Circadian-Clocks

404 M.S. Robles and M. MannCastel M, Belenky M, Cohen S, Wagner S, Schwartz WJ (1997) Light-induced c-Fos expression in the mouse suprachiasmatic nucleus: immunoelectron microscopy reveals co-localization in multiple cell types. Eur J Neurosci 9:1950–1960Chiu JC, Vanselow JT, Kramer A, Edery I (2008) The phospho-occupancy of an atypical SLIMB- binding site on PERIOD that is phosphorylated by DOUBLETIME controls the pace of the clock. Genes Dev 22:1758–1772Choudhary C, Mann M (2010) Decoding signalling networks by mass spectrometry-based proteo- mics. Nat Rev Mol Cell Biol 11:427–439Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Sci- ence 325:834–840Cox J, Mann M (2011) Quantitative, high-resolution proteomics for data-driven systems biology. Annu Rev Biochem 80:273–299Dallmann R, Viola AU, Tarokh L, Cajochen C, Brown SA (2012) The human circadian metabolome. Proc Natl Acad Sci USA 109:2625–2629Davidson AJ, Yamazaki S, Menaker M (2003) SNC: ringmaster of the circadian circus or conductor of the circadian orchestra? Novartis Found Symp 253:110–121Deery MJ, Maywood ES, Chesham JE, Sladek M, Karp NA, Green EW, Charles PD, Reddy AB, Kyriacou CP, Lilley KS, Hastings MH (2009) Proteomic analysis reveals the role of synaptic vesicle cycling in sustaining the suprachiasmatic circadian clock. Curr Biol 19:2031–2036Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP (2008) A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci USA 105:10762–10767Duffield GE (2003) DNA microarray analyses of circadian timing: the genomic basis of biological time. J Neuroendocrinol 15:991–1002Duong HA, Robles MS, Knutti D, Weitz CJ (2011) A molecular mechanism for circadian clock negative feedback. Science 332:1436–1439Eckel-Mahan KL, Patel VR, Mohney RP, Vignola KS, Baldi P, Sassone-Corsi P (2012) Coordi- nation of the transcriptome and metabolome by the circadian clock. Proc Natl Acad Sci USA 109:5541–5546Ficarro SB, McCleland ML, Stukenberg PT, Burke DJ, Ross MM, Shabanowitz J, Hunt DF, White FM (2002) Phosphoproteome analysis by mass spectrometry and its application to Saccharo- myces cerevisiae. Nat Biotechnol 20:301–305Geiger T, Cox J, Ostasiewicz P, Wisniewski JR, Mann M (2010) Super-SILAC mix for quantita- tive proteomics of human tumor tissue. Nat Methods 7:383–385Geiger T, Wisniewski JR, Cox J, Zanivan S, Kruger M, Ishihama Y, Mann M (2011) Use of stable isotope labeling by amino acids in cell culture as a spike-in standard in quantitative proteomics. Nat Protoc 6:147–157Gingras AC, Gstaiger M, Raught B, Aebersold R (2007) Analysis of protein complexes using mass spectrometry. Nat Rev Mol Cell Biol 8:645–654Goldman BD (2001) Mammalian photoperiodic system: formal properties and neuroendocrine mechanisms of photoperiodic time measurement. J Biol Rhythms 16:283–301Graumann J, Hubner NC, Kim JB, Ko K, Moser M, Kumar C, Cox J, Scholer H, Mann M (2008) Stable isotope labeling by amino acids in cell culture (SILAC) and proteome quantitation of mouse embryonic stem cells to a depth of 5,111 proteins. Mol Cell Proteomics 7:672–683Hanash S (2003) Disease proteomics. Nature 422:226–232Hatcher NG, Atkins N Jr, Annangudi SP, Forbes AJ, Kelleher NL, Gillette MU, Sweedler JV (2008) Mass spectrometry-based discovery of circadian peptides. Proc Natl Acad Sci USA 105:12527–12532Huang W, Ramsey KM, Marcheva B, Bass J (2011) Circadian rhythms, sleep, and metabolism. J Clin Invest 121:2133–2141Hubner NC, Bird AW, Cox J, Splettstoesser B, Bandilla P, Poser I, Hyman A, Mann M (2010) Quantitative proteomics combined with BAC TransgeneOmics reveals in vivo protein interactions. J Cell Biol 189:739–754

Proteomic Approaches in Circadian Biology 405Hughes ME, DiTacchio L, Hayes KR, Vollmers C, Pulivarthy S, Baggs JE, Panda S, Hogenesch JB (2009) Harmonics of circadian gene transcription in mammals. PLoS Genet 5:e1000442Johnson CH, Mori T, Xu Y (2008) A cyanobacterial circadian clockwork. Curr Biol 18: R816–R825Kaji H, Kamiie J, Kawakami H, Kido K, Yamauchi Y, Shinkawa T, Taoka M, Takahashi N, Isobe T (2007) Proteomics reveals N-linked glycoprotein diversity in Caenorhabditis elegans and suggests an atypical translocation mechanism for integral membrane proteins. Mol Cell Proteomics 6:2100–2109Kamphuis W, Cailotto C, Dijk F, Bergen A, Buijs RM (2005) Circadian expression of clock genes and clock-controlled genes in the rat retina. Biochem Biophys Res Commun 330:18–26Kim SC, Sprung R, Chen Y, Xu Y, Ball H, Pei J, Cheng T, Kho Y, Xiao H, Xiao L, Grishin NV, White M, Yang XJ, Zhao Y (2006) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 23:607–618Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP (2011) Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell 44(2):325–340Kivimae S, Saez L, Young MW (2008) Activating PER repressor through a DBT-directed phosphorylation switch. PLoS Biol 6:e183Ko CH, Takahashi JS (2006) Molecular components of the mammalian circadian clock. Hum Mol Genet 15(Spec No 2):R271–R277Kruger M, Moser M, Ussar S, Thievessen I, Luber CA, Forner F, Schmidt S, Zanivan S, Fassler R, Mann M (2008) SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function. Cell 134:353–364Lee J, Lee Y, Lee MJ, Park E, Kang SH, Chung CH, Lee KH, Kim K (2008) Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol Cell Biol 28:6056–6065Lee JE, Atkins N Jr, Hatcher NG, Zamdborg L, Gillette MU, Sweedler JV, Kelleher NL (2010) Endogenous peptide discovery of the rat circadian clock: a focused study of the suprachiasmatic nucleus by ultrahigh performance tandem mass spectrometry. Mol Cell Proteomics 9:285–297Lee HM, Chen R, Kim H, Etchegaray JP, Weaver DR, Lee C (2011) The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phos- phatase 1. Proc Natl Acad Sci USA 108:16451–16456Mallick P, Kuster B (2010) Proteomics: a pragmatic perspective. Nat Biotechnol 28:695–709Martino TA, Tata N, Bjarnason GA, Straume M, Sole MJ (2007) Diurnal protein expression in blood revealed by high throughput mass spectrometry proteomics and implications for transla- tional medicine and body time of day. Am J Physiol Regul Integr Comp Physiol 293: R1430–R1437McCarthy JJ, Andrews JL, McDearmon EL, Campbell KS, Barber BK, Miller BH, Walker JR, Hogenesch JB, Takahashi JS, Esser KA (2007) Identification of the circadian transcriptome in adult mouse skeletal muscle. Physiol Genomics 31:86–95Mehra A, Baker CL, Loros JJ, Dunlap JC (2009) Post-translational modifications in circadian rhythms. Trends Biochem Sci 34:483–490Minami Y, Kasukawa T, Kakazu Y, Iigo M, Sugimoto M, Ikeda S, Yasui A, van der Horst GT, Soga T, Ueda HR (2009) Measurement of internal body time by blood metabolomics. Proc Natl Acad Sci USA 106:9890–9895Moller M, Sparre T, Bache N, Roepstorff P, Vorum H (2007) Proteomic analysis of day-night variations in protein levels in the rat pineal gland. Proteomics 7:2009–2018Monetti M, Nagaraj N, Sharma K, Mann M (2011) Large-scale phosphosite quantification in tissues by a spike-in SILAC method. Nat Methods 8:655–658Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P (2008) The NAD+Àdependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329–340

406 M.S. Robles and M. MannOlsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127:635–648Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M (2010) Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal 3:ra3Ong SE, Mann M (2006) A practical recipe for stable isotope labeling by amino acids in cell culture (SILAC). Nat Protoc 1:2650–2660Ong SE, Blagoev B, Kratchmarova I, Kristensen DB, Steen H, Pandey A, Mann M (2002) Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol Cell Proteomics 1:376–386Ong SE, Mittler G, Mann M (2004) Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nat Methods 1:119–126Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB (2002) Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109:307–320Patel VR, Eckel-Mahan K, Sassone-Corsi P, Baldi P (2012) CircadiOmics: integrating circadian genomics, transcriptomics, proteomics and metabolomics. Nat Methods 9:772–773Porterfield VM, Piontkivska H, Mintz EM (2007) Identification of novel light-induced genes in the suprachiasmatic nucleus. BMC Neurosci 8:98Reddy AB (2013) Genome-wide analyses of circadian systems. In: Kramer A, Merrow M (eds) Circadian clocks, vol 217, Handbook of experimental pharmacology. Springer, HeidelbergReddy AB, Karp NA, Maywood ES, Sage EA, Deery M, O’Neill JS, Wong GK, Chesham J, Odell M, Lilley KS, Kyriacou CP, Hastings MH (2006) Circadian orchestration of the hepatic proteome. Curr Biol 16:1107–1115Reischl S, Kramer A (2011) Kinases and phosphatases in the mammalian circadian clock. FEBS Lett 585:1393–1399Robles MS, Boyault C, Knutti D, Padmanabhan K, Weitz CJ (2010) Identification of RACK1 and protein kinase Calpha as integral components of the mammalian circadian clock. Science 327:463–466Sahar S, Zocchi L, Kinoshita C, Borrelli E, Sassone-Corsi P (2010) Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation. PLoS One 5:e8561Sardiu ME, Washburn MP (2011) Building protein-protein interaction networks with proteomics and informatics tools. J Biol Chem 286:23645–23651Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, Chen W, Selbach M (2011) Global quantification of mammalian gene expression control. Nature 473:337–342Sewlall S, Pillay V, Danckwerts MP, Choonara YE, Ndesendo VM, du Toit LC (2010) A timely review of state-of-the-art chronopharmaceuticals synchronized with biological rhythms. Curr Drug Deliv 7:370–388Storch KF, Lipan O, Leykin I, Viswanathan N, Davis FC, Wong WH, Weitz CJ (2002) Extensive and divergent circadian gene expression in liver and heart. Nature 417:78–83Storch KF, Paz C, Signorovitch J, Raviola E, Pawlyk B, Li T, Weitz CJ (2007) Intrinsic circadian clock of the mammalian retina: importance for retinal processing of visual information. Cell 130:730–741Stratmann M, Schibler U (2006) Properties, entrainment, and physiological functions of mamma- lian peripheral oscillators. J Biol Rhythms 21:494–506Takahashi JS, Hong HK, Ko CH, McDearmon EL (2008) The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet 9:764–775Tatham MH, Matic I, Mann M, Hay RT (2011) Comparative proteomic analysis identifies a role for SUMO in protein quality control. Sci Signal 4:rs4ten Have S, Boulon S, Ahmad Y, Lamond AI (2011) Mass spectrometry-based immuno- precipitation proteomics - the user’s guide. Proteomics 11:1153–1159

Proteomic Approaches in Circadian Biology 407Tian R, Alvarez-Saavedra M, Cheng HY, Figeys D (2011) Uncovering the proteome response of the master circadian clock to light using an AutoProteome system. Mol Cell Proteomics 10 (M110):007252Tosini G, Menaker M (1996) Circadian rhythms in cultured mammalian retina. Science 272:419–421Tsuji T, Hirota T, Takemori N, Komori N, Yoshitane H, Fukuda M, Matsumoto H, Fukada Y (2007) Circadian proteomics of the mouse retina. Proteomics 7:3500–3508Ueda HR, Chen W, Adachi A, Wakamatsu H, Hayashi S, Takasugi T, Nagano M, Nakahama K, Suzuki Y, Sugano S, Iino M, Shigeyoshi Y, Hashimoto S (2002) A transcription factor response element for gene expression during circadian night. Nature 418:534–539Vanselow K, Kramer A (2007) Role of phosphorylation in the mammalian circadian clock. Cold Spring Harb Symp Quant Biol 72:167–176Vanselow K, Vanselow JT, Westermark PO, Reischl S, Maier B, Korte T, Herrmann A, Herzel H, Schlosser A, Kramer A (2006) Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev 20:2660–2672Vermeulen M, Hubner NC, Mann M (2008) High confidence determination of specific protein- protein interactions using quantitative mass spectrometry. Curr Opin Biotechnol 19:331–337Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C (2011) A proteome- wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol Cell Proteomics 10(M111):013284Walther DM, Mann M (2011) Accurate quantification of more than 4000 mouse tissue proteins reveals minimal proteome changes during aging. Mol Cell Proteomics 10(M110):004523Weaver DR (1998) The suprachiasmatic nucleus: a 25-year retrospective. J Biol Rhythms 13:100–112Wepf A, Glatter T, Schmidt A, Aebersold R, Gstaiger M (2009) Quantitative interaction proteo- mics using mass spectrometry. Nat Methods 6:203–205Yates JR 3rd, Gilchrist A, Howell KE, Bergeron JJ (2005) Proteomics of organelles and large cellular structures. Nat Rev Mol Cell Biol 6:702–714Zielinska DF, Gnad F, Wisniewski JR, Mann M (2010) Precision mapping of an in vivo N-glycoproteome reveals rigid topological and sequence constraints. Cell 141:897–907

IndexA BAccelerated aging, 253 Basic helix-loop-helix transcription factors,Acetylcholine, 209Actimetry, 278 167Adenosine, 160 Behavioral rhythms, 367, 369, 372Adenosine-5’-triphosphate (ATP), 74, 80, 85 Behavioural testing, 176Adipokines, 207–211 Biological clock, 188, 198, 201, 203, 206, 207,Adiponectin, 210Adipose tissue, 203, 204, 207–211 210, 212Adrenal cortex, 190, 191 Biomarker, 262, 274, 277, 279–281Adrenocorticotrophic hormone, 190–192 Bmal1. See Brain and muscle Arnt-like protein-1Afterhours, 372Ageing, 211, 212 (Bmal1)AhrR. See Aryl hydrocarbon receptor (AhrR) Body temperature, 4, 11, 12, 14, 15, 17, 18,Alcohol, 229, 230Amino acids, 233 273, 279AMP kinase, 53, 245 Brain and muscle Arnt-like protein-1 (Bmal1),Angiotensin II, 13, 113, 117Anterior pituitary, 190 5–9, 11, 12, 14, 15, 360, 363–367,Anteroventral periventricular nucleus (AVPV), 369, 373 Brainstem, 209 199, 200 Brattleboro rats, 194Apoptosis, 292, 297, 302ARC. See Arcuate nucleus (ARC) CArcuate nucleus (ARC), 188, 189, 199, 207 Caffeine, 115, 116, 160, 326Arginine vasopressin (AVP) Cancer, 30, 34–40, 261–281 and GRP, 49 chronotherapeutics, 261–281 signaling, 89, 95 risk, 266 V1aR, 110–111 survival, 267Aryl hydrocarbon receptor (AhrR), 245, 249 Cardiotrophin-like cytokine (CLC), 113, 188Astrocytes, 114–116 Casein kinases, 7ATP. See Adenosine-5’-triphosphate (ATP) CBT. See Core body temperature (CBT)ATP/purinergic receptors, 115–116 CCEs. See Clock-controlled elements (CCEs)Autonomic nervous system, 191, 192, 203, Cell-autonomous circadian physiology adrenal aldosterone production, 57 204, 206–209 cardiac and adrenal tissues, 57AVP. See Arginine vasopressin (AVP) genome-wide technologies—ChIPseq, 55AVPV. See Anteroventral periventricular kidney-intrinsic circadian oscillators and nucleus (AVPV) retinal clock, 56 PAR-B-ZIP transcription factors, 56, 57 REV-ERBα/β, 55–56A. Kramer and M. Merrow (eds.), Circadian Clocks, Handbook of Experimental 409Pharmacology 217, DOI 10.1007/978-3-642-25950-0,# Springer-Verlag Berlin Heidelberg 2013

410 IndexCell-autonomous circadian physiology (cont.) Circadian physiology rhythmic transcriptional control, 55 cell-autonomous, 55–57 skeletal muscle and adipocyte tissues, 57 direct endocrine control, 57–58 indirect control, 58Cell cycle, 263–265, 275, 276, 281 noncanonical clocks, 59Cerebral spinal fluid, 188, 189c-Fos, 200 Circadian signaling, drugs and effectsChIP. See Chromatin immunoprecipitation abundance/activity, receptors, 117 angiotensin II receptor antagonists, 117 (ChIP) caffeine, 116ChIP-chip, 381–383 neuropeptidergic receptors/signalingChIP-seq, 381–383 pathways, 116Chromatin immunoprecipitation (ChIP) neuropeptides, SCN, 116 pharmacology, 117 chip and seq, 381–383 phase shifting, clock, 116 circadian cycle, 381 cross-link, 381 Circadian transcriptomics description, 380–381 description, 382 and PCR and qPCR, 381 Drosophila, 382 transcription factors, 381 microarray analysis, gene expression,Chromatin remodeling, 31, 35 384, 385Chronobiotics, 281 Period and Cryptochrome gene families,Chronoefficacy, 263, 266–272, 280 382ChronoFLO, 270–272 RNA-seq, 384Chronomodulated therapy, 291, 292 tissue transcriptomes, 382, 384Chronopharmacodynamics, 276–277Chronopharmacokinetics, 276–277 Cistrome, 8Chronopharmacology, 70–72 CLC. See Cardiotrophin-like cytokine (CLC)Chronotherapy, 37–38, 261–281 Clock, 3–19Chronotolerance, 263, 264, 266–272, 277, 280Chronotype, 273 Bmal1, 134, 136, 139–141 CBT and sleep duration, 321 controlled genes, 163, 168, 169 children and genetic influence, 322 gene-knockout mice, 367 internal phase relationships, 320–321 genes, 4, 5, 10–13, 15, 162–170, 174, 176, MCTQ, 320, 321 MEQ, 320–322 262, 264–267, 275, 276, 360, 361, 363, MSF, 320 367, 369, 370, 372 rodents, 322 Clock-controlled elements (CCEs), 360–364, typical adolescent behaviour and genetic 367–371, 373 Clock-mutant mouse, 162, 164, 167, 174 predisposition, 322 Constant vs. entrained conditions, humanCiRC. See Circadian integrative response circadian clock basic free-running period (τ), 318 characteristic (CiRC) endogenous mechanism and free-runningCircadian, 3–19 rhythms, 318 mice and Drosophila, 319 biomarkers, 274, 279, 280 Neurospora crassa and CiRC, 319 clock/oscillator, 162, 167, 170 PRCs, 318–319 disruption, 262, 278, 280 Core body temperature (CBT), 321 misalignment, 228 Corticosterone, 190–193, 195, 196, 198 process, 158, 160, 161, 169, 175 Corticotrophin-releasing hormone, 189–192 rhythms, 262, 273, 276–279 Cortisol, 262, 273, 279–281 synchrony, 88, 90 Critical illness, 202, 203 timing system, 262, 263, 273, 274, 278–281 Cry. See Cryptochrome (Cry)Circadian integrative response characteristic Cry1, 245, 252 (CiRC), 319

Index 411Cryptochrome (Cry), 6–9, 12, 15, 16 EntrainmentCytochrome P450, 248 characteristic, oscillators, 49–50Cytokines, 56, 58, 107, 113, 188, 209, 211, 263 chronotype, 320–322 constant vs. entrained conditions, 318–319D direct nervous stimuli, 50–51Daylight savings time (DST), 323, 324, 327 intrinsic period, 316–317D-box-binding protein (DBP), 248, 249 peptides and hormones, 51–52DBP. See D-box-binding protein (DBP) SCN, 54–55DDEs. See Delay differential equations (DDEs) signals, SCN to peripheral oscillators, 50Deiodinase, 201 single cells, 340–344Delay, 359–373 social jetlag, 325–326Delay differential equations (DDEs), 337–339, social zeitgebers, 317–318 temperature and feeding, 53–54 347, 349–352 zeitgeber, 322–325Denervation, 191, 203, 204, 209Deoxyribonucleic acid (DNA) ENU-mutant, 372 Environmental enrichment/novelty, 173 “chip”, 381 Epigenetics, 29–40 damage, 291–297, 301, 303 Excitatory amino acids (EAAs), 116 repair, 291, 292, 294–296 Exercise, 212Depression, 202 Experimental models, 275, 280Detoxification, 263, 277dGAL4, 370 FdGAL4-VP16, 370 Familial advanced sleep-phase syndromeDichotomy index, 278Direct, 128–133, 139–142 (FASPS), 4, 371, 372Direct nervous stimuli FASPS. See Familial advanced sleep-phase autonomous nervous system, 51 GABAergic input and clock gene syndrome (FASPS) F-box and leucine-rich repeat protein 3 expression, 51 parasympathetic nervous system and phase- (FBXL3), 7 FBXL3. See F-box and leucine-rich repeat shift cellular clocks, 51 sleep and arousal regulations, 51 protein 3 (FBXL3) SPVZ, 50–51 FibroblastDiurnal, 189, 191, 192, 201–203DNA. See Deoxyribonucleic acid (DNA) cultured mammalian skin, 46, 48DNA-intercalating agents, 269 RAT1, 52Dopamine receptor, 231 FOLFOX2, 270, 272Dorsomedial hypothalamus, 189–192, 198, Food anticipatory activity, 246 Forced desynchrony, 160 200, 205 Free fatty acids, 208, 209Drugs, 234, 235 Free-running periodDST. See Daylight savings time (DST) central quality/dogma, circadian system,E 316EEG. See Electroencephalogram (EEG) entrainment models, 318Efficacy, 262, 263, 266, 268, 270, 272, 273, intrinsic, 316 temperature compensation, 313 276–278, 280, 281Efficacy of chronotherapeutic treatment, 344 GElectroencephalogram (EEG) GABA. See Gamma-aminobutyric acid delta power, 164–169 (GABA) slow wave activity (SWA), 159, 160, 163, Gamma-aminobutyric acid (GABA), 90, 166, 169, 173 112–113, 191, 192, 194, 195, 197, 198, theta activity/power, 160, 169 204–208 Gastric pH, 246, 247

412 IndexGastrin releasing peptide (GRP) Hepatic leukemia factor (HLF), 246, 248, 249 and AVP, 49 High-throughput screening, 297–303 signaling, 90 Histone acetylation, 31–33, 35 Histone acetyltransferase (HAT), 7, 32,Gender differences, 270, 274Genetic complementation assay, 365 245, 252Genome-wide analysis Histone deacetylase (HDAC), 32, 33, 35 Histone demethylase, 35 bacteria to mammals, 380 Histone methylation, 31, 32 cells and tissues, 380 HLF. See Hepatic leukemia factor (HLF) ChIP-chip and ChIP-seq, 381–383 Homeostatic ChIPing away at chromatin, 380–381 circadian transcriptomics, 382–384 process, 158, 159, 170 clock-relevant transcription factors, 380 Hopf bifurcation, 339, 349–350 cyanobacterium, 380 Hormones DNA and RNA, 379 24-h timescale, 379 agomelatine, 234 interferomics and manipulating, 384–386 ghrelin, 233 transcription, 386 leptin, 233Genotoxic stress, 291–297, 302 melatonin, 228GFAP. See Glial fibrillary acidic protein HPA. See Hypothalamic-pituitary-axis (HPA) Human circadian clock (GFAP) biological clocks and circa-24-h rhythmicity,Glia, circadian system 313 astrocytes communication, 114 chronobiology, 312 ebony, 114 description, 312 GFAP and SCN, 113–114 entrainment (see Entrainment) glia-to-neuron signaling, 116 programme, 312 in vivo and in vitro, 113 sleep per se and bedroom behaviour, 327 mammals, 114 temperature compensation and single-cell neuron-to-glia signaling, 114–116 protein and mRNA levels, 114 organisms, 313Glial fibrillary acidic protein (GFAP), 113, 114 ‘unforced’ sleep timing and DST, 327Glia-to-neuron signaling, 116 velocity and mechanism, 313Gliotransmission, 114 zeitgeber, 313–314Glucocorticoid receptor (GR), 52, 252 zeitnehmer, 314–315Glucose, 203–210, 212 Hypertension, 211, 212Glutamate, 73, 188, 195–198, 204–206 Hypothalamic-pituitary-axis (HPA), 142Glutathione-S-transferase (GST), 248 Hypothalamic–pituitary–gonadal, 198, 200Gonadotropin inhibitory hormone, 200 Hypothalamo–pituitary–thyroid, 201, 202Gonadotropin-releasing hormone, 189–200GPCR. See G-protein coupled receptor I Image forming (IF) responses, 170 (GPCR) In silico, 281G-protein coupled receptor (GPCR), 90, 252 Insulin, 188, 204, 206, 208–210GR. See Glucocorticoid receptor (GR) Intercellular coupling, 340, 341GRP. See Gastrin releasing peptide (GRP) InterferomicsGRP/BBR2, 109–110GST. See Glutathione-S-transferase (GST) canonical kinase pathways, 384, 386 clock gene, 384H description, 384HAI. See Hepatic arterial infusion (HAI) pre-eminent assay system, 384HAT. See Histone acetyltransferase (HAT) RNAi, 384HDAC. See Histone deacetylase (HDAC) siRNAs, 384Heme, 235 transcription–translation feedback loop,Hepatic arterial infusion (HAI), 270, 272 386 Intersubject differences, 272

Index 413Intrinsic period, human circadian clock receptors, 172 damped clock and sleep, 316 sleep promoting action/effect, 172 internal day and steady-state τ, 317 Mental health disorders, 174 intrinsic free-running period, 317 MEQ. See Morningness–eveningness self-created LD cycle and light exposure, 316 questionnaire (MEQ) sleep–wake cycle, 316–317 Metabolic syndrome, 29–30, 39, 233 zeitnehmer loops and oscillators, 316 Metabolomics, 386, 400 Microdialysis, 191, 195, 196, 198, 199, 209In vitro, 274, 281 Mid-phase of sleep on free days (MSF), 320In vivo, 274, 281 Modeling chronotherapy, 344–345 Molecular models, 3–19, 275, 276K Monoamine oxidase A (MAO-A), 250Kinases Mood disorders casein kinases, 228, 234 bipolar disorder, 229, 231 ERK2, 234 depression, 228, 229, 231, 234 GSK3beta, 234 schizophrenia, 229Kisspeptin, 199, 200 seasonal affective disorder (SAD), 228,L 229, 231Leptin, 188, 209, 210 Morningness–eveningness questionnaireLight as zeitgeber, human circadian clock (MEQ), 320–322 chronotype and geographical locations, MSF. See Mid-phase of sleep on free days 322, 323 (MSF) dependencies varying, season, 323, 325 Munich chronotype questionnaire (MCTQ), MCTQ, 323 people spend outdoors, 323, 324 273, 320, 321 seasonal changes in phase, entrainment, Mutagenesis, 166 323, 324 NLight/dark, 127, 129, 137, 138, 143 NAD+, 33, 34Light therapy, 234 NAMPT. See NicotinamideLimit cycle oscillator, 339–342, 352, 353Linear chain trick, 351 phosphoribosyltransferase (NAMPT)Lipid absorption, 247 Negative feedback, 336–340, 346–350, 361,Lipolysis, 208, 209Lithium, 229, 231, 234 365, 367, 371, 372Little SAAS, 111–112 Negative feedback loop, 360, 364–367,M 369, 373Mammals, peripheral clocks. See Peripheral Neuroendocrine neurons, 188–190, 192 Neuromedin U, 191 clocks Neuronal activity, 195, 209MAO-A. See Monoamine oxidase A (MAO-A) Neuronal PAS domain protein 2 (NPAS2), 12Mass spectrometry, 390, 392, 400, 402 Neuron–neuron signaling in SCNMathematical modeling, 274–278, 281MCTQ. See Munich chronotype questionnaire AVP/V1aR, 110–111 CLC, 113 (MCTQ) cognate receptors, 107–108Medial preoptic area, 189, 198–200 GABA, 112–113Melanin-concentrating hormone, 205 GRP/BBR2, 109–110Melatonin, 188, 192–198, 202, 204, 205, intercellular communication, 107 little SAAS, 111–112 210–212, 273, 279, 281 VIP/VPAC2R, 108–109 agonists, 172 Neurons, SCN alarm clock/master circadian pacemaker, 105 central timer in vivo and in vitro, 105–106 circadian system, 106

414 IndexNeurons (cont.) Paraventricular nucleus (PVN) competent circadian pacemakers, 106 circadian glucose production in liver, 51 dorsal shell and ventral core, 107 hypothalamus, 188–198, 201, 202, intracellular molecular events, 106 204, 206 multi-oscillator system, 107 neuron signaling (see Neuron–neuron PAR-B-ZIP. See Proline and acidic amino acid- signaling in SCN) rich basic leucine zipper (PAR-B-ZIP) population, heterogeneous, 107 Partial differential equations (PDEs), 276Neuron-to-glia signaling PCR. See Polymerase chain reaction (PCR) ATP/purinergic receptors, 115–116 PDEs. See Partial differential equations (PDEs) cFOS expression, 114–115 Peptides and hormones in vivo, circadian rhythms in ATP, 114 mouse motor cortex, 114 control, diurnal behavior, 51 VIP/VPAC2R, 115 daily fashion and glucocorticoid receptorNeuro psychiatric disorders, 174 (GR), 52Neurotransmitters, 250 diffusible factors, SCN, 52 myriad, signals controls circadian phase, 52 dopamine, 230 phase-shifting peripheral circadian clocks glutamate, 233Nicotinamide phosphoribosyltransferase and multiple signaling agents, 52 pituitary–adrenocortical axis and signaling (NAMPT), 245Nocturnal, 190–192, 194, 195, 197, 198, pathways, 52 Per, 5–9, 13, 14, 16 201–203 Per1, 198, 361–363, 367, 372Noise-driven oscillations, 340–342, 352 Perifornical area, 205, 207Non-image forming (NIF) responses, 170, 171 Peripheral clocksNon-transcriptional rhythms, 9–10NPAS2. See Neuronal PAS domain protein Bmal1 gene, 47 circadian physiology (see Circadian 2 (NPAS2)NPAS2/Bmal1, 140 physiology)Nuclear receptors, 233, 235 CLOCK and BMAL1 proteins, 47 direct and indirect signals, 59O DNA “reporters” and fruit flies, 46Obesity, 208, 210, 211, 233, 235 entrainment, 49–55ODEs. See Ordinary differential equations genes and proteins, 47–48 “master clock” pacemaker neurons, 46 (ODEs) mechanism, circadian clocks, 46Oestrogen receptors, 198–200 network synchrony, 48–49Opponent process model, 161 nuclear-receptor-mediated physiology, 60OPTILIV, 272 nuclear receptor ROR and REV-ERBOptimal phase of chronotherapeutic treatment, proteins, 47 345 Rev-Erba gene, 47Optimization, 266, 274, 275, 277–278 SCN (see Suprachiasmatic nucleus (SCN))Ordinary differential equations (ODEs), 276 Personalized chronotherapy schedules, 281Orexin, 205–207 Perturbation, 363–364Overexpression, 364 p-Glycoprotein, 246Overtime, 372 PGRC. See Photosensitive retinal ganglionOxaliplatin, 268–273, 276Oxidative stress, 252 cells (PGRC) Phase, 363, 367, 370, 371P Phase II metabolism, 248Pancreas, 203, 206, 207 Phase response curves (PRCs), 318–319Paralog compensation, 7 Phase vector model, 365, 367Parasympathetic, 201, 203, 204, 206, 208, 209 Photoentrainment, 170 Photoreceptors cones, 170, 171 melanopsin, 170, 171 rods, 170, 171

Index 415Photosensitive retinal ganglion cells (PGRC), Rev-Erb genes, 9 170 Reward systemPineal gland, 192–198, 201, 203 amygdala (AMY), 229, 230PK2. See Prokineticin 2 (PK2) nucleus accumbens (NAc), 229, 230Plasma proteins, 247 prefrontal cortex (PFC), 229, 230Poly-ADP polymerase, 245 striatum, 231Polymerase chain reaction (PCR), 381 ventral tegmental area (VTA), 229, 230, 233Post-translational circadian oscillator, 373 RF-amide-related peptide, 200Post-translational control, 372, 373 Rhythms, 128–135, 137–145Post-translational regulation, 360, 371–373 RNAi. See RNA interference (RNAi)PPAR-α. See Proliferator-activated receptor RNA interference (RNAi), 384 RNA-seq, 384 alpha (PPAR-α)PPAR-γ, 251 SPRCs. See Phase response curves (PRCs) SCN. See Suprachiasmatic nucleus (SCN)Pre-autonomic neurons, 188, 189, 194, 197, SD. See Sleep deprivation (SD) Selective serotonin reuptake inhibitors 198, 201, 203–208Prognostic, 273, 278, 280 (SSRIs), 251Programmable pumps, 266 Selenium, 301, 302Prokineticin 2 (PK2), 52, 188 Senescence, 292, 296–297Proliferator-activated receptor alpha Serotonin, 250, 251 Single cell modeling, 340, 341, 352 (PPAR-α), 251 Single nucleotide polymorphisms (SNPs),Proline and acidic amino acid-rich basic 229, 231 leucine zipper (PAR-B-ZIP), 56–57, siRNAs. See Small interfering RNAs (siRNAs) 248, 251 SIRT1, 32–34, 245Propranolol, 247 Skin surface temperature, 279Proteomics Sleep, 187, 193, 196, 201–206, 211 cells and tissues, 380 datasets, 386 active neurons, 159 expression, 390–396, 401, 402 deprivation, 158–161, 163, 164, 166–169, interaction, 390–399, 401 and metabolomics, 386 173 quantitative, 390, 391, 393, 395–397, homeostasis, 158–163, 166–170, 172, 400–402Purinergic receptor, 115–116 174–176PVN. See Paraventricular nucleus (PVN) regulation, 158–176 spindles, 167Q wake, 128, 131, 133, 137qPCR. See Quantitatively using real-time PCR Sleep deprivation (SD), 234 Small interfering RNAs (siRNAs), 384 (qPCR) SNPs. See Single nucleotide polymorphismsQuantitatively using real-time PCR (qPCR), (SNPs) 381 Social cues/interactions/conflict, 173–174 Social jetlagRRamelteon, 172 alarm clocks and chronic phenomenon, 325Repressilator, 366, 369 description, 325Resistin, 211 discrepancy internal and external time, 325Rest–activity, 262, 273, 278–280 internal and external timing, 325–326Reticular thalamic nucleus, 172 MSW and MSF, 325, 326Retina, 4, 11, 13 shorter habitual sleep and MCTQ database, 325 symptoms and travel-induced, 325

416 IndexSocial zeitgebers T Andechs bunker experiments, 318 Tau mutation, 7, 12, 371 blindness types and circadian rhythms, 317 TEF, 248 non-photic signals, 317–318 Temperature and feedingSpinal cord, 193, 205, 207 AMPK and circadian clock function, 53Splitting, 191, 200 cells and living mammals, 53SPVZ. See Subparaventricular zone (SPVZ) CLOCK and BMAL1, 53SSRIs. See Selective serotonin reuptake dependent hormones and cryptochrome inhibitors (SSRIs) clock proteins, 53Subparaventricular PVN (subPVN), 189, 191, ghrelin, 53–54 glucocorticoids and homeotherms, 53 192, 198 patterns and NAD+, 53Subparaventricular zone (SPVZ), 50 Temporal expression, 361subPVN. See Subparaventricular PVN Tetrodotoxin, 195 TGFα. See Transforming growth factor alpha (subPVN)Superior cervical ganglion, 193, 195 (TGFα)Suprachiasmatic nucleus (SCN), 5, 8, Therapeutic index, 344 Thyroid gland, 201, 202 10–18, 72–79, 83, 87–96, 188–201, Thyroid hormones, 201–203 203–212 Thyrotrophin-releasing hormone (TRH), 189, astrocyte release, 116 cells vs. intact slices, 49 201–203 clock protein and fibroblasts, 47 Time delay, 360, 367 controlled behavior, 46–47 Time-restricted feeding, 197 diffusible factors, 52 Toxicity, 263, 264, 269, 270, 272, 273, direct cascades leading, 53 driven timing signals, 49–50 275–278 electrical activity, 161, 169 Tracing, 189–191, 194, 200, 201, 203, 205, 209 and GFAP, 113–114 Transcriptional feedback loops, 162, 168–170, hypothalamus, 45 indirect and entrainment signals, 54 336, 339 intermittent oscillations, 48 Transcriptome analysis, 361 lesions, 159–162, 170 Transcriptomics, 390, 392, 394, 396, 401 light-dependent phase shifting, 54–55 Transforming growth factor alpha (TGFα), 52 nervous signals and hormone, 54 Translational feedback loops, 162, 168–170 neuron populations in vitro and lesioned Transneuronal virus tracing, 191, 201 animals, 49 Transplantation, 189, 191 neurons (see Neurons, SCN) TRH. See Thyrotrophin-releasing hormone peripheral and “master” clocks, 46 to peripheral oscillators, 50 (TRH) rhythmic gene expression and electrical Triglycerides, 207, 208 activity, 48 Two process model, 158 temperature resistance and network Type 2 diabetes, 211 properties render, 54 timing signals to multiple tissues and V PVN controls, 51 Vasoactive intestinal polypeptide (VIP), 49, VIP/VPAC2R, 115Survival, 262, 266, 267, 270, 272–274, 169, 188, 189, 191, 194, 200 278, 280 neuron-neuron signaling in SCN, 108–109Sympathetic, 193, 197, 201, neuron-to-glia signaling, 115 203–209 signaling, 90, 91Synchronization of circadian oscillators, Vasopressin (VP), 188–191, 194, 198–200, 211 340–344 Ventrolateral preoptic area (VLPO), 159–161,Synthetic approach, 369 171 Ventromedial nucleus of the hypothalamus (VMH), 206–208

Index 417VIP. See Vasoactive intestinal polypeptide circadian clock and temperature, 314 (VIP) environmental factor and evolutionaryVisfatin, 211 oldest clocks, 313VLPO. See Ventrolateral preoptic area (VLPO) LD cycles, 313VMH. See Ventromedial nucleus of the light, 322–326 plants and animals, 326 hypothalamus (VMH) single-cell organism Lingulodinium,VP. See Vasopressin (VP) 313–314W social, 317–318Weakly damped oscillator, 340, 341, 343, 346, Zeitnehmer cellular clocks and entrainment process, 352, 353Whole-body modeling, 277 315 clock’s rhythm generation, 314Z dual role, circadian clocks, 314Zeitgeber feedbacks and central pacemaker, 314 PRC concept and temperature forming, 315 SCN’s entrainment mechanism, 314–315