Circadian Clocks and Mood-Related Behaviors

  • Urs AlbrechtEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 217)


Circadian clocks are present in nearly all tissues of an organism, including the brain. The brain is not only the site of the master coordinator of circadian rhythms located in the suprachiasmatic nuclei (SCN) but also contains SCN-independent oscillators that regulate various functions such as feeding and mood-related behavior. Understanding how clocks receive and integrate environmental information and in turn control physiology under normal conditions is of importance because chronic disturbance of circadian rhythmicity can lead to serious health problems. Genetic modifications leading to disruption of normal circadian gene functions have been linked to a variety of psychiatric conditions including depression, seasonal affective disorder, eating disorders, alcohol dependence, and addiction. It appears that clock genes play an important role in limbic regions of the brain and influence the development of drug addiction. Furthermore, analyses of clock gene polymorphisms in diseases of the central nervous system (CNS) suggest a direct or indirect influence of circadian clock genes on brain function. In this chapter, I will present evidence for a circadian basis of mood disorders and then discuss the involvement of clock genes in such disorders. The relationship between metabolism and mood disorders is highlighted followed by a discussion of how mood disorders may be treated by changing the circadian cycle.


Depression Obesity Light Drugs 



I would like to thank Dr. Jürgen Ripperger for his comments on the manuscript. Financial support from the Swiss National Science Foundation and the State of Fribourg is gratefully acknowledged.


  1. Abarca C, Albrecht U, Spanagel R (2002) Cocaine sensitization and reward are under the influence of circadian genes and rhythm. Proc Natl Acad Sci USA 99(13):9026–9030PubMedCrossRefGoogle Scholar
  2. Akhisaroglu M et al (2005) Diurnal rhythms in quinpirole-induced locomotor behaviors and striatal D2/D3 receptor levels in mice. Pharmacol Biochem Behav 80(3):371–377PubMedCrossRefGoogle Scholar
  3. Atkinson M, Kripke DF, Wolf SR (1975) Autorhythmometry in manic-depressives. Chronobiologia 2(4):325–335PubMedGoogle Scholar
  4. Benedetti F et al (2003) Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression. Am J Med Genet B Neuropsychiatr Genet 123B(1):23–26PubMedCrossRefGoogle Scholar
  5. Benedetti F et al (2008) A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neurosci Lett 445(2):184–187PubMedCrossRefGoogle Scholar
  6. Castaneda TR et al (2004) Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: modulation by light. J Pineal Res 36(3):177–185PubMedCrossRefGoogle Scholar
  7. Challet E et al (2001) Sleep deprivation decreases phase-shift responses of circadian rhythms to light in the mouse: role of serotonergic and metabolic signals. Brain Res 909(1–2):81–91PubMedCrossRefGoogle Scholar
  8. Coon SL et al (1997) Regulation of pineal alpha1B-adrenergic receptor mRNA: day/night rhythm and beta-adrenergic receptor/cyclic AMP control. Mol Pharmacol 51(4):551–557PubMedGoogle Scholar
  9. DeBruyne JP, Weaver DR, Reppert SM (2007a) Peripheral circadian oscillators require CLOCK. Curr Biol 17(14):R538–R539PubMedCrossRefGoogle Scholar
  10. DeBruyne JP, Weaver DR, Reppert SM (2007b) CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat Neurosci 10(5):543–545PubMedCrossRefGoogle Scholar
  11. Dong L et al (2011) Effects of the circadian rhythm gene period 1 (per1) on psychosocial stress-induced alcohol drinking. Am J Psychiatry 168(10):1090–1098PubMedCrossRefGoogle Scholar
  12. Dzirasa K et al (2010) Lithium ameliorates nucleus accumbens phase-signaling dysfunction in a genetic mouse model of mania. J Neurosci 30(48):16314–16323PubMedCrossRefGoogle Scholar
  13. Ebert D, Berger M (1998) Neurobiological similarities in antidepressant sleep deprivation and psychostimulant use: a psychostimulant theory of antidepressant sleep deprivation. Psychopharmacology 140(1):1–10PubMedCrossRefGoogle Scholar
  14. Ehlen JC, Grossman GH, Glass JD (2001) In vivo resetting of the hamster circadian clock by 5-HT7 receptors in the suprachiasmatic nucleus. J Neurosci 21(14):5351–5357PubMedGoogle Scholar
  15. Emens J et al (2009) Circadian misalignment in major depressive disorder. Psychiatry Res 168(3): 259–261PubMedCrossRefGoogle Scholar
  16. Fitzgerald PJ et al (2010) Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder? Neurobiol Dis 40(3):608–621PubMedCrossRefGoogle Scholar
  17. Frank E, Swartz HA, Kupfer DJ (2000) Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder. Biol Psychiatry 48(6):593–604PubMedCrossRefGoogle Scholar
  18. Grant D et al (2010) GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erb alpha. ACS Chem Biol 5(10):925–932PubMedCrossRefGoogle Scholar
  19. Grassi Zucconi G et al (2006) ‘One night’ sleep deprivation stimulates hippocampal neurogenesis. Brain Res Bull 69(4):375–381PubMedCrossRefGoogle Scholar
  20. Guilding C, Piggins HD (2007) Challenging the omnipotence of the suprachiasmatic timekeeper: are circadian oscillators present throughout the mammalian brain? Eur J Neurosci 25(11): 3195–3216PubMedCrossRefGoogle Scholar
  21. Hafen T, Wollnik F (1994) Effect of lithium carbonate on activity level and circadian period in different strains of rats. Pharmacol Biochem Behav 49(4):975–983PubMedCrossRefGoogle Scholar
  22. Hampp G et al (2008) Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood. Curr Biol 18(9):678–683PubMedCrossRefGoogle Scholar
  23. Hasler BP et al (2010) Phase relationships between core body temperature, melatonin, and sleep are associated with depression severity: further evidence for circadian misalignment in non-seasonal depression. Psychiatry Res 178(1):205–207PubMedCrossRefGoogle Scholar
  24. Herxheimer A (2005) Jet lag. Clin Evid 13:2178–2183PubMedGoogle Scholar
  25. Hirota T et al (2010) High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKI alpha as a clock regulatory kinase. PLoS Biol 8(12):e1000559PubMedCrossRefGoogle Scholar
  26. Hirota T et al (2012) Identification of small molecule activators of cryptochrome. Science 337: 1094–1097PubMedCrossRefGoogle Scholar
  27. Hlastala SA, Frank E (2006) Adapting interpersonal and social rhythm therapy to the developmental needs of adolescents with bipolar disorder. Dev Psychopathol 18(4):1267–1288PubMedCrossRefGoogle Scholar
  28. Hood S et al (2010) Endogenous dopamine regulates the rhythm of expression of the clock protein PER2 in the rat dorsal striatum via daily activation of D2 dopamine receptors. J Neurosci 30(42):14046–14058PubMedCrossRefGoogle Scholar
  29. Iitaka C et al (2005) A role for glycogen synthase kinase-3beta in the mammalian circadian clock. J Biol Chem 280(33):29397–29402PubMedCrossRefGoogle Scholar
  30. Johnsson A et al (1983) Period lengthening of human circadian rhythms by lithium carbonate, a prophylactic for depressive disorders. Int J Chronobiol 8(3):129–147PubMedGoogle Scholar
  31. Kafka MS et al (1983) Circadian rhythms in rat brain neurotransmitter receptors. Fed Proc 42(11): 2796–2801PubMedGoogle Scholar
  32. Kennaway DJ (2010) Clock genes at the heart of depression. J Psychopharmacol 24(2 Suppl):5–14PubMedCrossRefGoogle Scholar
  33. King DP et al (1997) Positional cloning of the mouse circadian clock gene. Cell 89(4):641–653PubMedCrossRefGoogle Scholar
  34. Klemfuss H (1992) Rhythms and the pharmacology of lithium. Pharmacol Ther 56(1):53–78PubMedCrossRefGoogle Scholar
  35. Kojetin D et al (2011) Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB. ACS Chem Biol 6(2):131–134PubMedCrossRefGoogle Scholar
  36. Kripke DF et al (1978) Circadian rhythm disorders in manic-depressives. Biol Psychiatry 13(3): 335–351PubMedGoogle Scholar
  37. Kumar N et al (2010) Regulation of adipogenesis by natural and synthetic REV-ERB ligands. Endocrinology 151(7):3015–3025PubMedCrossRefGoogle Scholar
  38. Kumar N et al (2011) Identification of SR3335 (ML-176): a synthetic ROR alpha selective inverse agonist. ACS Chem Biol 6(3):218–222PubMedCrossRefGoogle Scholar
  39. Lavebratt C et al (2010) CRY2 is associated with depression. PLoS One 5(2):e9407PubMedCrossRefGoogle Scholar
  40. Lewy AJ et al (1998) Morning vs. evening light treatment of patients with winter depression. Arch Gen Psychiatry 55(10):890–896PubMedCrossRefGoogle Scholar
  41. Li J et al (2012) Lithium impacts on the amplitude and period of the molecular circadian clockwork. PLoS One 7(3):e33292PubMedCrossRefGoogle Scholar
  42. Lisman J, Buzsaki G (2008) A neural coding scheme formed by the combined function of gamma and theta oscillations. Schizophr Bull 34(5):974–980PubMedCrossRefGoogle Scholar
  43. Lopez-Rodriguez F, Kim J, Poland RE (2004) Total sleep deprivation decreases immobility in the forced-swim test. Neuropsychopharmacology 29(6):1105–1111PubMedCrossRefGoogle Scholar
  44. Magnusson A, Boivin D (2003) Seasonal affective disorder: an overview. Chronobiol Int 20(2): 189–207PubMedCrossRefGoogle Scholar
  45. Mansour HA et al (2006) Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia. Genes Brain Behav 5(2):150–157PubMedCrossRefGoogle Scholar
  46. McCarthy MJ et al (2012) A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response. PLoS One 7(2):e32091PubMedCrossRefGoogle Scholar
  47. McClung CA (2007) Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther 114(2):222–232PubMedCrossRefGoogle Scholar
  48. McClung CA et al (2005) Regulation of dopaminergic transmission and cocaine reward by the Clock gene. Proc Natl Acad Sci USA 102(26):9377–9381PubMedCrossRefGoogle Scholar
  49. McIntyre RS (2009) Managing weight gain in patients with severe mental illness. J Clin Psychiatry 70(7):e23PubMedCrossRefGoogle Scholar
  50. Meng QJ et al (2010) Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. Proc Natl Acad Sci USA 107(34):15240–15245PubMedCrossRefGoogle Scholar
  51. Mukherjee S et al (2010) Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. Biol Psychiatry 68(6):503–511PubMedCrossRefGoogle Scholar
  52. Nakahata Y et al (2009) Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324(5927):654–657PubMedCrossRefGoogle Scholar
  53. Nievergelt CM et al (2006) Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 141B(3): 234–241PubMedCrossRefGoogle Scholar
  54. Pandi-Perumal SR et al (2006) Melatonin: nature’s most versatile biological signal? FEBS J 273(13):2813–2838PubMedCrossRefGoogle Scholar
  55. Partonen T et al (2007) Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression. Ann Med 39(3):229–238PubMedCrossRefGoogle Scholar
  56. Prickaerts J et al (2006) Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania. J Neurosci 26(35):9022–9029PubMedCrossRefGoogle Scholar
  57. Ramsey KM et al (2009) Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324(5927):651–654PubMedCrossRefGoogle Scholar
  58. Roybal K et al (2007) Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci USA 104(15):6406–6411PubMedCrossRefGoogle Scholar
  59. Rutter J et al (2001) Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293(5529):510–514PubMedCrossRefGoogle Scholar
  60. Sahar S et al (2011) Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD+ oscillation. Aging 3(8):794–802PubMedGoogle Scholar
  61. Schmutz I et al (2010) The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors. Genes Dev 24(4):345–357PubMedCrossRefGoogle Scholar
  62. Scott AJ (2000) Shift work and health. Prim Care 27(4):1057–1079PubMedCrossRefGoogle Scholar
  63. Serretti A et al (2003) Genetic dissection of psychopathological symptoms: insomnia in mood disorders and CLOCK gene polymorphism. Am J Med Genet B Neuropsychiatr Genet 121B(1): 35–38PubMedCrossRefGoogle Scholar
  64. Shirayama M et al (2003) The psychological aspects of patients with delayed sleep phase syndrome (DSPS). Sleep Med 4(5):427–433PubMedCrossRefGoogle Scholar
  65. Solt LA et al (2012) Regulation of circadian behavior and metabolism by synthetic REV-ERB agonists. Nature 485:62–68PubMedCrossRefGoogle Scholar
  66. Souetre E et al (1989) Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main chronobiological abnormality. Psychiatry Res 28(3):263–278PubMedCrossRefGoogle Scholar
  67. Spanagel R et al (2005) The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 11(1):35–42PubMedCrossRefGoogle Scholar
  68. Spencer S et al (2012) A mutation in CLOCK leads to altered dopamine receptor function. J Neurochem 123:124–134PubMedCrossRefGoogle Scholar
  69. Sprouse J, Braselton J, Reynolds L (2006) Fluoxetine modulates the circadian biological clock via phase advances of suprachiasmatic nucleus neuronal firing. Biol Psychiatry 60(8):896–899PubMedCrossRefGoogle Scholar
  70. Terman M, Terman JS (2005) Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr 10(8):647–663; quiz 672Google Scholar
  71. Turek FW et al (2005) Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308(5724):1043–1045PubMedCrossRefGoogle Scholar
  72. Van Reeth O et al (1997) Comparative effects of a melatonin agonist on the circadian system in mice and Syrian hamsters. Brain Res 762(1–2):185–194PubMedCrossRefGoogle Scholar
  73. Vitaterna MH et al (1994) Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264(5159):719–725PubMedCrossRefGoogle Scholar
  74. Walton KM et al (2009) Selective inhibition of casein kinase 1 epsilon minimally alters circadian clock period. J Pharmacol Exp Ther 330(2):430–439PubMedCrossRefGoogle Scholar
  75. Wang Y et al (2010) Identification of SR1078, a synthetic agonist for the orphan nuclear receptors ROR alpha and ROR gamma. ACS Chem Biol 5(11):1029–1034PubMedCrossRefGoogle Scholar
  76. Wang X et al (2012) A promoter polymorphism in the Per3 gene is associated with alcohol and stress response. Transl Psychiatry 2:e73PubMedCrossRefGoogle Scholar
  77. Weber M et al (2004) Circadian patterns of neurotransmitter related gene expression in motor regions of the rat brain. Neurosci Lett 358(1):17–20PubMedCrossRefGoogle Scholar
  78. Weiner N et al (1992) Circadian and seasonal rhythms of 5-HT receptor subtypes, membrane anisotropy and 5-HT release in hippocampus and cortex of the rat. Neurochem Int 21(1):7–14PubMedCrossRefGoogle Scholar
  79. Wirz-Justice A, Van den Hoofdakker RH (1999) Sleep deprivation in depression: what do we know, where do we go? Biol Psychiatry 46(4):445–453PubMedCrossRefGoogle Scholar
  80. Wu JC et al (2009) Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder. Biol Psychiatry 66(3):298–301PubMedCrossRefGoogle Scholar
  81. Xu Y et al (2005) Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 434(7033):640–644PubMedCrossRefGoogle Scholar
  82. Yang X et al (2006) Nuclear receptor expression links the circadian clock to metabolism. Cell 126(4):801–810PubMedCrossRefGoogle Scholar
  83. Yin L et al (2006) Nuclear receptor Rev-erb alpha is a critical lithium-sensitive component of the circadian clock. Science 311(5763):1002–1005PubMedCrossRefGoogle Scholar
  84. Yin L et al (2007) Rev-erb alpha, a heme sensor that coordinates metabolic and circadian pathways. Science 318(5857):1786–1789PubMedCrossRefGoogle Scholar
  85. Zghoul T et al (2007) Ethanol self-administration and reinstatement of ethanol-seeking behavior in Per1(Brdm1) mutant mice. Psychopharmacology 190(1):13–19PubMedCrossRefGoogle Scholar
  86. Zheng B et al (1999) The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400(6740):169–173PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Biology, Unit of BiochemistryUniversity of FribourgFribourgSwitzerland

Personalised recommendations