidence for electrotonic coupling. Neuroscience 1983; 10: 333–348.

    CAS  Article  Google Scholar 

  12. White FJ . Synaptic regulation of mesocorticolimbic dopamine neurons. Annu Rev Neurosci 1996; 19: 405–436.

    CAS  Article  Google Scholar 

  13. Dzirasa K, Ribeiro S, Costa R, Santos LM, Lin SC, Grosmark A et al. Dopaminergic control of sleep-wake states. J Neurosci 2006; 26: 10577–10589.

    CAS  Article  Google Scholar 

  14. Dzirasa K, Fuentes R, Kumar S, Potes JM, Nicolelis MA . Chronic in vivo multi-circuit neurophysiological recordings in mice. J Neurosci Methods 2011; 195: 36–46.

    Article  Google Scholar 

  15. Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O'Shea DJ et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 2011; 477: 171–178.

    CAS  Article  Google Scholar 

  16. Mobley JaV-D T . Optical Properties of Tissue. Biomedical Photonics Handbook. CRC Press: Boca Raton, FL, 2003 pp 2–76.

    Google Scholar 

  17. Aravanis AM, Wang LP, Zhang F, Meltzer LA, Mogri MZ, Schneider MB et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J Neural Eng 2007; 4: S143–S156.

    Article  Google Scholar 

  18. Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 2011; 471: 358–362.

    CAS  Article  Google Scholar 

  19. Maywood ES, Fraenkel E, McAllister CJ, Wood N, Reddy AB, Hastings MH et al. Disruption of peripheral circadian timekeeping in a mouse model of Huntington's disease and its restoration by temporally scheduled feeding. J Neurosci 2010; 30: 10199–10204.

    CAS  Article  Google Scholar 

  20. Tsankova NM, Kumar A, Nestler EJ . Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J Neurosci 2004; 24: 5603–5610.

    CAS  Article  Google Scholar 

  21. Lena I, Parrot S, Deschaux O, Muffat-Joly S, Sauvinet V, Renaud B et al. Variations in extracellular levels of dopamine, noradrenaline, glutamate, and aspartate across the sleep-wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats. J Neurosci Res 2005; 81: 891–899.

    CAS  Article  Google Scholar 

  22. Maloney KJ, Mainville L, Jones BE . c-Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery. Eur J Neurosci 2002; 15: 774–778.

    Article  Google Scholar 

  23. Naylor E, Bergmann BM, Krauski K, Zee PC, Takahashi JS, Vitaterna MH et al. The circadian Clock mutation alters sleep homeostasis in the mouse. J Neurosci 2000; 20: 8138–8143.

    CAS  Article  Google Scholar 

  24. Haycock JW, Haycock DA . Tyrosine hydroxylase in rat brain dopaminergic nerve terminals. Multiple-site phosphorylation in vivo and in synaptosomes. J Biol Chem 1991; 266: 5650–5657.

    CAS  PubMed  Google Scholar 

  25. Kumer SC, Vrana KE . Intricate regulation of tyrosine hydroxylase activity and gene expression. J Neurochem 1996; 67: 443–462.

    CAS  Article  Google Scholar 

  26. Aumann TD, Egan K, Lim J, Boon WC, Bye CR, Chua HK et al. Neuronal activity regulates expression of tyrosine hydroxylase in adult mouse substantia nigra pars compacta neurons. J Neurochem 2011; 116: 646–658.

    CAS  Article  Google Scholar 

  27. Webb IC, Baltazar RM, Wang X, Pitchers KK, Coolen LM, Lehman MN . Diurnal variations in natural and drug reward, mesolimbic tyrosine hydroxylase, and Clock gene expression in the male rat. J Biol Rhythms 2009; 24: 465–476.

    CAS  Article  Google Scholar 

  28. Lowrey PL, Takahashi JS . Genetics of circadian rhythms in Mammalian model organisms. Adv Genet 2011; 74: 175–230.

    CAS  Article  Google Scholar 

  29. Lewis-Tuffin LJ, Quinn PG, Chikaraishi DM . Tyrosine hydroxylase transcription depends primarily on cAMP response element activity, regardless of the type of inducing stimulus. Mol Cell Neurosci 2004; 25: 536–547.

    CAS  Article  Google Scholar 

  30. Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW . Tyrosine hydroxylase phosphorylation: regulation and consequences. J Neurochem 2004; 91: 1025–1043.

    CAS  Article  Google Scholar 

  31. Bobrovskaya L, Gilligan C, Bolster EK, Flaherty JJ, Dickson PW, Dunkley PR . Sustained phosphorylation of tyrosine hydroxylase at serine 40: a novel mechanism for maintenance of catecholamine synthesis. J Neurochem 2007; 100: 479–489.

    CAS  Article  Google Scholar 

  32. Kim TI, McCall JG, Jung YH, Huang X, Siuda ER, Li Y et al. Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science 2013; 340: 211–216.

    CAS  Article  Google Scholar 

  33. Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 2013; 493: 537–541.

    CAS  Article  Google Scholar 

  34. Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 2013; 493: 532–536.

    CAS  Article  Google Scholar 

  35. Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K . Optogenetics in neural systems. Neuron 2011; 71: 9–34.

    CAS  Article  Google Scholar 

  36. Berndt A, Yizhar O, Gunaydin LA, Hegemann P, Deisseroth K . Bi-stable neural state switches. Nat Neurosci 2009; 12: 229–234.

    CAS  Article  Google Scholar 

  37. Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 1998; 280: 1564–1569.

    CAS  Article  Google Scholar 

  38. Shimomura K, Kumar V, Koike N, Kim TK, Chong J, Buhr ED et al. Usf1, a suppressor of the circadian Clock mutant, reveals the nature of the DNA-binding of the CLOCK:BMAL1 complex in mice. Elife 2013; 2: e00426.

    Article  Google Scholar 

  39. Kumar S, Chen D, Sehgal A . Dopamine acts through Cryptochrome to promote acute arousal in Drosophila. Genes Dev 2012; 26: 1224–1234.

    CAS  Article  Google Scholar 

  40. Chung S, Lee EJ, Yun S, Choe HK, Park SB, Son HJ et al. Impact of circadian nuclear receptor REV-ERBalpha on midbrain dopamine production and mood regulation. Cell 2014; 157: 858–868.

    CAS  Article  Google Scholar 

  41. Sidor MM, Macqueen GM . Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry 2011; 72: 156–167.

    CAS  Article  Google Scholar 

  42. Sidor MM, MacQueen GM . An update on antidepressant use in bipolar depression. Curr Psychiatry Rep 2012; 14: 696–704.

    Article  Google Scholar 

  43. Geddes JR, Miklowitz DJ . Treatment of bipolar disorder. Lancet 2013; 381: 1672–1682.

    CAS  Article  Google Scholar 

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This work was supported by funding from the McKnight Foundation, the National Alliance for Research on Schizophrenia and Depression, the National Institute of Mental Health (MH082876), the National Institute on Drug Abuse (DA023988) and the National Institute of Neurological Disorders and Stroke (NS058339). We would like to thank Dr Maisie Lo and members of the Deisseroth Lab for their generosity and assistance in performing the optogenetic experiments. We thank Joe Takahashi for the ClockΔ19 mice. The excellent technical assistance of Heather Buresch, Emily Webster, Edgardo Falcon, Elizabeth Gordon and Ariel Ketcherside is greatly appreciated.

Author Contributions

MMS designed experiments, performed and analyzed the optogenetic, western blotting and behavioral studies, assisted with the electrophysiology experiments and wrote the paper. SS performed the PCR and ChIP assays, collected tissue for western blotting, analyzed data and contributed to writing of the paper. KD performed the electrophysiology experiments with assistance by SK and contributed to writing of the appropriate sections. PKP performed immunohistochemistry and provided feedback on the manuscript. KT and MRW provided technical assistance and conceptual advice with optogenetic experiments along with KD, and provided substantial feedback on the manuscript. RA provided technical assistance with the PCR and ChIP assays. JFE and EMR performed the luciferase assays. JPRJ and MC provided dopamine synthesis data. CAM was responsible for designing and supervising the experiments, providing conceptual guidance and for editing of the manuscript.

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Correspondence to C A McClung.

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Sidor, M., Spencer, S., Dzirasa, K. et al. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice. Mol Psychiatry 20, 1406–1419 (2015).

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