The Enteric Nervous System II

Preface
Contents
1: Contribution of the Enteric Nervous System to Autoimmune Diseases and Irritable Bowel Syndrome
	1.1	 Enteric Nervous System and Autoimmune Disease
	1.2	 Enteric Nervous System and Irritable Bowel Syndrome
	References
2: Clinical and Pathological Features of Severe Gut Dysmotility
	2.1	 Introduction
	2.2	 Genetics of CIPO
		2.2.1	 RAD21
		2.2.2	 LIG3
	2.3	 Smooth Muscle Actin–Related Diseases: Visceral Myopathy Driven by ACTG2 Mutations
	2.4	 Conclusion and Future Perspectives
	References
3: Luminal Chemoreceptors and Intrinsic Nerves: Key Modulators of Digestive Motor Function
	3.1	 Introduction
	3.2	 Spectrum of Duodenal Chemosensing
	3.3	 Effects of Truncal Vagotomy on Duodenal Chemoreceptor Control of Gastric Emptying
	3.4	 Chemosensor Control of Proximal Gastric Motor Function
	3.5	 Duodenal Chemoreceptor Control of Antro-Pyloric Motor Function
		3.5.1	 Measurement of Antral and Pyloric Motor Functions
		3.5.2	 Chemoreceptor Control of Antral and Pyloric Motor Functions in Humans
		3.5.3	 Studies in Pigs and Dogs of Pathways via Which Duodenal Chemoreceptors Alter Antral and Pyloric Motor Function
	3.6	 Synthesis: Paths of Duodenal Chemoreceptor Control of Antral and Pyloric Motor Function During Normal Nutrient Processing
	3.7	 Duodenal Chemoreceptors and the Duodenal Brake Mechanism
		3.7.1	 Fluoroscopic Demonstration of the Duodenal Brake
		3.7.2	 Manometric Definition of the Duodenal Brake
	3.8	 Synthesis: Interpretation of Duodeno-Jejunal Complex Activity
		3.8.1	 Spatial Correlation of DJC Activity
		3.8.2	 The Mechanical Outcome of DJC Activity
		3.8.3	 Entry of Chyme into the Duodenum Stimulates DJC Activity
		3.8.4	 Physiological Significance of DJC Activity
		3.8.5	 Pathways of Stimulation of DJC Activity
	3.9	 Potential Clinical Significance of the Duodenal Brake
	References
4: Nitrergic and Purinergic Nerves in the Small Intestinal Myenteric Plexus and Circular Muscle of Mice and Guinea Pigs
	4.1	 Introduction
	4.2	 Materials and Methods
		4.2.1	 Animals
		4.2.2	 Tissue Preparation
		4.2.3	 Fluorescence Microscopy
	4.3	 Results
		4.3.1	 Nitric Oxide Synthase (NOS)
		4.3.2	 Choline Acetyltransferase (ChAT)
		4.3.3	 Calbindin (CalB)
		4.3.4	 Calretinin (CalR)
	4.4	 Discussion
		4.4.1	 VNUT-ir and NOS-ir
		4.4.2	 VNUT-ir and ChAT-ir
		4.4.3	 VNUT-ir and CalB-ir
		4.4.4	 VNUT-ir and CalR-ir
		4.4.5	 Summary and conclusions
	References
5: Mechanosensitive Enteric Neurons (MEN) at Work
	5.1	 Enteric Nervous System and Mechanosensitive Enteric Neurons
	5.2	 Methods Used to Identify MEN
	5.3	 Nature of the Mechanosensitive Stimuli Activating MEN: Sensitivity to Compression, Tension and Shear Stress
	5.4	 Properties of Isolated Myenteric MEN
	5.5	 Regional- and Species-Specific Differences in the Properties of MEN
	5.6	 Deformation Rate
	5.7	 Myenteric and Submucosal MEN
	5.8	 MEN Neurochemical Phenotype
	5.9	 Pharmacology of MEN
	5.10	 Multifunctionality
	5.11	 Outlook
	References
6: New Concepts of the Interplay Between the Gut Microbiota and the Enteric Nervous System in the Control of Motility
	6.1	 Introduction
	6.2	 Microbial Regulation of Enteric Neurons and Enteric Glia
	6.3	 Gut Bacteria Interact with Toll-Like Receptors and Enterochromaffin Cells to Regulate the Integrity of the ENS and Control GI Motility
	6.4	 Toll-Like Receptors as Regulators of Intestinal Motility
		6.4.1	 Deletion of TLR2 and TLR4 Impacts the Integrity of the ENS and Alters Motility
		6.4.2	 TLRs Are Modulated by Gut Microbiota Affecting Gut Transit, Neurogenesis, and Glial-Derived Neurotrophic Factor (GDNF)
	6.5	 Microbial Regulation of Serotonin in Enterochromaffin Cells
		6.5.1	 Potential Mechanisms for Microbiota Modulation of 5-HT Metabolism and GI Motility
	6.6	 Conclusions and Future Directions
	References
7: Optical Approaches to Understanding Enteric Circuits Along the Radial Axis
	7.1	 Introduction
	7.2	 The Development of the Intrinsic Sensory Innervation of Mucosa
	7.3	 Sensing Microbial Metabolites
	7.4	 Coordinating Activity in the Myenteric and Submucosal Plexus
	7.5	 Future Perspectives
	References
8: Serotonergic Paracrine Targets in the Intestinal Mucosa
	8.1	 Overview
	8.2	 Enterochromaffin Cells
	8.3	 Enterochromaffin Cells
	8.4	 Enteric Mast Cells
	8.5	 Paracrine Linkage of Enterochromaffin Cells to Mast Cells
	8.6	 Paracrine Linkage of Enteric Mast Cells to Spinal Afferents
	8.7	 Spinal Afferents Degranulate Enteric Mast Cells
	References
9: Enteric Control of the Sympathetic Nervous System
	9.1	 Central Sympathetic Circuits
	9.2	 Peripheral Sympathetic Circuits
	9.3	 Enteric Viscerofugal Neurons
	9.4	 The ENS-SNS Interface in Prevertebral Ganglia
	9.5	 Viscerofugal Neurons as Enteric Mechanoreceptors
	9.6	 Viscerofugal Neurons as Interneurons
	9.7	 Viscerofugal Neurons and Neurogenic Motor Behaviors
	9.8	 Enteric Control of the Sympathetic Nervous System
		9.8.1	 Effector Function of ENS-Driven Sympathetic Firing
	References
10: Embryonic Development of Motility: Lessons from the Chicken
	10.1	 The First Digestive Movements Are Just Calcium Waves in a Tube of Circular Smooth Muscle
	10.2	 Early Smooth Muscle Contractility Is Essential for Anisotropic Longitudinal Growth of the Gut
	10.3	 The Interstitial Cell of Cajal Transition
	10.4	 Early Enteric Nervous System Activity
	10.5	 Outlook
	References
11: Activation of ENS Circuits in Mouse Colon: Coordination in the Mouse Colonic Motor Complex as a Robust, Distributed Control System
	11.1	 Introduction
	11.2	 History of Evoked Colonic Migrating Motor Complexes
	11.3	 Coordination in the Colonic Migrating Motor Complex
		11.3.1	 Subthreshold Rapid Oscillations in the Smooth Muscle
		11.3.2	 Myenteric Potential Oscillations and the Role of Interstitial Cells
		11.3.3	 Enteric Neuron Synchronization During Motor Complex Initiation
		11.3.4	 Coordination in a Robust, Distributed Control System
	11.4	 Perturbing the Control System and the Colonic Migrating Motor Complex
		11.4.1	 Initiating a Colonic Migrating Motor Complex by Nonphysiological Stimulation
		11.4.2	 Disrupting Coordination in the Colonic Migrating Motor Complex
	11.5	 Concluding Remarks
	References
12: Colonic Response to Physiological, Chemical, Electrical and Mechanical Stimuli; What Can Be Used to Define Normal Motility?
	12.1	 Protocols and Catheter Types
	12.2	 Colonic Motor Patterns
	12.3	 Colonic Response to a Meal
	12.4	 Colonic Response to Chemical Stimulation
	12.5	 Colonic Response to Distension
	12.6	 Colonic Response to Gas Insufflation
	12.7	 Summary, Current Limitations and Future Directions
	References
13: New Insights on Extrinsic Innervation of the Enteric Nervous System and Non-neuronal Cell Types That Influence Colon Function
	13.1	 Introduction
	13.2	 Distinct ENS Organization and Function in Proximal and Distal Colon
	13.3	 Lumbosacral (LS) Pathway
	13.4	 Thoracolumbar (TL) Pathway
	13.5	 Vagal Pathway
	13.6	 Summary
	References
14: The Emerging Role of the Gut–Brain–Microbiota Axis in Neurodevelopmental Disorders
	14.1	 Introduction
	14.2	 Gastrointestinal Symptoms in Autism
	14.3	 Genetic Contributions to Autism
	14.4	 Microbial Dysbiosis
	14.5	 Preclinical Studies
	14.6	 Gastrointestinal Dysfunction in Patients and Mice Expressing the Autism-Associated R451C Mutation in Neuroligin-3
	14.7	 Neuroinflammation in Autism
		14.7.1	 Altered Caecal Neuroimmune Interactions in Mouse Models of Autism
	14.8	 The Gastrointestinal Mucus Environment and Implications for Neurodevelopmental Disorders
	14.9	 Region-Specific Motility Patterns
	14.10	 Examining Microbial Changes in Neurodevelopmental Disorders
	14.11	 Conclusion
	References
15: Interaction of the Microbiota and the Enteric Nervous System During Development
	15.1	 The ENS and Microbiota Develop Concurrently
	15.2	 Role of Microbiota on the Developing ENS
	15.3	 Implications of Antibiotic Exposure During Critical Developmental Windows
	15.4	 Conclusions and Future Directions
	References
16: Comparative and Evolutionary Aspects of the Digestive System and Its Enteric Nervous System Control
	16.1	 Nutritional Strategies of Simple Life Forms
	16.2	 Design Features of the Vertebrate Digestive System
		16.2.1	 Nutrient Exchange
	16.3	 Comparisons of Digestive Strategies in Mammals
		16.3.1	 Ruminant Foregut Fermenters
		16.3.2	 Autoenzyme Digesters: Carnivores, Omnivores and Cucinivores
		16.3.3	 Cucinivores
		16.3.4	 Extremes of Diversity
	16.4	 The Enteric Nervous System
	16.5	 Essential Nature of the ENS
		16.5.1	 Evolution of the Enteric Nervous System
	16.6	 Reciprocal and Convergent Connections of the ENS and CNS
	16.7	 Did an Ancient Nervous System Lead to the Enteric Nervous System in Cnidaria and the ENS and CNS in Vertebrates, Including Human?
	16.8	 Conclusions
	References
17: Enteric Glia and Enteric Neurons, Associated
	17.1	 Cytology of Glia
	17.2	 Glial Populations
	17.3	 Relative Extent of Glia
	17.4	 Glial Chondrioma
	17.5	 Research Limitations
	17.6	 Ganglionic Dense Packing
	17.7	 Dynamic Form of Ganglia
	17.8	 Life Times
	References
18: Circadian Control of Gastrointestinal Motility
	18.1	 Clock Genes
	18.2	 Circadian Cycle and the Gut
		18.2.1	 Nutrient Absorption and Metabolism
		18.2.2	 Regulation of Intestinal Epithelial Cell Proliferation and Cancer
		18.2.3	 Immune Function and Influence of the Microbiota
	18.3	 Gastrointestinal Motility and the Enteric Nervous System
		18.3.1	 Circadian Cycle and Gastrointestinal Motility
		18.3.2	 Molecular Mechanisms Underlying Circadian Control of Gut Motility
	18.4	 Conclusions
	Bibliography
		References
19: Generation of Gut Motor Patterns Through Interactions Between Interstitial Cells of Cajal and the Intrinsic and Extrinsic Autonomic Nervous Systems
	19.1	 ICC as Intermediary of Sensory and Motor Activities of the Vagus
	19.2	 The Migrating Motor Complex (MMC)
	19.3	 Duodenal Propulsive Activity
	19.4	 The Minute Rhythm Contraction Pattern in the Human Small Intestine
	19.5	 The Segmentation Motor Pattern as Described by Cannon
	19.6	 The High-Amplitude Propagating Pressure Wave (HAPW) in the Human Colon
	References
20: Refining Enteric Neural Circuitry by Quantitative Morphology and Function in Mice
	20.1	 Introduction
	20.2	 Quantitative Morphology
	20.3	 Functional Connectivity
	20.4	 Conclusion
	References
21: Molecular Targets to Alleviate Enteric Neuropathy and Gastrointestinal Dysfunction
	References
22: Ca2+ Signaling Is the Basis for Pacemaker Activity and Neurotransduction in Interstitial Cells of the GI Tract
	22.1	 Introduction
	22.2	 Basal Ca2+ Transients in Interstitial Cells
	22.3	 Neurotransduction by Interstitial Cells
	22.4	 Pacemaker Activity in Interstitial Cells
	22.5	 Conclusions
	References
23: Identifying Types of Neurons in the Human Colonic Enteric Nervous System
	23.1	 Classifying Neurons
		23.1.1	 Goals for Classification
	23.2	 The Opportunity to Study Human Enteric Nervous System
		23.2.1	 Technical Issues with Use of Human Tissue
	23.3	 Classification of Enteric Neurons
	23.4	 Chemical Coding
	23.5	 Limits of Chemical Coding
	23.6	 A New Approach to Chemical Coding
	23.7	 Discussion
	References
24: Neurons, Macrophages, and Glia: The Role of Intercellular Communication in the Enteric Nervous System
	24.1	 Introduction
	24.2	 The Role of EGCs in ENS Communication
	24.3	 Communication Between Neighboring EGCs
	24.4	 The Role of mMacs in ENS Communication
	24.5	 How Do mMac Interactions with Enteric Neurons Relate to Changes to Gastrointestinal Function?
	24.6	 Evidence for EGC and mMac Interactions in the Gut Wall
	24.7	 Conclusion
	References
25: Mas-Related G Protein-Coupled Receptors (Mrgprs) as Mediators of Gut Neuro-Immune Signaling
	25.1	 The Family of Mas-Related G Protein-Coupled Receptors
	25.2	 Mrgprs in the Skin Sensory Innervation
		25.2.1	 Mrgpra3 and MRGPRX1
		25.2.2	 Mrgpra1/MRGPRX4
		25.2.3	 Mrgprb4
		25.2.4	 Mrgprc11 and MRGPRX1
		25.2.5	 Mrgprd
	25.3	 Mrgprs in Skin Immune Cells
	25.4	 Mrgprs Expression in the Gastrointestinal (GI) Tract
		25.4.1	 Mrgprs in the Enteric Nervous System
		25.4.2	 Mrgprs in the Gut Spinal Afferent Innervation
			25.4.2.1	 Mrgpra3/c11 and Its Human Counterpart MRGPRX1
			25.4.2.2	 Mrgprd
		25.4.3	 Mrgprs: Novel Targets in Chronic Abdominal Pain Disorders?
		25.4.4	 Mrgprs in Gut Mast Cells
	25.5	 Conclusion
	References
26: Analysis of Intestinal Movements with Spatiotemporal Maps: Beyond Anatomy and Physiology
	26.1	 Introduction
	26.2	 The Origin of Graphic Representation in Physiology
	26.3	 The Kymograph and the Birth of Modern Physiology
	26.4	 First Recording of Intestinal Mechanical Events Using the Kymograph
	26.5	 Isolated Preparations of the Intestine
	26.6	 X-Rays in Gastroenterology at the Turn of the Twentieth Century
	26.7	 Direct Visual Recording In Vivo
	26.8	 Spatiotemporal Maps of Changes in Diameter (DMaps) and Length from Videos
	26.9	 Spatiotemporal Maps of Diameters In Vivo: The Challenges
		26.9.1 Videos
		26.9.2 Fluoroscopy
		26.9.3 Ultrasonography: Photoacoustic Imaging (PA)
		26.9.4 Magnetic Resonance Imaging (MRI)
	26.10	 Spatiotemporal Maps of Changes in Forces (PMaps)
		26.10.1 Myoelectrical Activity and Its Mechanical Equivalence
		26.10.2 Calcium Waves in Smooth Muscle and Pacemaker Cells
		26.10.3 Recording Forces of Contractions
			26.10.3.1	 Intraluminal Balloons
			26.10.3.2	 Force Transducers
			26.10.3.3	 Strain Gauges
			26.10.3.4	 Multiple Manometry: The Birth of PMaps
	26.11	 Examples of Kinetic and Kinematic Recordings Combined
		26.11.1 Earlier Combinations of Recording Methods
		26.11.2 Full Combination of Kinematics and Kinetics: DPMaps
		26.11.3 Combining Kinetics, Kinematics Forces and Flow, Propulsion and Transit Times
	26.12	 Concluding Remarks
	References
27: Rhythmicity in the Enteric Nervous System of Mice
	27.1	 Introduction
	27.2	 Motor Patterns in Mouse Colon
	27.3	 Sensitivity to Distension of CMCs
	27.4	 Potential Role of Endogenous 5HT from the Mucosa in Cyclical Neurogenic Motor Patterns
	27.5	 Coordinated Rhythmic Firing of Myenteric Neurons During CMCs Revealed by Neuronal Imaging of the ENS
	27.6	 Distinct Physiological Motor Patterns in the Mouse Colon
	27.7	 What Mechanisms Underlie Aboral Propulsion?
	27.8	 Rhythmic Activity of Myenteric Neurons During Propulsive Motor Patterns in the Mouse Colon
	27.9	 Are There ENS Pacemaker Neurons That Could Underlie the Rhythmic Generation of CMCs?
	27.10	 Comparison with Other Species
	27.11	 Conclusion
	References
28: The Shaggy Dog Story of Enteric Signaling: Serotonin, a Molecular Megillah
	28.1	 The History of 5-HT
	28.2	 5-HT and the Peristaltic Reflex
	28.3	 Did Bülbring Make a Mistake?
	28.4	 5-HT Is Essential for Mucosal Stimulation to Evoke the Peristaltic Reflex, But 5-HT Is Not Essential for Reflexes That Mechanosensitive Nerve Fibers Induce
	28.5	 Luminal Microbes Use EC Cells and 5-HT to Regulate the ENS
	28.6	 5-HT Is a Growth Factor for Enteric Neurons
	28.7	 SERT Plays a Critical Role in Enteric 5-HT Signaling
	28.8	 Inhibition of VMAT2
	28.9	 SERT Regulates Enteric Serotonergic Signaling
	28.10	 The Importance of Extraenteric TPH1 During Early Development
	28.11	 Tryptamine
	28.12	 Summary and Conclusions
	References
29: Upper Gastrointestinal Motility, Disease and Potential of Stem Cell Therapy
	29.1	 Introduction
	29.2	 Normal Motility in the Upper GI Tract: Esophagus and Stomach
		29.2.1	 Esophagus
		29.2.2	 Stomach
	29.3	 Upper GI Dysfunction at the Lower Esophageal and Pyloric Sphincters
		29.3.1	 Esophageal Achalasia
		29.3.2	 Gastroparesis
	29.4	 Advances in Cell Replacement of nNOS Neurons
	29.5	 Analysis of Neural Function and Network Integration
	29.6	 Protocols for Generation of ENS-Like Cells from iPSCs
	29.7	 Conclusion
	References
30: Epithelial 5-HT4 Receptors as a Target for Treating Constipation and Intestinal Inflammation
	30.1	 Expression of 5-HT4 Receptors by Colonic Epithelial Cells and Effects of Their Stimulation on Motility and Nociception [4]
	30.2	 Attenuation of Colitis by Luminally Administered 5-HT4 Agonists [12]
	30.3	 Prokinetic Effects of Luminally Acting 5-HT4 Receptor Agonists [8]
	30.4	 Concluding Remarks
	References
Index