Chronobiology: Biological Timekeeping

CB FM design 4/4/03 11:15 AM Page iii

Chronobiology Biological Timekeeping

Edited by Jay C. Dunlap Dartmouth Medical School

Jennifer J. Loros Dartmouth Medical School

Patricia J. DeCoursey University of South Carolina

Sinauer Associates, Inc. Publishers Sunderland, Massachusetts, U.S.A.

© Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. CB FM design 4/4/03 11:15 AM Page vi

Brief Contents

CHAPTER 1 Overview of Biological Timing from Unicells to Humans 3 Patricia J. DeCoursey CHAPTER 2 The Behavioral Ecology and Evolution of Biological Timing Systems 27 Patricia J. DeCoursey CHAPTER 3 Fundamental Properties of Circadian Rhythms 67 Carl Hirschie Johnson, Jeffrey Elliott, Russell Foster, Ken-Ichi Honma, ` and Richard Kronauer CHAPTER 4 Circannual Rhythms and Photoperiodism 107 Bruce Goldman, Eberhard Gwinner, Fred J. Karsch, David Saunders, Irving Zucker, and Gregory F. Ball CHAPTER 5 Functional Organization of Circadian Systems in Multicellular Animals 145 Patricia J. DeCoursey CHAPTER 6 Cell Physiology of Circadian Pacemaker Systems in Metazoan Animals 181 Patricia J. DeCoursey CHAPTER 7 Molecular Biology of Circadian Pacemaker Systems 213 Jay C. Dunlap CHAPTER 8 Adapting to Life on a Rotating World at the Gene Expression Level 255 Jennifer J. Loros, J. Woodland Hastings, and Ueli Schibler CHAPTER 9 Human Circadian Organization 291 James M. Waterhouse and Patricia J. DeCoursey CHAPTER 10 The Relevance of Circadian Rhythms for Human Welfare 325 James M. Waterhouse and Patricia J. DeCoursey CHAPTER 11 Looking Forward 359 Patricia J. DeCoursey

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Contents

1 Overview of Biological Timing from Unicells to Humans 3 Introduction: Structural Organization and Starting Up and Coming to Terms Is the First Time Organization Are Two Pivotal Step in Any New Scientific Adventure 14 Parallel Features of Living Organisms 3 Every scientific field has its specialty jargon 14 The rotating features of Earth have influenced the evolution of rhythmicity in all living organisms 3 Starting Up Also Involves Learning Basic Concepts and Methodologies 15 Clocks and Calendars Have Been Important Rhythm concepts encompass parameters of waves 15 to Humans from Earliest Recorded Biological clock regulation of physiology and behavior History 4 is more complex than direct triggering of responses Time measurement was crucial in early cultures 4 15 The rise of science in the Western world and in China Indirect measures of rhythmicity usually rely on long- promoted astronomy and math 6 term behavioral recording 16 Post-Renaissance scientific advances resulted in radical Data processing of circadian behavioral output is often changes in clock measurement devices 7 depicted in actograms 18 Circadian time differs from standard time-zone clock Awareness of Internal Biological Clocks time 18 Began Relatively Recently 9 A Brief Introduction to Basic Circadian Early knowledge of physiology was limited 9 Parameters Will Set the Stage for Early circadian pioneers had some first inklings of endogenous rhythms 10 Discussion of Circadian Behavior Later pioneers had good insights into circadian rhyth- and Ecology 19 micity 10 Circadian pacemakers are endogenous 19 Pittendrigh and Aschoff were founders of modern-day Entrainment requires an environmental time cue or chronobiology 11 synchronizer for locking on to local time 20 Interest in biological timing spread rapidly 12 The Rationale Chosen for the Text Is Simple An international community of chronobiologists soon and Logical 22 flourished 12

2 The Behavioral Ecology and Evolution of Biological Timing Systems 27

Introduction: Rhythmic Environmental Chronobiology deals with both proximate and ultimate Features Have Shaped the Temporal questions 27 Pattern of Behavior in Plants and Organisms are highly specialized for the diverse niches of the specific ecosystems in which they carry out Animals 27 their life cycles 28

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Organisms in natural environments encounter many Timing mechanisms differ among the three strategies temporal opportunities as well as challenges 28 48 Endogenous timing is based on cellular pacemaker systems 29 Evolutionary Theory Suggests the Derivation of Biological Timing 48 Circadian Timing Facilitates a Large Variety Darwin’s theory of evolution by natural selection pre- of Behavioral Functions 29 dicts the major steps in development of new traits in A big challenge for beginners in behavioral chronobiol- organisms 48 ogy is the design of experiments for organisms in Some caveats are necessary 49 both the laboratory and the field 29 Demonstration of adaptive evolutionary change for Circadian rhythms occur in both prokaryotic and any behavioral feature requires stringent criteria 49 eukaryotic unicells 33 Daily activity patterns are very widespread in animals Information about the Evolution of Biological 34 Timing Systems Comes from Several Daily torpor and hibernation bouts reduce metabolic Sources 51 demands in some mammals 37 Evidence for the genetic basis of circadian clocks is Time sense, time–place learning, and celestial naviga- substantial 51 tion are functions that require continuous consulta- Evidence for adaptive evolution of biological timing by tion of a circadian clock 38 natural selection is quite limited 51 Gated rhythms in development are one-time occur- Direct testing of circadian adaptiveness in the field has rences in a population 40 recently been carried out 55 Intra- and interindividual coordination is important for all rhythmic species 41 A Phylogenetic Survey of Plants and Animals Suggests Trends in the Evolutionary Circadian Rhythms Are Also Widespread in History of Biological Timing Systems 58 Higher Plants 41 The field of systematics offers tools for studying the The Behavior of Many Marine Organisms evolutionary history of traits 58 Reflects Tidal and Lunar Environmental The chronology of Earth’s early history gives insight into the origin of biological timing 59 Cycles 43 Some prokaryotes have well-developed circadian tim- Rhythmic complexity is prevalent in ocean niches 43 ing 60 Pacemaker systems have not been localized for tidal or Almost all eukaryotic organisms possess biological lunar-related rhythms 46 clocks with similar timing properties but great struc- Biological Timing Systems Are Involved in tural diversity 60 Seasonal Behavior of Some Animals and The Known, the Unknown, and the Wildly Plants 46 Speculative 60 Three basic strategies are used in seasonal rhythms of organisms 46

3 Fundamental Properties of Circadian Rhythms 67 Introduction: Circadian Clocks Are Most biochemical processes are very sensitive to tem- Important for Organisms 67 perature in a predictable way 70 Temperature compensation of circadian clocks means Major Defining Features Give Great Insight that the period of the clock is approximately the into the Clock Mechanism 67 same under different constant ambient conditions 71 The Free-Running Period Is Approximately Circadian clocks used in sun-compass orientation 24 Hours Long 68 require temperature compensation throughout their cycle 71 Free-Running Periods of Circadian Clocks Some circadian clocks have a Q10 value less than 1 72 Are Temperature Compensated 70

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Rhythmic Environmental Stimuli Entrain Continuous entrainment occurs through environmental Circadian Clocks 72 modulation of period length 89 Temperature transitions can also entrain circadian Entrainment of the circadian clock provides an internal clocks 89 estimate of external local time 72 Light and dark signals are the most important environ- Modeling Scientific Processes Is Useful 90 mental entraining agents 72 Two different models have been proposed to explain Circadian Pacemakers Are Limit-Cycle circadian entrainment 73 Oscillators 92 Phase response curves map the phase-dependent Phase response curves can be modeled in terms of limit responses of circadian clocks to entraining agents cycles 93 and form the basis of discrete models of entrainment Limit-cycle modeling can explain how a “critical” stim- 75 ulus could evoke arrhythmic and/or unpredictable Entrainment behavior of many organisms can be pre- behavior 94 dicted by the discrete entrainment model 80 Limit-cycle organization can explain Type 1 and Type 0 Stable entrainment occurs within certain limits 83 resetting 98 Phase angles are stabilized by free runs that are not Limit-cycle modeling provides an alternative explana- exactly 24 hours 83 tion for cases in which the clock appears to be stopped 99 Circadian pacemakers can entrain to skele- Limit-cycle modeling can provide an integrated ton photoperiods 85 entrainment mechanism 99 The discrete entrainment model may account for the Limit-cycle modeling establishes criteria for compo- pacemaker’s tracking of the seasons 87 nents of the central clockwork 102 Circadian oscillators exposed to complete photoperiods must also experience continuous entrainment 88

4 Circannual Rhythms and Photoperiodism 107 Introduction: The Lives of Most Plants and The role of photoperiodism in annual cycles of organ- Animals Are Organized on a Seasonal isms was first noted in plants 118 Schedule 107 Bünning first used resonance experiments to test a con- crete photoperiodic hypothesis 119 Many Seasonal Rhythms Are Based on Pittendrigh formulated the circadian hypotheses of Endogenous Circannual Rhythms 108 internal and external coincidence 119 Circannual rhythms are widely distributed in plants Plants Use Photoperiodic Timing Extensively and animals 108 120 Specific environmental conditions are sometimes Several photoperiodic responses are known in plants required for expression of circannual rhythms 110 120 The annual cycle of photoperiod is the most important The site of photoperiodic perception is in the leaves synchronizer of circannual rhythms 111 121 Circannual rhythms are ecologically adaptive 112 Multiple photoreceptors contribute to photoperiodic Attempts have been made to localize a circannual clock light perception 121 115 Genetic analysis has identified genes important in the Single- or multioscillator circannual pacemakers may photoperiodic induction of flowering 121 exist 116 Neuroendocrine enablers are important in annual Photoperiodism Is Widespread in Insects reproductive rhythms 116 122 The study of seasonal enablers sometimes leads to dis- Diapause is often timed by photoperiod in insects 122 covery of hormone functions 118 Insects can be exposed to a range of experimental pho- The Study of Photoperiodic Time Measure- toperiods to develop a photoperiodic response curve 122 ment in Plants and Animals Began Early Insects require exposure to several short or long days in the Twentieth Century 118 to reach a threshold for subsequent diapause 124

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Insect photoreceptors and clocks are often located in Circadian timing is part of mammalian photoperiodism the brain 124 129 Insect photoreceptors are probably based on Both absolute day length and photoperiod history are carotenoids 124 important in mammalian photoperiodism 130 A central problem in photoperiodism of insects is the Photosensitivity and photorefractoriness are important nature of photoperiod time measurement 125 in mammalian photoperiodism 131 Type I and Type II annual cycles share mechanistic sim- Photoperiodism Is Becoming More Widely ilarities 132 Recognized in the Lower Vertebrates Output signals include pineal melatonin as the pho- 125 toperiodic messenger in mammals 133 The relation between the circadian system and pho- A close relation exists between the actions of light and toperiodic time measurement has not been studied melatonin in mammals 134 extensively in cold-blooded vertebrates 125 Pineal melatonin secretion is regulated by the circadian Limited information is available for fish, amphibians, system in mammals 134 and reptiles 126 Melatonin physiology is influenced by photoperiod Photoperiodism Is Vitally Important in Avian history in mammals 135 Physiology 127 Melatonin mediates photoperiodic entrainment of mammalian circannual rhythms 136 Early observations of vertebrate photoperiodism began with birds 127 Multiple target sites for the photoperiodic actions of melatonin may exist 136 Photorefractoriness and photoperiod history effects are important concepts in avian photoperiodism 127 Comparative Studies Give Clues to the Birds use diverse nonretinal photoreceptors in pho- Evolutionary History of Mammalian toperiodic time measurement 129 Photoperiodism 138 The neuroendocrine basis for photoperiodic time mea- The neuroendocrine basis of photoperiodism shows surement in birds is poorly understood 129 both similarities and differences among the various Many Mammals Show Photoperiodic vertebrates 138 Responses in Reproduction, Seasonal Photoperiodism has a genetic basis 139 Fattening, and Other Functions 129

5 Functional Organization of Circadian Systems in Multicellular Animals 145

Introduction: Diverse Structural Elements of Other arthropods such as scorpions and horseshoe the Circadian System Provide Multiple crabs have many circadian adaptations 154 Patterns for Successful Living Clocks Many neural changes accompanied the rise of the ver- 145 tebrates 157 Nonmammalian Vertebrates Provide Insight Excellent Circadian Models Are Found in Two into the Structural Diversity of Invertebrate Groups: Molluscs and Circadian Pacemaker Systems 159 Arthropods 147 Many combinations of components reflect the varia- Details of pacemaker and photoreceptor locations, as tions in life history patterns of different species 159 well as the presence of multiple oscillators and their coupling, are known for two molluscs 147 Information on circadian rhythmicity in cyclostomes and fish has increased dramatically in recent years Structural elements and their function have also been because of new techniques for study 160 localized in the insect group of the arthropods, but much more structural diversity has been found than In amphibians, the retina of Xenopus has been studied in molluscs 150 intensively as a circadian pacemaker 162

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The major circadian pacemaker of most reptiles is the A major mammalian circadian pacemaker has been pineal gland, but details of circadian function differ localized to the suprachiasmatic nucleus of the ven- widely between species 163 tral hypothalamus 168 Great diversity is seen in avian oscillators and input Input pathways to the SCN include both neural projec- sensors 166 tions and humoral feedback signals 171 SCN output pathways for neuronal and humoral sig- In Mammals the SCN Is the Main Oscillator nals are numerous and depend on both target organ 168 and function 172 A streamlined mammalian circadian axis has evolved 174 6 Cell Physiology of Circadian Pacemaker Systems in Metazoan Animals 181

Introduction: The Important Cellular Light input for in vitro chick pineal cell cultures Questions Require an Appropriate involves at least two input pathways 195 Organism and Preparation 181 The circadian output rhythm in the chick pineal culture involves melatonin synthesis and secretion 196 Measuring Cellular Rhythmicity Requires The Mammalian SCN Circadian Pacemaker Sophisticated Assays 182 System Has Been Studied More The list of favorable models for circadian cell physiol- Extensively Than Any Other Pacemaker ogy has been narrowed to three 182 System 196 Methods should overlap and be artifact free 182 The circadian system in mammals has many advan- Two general approaches include in vivo and in vitro tages for study 196 cell culture 183 The SCN in slice culture is a self-sustained oscillator Many highly specific methods are available 184 198 The Mollusc Bulla Has Been a Highly Useful Single SCN cells in dispersed-cell culture are self-sus- Invertebrate Model for Studying tained oscillators 198 Cellular Circadian Physiology 190 Single SCN cells appear competent to restore rhythmicity in SCN hosts 199 Bulla eyes have many favorable properties for circadian physiology studies 190 The intercellular coupling mechanism in the SCN may involve GABA 200 The pacemakers have been localized in Bulla at the tis- sue and single-cell level 191 Mammalian circadian photoreceptors lie in photore- ceptive retinal ganglion cells 201 Bulla ocular pacemakers show two distinct levels of coupling 191 Recent research has pointed out some important functional aspects of circadian photodetection in mam- Light input for entrainment also involves the basal mals 204 retinal neurons 191 Progress is being made on cell physiology aspects of Circadian output in Bulla is mediated by electrical dis- the output signals of mammalian SCN pacemaker charges of the basal retinal neurons 192 systems 206 The Chick Pineal Circadian System Has Synthesis: Comparison of the Circadian Many Excellent Attributes for a Properties of the Three Model Systems Vertebrate Model 192 Highlights Functional Similarities and The cultured chick pineal is more favorable for circa- Differences 206 dian studies than are adult chickens 192 The pinealocytes of chick pineal gland in vitro are circadian oscillators 194

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7 Molecular Biology of Circadian Pacemaker Systems 213 Introduction: Both Conserved and Divergent The Cyanobacterial Clock Depends on a Elements Are Found in the Basic Negative Feedback Loop Involving Clockworks 213 Transcription, Translation, and Protein–Protein Interactions 230 For Many Years Theory Dominated Experiment in the Generation of Generic Core Circadian Feedback Loops in Models for the Feedback Loop Eukaryotes Involve Interlocking Positive Comprising the Clock 214 and Negative Regulation of Gene Common characteristics of all oscillators provided an Expression 232 intellectual focus to early work 214 A Basic Eukaryotic Clock in Neurospora Uses The glycolytic pathway is an example of a simple feedback oscillator 215 Several Components to Execute Coupling of simple oscillators enhances stability and Negative and Positive Feedback 232 adjusts the period length of the ensemble 217 Essential components of a circadian oscillator feedback Three different approaches were used to elucidate the loop in Neurospora are known 232 molecular mechanism of circadian clocks 218 The molecular basis of entrainment to light and temperature changes is understood in Neurospora 235 Development of Circadian Oscillator Models in the Pre-Molecular Genetics Era Was The Clockwork in Drosophila,a Model a Mirror of the Times 219 Animal, Relies on Patterns of Gene A sampling of early models reveals diverse attempts to Regulation and Feedback Similar to explain circadian characteristics in biochemical Neurospora but Reflects Increased terms 219 Complexity 236 All the early models were at some level plausible, but Many central components of the Drosophila circadian ultimately none were compelling 220 oscillator are known 237 A Brief Primer on Genetics, Biochemistry, The Drosophila clock is reset through light-promoted and Molecular Biology May Help protein degradation 239 Readers’ Understanding of the Single-Gene Mutations Have Been Used to Molecular Basis of Circadian Describe a Circadian Oscillator in Rhythmicity 221 Mammals 239 Modern molecular biology reflects the fusion of two One particularly informative single-gene mutant was independent fields: genetics and biochemistry 221 identified in a hamster 239 Classical genetics provides a way to organize the The central clockworks in vertebrates is best under- observation of heritable characteristics and to track stood in house mice 240 them over generations 221 Rapid progress has been made in identifying compo- The structure of DNA provided a molecular basis for nents of vertebrate circadian feedback loops 241 classical genetics 222 Light resets the vertebrate clock by activating tran- Gene expression involves sequential transcription and scription of negative elements in the feedback loop translation 224 244 The structure of a gene and the means through which it Many animals have evolved peripheral clocks that are is expressed differ in prokaryotes and eukaryotes distinct from the central-brain cellular clocks 245 224 Proteins are the ultimate products of most genes, and The Emerging Description of Plant Circadian changes in proteins are the results of most mutations Oscillators Includes Multiple Coupled 228 Oscillators, Each Apparently Involving An Understanding of the Molecular Bases for Transcription and Translation 246 Circadian Rhythmicity Is Emerging 229 Elucidation of the molecular mechanism of plant rhythms has been difficult 246 Common themes among circadian oscillators are evi- The organization of plant circadian oscillators suggests dent 229 the involvement of transcription and translation A generic core circadian feedback loop can be feedback loops 246 described 229

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Many light-sensing proteins contribute to light reset- Considerable diversity in mechanistic details is emerg- ting of plant clocks 248 ing among animal clocks 249 The many origins of circadian rhythmicity are still not A Diversity of Research Approaches Have entirely clear 250 Led to Similar Mechanisms 249 Current models for circadian oscillators continue to be A generic core circadian feedback loop can be traced in refined 250 many eukaryotes 249

8 Adapting to Life on a Rotating World at the Gene Expression Level 255

Introduction: An Important Aspect of An overview indicates that clock regulation of cellular Circadian Regulation of Biological physiology and behavior must relate in some way to changes in cellular biochemistry 264 Processes Is Conveying Output Signals In Gonyaulax, behavior patterns and rates of protein at the Gene Expression Level 255 synthesis are clock controlled 265 Many biological processes are timed by the clock in In Neurospora, clock-controlled genes play an important almost all eukaryotes and in some prokaryotes 255 role in the regulation of physiology 266 The advent of gene expression research in chronobiol- Control of behavior in Drosophila has been studied ogy is fairly recent 256 extensively 269 Large-scale molecular screening for clock-regulated output genes was begun in the 1980s 256 Molecular Mechanisms of Circadian Control Illustrate the Importance of Synthesis Many Cellular Processes Are Clock and Degradation Rates in Rhythms 272 Controlled 257 The clock has multiple points of control 272 Rhythms adapt organisms to temporal niches 257 The fidelity of the circadian signal is affected when Not all daily rhythms are circadian 257 output pathways have many steps 272 Interactions between the environment and the clock synchronize an organism to local time 257 Molecular Control Mechanisms at the Gating of molecular events is a form of clock Cellular Level May Include regulation 258 Transcriptional Processes 273 Not all biochemical rhythms necessarily lead to Gene transcription is a common target of circadian reg- observed rhythms 262 ulation 273 Differentiating Molecular Outputs from the Transcription processes are used in circadian regulation in Neurospora 273 Clock Machinery Aids in Construction Transcriptional control in plants is widespread 275 of a Working Clock Model 262 Transcriptional regulation contributes to rhythmic gene Clock outputs can be distinguished from oscillator expression in vertebrates 278 components 262 The entire Synechococcus transcriptome is clock con- Knowledge of output regulation may lead back to trolled 282 oscillator components 262 The eas gene in Neurospora helps elucidate circadian Circadian Regulation of Translation Is gene expression 263 Another Mechanism for Rhythmic Protein Synthesis 284 Outputs May Have Effects on Oscillator Components 263 Translational regulation is responsible for the rhythm of Gonyaulax LBP synthesis 284 Selected Case Studies Show the Molecular An RNA-binding protein may mediate circadian regu- and Biochemical Correlations of lation of the Drosophila eclosion rhythm 285 Physiological and Behavioral Rhythms 264

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9 Human Circadian Organization 291 Introduction: Humans Are Intensely Curious Entrainment is an important aspect of human circadian about Their Own Daily Rhythms 291 behavior 306 Interest in Time Measurement Has a Long Temporal Regulation of Several Physiological History 292 Functions Illustrates the Importance of Circadian Rhythms in Humans 309 Human awareness of daily, monthly, and annual cycles stretches back to prehistoric civilizations 292 Humans are more aware of the sleep–wake rhythm than any other circadian rhythm 309 The mind’s time sense has important implications for time perception and use by humans 292 Core body temperature has been studied extensively in humans 313 Interest in the physiological functions of humans grew in the nineteenth century 293 Alertness and mental performance show circadian vari- ation 314 Study of human circadian rhythms accelerated very quickly after 1950 294 Melatonin concentration is low in the daytime and high at night 315 New Methods Have Been Developed in the Plasma cortisol peaks at wake time and declines to a Past 25 Years 298 minimum at sleep onset 315 Methods must accommodate the unique parameters of Rhythm parameters vary considerably among individ- humans as research subjects 298 uals 316 Several distinct laboratory protocols have been devel- Circadian Rhythmicity Shows Marked but oped 299 Typical Changes from Birth to Old Age A different strategy must be developed for studies under field conditions 303 316 Circadian rhythms develop gradually in the first year Fundamental Circadian Principles Also Apply of life 316 in Humans 305 Changes in timing and amplitude of circadian rhythms In humans, the primary circadian pacemaker is the are seen in the elderly 319 suprachiasmatic nucleus 305 The Circadian System Plays a Critical Role Free-running rhythms have been documented 305 in Human Daily Performance 320

10 The Relevance of Circadian Rhythms for Human Welfare 325 Introduction: Circadian Rhythmicity Has Vital Traffic accident rates appear related to circadian timing Implications for Many Aspects of 328 Human Lifestyle in the World Today The Exxon Valdez supertanker accident had circadian 325 connotations 328 The accident at Three Mile Island was the most serious Several Fundamental Properties of Circadian in U.S. commercial nuclear power plant history 329 Systems Are Directly Applicable to Occupational or Travel Stresses May Affect Improvement of Human Performance Performance 329 327 Modern expectations place 24-hour demands on soci- The structure of the human SCN appears similar to ety 329 that of other mammals 327 Factory shift work is necessary for industrialized coun- The general picture of circadian physiology in humans tries 329 is similar to that of other diurnal mammals 327 Schedules of nurses, hospital interns, resident physi- Ignoring Circadian Rhythmicity May Increase cians, and hospital surgeries often involve extended work hours 334 Accident Rates 328

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Interstate trucking work schedules are very demanding Sleep disorders may be severe in those who are blind 335 347 Power plant operator schedules require extreme dili- Sleep in the elderly is often disrupted 347 gence over long hours under potentially hazardous The extreme photic environments of the arctic far north conditions 336 and Antarctica may cause circadian problems, par- Military operations offer another example of extended ticularly for nonnatives 348 work hours under high stress 337 Space flight poses unique scheduling and performance Treatment of Circadian Dysfunction by demands 339 Chronopharmacology Is Still Largely Jet lag varies directly with the number of time zones in the Experimental Stages 349 crossed 340 Several approaches can be used to achieve circadian well-being 349 Circadian Physiology Is Important in Human Human phase response curves to both light and mela- Health and Disease 341 tonin provide the theoretical basis for timing admin- Many human health parameters are circadian in nature istration of a synchronizer 350 341 Behavioral treatment has many applications 350 The onset of several acute medical conditions is corre- Light treatment is often very effective 350 lated with circadian phase 342 Melatonin used in physiological doses is a very effec- A knowledge of chronobiology helps in making some tive chronotherapeutic agent 351 medical diagnoses and in timing the treatment of some illnesses 342 Federal Legislation Has Been an Important Sleep and Mood Disorders Belong in the Part of Regulating Work Schedules Realm of Chronopathology 343 in the Public Interest Sector 351 Governments worldwide are beginning to recognize Phase disorders of the sleep–wake cycle include several the significance of circadian timing for human per- different syndromes 343 formance in critical industries 351 Duration disorders in the sleep–wake cycle include Circadian rhythms are related to public workplace several loosely related syndromes 346 safety and efficiency 352

11 Looking Forward 359 Introduction: Accurate Predictions about the Limitations on sleep research in humans will lead Future of Chronobiology Are Hard to increasingly to the use of animal models in the future 364 Make 359 A glance back at the history of human interest in time- Theme 2: Wild, Free-Living Vertebrate keeping will sharpen the focus of any forward pro- Species Are Being Used to Understand jections 359 the Circadian Basis of Sleep 364 Awareness of the adaptive importance of biological Studies of nonhuman vertebrate species, especially timing has grown rapidly in the past decade 361 wild mammals and birds, are a recent dynamic Six forward-looking themes have been chosen to close development in sleep research 364 Chronobiology: Biological Timekeeping 361 Although birds and wild mammals are good alterna- Theme 1: Sleep Research in Humans Is an tives to humans for circadian studies such as sleep, other even simpler models may be necessary in Important Area for Future Study 361 future circadian research 367 Numerous theories postulate the function and mechanism of sleep in humans 361 Theme 3: Simple Invertebrates Hold Out Sleep research and circadian research are increasingly Promise for Studying Molecular Aspects collaborative 362 of Sleep–Wake Rhythms 367 Chronic partial sleep loss is a major health issue in Many circadian questions about sleep remain unan- industrialized countries 362 swered 367 Sleep deficit aggravates many health conditions of the Studies have been carried out with Drosophila on an elderly 362 important cellular signaling pathway 368

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A second productive line of investigation focuses on A graded range of phenotypes is found in the Clock the role of Clock genes in regulating rest 369 chimeras, from typical wild-type circadian behavior Can single-gene mutants affecting sleep be identified? to homozygous mutant behavior 375 369 Theme 6: The Pressing Global Issue of Theme 4: Another Breakthrough Discovery Is Ecosystem Integrity and Biodiversity the Widespread Distribution of Has Circadian Aspects 375 Peripheral Pacemakers 370 Ecosystems are relatively stable configurations of bio- One of the first mammalian pacemakers to be discov- mass and species diversity coexisting in a particular ered was the retinal clock of golden hamsters 370 set of climatic and physiographic conditions 375 One recent promising development in circadian The geological record of life on Earth bears witness to research has been the application of transgenic tech- five worldwide major extinctions during the past nology to cell culture of insect and mammalian half-billion years 376 pacemaker tissues 370 The changing of ecosystem parameters may impact circadian entrainment 377 Theme 5: Single Independently Oscillating SCN Clock Cells Are Coordinated into a Closure: A Remarkable Island Symbolizes Multicellular Regulator of Behavioral Adaptive Rhythmicity 380 Output Rhythms 372 Biological timing is widespread in plants and animals 380 Chimera technology is providing answers about the control of circadian behavior by the ensemble of An allegory will portray the power of biological timing oscillators in the SCN 372 380

Appendix 383 Glossary 387 Photo Credits 391 Index 393