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A Circadian Genomic Signature Common to Ketamine and Sleep Deprivation in the Anterior Cingulate Cortex

      Abstract

      Background

      Conventional antidepressants usually require several weeks to achieve a full clinical response in patients with major depressive disorder, an illness associated with dysregulated circadian rhythms and a high incidence of suicidality. Two rapid-acting antidepressant strategies, low-dose ketamine (KT) and sleep deprivation (SD) therapies, dramatically reduce depressive symptoms within 24 hours in a subset of major depressive disorder patients. However, it is unknown whether they exert their actions through shared regulatory mechanisms. To address this question, we performed comparative transcriptomics analyses to identify candidate genes and relevant pathways common to KT and SD.

      Methods

      We used the forced swim test, a standardized behavioral approach to measure antidepressant-like activity of KT and SD. We investigated gene expression changes using high-density microarrays and pathway analyses (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis) in KT- and SD-treated mice compared with saline-treated control male mice.

      Results

      We show that KT and SD elicit common transcriptional responses implicating distinct elements of the circadian clock and processes involved in neuronal plasticity. There is an overlap of 64 genes whose expression is common in KT and SD. Specifically, there is downregulation of clock genes including Ciart, Per2, Npas4, Dbp, and Rorb in both KT- and SD-treated mice.

      Conclusions

      We demonstrate a potential involvement of the circadian clock in rapid antidepressant responses. These findings could open new research avenues to help design chronopharmacological strategies to treat major depressive disorder.

      Keywords

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      References

        • NIMH
        Major depression among adults. 2014; (Accessed September 18, 2016.)
        • Berman R.M.
        • Cappiello A.
        • Anand A.
        • Oren D.A.
        • Heninger G.R.
        • Charney D.S.
        • Krystal J.H.
        Antidepressant effects of ketamine in depressed patients.
        Biol Psychiatry. 2000; 47: 351-354
        • Bunney B.G.
        • Bunney W.E.
        Rapid-acting antidepressant strategies: mechanisms of action.
        Int J Neuropsychopharmacol. 2012; 15: 695-713
        • DiazGranados N.
        • Ibrahim L.A.
        • Brutsche N.E.
        • Ameli R.
        • Henter I.D.
        • Luckenbaugh D.A.
        • et al.
        Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder.
        J Clin Psychiatry. 2010; 71: 1605-1611
        • Larkin G.L.
        • Beautrais A.L.
        A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department.
        Int J Neuropsychopharmacol. 2011; 14: 1127-1131
        • Price R.B.
        • Nock M.K.
        • Charney D.S.
        • Mathew S.J.
        Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression.
        Biol Psychiatry. 2009; 66: 522-526
        • Murrough J.W.
        • Soleimani L.
        • DeWilde K.E.
        • Collins K.A.
        • Lapidus K.A.
        • Iacoviello B.M.
        • et al.
        Ketamine for rapid reduction of suicidal ideation: A randomized controlled trial.
        Psychol Med. 2015; 45: 3571-3580
        • Zarate Jr., C.A.
        • Brutsche N.E.
        • Ibrahim L.
        • Franco-Chaves J.
        • Diazgranados N.
        • Cravchik A.
        • et al.
        Replication of ketamine׳s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial.
        Biol Psychiatry. 2012; 71: 939-946
        • Price R.B.
        • Iosifescu D.V.
        • Murrough J.W.
        • Chang L.C.
        • Al Jurdi R.K.
        • Iqbal S.Z.
        • et al.
        Effects of ketamine on explicit and implicit suicidal cognition: A randomized controlled trial in treatment-resistant depression.
        Depress Anxiety. 2014; 31: 335-343
        • Dallaspezia S.
        • Suzuki M.
        • Benedetti F.
        Chronobiological therapy for mood disorders.
        Curr Psychiatry Rep. 2015; 17: 95
        • Masri S.
        • Sassone-Corsi P.
        The circadian clock: A framework linking metabolism, epigenetics and neuronal function.
        Nat Rev Neurosci. 2013; 14: 69-75
        • Bunney B.G.
        • Li J.Z.
        • Walsh D.M.
        • Stein R.
        • Vawter M.P.
        • Cartagena P.
        • et al.
        Circadian dysregulation of clock genes: Clues to rapid treatments in major depressive disorder.
        Mol Psychiatry. 2015; 20: 48-55
        • Hasler B.P.
        • Buysse D.J.
        • Kupfer D.J.
        • Germain A.
        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. 2010; 178: 205-207
        • Troxel W.M.
        • Kupfer D.J.
        • Reynolds 3rd, C.F.
        • Frank E.
        • Thase M.E.
        • Miewald J.M.
        • et al.
        Insomnia and objectively measured sleep disturbances predict treatment outcome in depressed patients treated with psychotherapy or psychotherapy-pharmacotherapy combinations.
        J Clin Psychiatry. 2012; 73: 478-485
        • Avery D.H.
        • Shah S.H.
        • Eder D.N.
        • Wildschiodtz G.
        Nocturnal sweating and temperature in depression.
        Acta Psychiatr Scand. 1999; 100: 295-301
        • Souetre E.
        • Salvati E.
        • Wehr T.A.
        • Sack D.A.
        • Krebs B.
        • Darcourt G.
        Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects.
        Am J Psychiatry. 1988; 145: 1133-1137
        • Bunney B.G.
        • Bunney W.E.
        Mechanisms of rapid antidepressant effects of sleep deprivation therapy: Clock genes and circadian rhythms.
        Biol Psychiatry. 2013; 73: 1164-1171
        • Bunney W.E.
        • Bunney B.G.
        Molecular clock genes in man and lower animals: Possible implications for circadian abnormalities in depression.
        Neuropsychopharmacology. 2000; 22: 335-345
        • Wu J.C.
        • Kelsoe J.R.
        • Schachat C.
        • Bunney B.G.
        • DeModena A.
        • Golshan S.
        • et al.
        Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder.
        Biol Psychiatry. 2009; 66: 298-301
        • Wisor J.P.
        • O׳Hara B.F.
        • Terao A.
        • Selby C.P.
        • Kilduff T.S.
        • Sancar A.
        • et al.
        A role for cryptochromes in sleep regulation.
        BMC Neurosci. 2002; 3: 20
        • Wisor J.P.
        • Pasumarthi R.K.
        • Gerashchenko D.
        • Thompson C.L.
        • Pathak S.
        • Sancar A.
        • et al.
        Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains.
        J Neurosci. 2008; 28: 7193-7201
        • Thompson C.L.
        • Wisor J.P.
        • Lee C.K.
        • Pathak S.D.
        • Gerashchenko D.
        • Smith K.A.
        • et al.
        Molecular and anatomical signatures of sleep deprivation in the mouse brain.
        Front Neurosci. 2010; 4: 165
        • Balsalobre A.
        • Damiola F.
        • Schibler U.
        A serum shock induces circadian gene expression in mammalian tissue culture cells.
        Cell. 1998; 93: 929-937
        • Maret S.
        • Dorsaz S.
        • Gurcel L.
        • Pradervand S.
        • Petit B.
        • Pfister C.
        • et al.
        Homer1a is a core brain molecular correlate of sleep loss.
        Proc Natl Acad Sci U S A. 2007; 104: 20090-20095
        • Bellet M.M.
        • Vawter M.P.
        • Bunney B.G.
        • Bunney W.E.
        • Sassone-Corsi P.
        Ketamine influences CLOCK:BMAL1 function leading to altered circadian gene expression.
        PLoS One. 2011; 6: e23982
        • Li J.Z.
        • Bunney B.G.
        • Meng F.
        • Hagenauer M.H.
        • Walsh D.M.
        • Vawter M.P.
        • et al.
        Circadian patterns of gene expression in the human brain and disruption in major depressive disorder.
        Proc Natl Acad Sci U S A. 2013; 110: 9950-9955
        • Drevets W.C.
        • Savitz J.
        • Trimble M.
        The subgenual anterior cingulate cortex in mood disorders.
        CNS Spectr. 2008; 13: 663-681
        • Salvadore G.
        • Cornwell B.R.
        • Colon-Rosario V.
        • Coppola R.
        • Grillon C.
        • Zarate Jr., C.A.
        • Manji H.K.
        Increased anterior cingulate cortical activity in response to fearful faces: A neurophysiological biomarker that predicts rapid antidepressant response to ketamine.
        Biol Psychiatry. 2009; 65: 289-295
        • Mulert C.
        • Juckel G.
        • Brunnmeier M.
        • Karch S.
        • Leicht G.
        • Mergl R.
        • et al.
        Prediction of treatment response in major depression: Integration of concepts.
        J Affect Disord. 2007; 98: 215-225
        • Hines D.J.
        • Schmitt L.I.
        • Hines R.M.
        • Moss S.J.
        • Haydon P.G.
        Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling.
        Transl Psychiatry. 2013; 3: e212
        • Can A.
        • Dao D.T.
        • Arad M.
        • Terrillion C.E.
        • Piantadosi S.C.
        • Gould T.D.
        The mouse forced swim test.
        J Vis Exp. 2012; 59: e3638
        • Orozco-Solis R.
        • Ramadori G.
        • Coppari R.
        • Sassone-Corsi P.
        SIRT1 relays nutritional inputs to the circadian clock through the Sf1 neurons of the ventromedial hypothalamus.
        Endocrinology. 2015; 156: 2174-2184
        • Surget A.
        • Wang Y.
        • Leman S.
        • Ibarguen-Vargas Y.
        • Edgar N.
        • Griebel G.
        • et al.
        Corticolimbic transcriptome changes are state-dependent and region-specific in a rodent model of depression and of antidepressant reversal.
        Neuropsychopharmacology. 2008; 34: 1363-1380
        • Berton O.
        • McClung C.A.
        • Dileone R.J.
        • Krishnan V.
        • Renthal W.
        • Russo S.J.
        • et al.
        Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
        Science. 2006; 311: 864-868
        • Eisen M.B.
        • Spellman P.T.
        • Brown P.O.
        • Botstein D.
        Cluster analysis and display of genome-wide expression patterns.
        Proc Natl Acad Sci U S A. 1998; 95: 14863-14868
        • Tabas-Madrid D.
        • Nogales-Cadenas R.
        • Pascual-Montano A.
        GeneCodis3: A non-redundant and modular enrichment analysis tool for functional genomics.
        Nucleic Acids Res. 2012; 40: W478-W483
        • Lopez-Rodriguez F.
        • Kim J.
        • Poland R.E.
        Total sleep deprivation decreases immobility in the forced-swim test.
        Neuropsychopharmacology. 2004; 29: 1105-1111
        • Scheuing L.
        • Chiu C.T.
        • Liao H.M.
        • Chuang D.M.
        Antidepressant mechanism of ketamine: Perspective from preclinical studies.
        Front Neurosci. 2015; 9: 249
        • Autry A.E.
        • Adachi M.
        • Nosyreva E.
        • Na E.S.
        • Los M.F.
        • Cheng P.F.
        • et al.
        NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
        Nature. 2011; 475: 91-95
        • Fillinger C.
        • Yalcin I.
        • Barrot M.
        • Veinante P.
        Afferents to anterior cingulate areas 24a and 24b and midcingulate areas 24a׳ and 24b׳ in the mouse.
        Brain Struct Funct. 2017; 222: 1509-1532
        • Annayev Y.
        • Adar S.
        • Chiou Y.Y.
        • Lieb J.D.
        • Sancar A.
        • Ye R.
        Gene model 129 (Gm129) encodes a novel transcriptional repressor that modulates circadian gene expression.
        J Biol Chem. 2014; 289: 5013-5024
        • Goriki A.
        • Hatanaka F.
        • Myung J.
        • Kim J.K.
        • Yoritaka T.
        • Tanoue S.
        • et al.
        A novel protein, CHRONO, functions as a core component of the mammalian circadian clock.
        PLoS Biol. 2014; 12: e1001839
        • Petryszak R.
        • Keays M.
        • Tang Y.A.
        • Fonseca N.A.
        • Barrera E.
        • Burdett T.
        • et al.
        Expression Atlas update—An integrated database of gene and protein expression in humans, animals and plants.
        Nucleic Acids Res. 2016; 44: D746-D752
        • Orozco-Solis R.
        • Sassone-Corsi P.
        Epigenetic control and the circadian clock: Linking metabolism to neuronal responses.
        Neuroscience. 2014; 264: 76-87
        • Janich P.
        • Pascual G.
        • Merlos-Suárez A.
        • Batlle E.
        • Ripperger J.
        • Albrecht U.
        • et al.
        The circadian molecular clock creates epidermal stem cell heterogeneity.
        Nature. 2011; 480: 209-214
        • Karpowicz P.
        • Zhang Y.
        • Hogenesch J.B.
        • Emery P.
        • Perrimon N.
        The circadian clock gates the intestinal stem cell regenerative state.
        Cell Reports. 2013; 3: 996-1004
        • Akashi M.
        • Nishida E.
        Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock.
        Genes Dev. 2000; 14: 645-649
        • Gerstner J.R.
        • Yin J.C.P.
        Circadian rhythms and memory formation.
        Nat Rev Neurosci. 2010; 11: 577-588
        • Ficek J.
        • Zygmunt M.
        • Piechota M.
        • Hoinkis D.
        • Rodriguez Parkitna J.
        • Przewlocki R.
        • Korostynski M.
        Molecular profile of dissociative drug ketamine in relation to its rapid antidepressant action.
        BMC Genomics. 2016; 17: 362
        • Mongrain V.
        • La Spada F.
        • Curie T.
        • Franken P.
        Sleep loss reduces the DNA-binding of BMAL1, CLOCK, and NPAS2 to specific clock genes in the mouse cerebral cortex.
        PLoS One. 2011; 6: e26622
        • Curie T.
        • Mongrain V.
        • Dorsaz S.
        • Mang G.M.
        • Emmenegger Y.
        • Franken P.
        Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation.
        Sleep. 2013; 36: 311-323
        • Garcia L.S.
        • Comim C.M.
        • Valvassori S.S.
        • Reus G.Z.
        • Barbosa L.M.
        • Andreazza A.C.
        • et al.
        Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus.
        Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 140-144
        • Weckmann K.
        • Labermaier C.
        • Asara J.M.
        • Muller M.B.
        • Turck C.W.
        Time-dependent metabolomic profiling of Ketamine drug action reveals hippocampal pathway alterations and biomarker candidates.
        Transl Psychiatry. 2014; 4: e481
        • Gene Ontology Consortium
        Gene Ontology Consortium: Going forward.
        Nucleic Acids Res. 2015; 43: D1049-D1056
        • Kanehisa M.
        • Sato Y.
        • Kawashima M.
        • Furumichi M.
        • Tanabe M.
        KEGG as a reference resource for gene and protein annotation.
        Nucleic Acids Res. 2016; 44: D457-D462
        • Abdallah C.G.
        • Adams T.G.
        • Kelmendi B.
        • Esterlis I.
        • Sanacora G.
        • Krystal J.H.
        Ketamine׳s mechanism of action: A path to rapid-acting antidepressants.
        Depress Anxiety. 2016; 33: 689-697
        • Beurel E.
        • Song L.
        • Jope R.S.
        Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice.
        Mol Psychiatry. 2011; 16: 1068-1070
        • Liu R.J.
        • Fuchikami M.
        • Dwyer J.M.
        • Lepack A.E.
        • Duman R.S.
        • Aghajanian G.K.
        GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine.
        Neuropsychopharmacology. 2013; 38: 2268-2277
        • Mathews D.C.
        • Zarate Jr., C.A.
        Current status of ketamine and related compounds for depression.
        J Clin Psychiatry. 2013; 74: 516-517
        • Kavalali E.T.
        • Monteggia L.M.
        Synaptic mechanisms underlying rapid antidepressant action of ketamine.
        Am J Psychiatry. 2012; 169: 1150-1156
        • Antle M.C.
        • Tse F.
        • Koke S.J.
        • Sterniczuk R.
        • Hagel K.
        Non-photic phase shifting of the circadian clock: Role of the extracellular signal-responsive kinases I/II/mitogen-activated protein kinase pathway.
        Eur J Neurosci. 2008; 28: 2511-2518
        • Duman C.H.
        • Schlesinger L.
        • Kodama M.
        • Russell D.S.
        • Duman R.S.
        A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment.
        Biol Psychiatry. 2007; 61: 661-670
        • Reus G.Z.
        • Vieira F.G.
        • Abelaira H.M.
        • Michels M.
        • Tomaz D.B.
        • dos Santos M.A.
        • et al.
        MAPK signaling correlates with the antidepressant effects of ketamine.
        J Psychiatr Res. 2014; 55: 15-21
        • Thomas G.M.
        • Huganir R.L.
        MAPK cascade signalling and synaptic plasticity.
        Nat Rev Neurosci. 2004; 5: 173-183
        • Nilsson E.K.
        • Bostrom A.E.
        • Mwinyi J.
        • Schioth H.B.
        Epigenomics of total acute sleep deprivation in relation to genome-wide DNA methylation profiles and RNA expression.
        OMICS. 2016; 20: 334-342
        • Cedernaes J.
        • Osler M.E.
        • Voisin S.
        • Broman J.E.
        • Vogel H.
        • Dickson S.L.
        • et al.
        Acute sleep loss induces tissue-specific epigenetic and transcriptional alterations to circadian clock genes in men.
        J Clin Endocrinol Metab. 2015; 100: E1255-E1261
        • Yoon K.
        • Gaiano N.
        Notch signaling in the mammalian central nervous system: Insights from mouse mutants.
        Nat Neurosci. 2005; 8: 709-715
        • Chiba S.
        Notch signaling in stem cell systems.
        Stem Cells. 2006; 24: 2437-2447
        • Ables J.L.
        • Breunig J.J.
        • Eisch A.J.
        • Rakic P.
        Not(ch) just development: Notch signalling in the adult brain.
        Nat Rev Neurosci. 2011; 12: 269-283
        • Alberi L.
        • Liu S.
        • Wang Y.
        • Badie R.
        • Smith-Hicks C.
        • Wu J.
        • et al.
        Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks.
        Neuron. 2011; 69: 437-444
        • Bagot R.C.
        • Cates H.M.
        • Purushothaman I.
        • Vialou V.
        • Heller E.A.
        • Yieh L.
        • et al.
        Ketamine and imipramine reverse transcriptional signatures of susceptibility and induce resilience-specific gene expression profiles.
        Biol Psychiatry. 2017; 81: 285-295
        • Papadopoulou A.
        • Siamatras T.
        • Delgado-Morales R.
        • Amin N.D.
        • Shukla V.
        • Zheng Y.L.
        • et al.
        Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: Implications to glucocorticoid actions and major depression.
        Transl Psychiatry. 2015; 5: e578
        • Duman R.S.
        • Aghajanian G.K.
        Synaptic dysfunction in depression: Potential therapeutic targets.
        Science. 2012; 338: 68-72
        • Mei L.
        • Xiong W.C.
        Neuregulin 1 in neural development, synaptic plasticity and schizophrenia.
        Nat Rev Neurosci. 2008; 9: 437-452
        • Karatsoreos I.N.
        • Bhagat S.
        • Bloss E.B.
        • Morrison J.H.
        • McEwen B.S.
        Disruption of circadian clocks has ramifications for metabolism, brain, and behavior.
        Proc Natl Acad Sci U S A. 2011; 108: 1657-1662
        • Maret S.
        • Faraguna U.
        • Nelson A.B.
        • Cirelli C.
        • Tononi G.
        Sleep and waking modulate spine turnover in the adolescent mouse cortex.
        Nat Neurosci. 2011; 14: 1418-1420
        • Mineur Y.S.
        • Obayemi A.
        • Wigestrand M.B.
        • Fote G.M.
        • Calarco C.A.
        • Li A.M.
        • Picciotto M.R.
        Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior.
        Proc Natl Acad Sci U S A. 2013; 110: 3573-3578
        • Berger M.
        • Riemann D.
        • Höchli D.
        • Spiegel R.
        The cholinergic rapid eye movement sleep induction test with rs-86: State or trait marker of depression?.
        Arch Gen Psychiatry. 1989; 46: 421-428
        • Benedetti F.
        • Dallaspezia S.
        • Lorenzi C.
        • Pirovano A.
        • Radaelli D.
        • Locatelli C.
        • et al.
        Gene-gene interaction of glycogen synthase kinase 3-β and serotonin transporter on human antidepressant response to sleep deprivation.
        J Affect Disord. 2012; 136: 514-519
        • Ressler K.J.
        • Mayberg H.S.
        Targeting abnormal neural circuits in mood and anxiety disorders: From the laboratory to the clinic.
        Nat Neurosci. 2007; 10: 1116-1124
        • Nestler E.J.
        • Hyman S.E.
        Animal models of neuropsychiatric disorders.
        Nat Neurosci. 2010; 13: 1161-1169
        • Serchov T.
        • Clement H.W.
        • Schwarz M.K.
        • Iasevoli F.
        • Tosh D.K.
        • Idzko M.
        • et al.
        Increased signaling via adenosine A1 receptors, sleep deprivation, imipramine, and ketamine inhibit depressive-like behavior via induction of Homer1a.
        Neuron. 2015; 87: 549-562