Handbook of Neurobehavioral Genetics and Phenotyping

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