Subject Index

A Ascending reticular activating system statistical properties, 407 (ARAS), 40 study results, 410 Aanat (arylalkylamine N-acetyltransferase Aschoff’s Rule, 2, 36, 334 Bipolar disorder. See Clock and bipolar mRNA), 148 ASD (advanced sleep disorders), 42–43, disorder AC (adenylyl cyclase), 88 98, 100 bizarre, 235 Acetabularia,59 Asperger syndrome, 645 Black-box experimental designs, 2 Acomys sp. (spiny mice), 616 ASPS (advanced sleep phase syndrome), Blind free-runners (BFRs), 626–628 ACTR, 107 274, 630 Blindness and biological , 42–43, 294, Adenosinergic system, 574 AtGenExpress, 353 583, 586, 623–624, 626–628 Adenylyl cyclase (AC), 88 AtGRP7, 147–148 Blue light photoreceptor, 63, 119–121. Adrenal gland and SCN, 553–554 ATPase activity of KaiC, 50–52 See also Structure and function Advanced sleep disorders (ASD), 42–43, Autism spectrum disorders (ASD) of animal cryptochromes 98, 100 atypical sleep and circadian rhythms, Blue light responses, 16–17, 119–121 Advanced sleep phase syndrome (ASPS), 649–650 BLUF, 123–124 274, 630 atypical synapses, 647–648 BMAL1 (brain and muscle ARNT-like Affymetrix ATH1 GeneChip data sets, 354 background, 645 ). See also Aftereffect, 2 circadian rhythms and, 648 CLOCK/BMAL1 After hours (Afh), 86–87 clock and, 648–649 acetylation by CLOCK, 108 Age and circadian clock in humans, 295 genetic causes of, 645–646 circadian rhythmicity and acetylation Aging and circadian rhythms. See Clock melatonin treatment in, 648–649, 650 of, 109–110 , aging, and pathways involved, 650–651 clock and cellular proliferation tumorigenesis; RNAi screen to study conclusions, 651–652 interactions, 468 identify longevity genes synaptic genes and, 646–647 FEO and (see Food-entrainable Aging and disease. See Sirtuins in aging AVP (arginine vasopressin), 26, 529, 530 oscillator) and disease in mammals, 12–14 Agomelatine, 638, 640 B in mice, 85–87, 254–258 ′ 5 -AMP as a mediator of procolipase negative feedback loop and, 414 expression, 288–289 Bacterial circadian programs role in premature aging, 478–479 Andante (And), 218 adaptive significance of circadian specificity of acetylation by CLOCK, Animal cryptochrome. See Structure and timing, 397–398 108–109 function of animal cell division vs. circadian oscillators, Bmal1 cryptochromes 397 impact of retina-specific deletion on Apis mellifera (honeybee), 615 circadian orchestration of global gene clock function, 312–315 Apnea, 590 expression, 396–397 retinal, and circadian rhythm Arabidopsis thaliana discovery of circadian clocks in responses, 315–316 AtGRP7, 147–148 bacteria, 395–396 retinal electrical activity in response to blue light photoreceptor research, mechanism and evolution/ecology light, 311–312 16–17, 119–121 study, 402–403 retinal gene expression rhythms and, CRY1 and CRY2 interactions, 125–126 structural biology of clock proteins, 310–311 cryptochrome photocycle, 127 398–399 Body temperature (Tb), 607. See also cryptochromes, 134–135 validity of TTFL model, 399–400 Hibernation F-box proteins in, 258 in vitro clockwork, 400 Bombyx mori (silkworm), 434 flowering pathway, 17 in vitro oscillator modeling, 400–402 Borbély-Daan model, 41–42 input, 16–17 band (bd), 204–205 Botany Array Resource, 353 microarray data analysis (see Basal forebrain (BF), 40 Brain and muscle ARNT-like protein. See DIURNAL project) Bats (Hipposideros speoris), 616 BMAL1 mRNA levels in, 15–16 Beavers (Castor canadensis), 615 Breast cancer, 462 oscillator, 15–16 Benzer, Seymour, 75 Bright-light therapy, 638 output, 17 BFRs (blind free-runners), 626–628 Bulla gouldiana,22 phosphorylation in, 197–198 Bioluminescence model Bünning, Erwin, 1 photoentrainment in, 194–195 background to studies, 405–406 Butterflies’ circadian clock. See Time- ARAS (ascending reticular activating balance of stability, coupling, and compensated sun compass system), 40 noise, 406 orientation Arctocephalinae,38 coculture experiment, 408–409 Butyrate response factor (BRF1), 163 Arcuate nucleus (Arc), 30–31 correspondence between phase and Arginase and Period 2 gene, 101 rate equation models, 409–410 C Arginine vasopressin (AVP), 26, 529, 530 envelope analysis, 408 Arginine vasopressin mRNA poly(A) interaction of phase oscillators, Caenorhabditis elegans length, 146 407–408 anti-aging genes in (see Sirtuins in ArrayExpress, 353 intercellular coupling, 406 aging and disease) Arrhythmicity, 29 mathematics of phase model, 406–407 longevity genes identification (see Arylalkylamine N-acetyltransferase observation of self-sustained RNAi screen to identify mRNA (Aanat), 148 oscillators, 406 longevity genes)

663 664 SUBJECT INDEX

Calbindin (CalB), 529, 532, 533 circadian-cancer connection and, cell cycle and, 459–460 Calcium/calmodulin-dependent protein 461–462 chromatin remodeling and, 461–462 kinase (CAMK), 14–17 enzymatic function of CLOCK, DNA-damage response and, 460–461 Calcium ions (Ca2+) and hibernation, 107–108 hormones and, 462 607–608, 611 histone acetyltransferase activity and, CIRCADIAN CLOCK ASSOCIATED 1 Calorie restriction (CR), 483. See also 105–106 (CCA1), 15–16 Sirtuins in aging and disease peripheral vs. central clocks, 106–107 Circadian clockwork of mice Calretinin, 529 plasticity in circadian regulation and, circadian organization and cAMP response element–binding (CREB) 107 synchronization, 91–93 protein, 24 specificity of BMAL1 acetylation by entrainment in Vipr2–/– mice, 89–90 Cancer biology and therapeutics CLOCK, 108–109 neuropeptide signaling and circadian chronotherapeutics and, 472–473 Chronic jet lag (CJL), 467–469 synchronization, 87–89 circadian gating of cell division, Chronobiology phase shifts of liver clockwork, 89–90 465–466 central molecular loops and, 656 Prok2 signaling and circadian output circadian rhythms and (see Circadian- circadian defined, 1 control by SCN, 90–91 cancer connection) circadian organization modeling, 658 proteasomal degradation and circadian clinical studies, 466–467 circadian rhythmicity in cyanobacteria, period, 85–87 clock and cellular proliferation 656 question of clock period setting, 86 interactions, 468–469 circadian rhythmicity in eukaryotes, transcriptional cascades related to clock proteins and (see Clock proteins, 656 protein expressions, 92 aging, and tumorigenesis) clock concept, 4 Circadian gene expression regulation in down-regulation of tumor growth by clocks distribution within multicellular the liver circadian timing system, 466 organisms, 657 background to studies, 319–320 model of timing system and tumor of cohabitation (see Chronobiology of feeding/fasting cycles as zeitgeber proliferation interactions, cohabitation) oscillators, 320–321 471–472 historical perspective, 655–656 signaling pathways, 324, 327–328 Period 2 gene and, 100 historical time line, 1–2 signals impacting synchronization of tumor growth rate experiments, 467 humans as experimental subjects, fibroblast oscillators, 321–322 tumorigenesis (see Clock proteins, 658–659 study conclusions and perspectives, aging, and tumorigenesis) increase in understanding of 328 CAR (constitutive androstane ), mechanisms, 655–656 systemically and oscillator-driven 390 interaction of sleep and circadian genes, 323–324, 325–326 Cardiovascular system and Period 2 gene, rhythms, 657–658 transgenic mouse model of system- 101 limitations to mice studies, 657 and oscillator-driven genes, Casein kinase (CK) 1 and 2 links between central and peripheral 322–323 in A. thaliana,16 clocks, 657 Circadian input kinase (CikA) protein, 8, biology of tau mutation and (see tau long time constant of circadian clock, 334–335 mutation in hamsters) 62 Circadian photoreception in vertebrates CK1 role in N. crassa clock (see mutations in humans, 658 background to research, 499 CK1a-dependent phase shifting and phase response, 3–4 contribution of the eyes to circadian phosphorylation of N. crassa) properties of a circadian rhythm, 3 entrainment, 501 in Drosophila clock model (see social costs of fatigue, 659 contribution of the eyes to free- Molecular clock in Symposium synopsis, 655–659 running period changes, Drosophila) temperature-compensation, 4 501–502 human circadian clock and (see terminology and methods, 2–3 evidence of extraretinal photoreceptors Genetics of human clocks) Chronobiology of cohabitation in sparrows, 500 phosphorylation in Drosophila and, cohousing and changes in τ values, eyes and LL-induced arrhythmicity, 168–174 616–618 502 temperature-compensation and, 65–67 focus of research, 618–619 lack of eye involvement in Casein kinase 2 (CK2), 70 studies distinguishing individual photoperiodic photoreception, Castor canadensis (beavers), 615 activity under social 502 Catastrophes theory, 445 conditions, 615–616 location of extraretinal photoreceptors Cavia porcellus (guinea pigs), 38 study conclusions, 619–620 in sparrows, 500–501 CCA1 (CIRCADIAN CLOCK temporal coupling between hamsters, mammalian photoentrainment, ASSOCIATED 1), 15–16 616 502–503 Ccgs. See Clock-controlled genes Chronogenetics rod pathways and control of temporal CDD (childhood disintegrative disorder), disconnected gene, 216–217 niche, 503, 505 645 genetic background related to clock rods and ipRGC interactions, 503, 504 Cellular redox state, prokaryotic systems, outputs, 221–225 study conclusions, 505–506 8–10 implications of genotypic variants of Circadian rhythms Cetaceans and sleep, 38 per, 225–229 aging and (see Clock proteins, aging, Chemotherapy and circadian clock, 413. inputs to Drosophila pacemaker, and tumorigenesis) See also Cancer biology and 219–221 ASD and, 648, 649–650 therapeutics isolation of abnormalities, 221–222 cancer biology and therapeutics and Chicks oscillator, 446 in mice, 216 (see Circadian-cancer Childhood disintegrative disorder (CDD), rhythm mutants in Drosophila, 215 connection) 645 sleep/wake cycles and, 221 characteristics in Neurospora clock, Chk2 (checkpoint kinase-2), 206 Chronopharmacology, 43 57–58 CHLAMY1, 149 Chronotypes, 41–42, 294–295 cohabitation and (see Chronobiology Chlamydomonas reinhardtii, 149 CHX10-Cre transgene, 312–315 of cohabitation) Cholinergic system, 574 CikA (circadian input kinase) protein, 8, evolution from 8-hour day, 421–422 Chromatin remodeling 334–335 genetics in humans (see Genetics of BMAL1 acetylation and circadian Circadian-cancer connection human clocks) rhythmicity, 109–110 background, 459 hibernation and, 611 SUBJECT INDEX 665

interaction of sleep and, 42–43, by, 107 interaction with PER2, 98 657–658 mammalian crytochromes and, 135–138 in mammals (see Structure and mood and, 637 oscillator loops, 348 function of mammalian Period 2 gene and, 99–100 quantitative model of mammalian cryptochromes) retinal responses to light and (see circadian clock, 414–415 in mice, 85–87, 254–258 Retinal responses to light and regulation of NR transcripts, 390–391 negative feedback loop and, 414 circadian rhythms) response to genotoxic stress, 477–478 origin of word, 119 Circadian systems of single cells role in bipolar disorder, 638–639 temperature cycles and the circadian alternative oscillators, 206–207 Clock Box, 59–61 clock, 233–235 ancillary oscillators effects, 209–210 Clock-controlled genes (ccgs), 203–205, Cryptochrome2 (CRY2) protein background to research, 201–202 346, 657 discovery, 114–116 clock-controlled gene, 203–205 Clock gene, 22. See also Clock and Cryptochrome gene in mammals, 12 clock in Neurospora, 202 bipolar disorder cwo (clockwork orange), 77–80 FRQ-less oscillators, 207–209 Clock neurons of Drosophila. See Cyanobacteria molecular basis of circadian oscillator, Drosophila clock neurons central oscillator (see Bacterial 202 Clock proteins, aging, and tumorigenesis circadian programs) molecular output effect on clock circadian rhythms and human disease, circadian rhythmicity in, 656 mechanisms, 206 477 clock system (see Prokaryotic molecular output feedback to input, CLOCK/BMAL1 response to circadian clock systems) 205–206 genotoxic stress, 477–478 Kai oscillator (see KaiC noncircadian oscillators, 202–203 premature aging after low-dose phosphorylation cycle) spectrum of clock-controlled genes radiation, 479–480 oscillators in (see Bioluminescence and growth conditions, premature aging in BMAL1-deficient model) 204–205 mice, 478–479 phase models of (see Bioluminescence study results, 210–211 study conclusions, 480–481 model) CJL (chronic jet lag), 467–469 clockwork orange (cwo), 77–80 S. elongatus model, 336–337 CK. See Casein kinase 1 and 2 CLP (procolipase), 287–290 temperature-compensation and, 396 CK1a-dependent phosphorylation of N. Cocaine, 639 TTFL model validity, 399–400 crassa Cohabitation and circadian rhythms. See Cyanothece. See Synechococcus elongatus biochemical properties of CK1a, Chronobiology of cohabitation Cycle (CYC), 10, 70. See also Molecular 178–179 Colipase, 287–288 clock in Drosophila constitutive active and dominant- Colorectal cancer, 472 negative casein kinase effects, Congenital scoliosis, 447–448 181 Conidial banding rhythms, 209–210 D interaction of CK1a with clock CONSTANS (CO), 17 proteins, 179–181 Constant darkness (DD), 2 D-box (DBP/E4BP4-binding element), 96 isoforms of CK1a, 177–178 hibernation and (see Hibernation and DBT. See Doubletime study results, 181–182 DD) dbt (doubletime), 70 CK1δ, 274–275, 275–276 rest/activity cycle in animals, 36 DD. See Constant darkness (DD) CK1ε mutation in mice. See tau mutation temperature entrainment in, 239–240 Deer mice (Peromyscus maniculatus), 615 in hamsters Constant light (LL), 2, 28 De-etiolated 1 (DET1), 16 CK2 (casein kinase 2), 10, 70 contribution of the eyes to free- Delayed sleep disorders (DSP), 42–43 Clock (CLK) protein running period changes in, Delayed sleep phase syndrome (DSPS), clock and cellular proliferation 501–502 274, 624, 630, 637 interactions, 468 eyes and LL-induced arrhythmicity, 502 DeltaC, 446 in Drosophila clock model (see rest/activity cycle in animals, 36 DeMairan, Jean-Jacques d’Ortous, 1 Drosophila circadian temperature entrainment in, 239–240 Desynchrony, 28 oscillator; Molecular clock in Constitutive androstane receptor (CAR), Developmental timing. See Oligodendro- Drosophila) 390 cyte precursor cells enzymatic function of, 107–108 Coordination theory of RNA operons and Dim light melatonin onset (DLMO), 623. FEO and (see Food-entrainable regulons. See PTRO theory See also Melatonin and the oscillator) COP1 (CONSTITUTIVELY PHOTO- circadian clock in mammals, 12–14 MORPHOGENIC 1), 16 disconnected (disco) gene, 216–217, 518. in mice, 85–87, 254–258 COSPOT and gene expression study, See also Clock neurons of mood disorders and (see Clock and 382–384 Drosophila bipolar disorder) Coupling signal, 2 DIURNAL project negative feedback loop and, 414 COUP-TFIII, 388–389 background, 353 specificity of BMAL1 acetylation by COX-1, 101 cis-regulatory elements identification CLOCK, 108–109 (see also CREB (cAMP response element–binding) with ELEMENT, 359–360 CLOCK/BMAL1) protein, 24 conclusions and future directions, Clock and bipolar disorder CRE-binding protein (CREB), 651 360–361 circadian gene expression outside of CRY/photolyase (FADH), 123–124 HAYSTACK, 356, 358–359 SCN, 640–642 Cryptochrome (CRY) protein interface design, features, and circadian rhythms and mood, 637 in animals (see Structure and function navigation, 354 CLOCK/BMAL1 complex role, of animal cryptochromes) use and attributes, 354–356, 357 638–640 in A. thaliana, 16–17, 125–127, DMH. See Dorsomedial hypothalamus clock-related treatments for mood 134–135 Dmpi8, 600–601 disorders, 637–638 BMAL1 acetylation and circadian DN (dorsal groups of clock neurons). See hippocampus and, 640 rhythmicity, 110 Clock neurons of Drosophila mood and the SCN and, 639–639 in butterflies, 114–117 (see also Time- DNA damage and cancer, 460–461 regulation of rhythms by SCN, 640 compensated sun compass Dopamine, 574 study conclusions, 642 orientation) Dopaminergic system in sleep and CLOCK/BMAL1 chronogenetics and, 219–220 arousal, 567–569 activation of clock-controlled genes in Drosophila clock model, 12, 245 Dorsal and medial raphé nuclei (DR), 40 666 SUBJECT INDEX

Dorsal groups of clock neurons (DN). See temperature and (see Temperature Eyes of vertebrates. See Blindness and Clock neurons of Drosophila cycles and clock biological clock; Circadian Dorsomedial hypothalamus (DMH), synchronization; Temperature photoreception in vertebrates 30–31, 530, 543, 544–545. See effects on clock function) also Food-entrainable Drowsy driving, 591 F oscillator Drug metabolism and circadian clock, 413 doubletime (dbt), 70, 218 DSP (delayed sleep disorders), 42–43 FAD, 15, 63, 122, 134 Doubletime (DBT) protein DSPS (delayed sleep phase syndrome), FADH (CRY/photolyase), 123–124 in Drosophila clock model, 10, 244, 274, 624, 630, 637 Familial advanced sleep phase syndrome 439 dusky (dy), 218 (FASPS), 170–174, 273, 274, Drosophila homolog (see CK1a-depen- 303, 637 dent phosphorylation of N. E Fast-delayed rectifier (FDR) potassium crassa) channel, 24 functional role in circadian system, 168 EARLY FLOWERING 4 (ELF4), 16–17 F-box proteins, 257–258 Doxycycline (Dox), 322–324 ebony (e), 222, 224 Fbx13, 87. See also Genetics of mouse DPER and phosphorylation, 168–170 Edinger Westphal nuclei, 513 clocks DR (dorsal and medial raphé nuclei), 40 EE (evening element), 15–16 FEO. See Food-entrainable oscillator Driving while drowsy, 591 EGFR pathway, 565 Fibroblast growth factor 21 (FGF-21), Drosophila circadian oscillator, 10–12 ELAV/Hu RBP family, 159, 161 324, 327 feedback loop oscillator function, ELEMENT, 353, 359–360 Fisher’s G-test and gene expression study, 437–438 ELF4 (EARLY FLOWERING 4), 16–17 382–384 key regulatory events governing Endocrine system and circadian-cancer Flavin adenine dinucleotide (FAD), 194 transcription, 438–439 connection, 462 Flip-flop model of sleep and wakefulness, PDP1 function within clock, 440–441 Enterostatin (VPDPR), 289–290 40–41 regulation of Clk spatial expression, Entrainment, 2 FLO (FRQ-less oscillator), 15–17, 442 aftereffects, 36–37 207–209, 346–347, 348–349 regulation of rhythmic transcription of circadian oscillators, 54 Fluoxetine, 638, 641 within Clk feedback loop, eating cycles and (see Food- Food-entrainable circuit, 29 439–440 entrainable oscillator) Food-entrainable oscillator (FEO) significance of rhythmic transcription, G. polyedra clock and, 293 afferent and efferent pathways, 438–439 of human clock (see Entrainment of 546–547 study conclusions, 442–443 human clock) background, 543 Drosophila clock neurons molecular explanations for, 62 DMH role in, 548 anatomical organization, 517–518 of Neurospora (see Entrainment of future directions, 548 DN role, 519 Neurospora crassa) interaction with SCN, 545–546 dual oscillator model, 520 phase angle, 36 molecular basis of function, 547 E cells, 524 Entrainment of human clock Period 2 gene and, 101 LN as master clocks, 518–519 background, 293–294 search for locus, 543–545 LPNs function, 519 chronotype, sex, and age, 295 FOXO proteins, 483, 559 M cells, 520–524 natural daylight as predominant Free-running period (FRP), 2 PDF role as internal synchronizer, 520 zeitgeber, 295–297 rest/activity cycle in animals, 36 Drosophila melanogaster phase of entrainment and chronotype, S. elongatus,10 activity rhythms and social interaction, 294–295 Frequency (frq) gene, 1, 58, 63 615 temporal environment and, 297 Frequency (FRQ) protein anti-aging genes in (see Sirtuins in Entrainment of Neurospora crassa clock feedback loops (see aging and disease) background, 279 Posttranslational control of chronogenetics of, 215, 219–221 circadian system properties, 280 Neurospora clock) circadian pacemaker (see feedback loops and oscillator network interaction with CK1a, 179–181 Transcriptional feedback and evidence, 282–283 mRNA splicing and, 602–603 circadian pacemaker) masking and, 283 in N. crassa, 14–15, 59–62 (see clock mutants and temperature at the molecular level, 280–282 Neurospora clock) entrainment, 235–236 study results and discussion, 283–284 temperature effects on Neurospora clock neurons (see Drosophila clock zeitgebers in the circadian system, 279 clock and, 64–67 neurons) Epidermal growth factor receptor (EGFR). transcriptional activator (see White clock workings (see Molecular clock See also Sleep control in collar complex) in Drosophila) Drosophila FRP (free-running period), 2 control of sleep (see Sleep control in ER-Per2 interaction, 462 FRQ/FRH complex (FFC), 14–17, 185. Drosophila) Estrous cycle, 462 See also Posttranslational genetic variants of circadian clocks Eukaryotic circadian clock systems control of Neurospora clock (see Chronogenetics) A. thaliana, 15–17 FRQ-interacting RNA helicase (FRH), input, 12 compartmentalization and 14–17, 61 intracellular clock mechanism, 114 translocation, 10–12 FRQ-less oscillator (FLO), 15–17, mRNA levels in, 77 mRNA levels in, 10 207–209, 346–347, 348–349 oscillator (see Drosophila circadian N. crassa, 14–15 Funambulus pennanti (palm squirrels), 615 oscillator) prokaryotic versus, 10 Fundulus heteroclitus (killifish), 615 output, 12 S. cerevisiae (see Yeast metabolic FWD-1 in Neurospora, 59–62 period mRNA, 148 cycle) PER/TIM/DBT interval timer in (see European Working Time Directive, 592 G PER/TIM/DBT interval timer) Evening cells (E), 520–524. See also phosphorylation in, 168–169, 197 Drosophila clock neurons G2 phase of cell division, 465 photoentrainment in, 193 Evening element (EE), 15–16 GABA (γ-amino-n-butyric acid), 26, 573, sleep/wake cycles analysis (see Evolution of circadian clock. See Period- 574 Sleep/wake cycle in doubling folds in cellular GABAergic system, 651 Drosophila) oscillator Gap 1 phase of cell division, 465 SUBJECT INDEX 667

GAPDH (glyceraldehyde-3-phosphate Hes7 oscillations. See Somite segmentation Immune system and Period 2 gene, dehydrogenase), 142, 204, 205 clock 100–101 Gastrin-releasing peptide (GRP), 26, 529, Hibernation Interpersonal and Social Rhythm Therapy, 530 circannual and circadian rhythms, 611 637 Gating of light responses, 205 circannual HP rhythm and life span, 611 Intracellular developmental timers. See GCMS (gas chromatographic–negative and constant darkness (see Oligodendrocyte precursor chemical ionization mass Hibernation and DD) cells spectrometric) assay, 623 essential role of circannually increased IpRGCs (intrinsically photosensitive Gender and chronotherapeutics, 472 brain HP20c, 610 retinal ganglion cells), 503, Genetics of human clocks hibernation complex and circannual 504. See also Melanopsin- advanced sleep phase syndrome, 274, rhythms, 608–609 containing retinal ganglion 630 increase in HP complex in CSF cells behavioral genetics and, 273 during, 610 circadian molecular clock model, 273 proposed role of HP complex, 610 J CK1δ and FASPS mutations, 274–275 sleep and, 612 CK1δ dosage experiments, 275–276 study conclusions, 612 Jak-Stat3-Socs3 negative feedback loop, effects of S662G mutation, 275 Hibernation and DD 454 FASPS, 273, 274, 303, 637 5′-AMP as a mediator of procolipase JETLAG (JET), 12 future directions and perspectives, 276 expression, 288–289 human chronotypes and, 276 endogenous metabolic rhythm and, K PER2 and FASPS mutations, 274 289–290 phosphorylation downstream from peripheral organ genes activation by KaiC phosphorylation cycle PER2 S662, 275 DD environment, 287–288 ATPase activity and, 50–52 Genetics of mouse clocks study results, 290 cellular circadian system, 53–54 effects of Ovtm mutation on clock Hibernation-specific proteins (HP) entrainment of oscillators and, 54 gene expression, 254–255 complex, 608–609 experimental results, 54–55 effects of Ovtm on CRY degradation, HIOMT, 649 importance of circadian regulation of 256–257 Hippocampus and bipolar disorder, 640 transcription, 76 interaction of Ovtm with clock Hipposideros speoris (microchiropteran Kai protein complex dynamics, 48–49 proteins, 255–256 bats), 616 sequential program, 49–50 prtm and Ovtm genes, 251–254 Histaminergic system, 574 synchronization of cycle rhythm, 52–53 study results, 257–258 Histone acetyltransferase (HAT) activity, thermal sensitivity, 50–52 tau mutation (see tau mutation in 13–14, 105–106 Kai gene and protein complex hamsters) Histones cyanobacterial central oscillator, 7–10 Genetic variants of circadian clocks. See modification in mammals, 13–14 KaiC phosphorylation cycle (see KaiC Chronogenetics PTRO theory and, 161 phosphorylation cycle) GENEVESTIGATOR, 353 HNF4α (hepatocyte nuclear factor), 92 phosphorylation of KaiC, 604 Geniculohypothalamic tract (GHT), 26, 529 Honeybee (Apis mellifera), 615 in S. elongatus, 332–334 Genotoxic treatments. See Clock proteins, Hormones and circadian-cancer structural biology of (see Bacterial aging, and tumorigenesis connection, 462 circadian programs) GEO, 353 Horne-Ostberg questionnaire, 274 Kanner, Leo, 645 GET effect, 206 HP. See Hibernation-specific proteins Killifish (Fundulus heteroclitus), 615 GHT (geniculohypothalamic tract), 26, 529 complex Kondotron screening, 331–332 Gigantea (GI) protein, 16, 194–195 hPVN (hypothalamic paraventricular Konopka, Ron, 75 Glucocorticoids, 389 nucleus), 27, 30–31 Kramer, Gustav, 4 Glutamate, 26 HSPs (heat shock proteins), 324 Kuramoto model, 407–408 Glyceraldehyde-3-phosphate dehydrogen- Humans. See also Mammals ase (GAPDH), 142, 204, 205 age and circadian clock, 295 L Glycogen synthase kinase (GSK), 168 circadian clock entrainment (see Glycogen synthase kinase 3β (GSK3β), 640 Entrainment of human clock) LabA (low-amplitude and bright) protein, Gonadotropin-releasing hormone neurons endogenous melatonin production in, 9–10 (GnRH), 27 632–633 LabA gene, 54 Gonyaulax polyedra clock as experimental subjects, 658–659 LATE ELONGATED HYPOTCOTL cellular communication, 143–144 genetic and molecular characterization (LHY), 15–16 circadian-regulated RBPs in, 149 of clock (see Genetics of Lateral clock neurons (LN). See Clock entrainment and, 293 human clocks) neurons of Drosophila GET effect, 206 mutations in humans, 658 Lateral hypothalamus (LH), 31, 40 loss of rhythmicity at low temperature, photoreceptors (see Circadian Laterodorsal tegmental (LDT), 40 143 photoreception in vertebrates) LBP (luciferin [substrate]-binding translational control, 141–143 rest/activity cycle in, 37 protein). See Gonyaulax GRP (gastrin-releasing peptide), 26, 529, sleep and ASD (see Autism spectrum polyedra clock 530 disorders [ASD]) LC (locus coeruleus), 40 gsk3β, 98, 640 sleep/wake cycle (see Sleep/wake LCF (luciferases). See Gonyaulax Guinea pigs (Cavia porcellus), 38 cycle in humans) polyedra clock Humoral release of signaling molecules, 27 LD (light/dark cycle), 35 H Hypometabolic state. See Hibernation and LdpA (light-dependent period) protein, 8, DD 334 Halberg, Franz, 1 Hypothalamic paraventricular nucleus LDT (laterodorsal tegmental), 40 HAT (histone acetyltransferase) activity, (hPVN), 27, 30–31 Leporidae, 38 13–14, 105–106 LH (lateral hypothalamus), 31, 40 HAYSTACK, 353, 356, 358–359, 360 I LH (luteinizing hormone), 27, 262 Heat shock proteins (HSPs), 324 LHY (LATE ELONGATED Hepatocyte nuclear factor 4α (HNF4α), 92 IGL (intergeniculate leaflet), 26, 529 HYPOTCOTL), 15–16 Her1, 446 IκB, 454 LHY/CCA1, 348 668 SUBJECT INDEX

Life-span regulation. See RNAi screen to mammalian cryptochromes oscillator, 446 identify longevity genes MCTQ. See Munich Chronotype premature aging after low-dose Light, oxygen, and voltage sensing questionnaire radiation, 479–480 (LOV), 122–124 Median eminence (ME), 378 premature aging in BMAL1-deficient Neurospora clock and, 63 Medical applications of sleep cycle mice, 478–479 photomodulation and, 194 studies, 589–591 retinal processes and circadian clock single-cell circadian systems and, Melanin-concentrating hormone (MCH), (see Retinal responses to light 205–206 574 and circadian rhythms) Light and clock reset, 63–64 Melanopsin, 26, 502–503 transgenic model of system- and Light/dark cycle (LD), 35 Melanopsin-containing retinal ganglion oscillator-driven genes in Light-dependent period (LdpA) protein, 8 cells hepatocytes, 322–323 Light therapy, 638 background to research, 509–510 microRNA Lingulodinium polyedrum. See Gonyaulax circadian oscillator in aDTA animals, regulation of gene expression by (see polyedra clock 513 PTRO theory) Lithium, 245, 425–426, 638, 639 decoding of light information, 512 in the SCN, 92 Liver and the circadian clock inadequacies of current models on the Mid-sleep on free days (MSF), 294–295 clock synchronization, 91–93, 657 contribution of photoreceptors, Migration of butterflies. See Time- entrainment and, 279 510–512 compensated sun compass phase shifts of, 89–90 maintainence of prolonged responses orientation regulation of circadian gene expression to light, 513–514 Mitogen-activated protein kinase (MAPk) in (see Circadian gene expres- for nonimage-forming functions, 512 signaling pathways, 15 sion regulation in the liver) photoentrainment without, 513 MO (DLMO for blind people), 625. See LL (constant light), 2, 28, 239–240 photoreceptor types contributing to also Melatonin and the LN (lateral clock neurons). See Clock nonimage-forming functions, circadian clock neurons of Drosophila 510 Molecular basis of rhythms generation Locus coeruleus (LC), 40 PLR signal and, 513 ATPase activity of KaiC, 50–52 Longevity genes. See RNAi screen to rods and ipRGC interactions, 503, 504 D. melanogaster, 10–12 identify longevity genes Melatonin and the circadian clock eukaryotic circadian clock systems, LOV. See Light, oxygen, and voltage ASD and, 648–649, 650 10–12 sensing average τ and human τ phenotypes, mammals, 12–14 Low-amplitude and bright (LabA) protein, 628–630 N. crassa, 14–15 9–10 circadian disorders in sighted people, prokaryotic circadian clock systems, Luciferases (LCF). See Gonyaulax 630 7–10 polyedra clock circadian phase-shifting effects of Molecular clock in Drosophila,10 Luciferin (substrate)-binding protein light, 624 background to studies, 243 (LBP). See Gonyaulax clock-gate model and the DLMO, cell-autonomous clocks, 247–248 polyedra clock 624–626 neurobiological focus of study, Luteinizing hormone (LH), 27, 262 entrainment of blind people to 246–247 melatonin, 626–628 neuropeptides as signals in brain clock M function of endogenous melatonin neurons, 248 production in humans, photoreceptors, 245 Magnetoreception, 128 632–633 second clock loop and antiphase Mammals. See also Humans GCMS assay, 623 rhythms, 245–246 cryptochromes (see Structure and melatonin suppression test, 623–624 status of PDP1 in the second loop, 246 function of mammalian nighttime suppression by light, 623 TIM protein, 439 cryptochromes) phase-shift hypothesis, 630–632 transcriptional regulation in the first hibernation and (see Hibernation) pineal melatonin secretion, 262–263, loop, 243–244 intracellular clock mechanism, 114 462 Monarch butterflies. See Time- molecular components model, 13 plasma melatonin profiles in blind compensated sun compass mouse chronogenetics, 216 (see also people, 624 orientation Genetics of mouse clocks) relative coordination to weak Monophasic sleep, 37, 38 mTim factor, 217–218 zeitgebers and τ entrainment Morning cells (M), 520–524. See also oscillator, 12 phase, 628 Clock neurons of Drosophila output via histone modification, 13–14 retinal function and, 309–310 Morningness-Eveningness Questionnaire pacemaker in mice (see Circadian sleep and, 588–589 (MEQ), 294 clockwork of mice) women and sensitivity to zeitgebers, 630 M phase of cell division, 465 phosphorylation and (see Melatonin suppression test (MST), mRNA Phosphorylation) 623–624 ccgs and in N. crassa, 346 photoreceptors (see Circadian MEQ (Morningness-Eveningness CK1a isoforms (see CK1a-dependent photoreception in vertebrates) Questionnaire), 294 phosphorylation of N. crassa) quantitative model of mammalian Mesocricetus auratus (Syrian hamster), coordination of groups of (see PTRO circadian clock, 414–415 38, 616 theory) regulation of clock output (see Mesp2 , 447 FRQ in Neurospora and mRNA Posttranscriptional regulation Metabolism and Period 2 gene, 101 splicing, 602–603 of mammalian clock output) Mice levels and period shortening in SCN master pacemaker (see SCN biology of tau mutation (see tau Drosophila,77 master pacemaker) mutation in hamsters) levels in A. thaliana, 15–16 MAPk (mitogen-activated protein kinase) chronogenetics, 216 levels in eukaryotic oscillators, 10 signaling pathways, 15 clockwork analysis (see Circadian levels in N. crassa, 14, 63 Masking, 283, 293–294 clockwork of mice) mammalian clock output and (see MB (mushroom bodies), 560, 569 genetics and neurobiology of circadian Posttranscriptional regulation MCH (melanin-concentrating hormone), 574 clocks (see Genetics of mouse of mammalian clock output) mCry1 and mCry2, 135. See also clocks) MSF (mid-sleep on free days), 294–295 Structure and function of limitations to studies, 657 MST (melatonin suppression test), SUBJECT INDEX 669

623–624. See also Melatonin Noctiluca miliaris, 143 signals impacting synchronization of and the circadian clock Nocturnin fibroblast oscillators, 321–322 MTim factor, 217–218 discovery, 150–151 similarities and differences between Munich ChronoType questionnaire in mice, 151 central and peripheral, (MCTQ), 274, 294, 295–296 mNOC and metabolism, 151–152 302–303 Mushroom bodies (MB), 560, 569 regulation of biological clocks and, 163 systemically and oscillator-driven Mycelial carotenogenesis, 63 Nonrapid eye movement (NREM) sleep, 39 genes, 322–326 MYST family of HATs, 106, 108 Non-small-cell lung cancer (NSCLC), 461 ultradian, in somite segmentation NORPA (no receptor potential A), 601 clock (see Somite N norpA and temperature entrainment, segmentation clock) 237–238 vertebrate segmentation clock, NAD-dependent protein deacetylase, 483 Notch pathway, 446–447, 452, 454 445–446 NADP(H) redox state, 26 NPAS2/BMAL1, 26 Overtime (Ovtm) NASC Arrays, 353 NREM (nonrapid eye movement) sleep, effects of mutation on clock gene National Highway Transportation Safety 39 expression, 251–254 Administration (NHTSA), 591 NSCLC (non-small-cell lung cancer), 461 effects on CRY degradation, 255–256 NER (nucleotide excision repair), 134 Nuclear receptors (NRs) interaction with clock proteins, Nervous system and Period 2 gene, background, 387 255–256 101–102 CAR, 390 mutagenesis, screening, and Neuroligins (NLGN3,4), 646–647 as circadian effectors of metabolism, identification of gene, 251–254 Neurospora clock 390 study results, 257–258 background to study, 345 complexity and specificity of circadian Overt outputs, 2 blue light photoreceptor, 63 regulation by, 391 Oxaliplatin, 472 characteristics of circadian rhythms, function within core clockwork, Oxidative, respiratory phase (OX), 339, 57–58 387–389 340 circadian system, 64–67 glucocorticoids and, 389 CK1 role (see CK1a-dependent multiple loops with core clock, 391 P phosphorylation of N. crassa) non-NR ligands, 389–390 components roles, 59 PPAR ligands, 389, 390 P27 proteins, 432–433 evidence of FRQ-independent retinoic acid, 389 , 483 oscillators, 34–349 SHP, 390–391 PACAP (pituitary adenylate-cyclase- frq gene and its regulation, 59–61 study conclusions, 391–392 activating polypeptide), 26 FRQ protein role, 61–62 thyroid hormones, 389 Pacemaker gating of light responses, 64 Nucleotide excision repair (NER), 134 in animals (see SCN master interlocked FRQ/WCC feedback pacemaker) loops, 345–346 O in Drosophila (see Transcriptional light and clock reset, 63–64 feedback and circadian molecular explanations for Obstructive sleep apnea, 590 pacemaker) entrainment, 62 Oligodendrocyte precursor cells (OPCs) PAD (phase angle difference), 631 multiloop clock model, 348 background to research, 431 Palm squirrels (Funambulus pennanti), posttranslational control (see intracellular timer in, 431–432 615 Posttranslational control of intrinsic maturation program, 433–434 Pancreatic-lipase-related protein 2 Neurospora clock) protein components of timer, 432–433 (PLRP2), 287–288 study conclusions, 349–350 timer protein in silkworm, 434 PAR1 (pseudo-autosomal region 1), 649 temperature and, 60, 64–67 Orexin, 574 Pars lateralis (PL), 114 transcription-translation feedback ORTHOMAP, 360 part-time (prtm) genes, 251–254 loop, 58–59 Oscillators par tuberalis (PT), 264 Neurospora crassa A. thaliana, 15–16 PAS (PER-ARNT-SIMS) CK and, 14–17, 62 communication between central and in D. melanogaster,10 intracellular oscillators (see Circadian peripheral, 301–302 Neurospora clock and, 63 systems of single cells) cyanobacteria (see Bioluminescence PAX6, 80 molecular basis of negative feedback model) PCC 7942. See Synechococcus elongatus loop (see Posttranslational D. melanogaster (see Drosophila PCG1α, 388 control of Neurospora clock) circadian oscillator) PDD-NOS (pervasive development mRNA levels in, 14, 63 eukaryotic versus prokaryotic, 10 disorder not otherwise oscillator, 14–15 feeding/fasting cycles as zeitgeber specified), 645 phosphorylation in, 197 oscillators in the liver, PDF (pigment-dispersing factor), 12, 240, photoentrainment in, 193–194 320–321 247 posttranslational control of circadian food-entrainable (see Food-entrainable PDP1 in Drosophila clock. See clock (see CK1a-dependent oscillator) Drosophila circadian phosphorylation of N. crassa; FRQ-less, 207–209 oscillator; Molecular clock in Posttranslational control of hierarchical organization of body Drosophila Neurospora clock) clocks, 29–30 Pedunculopontine nuclei (PPT), 40 Neurotensin, 529 individual SCN cells as, 22 PER. See Period (Per) protein NF-κB, 454 intracellular (see Circadian systems of PER1 (Period1) protein NHTSA (National Highway single cells) chromatin remodeling and, 461 Transportation Safety mammals, 12 clock and cellular proliferation Administration), 591 molecular basis of, 202 interactions, 468 NLGN3,4 (neuroligins), 646–647 N. crassa, 14–15 response to stress and, 460 NLGN/NRXN/SHANK3, 651 noncircadian, 202–203 Per1:Bmal1 mRNA expression, 29 N-methyl-D-aspartic acid (NMDA), 532 peripheral oscillators as probes of PER2 (Period2) protein no-action-potential (nap) mutant, 216–217 clock function, 303 chromatin remodeling and, 461 nocte and temperature entrainment, SCN pacemaker and, 27–29 clock and cellular proliferation 236–237 S. elongatus, 7–8 interactions, 468 670 SUBJECT INDEX

PER2 (Period2) protein (continued) Periodosome, 8 Photoreceptors genetics of human clock and, 274, 275 Peripheral clocks blue light photoreceptor, 63, 119–121 phosphorylation in mouse, 171–172 background, 301 (see also Structure and protein stability control, 415–416 characterizations of human disorders function of animal response to stress and, 460 using, 303–304 cryptochromes) PER2::luciferase (PER2::LUC), 267, 268, communication between central and melanopsin-containing RGC cells and, 269, 323, 324, 535–536 peripheral oscillators, 301–302 510–512 PER-ARNT-SIMS (PAS) peripheral oscillators as probes of molecular clock in Drosophila, 245 in D. melanogaster,10 clock function, 303 in vertebrates (see Circadian Neurospora clock and, 63 similarities and differences between photoreception in vertebrates) PER/CRY, 348 central and peripheral PHR dimerization and evolution of the period (per) gene oscillators, 302–303 mammalian clock, 138 in Drosophila clock model (see Peromyscus maniculatus (deer mice), 615 Phytochrome (PHY) proteins, 16–17 Molecular clock in PER/TIM/DBT interval timer Phytochrome interacting factor (PIF), 16–17 Drosophila) cytoplasmic foci formation, 73 Pigment-dispersing factor (PDF), 12, 247 FEO and (see Food-entrainable DBT effect on PER stability, 72 Pineal gland, 27 oscillator) delays caused by mutations, 71–72 Pineal melatonin secretion, 262–263. See implications of genotypic variants of, in Drosophila clock model (see also Melatonin and the 225–229 Drosophila circadian oscillator) circadian clock mutations in (see Chronogenetics) interaction in nuclear translocation, Pituitary adenylate-cyclase-activating Period (Per) protein 70–71 polypeptide (PACAP), 26 in Drosophila clock model (see nuclear accumulation profiles, 71 Pituitary gene expression. See Time Molecular clock in PER and DBT in TIM-producing cells, course analysis of pituitary Drosophila) 72–73 gene expression human circadian clock and (see S2 cells and nuclear translocation, 70 PKA (protein kinase A), 560 Genetics of human clocks) TIM and temporal delays, 69 PL (pars lateralis), 114 interaction with CRY, 97–98 Pervasive development disorder not PlexDB/Barleybase, 353 in mammals, 12 otherwise specified (PDD- PLRE (proximal light regulatory element), in mice, 85–87, 254–258 NOS), 645 59 negative feedback loop and, 414 Pex (Period extender) protein, 8 PLRP2 (pancreatic-lipase-related protein phosphorylation, 98–99, 168–169 PGC proteins, 483 2), 287–288 quantitative model of mammalian Phase angle difference (PAD), 631 POA (preoptic area), 530 circadian clock, 414–415 Phase models of cyanobacteria. See Polyphasic sleep, 38 sleep/wake cycle in Drosophila (see Bioluminescence model Posterior hypothalamus, 40 Sleep/wake cycle in Phase-response curve (PRC), 624, 625 Posttranscriptional regulation of Drosophila) Phenelzine, 425–426 mammalian clock output structural domains and functional Phosphatases (PP) Anant mRNA, 148 motifs in PER2, 97–98 in the circadian clock, 414 AVP mRNA poly(A) length, 146 turnover in tau mutant hamster, 265 regulation of mPER2 degradation, 418 circadian-regulated RBPs in period 2 gene Phosphorylation microalgae, 149 cancer and, 100 in A. thaliana, 197–198 circadian regulation of translation, 149 cardiovascular system and, 101 circadian phenotypes with altered PER examples involving mRNA decay, 148 circadian rhythms and, 99–100 phosphorylation, 170–171 factors involved, 147 general features, 95 in D. melanogaster, 168–169, 197 mNOC, 151–152 immune system and, 100–101 kinases and phosphatases, 168 mRNA decay pathways, 149–150 localization of PER2 in the cell, 98 mapping of sites in clock proteins, Nocturnin discovery, 150–151 metabolism and, 101 171–172 overview, 145–146 nervous system and, 101–102 molecular processes altered in FASPS, period mRNA, 148 phosphorylation of PER2, 98 172–174 regulation of splicing variants, 147–148 regulation of expression, 95 in N. crassa, 197 rhythmic posttranslational control by structural domains and functional overview, 167–168 noncoding RNAs, 149 motifs in PER2, 97–98 period protein, 98–99, 168–169 Posttranscriptional RNA operon (PTRO) Period-4 (PRD-4), 14–17 Photoadaptation in Neurospora clock, 64 theory. See PTRO theory Period-doubling folds in cellular oscillator Photoentrainment Posttranslational control of Neurospora circadian rhythms evolution from 8- in Arabidopsis, 194–195 clock hour day, 421–422 in Drosophila, 193 activation of frq transcription, 186–187 clustering of periods, 426–427 in Neurospora, 193–194 circadian feedback loops, 185–186 conservation and evolution of period, without image-forming visual cues CKII and repressor activity of FRQ, 427–428 (see Melanopsin-containing 187–188 describing and reconstructing an retinal ganglion cells) conservation of eurkaryotic systems, attractor, 426 Photolyase, 119–121. See also Structure 188–189 effect of phenelzine on, 425–426 and function of animal FRQ-CK1a interaction domain, 187 evidence for TRAC folding, 422–423 cryptochromes; Structure and FRQ phosphorylation and degradation gating of cells, 423–424 function of mammalian pathway, 188 phenotypic change from, 427 cryptochromes inhibition of WCC activity by FFC, 187 synchronization of TRAC, 423 action spectra of, 124 overview, 185 yeast as a stochastic tissue, 424–425 and CRY family proteins structure, Posttranslational photomodulation of Period extender (Pex) protein, 8 122, 133 circadian amplitude period gene, 1 reaction mechanism of, 122 control of clock elements without in mammals, 12 Photomodulation. See Posttranslational phosphorylation, 195–197 SCN master pacemaker and, 24 photomodulation of circadian phosphorylation, 197–198 period-luciferase (per-luc), 416, 417–418. amplitude photoentrainment, 193–195 See also Temperature cycles Photoperiodism, 377–378 Potassium conductance, 23–24, 24 and clock synchronization Photoreactivation, 133 PP (phosphatases) SUBJECT INDEX 671

in the circadian clock, 414 R S in Neurospora, 59–62 phosphorylation in mammalian clock Raphe nucleus, 26, 529 S2 cell line, 70, 76–77 and, 168 Rapid eye movement (REM) sleep, 39 S662, 275 regulation of mPER2 degradation, 418 Ras-1, 204–205 Saccharomyces cerevisiae PPAR ligands/proteins, 389, 390, 483 Rat-1, 416, 417–418 anti-aging genes in (see Sirtuins in PPT (pedunculopontine nuclei), 40 Reactive oxygen species (ROS), 485–486 aging and disease) PRC (phase-response curve), 624, 625 Red light responses, 16–17 evolution of circadian clock (see Prd-4 mutation, 206 Reductive, building phase (RB), 339, 340 Period-doubling folds in Preoptic area (POA), 530 Reductive, charging phase (RC), 339, 340 cellular oscillator) Presenilin2, 147–148 Regulator of phycobiliosome-associated metabolic cycle (see Yeast metabolic Presomitic mesoderm (PSM), 445–448, 451 (RpaA) protein, 9–10, 335 cycle [YMC]) Pretectum, 26 Regulatory feedback loops. See Transcrip- SAD (seasonal affective disorder), 624, Process C and S models, 41–42 tional/posttranslational 630, 637 Process S model, 41–42 regulatory feedback loops Sargent, Malcolm, 58 Procolipase (CLP), 287–290 Relish, 562 SasA (Synechococcus adaptive sensor), Prok2 signaling and circadian output REM (rapid eye movement) sleep, 39 9–10, 54, 335 control in mice, 90–91 Restricted feeding schedule (RFS), 543, SCN master pacemaker Prokaryotic circadian clock systems, 7–10. 544–545. See also Food- CJL and, 468–469 See also Bacterial circadian entrainable oscillator communication with peripheral clocks programs Resveratrol, 486–487 (see Peripheral clocks) Prokineticin 2 (Prok2), 90 Retinal-hypothalamic tract (RHT), 26, 529 construction from oscillators, 27–29 Prostate cancer, 462 Retinal responses to light and circadian firing rate modulation by sleep, 36 Protein kinase A (PKA), 560 rhythms hierarchical organization of body Protein phosphatase 1 and 2 (PP1 and PP2) background to studies, 307 oscillators, 29–30 in Drosophila clock model (see Bmal1 and retinal electrical activity in interaction with FEO, 545–546 Molecular clock in Drosophila) response to light, 311–312 ionic basis for rhythm, 22–24 sleep/wake cycle in Drosophila and, Bmal1 and retinal gene expression liver cells and, 89–90, 91–93, 279 558 rhythms, 310–311 location and function, 21 Protein phosphatases (PP) daily rhythms of retinal gene in mammals, 12–13 in N. crassa, 14–17 expression, 309–310 mood disorders and, 638–642 phosphorylation in mammalian clock experimental procedures, 307–308 neuropeptide signaling and circadian and, 168 impact of retina-specific deletion of synchronization in mice, 87–89 Protein phosphorylation Bmal1, 312–315 Per2 expression of, 95 background to research, 413–414 retinal Bmal1 and circadian rhythm physiological functions of clocks cell-based assay, 416 responses, 315–316 outside of (see Retinal responses experimental advances, 415 study results and discussion, 316 to light and circadian rhythms) inhibition of CKIε, 416–417 Retinal-hypothalamic tract (RHT), 26, physiological significance, 30–31 PER2 protein stability control, 415–416 527, 529 Prok2 signaling and circadian output phosphatases in the clock, 414 Retinoic acid, 389 control in mice, 90–91 phosphatases regulation of mPER2 Rett syndrome, 645 role of electrical activity and, 21–22 degradation, 418 REV-ERB family of proteins, 12, sleep regulation by, 42 proteasome inhibition effect on clock 387–388 spatiotemporal organization (see activity, 416 RFS. See Restricted feeding schedule Spatiotemporal organization of quantitative model of mammalian RGCs (retinal ganglion cells). See SCN circuits) circadian clock, 414–415 Melanopsin-containing retinal spike activity in neurons, 23 regulation of negative feedback loop, ganglion cells spike-associated conductances, 24 414 Rhomboid protein, 565. See also Sleep structural connectivity, 26–27 tau mutant gain of function, 417–418 control in Drosophila subthreshold basal potassium Proximal light regulatory element (PLRE), RHT (retinal-hypothalamic tract), 26, 527, conductance and, 23–24 59 529 time generation mechanism (see SCN prtm (part-time) genes, 251–254 Rhythm-related genetic variants of time generation mechanism) Pseudo-autosomal region 1 (PAR1), 649 circadian clocks. See transcription-translation feedback look Pseudo-response regulators (PRR), 16 Chronogenetics perturbation, 24–26 PSM (presomitic mesoderm), 445–448, 451 Rhythms generation. See Molecular basis SCN time generation mechanism PT (par tuberalis), 264 of rhythms generation adrenal gland and, 553–554 PTRO theory Ribonomics, 160–163 clock coordination of cell function, gene expression regulation, 157–158 RIP-Chip concept, 159–162 551–552 multitargeting of mRNAs by RNA-binding proteins (RBD). See PTRO intracellular molecular oscillator, 551 microRNAs, 159–160 theory regulation of peripheral organs, 553 multitargeting of mRNAs by RBPs, RNAi screen to identify longevity genes synchrony of clock cells, 552–553 158–159 background to studies, 489–490 ubiquitin-proteasome system study, 555 overview, 157 discussion, 495–496 Seasonal affective disorder (SAD), 624, potential for horizontal transfer of, 162 materials and methods, 490–492 630, 637 regulation of biological clocks and, 163 study results, 492–495 Seasonally regulated tolerance of hearts to ribonome concept, 162–163 RNP-immunoprecipitation-microchip. See low Tb. See Hibernation RIP-Chip multitargeting of mRNAs, RIP-Chip concept Serotonergic projections, 26 160–162 Rod and cone cells and photoentrainment, Serotonin, 573–574, 649 theory overview, 162 510–512 Sex and circadian clock, 295 Pyrocystis lunula, 142 ROR family of proteins, 12, 387–388 Shaggy (SGG) protein ROS (reactive oxygen species), 485–486 in Drosophila clock model, 10, Q RpaA (regulator of phycobiliosome- 244–245, 439 associated) protein, 9–10, 335 phosphorylation in Drosophila and, Q10 value, 4 RPE65, 503–505 168 672 SUBJECT INDEX

Shaggy gene, 218 control in Drosophila) gap junctions, 530 SHANK3, 647 non-light extrinsic factors affecting it, gates and oscillators, 534 SHP (small heterodimeric partner), 559–560 gating of light in the core, 532 390–391 study conclusions, 562–563 network organization, 528 Siberian chipmunk (Tamias sibericus), 38 usefulness as a sleep model, 560 optimization principle, 528–529 Silkworm (Bombyx mori), 434 Sleep/wake cycle in humans, 274 outputs, 530–531 Single cell circadian systems. See Circadian background to research, 579 phase dispersion of SCN oscillators, systems of single cells chronic sleep restrictions effects, 590 534–536 Sirtuins in aging and disease circadian amplitude, 580–581 study conclusions, 540 background, 483 circadian phase, 580 tides and waves of spatial change, calorie restriction, 483 circadian rhythm realignment, 591–592 536–540 CR pathway and mitochondria, 484–485 circadian system overview, 579–580 S phase of cell division, 465 metabolic and stress-sensing pathways dose-dependent resetting, 582–583 Spike threshold/rate, 21–22, 23 regulated by SIRT1, 483–484 drowsy driving, 591 SPINDLY (SPY), 17 metabolic syndrome mitigation by entrainment to light, 581 spineless, 235 SIRT1 mechanisms, 486–487 future initiatives, 591–592 Spiny mice (Acomys sp.), 616 mitochondrial biogenesis and damage homeostatic and circadian interaction, Sprague-Dawley rats (Rattus norvegicus), protection, 485–486 587–588 38 Sleep and rhythms medical applications, 589–591 sPVZ (subparaventricular zone), 30–31, aftereffects of entrainment, 36–37 melatonin, sleep, and alertness, 530, 545–546 chronopharmacology, 43 588–589 Star protein, 565. See also Sleep control chronotypes, 41–42 period of the circadian system, in Drosophila circadian rhythms disorders, 42–43 584–586 Structure and function of animal differences between species, 35–36 phase-dependent resetting, 581–582 cryptochromes flip-flop model of sleep and phase-resetting effects of intermittent action spectra of photolyases, 124 wakefulness, 40–41 light, 584 ATP binding and autokinase activity, historical use of rest/activity cycle, 35 photic history effects on resetting light 126 locomotor activity effect on responses, 584 blue light photoreceptor research, 119 rest/activity rhythm, 36 regulation of sleep/wake rhythm, cryptochrome photocycle, 127 measurement of human sleep 586–587 cryptochrome role in cycle regulation, architecture, 38–40 sleep deprivation and performance/ 128 monophasic vs. polyphasic sleep, 38 safety, 589–590 cryptochrome role in neuroanatomic and neurophysiologic sleep disorders, 590–591 magnetoreception, 128 basis of, 40–41 sleep inertia, 590 DNA binding, 124–125 phase angle of entrainment, 36 wavelength sensitivity of circadian history of research into, 119–121 regulation by circadian pacemaker, 42 response to light, 583–584 overview, 119 rest/activity cycle in humans, 37 Slow-wave sleep (SWS), 39 photolyase/CRY family proteins rest/activity in natural day, 35–36 Smad6, 454 structure, 122 rest/activity-sleep/wake timing in Small heterodimeric partner (SHP), 390–391 phototropin-like model, 127 animals, 36–37 Smith–Magenis syndrome (SMS), 649 phylogeny and functional sleep as an altered behavioral state, Social Zeitgeber Theory, 637 classification, 121–122 37–38 Socs3, 454 protein–protein interactions, 125–126 sleep cycles, 38–40 Sodium channels and SCN master quarternary structure, 124 sleep regulation models, 41–42 pacemaker, 24 reaction mechanism of photolyase, Sleep control in Drosophila Somite segmentation clock 122 dopaminergic system, 567–569 background, 451 spectroscopic properties, 124 EGFR pathway, 565 Hes1 oscillation in non-PSM cells, 454 trp triad, 126–127 integration of sleep signals, 569–570 Hes7 oscillation mathematical Structure and function of mammalian manipulation of EGFR pathway and, simulation, 452–453 cryptochromes 565–566 Hes7 oscillation mechanism in, 452 analysis methods, 136–137 Sleep debt, 295 other ultradian oscillators, 454–455 circadian core clock and, 135–136 Sleep deprivation, 36 possible significance of ultradian mCRY-binding partners study, 137 Sleep deprivation and performance/safety, oscillations, 455 opposite phenotypes study, 137 589–591 real-time monitoring of Hes photolyase/CRY protein family, 133 Sleep disorders, 590–591 oscillations, 453 photolyases and DNA repair, 133–134 Sleep inertia, 590 study conclusions, 455–456 phototransduction and, 134–135 Sleep/wake cycle Somitogenesis process, 445–448 PHR dimerization and evolution of the background, 573 SP (substance P), 529 clock, 138 in Drosophila (see Sleep/wake cycle Sparrows and photoreception, 500–502, 505 transcription repression study, in Drosophila) Spatiotemporal organization of SCN 137–138 in humans (see Sleep/wake cycle in circuits Subparaventricular zone (sPVZ), 30–31, humans) afferent inputs, 529–530 530, 545–546 molecular correlates of sleep need, changes in photoperiods and, 532–533 Substance P (SP), 529 574–576 changes in response to bimodal 6-sulphatoxymelatonin (6-SM), 649 neurochemistry of sleep, 573–574 light/dark cycle, 533–534 SUMOylation, 108–109 study conclusions, 576–577 changes in response to constant light, Suprachiasmatic nucleus (SCN). See SCN Sleep/wake cycle in Drosophila 533 master pacemaker entrainment of the clock to light, core and shell functions, 531–532 SWS (slow-wave sleep), 39 558–559 core and shell organization, 529 Symposium synopsis, 655–659 mapping of sleep-regulating loci, core and shell specializations, 530 Synechococcus adaptive sensor (SasA), 560–561 core’s role in SCN oscillation, 532 9–10, 335 molecular basis of clock, 557–558 distribution of peptidergic phenotypes, Synechococcus elongatus molecules that regulate sleep, 561–562 529 clock basis (see KaiC phosphorylation neuromodulatory system (see Sleep function of SCN, 527 cycle) SUBJECT INDEX 673

clock studies (see Bacterial circadian T cycles, 280 cycling transcripts analysis, 384–385 programs) Temperature statistical analysis, 383 connections between clock and clock synchronization by temperature transcriptional profiling, 382–383 cellular activities, 335–336 cycles (see Temperature cycles TIME FOR COFFEE (TIC), 17 emergence as a model organism, and clock synchronization) Timekeeper (Tik), 219 331–332 compensation (see Temperature- Timeless (TIM) protein input, 8, 9f compensation) in Drosophila clock model, 439 (see Kai oscillator, 332–334 loss of Gonyaulax rhythmicity at low also Molecular clock in oscillator, 7–8 temperature, 143 Drosophila) oscillator connection with clock- Neurospora clock and, 60 interval timer (see PER/TIM/DBT controlled processes, 335 Temperature-compensation interval timer) oscillator connection with chronobiology, 4 posttranslational mechanism and, environmental cues, 334–335 cyanobacterial central oscillator and, 238–239 output, 9–10 396 sleep/wake cycle in Drosophila (see usefulness as a model for effects on Neurospora clock, 65–67 Sleep/wake cycle in cyanobacteria, 336–337 systems biology and, 376 Drosophila) Syrian hamster (Mesocricetus auratus) Temperature cycles and clock timeless gene biology of tau mutation (see tau synchronization interaction with checkpoint proteins, 461 mutation in hamsters) clock mutants and temperature light-induction of tim expression, sleep cycle, 38 entrainment, 235–236 603–604 temporal coupling between, 616 location of thermal receptors, 235 TIMING OF CAB EXPRESSION 1 Systems biology neural substrates, 240 (TOC1), 196–197, 258, 348 analysis of clocks, 367, 369–371 nocte and temperature entrainment, TMN (tuberomammilary neurons), 40 as “biology after identification,” 365 236–237 Total sleep deprivation (TSD), 638 control of clocks, 371–373 norpA and temperature entrainment, TRAC (transcription redox attractor delay in feedback repression, 375–376 237–238 cycle), 421. See also Period- design of clocks, 373–374 overview, 233–235 doubling folds in cellular development of approaches and their PDF neurons, 240 oscillator application to clocks, 365–366 role of transcriptional and Transcriptional and translational levels identification of clocks, 366–367, 368, posttranscriptional regulation. See PTRO theory 369 mechanisms, 238–239 Transcriptional feedback and circadian mammalian circadian clock as a model study results, 241 pacemaker system, 365 temperature entrainment in LL and CLK role in clock cell specification, nonlinearity of molecular mechanisms, DD, 239–240 80–81 376 temperature receptors in the fly, 235 complexity in Drosophila,76 perfect adaptation, 377 Temperature effects on clock function correlation between CLK-CYC photoperiodism, 377–378 background to research, 599–600 complex activity and period synchronization of clocks, 376–377 basis for temperature-dependent length, 76–77 temperature-compensation and, 376 splicing of dmpi8, 601–602 CWO rhythmicity and, 77–80 Drosophila as a model system, 600 CYC-VP16 characterization, 76–77 T FRQ in Neurospora and mRNA in Drosophila clock model (see splicing, 602–603 Drosophila circadian oscillator) TAIR, 353 light-induction of tim expression, evolution of circadian clock, 81 Tamias sibericus (Siberian chipmunk), 603–604 importance of phosphorylation, 76 607. See also Hibernation study conclusions, 604–605 noncircadian cell CLK function, 78 Tan mutants, 222, 223 thermal-sensitive splicing of dmpi8, per mRNA levels and period τ entrainment phase (TEP), 628–630 600–601 shortening, 77 Tau mutation in hamsters thermosensitive splicing, 603 regulation of mammalian clock output accelerated clock’s impact on Temperature effects on Neurospora clock (see Posttranscriptional metabolism and activity, physiological limits for rhythmicity, regulation of mammalian clock 269–270 65 output) acceleration of period in CK1ε temperature-compensation, 65–67 research background, 75–76 mutation, 269 temperature resetting, 64–65 UAS-PER and, 77 action in peripheral tissues, 267–268 TEP (τ entrainment phase), 628–630 validity of TTFL model for background to research, 261 Tetrodotoxin (TTX), 21–22 cyanobacteria, 399–400 CK1ε action models, 265–266 Theory of mind, 645 Transcriptional/posttranslational discovery in the Syrian hamster, Thyroid hormones, 389, 432 regulatory feedback loops. See 261–262 Thyroid-stimulating hormone (TSH), 649 also Posttranscriptional endogenous protein degradation TIM. See Timeless (TIM) protein regulation of mammalian clock studies, 268–269 Time-compensated sun compass output; Posttranslational gain of function, 417–418 orientation control of Neurospora clock; inhibition of CKIε, 416–417 ancestral clock of monarch butterfly, Posttranslational mouse model, 266–267 116 photomodulation of circadian Per 1 and Per 2 expression, 170–171 clock-compass neural connections, amplitude; PTRO theory PER turnover, 265 116–117 A. thaliana, 15–16 reversible protein phosphorylation in CRY2 discovery, 114–116 in D. melanogaster (see (see Protein phosphorylation) focus for future studies, 117 PER/TIM/DBT interval timer) seasonal and photoperiodic time location of cellular clock in butterfly eurkaryotic system oscillators, 10–12 measurement, 263–265 brain, 114, 115 mammal oscillator, 12 targeted clock proteins, 268 overview, 113–114 N. crassa, 14–15 ultradian and daily endocrine rhythms, Time course analysis of pituitary gene Transcription redox attractor cycle 262–263 expression (TRAC), 421. See also Period- Tb (body temperature), 607. See also background to research, 381–382 doubling folds in cellular Hibernation bioinformatics research, 383–384 oscillator 674 SUBJECT INDEX

Transcription-translation feedback loop Vertebrate segmentation clock CK1a and FRQ-dependent (TTFL) amniote oscillators, 446 phosphorylation, 180–181 D. melanogaster, 58–59 clock and wave-front model, 445 clock feedback loops (see mammals, 58–59 congenital scoliosis and, 447–448 Posttranslational control of Neurospora clock, 58–59 fish oscillator, 445–446 Neurospora clock) βTrCP, 258 synchronization of oscillations in frq gene in Neurospora and, 59–62 Trp triad, 126–127 PSM, 446–447 in N. crassa, 14–15 TSD (total sleep deprivation), 638 wave front, 447 Widerborst (Wdb), 244 TSH (thyroid-stimulating hormone), 649 Vesicular glutamate transporter 1 TTX (Tetrodotoxin), 21–22 (vGLUT1), 101 X Tuberomammilary neurons (TMN), 40 VIP (vasoactive intestinal polypeptide), Tumor growth rate, 467 25, 87–89, 377, 529 Xenopus, 150–151 Tumorigenesis. See Clock proteins, aging, Vipr2–/– mice, 89–90 and tumorigenesis VirtualPlant, 353 Y vivid (vvd),64 U VIVID (VVD) protein, 15, 205–206 Yeast metabolic cycle (YMC). See also VLPO (ventrolateral preoptic area), 40, 591 Saccharomyces cerevisiae UAS-PER, 77 VMH (ventromedial nucleus of the absence of oscillations in common UAS-vri transgene, 245 hypothalamus), 544 yeast strains, 342 Ultradian oscillators in somite Von Linne, Carl, 1 background to study, 339 segmentation clock. See VP16, 76–77 biological function predictions based Somite segmentation clock VPAC2 receptor, 87–89, 377 on temporal expression pattern, VPDPR (enterostatin), 289–290 340–341 V VRI. See Drosophila circadian oscillator log-phase vs. continuous chemostat vrille (vri), 245 growth, 342–343 Valproate, 638, 641 VTA (ventral tegmental area), 640 metabolic phases of yeast cells, 340 Vascular endothelial growth factor periodic transcription of genes, 341 (VEGF), 101 W similarities to circadian cycle, Vasoactive intestinal polypeptide (VIP), 341–342 25, 87–89, 377, 529 Wasabi, 384 Ventral tegmental area (VTA), 640 WCC. See White collar complex Z Ventrolateral preoptic area (VLPO), 40, WC-FLO oscillator, 15–17 591 Wee-1, 91, 468 Zebra fish, 446–447 Ventromedial nucleus of the White collar complex (WCC) Zeitgebers, 2, 279 hypothalamus (VMH), 544 blue light photoreceptor, 63 ZEITLUPE (ZTL), 16, 194–197, 258