Serotonin Modulates Circadian Entrainment in Drosophila

Entrainment of the Drosophila circadian clock to light involves the light-induced degradation of the clock protein timeless (TIM). We show here that this entrainment mechanism is inhibited by serotonin, acting through the Drosophila serotonin receptor 1B (d5-HT1B). d5-HT1B is expressed in clock neurons, and alterations of its levels affect molecular and behavioral responses of the clock to light. Effects of d5-HT1B are synergistic with a mutation in the circadian photoreceptor cryptochrome (CRY) and are mediated by SHAGGY (SGG), Drosophila glycogen synthase kinase 3beta (GSK3beta), which phosphorylates TIM. Levels of serotonin are decreased in flies maintained in extended constant darkness, suggesting that modulation of the clock by serotonin may vary under different environmental conditions. These data identify a molecular connection between serotonin signaling and the central clock component TIM and suggest a homeostatic mechanism for the regulation of circadian photosensitivity in Drosophila.

[1]  U. Boschert,et al.  A family of Drosophila serotonin receptors with distinct intracellular signalling properties and expression patterns. , 1992, The EMBO journal.

[2]  R J Konopka,et al.  RECIPROCAL BEHAVIOUR ASSOCIATED WITH ALTERED HOMEOSTASIS AND PHOTOSENSITIVITY OF DROSOPHILA CLOCK MUTANTS , 1989, Journal of neurogenetics.

[3]  P. Albert,et al.  Receptor signaling and structure: insights from serotonin-1 receptors , 2001, Trends in Endocrinology & Metabolism.

[4]  F. Jackson,et al.  A role for CK2 in the Drosophila circadian oscillator , 2003, Nature Neuroscience.

[5]  I. Meinertzhagen,et al.  Neurotransmitter regulation of circadian structural changes in the fly's visual system , 1999, Microscopy research and technique.

[6]  M. Bianchi,et al.  Functional Studies of Shaggy/Glycogen Synthase Kinase 3 Phosphorylation Sites in Drosophila melanogaster , 2004, Molecular and Cellular Biology.

[7]  T. E. Dudley,et al.  Endogenous Regulation of Serotonin Release in the Hamster Suprachiasmatic Nucleus , 1998, The Journal of Neuroscience.

[8]  A. Sehgal,et al.  Role of Molecular Oscillations in Generating Behavioral Rhythms in Drosophila , 2001, Neuron.

[9]  Zuwei Qian,et al.  A light-entrainment mechanism for the Drosophila circadian clock , 1996, Nature.

[10]  K. White,et al.  Serotonin‐containing neurons in Drosophila melanogaster: Development and distribution , 1988, The Journal of comparative neurology.

[11]  C. Kyriacou,et al.  A constitutively active cryptochrome in Drosophila melanogaster , 2004, Nature Neuroscience.

[12]  R. Hen,et al.  Involvement of 5-HT1A Receptors in Homeostatic and Stress-Induced Adaptive Regulations of Paradoxical Sleep: Studies in 5-HT1A Knock-Out Mice , 2002, The Journal of Neuroscience.

[13]  Jeffrey C. Hall,et al.  A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. , 2000, Cell.

[14]  P. Gaspar,et al.  The developmental role of serotonin: news from mouse molecular genetics , 2003, Nature Reviews Neuroscience.

[15]  M. Esler,et al.  Effect of sunlight and season on serotonin turnover in the brain , 2002, The Lancet.

[16]  J. Hirsh,et al.  Temporal and spatial development of serotonin and dopamine neurons in the Drosophila CNS. , 1994, Developmental biology.

[17]  M. Roh,et al.  In Vivo Regulation of Glycogen Synthase Kinase-3β (GSK3β) by Serotonergic Activity in Mouse Brain , 2004, Neuropsychopharmacology.

[18]  K. Fukunaga,et al.  Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase‐3 protein expression in the mouse suprachiasmatic nuclei , 2004, The European journal of neuroscience.

[19]  M. W. Young,et al.  A Role for the Segment Polarity Gene shaggy/GSK-3 in the Drosophila Circadian Clock , 2001, Cell.

[20]  C. Smart,et al.  WAY-100635, a specific 5-HT1A antagonist, can increase the responsiveness of the mammalian circadian pacemaker to photic stimuli , 2001, Neuroscience Letters.

[21]  E. Meyer-Bernstein,et al.  Photic Signaling by Cryptochrome in the DrosophilaCircadian System , 2001, Molecular and Cellular Biology.

[22]  K. Martin,et al.  Circadian variation in the activity of the 5‐HT1B autoreceptor in the region of the suprachiasmatic nucleus, measured by microdialysis in the conscious freely‐moving rat , 2000, British journal of pharmacology.

[23]  J. Truman,et al.  Sequential Nuclear Accumulation of the Clock Proteins Period and Timeless in the Pacemaker Neurons of Drosophila melanogaster , 2002, The Journal of Neuroscience.

[24]  C. Helfrich-Förster,et al.  The Novel Drosophila timblind Mutation Affects Behavioral Rhythms but Not Periodic Eclosion , 2005, Genetics.

[25]  B. Doble,et al.  GSK-3: tricks of the trade for a multi-tasking kinase , 2003, Journal of Cell Science.

[26]  S. Shibata,et al.  Nonphotic Entrainment by 5-HT1A/7 Receptor Agonists Accompanied by Reduced Per1 and Per2 mRNA Levels in the Suprachiasmatic Nuclei , 2000, The Journal of Neuroscience.

[27]  L. Dinardo,et al.  Midbrain Raphe Modulation of Nonphotic Circadian Clock Resetting and 5-HT Release in the Mammalian Suprachiasmatic Nucleus , 2003, The Journal of Neuroscience.

[28]  L. P. Morin,et al.  Serotonin and the regulation of mammalian circadian rhythmicity. , 1999, Annals of medicine.

[29]  Jeffrey C. Hall,et al.  The cryb Mutation Identifies Cryptochrome as a Circadian Photoreceptor in Drosophila , 1998, Cell.

[30]  R. Refinetti.  Effects of Prolonged Exposure to Darkness on Circadian Photic Responsiveness in the Mouse , 2003, Chronobiology international.

[31]  K. Tomioka,et al.  Serotonin sets the day state in the neurons that control coupling between the optic lobe circadian pacemakers in the cricket Gryllus bimaculatus. , 2002, The Journal of experimental biology.

[32]  Jeffrey C. Hall,et al.  Temporal and Spatial Expression Patterns of Transgenes Containing Increasing Amounts of the Drosophila Clock Gene period and a lacZ Reporter : Mapping Elements of the PER Protein Involved in Circadian Cycling , 1996 .

[33]  G. E. Pickard,et al.  Serotonergic innervation of the hypothalamic suprachiasmatic nucleus and photic regulation of circadian rhythms , 1997, Biology of the cell.

[34]  B. Cymborowski.  Serotonin modulates a photic response in circadian locomotor rhythmicity of adults of the blow fly, Calliphora vicina , 1998 .

[35]  Jeffrey C. Hall,et al.  The Circadian Clock of Fruit Flies Is Blind after Elimination of All Known Photoreceptors , 2001, Neuron.

[36]  M. Buhot,et al.  Role of serotonin in memory impairment , 2000, Annals of medicine.

[37]  T. Page.  Serotonin Phase-Shifts the Circadian Rhythm of Locomotor Activity in the Cockroach , 1987, Journal of biological rhythms.

[38]  C. Phiel,et al.  Inhibitory Phosphorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium , 2003, Journal of Biological Chemistry.

[39]  A. Sehgal,et al.  Response of the Timeless Protein to Light Correlates with Behavioral Entrainment and Suggests a Nonvisual Pathway for Circadian Photoreception , 1998, Neuron.

[40]  Jian-Qiang Lu,et al.  Circadian rhythm in the response to intracerebroventricular administration of 8-OH-DPAT , 1997, Brain Research.

[41]  Michael W. Young,et al.  A TIMELESS-Independent Function for PERIOD Proteins in the Drosophila Clock , 2000, Neuron.

[42]  Jeffrey C. Hall,et al.  Evidence that the TIM Light Response Is Relevant to Light-Induced Phase Shifts in Drosophila melanogaster , 1998, Neuron.

[43]  Jeffrey C. Hall,et al.  Cryptochromes: sensory reception, transduction, and clock functions subserving circadian systems , 2000, Current Opinion in Neurobiology.

[44]  Jeffrey C. Hall,et al.  Drosophila CRY Is a Deep Brain Circadian Photoreceptor , 2000, Neuron.

[45]  Xiangzhong Zheng,et al.  Posttranslational Regulation of Drosophila PERIOD Protein by Protein Phosphatase 2A , 2004, Cell.

[46]  R Hen,et al.  Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[47]  M. Bourouis.  Targeted increase in shaggy activity levels blocks wingless signaling , 2002, Genesis.

[48]  A. Winfree.  Slow dark-adaptation inDrosophila's circadian clock , 1972, Journal of comparative physiology.

[49]  Diane Boivin,et al.  Seasonal Affective Disorder: An Overview , 2003, Chronobiology international.

[50]  Kevin P. Keegan,et al.  A role for casein kinase 2α in the Drosophila circadian clock , 2002, Nature.

[51]  A. Sehgal,et al.  Molecular components of the circadian system in Drosophila. , 2001, Annual review of physiology.

[52]  A. Sehgal,et al.  A role for the proteasome in the light response of the timeless clock protein. , 1999, Science.

[53]  Michael W Young,et al.  The Drosophila Clock Gene double-time Encodes a Protein Closely Related to Human Casein Kinase Iε , 1998, Cell.

[54]  U. Lahaie,et al.  Seasonal Affective Disorder , 1986, British Journal of Psychiatry.