Handbook of Neurobehavioral Genetics and Phenotyping

Table of Contents:
List 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

About the Author :
Valter Tucci graduated in Psychology in 2000, at the University of Padua, studying the cardiovascular changes associated with NREM and REM sleep states in humans. During his Ph.D studies he investigated the physiological and cognitive traits of narcoleptic patients. Then he moved to Boston where he studied sleep physiology and cognitive processes in rhesus monkeys and zebrafish. In 2003, he moved to Oxford (UK). At this time, he switched to work on behavioural neurogenetics. He was awarded a Career Development Fellowship by the MRC Mammalian Genetics Unit in Harwell and was then promoted to the post of Investigator Scientist two years later. Valter Tucci is currently Team Leader of the Neurobehavioural Group at the Italian Institute of Technology (IIT). His research focuses on analysis of the effects that genetic and epigenetic mechanisms exert on sleep and cognition.