List of Contributorsxiii
Prefacexvii
Part I Fundamental Concepts 1
1 Cytosolic and Transcriptional
Cycles Underlying CircadianOscillations 3
Michael H. Hastings and John S. ONeill
1.1 Introduction 3
1.2 Assembling the transcriptional feedback loop 5
1.3 Keeping the transcriptional clockworks in tune 9
1.4 Building posttranslational mechanisms into the circadian pacemaker 13
1.5 Is the transcriptional clock paramount? 15
1.6 Conclusion: cytoscillators, clocks and therapies 18
References 18
2 Molecular Determinants of HumanCircadian Clocks 25
Steven A. Brown
2.1 Molecular elements of human clocks: a brief review 25
2.2 Peripheral and central clocks 26
2.3 Signaling to peripheral circadian clocks 28
2.4 Human peripheral and central clocks 29
2.5 Human genetics 29
2.6 Technologies for measurement of human circadian clocks 30
2.7 Cellular methods 30
2.8 Omics?]based methods to analyze human clocks 32
2.9 Summary and outlook 33
References 33
3 The Suprachiasmatic Nucleus (SCN):Critical Points 37
Christopher S. Colwell, Paul Witkovsky,and Rae Silver
3.1 SCN is site of master circadian pacemaker in mammals 37
3.2 SCN receives photic information through a specialized light detection pathway 39
3.3 SCN neurons are endogenous single cell oscillators that generate rhythms in neural activity 40
3.4 The SCN has circuit level organization that is just beginning to be unraveled 42
3.5 Coupling with the SCN circuit is mediated by a set of peptides with VIP on top of the hierarchy 44
3.6 SCN outputs 44
3.7 SCN in aging and disease 50
References 51
4 Sleep and Circadian Rhythms: ReciprocalPartners in the Regulation of Physiologyand Behavior 57
Ralph Mistlberger
4.1 Introduction 57
4.2 What is sleep 59
4.3 Circadian regulation of sleep 60
4.4 Reciprocity: sleepwake feedback to the circadian clock 69
4.5 Conclusions: Circadian clocks and sleep are intertwined processes 73
References 73
5 Circadian Regulation of Arousal and itsRole in Fatigue 81
David R. Bonsall and Mary E. Harrington
5.1 Defining arousal 81
5.2 Brain structures important for arousal 83
5.3 Neurochemicals signaling the states of arousal 84
5.4 Circadian regulation of the arousal system 86
5.5 Influence of input pathways on circadian regulation of arousal 88
5.6 Sustained states of fatigue: a disorder of the arousal network? 88
5.7 Conclusions 90
References 91
Part II Circadian Regulationof Major PhysiologicalSystems 95
6 Physiology of the Adrenal and LiverCircadian Clocks 97
Alexei Leliavski and Henrik Oster
6.1 Introduction 97
6.2 Circadian control of adrenal function 98
6.3 Circadian control of liver function 101
6.4 Conclusion 105
References 105
7 Nutrition and Diet as Potent Regulatorsof the Liver Clock 107
Yu Tahara and Shigenobu Shibata
7.1 Introduction 107
7.2 Food is a zeitgeber: The FEO in the brain 107
7.3 The FEO in peripheral tissues 109
7.4 What should we eat? What types of food can stimulate the peripheral clock? 110
7.5 When should we eat? Application to human life science 112
7.6 Circadian rhythm and obesity and diabetes 113
References 116
8 The Cardiovascular Clock 119
R. Daniel Rudic
8.1 Introduction 119
8.2 The vascular clock 119
8.3 Circadian clock regulation of the endothelial cell layer of blood vessels 120
8.4 The circadian clock in vascular disease 121
8.5 The circadian clock and vascular cell signaling 122
8.6 The circadian rhythm in blood pressure, nighttime hypertension, and cardiovascular disease in humans 123
8.7 Diabetes, obesity, and blood pressure 125
8.8 AT influences the circadian rhythm in experimental hypertension 126
8.9 The circadian clock and fluid balance 127
8.10 The circadian clock and peripheral vascular resistance 127
8.11 Conclusion 130
References 130
9 Hypertension Caused by Disruption ofthe Circadian System: Blood PressureRegulation at Multiple Levels 135
Hitoshi Okamura, Miho Yasuda,Jean?]Michel Fustin, and Masao Doi
9.1 Introduction 135
9.2 Effects of deletingCrygenes 135
9.3 Reduced a-adrenoceptor responsiveness in peripheral vessels and primary aldosteronism ofCry-null mice 138
9.4 Rapid blood pressure control system: enhanced baroreflex inCry-null mice 139
9.5 Conclusion 141
References 141
10 Chronobiology of Micturition 143
Akihiro Kanematsu and Hiromitsu Negoro
10.1 Introduction 143
10.2 Human studies 144
10.3 Animal models 146
10.4 The circadian clock and micturition 147
10.5 The clock in the bladder 148
10.6 Future directions 150
References 151
11 Disruption of Circadian Rhythmsand Development of Type 2 DiabetesMellitus: Contributions to InsulinResistance and Beta?]cell Failure 155
Aleksey V. Matveyenko
11.1 Introduction 155
11.2 Mechanisms underlying pathophysiology of Type 2 diabetes mellitus: interaction between insulin resistance and beta-cell failure 156
11.3 Mechanisms underlying the association between circadian disruption and T2DM; potential role of obesity and insulin resistance 160
11.4 Mechanisms underlying the association between circadian disruption and T2DM; potential role of impaired beta-cell secretory function and mass 162
11.5 Conclusion 165
References 166
12 Circadian Clock Control of the CellCycle and Links to Cancer 169
T. Katherine Tamai andDavid Whitmore
12.1 Introduction 169
12.2 Epidemiology 169
12.3 Does circadian clock disruption have any relevance in a clinical setting? 170
12.4 Circadian clock control of the cell cycle in healthy tissues 171
12.5 How might the cellular circadian clock regulate cell cycle timing? 173
12.6 Clock disruption and cancer 177
12.7 Does alteration in clock gene expression in human tumors correlate with the survival of patients? 178
12.8 Circadian?]based chemotherapy (Chronotherapy): timing cancer treatment to improve survival 178
12.9 Conclusion 180
References 180
13 How Shift Work and a DestabilizedCircadian System may Increase Risk forDevelopment of Cancer and Type 2Diabetes 183
An Pan, Elizabeth Devore, andEva S. Schernhammer
13.1 Introduction 183
13.2 Shift work and cancer 184
13.3 Shift work and obesity, metabolic syndrome, and type 2 diabetes 194
13.4 Conclusions and perspective of future studies 205
References 205
14 Circadian Rhythms in ImmuneFunction 211
Kandis Adams, Oscar Castanon-Cervantes,and Alec J. Davidson
14.1 Introduction 211
14.2 Daily variations in health and disease 212
14.3 Early evidence of circadian regulation on immunity 212
14.4 Clinical relevance of circadian regulation of the immune system 213
14.5 The circadian system communicates time of day information to immune cells and tissues 214
14.6 Immune effector cells under circadian regulation 214
14.7 Circadian disruption role in immune pathology and disease 216
14.8 The effects of clock gene alterations on immune functions 217
14.9 Conclusions 217
References 218
Part III Clocks in the CentralNervous System 221
15 Circadian Clock, Reward and AddictiveBehavior 223
Urs Albrecht
15.1 Introduction 223
15.2 Evidence for a time of day basis of addictive behavior 223
15.3 Drugs, circadian clock genes and addictive behavior 224
15.4 Links between feeding, addictive behavior and the clock 228
15.5 Treatment of addiction changing the circadian clock 229
References 231
16 How a Disrupted Clock may Cause aDecline in Learning and Memory 235
Christopher S. Colwell
16.1 Introduction 235
16.2 Molecular clockwork expressed in brain regions central to learning and memory including the hippocampus, amygdala, and cortex 236
16.3 The circadian clockwork regulates intracellular signaling pathways known to be important to learning and memory 237
16.4 The circadian system impacts electrical activity and synaptic plasticity 238
16.5 The circadian system regulates neuroendocrine secretions that are well known to alter learning and memory processes 240
16.6 Disruptions of the circadian timing system alter learned behavior 241
16.7 Conclusions 245
References 245
17 Circadian Rhythms in MoodDisorders 249
Colleen A. McClung
17.1 Introduction 249
17.2 Categories of rhythm disruptions 251
17.3 Seasonal affective disorder 252
17.4 Treatments for mood disorders alter rhythms 253
17.5 Human genetic studies 257
17.6 Animal studies 257
17.7 SCN output?]rhythmic hormones and peptides 260
17.8 Regulation of mood?]related brain circuits by the SCN and circadian genes 262
17.9 Neuroinflammation 263
17.10 Cell cycle regulation/neurogenesis 264
17.11 Conclusions 265
References 265
18 Sleep and Circadian Rhythm Disruptionin Psychosis 271
Stuart N. Peirson and Russell G. Foster
18.1 Introduction 271
18.2 Psychosis 273
18.3 Sleep and circadian rhythm disruption in psychosis 275
18.4 Possible mechanisms underlying SCRD in psychosis 277
18.5 Conclusions 280
References 281
19 Alzheimers Disease and the Mistimingof Behavior 283
Roxanne Sterniczuk and Michael Antle
19.1 Introduction 283
19.2 Behavioral changes 283
19.3 Physiological changes 285
19.4 Neurological changes 286
19.5 Modeling AD 289
19.6 Chronobiological treatment of AD symptomology 290
19.7 Conclusion 292
References 293
20 Circadian Dysfunction in ParkinsonsDisease 295
Christopher S. Colwell
20.1 Introduction 295
20.2 Dysfunction in the circadian system may contribute to the nonmotor symptoms of PD 296
20.3 Dopaminergic treatments for the motor symptoms of PD may contribute to circadian disruption 297
20.4 PD models show sleep and possible circadian disruption 298
20.5 Possible underlying mechanisms 300
20.6 Conclusion 301
References 302
21 Circadian Dysfunction in HuntingtonsDisease 305
A. Jennifer Morton
21.1 Introduction 305
21.2 Mechanisms underlying sleep and circadian rhythm generation 305
21.3 Circadian disruption in HD 306
21.4 Circadian disruption in animal models of HD 306
21.5 Circadian disruption of peripheral clocks and metabolism in HD 311
21.6 Pharmacological manipulation of circadian disruption in HD mice 311
21.7 Environmental modulation of circadian disruption in HD mice 311
21.8 Clinical changes in sleep in HD 312
21.9 Disturbance in sleep architecture in HD 312
21.10 Pathology underlying changes in sleep and circadian activity in HD 313
21.11 The orexin system in HD 313
21.12 The role of non?]SCN oscillators in HD 314
21.13 Consequences of sleepwake disturbance in HD 314
21.14 Cognitive dysfunction and mood disturbance in HD 315
21.15 Management of circadian disturbance in HD 315
21.16 Conclusions 317
References 318
22 The Aging Clock 321
Stephan Michel, Gene D. Block, andJohanna H. Meijer
22.1 Introduction 321
22.2 The effects of aging on rhythmic behaviors 321
22.3 The effects of aging on components of the circadian system 323
22.4 Molecular rhythms in steady state 328
22.5 The effects of aging on the resetting behavior of central and peripheral oscillators 329
22.6 The effects of the circadian system on aging and age?]related disease: Circadian misalignment and
longevity 330
22.7 Therapeutic possibilities for agerelated circadian disorders 331
22.8 Conclusions 332
References 332
23 Can we Fix a Broken Clock? 337
Analyne M. Schroeder and ChristopherS. Colwell
23.1 Introduction 337
23.2 Light therapy 339
23.3 Scheduled meals 340
23.4 Scheduled exercise 341
23.5 Scheduled sleep 343
23.6 Pharmacological targeting of the circadian system 343
23.7 Conclusions 345
References 346
Index351
