Handbook of Neurobehavioral Genetics and Phenotyping

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.

• List of Contributors xixPreface xxv1 Genetic Screens in Neurodegeneration 1Abraham Acevedo Arozena and Silvia CorrochanoIntroduction 1The Genetics of Neurodegenerative Disorders 2Neurodegeneration Disease Models 4Genetic Approaches to Discover New Genes Related to Neurodegeneration Using Disease Models 5Saccharomyces cerevisiae 6Caenorhabditis elegans 8Drosophila melanogaster 9Danio rerio 10Mus musculus 11Human Cellular Models and Post-mortem Material 14The Future 14Acknowledgments 15References 152 Computational Epigenomics 19Mattia PelizzolaBackground 19Profiling and Analyzing the Methylation of Genomic DNA 19Experimental Methods 20Data Analysis 20Array-based Methods 20Sequencing-based Methods 20Profiling and Analyzing Histone Marks 26Experimental Methods 26Data Analysis 27Issues of Array-based Methods 27Issues of NGS-based Methods 27Integration with Other Omics Data 31Chromatin States 32Unraveling the Cross-talk Between Epigenetic Layers 33References 333 Behavioral Phenotyping in Zebrafish: The First Models of Alcohol Induced Abnormalities 37Robert GerlaiIntroduction 37Alcohol Related Human Disorders: A Growing Unmet Medical Need 37Unraveling Alcohol Related Mechanisms: The Importance of Animal Models 38Face Validity: The First Step in Modeling a Human Disorder 39Acute Effects of Alcohol in Zebrafish: A Range of Behavioral Responses 39Chronic Alcohol Exposure Induced Behavioral Responses in Zebrafish 41Effects of Embryonic Alcohol Exposure 42Behavioral Phenotyping: Are We There Yet? 46Assembling the Behavioral Test Battery 49Concluding Remarks 50References 504 How does Stress Affect Energy Balance? 53Maria Razzoli, Cheryl Cero, and Alessandro BartolomucciIntroduction 53Stress 54Energy Balance and Metabolic Disorders 55Pro-adipogenic Stress Mediators 57Pro-lipolytic Effect of Stress Mediators 57How does Stress Affect Energy Balance? 57Animal Models of Chronic Stress and their Impact on Energy Balance 58Physical and Psychological (non-social) Chronic Stress Models 58Mild Chronic Pain Models – Mild Tail Pinch, Foot Shock 58Thermal Models – Cold and Heat Stress 64Chronic Mild Stress Models: Chronic Mild Stress, Chronic Variable Stress, etc. 64Restraint or Immobilization 65Chronic Social Stress Models 66Social Isolation, Individual Housing 66Unstable Social Settings 66Visible Burrow System 67Intermittent Social Defeat (Resident/Intruder Procedure) 67Chronic Psychosocial Stress, Sensory Contact, and Chronic Defeat stress 68Stress, Recovery, and Maintenance: Insights on Adaptive and Maladaptive Effects of Stress 69Molecular Mechanisms of Stress-Induced Negative and Positive Energy Balance 70Serotonin (5-hydroxytryptamine, 5HT) 71Orexin 71Neuropeptide Y (NPY) 72Ghrelin and Growth Hormone Secretagogue Receptor (GHSR) 72Glucagon like Peptide 1 (GLP1) 73Leptin 73Amylin 74Norepinephrine and β3-Adrenergic Receptor 74Conclusion 74References 755 Interactions of Experience-Dependent Plasticity and LTP in the Hippocampus During Associative Learning 91Agnès Gruart, Noelia Madroñal, María Teresa Jurado-Parras, and José María Delgado-GarcíaIntroduction: Study of Learning and Memory Processes in Alert Behaving Mammals 91Changes in Synaptic Strength During Learning and Memory 92Classical Conditioning 92Instrumental Conditioning 95Changes in Synaptic Strength Evoked by Actual Learning can be Modified by Experimentally Evoked Long-term Potentiation 96Other Experimental Constraints on the Study of the Physiological Basis of Learning Processes 100Factors Modifying Synaptic Strength (Environment, Aging, and Brain Degenerative Diseases) 101Different Genetic and Pharmacological Manipulations Able to Modify Synaptic Strength 103Functional Relationships Between Experimentally Evoked LTP and Associative Learning Tasks 106Future Perspectives 108Context and Environmental Constraints 108Other Forms of Learning and Memory Processes 109Cortical Circuits and Functional States During Associative Learning 109References 1106 The Genetics of Cognition in Schizophrenia: Combining Mouse and Human Studies 115Diego Scheggia and Francesco PapaleoBackground 115Genetics of Schizophrenia 116Cognitive (dys)functions in Schizophrenia 117Translating Cognitive Symptoms in Animal Models 119Executive Control 120Performance in Schizophrenia 122Animal Models 124Working Memory 125Performance in Schizophrenia 126Animal Models 127Control of Attention 128Performance in Schizophrenia 130Animal Models 130Concluding Remarks 131References 1327 The Biological Basis of Economic Choice 143David Freestone and Fuat BalciIntroduction 143Translating from Animals to Humans 144Reinforcement Learning in the Brain 145Subjective Value 146The Midbrain Dopamine System Updates Value 147From Stimulus Value to Action Value 150Model Based Learning 150The Prefrontal Cortex Encodes Value 152The Basal Ganglia Selects Actions 153Optimal Decisions: Benchmarks for the Analysis of Choice Behavior 155The Drift Diffusion Model 157Temporal Risk Assessment 158Timed-response Inhibition for Reward-rate Maximization 160Timed Response Switching 163Temporal Bisection 164Numerical Risk Assessment 166Rodent Version of Balloon Analog Risk Task 167Conclusion 167Acknowledgments 168References 1688 Interval-timing Protocols and Their Relevancy to the Study of Temporal Cognition and Neurobehavioral Genetics 179Bin Yin, Nicholas A. Lusk, and Warren H. MeckIntroduction 179Application of a Timing, Immersive Memory, and Emotional Regulation (Timer) Test Battery 190Neural Basis of Interval Timing 191What Makes a Mutant Mouse “Tick”? 193Proposal of a TIMER Test Battery and Its Application in Reverse Genetics 199Behavioral Test Battery Applications in Forward Genetics 202Order of Behavioral Tasks 205Location and Time of Behavioral Testing 205Summary 205References 206Appendix I 226Limitations of the individual-trials analysis for data obtained in the peak-interval (PI) procedure 2269 Toolkits for Cognition: From Core Knowledge to Genes 229Giorgio Vallortigara and Orsola Rosa SalvaIntroduction 229Core Knowledge: The Domestic Chick as a System Model 230Numerical Competence 230Physical Properties 230Geometry of Space 232Animate Agents 232A Comparative Perspective on the Genetic and Evolutionary Bases of Social Behavior 236From Social Experience to Genes 239From Genes to Social Behavior 241Future Directions 243Conserved Mechanisms for Social Core Knowledge 243Interactions Between Experience and Genomic Information 243Neurogenetic Basis of Social Predispositions 243Epigenetics and the Development of the Social Brain 244Spatial Cognition, Another Promising Core-knowledge Domain 244References 24510 Quantitative Genetics of Behavioral Phenotypes 253Elzbieta Kostrzewa and Martien J.H. KasHuman Studies of Quantitative Traits 253Mouse Studies of Quantitative Traits 254Classical Inbred Mice 254Quantitative Trait Loci (QTL) Analysis 254Knock-out (KO) Mouse Lines 256Use of Mice as Animal Model for Complex Human Traits 257Comparative Genomic Approaches 257Evolutionarily Conserved Behavioral Phenotypes 257Physical Activity – Definitions and Methods of Phenotypic Measurement 258Current Results of Quantitative Genetic Basis of PA in Humans 259Current Results of Quantitative Genetic Basis of PA in Mice 260KO Studies 260QTL Studies 261An Overlap of Genetic Findings Between the Species 261Conclusions 265References 26511 Behavioral Phenotyping in Genetic Mouse Models of Autism Spectrum Disorders: A Translational Outlook 271Maria Luisa Scattoni, Caterina Michetti, Angela Caruso, and Laura RicceriIntroduction 271Measuring Social behavior in ASD Mouse Models 272Social Interaction Tests 272Male-female 277Female-female 278Male-male 278Social-approach 279Sociability Test Phase 280Social Novelty 280Social Recognition 280Repetitive Behavior 281Motor Stereotypies 281Restricted Interests 281Behavioral Inflexibility 282Behavioral Tests Targeting other ASD Symptoms 282Anxiety 282Epilepsy 283Behavioral Phenotyping in ASD Mouse Pups 283Future Directions: ASD Mouse Models as a Resource for Gene-environment Interaction Studies 284Acknowledgments 285References 28512 Genetics of Human Sleep and Sleep Disorders 295Birgitte Rahbek KornumThe Mystery of Human Sleep 295Sleep is Essential for Mammalian Life 295The Function of Sleep 296Extended Wakefulness Induces Sleep 296Homeostatic and Circadian Regulation of Sleep and Wake 297Adenosine and Sleep Homeostasis 298Resistance to Sleep Loss is a Stable Phenotype 299Genetic Markers of Response to Sleep Loss 299A Unique Activity Pattern Characterizes the Sleeping Brain 300Sleep Stages and Sleep Cycles 300Genetics of the Human Sleep Electroencephalography 301Normal Sleep Architecture is Lost in Fatal Familial Insomnia 303Circadian Regulation of Sleep and Associated Disorders 304Circadian Regulation of Sleep 304Molecular Regulation of the Circadian Clock 305The Central Circadian Clock is Entrained By Light 306Circadian Rhythm Sleep Disorders 307Advanced Sleep Phase Syndromes 307Delayed Sleep Phase Syndromes 308Short Sleep Times in Healthy Individuals 308Destabilization of Sleep States and Narcolepsy 309Normal Regulation of Sleep Architecture 309Wakefulness is Associated with Cortical Activation 309The Preoptic Area Contains Sleep-promoting Neurons 309Mutual Inhibition Regulates Transitions Between Wake and Sleep 310Regulation of REM Sleep 311Narcolepsy, A Disorder of Wakefulness and REM Sleep 311Narcolepsy with Cataplexy is Caused By Hypocretin Deficiency 312Autoimmunity Toward Hypocretin Neurons 312Genetic Evidence Supports the Autoimmune Hypothesis of Narcolepsy 313Restless Legs Syndrome, A Developmental Sleep Disorder 314Restless Legs Syndrome, A Mysterious Urge to Move 314Restless Legs Syndrome and Dopamine Disturbances 315Iron Deficiency Exacerbates RLS Symptoms 315Genetic Studies Suggest Developmental Defects 316Unresolved Issues and Future Perspectives 316What is the Molecular and Neuroanatomical Basis for the Ultradian Rhythm of NREM-REM Sleep? 317What is the Genetic Basis for Individual Variation in Complex Sleep Features such as Sleep Spindles and K-Complexes? 317What is the Basis for the Individual Differences in Resistance to Sleep Loss? 317Are Homeostatic and Circadian Mechanisms Genuinely Independent or Are They Intimately Linked? 318What Controls the Molecular and Anatomical Diversity of Sleep Regulatory Networks Across Species? 318References 31913 The Endocannabinoid System in the Control of Behavior 323Edgar Soria-Gomez, Mathilde Metna, Luigi Bellocchio, Arnau Busquets-Garcia, and Giovanni MarsicanoIntroduction 323Cannabinoid Effects and Endocannabinoid Functions 324Role of the ECS in Memory Processes 325Memory: General Background 325Role of the ECS in Synaptic Plasticity 325Memory Impairment Produced by Exogenous Cannabinoids 326Cannabinoid Regulation of Memory: Neurobiological Mechanisms 327Role of the ECS in Fear Processes 329Fear: General Background 329The ECS as an Endogenous Regulator of Fear Responses 331Cannabinoid Regulation of Fear: Neurobiological Mechanisms 332Implication of the ECS in Fear Coping Behaviors 333Role of the ECS in Feeding Behavior 336Feeding Behavior: General Background 336The ECS as an Endogenous Regulator of Feeding Behavior 337The ECS and Food Reward Circuits 338The ECS in the Hypothalamic Appetite Network 338The ECS in the Caudal Brainstem and Gastrointestinal Tract 340Bimodal Control of Stimulated Food Intake by the ECS in the Brain 341Paraventricular Hypothalamus Versus Ventral Striatum in Hypophagia induced by the ECS 342The Olfactory Bulb and the Hyperphagic Action of the ECS 342Conclusions 343References 34414 Epigenetics in Brain Development and Disease 357Elisabeth J. Radford, Anne C. Ferguson-Smith, and Sacri R. FerrónIntroduction 357Epigenetics and Neurodevelopment 358Histone Modifications 358DNA Methylation 361Hydroxymethylation 364Genomic Imprinting 364Non-coding RNAs 365Neurodevelopmental Disorders with an Epigenetic Basis 366Rett Syndrome 366Coffin–Lowry Syndrome 367Rubinstein–Taybi Syndrome 367Alpha-thalassemia Mental Retardation Syndrome 367Imprinted Neurodevelopmental Disorders 368Trinucleotide Repeat Disorders 368Fragile X Syndrome 370Friedreich’s Ataxia 370Myotonic Dystrophy 371Huntington’s Disease (HD) 371Epigenetics of Neurodegenerative Disorders 372Parkinson´s Disease (PD) 372Alzheimer´s Disease (AD) 373The Impact of the Environment on the Epigenome 374Epigenetic Therapy in Neurodevelopment 375Untargeted Treatment 375Targeted Epigenetic Modulation 377Concluding Remarks 377Acknowledgments 377References 37815 Impact of Postnatal Manipulations on Offspring Development in Rodents 395Diego Oddi, Alessandra Luchetti, and Francesca Romana D’AmatoIntroduction 395Early Postnatal Environment in Laboratory Altricial Rodents 396Rodents’ Responses to Postnatal Environment and Early Manipulations 397Assessing Pups’ Responses to Postnatal Environment and Early Manipulation 397Neonatal Ultrasonic Calls: Isolation-induced Vocalizations and Maternal Potentiation 397Searching for Social Contact: Homing and Huddling Behaviors 398Early-life Environment and Stress-Response 398Separation from the Mother 399Mother’s Stress 400The Cross-fostering Paradigm 401Repeated Cross-fostering as a Model of Early Maternal Environment Instability 403Environmental Enrichment 405Conclusions 406References 40716 Exploring the Roles of Genetics and the Epigenetic Mechanism DNA Methylation in Honey Bee (Apis Mellifera) Behavior 417Christina M. Burden and Jonathan E. BobekIntroduction 417Genetics of Adult Honey Bee Biology and Behavior 418Nurse to Forager Transition 418Forager Preference 420Techniques for Investigating the Genetic Bases of Behavior 420QTL Mapping 421RNA Techniques 421Microarrays 421RNA Sequencing 422Experimentally Modulating the Genes Correlated with Specific Behaviors to Test Causality 422DNA Methylation and Honey Bee Behavior 423Honey Bee DNA Methylation Machinery and Genome-Wide Patterns 423DNA Methylation and Task Specialization 424DNA Methylation and Memory Consolidation 425Techniques for Detecting and Assaying DNA Methylation 426The Technological Bases for Most DNA Methylation Assays 426Methylation-specific Restriction Endonucleases 426Protein-mediated Precipitation of Methylated DNA 428Bisulfite Conversion 428Assaying Single CpGs, Short Sequences, and Target Regions 429Analyzing Genome-wide DNA Methylation Patterns: Microarray-based Methodologies 431Analyzing Genome-wide DNA Methylation Patterns: Sequencing-based Methodologies 432Techniques for Manipulating DNA Methylation 434Pharmacological Manipulation of DNA Methylation 434RNA Interference as a DNMT Blockade 434Concluding Remarks and Future Perspectives 435References 43617 Genetics and Neuroepigenetics of Sleep 443Glenda Lassi and Federico TinarelliDefining Sleep 443Sleep is Genetically Determined 445EEG and Heritable Traits 445Sleep Disorders and Genes 446Sleep and Gene Expression 447Epigenetics 448DNA Methylation 450Posttranslational Modifications (PTMs) 450RNA interference 452Neuroepigenetics 453Two Neurodevelopmental Disorders with Opposing Imprinting Profiles and Opposing Sleep Phenotypes 453Neuroepigenetics of Sleep 454Fruit Fly 454Rodent Models 454Human Beings 456Sleep and Parent-of-origin Effects 458Conclusions 460References 46018 Behavioral Phenotyping Using Optogenetic Technology 469Stephen Glasgow, Carolina Gutierrez Herrera, and Antoine AdamantidisIntroduction 469Microbial Opsins 470Fast Excitation Using Channelrhodopsin-2 and Its Variants 470Fast Optical Silencing 474Alternative strategies for cell-type specific modulation of neural activity 476Targeting systems 476Light Delivery in the Animal Brain 478Recording Light-evoked Neuronal Activity 479Behavioral Phenotyping 479In-vivo Optogenetics: Defining Circuits 480Perspectives 484Acknowledgments 484References 48419 Phenotyping Sleep: Beyond EEG 489Sibah Hasan, Russell G. Foster, and Stuart N. PeirsonSleep Research 489Phenotyping Sleep in Humans 490Introduction 490Actigraphy 490Cardiorespiratory Signals 491EEG 492Phenotyping Sleep in Animal Models 494Introduction 494EEG 494Introduction 494Tethered EEG 496Telemetered EEG 496NeuroLogger EEG 498Beyond EEG 498Infrared Beam Break 499Movement Based on Implanted Magnets 499Piezo-electric Sensors 499Video Tracking 500Future Perspectives 501Acknowledgements 502References 50220 A Cognitive Neurogenetics Screening System with a Data-Analysis Toolbox 507C.R. Gallistel, Fuat Balci, David Freestone, Aaron Kheifets, and Adam KingIntroduction 507Mechanisms, Not Procedures 508Functional Specificity 508No Group Averages 509Physiologically Meaningful Measures 509Importance of Large-scale Screening and Minimal Handling 511Utilizable Archived Data with Intact Data Trails 511The System 512The Toolbox 513Core Commands 516Powerful Graphics Commands 517Results 518Summary 523References 52421 Mapping the Connectional Architecture of the Rodent Brain with fMRI 527Adam J. Schwarz and Alessandro GozziIntroduction 527MRI Mapping of Functional Connectivity in the Rodent Brain 528Networks of Functional Covariance 528Connectivity of Neurotransmitter Systems 529The Dopaminergic System 529The Serotonergic System 531Resting State BOLD fMRI 532Connectivity Networks of the Rodent Brain 533Do Rodent Brains have a Default Mode Network? 536Use of Anesthesia and Other Methodological Considerations 539Transgenic Models: Genetic Manipulation of Functional Connectivity Patterns 541Future Perspectives 543References 54522 Cutting Edge Approaches for the Identification and the Functional Investigation of miRNAs in Brain Science 553Emanuela de Luca, Federica Marinaro, Francesco Niola, and Davide De Pietri TonelliIntroduction 553History 553Biology and Functions in the Brain 553Identification of Novel MicroRNAs in the Brain 555miRNA Extraction and Purification 556miRNA Cloning 556Computational Identification of Novel miRNAs 557RNA Sequencing (RNA-Seq) 558miRNA expression analysis in the brain 559miRNA profiling 559Analysis of miRNA Expression in Tissue 559Target Identification 560Computational Identification of Targets 561Proteomics 561RISC-associated miRNA Targets 562RNomics 563miRNA Manipulation/Target Validation 565miRNA Inhibition 565miRNA Over-expression 566Target Validation 567New Frontiers in Small RNA-based Technologies to Cure Nervous System Deficits 567Use of miRNAs in Gene Therapy 567Use of miRNAs in Gene Therapy in the Brain Requires Improved Delivery Strategies 571Conclusion and Perspectives 572Are Circulating miRNAs Novel Biomarkers for Brain Diseases? 572Use of miRNAs in Cell Reprogramming Technology 573Are miRNAs Just the “Tip of the Iceberg”? Emerging Classes of Noncoding RNAs and Novel Scenarios 574Acknowledgments 575Competing Financial Interests 575References 575Index 585