Title Details

List of Contributors xiii

Preface xvii

Part I Fundamental Concepts 1

1 Cytosolic and Transcriptional

Cycles Underlying Circadian Oscillations 3
Michael H. Hastings and John S. O’Neill

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 Human Circadian 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: Reciprocal Partners in the Regulation of Physiology and Behavior 57
Ralph Mistlberger

4.1 Introduction 57

4.2 What is sleep 59

4.3 Circadian regulation of sleep 60

4.4 Reciprocity: sleep–wake 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 its Role 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 Regulation of Major Physiological Systems 95

6 Physiology of the Adrenal and Liver Circadian 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 Regulators of 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 of the Circadian System: Blood Pressure Regulation at Multiple Levels 135
Hitoshi Okamura, Miho Yasuda, Jean?]Michel Fustin, and Masao Doi

9.1 Introduction 135

9.2 Effects of deleting Cry genes 135

9.3 Reduced a-adrenoceptor responsiveness in peripheral vessels and primary aldosteronism of Cry-null mice 138

9.4 Rapid blood pressure control system: enhanced baroreflex in Cry-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 Rhythms and Development of Type 2 Diabetes Mellitus: Contributions to Insulin Resistance 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 Cell Cycle and Links to Cancer 169
T. Katherine Tamai and David 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 Destabilized Circadian System may Increase Risk for Development of Cancer and Type 2 Diabetes 183
An Pan, Elizabeth Devore, and Eva 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 Immune Function 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 Central Nervous System 221

15 Circadian Clock, Reward and Addictive Behavior 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 a Decline 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 Mood Disorders 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 Disruption in 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 Alzheimer’s Disease and the Mistiming of 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 Parkinson’s Disease 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 Huntington’s Disease 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 sleep–wake 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, and Johanna 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 Christopher S. 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

Index 351