Neuroscience in the 21st Century: From Basic to Clinical

Preface to the Third Edition
Neuroscience Addresses Medical and Public Health Problems, Worldwide
Preface to the Second Edition
Neuroscience Addresses Medical and Public Health Problems, Worldwide
Preface to the First Edition
Neuroscience Addresses Medical and Public Health Problems, Worldwide
Further Reading
Editors-in-Chief
Supervisory Editors
Contents
Contributors
Part I: Basic Neuroscience: Biophysics
1 Voltage-Gated Ion Channels
Brief History
Introduction
Voltage-Gated Ion Channels are Multimeric Protein Complexes
Changes in the Conformation of the Pore-Forming Subunits Determine the State of the Channel
VGSC States and Na+ Current Properties
Modulation of Voltage-Gated Ion Channels Function
Abnormalities in Voltage-Gated Ion Channel Functions Can Result in Human Disease
Voltage-Gated Ion Channels are Targets of Therapeutic Agents
Outlook
Cross-References
References
2 Water, Ions, Membranes, Pumps, and Transporters
Brief History
Water
Water as a Solvent
Membranes
Pumps and Pores
The Resting Membrane Potential
Electrical Models of the Cell Membrane
Homeostasis Versus Electrical Excitability
Outlook
Glossary
References
3 Ionotropic Glutamate Receptors (and Their Role in Health and Disease)
Brief History
Why Does the Brain Need Ligand-Gated Ion Channels?
From the Primary to the 3D Structure of Ionotropic Glutamate Receptors
Primary Structure
Secondary Structure
3D Structure
The Physiological Function of Ionotropic Glutamate Receptors in Rodents
Primary Function
Orphan Receptors
Kainate Receptors
AMPA Receptors
NMDA Receptors
AMPA and NMDA Receptors in Learning and Memory
The NMDA Receptor Function of Coincidence Detection in Learning
Function of AMPA and NMDA Receptors in the Behavior of Experimental Animals
NMDA Receptor Dysfunction During Development
NMDA Receptor Hypofunction
NMDA Receptor Hyperfunction
Conditional NMDA Receptor Knockouts
AMPA Receptor Gene-Targeted Mice
AMPA and NMDA Receptor Dysfunction in CNS Disorders
Auxiliary Subunits of iGluRs
AMPA and NMDA Receptor Interactors in the Postsynaptic Density
Outlook
Cross-References
References
4 Signal Transduction-Dependent Channels
Brief History
Introduction
Relationships Between Structure and Function
Slo1 Transmembrane Segments: S0, the Voltage Sensor, and the Pore
Carboxy-Terminus
Two RCK Domains Are Present in the C-Terminus of the Slo1 Channel
Structure of the Slo1 RCK Domains
Coupling Between Ca2+ Binding and Pore Opening
Location and Structure of Divalent Binding Sites in the Slo1 RCK Domains
C-Terminus and Ion-Binding Sites in Slo2 and Slo3
Allosteric Models Account for Most of the Slo1 Channel Gating Properties
Slo1: Diversity, Pharmacology, Function, and Localization
β-Subunits of Slo1 Channels
Changes in Biophysical Properties of Slo1 Channels Induced by Slo1 β-Subunits
Slo1 Tissue Distribution and Function
The Brain
The Smooth Muscle
Role in Secreting Cells
Cochlea
Slo2
Slo3
Outlook
Further Reading
5 Post-Synaptic Potentials and Action Potentials: Membrane Potentials
Resting Membrane Potential
Synaptic Potentials
Action Potentials
Part II: Basic Neuroscience: Development
6 Basics of Stem Cell Biology as Applied to the Brain
Brief History
Stem Cells Can Be Classified into Different Types
Mouse Embryonic Stem Cells and Human Embryonic Stem Cells Have Different Properties
Pluripotency Can Be Determined Based on a Series of Functional Tests
Stem Cells Can Be Used to Study and Repair the Nervous System in a Variety of Ways
Reprogramming Approaches Allow Us to Obtain Stem Cells That Are (Mostly) Genetically Matched to Patients
Several Different Kinds of Neurons Can Be Successfully Differentiated from Pluripotent Stem Cells
Direct Reprogramming Is an Alternative Pathway to Obtaining Patient-Matched Neuronal-Like Cells
Defining Whether a Cell in a Dish Is Similar to a Cell in the Brain Is Quite Complex
Outlook
References
7 Neural Stem Cells in Cerebral Cortex Development
Introduction
Definition and General Features of Neural Stem Cells
Neural Stem Cells Generate All Neural Cells in a Temporally Controlled Manner
Embryonic Origin and Early Development of the Nervous System
The Cell Biology of Neural Stem and Progenitor Cells
Cell Division Modes Impact Proliferation vs. Neurogenesis
Cell Division Modes Change During Development
Main Characteristics of Neural Stem Cells in the Developing Neocortex
The Main Types of Neocortical Stem and Progenitor Cells
The Epithelial Nature of the Primary Neural Stem Cells
Apical Progenitors Are Elongated and Highly Polarized
Different Zones Arise from the Neuroepithelium During Neurogenesis
The Apical Components of Neural Stem Cells
The Apical Plasma Membrane
The Adherens Junctions and Apical Cell Cortex
The Primary Cilium and Centrosomes
The Basolateral and Basal Components of Neural Stem Cells
The Basolateral Membrane and Radial Processes
The Basal Lamina and Pial Surface
Nuclear Movements and Cell Cycle Progression
The Advantages of an Apical Mitosis for APs
The Advantages of a Basal Mitosis for BPs
Mechanisms of Interkinetic Nuclear Migration
Interdependence of Interkinetic Nuclear Migration and Cell Cycle Progression
Cell Cycle Progression and Stem Cell Fate
Neural Stem Cell Divisions in Proliferation Versus Neurogenesis
Cell Division Machinery and Progression
Cell Cortex and Cytokinesis
The Distribution of Polarized Components During Neural Stem Cell Division
Neural Stem Cell Divisions and Contact Inheritance
Spindle Structure and Orientation in NSC Fate Determination
Molecular Mechanisms of Neural Stem Cell Maintenance and Differentiation
The Fate of NSCs Is Influenced by a Diversity of Molecular Factors
Signaling in Neural Stem Cells
Shh Acts Mainly in Patterning
Wnt/Beta-Catenin Signaling Has a Dorsalizing Effect
Notch Inhibits Neurogenesis
BMPs Have Multiple Effects in Neurogenesis
FGFs Can Inhibit or Promote Neurogenesis
Intrinsic Mechanisms of Neural Stem Cell Maintenance
Numerous Transcription Factors and Species-Specific Transcripts Contribute to NSC Maintenance and Fate Determination
MicroRNAs
Epigenetic and Epitranscriptomic Regulators
Radial Glial Cells Link Embryonic and Adult Neurogenesis
Adult NSCs Come from Embryonic NSCs
Perspectives in Embryonic Neural Stem Cell Research
Further Reading
8 Induction and Patterning in the Telencephalon
Brief History of the Field
The Telencephalon Follows Shared Rules of Development
The ``French Flag´´ Model: Organizers, Morphogen Gradients, and Transcription Factors
Anatomy of the Early CNS and Telencephalic Development
Induction and Patterning of the Early Telencephalon Follow the French Flag Model
Induction by Organizers Outside the Telencephalon
Patterning by Midline Centers Within the Telencephalon
Morphogen Gradients in the Early Telencephalon
Maintaining Graded Information in Cortical Progenitor Fields
Converting Graded Information into Discrete Telencephalic Fates and Borders
The Telencephalon Uses Additional Strategies Shared with Other Developing Tissues
Solving an ``Ends´´ Problem: Morphogen Interactions
Expanding Morphogenic Ranges: Expansion of Morphogen Families
Expanding Morphogenic Ranges: Secondary Organizers
Expanding Morphogenic Ranges: Cell Migrations
The Telencephalon Has Also Adopted Its Own Unique Rules
Evolutionary Pressure for More Neocortex Without an Oversized Head
Adjacent Tissues Co-evolved to Support a Larger Neocortex
Support Inside and Out: The Superarachnoid Reticulum and Choroid Plexus ``Bloom´´
Patterning in the Radial Dimension Diversifies Neocortical Development
Intermediate Progenitors and Outer Radial Glia
Cortical Folding Enables Even More Neocortex
The Neocortical Areal Map Is Patterned by Both Intrinsic and Extrinsic Programming
Intrinsic Patterning of Cortical Areas: Support for the ``Protomap´´ Hypothesis
Extrinsic Patterning of Cortical Areas: Support for the ``Protocortex´´ Hypothesis
The Neocortex Does Not Regenerate
Outlook
References
9 Specifying Neuronal Cell Identities in the Central Nervous System: A Complex Tale of Proneural Gene Regulation
Brief History
Proneural Genes Encode Basic-Helix-Loop-Helix Transcription Factors
Proneural Genes Are Required to Specify Neuronal Cell Fates in the Neocortex
Notch Signaling Regulates Proneural Gene Expression to Control the Choice by Neural Progenitor Cells to Proliferate or Differe...
Dorsal Telencephalic Identity Is Influenced by Extrinsic Factors
Epigenetic Factors Regulate bHLH Function
Proneural Genes Are Key Drivers of Direct Neuronal Reprogramming
Outlook
References
10 Gene-Regulatory Networks in Brain Development
Brief History and Introduction to GRNs
The Molecular Basis of GRNs
First Principles of Gene Regulation and GRNs
Transcription Factors
Cis-Regulatory DNA: Promoters and Enhancers
Transcriptional Cofactors, Epigenetics, and GRNs
Posttranscriptional Mechanisms and Gene-Regulatory Networks
Section Summary: Description and Molecular Basis of GRNs in the Brain
Mapping GRNs in Brain Development and Disorders
Building GRNs in Model Organisms Using Genetics
Defining GRNs at the Systems Level
Resolving Direct from Secondary Regulation and Molecular Control of GRNs
Example: PAX6 in Cortex Development
GRN Disruption in Neurodevelopmental Disorders
Outlook
Toward Comprehensive and Mechanistic Understanding of GRNs
Reprogramming and Engineering GRNs in the Lab and Clinic
References
11 Post-transcriptional Gene Regulation During Cortical Development
Brief History
The Role of RNA Binding Proteins in Post-transcriptional Gene Regulation
Alternative Pre-mRNA Processing Diversifies the Transcriptome
Alternative Splicing
Alternative Polyadenylation
RNA Editing and Modifications Influence mRNA Function and Fate
RNA Editing
RNA Modifications
mRNA Localization Gives Specialized Function to Subcellular Niches
Translational Regulation Fine-Tunes When and Where Proteins Are Made
mRNA Degradation Remodels the Transcriptome
Mis-regulation of Post-transcriptional Processes in Neurodevelopmental Disease
Outlook
References
12 Neurogenesis of Cerebral Cortex Projection Neurons
Brief History
Developing Cortex Has Epithelial, Zonal, and Regional Organization
Projection Neurons Are Generated Sequentially in Regional and Laminar Gradients
Cajal-Retzius Cells and Subplate Neurons Are Early-Born, Mostly Transient PNs
Most Projection Neurons Differentiate from Radial Glia Via Intermediate Progenitors
Spatiotemporal Gradients of Gene Expression Drive Areal and Laminar Identity
Intermediate Progenitors Regulate RGP Differentiation and Interneuron Migration
Intermediate Progenitors Regulate PN Axogenesis
Multipolar Migration Facilitates Clonal Dispersion, Layer Formation, and Axogenesis
Basal Progenitors Contribute to Cortex Gyrification
Outlook
References
13 Genesis and Migration of Cerebral Cortical Inhibitory Interneurons: An Overview
Introduction
Cortical Interneuron Genesis and Subtype Fate Determination
The Neural Tube and Radial Versus Non-radial Modes of Neuronal Migration
Generation of Cortical Interneuron Numbers and Their Matching to Pyramidal Neurons
Fate Determination of Cortical Interneurons
Cortical Interneuron Migration
Guidance of Interneuron Migration
Bioenergetic Implications of Non-radial Migration
Fate Memory During Migration
Key Unsolved Questions
Brief History/Outlook
References
14 Spinal Cord Neurogenesis
Introduction
The Spinal Cord Derives from the Caudal Neural Plate
Spinal Cord Circuits Interconnect Cells Located in Specific Positions
Molecularly Distinct Cells Are Generated in Specific DV and AP Positions
Neural Fate Decisions Are Made at the Progenitor Level
Diffusible Morphogen Signaling Direct Regional Generation of Neurons by Inducing Patterned Gene Expression in Progenitors
Cell Contact-Mediated Signaling Diversifies Neuronal Subtypes and Balances Neurogenesis and Gliogenesis
Adult Neurogenesis and Injury
Outlook
References
15 Adult Neurogenesis
Brief History
Adult Neurogenesis Is Neuronal Development Under the Conditions of the Adult Brain
Of Neurogenic and Non-neurogenic Regions
All Adult Neurogenesis Originates from Neural Stem Cells
Adult Hippocampal Neurogenesis
Neurogenesis in the Adult SVZ/Olfactory Bulb
Neurogenesis in the Adult Olfactory Epithelium and Other Parts of the Peripheral Nervous System
Reactive Neurogenesis
Regulation
Function
Medical Relevance of Adult Neurogenesis
Outlook
Further Reading
16 Generation of Axons and Dendrites
Brief History
Introduction
Neuronal Polarization: How to Specify Axons and Dendrites
Growth and Guidance: How to and Where to Grow Axons and Dendrites
Branch Formation: When and Where to Make Branches
Arborization: How to Control Size and Shape
Remodeling: How to Remove Axons and Dendrites
Outlook
References
17 Axonal Guidance
A Brief History of Axon Guidance: From Cajal´s Speculations to the Chemoaffinity Theory
Neuronal Polarization Results in the Selection of Neurite that Will Develop into the Axon
The Axonal Growth Cone Is a Dynamic Sensory Structure
Guidepost Cells and Pioneer Axons Are Cellular Cues Used by Growth Cones
Specific Assays Are Used Identify and Characterize Axon Guidance Molecules
Axon Guidance Proteins Share Evolutionarily Conserved Domains
Localized Changes in Growth Cone Cytoskeletal Stability Result in Its Turning
Long-Distance Axon Guidance Involves a Series of Navigation Decision Points and Sequential Integration of Guidance Cues
Simultaneous Integration of Axon Guidance Signals Can Potentiate Their Low Diversity
Transcription Factor Cascades Link Axon Guidance to Neuronal Identity
``Hard-Wired´´ Specification of Neuronal Connections Is Refined by Apoptosis and Neuronal Activity
Mutations in Human Genes Encoding Axon Guidance Molecules Cause Neurological Defects
Some Axon Guidance Molecules Continue to Function in the Adult Nervous System
Some Axon Guidance Molecules Prevent Axonal Regeneration
Outlook
References
18 Axonal Guidance: Making Connections
A Brief History of Axon Guidance
The Biology of Growth Cones and Modulation of the Axonal Cytoskeleton
Guidance Cues
Intermediate Guidance Targets and Pioneering Axons
Axon Guidance Molecules
Netrins
Ephrins
Semaphorins
Slits
Morphogens
Cell Adhesion Molecules
Proteoglycans
In Vitro Assays of Axon Guidance
Coculture Assay
Micropipette Assay
Stripe Assay
Microcontact Printed Assay
Collagen Gel Pump Assay
Outlook
References
19 Dendritic Elaboration: Morphology and Chemistry
Structure of Dendrites
Dendritic Arborization Patterns
Subcellular Structure of Dendrites
Dendritic Specializations and Appendages
Fine Structure of Dendritic Spines
Functional Plasticity
Dendritic Plasticity
Long-Term Potentiation
Properties of the NMDA Receptor
Dendritic Integration and Its Role in Synaptic Plasticity
Spike-Timing-Dependent Plasticity
Dendritic Excitability and Synaptic Plasticity
Structural Plasticity
Experience Induced Structural Dendritic Plasticity
Sensory Deprivation, Enriched Environment and Behavioral Training
Hormone Induced Structural Dendritic Plasticity
Structural Pathology
Outlook
References
20 Synapse Formation
Brief History
Cellular Mechanisms
Trafficking of Pre- and Postsynaptic Proteins Before Synapse Formation
Early Events in Synapse Formation After Contact
Maturation
Synapse Elimination
Molecular Mechanisms
Defining the Molecules at the Synapse
Synaptogenic Molecules
Transsynaptic Adhesion Molecules
Secreted Molecules
Glial-Derived Factors
Synapse-Limiting Molecules
Outlook: Synapse Formation and Disease
References
21 Cell Migration in the Mammalian Cortex
Brief History
From Neurogenesis to Radial Migration of Excitatory Neurons
Two Modes of Radial Migration
Tangential Migration of Inhibitory Neurons
Extracellular Signaling Regulation of Neuronal Migration
Cell Adhesion Molecules
Growth Factors
Reelin Signaling Via VLDLR/ApoER2
CXCL12 Signalling Via CXCR4/7
Neurotransmitters
Intracellular Cascade for Neuronal Migration
Cytoskeletal Machinery
Intracellular Molecular Cascades
Ca2+ Changes
Postnatal Migrations
Glial Migration
Disorders in Cell Migration
Outlook
Further Reading
22 Neuronal Differentiation: Focus on the Action Potential
Brief History
RB Cells Serve as Ideal Neurons for Study of AP Development
Transient Excitability Properties Emerge as Neurons Differentiate
Direct Study of Voltage-Gated Ion Currents Underlying Developmentally Regulated Action Potentials Provide a Significant and Su...
Cloning of Ion Channel Genes Allow New Insights and Raises New Questions Regarding Underlying Molecular Mechanisms
Transcriptional Mechanisms Regulate Functional Expression of Voltage-Gated Ion Channels
Translational Mechanisms Regulate Voltage-Gated Ion Channel Functional Expression
Post-Translational Mechanisms Regulate Voltage-Gated Sodium Channel Function
Extrinsic Mechanisms Also Regulate Development of Neuronal Excitability
Outlook
References
23 Regressive Phenomena: Refining Connections
Brief History
Trophic Support and Apoptosis
Axon Pruning
Overview
Molecular Mechanisms of Axon Pruning
Self-destruction Pathways and Neurotrophic Support
Repulsive Cues in Axon Pruning
Axon Pruning and Neuronal Activity
Mechanisms Underlying Synapse Organization and Elimination
Synaptic Tiling
Glial-Mediated Synapse Elimination
Dendrite Pruning
Overview
C. elegans Menorahs
Drosophila Sensory Neurons
Dendritic Process and Spine Remodeling
Spatial Constraint of Regressive Events
Spatial Distribution of Receptors and/or Ligands
Restriction of Caspase Activation
Calcium Restriction
Common and Distinct Mechanisms Direct Developmental Axon Pruning and Axon Degeneration
Outlook
References
24 Myelination
Brief History
Structure and Function of Myelin
The Development of OL Lineage Cells
Myelination Process and Myelin Maintenance
Myelin Disorders
Myelin Plasticity: A New Front in Brain Plasticity Research
The Emerging Role of OLs and Myelination in the Pathophysiology of Mental Disorders
Outlook
References
25 Cerebral Organoids in Developmental Neuroscience
Introduction
Neurodevelopment
Human Pluripotent Stem Cells as a New Source to Generate Human Neural Tissue
Cerebral Organoids Recapitulate Key Events of Human Brain Development
Assembloids: Stimulating Circuit Formation in Organoids
Forebrain Assembloids
Cortico-striatal assembloids
Cortico-motor Assembloids
Cerebral Organoids and Neurodevelopmental Disease Modeling
Outlook
References
Part III: Basic Neuroscience: Cell Biology of Neurons and Glia
26 Dendritic Morphology and Function
Brief History
Introduction
Dendritic Arborizations
The Neocortex
A General Classification of Cortical Neurons
Pyramidal Neurons
How Does Excitatory Information Flow in the Neocortex?
Dendritic Spines
Types of Spines
Dendritic Spine Function
Spines as Biochemical Compartments
Spines as Electrical Compartments
Active Spine
Spine as an Electrical Compartment: Its Implications for Synaptic Transmission, Plasticity, and Synaptic Integration
What Is the Purpose of the Electrical Function of Dendritic Spines in the Neocortex?
Spines as Coincidence Detectors
Dendritic Excitability
Types and Locations of Dendritic Spikes
What Are the Functional Consequences of Dendritic Spikes?
Neocortical Pyramidal Neurons as Associative Units
Electrotonic Properties of Dendrites: A Theoretical View
Spread of Electrotonic Potentials in Dendrites
Outlook
References
27 Axonal Transport
Brief History
Axonal Transport
Three Ways to Study Axonal Transport
Accumulation Techniques
Pulse-Labeling Techniques
Imaging Techniques
Axonal Cytoplasm Contains a Dynamic Network of Protein Polymers Called the Cytoskeleton
Microfilaments and Microtubules Are Tracks for Axonal Transport
Neurofilaments Are Space-Filling Structural Elements That Maximize Axonal Caliber
Molecules Move in Association with Distinct Cargo Structures
The Cargoes of Axonal Transport Are Very Diverse
There Are Distinct Fast and Slow Components of Axonal Transport
The Cargo Structures of Slow Axonal Transport Are Largely Unknown
The Cargoes of Fast and Slow Axonal Transport All Move Rapidly but Differ in Their Duty Ratio
Axonal Transport Is Bidirectional
All Cargoes Are Propelled by Molecular Motors
Motor Proteins Move Unidirectionally Along Their Polymer Tracks
Single Cargoes Interact with Multiple Types of Motors
Motors Mostly Interact with Their Cargoes via Adapter Proteins
Motors Are Targets for Axonal Transport Regulation
The Axon Initial Segment May Function as a Gate Keeper for Axonally Transported Cargoes
Axonal Transport Supplies mRNAs for Local Protein Synthesis
Axonal mRNAs Are Transported as Ribonucleoprotein Complexes
Axonal Transport of mRNAs Is Critical for Axonal Development
Axonal Transport Regulates Presynaptic Development and Plasticity
Retrograde Axonal Transport Relays Signals from the Target Environment
Retrograde Transport of Locally Synthesized Proteins Is Important in the Axonal Response to Injury
Retrograde Axonal Transport Is Also a Pathway for Degradation and Recycling
Axonal Transport Is Disrupted in Many Neurodegenerative Diseases
Alterations in Retrograde Transport Can Cause Degeneration
Outlook
References
28 Cell Biology of the Synapse
Brief History
Synapses Are the Sites of Contact Between Neurons
Key Discoveries in the Mid-nineteenth and Early to Mid-twentieth Centuries Form the Basis of Our Current View of the Synapse
Synaptic Structure and Function
Synapses Consist of Pre- and Postsynaptic Elements
Presynaptic Terminals Are the Sites of Neurotransmitter Release
The Active Zone of the Presynaptic Membrane Is the Site of Synaptic Vesicle Release
Synaptic Vesicles Vary in Ultrastructure, Content, and Function
Synaptic Vesicles Cycle Within the Presynaptic Terminal
The SNARE Complex Is the Key to Exocytosis
Docking Vesicles Populate the Active Zone
Priming Sets the Stage for Vesicle Release
Fusion Involves ``Zippering´´ of the SNARE Complex
Synaptic Vesicle Membranes Are Retrieved Via Endocytosis Following Fusion
Postsynaptic Processes Form the Receptive Surfaces of Neurons
The Postsynaptic Density (PSD) Is a Complex Array of Proteins Intimately Associated with the Postsynaptic Membrane
Dendrites Are Receptive Surfaces and Branch to Form Extensive Dendritic Trees
Axospinous Synapses Are Complex Structures That Undergo Architectural Changes with Physiological and Behavioral Inputs
Actin Is a Major Component of Dendritic Spines
Actin Networks May Be Compartmentalized in Terms of Structure and Function
The Actin Cytoskeleton in Dendritic Spines Is Involved in Long-Term Plasticity
The Spine Apparatus and Other Membranous Organelles Are Involved in Ca2+ Sequestration and Release
Activity-Dependent Synaptic Plasticity May Depend upon Local Regulation of Protein Translation
Spine Morphology Is Altered with Physiological and Behavioral Inputs and Brain Disorders
Advantages of Axo-axonic Circuits
The Synaptic Cleft of Mature Synapses Contains Adhesion Molecules
Cadherins May Act as Transsynaptic Activity Sensors and Are Involved in Synaptic Plasticity
Neuroligins and Neurexins Play a Role in Adhesion, Transsynaptic Signaling, and Synaptic Development
Adhesion Molecules Are Associated with Neurodevelopmental Disorders
Some Synapses Have Unique Characteristics
Neuromuscular Junctions Consist of Presynaptic Terminals Impinging on Skeletal Muscle
Ribbons Are Specialized Structures of Synapses in Sense Organs of the Visual, Auditory, and Vestibular Systems
Giant Synapses Are Found in Squid and Are an Important Model for Understanding Synaptic Structure and Function
Outlook
Glossary
References
29 Molecular Regulation of Synaptic Release
Key Discoveries That Shaped the Present-Day Understanding of Presynaptic Function
Membrane Traffic in Neurons
Overview of the Secretory Pathway in Eukaryotic Cells
The Secretory Pathway in Neurons
Exo-Endocytotic Cycling of Synaptic Vesicles
Synaptic Vesicles
Synaptic Vesicles: Trafficking Organelles Specialized for Neurotransmitter Storage and Fast Exocytosis
Uptake and Storage of Neurotransmitters by Synaptic Vesicles
Trafficking Proteins of Synaptic Vesicles
Molecular Mechanisms Underlying Exocytosis of Synaptic Vesicles
Overview
Active Zones and Vesicle Docking
Exocytotic Membrane Fusion: The Job of SNARE Proteins
Activation of the Fusion Machinery: Priming and Other Reactions
Calcium-Dependent Triggering of Exocytosis
Molecular Mechanisms Underlying Endocytosis and Recycling
Overview
The Molecular Steps of Clathrin-Mediated Endocytosis
Synapse-Specific Adaptations of Clathrin-Mediated Endocytosis
Endosomes and Regeneration of Synaptic Vesicles
Recycling: How Do Vesicles Move Within the Synapse?
References
30 The Postsynaptic Density
Brief History
The Postsynaptic Density Is a Dense Submembranous Structure Containing an Array of Molecules Important in Synaptic Transmissio...
The Structure of the PSD Reflects Its Complex Molecular Organization
PSDs Display Perforations
The Presence of Particulate Components in PSDs and Some Proteins in PSD Fractions Depends on Brain Area and PSD Surface
Filamentous Components of the PSD Are Present Within and on the Cytoplasmic Face of the PSD
The Arrangement of Molecular Components of the PSD Mediates Communication of Signaling Events in Space and Time
Alterations in Scaffold Proteins May Influence Excitatory Synaptic Transmission Through Their Interactions with Neurotransmitt...
The NMDA Receptor (NMDAR) Associates with the MAGUK Family Scaffolding Proteins
The AMPA Receptor (AMPAR) Associates with TARP, GRIP, PICK1, and NSF
Metabotropic Glutamate Receptors Associate with Members of the Homer Family
Shank Organizes Other PSD Scaffolding Proteins
Some Ion Channels Are Present in PSDs of Excitatory Synapses
Scaffold Proteins Are Also Present at Inhibitory Synapses
CaMKII Is a Major PSD Protein that Modulates Signal Transduction at Synapses
Cytoskeleton and Associated Proteins Constitute a Large Proportion of PSD Proteins
Cytoskeletal and Scaffolding Proteins Contribute to Structural Dynamics of the PSD
Reconstituted PSDs as a Window to PSD Formation
Environment, Hormones, and Electrophysiological Input Influence PSD Structure
The PSD in Neurological Disorders
Outlook
Future Directions Combine State-of-the Art Imaging Techniques, Electrophysiology, Molecular Approaches, and Genetic Animal Mod...
Glossary
References
31 Gap Junctions and Electric Synapses
Brief History
Visualizing Gap Junctions
Visualizing and Measuring Gap Junctions
General Architecture of Gap Junctions and Their Molecular Composition
Gap Junction-Forming Proteins
Molecular Composition
What Makes Electrical Synapses Different from Chemical Synapses?
Directionality and Speed
Excitability
Plasticity
Gain of Electrotonic Coupling in Neuronal Settings Might Be Extraordinary High
Recruitment of New Channels Is Fast
Posttranslational Modifications Influence Strength of Electrical Coupling
What Can Electrical Synapses Do Better Than Chemical Synapses?
Gap Junction Channels and Hemichannels Are Important for Brain Development
Electrical Coupling in the Adult Brain
GABAergic Interneurons Are Extensively Coupled by Gap Junctions
Desynchronization of Network Firing Can Result in Inhibition
Are Principal Neurons in the Adult Brain Electrically Coupled and What Might the Function of Such Coupling Be?
Pharmacology of Gap Junctions and Electrical Synapses
Intracellular pH and the Issue of Calcium
Voltage Sensitivity
Phosphorylation and Dephosphorylation
Real Pharmacological Agents
Are ``Connexin Mimetic´´ Peptides Effective?
Glial Coupling Is Extensive
Gap Junctions and the Diseased Brain
Gap Junctions and Deafness
Epileptic Seizure and Stroke: Their Gap Junction Connections
Outlook
References
32 Glial Cells: Neuroglia
Introduction: Short History of the Neuroglia
Neuroglia: Definition and Evolution
Evolution of Neuroglia
Astroglia
Heterogeneity of Astroglia
Morphology of Astrocytes
Functions of Astrocytes
Concept of Radial Glial Cells as Stem Cells
Astrocytes Define the Brain Micro-Architecture
Astrocytes Control Extracellular K+ Homeostasis
Astrocytes Remove Excess Glutamate
Astrocytes Supply Glutamine to Maintain Glutamatergic Neurotransmission
Astrocytes Control Local Blood Flow and Provide Neurons with Metabolic Support
Astroglia Control Synaptogenesis and Synaptic Maintenance
Neuronal-Glial Signaling: The Concept of the Tripartite Synapse and Astroglial Cradle
Synaptic Transmission onto Astroglia
Signaling in Glial Syncytia
Astrocytes as Secretory Cells of the CNS: The Concept of Gliocrine System
Astrocytes in Neuropathology
Oligodendrocytes and Schwann Cells
Morphology of Oligodendrocytes
Development of Oligodendrocytes
Schwann Cells
The Myelin Sheaths
Myelin Enables Saltatory Nerve Conduction
Myelinating Cells and Diseases
Microglia
The ``Surveilling´´ Microglia Are the Fastest Moving Cells in the Brain
Reactivity of Microglia
Migration and Motility
Phagocytosis
Antigen Presentation
Conclusion
References
33 Immune System Cells
Brief History
Microglia
Microglia Are the Major Immunological Cell Type in the Brain
Surveying Microglia
Effector Microglia
Overactive Microglia Are Detrimental
Microglia Involvement in Adult Neurogenesis
T Lymphocytes
T Cells in the CNS
T Cells in the Brain Are Involved in Repair following Injury: Protective Autoimmunity
The Bad Side of T Cells in the Brain: Autoimmunity
T Cells Are Involved in Neurogenesis
Other Beneficial Effects of CNS Autoimmune T Cells
Dendritic Cells
Dendritic Cells Are the Professional Antigen-Presenting Cells in the Immune System
Dendritic Cells Are Located Throughout the Brain
Brain Dendritic Cells Originate Both from Differentiated Resident Brain Cells and from the Entry of Dendritic Cells Arisen fro...
Brain Dendritic Cells Are Involved in Immune Regulation in the Pathological State
Are Brain Dendritic Cells Involved in Adult Neurogenesis?
Mast Cells
Mast Cells Are Located in the Brain
Brain Mast Cells Are Affected by Behavioral and Physiological State
One Proposed Physiological Function of Brain Mast Cells
Do Mast Cells Affect Neurogenesis?
Mast Cells Affect Angiogenesis
Outlook
References
34 Neuroimmune Signaling: Cytokines and the Central Nervous System
Brief History
Two Arms of the Immune System: Innate and Adaptive Immunity
Cytokines of the Innate Immune System
Cytokines of the Adaptive Immune System
Cytokines in the CNS
Peripheral Immune Cells and Cytokines Cross the BBB
The BBB
Cytokine Transport Across the BBB
Cells Crossing the BBB
Microglia and Other Resident CNS Cells Produce Cytokines
Microglial Function
Microglia as a Source of Cytokines
Other Brain-Resident Cells are Sources of Cytokines
Neuroinflammation
Neural Regulation of Inflammation
Cytokines Activate the HPA Axis
Behavioral Responses to Cytokines
Outlook
34.0 Appendix: Cytokine Families
Interleukins
Chemokines
Growth Factors
Tumor Necrosis Factor
Interferon
Colony-Stimulating Factors
Neurotrophins
Neuropoetins
Further Reading
35 Psychoneuroimmune Phenomena: Neuroimmune Interactions
Brief History
The Immune System Is Responsible for Innate and Adaptive Immunity
Psychosocial Factors Impact on Innate and Adaptive Immunity
The Immune System Needs the Brain for Regulatory Control
Immune Mediators are Expressed in the Central Nervous System
Cytokine Receptors Are Expressed in the Central Nervous System
Peripheral Inflammation Propagates to the Brain Via Multiple Communication Pathways
Cytokines Act in the Brain to Induce Fever, Activate the Hypothalamic-Pituitary-Adrenal Axis, and Increase Non-REM Sleep
Cytokines Act in the Brain to Induce Sickness, and Prolonged Sickness Can Lead to Depression
Outlook
From the Mind to Immunity and Vice Versa
References
Part IV: Basic Neuroscience: Sensory Systems (Neuroanatomy and Physiology)
36 Retina: Neuroanatomy and Physiology
Brief History
Retina- Development, Structure, and Function
Evolutionary Background
Light Perception in Animals Goes Back to Common Origins
The Vertebrate Retina Is a Part of the Brain
Light Sensitivity in Vertebrates Is Not Restricted to the Retina of the (Lateral) Eyes
Vertebrate Cones and Rods Differ in Their Development, Function, and Neuronal Circuits
Basic Ontogenetic Mechanisms of Retinogenesis
The Number of Cell Cycles of Retinal Progenitor Cells Matters
Retinal Layers and Mosaics Are Formed Early After Cytogenesis
Late Shaping Processes Occur During Retina Expansion and Foveation
Structural Organization of the Mammalian Retina
The Retina Is Composed of Two Main Layers
The Neuroretina Contains Several Different Types of Neurons and Glial Cells
Photoreceptor, Bipolar, and Ganglion Cells Mediate the Forward Transmission of Visual Information
Interneurons Mediate Processing of Visual Information
Rods and Cones as the Main Light Sensors in the Retina
Rods and Cones Operate Under Different Lighting Conditions
Rod Vision Is Highly Sensitive and Cone Vision Has High Acuity
The Optical Properties of the Tissue Are Important in the Inverted Retina
The Fovea Is an Adaptation to Increase the Sensitivity and Acuity of Cone Vision
Müller Glial Cells Are Living Optical Fibers Which Increase the Sensitivity and Acuity of Peripheral Vision
Rows of Rod Nuclei Act as Chains of Lenses
Vertebrate Photoreceptors Are Inactivated by Light
Light Induces Bleaching of Vertebrate Photopigments
Phototransduction Results in a Decrease of the Dark Current
Invertebrate Photoreceptors Are Activated by Light
Phototransduction Is Turned Off by Inactivation of Transducin and Metarhodopsin
Phototransduction Is Amplified at Several Steps
The Light Sensitivity of Photoreceptors Is Controlled by Ca2+
The Recovery of Light Sensitivity Is Slower in Rods than in Cones
The Type of Opsin Defines the Spectral Sensitivity of Photopigments
Color Is Processed in the Retina, Thalamus, and Cortex
Red-Green Blindness Is Evolutionary Conserved
The Yellow Macula Acts as a Sunglass
Retinal Neurons Mediate Processing of Visual Information Before It Is Transmitted to the Optic Nerve
Horizontal Cells Provide Contrast Enhancement Through Lateral Inhibition
Bipolar Cells Transfer Visual Information to Ganglion and Amacrine Cells
Different Glutamate Receptors in Bipolars Underlie the ON- and OFF-Dichotomy of the Cone Pathway
Midget Bipolar Cells Underlie the Color-Opponent Receptive Fields of Ganglion Cells
Rod Bipolars Are Not Directly Connected to Ganglion Cells
Amacrine Cells Process Visual Information According to Alterations in the Environmental Visual Signals
AII Amacrines Connect the Rod Pathway to the Cone Output Pathway
Cholinergic Amacrines Play a Role in Movement Detection
Dopamine and Melatonin Are the Chemical Surrogates of Night and Day in the Retina
Retinal Ganglion Cells Act as Parallel Operating Filters That Extract Distinct Aspects of the Image
Retinal Ganglion Cells Are Coincidence Detectors for Weak Visual Signals
Photosensitive Ganglion Cells Control Non-image-forming Vision
Visual Cortex Preserves a Topological Map of the Retina
Visual Information Is Compressed in the Retina
Most Retinal Neurons Produce Graded Potentials
RPE Cells Are the Major Photoreceptor-Supporting Cells
RPE Cells Support the Function of Photoreceptors
RPE Cells Maintain the Structural Integrity of Photoreceptors
RPE Cells Protect Photoreceptors from Photooxidative Damage
RPE Cells Absorb Photoreceptor-Derived Water and Lactate
Retinal Glial Cells Mediate Neuronal Nutrition, Waste Management, and Inflammation
Microglial Cells Are the Blood-Borne Resident Immune Cells of the Retina
Macroglial Cells Provide Metabolic and Functional Support for Retinal Neurons
Müller Cells Are Involved in Synaptic Signaling by Uptake of Neurotransmitters
Müller Cells Provide Glutamine as Precursor of Neuronal Transmitter Synthesis
Müller Cells Maintain the Ion and Osmohomeostasis in the Neuroretina
Müller Cells Clear Excess K+ from the Extracellular Fluid
Müller Cells Dehydrate the Inner Retina
Outlook
Glossary
References
37 The Superior Colliculus and Visual Thalamus
The Superior Colliculus
The SC Is a Layered Structure
The SC Consists of Functional Subdivisions
Sensory and Motor Maps Are Critical to SC Function
Sensory Maps Are Aligned
Motor Maps Represent Movement Metrics
SC Neurons Have Movement Fields
The SC Interacts with Cortex
The SC Is Intimately Related to the Basal Ganglia
The SC Is a Multisensory Structure
Summary
The Visual Thalamus
The Thalamus Is the Primary Visual Relay from the Eye to the Cortex
Visual Streams Are Encoded in the Retina and Maintained in the Thalamus
LGN Synaptic Organization Reflects Ascending and Descending Influences
Interneurons Inhibit the Retinal Signal
The Cortex Provides Massive Feedback to Relay Neurons
The LGN Processes Visual Information Depending on Behavioral State
LGN Organization Reflects a Common Pattern
Summary
Some Special Roles of SC and Thalamus
SC and LGN May Mediate Forms of Blindsight
SC May Mediate Unseen Fear Responses
Subcortical Visual Pathways May Facilitate Rehabilitation from Cortical Blindness
A Final Thought
References
38 Cortical Processing of Visual Signals
Brief History
Chapter Goals
Primary Visual Cortex Receives Stream-Specific Input from the LGN
Primary Visual Cortex Has Six Main Layers and Many More Sublayers
Simple Cells and Complex Cells in V1 Process Information About Edges and Orientation
V1 Has Columnar Organization
V1 Has Visuotopy
V1 Contains Ocular Dominance Columns
V1 Contains Orientation Columns
V1 Cells Are Tuned to a Multitude of Stimulus Properties
More Elaborate Details in Visual Scenes Are Processed Beyond the Primary Visual Cortex
Outlook
References
Helpful Links
39 Audition: Hearing and Deafness
Brief History
Introduction
Hearing
Auditory Perception: Its Requirements and Its Achievements
Bases of Physical Acoustics
Acoustic Pressure: Temporal and Spectral Features
Pure Tones
Complex Sounds
Acoustic Pressure, Spatial Properties
Acoustic Pressure: Energetic Properties
From the Physical Description of the Auditory World to Its Perception and Analysis
The Challenges Met by the Auditory System
To Detect (Pressure P0, at Frequency f)
To Quantify (Pressure P0, at Frequency f)
To Discriminate and Select (P0 Versus P′0, f Versus f′)
To Communicate (Answer One Detected Sound by Emitting Another Sound)
To Locate (the Direction of the Source of a Sound)
Auditory Abilities
Psychophysics
The Decibel (dB)
The Auditory Thresholds
Suprathreshold Performances
Loudness, Its Metrology
Equal Loudness Contours
Threshold of Pain and Notion of Auditory Hazard
Quantification of Loudness
Other Performances
Auditory Abilities in Summary
Peripheral Organs of Auditory Perception
Conduction of Sound Through the Middle Ear
Acoustic Impedance
The Tympano-Ossicular Chain Seen as a Transformer
Modulations of Sound Transmission
Perception, the Organ of Corti in the Cochlea
A Brief Overview of Cochlear Anatomy
Cochlear Resonance, from Hermann Von Helmholtz to Georg Von Békésy, the Two Pioneers
Basic Resonating Properties of a Mass-Spring System
Failure of So-Called Passive Mechanical Theories
Auditory Sensory Cells
Experimental Access to Cochlear Transduction
Synchronous Averaging for Objective Audiological Measurements
Hearing Impairment
Introduction
Classification and Causes
Monogenic Forms of Sensorineural Hearing Impairment
Pathogenesis of Sensorineural Monogenic Forms of Deafness: From Clinical Evaluation to Multidisciplinary Studies of Mouse Mode...
DFNB1, a Gap Junction Channel Defect
Deafness in Usher Syndrome
Usher Syndrome of Type I
Usher Syndrome of Type II
Auditory Neuropathy Spectrum Disorders
DFNB9, Caused by a Defect in Otoferlin, Is a Synaptopathy of the Inner Hair Cells
DFNA25, Caused by a Defect in the Vesicular Glutamate Transporter-3 (VGLUT3), Is another Synaptopathy of the Inner Hair Cells
DFNB59, Caused by a Defect in Pejvakin, Affects Both Cochlear Hair Cells and Neurons of the Auditory Pathway
Outlook
References
40 Somatosensation
Brief History
Touch
Morphology of the Skin
The Role of the Skin in Signal Transduction
Sensory Axons
Touch and Pain
Temperature
Itch
Pleasant Touch
Transmission of Impulses to CNS
Outlook
References
41 Taste
From Taste Buds to the Brain: Anatomy and Physiology of Taste
Papillae and Taste Buds
Taste Bud Structure
Extraoral Taste Buds
Nontaste Receptors in the Oral and Nasal Cavity
Vulnerability of Taste Pathways
Taste Pathway into the Central Nervous System
Mechanisms of Taste Qualities
Salty
Sour
Bitter
Sweet
The Myth of the Tongue Map
Why Should We Care About Basic Tastes?
Nineteenth Century View: Müller´s Doctrine of Specific Nerve Energies
Pfaffmann: Across-Fiber Patterning (1941-1974): No Basic Tastes
Pfaffmann, 1974, Labeled-Line Code for Taste Quality
Basic Tastes Are Back
Biological Function of Basic Tastes
Taste Affect Is Hard-wired
Specific Hungers and Taste Signals
The Special Case of Umami
The Special Case of Fat
Genetic Variation
Bitter: Tuned to Include Multiple Toxins
Sweet: Tuned to Exclude Sugar-Like Structures
Supertasters: How Can We Measure ``Subjective´´ Taste Intensities?
Scales That Permit Magnitude Matching
Supertasters Perceive Unusually Intense Oral Sensations
Taste Is Linked to Other Oral Sensations
Retronasal Olfaction and Somatosensation
Taste Damage, Release of Inhibition, and Oral Sensory Phantoms
Purpose of Taste Inhibition
Outlook
Taste Quality
Taste Disorders
Psychophysical Methodology
References
42 The Sense of Smell: Role of the Olfactory System in Social Behavior
Brief History
Introduction
Organization of the Olfactory System
Architecture of the Main Olfactory System
Architecture of the Accessory Olfactory System
Pathways from Distinct Olfactory Subsystems Have Overlapping Neuroanatomical Targets
Involvement of Both Main and Accessory Olfactory Systems in the Detection of Pheromones Affecting Reproductive Behavior
Role of Olfaction in Mate Recognition and Mate Attraction
Role of Olfaction in the Manifestation of Copulatory Behavior
Role of Olfaction in the Control of Male Copulatory Behavior
Role of Olfaction in the Control of Female Copulatory Behavior
Role of Olfaction in Parental and Neonate-Oriented Behavior
Role of Olfaction in Humans
Olfactory Cues Inducing Behavior in Young Children
Olfactory Processing in Humans
General Conclusions
Outlook
References
43 Visuomotor Integration
Introduction
What Does the Brain Need to Tell the Muscles to Make Accurate Eye Movements?
Overview and Classification of Eye Movement Types
Ocular Structure and Its Functional Implications
The Motor Control of Eye Movements
Ocular Dynamics and the Premotor Control of Saccadic Eye Movements
The Motor Control of Conjugate Versus Disconjugate (i.e.,Vergence) Eye Movements
How Does the Brain Control the Five Classes of Eye Movements?
Gaze Redirection: Saccades and Gaze Shifts
Gaze Redirection: Smooth Pursuit
Gaze Redirection: Vergence
Gaze Stabilization: The Vestibulo-ocular and Optokinetic Reflexes
Interactions Between Eye Movement Pathways
Motor Learning, Calibration, Plasticity, and Reward in the Oculomotor System
Outlook
References
44 Vestibular Inputs: The Vestibular System
Brief History
Introduction
Vestibular Receptors are Proprioceptors
Vestibular Organs Monitor Angular and Linear Forces in Three Dimensions
Vestibular System Contributes to Many Central Functions
Peripheral Vestibular System
Semicircular Canals are Rotational Sensors
Otolith Organs are Linear Sensors
Canals and Otolith Organs are Both Orthogonally Disposed
Hair-Cell Transduction Couples Head Motion to Afferent Discharge
Transduction Channels Convert Mechanical Deflections into Electrical Signals
Basolateral Currents Shape Hair-Cell Potentials
Hair-Cell Neurotransmitter Release Depolarizes Afferent Terminals
Afferents Have a Resting Discharge
Hair-Bundle Orientation Influences Directional Properties
Afferent Diversity Is Related to Discharge Regularity
Response Diversity
Innervation Patterns
Efferent System
Vestibular Nuclei and Vestibulocerebellum
The Vestibular Nuclei Consist of Four Major Divisions
Vestibular-Nerve Inputs Distribute Widely in the Vestibular Nuclei
The Vestibular Nuclei Contain Projection and Nonprojection Neurons
Commissural Pathways Integrate Bilateral Inputs
The Vestibular Nerve Is a Major Source of Brain-Stem Excitation
Unilateral Asymmetry Leads to Oculomotor and Postural Imbalances
The Vestibular Nuclei Receive Spinal Inputs
Secondary Vestibular Neurons Carry Oculomotor Signals
The Vestibular Nuclei Mediate Visually Driven Oculomotor Responses
The Vestibular Nuclei and the Cerebellum are Strongly Interconnected
Nodulus-Ventral Uvula
Flocculus/Ventral Paraflocculus
Anterior Lobe
Oculomotor Vermis
Vestibulo-Ocular Reflexes
The Vestibulo-Ocular Reflex and Visual Acuity
The AVOR is Essential During Rapid Head Movements
Each Semicircular Canal Contributes to Specific VOR Pathways
The VOR Engages Both Direct and Indirect Pathways
The VOR Needs Continual Recalibration
Postural Control
Both Reflexes and Learned Strategies Contribute to Postural Control
Postural Control Involves Multisensory Strategies
Postural Strategies Involve Hierarchies of Learned Behaviors
Reflexes Compensate for External Disturbances
Descending Tracts Place the Spinal Cord Under Vestibular Control
Vestibulospinal Activity Contributes to Postural Tone
Vestibulocollic (VCR) Reflexes Stabilize the Head in Space
Short-Latency Pathways Interconnect Ampullae with Neck Motoneurons
The Functional AVCR Requires Indirect Pathways
Function of the AVCR
Linear VCRs Link Otolith Organs and Neck Muscles
Cervicocollic Reflexes Interact with the VCR
Descending Actions on Limbs may Stabilize the Trunk
Outlook
References
45 Kinesthetic Inputs
Brief History
Introduction
Kinesthesia and Proprioception Are Synonymous
Kinesthesia Is a Sensory System
Kinesthesia and Motor Control Are Closely Linked
Sensory Receptors Contribute to Kinesthesia
Muscle Spindles
Muscle Spindles Are Complex Receptors
Muscle Spindles Have Two Types of Sensory Endings
Muscle Spindles Have Motor Innervation
Muscle Spindle Primary and Secondary Endings Respond to Stretch of the Passive Muscle
In Humans, Alpha and Gamma Motoneurons Are Activated Together
Golgi Tendon Organs
Joint Afferents
Cutaneous Afferents
Central Pathways for Kinesthetic Afferents
Kinesthetic Afferents Affect Motor Output at a Segmental Level
Kinesthetic Afferents Have Different Ascending Pathways for the Upper and Lower Limb
Kinesthetic Sensory Signals Go to the Cerebellum
Kinesthetic Sensory Signals Go to the Cerebral Cortex
Central Signals Contribute to Kinesthesia
Corollary Discharge Can Contribute Information About the Strength and Timing of Muscle Contractions
Corollary Discharge Is Needed to Identify the Body´s Actions from Those of the Environment
Corollary Discharge Is Required for Kinesthetic Interpretation of Muscle Spindle Firing
Testing Kinesthetic Sensations
Joint Position and Movement Sense
Movement Sense Can Be Tested by Imposing Passive Movements About a Joint
Position Sense Can Be Tested Separately from Movement Sense but Most Common Tests Do Not Differentiate
Sensations of Force and Effort
Sensations of Force and Effort and the Judgment of Heaviness
Evidence for the Contribution of Afferent and Central Signals to Kinesthetic Sensations
Senses of Position and Movement
Joint Receptors Contribute to the Senses of Joint Position and Movement
Cutaneous Receptors Contribute to the Senses of Joint Position and Movement
Muscle Spindles Contribute to the Senses of Joint Position and Movement
Muscle Spindles Give Poor Signals of Joint Position and Movement during Voluntary Contraction
Corollary Discharge May Contribute to the Senses of Joint Position and Movement
Senses of Force and Effort
Golgi Tendon Organs Contribute to the Sense of Muscle Force
Corollary Discharge Contributes to the Sense of Effort
The Senses of Force and Effort Both Contribute to Judging the Heaviness of Objects
Cutaneous Receptors Are Also Important in the Perception of Force
Kinesthetic Signals Are Studied Separately but Are Used Together
Some Properties of Objects Are Assessed Through Combinations of Kinesthetic Signals
Proprioceptive Signals Are Combined with Exteroceptive Signals to Provide Orientation in the Environment
Kinesthetic Signals and Body Representations
Summary
Outlook
References
46 Pain
Brief History
Before 1800
After 1800
Peripheral Nociceptors and Nociception
Peripheral Nociceptors and Transducers
Peripheral Mechanisms of Pain and Hyperalgesia
The Spinal Cord Dorsal Horn
Organization of the Dorsal Horn
Spinal Mechanisms of Hyperalgesia and Allodynia
Cortical and Subcortical Processing of Pain
Multimodal Neuroimaging for Human Pain Studies
Brain ``Matrix´´ of Pain
Modulation of Clinical Pain
Placebo Modulation of Pain
Acupuncture Modulation of Pain
Neuromodulation of Pain
Psychological Modulation of Pain
Drug Modulation of Pain
Gene Therapy and Stem Cells Used in Pain Treatment
Outlook
Changing the Definition of Pain
Understanding the Brain Mechanisms of Pain
Glossary
References
Part V: Basic Neuroscience: Motor Control
47 Spinal Motoneurons
Brief History
Definitions
Anatomy
Motoneuron Morphology: General Properties
Alpha Motoneurons
Gamma Motoneurons
Motor Nuclei
Physiology
General Cellular Properties
Passive Membrane Properties: Input Resistance, Dendritic Dominance, and Time Constant
Action Potentials
Afterhyperpolarization
Excitability and Firing Frequency
Plateau Potentials and Bistability
Motor Units
Definition
Muscle Unit Anatomy
Muscle Fiber Types
Motor Unit Types
Motoneuron Specializations in FF, FR, and S Motor Units
Beta Motor Units
Synaptic Input Organization and Motor Unit Recruitment
Group Ia Excitatory Synapses: The Stretch Reflex
Recruitment Order in Stretch Reflexes and Beyond
Other Synaptic Inputs to Motoneurons
Are Other Recruitment Sequences Possible?
Outlook
Basic Research
Clinical Relevance
References
48 Spinal Interneurons
Brief History
Mammalian Spinal Interneurons
Subdivision of Spinal Neurons
Identification of Different Classes of Interneurons
Examples of the Most Completely Functionally Identified Mammalian Interneurons and Their Properties
Premotor Interneurons Mediating Inhibition Between Antagonists: Ia Inhibitory Interneurons
Renshaw Cells
Premotor Interneurons Processing Information from Both Group I and II Muscle Afferents
Commissural Interneurons
Other Interneurons
Propriospinal Neurons Mediating Descending Commands
Interneurons Mediating Descending Commands from Supraspinal Neurons
Plasticity of Operation of Spinal Interneurons and Their Networks
Elementary Neuronal Networks
How to Analyze Operation of Spinal Interneurons in Humans?
Development of Various Types of Interneurons from Spinal Progenitor Cells
New Experimental Approaches to Studies of Functions of Various Types of Interneurons in Neuronal Networks In Vitro and In Vivo
Outlook
References
Further Reading
49 Systems Descending from the Brainstem: Basic Principles - Other Descending Pathways and Motor Control
Brief History
Other Descending Pathways and Motor Control
There Are Several Different Extrapyramidal Motor Pathways
Nonpyramidal Systems Operate in Parallel with the Pyramidal System
Nonpyramidal Structures Participate in Several Control Loops
Two Groups of Tracts Descend from the Brain Stem
Most Descending Fiber Tracts Have Low Conduction Velocities
The Ventromedial Group of Tracts
Vestibulospinal Tract
Reticulospinal Tract
Tectospinal Tract
Other Medial Tracts
The Dorsolateral Group of Tracts
The Red Nucleus and Rubrospinal System
Brain Stem Lesions and Decerebrate Rigidity
Outlook
References
50 Systems Descending from the Cortex and Brain Stem: Functional Recovery Following Damage
Brief History
Neural Mechanisms Underlying the Motor Recovery from CST Injuries
Outlook
References
51 Basal Ganglia: Basic Principles
Brief History
Anatomy and Connections
Summary of Anatomy and Function
Circuits Through the Basal Ganglia
The Direct Circuit
The Indirect Circuit
A Modulating Circuit
Neural Response Patterns in the Basal Ganglia
Disorders of the Basal Ganglia
Hypokinetic Syndromes: Parkinson´s Disease
Hyperkinetic Syndromes: Huntington´s Disease and Ballismus
Outlook
References
52 Basal Ganglia: Dystonia
Brief History
Basal Ganglia Circuitry
Decreased GPi and GPe Activity in Dystonia
Cortically Evoked Long-Lasting Inhibition in GPi and GPe Neurons in Dystonia
Somatotopic Disorganization in the GPi and GPe in Dystonia
Pathophysiology of Dystonia
Contribution of the Integrated Network of the Basal Ganglia and Cerebellum to Dystonia
Outlook
References
53 Cerebellum: Anatomy and Function
An Overview
The Cortex of the Cerebellum Is Geometrically Organized
Two Cell Types Provide the Major Inputs to the Cerebellum
There Are Three Main Divisions of the Cerebellar Cortex
Cerebellar Dysfunction
Ataxia
Intention Tremor
Hypotonia
Charcot´s Triad
Affective Disorders
What Does the Cerebellum Do?
Outlook
References
54 Cerebellum: Eye Movements
Brief History
Overview
The Oculomotor Cerebellum
The Flocculus-Paraflocculus Complex
Flocculus and Ventral Paraflocculus
Dorsal Paraflocculus
Nodulus/Uvula
The Hemispheric Oculomotor Region
The Oculomotor Vermis
How the Oculomotor Vermis Controls Eye Movements
Saccade-Related Activity of Purkinje Cells
Cerebellar Mechanisms for Saccadic Adaptation
Purkinje Cell Complex Spike Activity During Adaptation
Purkinje Cell Simple Spike Activity During Adaptation
Outlook
References
55 Cortical Motor Control
Brief History
Cortical Motor Control
The Cerebral Cortex Has Multiple Motor Areas
The Supplementary Motor Area Is Involved in Planning Complex Movements
The Premotor Cortex Is Involved in Sensory Initiation of Movement
The Posterior Parietal Cortex Provides Spatial Information for Motor Planning
The Primary Motor Cortex Is the Area Most Directly Involved with the Final Movement
Connections with Other Cortical Areas
The Motor Cortex Contributes to the Corticospinal Pyramidal Tract
The Motor Cortex Is Topographically Arranged
What Is Encoded in the Motor Cortex?
Motor Areas of the Cortex Are Prone to Stroke
Motor Areas of the Cortex Cooperate to Generate Voluntary Movement
Outlook
References
56 Locomotion: Circuits and Physiology
Brief History
Basal Ganglia Select Locomotion
The Mesencephalic Locomotor Region and Reticulospinal Neurons Initiate Locomotion
Spinal Networks Are Complex Networks that Generate the Rhythm and Pattern of Locomotor Behavior
A Molecular Code May Determine the Layout of the Spinal CPG and Provide Insights into Its Function
Cellular Properties Contribute to CPG Activity
Bursting and Plateau Properties Amplify Cellular Responses
Phase Transition Is Regulated by Ionic Conductances
Regulation of Spiking by Intrinsic Membrane Properties Affects the Function of CPG Neurons
Activation of Muscle Afferents and Skin Afferents Modulates Ongoing Locomotor Activity
Cerebellar Motor Circuits Integrate Internal Locomotor Commands with External Movements and Coordinate Locomotion
Neuronal Circuits in Cortex Allow Visual Adjustment of Locomotor Movements
Neuromodulatory Systems Cause Long-Lasting Changes in Synaptic Strength and Ionic Conductances of the Locomotor CPG
Outlook
Glossary
References
57 Posture and Movement
Brief History
Posture and Movement
Supraspinal Regulation of Posture
Control of Muscle Tone
Descending Brain Stem Tracts That Influence the State of Muscle Tone
Reticulospinal Control of Muscle Tone
Vestibulospinal Control of Muscle Tone
Postural Reflexes Involving the Midbrain
Righting Reflex
Tonic Neck Reflex
Vestibular Reflexes
Labyrinthine Neck Reflexes
Vestibulo-ocular Reflexes
The Basal Ganglia Are Involved in Postural Reflexes
Many Reflexes Involve the Cortex
Positive Supporting Reaction
Negative Supporting Reaction
Tactile Placing Reaction
Visual Placing Reaction
Hopping Reaction
Postural Set
Locomotion
Central Pattern Generators and Reflex Chains
Afferent Input Assists the CPG to Switch Phase
Reflex Gating and Reflex Reversal
Outlook
References
Part VI: Basic Neuroscience: Neurophysiology of Other Specific CNS Regions and Networks
58 Basic Principles of Mammalian CNS Systems: Nervous System Organization - Connectomics and the Connectome
Introduction
Perspective Can Be Gained from History
Exploration Requires Compass and Maps
Description of the Body´s Structure-Function Organization Can Be Done in Two Ways
The Nervous System Can Also Be Described Topographically and Systemically
Topographic Divisions of the Nervous System Are Hierarchically Organized
Subsystems Microarchitecture of the Nervous System Is Based on Cellular Organization
Gray Matter Is Regionalized and White Matter Forms Tracts
How Complex Is Mammalian Nervous System Circuitry?
Experimental Analysis Is Based on the Principle of Localization of Function
The Vertebrate Nervous System Can Be Described by a Four-\Subsystem Network Model
The Motor System Has Three Components and Is Hierarchically Organized
The Behavioral State System Has a Circadian Clock and Diffusely Organized Components
The Cognitive System Is in the Cerebral Hemispheres and Has a Network Organization
The Sensory System Transmits External Stimuli and Is Arranged in Parallel
Neural Network Structure Is Determined with Two Anatomical Methods
Neural Network Organization Is Described at Different Levels of Abstraction: Overview
References
59 Frontal Cortex
Brief History
The Prefrontal Cortex Has Functionally Distinct Lateral, Orbital, and Medial Sectors
The Orbitofrontal Cortex Has a Role in Social Interactions
The Anterior Cingulate Cortex Is Part of a Classical Circuit for Emotions
The Lateral Prefrontal Cortex Is Associated with Cognition
The Prefrontal Cortex Guides Behavior
Architecture
The Frontal Cortex Has a Diverse Architecture
The Premotor Cortex Has Ventral, Dorsal, and Medial Parts
The Architecture of Prefrontal Cortices Changes Gradually
The Posterior Parts of the Orbitofrontal and Medial Sectors Are Old in Phylogeny
Eulaminate Cortex Has Six Layers
Summary of Prefrontal Architecture
Connections
The Prefrontal Cortex Is Widely Connected
Brain Connections Can Be Studied Using Three Types of Tracers
The Frontal Cortex Is Connected with Ventral and Mediodorsal Thalamic Nuclei
The Prefrontal Cortex Is Connected with the Mediodorsal Nucleus and Other Thalamic Nuclei
There Are Two Parallel Pathways That Link the Prefrontal Cortex with the Thalamus
The Frontal Cortex Has Return Pathways to the Thalamus
The Prefrontal Cortex Has Widespread Projections to the Thalamic Reticular Nucleus
The Frontal Cortex Has a Special Relationship with the Basal Ganglia
There Are Two Major Pathways Through the Basal Ganglia
The Two Pathways Through the Basal Ganglia Have Opposite Functions
The Direct and Indirect Pathways Are Innervated by Dopaminergic Neurons
The Frontal Cortex Receives Indirect Feedback from the Basal Ganglia
The Prefrontal Cortex Is Connected with Other Cortices
The Orbitofrontal Cortex Has a Panoramic View of the Environment
Medial Prefrontal Cortices Are Connected with Auditory, Prefrontal, and Memory-Related Areas
Lateral Prefrontal Cortices Are Connected with Auditory, Visual, and Somatosensory Cortices
The Prefrontal Cortex Is a Polymodal Cortex
The Prefrontal Cortex Is Connected with Premotor Cortices
Corticocortical Connections Are Reciprocal But Unequal in Each Direction
Other Subcortical Connections of the Prefrontal Cortex
The Hypothalamus Projects to the Entire Prefrontal Cortex
The Claustrum Projects to the Entire Prefrontal Cortex
Neurotransmitter-Specific Structures Project to All Prefrontal Cortices
The Amygdala and Hippocampus Are Strongly Associated with pOFC and the ACC
Connections with the Amygdala Are Bidirectional
One-Way Projections from the Hippocampus Reach the ACC
Functions
The Prefrontal Cortex Selects Relevant Information and Ignores Irrelevant Information
Inhibitory Neurons in the Cortex Are Diverse
The Connections of Prefrontal Cortices Suggest Their Functional Specialization
The Orbitofrontal Cortex Has a Key Role in Processing the Value of Stimuli
The Anterior Cingulate Cortex Has a Key Role in Emotional Communication and Attention
Lateral Prefrontal Cortex Has a Key Role in Working Memory and Cognitive Processes
Cognitive-Emotional Interactions and Their Breakdown in Mental Disease
Outlook
References
60 Anatomy of Emotion
Brief History
The Limbic Cortex
Hippocampal Formation
Amygdala
Hypothalamus
Nucleus Accumbens: A Critical Node of the Limbic Circuit to Translate Motivation into Action
Future Directions
References
61 Limbic Cortex: The Functional Neuroanatomy of Emotion and Hedonic Processing
Brief History
Theories of Emotion
Experimental Paradigms
Neuroanatomy of Emotion and Motivation
Emotion and Hedonic Processing
Pleasure Definitions
Brain Networks for Emotion Processing
The Primate Orbitofrontal Cortex
Neuroanatomy of the Orbitofrontal Cortex
Functional Neuroanatomy of the Human Orbitofrontal Cortex
Amygdala
Cytoarchitectonics
Input and Output Connections
Cingulate Cortex
Cytoarchitectonics
Input and Output Connections
Food Intake and Sensory Pleasures
From Sensory Processing to Hedonic Experience of Food
Other Sensory Pleasures
The Social Pleasures: Face Processing
Infant and Infantile Faces as a Tool for Understanding Social Attachment
Changes in Facial Expression as a Tool for Social Learning
Deep Brain Pleasures
Measuring Whole-Brain Activity from DBS
Outlook
References
Further Readings
62 Hypothalamus
Brief History
Hypothalamic History
The Neuroendocrine Pathway
The Autonomic Nervous System
History of the Hypothalamic Control of Energy Metabolism
Hypothalamic Neuroanatomy
Hypothalamic Output: The Hypothalamic Paraventricular Nuclei
PVN Control of the Neuroendocrine System
PVN Control of the Autonomic Nervous System
PVN Integration of Sensory Information
Hypothalamic Integration of Time of Day: The Suprachiasmatic Nuclei
SCN Control of Neuroendocrine Rhythms
SCN Control of the Autonomic Nervous System
Hormonal Feedback to the Brain: The Arcuate Nucleus
The Endocrine Effects of Arcuate Nucleus Output
Outlook
References
63 Brain Control over the Autonomic Nervous Systems: Coordination of Physiology and Behavior
Introduction
The Autonomic Motor Centers in the Brain
The Basic Plan of the Autonomic Nervous System
The Hypothalamus Has Separate Parasympathetic and Sympathetic Output and Autonomic Somatotopy
The Metabolic Syndrome a Matter of Timing?
What Is the Significance of This Highly Differentiated Autonomic Output?
The SCN as Coordinator of Behavior, Hormone Secretion, and the ANS
The SCN Affects Cortisol Secretion via Hormonal and Autonomic Pathways
Coordination Between Autonomic and Behavioral Functions: The Communication Between Body and Brain
Signaling the State of the Body to the Brain
Circulation: Brain Communication
The Brain Mediates the Requirements of the Immune System
Outlook
Further Reading
64 Respiration
Brief History
Introduction and Historical Perspective
Respiratory Rhythm Is Generated Within the Brainstem
Discovery of the Respiratory-Rhythm-Generating Center
Neuronal and Network Properties Underlying Respiratory Rhythmogenesis
Neuromodulation of Central Respiratory Rhythmogenesis
Breathing Movements Are Generated by a Pattern Generator that Underlies the Coordinated Recruitment of Rib Cage, Abdominal and...
Respiratory Muscles Controlling the Rib Cage and Abdomen
Respiratory Spinal Motoneurons
Control of the Upper Airway
Spinal Cord Injury and Breathing
Respiratory Rate and Pattern Are Regulated by Chemoreceptive and Mechanoreceptive Feedback
Chemoreception
Hypoxia
Hypercapnia
Peripheral Chemoreceptors
Central Chemoreceptors
Mechanoreception
Respiratory Network Activity Is Integrated with Networks Controlling Sleep, Exercise, and Locomotion
Sleep
Exercise
Coordination of Breathing with Other Behaviors
The Respiratory Control Network Is Highly Plastic
Perinatal Environment
Plasticity in the Adult System
Respiratory Pathologies Result from Abnormal Neural Control Mechanisms
Summary of Major Concepts
Outlook
References
65 Spinal Reflexes
Brief History
Spinal Cord
Selection of Motoneurons Ensuring Properly Coordinated Motor Reactions
Spinal Reflexes: Reactions Mediated by Spinal Neuronal Networks
Are They Automatic and Stereotype, or Adjustable?
Different Ways of Analyzing Spinal Reflexes
Stretch Reflex
The Basic Mechanisms of the Stretch Reflex Evoked by Group Ia Muscle Spindle Afferents
Stretch Reflex in Its Wider Context
Modulation and Role of Stretch Reflexes During Different Motor Tasks
Pathological Changes in Stretch Reflexes
Reflexes Evoked from Other Muscle, Tendon, and Joint Receptors
Reflex Actions from Tendon Organs (Group Ib Afferents)
Reflex Actions from Tendon Organs During Different Motor Tasks and Their Pathological Changes
Reflex Actions from Secondary Muscle Spindle Afferents (Group II Muscle Afferents)
Reflex Actions from Secondary Muscle Spindle Afferents During Different Motor Tasks
Pathological Changes in Reflex Actions from Secondary Muscle Spindle Afferents
Reflex Actions of Joint Afferents
Selection of Interneurons Mediating Reflex Actions of Group I, Group II, and Joint Afferents
Reflexes Evoked by Skin Stimulation
Basic Organization
Diversity of Reflexes Evoked by Skin Afferents
Spinal Reflexes Are Intrinsic Components of All Motor Acts
Outlook
References
Part VII: Basic Neuroscience: Network Analyses in Mammalian Brains
66 Intrinsic Brain Activity and Resting State Networks
Overview of Intrinsic Brain Activity
An Introduction to Resting State fMRI
Major Spatiotemporal Features of Intrinsic BOLD Fluctuations
Some Remarks Concerning the Default Mode Network (DMN)
Anatomical Versus Functional Connectivity
Relation of RSNs to Task-fMRI Responses
Intrinsic Activity Is Task State-Dependent
Functional Connectivity Depends on Level of Arousal
Functional Connectivity Is Plastic
BOLD fMRI Functional Connectivity Changes Over the Lifespan
Practical RS-fMRI
BOLD RS-fMRI Acquisition
Artifact
Nonneural Low-Frequency Oscillations
RS-fMRI Preprocessing, Artifact Reduction, and Frame Censoring
Approaches to Evaluating Intrinsic Brain Activity Imaged by RS-fMRI
Resting State fMRI Studies of Neurologic and Psychiatric Conditions
RS-fMRI Studies of Autism Spectrum Disorders: A Cautionary Tale
Outlook
References
Selected References
67 Networks Associated with Reward
Brief History
Different Facets of Reward
A Brief History of Reward-Processing Research
Evolving Perspectives: Centers, Circuits, and Networks
Centers, Circuits, and Networks
Outline of This Chapter
An Overview of Reward Centers and Circuitry
The Mesocorticolimbic (MCL) System
The Midbrain
The Striatum
The Prefrontal Cortex
The Amygdala
Other Structures
Parallel and Overlapping Loops: A Ventral-to-Dorsal Cascade
Capturing Nodes in the Reward Network with Neuroimaging
Whole-Brain Imaging of Reward Processing
Reward Anticipation and Receipt, and Economic Decision-Making
Disordered Reward Responses in Addiction
Brain Networks Associated with Reward
Noninvasive Neuroimaging Techniques Capture Structural and Functional Connectivity
Resting-State Networks in Reward
Resting-State Functional Connectivity with the MCL System
Triple Network Model
Outlook
References
68 Attention Networks
Introduction
The Logic of Lesion-Deficit Data
The Logic of Behavioral Data
The Logic of Brain Imaging
Network Models of the Attention System
Alerting Network
Orienting Network
Executive Network
Outlook
Clinical Applications
References
69 Corticostriatal Circuitry
Brief History
Overview of the Basal Ganglia Structures and Circuit
The Striatum
Main Outputs of the Striatum
Striatal Projections to the Midbrain
Relationship of the SN/VTA Connections to the Corticostriatal Organization
Striatal Connections to the Pallidal Complex and SNR
Thalamocortical Projections
Other Key Elements to the Cortico-Basal Ganglia Network
Outlook
References
Further Readings
Part VIII: Basic Neuroscience: Neurochemistry and Neuropharmacology
70 Transmitters and Peptides: Basic Principles
Brief History
Introduction: Overview of Cell-Cell Signaling Molecules
Classical Neurotransmitters
Acetylcholine
Dopamine
Serotonin (5-Hydroxytryptamine)
Gamma-Aminobutyric Acid (GABA)
Glutamate
Nonclassical Neurotransmitters
Nitric Oxide (NO)
Lipid-Derived Endocannabinoids
Other Classical and Nonclassical Neurotransmitters
Classical Neuropeptides
Neuropeptide Y (NPY)
The Enkephalins
Other Classical Neuropeptides
Nonclassical Neuropeptides
Outlook
Future Perspectives
References
71 Transmitter and Peptide Receptors: Basic Principles
Brief History
Introduction: Overview of Receptors
Ligand-Gated Ion Channels
G-Protein-Coupled Receptors
Enzyme-Linked Receptors
Nuclear Hormone Receptors
Major Receptor Systems in the Nervous System
Acetylcholine Receptors
Glutamate Receptors
Gamma-Aminobutyric Acid (GABA) Receptors
Dopamine Receptors
Serotonin Receptors
Opioid Receptors
Neuropeptide Y Receptors
Trk Receptor
Glucocorticoid Receptor
Estrogen Receptor
Outlook
Future Perspectives
References
72 Opioid Peptides and Their Receptors
Brief History: Discovery of Opioid Peptides and Their Receptors
Multiple Opioid Systems
Opioid Peptides
Opioid Receptors and Their Endogenous Ligands
Functional Anatomy of Opioid Peptides and Their Receptors
Proopiomelanocortin System
Proenkephalin System
Prodynorphin System
Opioid Receptors
Molecular and Cellular Mechanisms of Opioid Peptide Action
Genetic Alterations of Opioid Systems
Opioid Peptide Knockout Mice
Opioid Receptor Knockout Mice
Involvement of Endogenous Opioids in Behavioral and Physiological Responses
Involvement of EOPs in Modulation of the Hypothalamo-Pituitary-Adrenal (HPA) Axis
Autonomic Nervous System
Immune System
Endogenous Opioid System Functions. Implications for Human Pathology
Pain
Stress-Related Diseases
Eating and Gastric Disorders
Cardiovascular Disorders
Psychiatric Disorders
Outlook
References
73 Cannabinoids and Endocannabinoids
Brief History
The Endocannabinoid System
Cannabinoid Receptors
2-Arachidonoyl-sn-Glycerol (2-AG)
2-AG Formation and Degradation
The 2-AG Signalosome
Bioactive 2-AG Metabolites
Anandamide
Anandamide Formation
Anandamide Deactivation
Additional Endogenous Cannabinoid Ligands
Cannabinoid-Based Therapeutics
CB1 Receptor Agonists
CB1 Receptor Antagonists
CB2 Receptor Agonists
Endocannabinoid Deactivation Inhibitors
Outlook
References
74 Trophic Factors: Neurotrophic Factors
Brief History
Introduction
Neurotrophic Factor Families
Neurotrophin Family
Receptors for Neurotrophic Factors
Developmental and Physiological Functions of Neurotrophic Factors
Neurotrophic Factors in the CNS
BDNF Promotes the Growth and Branching of Axonal and Dendritic Branches
Neurotrophic Factors and Neuronal Plasticity
Cell Death and Retraction Mediated by the p75 Neurotrophin Receptor
Neurotrophic Factors and Synaptic Strength
Neurotrophic Factors and the Development of Neuronal Networks
Behavioral Effects of Neurotrophins
Cognition
Emotional Learning
Eating Behavior
Neurotrophic Factors in Neuronal Disorders
Neurotrophic Factors in Neurodegenerative Disorders
Alzheimer Disease
Parkinson Disease
Huntington Disease
Amyotrophic Lateral Sclerosis
Neurotrophic Factors and Pain
Neurotrophic Factors in Psychiatric Disorders
Mood Disorders
Schizophrenia
Addiction
Drugs Acting on Neurotrophic Factors
Outlook
References
Further Reading
Part IX: Basic Neuroscience: Brain Energetics
75 Brain Energy and Metabolism
Introduction
Energy Metabolism of the Brain as a Whole Organ
Glucose Is the Main Energy Substrate for the Brain
Ketone Bodies Become Energy Substrates for the Brain in Particular Circumstances
Lactate and Pyruvate Serve as Instructive Cases
Summary
Tight Coupling of Neuronal Activity, Blood Flow, and Energy Metabolism
Some Mechanisms Couple Neuronal Activity to Blood Flow
Blood Flow and Energy Metabolism Can Be Visualized in Humans
Summary
Energy-Producing and Energy-Consuming Processes in the Brain
Glucose Metabolism Produces Energy
Glycolysis Is the First Step
The Tricarboxylic Acid Cycle Produces ATP
The Pentose Phosphate Pathway Produces NADPH
NADPH and Glutathione Protect Against Oxidative Damage by Reactive Oxygen Species
Processes Linked to Neuronal Function Consume Energy
Summary
Brain Energy Metabolism at the Cellular Level
Glia and Vascular Endothelial Cells, in Addition to Neurons, Contribute to Brain Energy Metabolism
A Tightly Regulated Glucose Metabolism Occurs in All Cell Types of the Brain, Neuronal and Nonneuronal
There Are Multiple Glucose Transporters in the Brain
Cell-Specific Glucose Uptake and Metabolism Has Been Studied Extensively
Glutamate-Stimulated Uptake of Glucose by Astrocytes Is a Source of Insight into the Cellular Bases of 18F-2-DG PET In Vivo
Lactate Released by Astrocytes Is a Metabolic Substrate for Neurons
Glycogen, the Storage Form of Glucose, Is Localized in Astrocytes
Glycogen Metabolism Is Coupled to Neuronal Activity
Certain Neurotransmitters Regulate Glycogen Metabolism in Astrocytes
Summary
Glutamate and Nitrogen Metabolism: A Coordinated Shuttle Between Astrocytes and Neurons
Summary
The Astrocyte-Neuron Metabolic Unit
Outlook
References
76 Blood-Brain Barrier
Brief History
Cellular Framework
Permeability
Physical Barrier
Transport Barrier
Metabolic Barrier
Fine-Tuning
Circumventricular Organs (CVOs)
Area Postrema
Median Eminence and Posterior Pituitary
Vascular Organ of the Lamina Terminalis and Subfornical Organ
Subcommissural Organ and Pineal Gland
Pathological Dysregulation
Blood-Brain Barrier Disruption
Focused Ultrasound Disruption
Radiotherapy Disruption
Blood-Brain Barrier Bypassing
Convection-Enhanced Delivery
Outlook
References
77 Cerebral Microvessels
Introduction
The Meningeal Extracortical Vascular Compartments
The Pial Anastomotic Capillary Plexus Compartment
Pial Capillary Perforation and Entrance into the Cerebral Cortex
Intracerebral Extrinsic Microvascular Compartment
Intracerebral Intrinsic Microvascular Compartment
Outlooks
References
78 Glymphatic System
Short History of the Glymphatic System
Anatomical and Functional Features of the Glymphatic System
Efflux Pathways for CSF, CSF-ISF, and Solutes from the Glymphatic System
Factors That Influence Glymphatic System Transport
Interstitial Space Size
Removal of Protein Waste Products, Including Aβ and Tau via the Glymphatic Pathway
Traumatic Brain Injury
Biomarkers of Traumatic Brain Injury Exit the Brain via the Glymphatic System Rather Than by Crossing the BBB
Outlook
References
Part X: Basic Neuroscience: Neuroendocrinology
79 Brain Control over Pituitary Gland Hormones
Brief History
Studies on the Hypothalamo-Hypophyseal Unit Led to the Birth of Neuroendocrinology
The Pituitary Gland Is a Structure Made up of Glandular and Neural Tissue
Multiple Cell Types Integrate a Highly Complex and Dynamic Cell Network in the Adenohypophysis
Adenohypophyseal Cells Are Electrically Excitable and Very Heterogeneous
Folliculostellate Cells: Subtle Architects of Adenohypophyseal Organization, Function, and Plasticity
The Neurohypophysis as an Array of Hypothalamic Nerve Fibers That Form Neurohemal Connections with Blood Vessels
The Hypothalamus Communicates with the Pituitary Gland by Means of Vascular and Neural Connections
The Internal Layer of the ME and the Hypothalamo-Hypophyseal Tract
The External Layer of the Median Eminence and the Hypothalamo-Hypophyseal Portal System
A ``Master Gland´´ That Controls Body Functions by Regulating Other Glands Through Endocrine Messengers
ACTH Is the Essential Orchestrator of the Stress Response and Adaptive Mechanisms for Survival
GH as the Pituitary Mediator of Body Growth
PRL Is a Pleiotropic Hormone That Promotes Lactogenesis in Mammals
TSH Coordinates Body Metabolism
LH and FSH Have Essential Roles in Reproduction
POMC Products from the Pars Intermedia Control Pigmentation and Mediate Analgesia
Neurohypophyseal Neurohormones VP and OT Are Structurally Related but Exert Different Functions
Vasopressin Controls Water Balance and Blood Pressure
OT Promotes Uterine Contractions During Delivery and Milk Ejection During Lactation
Synthesis and Secretion of Pituitary Hormones Are Controlled by Positive and Negative Feedback Mechanisms
Several Characteristics Must Be Met by a Given Molecule to Be Considered as a Physiological Releasing or Release-Inhibiting Ho...
Control of the Secretion of Anterior Pituitary Hormones by the Hypothalamus
Regulation of Gonadotropins, the Pituitary Hormones of the Hypothalamo-Gonadal Axis, Is Gender Specific and Displays Both Posi...
PRL, the Only Anterior Pituitary Hormone Known to Be Regulated by a Dominant Hypothalamic Inhibitory Tone
Regulation of TSH Secretion Results from the Balance Between a Stimulatory Hypothalamic Drive and the Negative Feedback Exerte...
Regulation of ACTH Involves Two Hypothalamic Stimulatory Peptides as Well as Negative Feedback Mediated by Adrenal Corticoster...
Feedback Control of GH Secretion Does Not Completely Fit the Models of Classical Negative or Positive Feedback by Target Endoc...
A Reversible and Dynamic Remodeling of Cell Populations Emerges as a New Mechanism of Cell Plasticity to Tailor Anterior Pitui...
The Hypothalamus and Secretion of Hormones from the Posterior Pituitary Gland
Posterior Pituitary Hormones Are Synthesized in Cell Bodies of the Hypothalamus, Transported Down Axonal Projections, and Rele...
Central Osmoreceptors and Peripheral Pressure Receptors Trigger Afferent Impulses That Stimulate VP Release to Respond to Incr...
Suckling Stimulus and Activation of Stretch Receptors in the Uterus Trigger a Neuroendocrine Reflex That Results in OT Release...
The Hypothalamo-Pituitary-Gonadal Axis Is the Most Exquisitely Complex Regulatory System That Exhibits Negative and Positive F...
The Ontogeny of Gonadotropin Release Reflects the Maturation of the GnRH Neuron Network, the Changing Responsiveness of Gonado...
The Preovulatory Gonadotropin Surge of Adult Females Depends on a Switch from a Negative Feedback Control to a Positive Feedba...
Regulation of FSH Secretion Shares Common Elements with LH But Also Exhibits Different Mechanisms
At the Pituitary Level, Basal and GnRH-Stimulated Gonadotropin Release Is Modulated by Hypothalamic Neurohormones, Local Parac...
At the Central Nervous System Level, Environmental and Endogenous Cues Relevant to Reproduction Are Integrated by Multiple Neu...
Redundancy in the Control Mechanisms That Regulate the HPG Axis Ensures Reproductive Success
Outlook
Suggested Reading
80 Hormone Effects on Behavior
Brief History
Brief Historical Introduction
Introduction
Principle 1. Neuroendocrine Mechanisms Have Been Conserved to Provide Biologically Adaptive Body/Brain/Behavior Coordination
Oxytocin and Arginine Vasopressin
Principle 2. Hormones Can Either Facilitate or Repress Behavioral Responses
Play Fighting
Aggression
Principle 3. Hormone Metabolites, Combinations of Two or More Hormones, and the Sequence of Hormone Treatment Can be Important...
Hormone Metabolites
Combination of Hormones
Sequence of the Hormone Treatment
Principle 4. Hormones Can Facilitate Rapid or Prolonged Physiological and/or Behavioral Actions
The Stress Response
Sex Differences in Stress Reactivity
Sexual Responsivity
Principle 5. Hormones Do Not Cause Behavior; They Alter Probabilities of Responses to Given Stimuli
Predation and Defense
Intermale Aggression
Social Behavior
Lordosis Behavior
Principle 6. Effects of Hormones Can Be Widespread Across the Body; Effects in the Brain Consonant with Peripheral Effects For...
Food Intake and Weight Regulation
Appetite for Salt; Natriorexegenia
Principle 7. Genes Coding for Hormones, Hormone Receptors and Associated Systems Affect Behavior
Anxiety
Thyroid Hormone Resistance
Precocious Puberty
Pseudohermaphroditism
Principle 8. Genes Interact with Experience to Influence Hormone Responsiveness in the CNS During Adulthood
Early-Life Experience Affects Adult Stress Reactivity
Sexual Differentiation
Outlook
References
81 Critical Periods During Development: Hormonal Influences on Neurobehavioral Transitions Across the Life Span
Brief History
Actions of Gonadal Steroid Hormones
Influences of Endogenous Gonadal Hormones During Perinatal Life
Cellular Mechanisms of Perinatal Sexual Differentiation
Influences of Exogenous Hormones on Early Brain Development
Hormonal Influences During Puberty and Adolescence
Cellular Mechanisms of Peripubertal Sexual Differentiation
Developmental Exposure to EDCs and Puberty
Hormonal Influences During Pregnancy and Lactation
Endocrine Events Associated with Motherhood
Neural Plasticity Associated with Motherhood
Long-Term Neurobehavioral Consequences of Mothering
Hormonal Influences During Reproductive Aging
The Aging Female Hypothalamus
Hormones, Behavior and Aging
Outlook
References
82 Mechanisms of Homeostatically Regulated Behaviors
Introduction
Structure: Function Relationships of the Hypothalamus
The Hypothalamus Integrates Diverse Inputs into Coordinated Endocrine, Autonomic, and Behavioral Responses
Hypothalamic Control of Endocrine Systems
The Thyroid Gland
Thyroid Hormone Synthesis, Transport, and Mechanism of Action
Stimulation of Thyroid Hormone Production
Maintenance of Thyroid Hormone Levels by Negative Feedback Regulation
Regulation of the H-P-T Axis by Cold Exposure
Dysregulation of the H-P-T Axis
The Role of the Hypothalamus in Regulating Complex Behaviors
Hypothalamic Control of Autonomic Function
Hypothalamic Mechanisms Underlying Coordinated Control of Energy Balance
Involvement of Ghrelin in Body Weight Homeostasis
Ghrelin Signals States of Energy Insufficiency
Ghrelin Responds to States of Energy Insufficiency in Many Ways
Ghrelin Action in the Hypothalamus Contributes to Its Many Effects
Ghrelin Levels Fall in Energy-Sufficient States
Conclusion
References
83 The Neurobiology of Thirst and Sodium Appetite
Brief History
Physiology of Thirst and Sodium Appetite
Intracellular Fluid Regulation
Extracellular Fluid Regulation
Integrated Physiology of Body Fluid Regulation
Hormones
Angiotensin (AngII)
Sympathetic Hormones
Steroid Hormones
Neural Control
Signals for Thirst and Na-Appetite
Peripheral Receptors for Water and Sodium
Central Gustatory and Visceral Afferent Systems
Motivation and Reward: Thirst and Sodium Appetite
Reward: Sodium Deficiency
Neural Mechanisms
Satiety or Inhibition
Outlook
References
84 Sexual Differentiation of the Brain and Behavior: A Primer
Introduction
A Conceptual Framework for Understanding Sexual Differentiation
Early Experiments to Find the Causes of Sexual Differentiation
A Hormonal Theory of Brain Sexual Differentiation
Toward a Cellular-Molecular Appreciation of Brain Sexual Differentiation
Sex Chromosome Effects
A General Theory of Sexual Differentiation
Revisiting the Notion of the Female Default
The Neuroscience and Molecular Cell Biology of Sex Differences
Regulation of Cell Number Is One Mechanism of Brain Sexual Differentiation
Synapse Formation and Elimination Builds Sexually Differentiated Circuits
A Surprising Role for the Immune System
Sex Chromosome Effects
Hormones Cause Epigenetic Changes as Part of Sexual Differentiation
The Brain Is a Sexually Differentiated Mosaic
Evidence That the Human Brain Is Sexually Differentiated Is Debated
Sex Differences in Diseases of the Brain
Summary and Outlook
References
Further Reading
85 Mechanisms of Behaviors Related to Reproduction
Introduction
Brief History
Sex Hormone and Sexual Behavior
Organizational Action of Estrogen and Aromatase Hypothesis
Sex Difference in Reproductive Endocrinology
Morphological Sex Difference of Rat Brain
Behavioral Manifestation of Brain Sex Difference
Courtship, Solicitatory Behavior, or Proceptivity
The Lordosis Behavior or Receptivity
Facilitatory Neural Circuit for the Lordosis Behavior
Inhibitory Neural Circuit for the Lordosis Behavior
Electrophysiological Recording Studies
Outlook
Conclusion
References
86 Seasonal Rhythms in Behavior
Brief History
Introduction
The Evolution of Seasonal Rhythms
Photoperiodism: Type I
Circannual Rhythms: Type II
Neuroendocrine Transduction of Seasonal Time
Regulation of Reproductive Systems
Photoperiodic Regulation of Metabolism
Seasonal Rhythms of Behavior
Climate Change and Seasonality
Outlook
References
Part XI: Basic Neuroscience: Regulation of Natural Behaviors
87 Circadian Physiology
Brief History
The Circadian System
In Mammals the Circadian Rhythm Generator Is Located in the Suprachiasmatic Nuclei of the Hypothalamus
The Mammalian Molecular Clockwork
The Circadian Rhythm Generator in the SCN Is Entrained by Light
Output Pathways of the Central Circadian Rhythm Generator in the SCN Employ Neuronal, Neuroendocrine, and Hormonal Mechanisms
Behavioral, Autonomic, and Endocrine Rhythms Mirror the Functional Activity of the Circadian System
Melatonin Is an Important Neuroendocrine Hand of the Circadian System
Melatonin Affects the Activity of the SCN
Melatonin Is a Seasonal Time Cue and Controls the Hypophysial Pars Tuberalis
Melatonin Affects Various Physiological Processes
Glucocorticoids Provide Circadian Information
The Circadian System Influences the Sleep-Wake Cycle
The Circadian System Is Involved in the Control of Body Temperature
The Circadian System Is Involved in the Control of the Female Reproductive Cycle
The Circadian System Is Involved in the Control of Food Intake
Restricted Feeding Provides an Important Zeitgeber
Molecular Clocks Are Ticking in Peripheral Organs
Subsidiary Clocks Need to Be Synchronized
The Molecular Clockwork Influences the Cell Cycle
When the Circadian System Becomes Altered
Outlook
References
88 The Suprachiasmatic Nucleus and the Circadian Timekeeping System of the Body
Introduction
Brief History: Centuries of Scientific Discoveries Demonstrate a Biological Basis for Daily Timekeeping
Inputs: The SCN Receives Input from a Variety of Sources
The SCN Master Clock: A Neuronal Network of Interacting Oscillators
Outputs: SCN Signals Are Mediated by Several Routes
Outlook
Basic Research
Translational Research
Clinical Research
Glossary
References
89 Sleep Regulation and Insomnia
Brief History
Phenomenology
The Neurobiology of Sleeping and Waking
Neuronal Control of Wakefulness
Neuronal Control of Non-REM Sleep
Sleep-Wake Transitions and Stability: A Flip-Flop System
Neuronal Control of REM Sleep
The Neurobiological Basis of the C Factor
Sleep Disorders
Insomnia
Affective Disorders and Sleep Disorders
Treatment of Sleep Disorders
Pharmacology
Behavioral Interventions
Cognitive-Behavioral Model of the Emergence of Insomnia
Stimulus Control
Sleep Restriction
Cognitive Restructuring
Relaxation
Psychoeducation: Sleep Hygiene
Outlook
References
90 Genomic Imprinting and Brain Function
Brief History
The Imprinting Process
Developmental Consequences of Imprinting
Evolutionary Ideas
Intragenomic Conflict
Coadaptation
How Have Imprinted Genes Evolved to Influence Adult Brain Function?
Overall Patterns of Genomic Imprinting in the Brain
Early Brain Development Studies
Imprinted Gene Expression in the Brain
Behaviors Influenced by Genomic Imprinting
Maternal Care and Reproductive Behavior
PWS and Feeding Behavior
Genomic Imprinting and the Monoamine System
Genomic Imprinting and the Human Brain
Brain Evolution
Neurodevelopmental and Psychiatric Disorders
Summary and Conclusions
Outlook
Gene-Environment Interaction and Genomic Imprinting
References
91 Epigenetic Mechanisms: DNA Methylation and Histone Protein Modification
In Eukaryotic Cells DNA Is Packaged into Chromatin
Posttranslational Modifications of Histone Proteins Regulate Transcription
Histone Acetylation Is Associated with Transcriptional Activation
Histone Methylation Can Lead to Transcriptional Activation or Heterochromatin Formation
Replacement Histone Variants Perform Specialized Functions
Chromatin Remodeling Complexes Alter Chromatin Structure
In Mammalian Cells DNA Is Modified by Methylation of the Cytosine Base
DNA Methylation Regulates Gene Expression by Recruiting Methyl-DNA-Binding Proteins
X-Chromosome Inactivation Is the Result of Combinatorial Epigenetic Processes
Dysregulation of Epigenetic Mechanisms Leads to Neurodevelopmental Disorders
Epigenetic Mechanisms Regulate Neuronal Activity and Memory Formation
Epigenetic Processes Regulate Stress Responses
Outlook
References
92 Stress Research: Past, Present, and Future
Brief History
From Stress Concept to Allostatic State
Introduction
Basal Pulsatility and Stress Adaptation
The Essentials of Glucocorticoid Action
Five Highlights
Highlight 1: The Dexamethasone Story: How a Student Project Evolves in a Scientific Career
Highlight 2: The MR:GR Balance Concept: A Product of Serendipity
Discovery
MR:GR Balance Hypothesis
MR:GR Balance in Neuroendocrine Regulation
Relevance of MR:GR Balance for Behavior
Gene Variants
Highlight 3: The U-Shaped Response to Corticosterone (B): How It All Began
Highlight 4: Metaplasticity of the Response to Corticosterone (B): Serendipity All Over Again
Highlight 5: Nothing Is Written in Stone: SHRP, Early Adversity, and Programming the Brain
SHRP: The Effect of Early Adversity
Later Life Outcome: Three-Hit Hypothesis and the Match-Mismatch Concept
Outlook
Concluding Remarks
Neuroendocrinology Remains Alive and Kicking
Context-Dependent Glucocorticoid Action
Sex Differences
Bottom-Up and Top-Down Control of Stress Coping
Mental Health and Quality of Life
References
93 Fear
Brief History
Fear Is a Bodily Response to Threat
Fear Learning Is Studied with Experimental Fear Conditioning
The Brain Mechanism of Fear Learning Is Conserved Across Species
The Amygdala Is a Crucial Node in Fear Circuitry
Regulating the Expression of Fear Memories
Consolidation and Reconsolidation of Fear
Extinction of Fear
Active Avoidance
Stress and Fear
Human Fear Circuits Resemble Those in Rodents
Clinical Applications of Fear Conditioning
Outlook
References
94 Aggression
Brief History
Aggression
Forms of Aggression
Violence Is the Pathology of Functional Aggressive Behavior
Neuronal Network of Aggression
Brain Regions and Neural Circuit Mechanisms Underlying The Regulation of Aggressive Behavior
Network Components of the Aggressive Brain
Hypothalamus
Amygdala/BNST
Septum/Hippocampus
Prefrontal Cortex (PFC), Orbitofrontal Cortex (OFC), Anterior Cingulate Cortex (ACC), and Insular Cortex (IC)
Periaqueductal Gray (PAG)
Lateral Habenula (LHb)
Neurochemistry of the Neuronal Network
Serotonin Is the Main Orchestrator
Dopamine
Glutamate/GABA
Modulation of the Network
Hormones of the HPA (Cortisol/Corticosterone) and HPG-Axis (Testosterone, Estradiol)
Vasopressin and Oxytocin
Cytokines
Neurogenetics of Aggression
Outlook
References
95 Emotions Studied by Imaging of the Human Brain: The Somatic and Emotional Motor Systems
Brief History
Introduction
The Somatic or Voluntary Motor System
Motoneurons in Spinal Cord and Brainstem
Medial Component of the Somatic Motor System
Lateral Component of the Somatic Motor System
Red Nucleus
Motor Cortex
Speech
The Emotional Motor System
Medial Component of the EMS
Ventromedial Medulla
Neurotransmitters in the Ventromedial Medulla
Afferent Projections to the Ventromedial Medulla
A5, A7, and A11
Role of the PAG in the Medial Component of the EMS
Lateral Component of the EMS
Blood Pressure and Heart Rate Control
Breathing
Vocalization
Micturition, Parturition, and Defecation
Sexual Activity
Sexual Intercourse in Humans
Outlook
References
96 Sexual Behavior
Brief History
The Brain Is Sexually Differentiated
Sexual Behavior Is Regulated by Sex Hormones
In Females
In Males
Neurons Express Sex Hormone Receptors
Estrogen Receptors
Androgen Receptors
We Are Discovering Neural Circuits That Produce Sexual Behaviors
In Females
In Males
Erection and Ejaculation Reflexes
Excitatory and Inhibitory Modulation of Erection and Ejaculation
The Hypothalamus, Amygdala, and Midbrain
In Both Males and Females
Genitosensation and Orgasm Have Their Own Circuitry
A Panoply of Genes Affect Sexual Behaviors
Outlook: Future Research on Sexual Behavior
References
97 Parental Behavior
Introduction
Maternal Behavior in Selected Mammals
Main Hormones Involved
Estradiol and Progesterone
Prolactin
Oxytocin
Vasopressin (VP)
Brain Structures Involved
MPOA
Olfactory System
Septum and Bed Nucleus of the Stria Terminalis (BNST)
Paraventricular Nucleus (PVN)
How Is Maternal Behavior Maintained?
How Does Maternal Behavior End?
Long-Lasting Consequences of Maternal Behavior on the Mother
Parental Behavior in Humans
Introduction
Definition of Terms
What Can We Study in Human MB?
What Factors Promote the Onset and Maintenance of Parental (i.e., Maternal and Paternal) Behavior?
Pregnancy, Parturition and Lactation
Hormonal and Physiological Changes Through Pregnancy and the Prepartum Period
Vaginal Delivery vs. Cesarea Section (CS): Effects on MB
Breastfeeding and Its Effects on MB
Correlation Between Hormones and MB
Maternal Behavior
Psychological Factors, Sensory Stimuli, and Anatomical Changes in the Brain Associated with the ``Mental Construction´´ and Di...
Neural Correlates of Parenting: Responses to Infant Stimuli
Auditory Stimuli
Visual Stimuli
Maternal Experience: Its Effects on Subsequent Mothering and Health
When Mothering Goes Wrong
Chronic Stress
Postpartum Depression (PPD)
Mental Illness
Substance Abuse
Teen Mothers
Preterm Infants
Paternal Care (Fathering) and Adoptive Mothers. Genetic Factors in MB
Effects of Parenting on Offspring Development in Animals and Humans
Conclusions and Future Directions
Further Reading
98 Social Behavior: Social Neurosciences and Social Behavior: An Introduction
Brief History
Brain Lesion Research Has Been Critical to the Growth of Social Neuroscience
Social Neuroscience Requires an Understanding of Neuroscience and Cognitive Science
Methods in the Neuroscience of Social Cognition
Measuring Neural Processes Via fMRI Requires Attention to ``Differential Activation´´
Lesion-Deficit Analysis Identifies Areas Required for Cognition
The Social Brain and Its Functions
The Social Brain Hypothesis States that Humans Have the Kinds of Brains They Do Primarily Because of Evolutionary Pressures Fa...
The Amygdala Is Important for Recognition of Facial Emotions
The Amygdala Is Important for Guiding Social Gaze
Differential Activation for Faces in the Fusiform Gyrus
Emotion Is a Critical Component of Social Decision Making and Reasoning, Especially in Real Life
Forming a ``Theory of Mind´´ About Another Person Involves Implicit and Explicit Processes Grounded in Emotional Salience and ...
Moral Action Involves Neural Systems That Rely on Integration of Emotion with Other Kinds of Information
Outlook
References
Part XII: Basic Neuroscience: Cognitive Neuroscience
99 Elementary Central Nervous System Arousal
Brief History
Elevated Generalized CNS Arousal (GA) Refers to a Range of Behavioral States Marked by Increases in Motor, Sensory, and Emotio...
CNS Arousal Is Reflected in Quantitative Electrophysiological, Brain Scanning, and Behavioral Measurements
Electroencephalography (EEG)
Electromyography (EMG)
Functional Magnetic Resonance Imaging (fMRI)
Local Field Potentials
Behavior
Neuroanatomical Components of CNS Arousal Systems Have Been Described
Brainstem
Thalamus
Hypothalamus
Basal Forebrain
Behavioral States Comprise the Fundamental Measures of GA
High Brain Activity States
Wakefulness
Alertness
Orientation
Attention
Low Brain Activity States
Slow-Wave Sleep
Drowsiness/Somnolence
Anesthesia
Several Genes and Neurochemical Systems Drive CNS Arousal
Noradrenaline/Norepinephrine
Acetylcholine
Dopamine
Hypocretin
Serotonin
Glutamate/GABA
Neuropeptide S
Histamine
Adenosine
Redundancy in Genomic Controls Prevents System Failure
Specific Example: Elementary Arousal and Sex Behavior
Outlook
References and Further Readings
References
Further Readings
100 Learning and Memory
Brief History
Multiple Types and Processes of Memory
The Loss of Memory in Neurological Disorders Has Revealed Important Dissociations Between Different ``Types´´ of Memory
Distinct Brain Systems Mediate Different Types of Learning and Memory
The Existence of Different Memory Processes is Orthogonal to the Concept of Distinct Types of Memory
The Study of Learning and Memory Involves Combining Methods from Numerous Levels of Analysis in Neuroscience
The Basic Task
Distinction Between the Apparatus and the Tasks Trained within It
Apparatus
Training Protocols
Spatial Reference Memory
Probe Trials to Test Memory
Impact of Overtraining
Reversal Learning
The Atlantis Platform
Delayed Matching-To-Place and One-Trial Learning
Other Protocols
Treatments and Control Procedures
Strengths and Limitations of the Watermaze as an Assay or Learning and Memory
Making Declarative Memories
There Are Three Types of Declarative Memory: Semantic Memory, Episodic Memory, and Spatial Memory
Physiological, Pharmacological, and Molecular Engineering Approaches to the Study of Memory
Mechanisms of Activity-Dependent Synaptic Plasticity Are Involved in Encoding and Storing Information into Long-Term Spatial M...
Synaptic Plasticity is Critical for Storing Information in Specific Neural Networks
The Structural and Functional Expression of Memory Traces
The Structural and Biochemical Changes at Synapses Associated with Long-Term Potentiation May Reflect the Various Stages of Me...
Making Lasting Changes at Synapses Involves Them Being Tagged and the Tags Then Sequestering Plasticity-Related Proteins
Consolidation Need Not Happen Only after Memory Encoding
Outlook
References
101 Memory Systems and Neural Dynamics
Brief History
Multiple Memory Systems in the Human
Testing Memory in Animal Models
Understanding Neural Computation Through Recordings and Targeted Manipulations
Coincident Activity Changes Connection Strength Between Neurons
Brain Rhythms Organize Spike-Timing Relationships Between Neurons
Outlook
Conclusion
References
102 Declarative Association Memory
Brief History
What is Memory?
Characteristics of Declarative Association Memory
Episodic Memory and Semantic Memory
Medial Temporal Lobe and Anatomically Related Areas
Neural Mechanisms of Within-domain Semantic Association
Neural Mechanisms of Between-domain Semantic Association
Episodic Association
Association with Spatiotemporal Context
Past and Future
Flexible Use of Memory
Outlook
References
103 Working Memory
Brief History
Storage of Information Is Different from Its Manipulation and Use
Manipulation and Other Executive Processes Depend on the Prefrontal Cortex
Different Types of Information Are Stored (Somewhat) Separately
Brain Imaging Methods in Humans Have Revealed More Distinctions Between Different Types of Information in Working Memory
Working Memory Has a Very Limited Capacity
How Much Information Fits into Working Memory Depends on How You Measure It
The Capacity of Working Memory Will Seem Smaller If You Remember Things You Do Not Need Right Now
The Prefrontal Cortex Has the Anatomy and Physiology Necessary for Working Memory
Functional Organization of the Prefrontal Cortex Is Related to the Different Types of Information That Can Be Held in Working ...
Outlook
Further Reading
104 Long-Term Potentiation
Brief History
Brief Tetanic Stimulation Induces LTP in Hippocampal Pathways
Temporal Components of LTP: STP, E-LTP, and L-LTP
Associativity and Cooperativity
Induction Rules for LTP
Expression Mechanisms of LTP
Postsynaptic Mechanisms
Presynaptic Mechanisms
Retrograde Messengers
Transition from E-LTP to L-LTP: The Synaptic Tag Hypothesis
Mossy Fiber LTP
LTP Outside the Hippocampus
Evidence for LTP in the Human Hippocampus
Other Forms of Synaptic Plasticity: LTD, STDP, and Metaplasticity
LTP and Its Relation to Learning and Memory
The Synaptic Plasticity and Memory Hypothesis
From Pathway to Network: Optogenetic Approaches to the Cellular Basis of Learning
Identifying the Synaptic Engram in Motor Cortex
Conclusion
References
References listed here are freely available via PubMed with the exception of those marked with an asterisk
105 Social Behavior: Theory of Mind
Brief History
The Term ``Theory of Mind´´ Has Several Interpretations
Theory of Mind Has More than One Form
Theory of Mind Must Be ``Deconstructed´´ into Component Processes
Following Deconstruction, Elementary Processes Can Be ``Reconstructed´´ to Achieve Varieties of ToM
Outlook
References
Further Reading
106 Cognitive Functions as Revealed by Imaging of the Human Brain
Brief History
Functional Brain Imaging
What Is a Brain Imaging Technique?
Functional Brain Imaging Plays a Role in Modeling Cognitive Processes
Functional Brain Imaging Plays a Role in Modeling Neural Organization
Neuroimaging Techniques Have Distinct Capabilities and Limitations
Key Properties: Contrast, Temporal Resolution, and Spatial Resolution
Integration Across Techniques Carries Complementary Advantages
The Core Goal of Neuroimaging Is Functional Resolution
Examples of Functional Brain Imaging: fMRI Research on Decision Making
Assessing Variability: State Effects, Context Effects, Group Differences, and Individual Differences
Computational Models: The Case of Reinforcement Learning
Guiding Development of New Models: The Case of Intertemporal Choice
Outlook
The Next Generation of Researchers: Who? Where? and, How Many?
New Analyses and New Research Questions
New Ways of Synthesizing the Neuroimaging Literature
Final Thoughts
References
107 Aging of the Brain
Brief History
Age-Related Memory Impairment Affects Mainly Effortful Processing But Spares Automatic Cognitive Processing Mechanisms
Cognitive Decline and Its Underlying Mechanisms Can Be Investigated Well in Mammals as Models for the Study of Human Cognitive...
Mechanisms of Brain Aging
During Aging, Neurons Rarely Die But Change at the Level of Cytoskeleton, Synapse, and Synthetic Activity Negatively Affecting...
Neuronal Membrane Structure and Composition Changes at Older Ages and Influences Membrane Fluidity and Membrane Signaling. The...
Neurotransmitter Systems Projecting to the Forebrain Appear Particularly Vulnerable to the Aging Process
Cognitive Dysfunction Parallels Degenerative Changes in Cortical Projection Transmitter Systems
Aging Has Serious Consequences for the Calcium Homeostasis of Neurons, Which Has a Major Impact on Neuronal Physiology and Sig...
Aged Neurons in the Hippocampus Show an Enlarged Afterhyperpolarization Which Parallels Impaired Learning and Conditioning
In the Aged Mammalian Brain, Blood Supply Is Decreased and the Vascular Condition Is Subject to Degenerative Mechanisms
Nervous Tissue Is Highly Dependent on Optimal Blood Flow for Its Energy Generation
Cerebral Blood Flow Decreases with Advancing Age
Brain Microvessels Undergo a Progressive Structural Degenerative Decline During Aging
Cortical Microvascular Decline Correlates with Cognitive Decline
The Innate Inflammatory System of the Brain Can Both Damage and Protect the Brain Against Breakdown Processes
Challenging Conditions in the Brain Lead to Activation of Microglia
Neuroinflammatory Mechanisms and Release of Cytokines by Microglia Can Protect Against External Threats
The Dynamic Activation of Microglia Changes in Later Life
Neuroinflammatory Processes Affect Cognitive Functions During Aging
Outlook
References
Part XIII: Basic Neuroscience: Emerging Experimental Techniques in Neuroscience - Genetics
108 Revolution in Genetics
Brief History
Methods for Mapping Genes
Linkage
Search for Disease-Causing Variants for Monogenic Traits by Next-Generation Sequencing
454 Pyrosequencing
Applied Biosystem SOLiD Sequencing Technology
Illumina Dye Sequencing by Synthesis
Association-Based Methods Are More Powerful Than Linkage for Identifying Gene Variants for Complex Traits
Family-Based Association Studies
Case-Control Association Analysis and Genome-Wide Association Studies
Genome-Wide Association Studies for Brain Disorders
Shared GWAS Hits Across Clinical Phenotypes Suggest Pleiotropy
Missing Heritability
Parent-of-Origin Effect
Mobile DNA: Structural Variants, Transposable Elements, and Repetitive Sequences
GWAS SNPs Target Gene Expression
Noncoding RNAs and Their Regulation May Underlie the Function of Noncoding GWAS Variants
Small Noncoding RNAs
miRNA
SnoRNAs
piRNA (Piwi-Interacting RNAs)
Long Noncoding RNAs (lncRNAs)
Posttranscriptional Regulation of Gene Expression by lncRNAs
Transcriptional Regulation by lncRNAs
Outlook
References
109 Optogenetics
Brief History
Optogenetic Examinations of Neuronal Activity Involvement in Normal and Disease-Related Neurobiology and Behavior
Experimental Considerations for Performing Optogenetic Experiments
Outlook
References
110 Chemogenetics: DREADDs
Brief History
Spatiotemporal Control of DREADD Expression in Living Organisms
Neuroscience Applications of DREADDs in Preclinical Models
Outlook
References
111 Epigenomic Measurements in Brain Tissues
Brief History
What Is Neuroepigenomics?
Neuroepigenomics and Disease
Epigenomic Information Has Great Utility
Improved Epigenomic Measurement
Detecting DNA Modifications
DNA Modification Basics
DNA Modifications and Neurobiology
DNA Modifications and Brain Disorders
Detecting DNA Methylation
Limitations and the Future of DNA Methylation Assays
Single-Cell Approaches
Single-Molecule Approaches
Assay of 5hmC, 5fC, 5caC, and 6mA
Measuring Histone Modifications
Histone Modification Basics
Histone Modification and the Brain
Histone Modifications and Brain Disorders
Measuring Histone Modifications
Current Limitations and the Future of Histone Modification Assays
Antibody Specificity, Renewability, and Availability
ChIP Controls
Moving Toward Single-Cell Approaches
Moving Toward Single-Molecule Approaches
Assays that Complement ChIP-seq
Nucleosome and Higher-Order Structural Assays
Chromatin Structure and the Brain
Chromatin Structure and Brain Diseases
Chromatin Accessibility Assays
Chromatin Interaction Assays
Chromatin Interactions with Long Noncoding RNAs
Chromatin/Nuclear Structure Assays
Outlook
Brain Epigenomics
Brain-Specific Epigenomic Processes
Handling Heterogenous Tissues
Human Brain Epigenomics
Brain Epigenome Atlas
Complementary Neuroepigenomic Studies
Epigenomic Data Analysis
Integration of Epigenomic Information with Complementary Information
The Four-Dimensional Neuronal Genome
Functional Neuroepigenomics
Functional Manipulation of the Epigenome
Epigenomic Mechanisms of Intergenerational Inheritance
Epigenome Perdurance, Malleability, and Therapeutics
References
Part XIV: Basic Neuroscience: Emerging Experimental Techniques in Neuroscience - Imaging
112 Optical Neuroimaging: Studies of the Neuronal and Vascular Effects of Cocaine
Brief History
Optical Imaging and Technological Advances
Effects of Cocaine on Neurovascular Networks
Effects of Cocaine on Neurons
Outlook
References
113 Molecular Imaging: Positron Emission Tomography
Brief History
Introduction
PET Technology
Positron Decay and Positron Emission Tomography
Rapid Chemistry: PET Radioisotopes and Radiotracers
18FDG: An Early Milestone for PET Imaging
How Are Radiotracers for New Molecular Targets Designed and Validated?
How Can PET Facilitate Drug R&D?
Outlook
References
Further Reading
114 Functional Imaging: Magnetic Resonance Imaging
Introduction
Functional MRI
Susceptibility Contrast
Blood Oxygenation-Level-Dependent Contrast
Blood Volume Contrast
Blood Perfusion Contrast
Calibration of fMRI
Functional MRI Contrasts being Developed
Resting State fMRI
Issues Regarding Interpretation of fMRI Signal
Most Important Trends in fMRI
Technology
Methodology
Interpretation
Applications
Conclusions
References
Part XV: Basic Neuroscience: Emerging Experimental Techniques in Neuroscience - Computational Neuroscience
115 Modeling Neuronal Systems
Brief History
Artificial Intelligence
Artificial Neural Networks
More Realistic Brain Models
Approaches to Modeling and Types of Models
Single-Area Models
Large-Scale Models
Robotics
Choice of Model Type
Multicompartment Versus Single- or Two-Compartment Models
Physiology-Based Cells Versus Integrate-and-Fire Cells Versus Rate-Coded Cells
Neuronal Dynamics and Ensemble Models
Constant-Time-Step Versus Event-Driven Modeling
Synaptic Strength Modification
The Bienenstock-Cooper-Munro Rule
Synaptic Modification in Spiking Models
Modeling Tools
Nervous System Components Often Omitted from Models
Electrical Synapses
Glia
Diffusion of Signal Molecules
Changes in Connectivity, Not Just Connection Strengths; Ontogeny
Modeling Tumor Growth
Pitfalls
Outlook
References
116 Computational Neuroscience of Synapses and Neurons
Brief History
Modeling Membranes: The Conceptual Model
Modeling Transformation #1: From Membrane to Electrical
Modeling Transformation #2: From Electrical to Equations
Modeling Transformation #3: From Equation to Simulation
Modeling Transformation #4: From Simulation to Information Processing
Transformation #5: From One Membrane Patch to Many - Compartmental Modeling
Transformation #6: From Passive to Active
Putting It All Together
Chemophysiology
Extracellular Space and Spreading Depression
Outlook
Glossary
References
117 Generalized Cable Models of Neurons and Dendrites
Introduction
Theory
Traditional Cable Equations
Generalized Cable Equations
Numerical Simulations of the Cable Models
Discussion
Appendices
Method to Solve the Generalized Cable
References
118 Computational Neuroscience of Neuronal Networks
Brief History
History: Missing Links
Simplifications
Simplification #1: Dichotomies
Simplification #2: Biophysical Omission
Simplification #3: Dynamic Replacement
Simplification #4: Plasticity
Simplification #5: Whence Activity?
Simplification #6: Network Replacement
Neural Mass Models of the Brain
Themes and Measures
Visualization
Emergent Properties
Multiple Interneuron Classes Generate Multiple Embedded Rhythms
Connectomics and Graph Theory
Graph Theoretic Measures
Information Flow
Activity Spread: Avalanches and Traveling Waves
Homeostasis
Data-Driven Modeling
Outlook
Glossary
References
119 Dynamics in Neural Systems
Brief History: Introductory Remarks
Dynamical Systems and Their Family: Phase Space, Phase Plane Analysis, Bifurcation Analysis, and Chaos
Definitions of Dynamical Systems and Measurement Processes
Phase Plane Analysis
Bifurcation Analysis
What Is a Bifurcation?
Linear Stability Analysis
Classification of Steady States
Bifurcations
Chaos
Steps to Dynamical Models of Neural Dynamics
Formal Neuron by McCulloch and Pitts
Physiology-Oriented Models
Simplification of Physiology-Oriented Models
Dynamical Model for Neural Networks Describing Local Field Potential
Generalized Model of Neural Dynamics in Terms of Coupled Map Systems
Evolutionary Dynamical Model
Outlook
References
120 Computational Neuroscience: Hippocampus
Brief History
Anatomical Overview
Types of Models
Models of Behavioral Functions of the Hippocampus
Human Memory Function
Rat Memory-Guided Behavior
Function of Hippocampal Subregions
Dentate Gyrus
Region CA3
Region CA1
Medial Septum
Entorhinal Cortex
Physiological Phenomena
Long-Term Potentiation and Long-Term Depression
Intrinsic Properties
Spiking Activity in Behaving Animals
Local Field Potential Dynamics
Theta Phase Precession of Spiking Relative to Local Field Potentials
Outlook
References
121 Models of the Cortico-cerebellar System
Introduction
A Plethora of Models
Forward and Inverse Models
Functional Models
Marr-Albus Type Models
Relationship with Reality: Are Purkinje Neurons Perceptrons?
Extensions of MAI Model: Adaptive Filter Model and Distributed Synaptic Plasticity
Information Encoding and Channel Capacity
Successes and Failures of the MAI Model
Purkinje Neuron Single Cell Modeling
Dynamical Models
The Cerebellum Implements Spatiotemporal Transformations
Mathematical Properties of the Circuit (Tidal Waves)
Reverberating Loops and Golgi Gating
Single Cell Models of the Granular Layer
Inferior Olivary Models
Coupled Oscillators and Electrotonic Coupling
Phase Resets and Synchronous Groups
Echo State Machines
Cerebellar Nucleus
Conclusion
Consilience: Meeting in the Middle
References
122 Gaseous Signaling in the Central Nervous System
Nitric Oxide
Enzymatic Production of Nitric Oxide
Nitric Oxide Synthase Homology and Localization in the CNS
Signal Transduction in Physiology and Disease
Soluble Guanylate Cyclase/cGMP
Protein S-Nitrosylation
Carbon Monoxide
Biosynthesis of CO
Heme Oxygenase Homology and Localization in the CNS
CO Signal Transduction in Physiology and Disease
Heme-Dependent Regulation of Biological Function
Hydrogen Sulfide
Biosynthesis
CBS/3-MST Homology and Localization in the CNS
H2S Signal Transduction in Physiology and Disease
Cysteine S-Sulfhydration
Conclusions and Outlook
References
123 Statistical Models of Spike Train Data
Introduction
Spiking Models Can Be Specified in Terms of Spike Times, Interspike Intervals, or Spike Counts
Spiking Activity Is Often Influenced by Its Past History
The Conditional Intensity Function Specifies the Instantaneous Likelihood of Spiking at Any Time
A Point Process Model Expresses the Conditional Intensity as a Function of Time, History, and Other Variables
Example 1: Spontaneous Activity of a Retinal Ganglion Cell in Culture
Example 2: Place Fields in Hippocampus
Generalized Linear Models (GLMs) of Spiking Data Are Easy to Fit by Maximum Likelihood
Time Rescaling Provides an Approach for Determining the Goodness-of-Fit of Neural Spiking Models
Example 2 (Continued): KS and Q-Q Plots of a Place Field Model
Conclusions
References
Part XVI: Clinical Neuroscience: Developmental Disorders
124 Prader-Willi Syndrome
Brief History
Genetics of Prader-Willi Syndrome
Genomic Imprinting
Prader-Willi Syndrome Candidate Genes and Genetic Subtypes
15q11-q13 Deletions
Maternal Disomy 15
Imprinting Defects
Application of Advances in Genetic Technology
Clinical Findings in Prader-Willi Syndrome Subjects with Atypical Deletions
Clinical Presentation and Natural History of Prader-Willi Syndrome
Hypotonia, Failure to Thrive, and Musculoskeletal Findings
Hypogonadism and Hypogenitalism
Obesity, Metabolism, and Energy Expenditure in Prader-Willi Syndrome
Behavioral and Cognitive Findings in Prader-Willi Syndrome
Cognitive and Academic Abilities
Behavioral and Psychological Issues
Clinical Comparison of Genetic Subtypes in Prader-Willi Syndrome
Genetics of Angelman Syndrome
Angelman Syndrome Candidate Genes and Genetic Subtypes
Ubiquitin Ligase E3A (UBE3A)
15q11-q13 Deletions
Paternal Disomy 15
Imprinting Defects
Clinical Presentation and Natural History of Angelman Syndrome
Orthopedic and Movement Difficulties
Language and Developmental Impairment
Adult Life
Outlook
References
125 Fragile X Syndrome and Premutation Disorders
Brief History
Fragile X-associated Disorders Are Caused by CGG Repeat Expansion
The Full Mutation (>200 CGG Repeats) Is Caused by Methylation-Induced Gene Silencing
The Premutation (Between 55 and 200 CGG Repeats) Has Elevated Levels of mRNA
Full Mutation Transmission Occurs from Mother to Child
Epidemiological Studies Reveal Widespread Involvement
The Phenotype of Fragile X Syndrome Consists of Physical, Behavioral, and Cognitive Abnormalities
Physical Characteristics Are Related to Connective Tissue Dysplasia and Endocrinological Irregularities
Fragile X Causes a Number of Medical Issues
The Behavioral Phenotype Is Exacerbated by Hyperarousal
Attention Regulation and Hyperactivity Are Common Problems
Anxiety Afflicts Many Individuals with Fragile X
There Is a High Comorbidity Between Autism and Fragile X
Intellectual Disability Affects Most Males and Some Females
Distinct Neurological and Neuroanatomical Differences Exist
The Phenotype of Premutation Carriers Is Related to RNA Toxicity
Fragile X-associated Primary Ovarian Insufficiency Affects Women with the Premutation
Fragile X-associated Tremor/Ataxia Syndrome Affects Most Aging Men with the Premutation and Some Women
RNA Toxicity Can Cause Fragile X-associated Neuropsychiatric Disorders (FXAND)
Targeted Treatments for FXS
Outlook
References
126 Fetal Alcohol Syndrome
Introduction
Animal Studies
Neuroimaging
Elementary Functions
Eyeblink Conditioning (EBC)
Prosaccades
Orienting Responses
Complex Functions
Intellectual Functions
Attention and Executive Functions
Learning and Memory
Language
Visual Perception and Visual Construction
Social Cognition
Parent- and Teacher-Rated Behaviors
An Integrative Framework
Outlook
References
127 Autism
Brief History
Autism Is a Behaviorally Defined Syndrome
Clinical Assessment Has to Be Completed for Each Subject with Autism
The Broadening Definition of the Disorder Has Led to the Concept of Autism Spectrum Disorders
Neurofunctional Models Are Rooted in Clinical Observations
Autism Results from Abnormal Brain Development
Autism Could Be Linked to Abnormal Neurotransmission and Neuromodulation
Autism Is a Strongly Genetic Disorder
Treatment of Autism Is Essentially Based on Behavioral Methods and Education
Outlook
References
128 Obesity: Brain Mechanisms in Hypothalamic and Extrahypothalamic Regions
Brief Background
Hypothalamic Mechanisms
Brainstem and Spinal Cord
Cortical Mechanisms
Hippocampus
Striatal Mechanisms
Outlook
References
129 Obesity: Peripheral Signals, Neural and Peptidergic
History and Context
Progressing from the Nonobese to the Obese Phenotype
Overweight Versus Obese
Metabolic Syndrome
Primary Circuits in the CNS Controlling Feeding
Brainstem Circuits
Primary Controls of Food Intake
Gastrointestinal Feedback Via Primary Vagal Afferent Neurons
Secondary Integration of Oral, Gastrointestinal, and Humoral Food-Related Signals
Obesity as a Disorder of Body-Brain Communication: The Hypothalamus and the Neuroendocrine Connection
Glucocorticoids in Obesity: Central and Peripheral Mechanisms
Interactions Between Glucocorticoids and Insulin
Extrahypothalamic Circuits: Focus on the Reward System
Circadian Influences on Obesity: A New Perspective
Summary and Clinical Implications
References
130 Anorexia Nervosa and Bulimia
Brief History
Historical Perspectives on Anorexia Nervosa and Bulimia Nervosa
Anorexia Nervosa
Bulimia Nervosa
Modern Overlap
Neurobiological Models of Anorexia Nervosa
Development Versus Maintenance
Genetic Vulnerability to Anorexia Nervosa
Dysregulation in Hormonal Systems
Neurotransmitter Dysregulation
Neurocircuitry Implicated in Anorexia Nervosa
Starvation Versus Psychopathology
Gender Differences
Temperament and Anorexia Nervosa
Personality Subtypes
Neurobiological Models of Bulimia Nervosa
Developmental Model of Bulimia Nervosa
Genetic Vulnerability to Bulimia Nervosa
Prenatal Risk
Dysregulation in Hormonal Systems
Neurotransmitter Dysregulation
Neurocircuitry Implicated in Bulimia Nervosa
Outlook
References
Part XVII: Clinical Neuroscience: Systems Disorders
131 Sleep Disorders
Brief History
History of Sleep Medicine
Insomnia
Psychophysiologic Insomnia
Secondary Insomnia
Inadequate Sleep Hygiene
Sleep-Related Breathing Disorders
Obstructive Sleep Apnea Syndrome
Central Sleep Apnea
Hypersomnias of Central Origin
Narcolepsy
Idiopathic Hypersomnia
Recurrent Hypersomnia
Circadian Rhythm Sleep Disorder
General Diagnostic Criteria for CRSD
Advanced Sleep Phase Type
Delayed Sleep Phase Type
Irregular Sleep-Wake Type
Free Running Type
Jet Lag Type
Shift Work Type
Parasomnias
Risk Factors Exacerbating or Precipitating Disorders of Arousal
Confusional Arousals
Sleepwalking
Sleep Terror
REM Sleep Behavior Disorder
Nightmares
Sleep-Related Movement Disorders
Restless Legs Syndrome
Diagnostic Criteria for RLS in Adults
Periodic Limb Movement Disorder
PSG Diagnostic Criteria for PLMD
Sleep-Related Leg Cramps
Sleep-Related Bruxism
Sleep-Related Rhythmic Movement Disorder
Outlook
Future Directions
References
132 Severe Brain Damage: Coma and Related Disorders of Consciousness
Brief History
Measuring Consciousness
Coma
Brain Death and ``Clinical´´ Death
``Near´´ Death
Locked-in Syndrome
Unresponsive Wakefulness Syndrome
Minimally Conscious State
Ethical Issues and End-of-Life Decisions
Pain
Quality of Life
Therapeutic Interventions
Neural Signature of Consciousness
Outlook
References
133 Spinal Cord Damage
Introduction: The Requirements for Spinal Cord Repair: Neuroprotection, Regeneration, and Restoration
The Shift in Understanding the Local Innate Immune Response to Injury: From a Foe that Requires Elimination to a Pivotal Repar...
Changes in the Perception of the Role of Self-Reactive T Cells: From Mediating Autoimmune Disease to Protective by Default
The Bright Side of the Glial Scar
Clinical Implications for Acute Spinal Cord Injury
References
134 Ischemic Stroke: Basic Pathophysiology and Clinical Implication
Brief History
Introduction
Cellular and Molecular Pathophysiology of Stroke
The Concept of the Ischemic Penumbra: Temporal and Spatial Events After Stroke
Damage of the Blood-Brain Barrier
Mechanisms of Cell Death in Stroke
Peri-infarct Depolarization
Excitotoxicity
Oxidative and Nitrosative Stress
Tissue Acidosis
Apoptosis
Inflammation and Cellular Mechanisms
Stroke-Induced Immunodepression (SIDS)
Endogenous Neuroprotection, Ischemic Tolerance, and Conditioning of the Brain
Bench to Bedside: Clinical Implications of Ischemic Stroke
Cerebrovascular Anatomy and Major Cerebral Artery Territories
Risk Factors of Ischemic Stroke
Clinical Syndromes of Ischemic Stroke
Transient Ischemic Attacks (TIAs)
The Anterior Cerebral Artery Syndrome
The Middle Cerebral Artery Syndrome
The Posterior Cerebral Artery Syndrome
Lacunar Stroke
Diagnostic Strategies in Acute Ischemic Stroke
Treatment of Patients with Acute Ischemic Stroke
Recanalizing Therapy
General Supportive Care
Outlook
References
Part XVIII: Clinical Neuroscience: Pain
135 Non-migrainous Headache
Brief History
Introduction
Primary Headaches
Tension-Type Headache (TTH)
Trigeminal Autonomic Cephalgias (TACs)
Cluster Headache (CH)
Paroxysmal Hemicrania (PH)
Hemicrania Continua (HC)
SUNCT/SUNA
Other Primary Headaches
Primary Stabbing Headaches
Nummular Headache (NH)
Primary Cough Headache
Primary Exertional Headache
Primary Headache Associated with Sexual Activity
Hypnic Headache
Secondary Headaches
Headache as a Symptom of Cerebrovascular Disease
Giant Cell Arteritis
Headache as a Symptom of Brain Tumor
Idiopathic Intracranial Hypertension
Headache Associated with Head and Neck Trauma
Headache Associated with Infection
Headache Associated with Disorders of Homeostasis (Metabolic and Systemic Disease)
Headache Associated with a Substance or its Withdrawal
Headache (or Facial Pain) Attributed to Disorders of Cranium, Neck, Eyes, Ears, Nose, Sinuses, Teeth, Mouth, or Other Facial o...
Intracranial Hypotension
Headache Attributed to Psychiatric Disorders
Cranial Neuralgias
Trigeminal Neuralgia
Glossopharyngeal Neuralgia
Eagle Syndrome
Outlook
References
136 Migraine
Brief History
Suffices
Migraine: Explaining the Clinical Features
Genetics of Migraine
Genetic Epidemiology
Familial Hemiplegic Migraine (FHM)
Migraine Aura
Headache Anatomy
Headache Physiology: Peripheral Connections
Plasma Protein Extravasation
Neuropeptide Studies
Headache Physiology: Central Connections
Serotonin: 5-HT1F Receptor Agonists and Migraine
Glutamatergic Transmission in the Trigeminocervical Complex
The ``Vascular Hypothesis´´: A Good Story Ruined by the Facts
Central Modulation of Trigeminal Pain
Brain Imaging in Humans
Animal Experimental Studies of Sensory Modulation
Electrophysiology of Migraine in Humans
Outlook
What Is Migraine?
References
137 Central Mechanisms of Pain Suppression: Central Mechanisms of Pain Modulation
Brief History
Central Pain-Modulatory Systems
Activity in Pathways that Transmit Signals Related to Pain Is Regulated by Brain Modulatory Systems that Can Inhibit Pain (Pro...
Variability of Pain and the Influence of Cognitive and Emotional Variables on the Pain Response Are Explained by Intrinsic Bra...
The PAG-RVM System Emerged as a Pain-Modulating Circuit
Pontine Noradrenergic Systems Also Contribute to Pain Modulation
The PAG-RVM System Serves as a Critical Target for Opioid Analgesic Drugs
The Endogenous Opioid System of Peptides and Receptors Maps Well onto Pain-Modulating Circuits
Interactions Occur Among Opioid-Sensitive Sites
Environmental Analgesia: Severe Stress and Other Biologically Significant Events Engage Pain-Modulating Systems
The Neurochemistry of Stress (Environmental)-Induced Analgesia Involves Opioid and Nonopioid Systems as well as Neurohormonal ...
Sex Differences Have Been Observed in the Central Control of Pain Inhibition in Animals
Gonadal Hormones Interact with Pain-Modulatory Systems to Mediate Analgesic Sex Differences
Sex Differences Are Also Observed for Opioid Tolerance and Dependence
Sex Differences in Analgesia Are Less Well Characterized in Humans
The PAG-RVM System Facilitates, as well as Inhibits, Pain
Two RVM Cell Populations, ``ON-Cells´´ and ``OFF-Cells,´´ Are the Basis for Bidirectional Pain Control from this Region
NEUTRAL-Cells and Serotonin
Recruitment of OFF-Cells Suppresses Pain
Opioid Analgesic Drugs Disinhibit RVM OFF-Cells to Produce Analgesia
Physiological Recruitment of RVM OFF-Cells Inhibit Pain
Recruitment of RVM ON-Cells Facilitate Pain
Top-Down Mechanisms Engage the PAG-RVM System
Negative Feedback, or ``Pain Inhibits Pain,´´ Is a Central Premise of ``Diffuse Noxious Inhibitory Controls´´ (DNIC)
Emerging Evidence for Action of Pain-Modulating Systems in Humans Includes Anatomical, Deep-Brain Stimulation, Imaging, and Ps...
Outlook
References
Part XIX: Clinical Neuroscience: Neuroimmune Disorders
138 Multiple Sclerosis
Introduction
Clinical Aspects of MS
Clinical Features of MS
Differential Diagnosis of MS
Clinical Spectrum of MS
Primary Progressive MS
Pediatric Multiple Sclerosis
Neuromyelitis Optica (NMO)
Genetic Aspects of MS
Epidemiology
Environmental Factors
Infection
Vitamin D and Sunlight
Immunology
The Cellular Elements
Markers of Immunological Damage in MS
Neuropathology
Demyelinating Diseases
The Use of Animal Models or of Other Human Conditions in Understanding the Development of Multiple Sclerosis
Staging and Timing of Lesion Pathology
The Morphology of MS Lesions
The Chronic or Inactive (Classical) Plaque
The Acute or Active Lesion
The Chronically Active or Subacute Plaque
Mechanisms of Demyelination in MS
Axonal Damage in MS
Gray Matter Pathology in MS
Pathology of the Normal-Appearing White Matter
Remyelination
Imaging in MS
Visualizing the Pathology of MS In Vivo
Diagnosis of MS Using MRI
Monitoring of Treatment by MRI
Clinically Isolated Syndromes Suggestive of MS
Untreated Patients with RRMS
Treated Patients with RRMS
Progressive MS
Recommendations for MRI Monitoring in the Clinic
Therapy of MS
Regulatory-Approved Agents
Interferon β and Glatiramer Acetate (GA)
Natalizumab
Mitoxantrone
Fingolimod (FTY720)
Lessons from Clinical Trials
Neurobiologic-Directed Therapies
Symptomatic Therapy in MS
Future Directions in MS
References
139 Myasthenia Gravis
Brief History
Understanding MG Pathogenesis and Current Diagnostic and Treatment Options
Clinical Features of MG
MG Is an Autoimmune Disease Affecting the Muscles
MG Symptoms
Prevalence of Different Types of MG
Pathogenic Mechanisms in MG
The NMJ and Nerve to Muscle Signal Transduction in Health
The AChR and MuSK Proteins
Anti-AChR Antibodies Are the Major Cause of Impaired Neuromuscular Transmission
Pathogenic Antibodies Against Additional Targets on the Muscle Membrane
Nonpathogenic MG-Associated Autoantibodies Are Present in Many Patients
The Thymus Is Involved in the Pathogenesis of MG
MG Is a T-Cell-Dependent Disease
Expression of Cytokines and Their Receptors Are Often Deregulated in MG
Genetic Factors Contribute to the Development of MG
HLA Alleles Are Commonly Associated with Increased Risk for MG
Polymorphisms in the CHRNA1 and PTPN22 Genes Are MG Predisposing Factors
Diagnosis of MG
Electrodiagnostic Tests
Serological Tests
Pharmacological Tests
MG Therapy
ACHE-I s
Corticosteroids
Nonsteroid Immunosuppressants
Thymectomy
Intravenous Immunoglobulin (IVIg)
Plasmapheresis and Related Procedures
Rituximab and Etanercept
Experimental MG
Outlook
Future Perspectives
Improved Diagnosis Promises Higher Sensitivity Levels
Novel Therapeutic Approaches
Conclusions
Further Reading
140 Infectious Diseases (esp. Equatorial): Infections of the Nervous System
Brief History
Infections and the Brain: Pathogenesis and Diseases
Attacks of Microbes on the Nervous System: Routes, Immune Responses, Outcomes
Routes for Spread of Pathogens to the Nervous System and Localization: Meningitis, Encephalitis, Myelitis
Blood-Borne Infections
Spread of Infections Through Peripheral Nerves
Pathogens and Immune Responses. What Makes the Nervous System So Special?
Outcome of an Infection: Slow Infections, Clearance Versus Persistency-Latency of Infection, and Functional or Late-Appearing ...
Nervous System Infections Prevalent in Tropical or Resource-Poor Countries
Bacterial Infections
Bacterial Meningitis
Tuberculosis and Leprosy
Listeria
Parasitic Infections
Malaria
Cysticercosis
Trypanosoma brucei
Trypanosoma cruzi
Toxoplasma gondii
Amoeba Infections
Viral Infections
Rabies Virus
Arboviruses
Herpesviruses
Retroviruses: HIV, HTLV1
Fungal Infections
Outlook
References
Part XX: Clinical Neuroscience: Addictive Disorders
141 Stimulant Drugs: Psychostimulants and Addiction
Introduction to Psychostimulants
Pharmacology
Effects on Physiological and Behavioral Functions
Medical Uses
Abuse and Addiction Potential
Psychostimulant Abuse Cycle
Withdrawal and Tolerance
Neurobiological Mechanisms of Addictive Behavior
Acute Reinforcing and Stimulant Effects of Psychostimulants
Psychostimulant Withdrawal and Dependence
Reinstatement of Cocaine-Seeking Behavior
References
142 Alcohol: Neurobiology of Alcohol Addiction
Brief History
Psychological and Neurobiological Aspects of Alcohol Addiction
Epidemiology of Alcohol Consumption and Alcohol-Related Disorders
Key Symptoms of Alcohol Addiction
Fetal Alcohol Syndrome-Related Disorders Represent the Most Common Form of Acquired Mental Disabilities, Affecting up to 7 per...
Excessive Alcohol Drinking and Addictive Behavior Often Comes with Other Psychiatric Conditions: Comorbidities of Alcohol Addi...
Drinking Alcohol Is Reinforcing by Activating the Mesolimbic Dopamine (DA) System
Alcohol Induces Long-Lasting Synaptic Changes Within the Reinforcement System
People Like to Drink Alcohol Because of Its Ability to Alter Emotional States and Many Other Reasons
Individuals Vary Highly in Their Responses to Alcohol, Which May Allow Some People to Drink Excessively
Gene Variants Contribute to the Risk of Developing Alcoholism
Excessive Alcohol Consumption Is Often a Result of Complex Gene Environment Interaction
The CRH System Is Involved in the Progression of Addictive Behavior
The Glutamate Theory of Alcoholism
Translational Approach in Medication Development
Outlook
References
143 Opioids and Opiates: Pharmacology, Abuse, and Addiction
Brief History
Terminology
Opioid Effects
Effects on the Nervous System
Effects on the Immune System
Opioid Receptor Ligands
Endogenous Opioid Peptides
Morphine and its Derivatives
Chemical Classes
Agonists, Antagonists, Agonist-Antagonists, and Inverse Agonists
Clinically Relevant Opioids
Agonists
Agonist-Antagonists
Antagonists
Absorption, Distribution, Metabolism, and Excretion
Opioid Receptors
Structure
Receptor Types and Subtypes
Alternative mRNA Splicing
Polymorphisms
Dimerization
Cellular Signaling
G-Protein Dependent Signaling
Phosphorylation, Desensitization, and Opioid Receptor Internalization
β-Arrestin-Dependent Signaling
Additional Regulatory Mechanisms of Opioid Receptors
Biased Agonism
Allosteric Regulation
Epigenetic Regulation
Addiction, Physical Dependence, and Tolerance
Synthetic Opioids as New Psychoactive Substances
Outlook
References
144 Nicotine Pharmacology, Abuse, and Addiction
A Brief History of Tobacco Use
Tobacco Use Is One of the World´s Largest Public Health Concerns
Animal Models Are Useful for Studying Nicotine Addiction
Neurobiological Studies Inform Understanding of Nicotine Addiction
Nicotinic Acetylcholine Receptors Are the Primary Targets for Nicotine in the Brain
nAChRs Are Activated, Upregulated, and Desensitized by Nicotine
Nicotine Activates the Dopamine System
Aversive Effects of Nicotine Are Mediated by the Habenulo-Interpeduncular Pathway
Tobacco Smoking Is Associated with Higher Incidence of Other Substance Use Disorders
Individuals with Schizophrenia Exhibit a High Rate of Smoking
Neurobiological Factors May Underlie the Comorbidity Between Smoking and Depression
Outlook
References
145 Cannabinoids Pharmacology, Abuse, and Addiction
Brief History
Cannabis Pharmacology
Endogenous Cannabinoid System
Cannabinoid Pharmacodynamic Effects
Cannabinoid Pharmacokinetics
Cannabis Abuse and Dependence
Outlook
References
146 Internet Addiction
Brief History
Historical Development
Interventions for Internet Addiction
Relevant Journals and Websites
Conceptualization of Internet Addiction
Assessment of Internet Addiction
Young´s Brief Eight-Item Questionnaire
Young´s 10-Item Questionnaire
Young´s Seven-Item Questionnaire
Prevalence of Internet Addiction
Theories of Internet Addiction
Biological Perspective
Psychoanalytic Perspective
Behavioral, Cognitive, and Cognitive-Behavioral Perspectives
Humanistic Perspective
Interpersonal and Family Perspectives
Sociocultural Perspective
Ecological Perspective
Psychosocial Correlates
Treatment of Internet Addiction
Outlook
Conclusions and Future Directions
References
147 Abuse of Performance-Enhancing Drugs
Brief History
History of Appearance and Performance-Enhancing Drug Use
Human Uses of APEDs and AASs
Medical Side Effects Associated with AAS Use
Psychiatric Side Effects Associated with AAS Use
Mechanisms of Action
Androgen Receptor Mechanisms
Biobehavioral Effects of AAS Misuse
Central Nervous System Effects: AAS Intoxication
Central Nervous System Effects: Motivation Reward
Exercise as a Unique Hormonal Environment for AASs
Outlook
References
148 Food Addiction
Brief History
A Primer on Sweet Taste Perception
Taste Receptors
Receptors for Sweet and Umami
Receptors for Bitter
Receptors for Salty and Sour
Signal Transduction Pathway of T1Rs and T2Rs
Encoding Taste Quality
Sweet Taste Sensitivity and Consumption
Genetic Variations
Structural Variations
The Ascending Neural Pathways of Food Reward
Sweet Taste Ascends from the Brainstem
Forebrain Structures for Food Reward
Generating ``Liking´´ for Food Reward
Generating ``Wanting´´ for Food Reward
Brain Reward Circuits Interact with Hypothalamic Regulatory Circuits of Hunger and Satiety
Evidence for Food Addiction: The Case for Sugar Addiction
Evidence for Food Addiction from Animal Models
Evidence for Food Addiction from Clinical Research
Neurobiology of Food Addiction
Food-Induced Changes in Brain Dopamine Signaling
Food-Induced Changes in Brain Opioid Signaling
Food-Induced Changes in Brain Acetylcholine Signaling
Food-Induced Changes in Brain Stress Pathways
Neuroadaptive Changes Associated with Obesity in Humans
Assessment of the Relative Addictive Potential of Sugar
Implications for the Current Obesity Epidemic
Outlook
References
Part XXI: Clinical Neuroscience: Degenerative Diseases
149 Motor Neuron Disease: Amyotrophic Lateral Sclerosis
Introduction
Brief History
Diagnostic Criteria
Epidemiology and Prognosis
Clinical Features of ALS
Symptoms
Physical Examination
ALS and Frontotemporal Lobar Dementia
Clinical Features of ALS Variants
Differential Diagnosis
Diagnostic Methods
Electrophysiological Studies
The Electrophysiological Hallmarks of ALS and Motor Neuron Diseases
Criteria for the Electrodiagnosis of ALS
Electrophysiological Evaluation of LMN Dysfunction: Nerve Conduction Studies
Electrophysiological Evaluation of LMN Dysfunction: Conventional Electromyography
Fasciculations in ALS
Choice of Muscles for Needle EMG Evaluation
Electrophysiological Evaluation of UMN Dysfunction: Transcranial Magnetic Stimulation and Central Motor Conduction Studies
Specialized Neurophysiological Tests for Detecting LMN Dysfunction
Other Neurophysiological Studies in ALS
Quantitative Markers of LMN Dysfunction
Neuroimaging Studies
Laboratory Studies
Muscle Biopsy
Histopathological Features of ALS
The Genetics of ALS
Introduction
ALS Genes with High Penetrance
ALS1: SOD1
ALS2: Alsin
ALS4: SETX, Senataxin
ALS6: FUS/TLS
ALS8: VAPB
ALS10: TARDBP, TDP-43
ALS12: OPTN, Optineurin
ALS15 UBQLN2
ALS20 - HNRNPA1
ALS23 - ANXA11
ALS25 - KIF5A
FTDALS1 - C9orf72
FTDALS3 - SQSTM1
FTDALS4 - TBK1
FTDALS6/IBMPFTD1 - VCP
ALS Genes with Lower Penetrance
Grand Unifying Theories of ALS Pathogenesis
Oxidative Stress
Axonal Transport and Cytoskeletal Disruption
Intermediate Filaments: Neurofilaments and Peripherin
Protein Aggregation: Toxic, Protective, or Tombstone?
Excitotoxicity and Calcium Homeostasis
Glial Cells and Non-cell Autonomy
Mitochondrial Dysfunction and Apoptosis
RNA Processing and Phase Separation
Aberrant TDP-43 Homeostasis
Stress Granules
Nucleocytoplasmic Transport
The Clinical Management of ALS
Symptomatic Treatments
Ventilatory Management
Nutritional Management
Disease-Modifying Treatments
Outlook
References
150 Parkinson´s Disease
Parkinson´s Disease: A Disorder of Movement
History of Parkinson´s Disease
Clinical Symptoms
Neuropathology of Parkinson´s Disease
When Does Parkinson´s Disease Begin?
Etiology of Parkinson´s Disease
Pharmacological Treatments for Parkinson´s Disease
l-DOPA
Glutamate Receptor Antagonists
Dopamine Agonists
Other Pharmacological Approaches
Monoamine Oxidase Inhibitors
COMT Inhibitors
Additional Therapeutic Drug Strategies
Antioxidants
Surgical Approaches
Allied Health and Complementary Therapies
Putative Treatments Under Development
Outlook
References
151 Huntington´s Disease
Historical Background
The Prevalence of HD in Western Societies Range from 4.1 to 8.4 Cases per 100,000 Persons
HD Is Caused by an Abnormal Expansion of the CAG Trinucleotide Repeat in Exon 1 of Huntingtin
The Major Neuropathological Feature of HD Is Striatal Atrophy as a Consequence of Medium-Sized Spiny Neuron Loss, Protein Incl...
The Main HD Clinical Features Are the Motor Abnormalities, Cognitive Impairment, and Behavioral Disorders
The Huntingtin Protein
Huntingtin Displays Functional Pleiotropy
Huntington´s Disease: A Gain or Loss of Function Pathology?
Pathogenic Mechanisms in Huntington´s Disease
Late-Onset Cell Death in Huntington´s Disease: One- or Two-Hit Model?
Outlook
References
152 Alzheimer´s Disease
Brief History
Clinical Features
Mild Cognitive Impairment
Diagnosis of Alzheimer´s Disease
Epidemiology and Pathology of Alzheimer´s Disease
Neurofibrillary Tangles and the Tau Protein
Genetics
APP Processing and Production of Aβ
The Amyloid Cascade Hypothesis
Genetic Risk Factors
Apolipoprotein E
Modifiable Risk Factors for AD
Diabetes
Hypertension
Physical Activity
Current Therapeutic Interventions
Approaches for Alzheimer Therapy
Targeting Secretases
Immunotherapy
Other Therapeutic Approaches
Transgenic Mouse Models of Alzheimer´s Disease
Outlook
References
Part XXII: Clinical Neuroscience: Gender Identity
153 Sexual Differentiation of the Human Brain in Relation to Gender-Identity, Sexual Orientation, and Neuropsychiatric Disorde...
Brief History
Introduction
Organizational Effects of Sex Hormones During Early Development
Sex Differences in the Human Brain in Relation to Gender Identity
Programmed Gender Identity Is Irreversible
Brain Structures in Relation to Gender Identity
Factors Influencing Sexual Orientation
Brain Structures in Relation to Sexual Orientation
Brain Changes in Pedophilia
Neurobiological Mechanisms of Sexual Differentiation of the Brain
Sex Differences in the Prevalence of Brain Disorders
Sex Differences in Stress-Coping Behavior
Sex and Age Differences in the Hypothalamo-Pituitary-Adrenal (HPA) Axis
The Basis of the Sex Differences in Prevalence of Depression
Sex Differences in the Prevalence of Posttraumatic Stress Disorder
Symptoms and Prevalence
Sex Difference in Vulnerability for PTSD
Outlook
References
154 Psychological and Biological Influences on Gender Roles
Brief History
The John/Joan Case Has Had a Significant Impact on the Study of Gender
The Field of Gender Studies Uses Very Specific Terminology
Nature and Nurture Are Not Opposing Forces
Science Is Partly Subjective
``Biological´´ Theories About Gender Identity and Sexuality Are Very Similar
Adult Hormone Levels Have Not Been Shown to Correlate with Gender Identity
There Is Some Evidence for a Genetic Influence on Gender Identity, But No Specific Genes Have Been Discovered
A Popular Theory Is That Prenatal Hormone Levels Influence Gender Identity, But We Have No Direct Method of Measuring These Le...
Many Studies Rely on Proxy Markers for Intrauterine Hormone Exposure
There Is Great Interest in the Effects of Medications and Environmental Estrogens on Gender Identity, But Little Convincing Re...
Animal Studies Suggest a Role for Prenatal Hormones in Gender Identity and Sexuality, But They Are Limited in Their Applicabil...
Gender Identity in Intersex People Provides Evidence That Both Intrauterine Hormones and the Social Environment May Influence ...
The Social Environment May Not Determine Gender Identity, But It Is Likely to Play a Role
Histology Was the First Method Used to Examine Brain Structure in Transgender People
Many Recent Studies Involve Structural and Functional Imaging of the Brain
Outlook
References
Part XXIII: Clinical Neuroscience: Other Psychiatric Disorders
155 Depressive Disorders: Depression
Brief History
MDD Is a Common Psychiatric Disorder with a Large Impact on Society
Altered Activity of Neurotransmitter Systems Is Observed in Some Patients with Depression
Serotonin and Depression
Norepinephrine and Depression
Dopamine and Depression
Disturbance in the Function of the Hypothalamic-Pituitary-Adrenal Axis May Be Observed in Some Patients with Depression
Functional Organization of the HPA Axis
Depression and Pathophysiology of the HPA Axis
Experimental Studies in Animals and Clinical Studies in Humans Have Demonstrated a Prominent Role of the Immune System in Some...
Brain Imaging Studies Have Identified Structural Changes and Altered Activity of Brain Circuits in Some Patients with Depressi...
Frontal and Prefrontal Cortex
Hippocampus
Subgenual Cingulate
Individual and Environmental Factors, Genetic Variation, and Interaction Between Genes and the Environment Alter Risk for MDD
Outlook
References
156 Neurobiology of Bipolar Disorder
Brief History
Major Neurotransmitter Systems in BD
Neuroendocrine System
Circadian Rhythms and Sleep
Intracellular Signaling Cascades
Genetics
Neurocognition
Neuroanatomic and Functional Neuroimaging Findings
Neuroprogression
Structural and Functional Aspects of Neuroprogression in BD
Neuroprogression as a Model
Inflammation as a Mechanism of Neuroprogression
Oxidative Stress and Mitochondrial Function
Neurotrophins
Neuroprotection
Outlook
References
157 Schizophrenic Syndromes: Schizophrenia
Brief History
Medical Aspects of Schizophrenia
Diagnosis of Schizophrenia
Treatment
Neuroscience of Schizophrenia
Brain Regions Involved in Schizophrenia
Structural Studies
Neuropathological Changes
Functional Brain Imaging
Brain Networks in Schizophrenia
Understanding the Symptoms of Schizophrenia from Neuroscience Evidence
From the Neurobiology of Manifest Illness Toward an Understanding of the Origin of Schizophrenia
Mechanisms of Genetic Risk in Schizophrenia
Environmental Risk
Summary
Outlook
References
158 Attention-Deficit Hyperactivity Disorder
Diagnosis: Has Continued Revision of Manuals Improved Diagnosis?
Epidemiology: Has the Prevalence of ADHD Increased?
Treatment: How Effective Are Treatments for ADHD?
Prognosis: What Are Some Adverse Outcomes Associated with ADHD?
Pathophysiology: Have Biological Bases Been Established?
Summary
Appendix A
References
159 Obsessive Compulsive Disorders
Brief History
OCD Is a Common and Disabling Psychiatric Disorder
Causes and Pathogenesis of OCD
Neurocognition
Neurobiology
Neurotransmitter Systems Implicated in OCD
Serotonin
Dopamine
Glutamate
Hypothalamic-Pituitary-Adrenal Axis
The Immune System in OCD
Neuroanatomical Circuits in OCD
Genetic Factors
Animal Models of OCD
Outlook
Further Reading
160 Posttraumatic Stress Disorder
Brief History
What Is PTSD?
The Fear Conditioning Model of PTSD
Some History of Fear Conditioning and Extinction Studies
Fear Conditioning Behavior in Rodents
Fear Conditioning and Extinction Neurocircuitry in Rodents
Fear Extinction Is New Learning, Not Unlearning
Psychophysiological Studies of Fear Conditioning and Extinction in Healthy Humans Have Replicated Rodent Studies
Functional Neuroimaging Can Be Used During Human Fear Conditioning and Extinction
The Neurocircuitry of Fear Conditioning and Extinction Is Similar in Humans and Rodents
Some Caveats About Functional Neuroimaging Studies
The Functional Neurocircuitry of PTSD Reflects Increased Fear Conditioning and Decreased Fear Extinction
Several Genes that Cause Increased Fear Conditioning and Decreased Fear Extinction Also Confer Risk to PTSD
Exposure Therapy Utilizes the Concept of Fear Extinction
Reconsolidation Provides Hope for Weakening Traumatic Memories During Their Recall
Beyond the Fear Conditioning Model of PTSD
The Fear Conditioning Model of PTSD Is Helpful but Incomplete
People with PTSD Are More Sensitive to Stress Hormones
Glucocorticoid Receptor Function Is a Possible Mechanism for Increased Sensitivity to Cortisol in PTSD
Epigenetic Changes to DNA May Be the Reason that Previous Trauma Is a Vulnerability Factor for PTSD
Outlook
References
Part XXIV: Appendix
161 Seven Steps to Setting Up a Neuroscience Program at Universities in Developing Countries
What Is Neuroscience?
Seven Steps to Setting Up a Neuroscience Program
Step 1. An Undergraduate Neuroscience Program
Step 2. An Integrated Graduate (MSc and PhD) Neuroscience Program: Pooling Resources
Step 3. Integrated Neuroscience Research Resources: Multidisciplinary Cooperation
Step 4. Human and Animal Ethics Programs/Animal Welfare
Human Research Ethics Committees
Animal Research Ethics
Animal Welfare
Step 5. National, Regional, and International Neuroscience Society Involvement
Step 6. Student Societies
Step 7. Community Involvement and Outreach
Summary and Conclusions
Index