Description
Book SynopsisThe Handbook of Behavioral Genetics and Phenotyping represents an integrative approach to neurobehavioural genetics; worldwide experts in their field will review all chapters. Advanced overviews of neurobehavioural characteristics will add immense value to the investigation of animal mutants and provide unique information about the genetics and behavioural understanding of animal models, under both normal and pathological conditions. Cross-species comparisons of neurobehavioural phenotypes will pave the way for an evolutionary understanding of behaviour. Moreover, while biological sciences are progressing towards a holistic approach to investigate the complexity of organisms (i.e., systems biology approach), an integrated analysis of behavioural phenotyping is still lacking. The Handbook of Behavioral Genetics and Phenotyping strengthens the cross-talk within disciplines that investigate the fundamental basis of behaviour and genetics. This will be the first volume in which traditio
Table of ContentsList of Contributors xix
Preface xxv
1 Genetic Screens in Neurodegeneration 1
Abraham Acevedo Arozena and Silvia Corrochano
Introduction 1
The Genetics of Neurodegenerative Disorders 2
Neurodegeneration Disease Models 4
Genetic Approaches to Discover New Genes Related to Neurodegeneration Using Disease Models 5
Saccharomyces cerevisiae 6
Caenorhabditis elegans 8
Drosophila melanogaster 9
Danio rerio 10
Mus musculus 11
Human Cellular Models and Post-mortem Material 14
The Future 14
Acknowledgments 15
References 15
2 Computational Epigenomics 19
Mattia Pelizzola
Background 19
Profiling and Analyzing the Methylation of Genomic DNA 19
Experimental Methods 20
Data Analysis 20
Array-based Methods 20
Sequencing-based Methods 20
Profiling and Analyzing Histone Marks 26
Experimental Methods 26
Data Analysis 27
Issues of Array-based Methods 27
Issues of NGS-based Methods 27
Integration with Other Omics Data 31
Chromatin States 32
Unraveling the Cross-talk Between Epigenetic Layers 33
References 33
3 Behavioral Phenotyping in Zebrafish: The First Models of Alcohol Induced Abnormalities 37
Robert Gerlai
Introduction 37
Alcohol Related Human Disorders: A Growing Unmet Medical Need 37
Unraveling Alcohol Related Mechanisms: The Importance of Animal Models 38
Face Validity: The First Step in Modeling a Human Disorder 39
Acute Effects of Alcohol in Zebrafish: A Range of Behavioral Responses 39
Chronic Alcohol Exposure Induced Behavioral Responses in Zebrafish 41
Effects of Embryonic Alcohol Exposure 42
Behavioral Phenotyping: Are We There Yet? 46
Assembling the Behavioral Test Battery 49
Concluding Remarks 50
References 50
4 How does Stress Affect Energy Balance? 53
Maria Razzoli, Cheryl Cero, and Alessandro Bartolomucci
Introduction 53
Stress 54
Energy Balance and Metabolic Disorders 55
Pro-adipogenic Stress Mediators 57
Pro-lipolytic Effect of Stress Mediators 57
How does Stress Affect Energy Balance? 57
Animal Models of Chronic Stress and their Impact on Energy Balance 58
Physical and Psychological (non-social) Chronic Stress Models 58
Mild Chronic Pain Models – Mild Tail Pinch, Foot Shock 58
Thermal Models – Cold and Heat Stress 64
Chronic Mild Stress Models: Chronic Mild Stress, Chronic Variable Stress, etc. 64
Restraint or Immobilization 65
Chronic Social Stress Models 66
Social Isolation, Individual Housing 66
Unstable Social Settings 66
Visible Burrow System 67
Intermittent Social Defeat (Resident/Intruder Procedure) 67
Chronic Psychosocial Stress, Sensory Contact, and Chronic Defeat stress 68
Stress, Recovery, and Maintenance: Insights on Adaptive and Maladaptive Effects of Stress 69
Molecular Mechanisms of Stress-Induced Negative and Positive Energy Balance 70
Serotonin (5-hydroxytryptamine, 5HT) 71
Orexin 71
Neuropeptide Y (NPY) 72
Ghrelin and Growth Hormone Secretagogue Receptor (GHSR) 72
Glucagon like Peptide 1 (GLP1) 73
Leptin 73
Amylin 74
Norepinephrine and β3-Adrenergic Receptor 74
Conclusion 74
References 75
5 Interactions of Experience-Dependent Plasticity and LTP in the Hippocampus During Associative Learning 91
Agnès Gruart, Noelia Madroñal, María Teresa Jurado-Parras, and José María Delgado-García
Introduction: Study of Learning and Memory Processes in Alert Behaving Mammals 91
Changes in Synaptic Strength During Learning and Memory 92
Classical Conditioning 92
Instrumental Conditioning 95
Changes in Synaptic Strength Evoked by Actual Learning can be Modified by Experimentally Evoked Long-term Potentiation 96
Other Experimental Constraints on the Study of the Physiological Basis of Learning Processes 100
Factors Modifying Synaptic Strength (Environment, Aging, and Brain Degenerative Diseases) 101
Different Genetic and Pharmacological Manipulations Able to Modify Synaptic Strength 103
Functional Relationships Between Experimentally Evoked LTP and Associative Learning Tasks 106
Future Perspectives 108
Context and Environmental Constraints 108
Other Forms of Learning and Memory Processes 109
Cortical Circuits and Functional States During Associative Learning 109
References 110
6 The Genetics of Cognition in Schizophrenia: Combining Mouse and Human Studies 115
Diego Scheggia and Francesco Papaleo
Background 115
Genetics of Schizophrenia 116
Cognitive (dys)functions in Schizophrenia 117
Translating Cognitive Symptoms in Animal Models 119
Executive Control 120
Performance in Schizophrenia 122
Animal Models 124
Working Memory 125
Performance in Schizophrenia 126
Animal Models 127
Control of Attention 128
Performance in Schizophrenia 130
Animal Models 130
Concluding Remarks 131
References 132
7 The Biological Basis of Economic Choice 143
David Freestone and Fuat Balci
Introduction 143
Translating from Animals to Humans 144
Reinforcement Learning in the Brain 145
Subjective Value 146
The Midbrain Dopamine System Updates Value 147
From Stimulus Value to Action Value 150
Model Based Learning 150
The Prefrontal Cortex Encodes Value 152
The Basal Ganglia Selects Actions 153
Optimal Decisions: Benchmarks for the Analysis of Choice Behavior 155
The Drift Diffusion Model 157
Temporal Risk Assessment 158
Timed-response Inhibition for Reward-rate Maximization 160
Timed Response Switching 163
Temporal Bisection 164
Numerical Risk Assessment 166
Rodent Version of Balloon Analog Risk Task 167
Conclusion 167
Acknowledgments 168
References 168
8 Interval-timing Protocols and Their Relevancy to the Study of Temporal Cognition and Neurobehavioral Genetics 179
Bin Yin, Nicholas A. Lusk, and Warren H. Meck
Introduction 179
Application of a Timing, Immersive Memory, and Emotional Regulation (Timer) Test Battery 190
Neural Basis of Interval Timing 191
What Makes a Mutant Mouse “Tick”? 193
Proposal of a TIMER Test Battery and Its Application in Reverse Genetics 199
Behavioral Test Battery Applications in Forward Genetics 202
Order of Behavioral Tasks 205
Location and Time of Behavioral Testing 205
Summary 205
References 206
Appendix I 226
Limitations of the individual-trials analysis for data obtained in the peak-interval (PI) procedure 226
9 Toolkits for Cognition: From Core Knowledge to Genes 229
Giorgio Vallortigara and Orsola Rosa Salva
Introduction 229
Core Knowledge: The Domestic Chick as a System Model 230
Numerical Competence 230
Physical Properties 230
Geometry of Space 232
Animate Agents 232
A Comparative Perspective on the Genetic and Evolutionary Bases of Social Behavior 236
From Social Experience to Genes 239
From Genes to Social Behavior 241
Future Directions 243
Conserved Mechanisms for Social Core Knowledge 243
Interactions Between Experience and Genomic Information 243
Neurogenetic Basis of Social Predispositions 243
Epigenetics and the Development of the Social Brain 244
Spatial Cognition, Another Promising Core-knowledge Domain 244
References 245
10 Quantitative Genetics of Behavioral Phenotypes 253
Elzbieta Kostrzewa and Martien J.H. Kas
Human Studies of Quantitative Traits 253
Mouse Studies of Quantitative Traits 254
Classical Inbred Mice 254
Quantitative Trait Loci (QTL) Analysis 254
Knock-out (KO) Mouse Lines 256
Use of Mice as Animal Model for Complex Human Traits 257
Comparative Genomic Approaches 257
Evolutionarily Conserved Behavioral Phenotypes 257
Physical Activity – Definitions and Methods of Phenotypic Measurement 258
Current Results of Quantitative Genetic Basis of PA in Humans 259
Current Results of Quantitative Genetic Basis of PA in Mice 260
KO Studies 260
QTL Studies 261
An Overlap of Genetic Findings Between the Species 261
Conclusions 265
References 265
11 Behavioral Phenotyping in Genetic Mouse Models of Autism Spectrum Disorders: A Translational Outlook 271
Maria Luisa Scattoni, Caterina Michetti, Angela Caruso, and Laura Ricceri
Introduction 271
Measuring Social behavior in ASD Mouse Models 272
Social Interaction Tests 272
Male-female 277
Female-female 278
Male-male 278
Social-approach 279
Sociability Test Phase 280
Social Novelty 280
Social Recognition 280
Repetitive Behavior 281
Motor Stereotypies 281
Restricted Interests 281
Behavioral Inflexibility 282
Behavioral Tests Targeting other ASD Symptoms 282
Anxiety 282
Epilepsy 283
Behavioral Phenotyping in ASD Mouse Pups 283
Future Directions: ASD Mouse Models as a Resource for Gene-environment Interaction Studies 284
Acknowledgments 285
References 285
12 Genetics of Human Sleep and Sleep Disorders 295
Birgitte Rahbek Kornum
The Mystery of Human Sleep 295
Sleep is Essential for Mammalian Life 295
The Function of Sleep 296
Extended Wakefulness Induces Sleep 296
Homeostatic and Circadian Regulation of Sleep and Wake 297
Adenosine and Sleep Homeostasis 298
Resistance to Sleep Loss is a Stable Phenotype 299
Genetic Markers of Response to Sleep Loss 299
A Unique Activity Pattern Characterizes the Sleeping Brain 300
Sleep Stages and Sleep Cycles 300
Genetics of the Human Sleep Electroencephalography 301
Normal Sleep Architecture is Lost in Fatal Familial Insomnia 303
Circadian Regulation of Sleep and Associated Disorders 304
Circadian Regulation of Sleep 304
Molecular Regulation of the Circadian Clock 305
The Central Circadian Clock is Entrained By Light 306
Circadian Rhythm Sleep Disorders 307
Advanced Sleep Phase Syndromes 307
Delayed Sleep Phase Syndromes 308
Short Sleep Times in Healthy Individuals 308
Destabilization of Sleep States and Narcolepsy 309
Normal Regulation of Sleep Architecture 309
Wakefulness is Associated with Cortical Activation 309
The Preoptic Area Contains Sleep-promoting Neurons 309
Mutual Inhibition Regulates Transitions Between Wake and Sleep 310
Regulation of REM Sleep 311
Narcolepsy, A Disorder of Wakefulness and REM Sleep 311
Narcolepsy with Cataplexy is Caused By Hypocretin Deficiency 312
Autoimmunity Toward Hypocretin Neurons 312
Genetic Evidence Supports the Autoimmune Hypothesis of Narcolepsy 313
Restless Legs Syndrome, A Developmental Sleep Disorder 314
Restless Legs Syndrome, A Mysterious Urge to Move 314
Restless Legs Syndrome and Dopamine Disturbances 315
Iron Deficiency Exacerbates RLS Symptoms 315
Genetic Studies Suggest Developmental Defects 316
Unresolved Issues and Future Perspectives 316
What is the Molecular and Neuroanatomical Basis for the Ultradian Rhythm of NREM-REM Sleep? 317
What is the Genetic Basis for Individual Variation in Complex Sleep Features such as Sleep Spindles and K-Complexes? 317
What is the Basis for the Individual Differences in Resistance to Sleep Loss? 317
Are Homeostatic and Circadian Mechanisms Genuinely Independent or Are They Intimately Linked? 318
What Controls the Molecular and Anatomical Diversity of Sleep Regulatory Networks Across Species? 318
References 319
13 The Endocannabinoid System in the Control of Behavior 323
Edgar Soria-Gomez, Mathilde Metna, Luigi Bellocchio, Arnau Busquets-Garcia, and Giovanni Marsicano
Introduction 323
Cannabinoid Effects and Endocannabinoid Functions 324
Role of the ECS in Memory Processes 325
Memory: General Background 325
Role of the ECS in Synaptic Plasticity 325
Memory Impairment Produced by Exogenous Cannabinoids 326
Cannabinoid Regulation of Memory: Neurobiological Mechanisms 327
Role of the ECS in Fear Processes 329
Fear: General Background 329
The ECS as an Endogenous Regulator of Fear Responses 331
Cannabinoid Regulation of Fear: Neurobiological Mechanisms 332
Implication of the ECS in Fear Coping Behaviors 333
Role of the ECS in Feeding Behavior 336
Feeding Behavior: General Background 336
The ECS as an Endogenous Regulator of Feeding Behavior 337
The ECS and Food Reward Circuits 338
The ECS in the Hypothalamic Appetite Network 338
The ECS in the Caudal Brainstem and Gastrointestinal Tract 340
Bimodal Control of Stimulated Food Intake by the ECS in the Brain 341
Paraventricular Hypothalamus Versus Ventral Striatum in Hypophagia induced by the ECS 342
The Olfactory Bulb and the Hyperphagic Action of the ECS 342
Conclusions 343
References 344
14 Epigenetics in Brain Development and Disease 357
Elisabeth J. Radford, Anne C. Ferguson-Smith, and Sacri R. Ferrón
Introduction 357
Epigenetics and Neurodevelopment 358
Histone Modifications 358
DNA Methylation 361
Hydroxymethylation 364
Genomic Imprinting 364
Non-coding RNAs 365
Neurodevelopmental Disorders with an Epigenetic Basis 366
Rett Syndrome 366
Coffin–Lowry Syndrome 367
Rubinstein–Taybi Syndrome 367
Alpha-thalassemia Mental Retardation Syndrome 367
Imprinted Neurodevelopmental Disorders 368
Trinucleotide Repeat Disorders 368
Fragile X Syndrome 370
Friedreich’s Ataxia 370
Myotonic Dystrophy 371
Huntington’s Disease (HD) 371
Epigenetics of Neurodegenerative Disorders 372
Parkinson´s Disease (PD) 372
Alzheimer´s Disease (AD) 373
The Impact of the Environment on the Epigenome 374
Epigenetic Therapy in Neurodevelopment 375
Untargeted Treatment 375
Targeted Epigenetic Modulation 377
Concluding Remarks 377
Acknowledgments 377
References 378
15 Impact of Postnatal Manipulations on Offspring Development in Rodents 395
Diego Oddi, Alessandra Luchetti, and Francesca Romana D’Amato
Introduction 395
Early Postnatal Environment in Laboratory Altricial Rodents 396
Rodents’ Responses to Postnatal Environment and Early Manipulations 397
Assessing Pups’ Responses to Postnatal Environment and Early Manipulation 397
Neonatal Ultrasonic Calls: Isolation-induced Vocalizations and Maternal Potentiation 397
Searching for Social Contact: Homing and Huddling Behaviors 398
Early-life Environment and Stress-Response 398
Separation from the Mother 399
Mother’s Stress 400
The Cross-fostering Paradigm 401
Repeated Cross-fostering as a Model of Early Maternal Environment Instability 403
Environmental Enrichment 405
Conclusions 406
References 407
16 Exploring the Roles of Genetics and the Epigenetic Mechanism DNA Methylation in Honey Bee (Apis Mellifera) Behavior 417
Christina M. Burden and Jonathan E. Bobek
Introduction 417
Genetics of Adult Honey Bee Biology and Behavior 418
Nurse to Forager Transition 418
Forager Preference 420
Techniques for Investigating the Genetic Bases of Behavior 420
QTL Mapping 421
RNA Techniques 421
Microarrays 421
RNA Sequencing 422
Experimentally Modulating the Genes Correlated with Specific Behaviors to Test Causality 422
DNA Methylation and Honey Bee Behavior 423
Honey Bee DNA Methylation Machinery and Genome-Wide Patterns 423
DNA Methylation and Task Specialization 424
DNA Methylation and Memory Consolidation 425
Techniques for Detecting and Assaying DNA Methylation 426
The Technological Bases for Most DNA Methylation Assays 426
Methylation-specific Restriction Endonucleases 426
Protein-mediated Precipitation of Methylated DNA 428
Bisulfite Conversion 428
Assaying Single CpGs, Short Sequences, and Target Regions 429
Analyzing Genome-wide DNA Methylation Patterns: Microarray-based Methodologies 431
Analyzing Genome-wide DNA Methylation Patterns: Sequencing-based Methodologies 432
Techniques for Manipulating DNA Methylation 434
Pharmacological Manipulation of DNA Methylation 434
RNA Interference as a DNMT Blockade 434
Concluding Remarks and Future Perspectives 435
References 436
17 Genetics and Neuroepigenetics of Sleep 443
Glenda Lassi and Federico Tinarelli
Defining Sleep 443
Sleep is Genetically Determined 445
EEG and Heritable Traits 445
Sleep Disorders and Genes 446
Sleep and Gene Expression 447
Epigenetics 448
DNA Methylation 450
Posttranslational Modifications (PTMs) 450
RNA interference 452
Neuroepigenetics 453
Two Neurodevelopmental Disorders with Opposing Imprinting Profiles and Opposing Sleep Phenotypes 453
Neuroepigenetics of Sleep 454
Fruit Fly 454
Rodent Models 454
Human Beings 456
Sleep and Parent-of-origin Effects 458
Conclusions 460
References 460
18 Behavioral Phenotyping Using Optogenetic Technology 469
Stephen Glasgow, Carolina Gutierrez Herrera, and Antoine Adamantidis
Introduction 469
Microbial Opsins 470
Fast Excitation Using Channelrhodopsin-2 and Its Variants 470
Fast Optical Silencing 474
Alternative strategies for cell-type specific modulation of neural activity 476
Targeting systems 476
Light Delivery in the Animal Brain 478
Recording Light-evoked Neuronal Activity 479
Behavioral Phenotyping 479
In-vivo Optogenetics: Defining Circuits 480
Perspectives 484
Acknowledgments 484
References 484
19 Phenotyping Sleep: Beyond EEG 489
Sibah Hasan, Russell G. Foster, and Stuart N. Peirson
Sleep Research 489
Phenotyping Sleep in Humans 490
Introduction 490
Actigraphy 490
Cardiorespiratory Signals 491
EEG 492
Phenotyping Sleep in Animal Models 494
Introduction 494
EEG 494
Introduction 494
Tethered EEG 496
Telemetered EEG 496
NeuroLogger EEG 498
Beyond EEG 498
Infrared Beam Break 499
Movement Based on Implanted Magnets 499
Piezo-electric Sensors 499
Video Tracking 500
Future Perspectives 501
Acknowledgements 502
References 502
20 A Cognitive Neurogenetics Screening System with a Data-Analysis Toolbox 507
C.R. Gallistel, Fuat Balci, David Freestone, Aaron Kheifets, and Adam King
Introduction 507
Mechanisms, Not Procedures 508
Functional Specificity 508
No Group Averages 509
Physiologically Meaningful Measures 509
Importance of Large-scale Screening and Minimal Handling 511
Utilizable Archived Data with Intact Data Trails 511
The System 512
The Toolbox 513
Core Commands 516
Powerful Graphics Commands 517
Results 518
Summary 523
References 524
21 Mapping the Connectional Architecture of the Rodent Brain with fMRI 527
Adam J. Schwarz and Alessandro Gozzi
Introduction 527
MRI Mapping of Functional Connectivity in the Rodent Brain 528
Networks of Functional Covariance 528
Connectivity of Neurotransmitter Systems 529
The Dopaminergic System 529
The Serotonergic System 531
Resting State BOLD fMRI 532
Connectivity Networks of the Rodent Brain 533
Do Rodent Brains have a Default Mode Network? 536
Use of Anesthesia and Other Methodological Considerations 539
Transgenic Models: Genetic Manipulation of Functional Connectivity Patterns 541
Future Perspectives 543
References 545
22 Cutting Edge Approaches for the Identification and the Functional Investigation of miRNAs in Brain Science 553
Emanuela de Luca, Federica Marinaro, Francesco Niola, and Davide De Pietri Tonelli
Introduction 553
History 553
Biology and Functions in the Brain 553
Identification of Novel MicroRNAs in the Brain 555
miRNA Extraction and Purification 556
miRNA Cloning 556
Computational Identification of Novel miRNAs 557
RNA Sequencing (RNA-Seq) 558
miRNA expression analysis in the brain 559
miRNA profiling 559
Analysis of miRNA Expression in Tissue 559
Target Identification 560
Computational Identification of Targets 561
Proteomics 561
RISC-associated miRNA Targets 562
RNomics 563
miRNA Manipulation/Target Validation 565
miRNA Inhibition 565
miRNA Over-expression 566
Target Validation 567
New Frontiers in Small RNA-based Technologies to Cure Nervous System Deficits 567
Use of miRNAs in Gene Therapy 567
Use of miRNAs in Gene Therapy in the Brain Requires Improved Delivery Strategies 571
Conclusion and Perspectives 572
Are Circulating miRNAs Novel Biomarkers for Brain Diseases? 572
Use of miRNAs in Cell Reprogramming Technology 573
Are miRNAs Just the “Tip of the Iceberg”? Emerging Classes of Noncoding RNAs and Novel Scenarios 574
Acknowledgments 575
Competing Financial Interests 575
References 575
Index 585
