Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
McClung CA . Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther 2007; 114: 222–232.
Plante DT, Winkelman JW . Sleep disturbance in bipolar disorder: therapeutic implications. Am J Psychiatry 2008; 165: 830–843.
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.
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.
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.
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.
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.
Cousins DA, Butts K, Young AH . The role of dopamine in bipolar disorder. Bipolar Disord 2009; 11: 787–806.
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.
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.
Grace AA, Bunney BS . Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—3. Evidence for electrotonic coupling. Neuroscience 1983; 10: 333–348.
White FJ . Synaptic regulation of mesocorticolimbic dopamine neurons. Annu Rev Neurosci 1996; 19: 405–436.
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.
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.
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.
Mobley JaV-D T . Optical Properties of Tissue. Biomedical Photonics Handbook. CRC Press: Boca Raton, FL, 2003 pp 2–76.
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.
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.
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.
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.
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.
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.
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.
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.
Kumer SC, Vrana KE . Intricate regulation of tyrosine hydroxylase activity and gene expression. J Neurochem 1996; 67: 443–462.
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.
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.
Lowrey PL, Takahashi JS . Genetics of circadian rhythms in Mammalian model organisms. Adv Genet 2011; 74: 175–230.
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.
Dunkley PR, Bobrovskaya L, Graham ME, von Nagy-Felsobuki EI, Dickson PW . Tyrosine hydroxylase phosphorylation: regulation and consequences. J Neurochem 2004; 91: 1025–1043.
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.
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.
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.
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.
Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K . Optogenetics in neural systems. Neuron 2011; 71: 9–34.
Berndt A, Yizhar O, Gunaydin LA, Hegemann P, Deisseroth K . Bi-stable neural state switches. Nat Neurosci 2009; 12: 229–234.
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.
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.
Kumar S, Chen D, Sehgal A . Dopamine acts through Cryptochrome to promote acute arousal in Drosophila. Genes Dev 2012; 26: 1224–1234.
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.
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.
Sidor MM, MacQueen GM . An update on antidepressant use in bipolar depression. Curr Psychiatry Rep 2012; 14: 696–704.
Geddes JR, Miklowitz DJ . Treatment of bipolar disorder. Lancet 2013; 381: 1672–1682.
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website
Supplementary information
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1038/mp.2014.167
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2014.167