Circadian neurogenetics of mood disorders

  • Jorge MendozaEmail author
  • Guillaume Vanotti


Mood state alterations are often accompanied by disruptions of daily rhythms of physiology. Circadian rhythms of physiology are controlled by a central clock harbored in the suprachiasmatic nucleus (SCN), which is functionally dependent on the rhythmic expression of several clock genes. The molecular clockwork has been identified in other extra-SCN brain regions, some of which are implicated in the regulation of motivational and emotional states, although their specific circadian role is not fully known. In mood disorders, alterations of the molecular clock have been reported. Thus, functional expression of circadian genes in the brain is compromised in mood diseases. In the present review, we describe the current evidence that implicates the clock gene alterations as an important factor in the development of mood-related disorders. Furthermore, we describe the possible role of other brain clocks, beyond the SCN, in the circadian control of mood. The comprehension of the circadian neural and genetic mechanisms underlying mood alterations might guide towards the identification of optimal drug and non-drug therapies for the cure of depression and other mood disorders.


Circadian Clock genes Depression Mood Suprachiasmatic nucleus Habenula 



We thank Dr. Ipek Yalcin for the invitation to contribute to the special issue and Dr. Tando Maduna and Dr. Cristina Sandu for comments on the manuscript.

Funding information

Funding sources are provided by the Agence National de la Recherche (ANR-14-CE13-0002-01 ADDiCLOCK JCJC), the Centre National de la Recherche Scientifique and the Institut Danone France-Fondation pour la Recherche Médicale Consortium.


  1. Abe M, Herzog ED, Block GD (2000) Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. Neuroreport 11(14):3261–3264CrossRefPubMedGoogle Scholar
  2. Aizawa H, Cui W, Tanaka K, Okamoto H (2013) Hyperactivation of the habenula as a link between depression and sleep disturbance. Front Hum Neurosci 7:826. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Albrecht U (2012) Timing to perfection: the biology of central and peripheral circadian clocks. Neuron 74(2):246–260. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Albrecht U, Sun ZS, Eichele G, Lee CC (1997) A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light. Cell 91(7):1055–1064CrossRefPubMedGoogle Scholar
  5. Archer SN, Robilliard DL, Skene DJ, Smits M, Williams A, Arendt J, von Schantz M (2003) A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep 26(4):413–415CrossRefPubMedPubMedCentralGoogle Scholar
  6. Archer SN, Schmidt C, Vandewalle G, Dijk DJ (2018) Phenotyping of PER3 variants reveals widespread effects on circadian preference, sleep regulation, and health. Sleep Med Rev 40:109–126. CrossRefPubMedGoogle Scholar
  7. Artioli P, Lorenzi C, Pirovano A, Serretti A, Benedetti F, Catalano M, Smeraldi E (2007) How do genes exert their role? Period 3 gene variants and possible influences on mood disorder phenotypes. Eur Neuropsychopharmacol 17(9):587–594. CrossRefPubMedGoogle Scholar
  8. Barthas F, Sellmeijer J, Hugel S, Waltisperger E, Barrot M, Yalcin I (2015) The anterior cingulate cortex is a critical hub for pain-induced depression. Biol Psychiatry 77(3):236–245. CrossRefPubMedGoogle Scholar
  9. Benedetti F, Dallaspezia S, Fulgosi MC, Lorenzi C, Serretti A, Barbini B, Colombo C, Smeraldi E (2007) Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns in patients affected by bipolar depression. Am J Med Genet B Neuropsychiatr Genet 144B(5):631–635. CrossRefPubMedGoogle Scholar
  10. Benedetti F, Riccaboni R, Dallaspezia S, Locatelli C, Smeraldi E, Colombo C (2015) Effects of CLOCK gene variants and early stress on hopelessness and suicide in bipolar depression. Chronobiol Int 32(8):1156–1161. CrossRefPubMedGoogle Scholar
  11. Besing RC, Paul JR, Hablitz LM, Rogers CO, Johnson RL, Young ME, Gamble KL (2015) Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus. J Biol Rhythm 30(2):155–160. CrossRefGoogle Scholar
  12. Bollettini I, Melloni EM, Aggio V, Poletti S, Lorenzi C, Pirovano A, Vai B, Dallaspezia S, Colombo C, Benedetti F (2017) Clock genes associate with white matter integrity in depressed bipolar patients. Chronobiol Int 34(2):212–224. CrossRefPubMedGoogle Scholar
  13. Brinschwitz K, Dittgen A, Madai VI, Lommel R, Geisler S, Veh RW (2010) Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain. Neuroscience 168(2):463–476. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Buijs RM, Scheer FA, Kreier F, Yi C, Bos N, Goncharuk VD, Kalsbeek A (2006) Organization of circadian functions: interaction with the body. Prog Brain Res 153:341–360. CrossRefPubMedGoogle Scholar
  15. Callaway E, Ledford H (2017) Medicine Nobel awarded for work on circadian clocks. Nature 550(7674):18. CrossRefPubMedGoogle Scholar
  16. Chang AM, Reid KJ, Gourineni R, Zee PC (2009) Sleep timing and circadian phase in delayed sleep phase syndrome. J Biol Rhythm 24(4):313–321. CrossRefGoogle Scholar
  17. Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, Ferguson D, Tsai HC, Pomeranz L, Christoffel DJ, Nectow AR, Ekstrand M, Domingos A, Mazei-Robison MS, Mouzon E, Lobo MK, Neve RL, Friedman JM, Russo SJ, Deisseroth K, Nestler EJ, Han MH (2013) Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493(7433):532–536. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Chung S, Lee EJ, Yun S, Choe HK, Park SB, Son HJ, Kim KS, Dluzen DE, Lee I, Hwang O, Son GH, Kim K (2014) Impact of circadian nuclear receptor REV-ERBalpha on midbrain dopamine production and mood regulation. Cell 157(4):858–868. CrossRefPubMedGoogle Scholar
  19. Costemale-Lacoste JF, Colle R, Martin S, Asmar KE, Loeb E, Feve B, Verstuyft C, Trabado S, Ferreri F, Haffen E, Polosan M, Becquemont L, Corruble E (2018) Glycogen synthase kinase-3beta genetic polymorphisms and insomnia in depressed patients: a prospective study. J Affect Disord 240:230–236. CrossRefPubMedGoogle Scholar
  20. Cui W, Mizukami H, Yanagisawa M, Aida T, Nomura M, Isomura Y, Takayanagi R, Ozawa K, Tanaka K, Aizawa H (2014) Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. J Neurosci 34(49):16273–16285. CrossRefPubMedGoogle Scholar
  21. Dallaspezia S, Lorenzi C, Pirovano A, Colombo C, Smeraldi E, Benedetti F (2011) Circadian clock gene Per3 variants influence the postpartum onset of bipolar disorder. Eur Psychiatry 26(3):138–140. CrossRefPubMedGoogle Scholar
  22. De Bundel D, Gangarossa G, Biever A, Bonnefont X, Valjent E (2013) Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice. Front Behav Neurosci 7:152. CrossRefPubMedPubMedCentralGoogle Scholar
  23. DeCoursey PJ (2014) Survival value of suprachiasmatic nuclei (SCN) in four wild sciurid rodents. Behav Neurosci 128(3):240–249. CrossRefPubMedGoogle Scholar
  24. Dibner C, Schibler U, Albrecht U (2010) The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol 72:517–549. CrossRefPubMedGoogle Scholar
  25. Dudley TE, DiNardo LA, Glass JD (1998) Endogenous regulation of serotonin release in the hamster suprachiasmatic nucleus. J Neurosci 18(13):5045–5052CrossRefPubMedGoogle Scholar
  26. Ebisawa T, Uchiyama M, Kajimura N, Mishima K, Kamei Y, Katoh M, Watanabe T, Sekimoto M, Shibui K, Kim K, Kudo Y, Ozeki Y, Sugishita M, Toyoshima R, Inoue Y, Yamada N, Nagase T, Ozaki N, Ohara O, Ishida N, Okawa M, Takahashi K, Yamauchi T (2001) Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep 2(4):342–346. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Elmore SK, Dahl K, Avery DH, Savage MV, Brengelmann GL (1993) Body temperature and diurnal type in women with seasonal affective disorder. Health Care Women Int 14(1):17–26. CrossRefPubMedGoogle Scholar
  28. Etain B, Jamain S, Milhiet V, Lajnef M, Boudebesse C, Dumaine A, Mathieu F, Gombert A, Ledudal K, Gard S, Kahn JP, Henry C, Boland A, Zelenika D, Lechner D, Lathrop M, Leboyer M, Bellivier F (2014) Association between circadian genes, bipolar disorders and chronotypes. Chronobiology Int 31(7):807–814.
  29. Fernandez DC, Fogerson PM, Lazzerini Ospri L, Thomsen MB, Layne RM, Severin D, Zhan J, Singer JH, Kirkwood A, Zhao H, Berson DM, Hattar S (2018) Light affects mood and learning through distinct retina-brain pathways. Cell.
  30. Foster RG, Peirson SN, Wulff K, Winnebeck E, Vetter C, Roenneberg T (2013) Sleep and circadian rhythm disruption in social jetlag and mental illness. Prog Mol Biol Transl Sci 119:325–346. CrossRefPubMedGoogle Scholar
  31. Godinho SI, Maywood ES, Shaw L, Tucci V, Barnard AR, Busino L, Pagano M, Kendall R, Quwailid MM, Romero MR, O’Neill J, Chesham JE, Brooker D, Lalanne Z, Hastings MH, Nolan PM (2007) The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316(5826):897–900. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Golombek DA, Rosenstein RE (2010) Physiology of circadian entrainment. Physiol Rev 90(3):1063–1102. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Granados-Fuentes D, Prolo LM, Abraham U, Herzog ED (2004) The suprachiasmatic nucleus entrains, but does not sustain, circadian rhythmicity in the olfactory bulb. J Neurosci 24(3):615–619. CrossRefPubMedGoogle Scholar
  34. 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):3195–3216. CrossRefPubMedGoogle Scholar
  35. Guilding C, Hughes AT, Piggins HD (2010) Circadian oscillators in the epithalamus. Neuroscience 169(4):1630–1639. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 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):975–983CrossRefPubMedGoogle Scholar
  37. Hakkarainen R, Johansson C, Kieseppa T, Partonen T, Koskenvuo M, Kaprio J, Lonnqvist J (2003) Seasonal changes, sleep length and circadian preference among twins with bipolar disorder. BMC Psychiatry 3:6. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Hampp G, Ripperger JA, Houben T, Schmutz I, Blex C, Perreau-Lenz S, Brunk I, Spanagel R, Ahnert-Hilger G, Meijer JH, Albrecht U (2008) Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood. Curr Biol 18(9):678–683. CrossRefPubMedGoogle Scholar
  39. Hannibal J (2002) Neurotransmitters of the retino-hypothalamic tract. Cell Tissue Res 309(1):73–88. CrossRefPubMedGoogle Scholar
  40. Hastings MH, Maywood ES, Brancaccio M (2018) Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci 19(8):453–469. CrossRefPubMedGoogle Scholar
  41. Hattar S, Kumar M, Park A, Tong P, Tung J, Yau KW, Berson DM (2006) Central projections of melanopsin-expressing retinal ganglion cells in the mouse. J Comp Neurol 497(3):326–349. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Herzog ED (2007) Neurons and networks in daily rhythms. Nat Rev Neurosci 8(10):790–802. CrossRefPubMedGoogle Scholar
  43. Herzog ED, Hermanstyne T, Smyllie NJ, Hastings MH (2017) Regulating the suprachiasmatic nucleus (SCN) circadian clockwork: interplay between cell-autonomous and circuit-level mechanisms. Cold Spring Harb Perspect Biol 9(1).
  44. Hikosaka O, Sesack SR, Lecourtier L, Shepard PD (2008) Habenula: crossroad between the basal ganglia and the limbic system. J Neurosci 28(46):11825–11829. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Hood S, Cassidy P, Cossette MP, Weigl Y, Verwey M, Robinson B, Stewart J, Amir S (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):14046–14058. CrossRefPubMedGoogle Scholar
  46. Horne JA, Ostberg O (1976) A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 4(2):97–110PubMedGoogle Scholar
  47. Hua P, Liu W, Chen D, Zhao Y, Chen L, Zhang N, Wang C, Guo S, Wang L, Xiao H, Kuo SH (2014) Cry1 and Tef gene polymorphisms are associated with major depressive disorder in the Chinese population. J Affect Disord 157:100–103. CrossRefPubMedGoogle Scholar
  48. Iitaka C, Miyazaki K, Akaike T, Ishida N (2005) A role for glycogen synthase kinase-3beta in the mammalian circadian clock. J Biol Chem 280(33):29397–29402. CrossRefPubMedGoogle Scholar
  49. Iwahana E, Akiyama M, Miyakawa K, Uchida A, Kasahara J, Fukunaga K, Hamada T, Shibata S (2004) Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase-3 protein expression in the mouse suprachiasmatic nuclei. Eur J Neurosci 19(8):2281–2287. CrossRefPubMedGoogle Scholar
  50. Jaeger C, Sandu C, Malan A, Mellac K, Hicks D, Felder-Schmittbuhl MP (2015) Circadian organization of the rodent retina involves strongly coupled, layer-specific oscillators. FASEB J 29(4):1493–1504. CrossRefPubMedGoogle Scholar
  51. Jager J, O’Brien WT, Manlove J, Krizman EN, Fang B, Gerhart-Hines Z, Robinson MB, Klein PS, Lazar MA (2014) Behavioral changes and dopaminergic dysregulation in mice lacking the nuclear receptor Rev-erbalpha. Mol Endocrinol 28(4):490–498. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Jankowski KS, Dmitrzak-Weglarz M (2017) ARNTL, CLOCK and PER3 polymorphisms—links with chronotype and affective dimensions. Chronobiol Int 34(8):1105–1113. CrossRefPubMedGoogle Scholar
  53. Jhou TC, Geisler S, Marinelli M, Degarmo BA, Zahm DS (2009) The mesopontine rostromedial tegmental nucleus: a structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta. J Comp Neurol 513(6):566–596. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Johansson C, Willeit M, Smedh C, Ekholm J, Paunio T, Kieseppa T, Lichtermann D, Praschak-Rieder N, Neumeister A, Nilsson LG, Kasper S, Peltonen L, Adolfsson R, Schalling M, Partonen T (2003) Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology 28(4):734–739. CrossRefPubMedGoogle Scholar
  55. Johnsson A, Engelmann W, Pflug B, Klemke W (1983) Period lengthening of human circadian rhythms by lithium carbonate, a prophylactic for depressive disorders. Int J Chronobiol 8(3):129–147PubMedGoogle Scholar
  56. Jones KH, Ellis J, von Schantz M, Skene DJ, Dijk DJ, Archer SN (2007) Age-related change in the association between a polymorphism in the PER3 gene and preferred timing of sleep and waking activities. J Sleep Res 16(1):12–16. CrossRefPubMedGoogle Scholar
  57. Jones JR, Simon T, Lones L, Herzog ED (2018) SCN VIP neurons are essential for normal light-mediated resetting of the circadian system. J Neurosci 38(37):7986–7995. CrossRefPubMedGoogle Scholar
  58. Kaidanovich-Beilin O, Milman A, Weizman A, Pick CG, Eldar-Finkelman H (2004) Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus. Biol Psychiatry 55(8):781–784. CrossRefPubMedGoogle Scholar
  59. Kaiser C, Kaufmann C, Leutritz T, Arnold YL, Speck O, Ullsperger M (2019) The human habenula is responsive to changes in luminance and circadian rhythm. Neuroimage.
  60. Kalsbeek A, Fliers E, Hofman MA, Swaab DF, Buijs RM (2010) Vasopressin and the output of the hypothalamic biological clock. J Neuroendocrinol 22(5):362–372. CrossRefPubMedGoogle Scholar
  61. Katzenberg D, Young T, Finn L, Lin L, King DP, Takahashi JS, Mignot E (1998) A CLOCK polymorphism associated with human diurnal preference. Sleep 21(6):569–576CrossRefPubMedGoogle Scholar
  62. Kennaway DJ (2010) Clock genes at the heart of depression. J Psychopharmacol 24(2 Suppl):5–14. CrossRefPubMedGoogle Scholar
  63. Kim HI, Lee HJ, Cho CH, Kang SG, Yoon HK, Park YM, Lee SH, Moon JH, Song HM, Lee E, Kim L (2015) Association of CLOCK, ARNTL, and NPAS2 gene polymorphisms and seasonal variations in mood and behavior. Chronobiol Int 32(6):785–791.
  64. Klarsfeld A, Leloup JC, Rouyer F (2003) Circadian rhythms of locomotor activity in Drosophila. Behav Process 64(2):161–175CrossRefGoogle Scholar
  65. Kondratova AA, Dubrovsky YV, Antoch MP, Kondratov RV (2010) Circadian clock proteins control adaptation to novel environment and memory formation. Aging (Albany NY) 2(5):285–297. CrossRefGoogle Scholar
  66. Kripke DF, Nievergelt CM, Joo E, Shekhtman T, Kelsoe JR (2009) Circadian polymorphisms associated with affective disorders. J Circadian Rhythms 7:2. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Kurabayashi N, Hirota T, Sakai M, Sanada K, Fukada Y (2010) DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol Cell Biol 30(7):1757–1768. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Landgraf D, Long JE, Proulx CD, Barandas R, Malinow R, Welsh DK (2016) Genetic disruption of circadian rhythms in the suprachiasmatic nucleus causes helplessness, behavioral despair, and anxiety-like behavior in mice. Biol Psychiatry 80(11):827–835. CrossRefPubMedPubMedCentralGoogle Scholar
  69. Lavebratt C, Sjoholm LK, Soronen P, Paunio T, Vawter MP, Bunney WE, Adolfsson R, Forsell Y, Wu JC, Kelsoe JR, Partonen T, Schalling M (2010) CRY2 is associated with depression. PLoS One 5(2):e9407. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Lecca S, Meye FJ, Mameli M (2014) The lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview. Eur J Neurosci 39(7):1170–1178. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Lecca S, Pelosi A, Tchenio A, Moutkine I, Lujan R, Herve D, Mameli M (2016) Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nat Med 22(3):254–261. CrossRefPubMedGoogle Scholar
  72. LeGates TA, Fernandez DC, Hattar S (2014) Light as a central modulator of circadian rhythms, sleep and affect. Nat Rev Neurosci 15(7):443–454. CrossRefPubMedPubMedCentralGoogle Scholar
  73. LeSauter J, Silver R (1993) Lithium lengthens the period of circadian rhythms in lesioned hamsters bearing SCN grafts. Biol Psychiatry 34(1–2):75–83CrossRefPubMedGoogle Scholar
  74. Li JY, Schmidt TM (2018) Divergent projection patterns of M1 ipRGC subtypes. J Comp Neurol.
  75. Li JZ, Bunney BG, Meng F, Hagenauer MH, Walsh DM, Vawter MP, Evans SJ, Choudary PV, Cartagena P, Barchas JD, Schatzberg AF, Jones EG, Myers RM, Watson SJ Jr, Akil H, Bunney WE (2013a) Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proc Natl Acad Sci U S A 110(24):9950–9955. CrossRefPubMedPubMedCentralGoogle Scholar
  76. Li K, Zhou T, Liao L, Yang Z, Wong C, Henn F, Malinow R, Yates JR 3rd, Hu H (2013b) betaCaMKII in lateral habenula mediates core symptoms of depression. Science 341(6149):1016–1020. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Liberman AR, Halitjaha L, Ay A, Ingram KK (2018) Modeling strengthens molecular link between circadian polymorphisms and major mood disorders. J Biol Rhythm 33(3):318–336. CrossRefGoogle Scholar
  78. Liu WH, Valton V, Wang LZ, Zhu YH, Roiser JP (2017) Association between habenula dysfunction and motivational symptoms in unmedicated major depressive disorder. Soc Cogn Affect Neurosci 12(9):1520–1533. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Malhi GS, Gessler D, Outhred T (2017) The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines. J Affect Disord 217:266–280. CrossRefPubMedGoogle Scholar
  80. Matsumoto M, Hikosaka O (2007) Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447(7148):1111–1115. CrossRefPubMedGoogle Scholar
  81. Mazuski C, Abel JH, Chen SP, Hermanstyne TO, Jones JR, Simon T, Doyle FJ 3rd, Herzog ED (2018) Entrainment of circadian rhythms depends on firing rates and neuropeptide release of VIP SCN neurons. Neuron 99(3):555–563 e555. CrossRefPubMedGoogle Scholar
  82. Mazzoccoli G, Laukkanen MO, Vinciguerra M, Colangelo T, Colantuoni V (2016) A timeless link between circadian patterns and disease. Trends Mol Med 22(1):68–81. CrossRefPubMedGoogle Scholar
  83. McCarthy MJ, Nievergelt CM, Shekhtman T, Kripke DF, Welsh DK, Kelsoe JR (2011) Functional genetic variation in the rev-Erbalpha pathway and lithium response in the treatment of bipolar disorder. Genes Brain Behav 10(8):852–861. CrossRefPubMedPubMedCentralGoogle Scholar
  84. McClung CA, Sidiropoulou K, Vitaterna M, Takahashi JS, White FJ, Cooper DC, Nestler EJ (2005) Regulation of dopaminergic transmission and cocaine reward by the clock gene. Proc Natl Acad Sci U S A 102(26):9377–9381. CrossRefPubMedPubMedCentralGoogle Scholar
  85. Meijer JH (1990) Physiological basis for photic entrainment. Eur J Morphol 28(2–4):308–316PubMedGoogle Scholar
  86. Mendoza J (2017) Circadian neurons in the lateral habenula: clocking motivated behaviors. Pharmacol Biochem Behav.
  87. Meng QJ, Logunova L, Maywood ES, Gallego M, Lebiecki J, Brown TM, Sladek M, Semikhodskii AS, Glossop NRJ, Piggins HD, Chesham JE, Bechtold DA, Yoo SH, Takahashi JS, Virshup DM, Boot-Handford RP, Hastings MH, Loudon ASI (2008) Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58(1):78–88. CrossRefPubMedPubMedCentralGoogle Scholar
  88. Merikanto I, Lahti T, Kronholm E, Peltonen M, Laatikainen T, Vartiainen E, Salomaa V, Partonen T (2013) Evening types are prone to depression. Chronobiol Int 30(5):719–725. CrossRefPubMedGoogle Scholar
  89. Metzger M, Bueno D, Lima LB (2017) The lateral habenula and the serotonergic system. Pharmacol Biochem Behav.
  90. Mizumori SJY, Baker PM (2017) The lateral Habenula and adaptive behaviors. Trends Neurosci 40(8):481–493. CrossRefPubMedGoogle Scholar
  91. Moore RY (1995) Organization of the mammalian circadian system. CIBA Found Symp 183:88–99 discussion 100-106PubMedGoogle Scholar
  92. Moore RY, Speh JC, Card JP (1995) The retinohypothalamic tract originates from a distinct subset of retinal ganglion cells. J Comp Neurol 352(3):351–366. CrossRefPubMedGoogle Scholar
  93. Mukherjee S, Coque L, Cao JL, Kumar J, Chakravarty S, Asaithamby A, Graham A, Gordon E, Enwright JF 3rd, DiLeone RJ, Birnbaum SG, Cooper DC, McClung CA (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):503–511. CrossRefPubMedPubMedCentralGoogle Scholar
  94. Mutz J, Edgcumbe DR, Brunoni AR, Fu CHY (2018) Efficacy and acceptability of non-invasive brain stimulation for the treatment of adult unipolar and bipolar depression: a systematic review and meta-analysis of randomised sham-controlled trials. Neurosci Biobehav Rev 92:291–303. CrossRefPubMedGoogle Scholar
  95. Namboodiri VM, Rodriguez-Romaguera J, Stuber GD (2016) The habenula. Curr Biol 26(19):R873–R877. CrossRefPubMedGoogle Scholar
  96. Ono D, Honma KI, Yanagawa Y, Yamanaka A, Honma S (2018) Role of GABA in the regulation of the central circadian clock of the suprachiasmatic nucleus. J Physiol Sci 68(4):333–343. CrossRefPubMedGoogle Scholar
  97. Orozco-Solis R, Montellier E, Aguilar-Arnal L, Sato S, Vawter MP, Bunney BG, Bunney WE, Sassone-Corsi P (2017) A circadian genomic signature common to ketamine and sleep deprivation in the anterior cingulate cortex. Biol Psychiatry 82(5):351–360. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Parekh PK, Becker-Krail D, Sundaravelu P, Ishigaki S, Okado H, Sobue G, Huang Y, McClung CA (2018) Altered GluA1 (Gria1) function and accumbal synaptic plasticity in the ClockDelta19 model of bipolar mania. Biol Psychiatry 84(11):817–826. CrossRefPubMedGoogle Scholar
  99. Partonen T, Treutlein J, Alpman A, Frank J, Johansson C, Depner M, Aron L, Rietschel M, Wellek S, Soronen P, Paunio T, Koch A, Chen P, Lathrop M, Adolfsson R, Persson ML, Kasper S, Schalling M, Peltonen L, Schumann G (2007) Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression. Ann Med 39(3):229–238. CrossRefPubMedGoogle Scholar
  100. Patton AP, Hastings MH (2018) The suprachiasmatic nucleus. Curr Biol 28(15):R816–R822. CrossRefPubMedGoogle Scholar
  101. Pawlak J, Dmitrzak-Weglarz M, Maciukiewicz M, Wilkosc M, Leszczynska-Rodziewicz A, Zaremba D, Kapelski P, Hauser J (2015) Suicidal behavior in the context of disrupted rhythmicity in bipolar disorder—data from an association study of suicide attempts with clock genes. Psychiatry Res 226(2–3):517–520. CrossRefPubMedGoogle Scholar
  102. Pawlak J, Szczepankiewicz A, Kapelski P, Rajewska-Rager A, Slopien A, Skibinska M, Czerski P, Hauser J, Dmitrzak-Weglarz M (2017) Suicidal behavior in the context of disrupted rhythmicity in bipolar disorder—complementary research of clock genes with suicide risks factors and course of disease. Psychiatry Res 257:446–449. CrossRefPubMedGoogle Scholar
  103. Peschel N, Helfrich-Forster C (2011) Setting the clock—by nature: circadian rhythm in the fruitfly Drosophila melanogaster. FEBS Lett 585(10):1435–1442. CrossRefPubMedGoogle Scholar
  104. Pittendrigh CS (1993) Temporal organization: reflections of a Darwinian clock-watcher. Annu Rev Physiol 55:16–54. CrossRefPubMedGoogle Scholar
  105. Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (2002) The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110(2):251–260CrossRefPubMedPubMedCentralGoogle Scholar
  106. Proulx CD, Hikosaka O, Malinow R (2014) Reward processing by the lateral habenula in normal and depressive behaviors. Nat Neurosci 17(9):1146–1152. CrossRefPubMedPubMedCentralGoogle Scholar
  107. Roenneberg T, Wirz-Justice A, Merrow M (2003) Life between clocks: daily temporal patterns of human chronotypes. J Biol Rhythm 18(1):80–90. CrossRefGoogle Scholar
  108. Rosenwasser AM (2010) Circadian clock genes: non-circadian roles in sleep, addiction, and psychiatric disorders? Neurosci Biobehav Rev 34(8):1249–1255. CrossRefPubMedGoogle Scholar
  109. Rouyer F (2015) Clock genes: from Drosophila to humans. Bull Acad Natl Med 199(7):1115–1131PubMedGoogle Scholar
  110. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, Chakravarty S, Peevey J, Oehrlein N, Birnbaum S, Vitaterna MH, Orsulak P, Takahashi JS, Nestler EJ, Carlezon WA Jr, McClung CA (2007) Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A 104(15):6406–6411. CrossRefPubMedPubMedCentralGoogle Scholar
  111. Ruan GX, Allen GC, Yamazaki S, McMahon DG (2008) An autonomous circadian clock in the inner mouse retina regulated by dopamine and GABA. PLoS Biol 6(10):e249. CrossRefPubMedGoogle Scholar
  112. Russo SJ, Nestler EJ (2013) The brain reward circuitry in mood disorders. Nat Rev Neurosci 14(9):609–625. CrossRefPubMedPubMedCentralGoogle Scholar
  113. Sakhi K, Belle MD, Gossan N, Delagrange P, Piggins HD (2014a) Daily variation in the electrophysiological activity of mouse medial habenula neurones. J Physiol 592(4):587–603. CrossRefPubMedGoogle Scholar
  114. Sakhi K, Wegner S, Belle MD, Howarth M, Delagrange P, Brown TM, Piggins HD (2014b) Intrinsic and extrinsic cues regulate the daily profile of mouse lateral habenula neuronal activity. J Physiol 592(22):5025–5045. CrossRefPubMedPubMedCentralGoogle Scholar
  115. Salaberry NL, Hamm H, Felder-Schmittbuhl MP, Mendoza J (2018) A suprachiasmatic-independent circadian clock(s) in the habenula is affected by Per gene mutations and housing light conditions in mice. Brain Struct Funct.
  116. Schmidt TM, Chen SK, Hattar S (2011a) Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions. Trends Neurosci 34(11):572–580. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Schmidt TM, Do MT, Dacey D, Lucas R, Hattar S, Matynia A (2011b) Melanopsin-positive intrinsically photosensitive retinal ganglion cells: from form to function. J Neurosci 31(45):16094–16101. CrossRefPubMedPubMedCentralGoogle Scholar
  118. Schnell A, Sandrelli F, Ranc V, Ripperger JA, Brai E, Alberi L, Rainer G, Albrecht U (2015) Mice lacking circadian clock components display different mood-related behaviors and do not respond uniformly to chronic lithium treatment. Chronobiol Int 32(8):1075–1089. CrossRefPubMedGoogle Scholar
  119. Sego C, Goncalves L, Lima L, Furigo IC, Donato J Jr, Metzger M (2014) Lateral habenula and the rostromedial tegmental nucleus innervate neurochemically distinct subdivisions of the dorsal raphe nucleus in the rat. J Comp Neurol 522(7):1454–1484. CrossRefPubMedGoogle Scholar
  120. Shearman LP, Jin X, Lee C, Reppert SM, Weaver DR (2000) Targeted disruption of the mPer3 gene: subtle effects on circadian clock function. Mol Cell Biol 20(17):6269–6275CrossRefPubMedPubMedCentralGoogle Scholar
  121. Shirakawa T, Moore RY (1994) Glutamate shifts the phase of the circadian neuronal firing rhythm in the rat suprachiasmatic nucleus in vitro. Neurosci Lett 178(1):47–50CrossRefPubMedGoogle Scholar
  122. Siepka SM, Yoo SH, Park J, Song W, Kumar V, Hu Y, Lee C, Takahashi JS (2007) Circadian mutant overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129(5):1011–1023. CrossRefPubMedPubMedCentralGoogle Scholar
  123. Sjoholm LK, Backlund L, Cheteh EH, Ek IR, Frisen L, Schalling M, Osby U, Lavebratt C, Nikamo P (2010) CRY2 is associated with rapid cycling in bipolar disorder patients. PLoS One 5(9):e12632. CrossRefPubMedPubMedCentralGoogle Scholar
  124. Spencer S, Falcon E, Kumar J, Krishnan V, Mukherjee S, Birnbaum SG, McClung CA (2013) Circadian genes period 1 and period 2 in the nucleus accumbens regulate anxiety-related behavior. Eur J Neurosci 37(2):242–250. CrossRefPubMedGoogle Scholar
  125. Stambolic V, Ruel L, Woodgett JR (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 6(12):1664–1668CrossRefPubMedGoogle Scholar
  126. Takahashi JS (2015) Molecular components of the circadian clock in mammals. Diabetes Obes Metab 17(Suppl 1):6–11. CrossRefPubMedPubMedCentralGoogle Scholar
  127. Takahashi JS, Hong HK, Ko CH, McDearmon EL (2008) The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet 9(10):764–775. CrossRefPubMedPubMedCentralGoogle Scholar
  128. Utge SJ, Soronen P, Loukola A, Kronholm E, Ollila HM, Pirkola S, Porkka-Heiskanen T, Partonen T, Paunio T (2010) Systematic analysis of circadian genes in a population-based sample reveals association of TIMELESS with depression and sleep disturbance. PLoS One 5(2):e9259. CrossRefPubMedPubMedCentralGoogle Scholar
  129. Wirz-Justice A (2018) Seasonality in affective disorders. Gen Comp Endocrinol 258:244–249. CrossRefPubMedGoogle Scholar
  130. Wirz-Justice A, Terman M, Oren DA, Goodwin FK, Kripke DF, Whybrow PC, Wisner KL, Wu JC, Lam RW, Berger M, Danilenko KV, Kasper S, Smeraldi E, Takahashi K, Thompson C, van den Hoofdakker RH (2004) Brightening depression. Science 303(5657):467–469. CrossRefPubMedGoogle Scholar
  131. Yan L, Takekida S, Shigeyoshi Y, Okamura H (1999) Per1 and Per2 gene expression in the rat suprachiasmatic nucleus: circadian profile and the compartment-specific response to light. Neuroscience 94(1):141–150CrossRefPubMedGoogle Scholar
  132. Yin L, Wang J, Klein PS, Lazar MA (2006) Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science 311(5763):1002–1005. CrossRefPubMedGoogle Scholar
  133. Zhang L, Hirano A, Hsu PK, Jones CR, Sakai N, Okuro M, McMahon T, Yamazaki M, Xu Y, Saigoh N, Saigoh K, Lin ST, Kaasik K, Nishino S, Ptacek LJ, Fu YH (2016) A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. Proc Natl Acad Sci U S A 113(11):E1536–E1544. CrossRefPubMedPubMedCentralGoogle Scholar
  134. Zhao H, Rusak B (2005) Circadian firing-rate rhythms and light responses of rat habenular nucleus neurons in vivo and in vitro. Neuroscience 132(2):519–528. CrossRefPubMedGoogle Scholar
  135. Zheng B, Albrecht U, Kaasik K, Sage M, Lu W, Vaishnav S, Li Q, Sun ZS, Eichele G, Bradley A, Lee CC (2001) Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105(5):683–694CrossRefPubMedGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of Cellular and Integrative NeurosciencesCNRS UPR-3212 University of StrasbourgStrasbourgFrance

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