Enteric Nervous System: Physiologyq

Jackie D Wood, The Ohio State University, Columbus, OH, United States
© 2017 Elsevier Inc. All rights reserved.

Introduction 1
Myenteric and Submucosal Plexuses 2
Heuristic Model for the ENS 3
Neuronal Types 3
Electrical Behavior 4
Neurotransmission 4
Fast Excitatory Postsynaptic Potentials 6
Slow Excitatory Postsynaptic Potentials 6
Slow Inhibitory Postsynaptic Potentials 6
Neurogastroenterology 6
Level 1: Neurons and Neurotransmission 7
Level 2: Polysynaptic Propulsive Motility Circuit 8
Level 3: Central Pattern Generators 9
Level 4: Plasticity 10
Interdigestive App 11
Postprandial App 11
Power Propulsion App 12
Aboral Power Propulsion App 12
Emesis App 12
Physiological Ileus App 12
Summary 13
Further Reading 13

Introduction

The enteric nervous system (ENS) is a subdivision of the autonomic nervous system (Fig. 1). Neural control of the digestive tract is
actioned by the autonomic nervous system. Three subdivisions of the autonomic nervous system, known as the sympathetic,
parasympathetic and enteric divisions, makes up the autonomic innervation of the alimentary tract. The enteric division, which
is also termed the ENS, functions like a minibrain in the gut. It is an independent integrative nervous system which has its neural
networks placed in close apposition to the effector systems it controls in the stomach, in the approximately 30 ft of small intestine,
and in the 8 ft of large intestine as well as the esophagus, gallbladder and pancreas. The effector systems are smooth muscle,
secretory glands and blood vasculature. There are approximately 100 million neurons in the ENS, which is about the same number
as in the spinal cord. Rather than packing the 100 million neurons required for control of gut functions into the skull as part of
the brain and relying on signal transmission over long, neural pathways to the gut, evolutionary natural selection distributed
the integrative neural networks of the ENS along the gut in immediate proximity to the effector systems it controls.

Figure 1 The digestive tract is innervated by three divisions of the autonomic nervous system: the sympathetic, parasympathetic and enteric
divisions. The parasympathetic division is subdivided into cranial and sacral divisions based on the anatomical location of the preganglionic cell
bodies in the brain stem and spinal cord. Preganglionic cell bodies of the sympathetic division are in the thoracolumbar regions of the spinal cord.
Cell bodies of the enteric division are in its myenteric and submucosal divisions.

1
2 Enteric Nervous System: Physiology

The networks at the effector sites have evolved as an organized array of different kinds of neurons interconnected by neuro-
effector junctions. Functions in the network are determined by generation of action potentials within single neurons and chemical
transmission of information at various points of contact between individual neurones, muscular and glandular elements. Coded
information is transmitted from one region of a neuron to another by action potentials. The action potential codes are transformed
into chemical codes at synaptic connections with other neural elements within a given network. Action potential codes, arriving in
presynaptic neuronal terminals, are transformed to chemical signals for transmission across synapses to receptors on postsynaptic
neural elements where reconversion into action potential codes occurs in the postsynaptic neurons. Postsynaptic neurons integrate
large numbers of synaptic inputs, which may be excitatory or inhibitory. Postsynaptic integration is fundamental for computation
and processing of neural information.
The ENS microcircuits in the various specialized compartments of the digestive tract are wired with the very large numbers of
neurons and neuroeffector junctions where information processing occurs. Multisite computation generates output behavior
from the integrated circuits that could not be predicted from the properties of their individual neurons, synapses and neuroeffector
junctions. Emergence of complex behaviors is a fundamental property of the neural networks of the ENS, in the same way as in the
brain and spinal cord.
In much the same manner, the enteric microcircuitry processes information and generates patterns of signals that determine the
timing and sequencing of behavior of the muscle groups and secretory glands, and the distribution and dynamics of blood flow
within the gut wall. Processing of information in the circuits is a function whereby computation of input signals results in output
to the effectors that is a meaningful transform of the input.
Processing of sensory signals is among the major functions of the microcircuits in the ENS. The sensory signals are generated at
sensory nerve endings and coded in the form of action potential discharge frequencies. The codes may represent the status of an
effector system (e.g., contractile tension in a smooth muscle) or may signal a change in parameters, such as pH and osmolarity,
in the luminal environment of a specialized compartment, such as the small intestine. Sensory signals are deciphered by the neural
networks to generate output signals that initiate homeostatic adjustments in the behavior of each individual effector system and
the integrated behavior of the whole organ.

Myenteric and Submucosal Plexuses

The ENS consists of ganglia, primary interganglionic fiber tracts, and secondary and tertiary fiber projections to the effector systems
(i.e., musculature, glands and blood vessels). Two plexuses are obvious histological structures in the ENS (Fig. 2). The myenteric
plexus, also known as Auerbach’s plexus, is located between the longitudinal and circular muscle layers of the esophagus, stomach,
and small and large intestine. The submucosal plexus, also known as Meissner’s plexus, is situated in the submucosal region
between the circular muscle and mucosa. The submucosal plexus is most prominent as a ganglionated network in the small and
large intestine. It does not exist as a ganglionated plexus in the esophagus and is sparse in the submucosal space of the stomach.
In larger mammals (e.g., humans), the intestinal submucosal plexus consists of an inner submucosal network (Meissner’s plexus)
located at the serosal side of the muscularis mucosae and an outer plexus (Schabadasch’s plexus) adjacent to the luminal side of the
circular muscle coat. In human small and large intestine, a third intermediate plexus lies between Meissner’s and Schabadasch’s
plexus.
The motor innervation of the circular and longitudinal smooth muscle of the esophagus, stomach and small and large intestine
originates from neurons that have their cell bodies in the myenteric plexus. The innervation of the intestinal secretory glands
(i.e., Brunner’s glands in the duodenum and crypts of Lieberkühn in both small and large intestines) originates in the submucosal

Figure 2 Structural relations of the intestinal musculature and the ENS. Longitudinal and circular muscle coats are the main components of
the musculature involved in propulsive motility; secretory glands are in the mucosa. Ganglia and interganglionic fiber tracts of the myenteric and
submucosal plexuses are the main constituents of the ENS. The myenteric plexus is situated between the circular and longitudinal muscle coats;
the submucous plexus is between the mucosa and circular muscle coat.
 Enteric Nervous System: Physiology 3

plexus. Neurons in the submucosal ganglia send axons to the myenteric plexus and also receive synaptic inputs from axons
projecting from the myenteric plexus. The interconnections link the two plexuses into a functionally integrated nervous system.
The structure, function and neurochemistry of ganglia in the ENS are reminiscent of those in the CNS but differ considerable
from ganglia of the sympathetic and parasympathetic autonomic divisions. Unlike most sympathetic or parasympathetic
autonomic ganglia, where function is mainly as relay-distribution centers for signals transmitted from the brain and spinal cord
to systems in the periphery, enteric ganglia are interconnected to form a nervous system with mechanisms for integration and
processing of information like those in the brain and spinal cord. This is the justification for referring to the ENS as a ‘minibrain
in the gut’.

Heuristic Model for the ENS

The heuristic (rule of thumb) model for the ENS is the same as for the brain and spinal cord and, for that matter, any other
independent integrative nervous system, such as found in fish, reptiles or invertebrates (Fig. 3). As in most independent integrative
nervous systems, sensory neurons, interneurons and motor neurons in the ENS are connected synaptically to facilitate the flow of
information from sensory neurons to interneuronal integrative networks to motor neurons to effector systems, respectively. The
job of the ENS is to organize and coordinate the activity of each effector system into meaningful functional behavior of the whole
organ. It is integrated with the sympathetic and parasympathetic autonomic centers in the CNS and bidirectional communication
occurs between centers in the CNS and the ENS.

Neuronal Types

Dogiel types I and II are the principal morphological classes of neurons in the ENS. The Russian neuroanatomist, Alexander S.
Dogiel, described these two morphological types of enteric ganglion cells that were named after him. Dogiel types I and II are
distributed in both the myenteric and submucosal plexuses in a two-dimensional plane (i.e., the cell bodies are not stacked one
on top of the other). Cell bodies are flat, coin-like disks with multiple neurites exiting around the perimeter, which may adapt
to the changing forces within the gut wall experienced during contraction and relaxation of the musculature, or stretching of the
wall as the hollow organs fill and empty.
Dogiel type I neurons have cell bodies with many short processes and a single long process (Fig. 4). These are flat neurons with
the processes extending from the cell body in the circumferential and longitudinal planes of the wall. The short processes are
dendrites, which receive synaptic inputs; the long process is an axon. The axon of Dogiel type I neurons projects for long relatively
distances through interganglionic fiber tracts and through many rows of ganglia. However, the projections are not long in absolute
length; the longest projections of any enteric ganglion cell are only approximately 2–3 cm long. Dogiel I neurons projecting in
a particular direction often express specific types of neurotransmitters. Aborally projecting Dogiel I axons release nitric oxide
(NO) and vasoactive intestinal polypeptide (VIP) as inhibitory neuromuscular transmitters; those projecting in the oral direction
release substance P and acetylcholine (ACh). Some of the Dogiel type I neurons innervate the musculature and secretory glands;
others are interneurons with synaptic connections in internuncial processing circuits. The cell bodies of ENS neurons with Dogiel
type II morphology have smooth surfaces with long and short processes arising in a variety of configurations (Fig. 4). The long
processes may extend through interganglionic fiber tracts across several rows of ganglia in the circumferential direction, the oral

Figure 3 Sensory neurons, interneurons, and motor neurons are synaptically interconnected to form the integrated microcircuits of the ENS. Like
the CNS, sensory neurons, interneurons and motor neurons are connected synaptically to permit the flow of information from sensory neurons to
interneuronal integrative networks to motor neurons and ultimately to effector systems. The ENS organizes and coordinates the activity of each
effector system into meaningful behavior of the whole organ. Bidirectional communication occurs between the CNS and the ENS.
4 Enteric Nervous System: Physiology

Figure 4 Histoanatomy of Dogiel morphologic type I and II cells in the ENS. (A1, A2) Dogiel morphologic type II neurons in the myenteric
plexus of the guinea-pig small intestine. Dogiel II neurons have multiple long processes with variable lengths and shapes that ramify throughout
the ganglion and into interganglionic fiber tracts. (B1, B2) Dogiel morphologic type I neurons in the submucosal plexus of the small intestine of the
guinea-pig. Dogiel I neurons have multiple short dendrites at the edges of the cell body and a single axon. The neurons were marked by the injection
of biocytin from micropipettes that also served as recording microelectrodes.

direction or aborally. Shorter processes may only project within the home ganglion. Almost all Dogiel II neurons in the myenteric
plexuses of the small and large bowel project processes to the submucosa/mucosa. Endings of the Dogiel II processes in the mucosal
regions express the 5-HT3 serotonergic receptor subtype and are activated by serotonin released from mucosal enterochromaffin
cells during mechanical and chemical stimulation of the mucosa. Dogiel II neurons express the neurotransmitters substance P
and ACh.
A population of Dogiel II neurons, which are characterized electrophysiologically by long-lasting after-hyperpolarization
following generation of an action potential, have been proposed to be intrinsic primary afferent neurons referred to by the acronym
IPAN. Nevertheless, these neurons are not primary sensory neurons. They do not behave at all like spinal or vagal primary sensory
afferent neurons, which faithfully encode changes in stimulus energy into the firing of action potential codes that are a transform of
the rate of change of stimulus strength. Instead, variability in excitability of enteric afterhyperpolarization (AH)-type neurons and
their synaptic interconnections suggest that they may be multifunctional interneurons and play an important role in programming
the output of integrated motor circuits to the musculature and secretory glands. Actually, the only neurons in the gut, which behave
like real sensory neurons, have their cell bodies in dorsal root spinal and nodose/jugular ganglia.

Electrical Behavior

Intracellular microelectrodes have been used to record and study the electrical and synaptic behavior of ENS neurons in
preparations removed from the various organs along the digestive tract. Differences in electrical and synaptic behavior establish
a basis for classification of ENS neurons into two main subgroups termed AH- and S-type neurons.
S-type neurons were first identified on the basis of nearly universal occurrence of fast nicotinic excitatory postsynaptic potentials
(EPSPs) (Fig. 5) and AH-type neurons were identified based on the occurrence of long-lasting hyperpolarizing after potentials (AH)
associated with the action potential (Fig. 6). AH-type electrophysiological behavior is found mainly in enteric neurons with Dogiel
type II morphology and S-type behavior is found mainly in Dogiel type I neurons.
Repetitive action potential discharge is common in S-type neurons but repetitive discharge generally does not occur in AH-type
enteric neurons (Fig. 6). Membrane excitability is higher in S-type enteric neurons than in AH-type neurons. S-type neurons fire
repetitively during the intraneuronal injection of long-duration depolarizing current pulses through the recording microelectrode.
The frequency of the repetitive spike discharge increases in proportion to the amplitude of the depolarization produced by the
injected pulses. AH-type neurons do not fire repetitively during sustained membrane depolarization when they are in a resting state.
Irrespective of the strength of a depolarizing pulse, these neurons fire only one or two spikes at the onset of the pulse. During slow
synaptic excitation (Fig. 5), AH neurons become hyperexcitable and fire repetitively much like S-type neurons.
In the guinea pig, which is the most commonly studied model, the occurrence of AH-type neurons is limited to the gastric
antrum and the small and large intestine. S-type neurons are found throughout the digestive tract, including the gastric corpus
and antrum, gallbladder, esophagus and pancreas.

Neurotransmission

Synaptic events in the ENS are generally the same as in the brain and spinal cord. EPSPs, inhibitory postsynaptic potentials (IPSPs),
and presynaptic inhibition and facilitation are the principal synaptic events in the enteric microcircuitry. Slow and fast synaptic
 Enteric Nervous System: Physiology 5

Figure 5 Fast and slow excitatory postsynaptic potentials (EPSPs) and slow inhibitory postsynaptic potentials (IPSPs) are the primary types
of synaptic potentials in enteric neurons. (A) Slow EPSP evoked by repetitive electrical stimulation of the synaptic input to the neuron. Slowly
activating depolarization of the membrane potential continues for more than 2 min after termination of the stimulus. Repetitive discharge of
action potentials reflects enhanced neuronal excitability during the slow EPSP. (B) Two fast EPSPs were evoked by successive stimuli and are
shown as superimposed records. Only one of the EPSPs reached threshold for discharge of an action potential. The time course of the EPSPs is
in the ms range. The fast EPSPs were evoked by single electrical shocks applied to the axon that formed the synapse with the recorded neuron.
(C) Slow IPSP evoked by stimulation of an inhibitory input to the neuron. This is a hyperpolarizing synaptic potential that will suppress excitability
(i.e., decrease probability of action potential discharge) compared with enhanced excitability during slow EPSPs.

Figure 6 Enteric neurons are classified as S type 1 or AH type 2 based on their electrophysiological behavior. (A) AH type 2 neuron had low
excitability reflected by discharge of only a single action potential during intraneuronal injection of a 200 ms depolarizing current pulse. (B) S type
1 neuron had relatively high excitability reflected by repetitive discharge of action potentials during intraneuronal injection of a 200 ms depolarizing
current pulse. The bottom traces in (A) and (B) show the current pulses and the top traces show the neuronal responses to the depolarizing current
pulses. (C) AH type 2 neurons are characterized by long-lasting membrane hyperpolarization (i.e., afterhyperpolarization) following the discharge of
an action potential.
6 Enteric Nervous System: Physiology

mechanisms are commonly expressed in neurons with AH-type electrophysiological behavior and Dogiel II morphology, as well as
in neurons with S-type electrophysiological behavior and uniaxonal Dogiel I morphology. Fast synaptic potentials have durations in
the ms range; slow synaptic potentials last for several seconds or minutes. Fast synaptic potentials are usually EPSPs. The slow
synaptic events may be either EPSPs or IPSPs. Paracrine signals, such as the actions of histamine and proteases released from enteric
mast cells, mimic slow synaptic excitation.

Fast Excitatory Postsynaptic Potentials

Fast EPSPs are membrane depolarizations with durations less than 50 ms (Fig. 5). They are found at synapses in both the myenteric
and submucosal plexuses, where they appear most prominent in neurons with S-type electrophysiological behavior in all of the
specialized organs of the digestive tract. Most of the fast EPSPs are mediated by acetylcholine (ACh) at nicotinic postsynaptic
receptors. The actions of serotonin at the serotonergic 5-HT3 receptor subtype and purine nucleotides acting at P2X purinergic
receptors generally mimic fast EPSPs.

Slow Excitatory Postsynaptic Potentials

Slow EPSPs are involved in neurotransmission in both the myenteric and submucosal plexuses and in AH- and S-type neurons. They
are most pronounced in Dogiel morphologic type II neurons with AH-type electrophysiological behavior where conversion from
states of hypo-to hyperexcitability occurs. ENS neurons with slow excitatory synaptic inputs are found in the small and large
intestine and gastric antrum but not the gastric corpus or gallbladder. They seem to be associated with specialized regions of the
gut where propulsive motility is a significant function.
Slowly activating membrane depolarization, continuing for several seconds to minutes after termination of release of the
neurotransmitter from the presynaptic terminal, characterizes slow EPSPs (Fig. 5). Enhanced excitability, reflected by long-
lasting trains of action potentials, is the hallmark of slow excitatory postsynaptic neurotransmission. Enhanced excitability is
apparent experimentally as repetitive action potential discharge during depolarizing current pulses. AH-type neurons, which usually
fire only a single spike at the beginning of a membrane depolarizing current pulse in the low activated state, will fire repetitively in
response to depolarizing pulses when a slow EPSP is in effect. When activated by slow synaptic inputs, the behavior of AH-type
neurons is much like that of S-type neurons and may be confused as such if they happen to be in an activated state due to ongoing
release of neurotransmitter or a paracrine mediator that mimics slow synaptic excitation. Postspike hyperpolarization in AH-type
neurons is suppressed during slow excitatory neurotransmission. Suppression of the AH is part of the mechanism that permits
repetitive spike discharge at increased frequencies during the enhanced state of excitability.
Slow EPSPs are a mechanism for long-lasting activation or inhibition of gastrointestinal effector systems. The prolonged
neuronal firing during a slow EPSP drives the release of neurotransmitter from the neuron’s axon for the duration of the spike
discharge. Prolonged inhibition, or excitation at neuronal synapses in the processing circuits and at neuroeffector junctions, is
the functional outcome of slow synaptic excitation. This governs the functional behavior of the effector systems. Compared to
twitches of skeletal muscles, contractile responses of the gut smooth musculature and glandular secretory responses are sluggish
events that last for several seconds from start to completion. The prolonged train-like firing during slow EPSPs is the neural correlate
of long-lasting excitatory or inhibitory responses of the smooth muscle coat in the functioning gastrointestinal tract. Prolonged
secretory responses in the intestinal crypts are likewise related to the sustained neuronal firing taking place during slow synaptic
excitation.

Slow Inhibitory Postsynaptic Potentials

Slow IPSPs are hyperpolarizing synaptic potentials found in neurons in both the myenteric and submucosal plexuses of the small
and large intestine and in the myenteric neurons of the gastric antrum. Slow IPSPs activate relatively slowly and continue for several
seconds after termination of the stimulation (Fig. 5). The characteristics of slow synaptic inhibition are the inverse of slow synaptic
excitation in that hyperpolarization instead of depolarization of the membrane potential occurs (e.g., a change from
50
to
75 mV). Hyperpolarization of the membrane potential reduces excitability and the probability that the neuron will fire action
potentials. IPSPs are more readily demonstrated in the submucosal rather than in the myenteric plexus of experimental animal
preparations.
Several putative neurotransmitters or paracrine mediators evoke responses similar to slow IPSPs when experimentally
applied to enteric neurons. Some of these substances are peptides, others are purine compounds, and another is norepinephrine
(noradrenaline). Receptors for two or more of these substances may be localized to the cell body of the same neuron.

Neurogastroenterology

Neurobiology of the ENS is a subcategory of neurogastroenterology, which is a recognized subspecialty of clinical gastroenterology and
basic digestive sciences. As such, it embraces research dealing with functions, malfunctions and malformations of the sympathetic,
 Enteric Nervous System: Physiology 7

Figure 7 Enteric nervous system (brain-in-the-gut) hierarchy of organization. Neuronal subcellular physiology and synaptic transfer of information
from neuron to neuron are at the bottom two levels of the hierarchical organization. Synaptic connectivity of neurons into a single hardwired polysynaptic
reflex circuit, which becomes the basis for all patterns of propulsive motility and presumably any linked secretory behavior, is an intermediate level as
are neuronal pattern generators that drive the timing of repetitive activity of the reflex circuit. Near the top level of neural organization are programs for
behaviors that emerge from the organization of the different kinds of neurons, their synaptic connections and their connectivity into microcircuits in the
lower levels. A library, which stores a neural program for each of the digestive states mentioned in the above paragraph, fills-out the top level. Plasticity/
adaptability of programmed organ system behavior is a distinguishing property of the top tier. Functioning of each program in the library of behaviors is
reminiscent of mobile ‘apps’ (software applications) that run on modern smart phones, tablet computers and comparable devices.

parasympathetic and ENS divisions of the autonomic innervation of the digestive tract, as well as in the brain and spinal cord.
Psychological and psychiatric aspects of gastrointestinal disorders are significant components of neurogastroenterology, especially
in relation to conscious projections of discomfort and pain to the digestive tract.
The perception of the ENS as a brain-in-the-gut suggests that, like the CNS, the ENS is assembled in hierarchical levels of neural
organization (Fig. 7). Output from the hierarchal system determines the moment-to-moment behavior of the gastrointestinal
musculature, secretory glands and blood vasculature in the functioning gut. Integration of output to the muscles and secretory
glands is reflected by coordinated patterns of motility and secretion, recognizable during specifically defined states of digestive
behavior. Some of the perceptible digestive states in the small intestine are: 1) absence of any smooth muscle contractile activity,
termed physiological ileus; 2) postprandial state with segmenting (mixing) motility; 3) interdigestive state; 4) defensive state. Neurogenic
behavioral states in the large intestine are recognized as: a) haustral formation; b) physiological ileus; c) defecatory power propulsion;
d) neurogenic defence.
Neuronal subcellular physiology and synaptic neurotransmission of information from neuron to neuron occupy the two lowest
levels of the hierarchical organization. Synaptic connectivity of neurons into a single hardwired polysynaptic reflex circuit, which
becomes the basis for all patterns of propulsive motility and any linked secretory behavior, is at an intermediate level, as are
neuronal pattern generators that drive the timing of repetitive activity of the reflex circuit. Near the top level of neural organization
are ‘programs’ for behaviors that emerge from the organization of the different kinds of neurons, their synaptic connections and
their connectivity into microcircuits at the lower levels. A library, which stores a neural program for each of the digestive states
mentioned above, sits at the uppermost level. Functioning of each program in the library of behaviors is reminiscent of mobile
‘apps’ (software applications) that run on modern smart phones, tablet computers and comparable devices.

Level 1: Neurons and Neurotransmission

As mentioned earlier, the brain-in-the-gut functions with chemical synaptic connections between sensory neurons, interneurons
and motor neurons (Fig. 3). Interneurons are synaptically interconnected in neural networks which do the following: 1) process
sensory information on the state of the gut; 2) contain an app library; 3) control the activity of motor neurons that innervate
the musculature, secretory glands and blood vasculature. Musculomotor neurons initiate or inhibit the contractile activity of the
musculature when they fire. Modulation of their firing frequency, by input from interneuronal microcircuitry, determines
minute-to-minute contractile tension. Secretomotor neurons stimulate glandular secretion of chloride, bicarbonate and mucus
when they are active. Secretomotor control of chloride secretion determines the osmolarity and liquidity of the luminal contents.
Neurogenic control of bicarbonate secretion maintains a physiological pH setpoint in the lumen and accounts for some of the
mucosal protection against acid delivery from the stomach. A subset of secretomotor neurons simultaneously innervates both
secretory glands and periglandular arterioles and thereby enhances blood flow in support of stimulation of secretion, when they
are active.
8 Enteric Nervous System: Physiology

Level 2: Polysynaptic Propulsive Motility Circuit

Propulsion of luminal contents is a fundamental function in each of the specialized digestive compartments including the
esophagus, stomach, and small and large intestine. Propulsive motility in the esophagus and the small and large intestine occurs
as a stereotypic two-phase complex based in a polysynaptic reflex circuit that controls the contractile behavior of the longitudinal
and circular muscle coats. The two phases, illustrated in Fig. 8, are labeled as propulsive and receiving segments. The circular muscle
coat of the propulsive segment is in a contractile state that reduces the diameter of the segment and exerts compressive forces on the
contents. The circular muscle coat is in a relaxed state in the receiving segment while contraction of the longitudinal muscle shortens
the segment and expands its circumference. Compressive forces in the propulsive segment forces the luminal contents into the
expanded chamber of the receiving segment in the downstream direction of propulsion. Because the esophagus and intestine
behaves geometrically as a cylinder with a constant surface area, contraction of the circular muscle coat reduces the intestinal
circumference and obligatorily extends the longitudinal axis. Relaxation of contractile tension in the circular muscle coat and
contraction of the longitudinal muscle coat shortens the receiving segment, expands its circumference and thereby prepares it as
a luminal chamber that receives the forwardly traveling contents. Propulsion progresses along a length of bowel or esophagus
when the next downstream reflex circuit is activated to generate another stereotypic propulsive complex of circular and longitudinal
muscle contractile behavior.
Activation of the ‘hardwired’ polysynaptic reflex circuit in level 2 accounts for configuration of the stereotypic complex of muscle
contractile behavior that characterizes all propulsive motility in the cylindrical gut (Fig. 9). The circuit in the esophageal ENS is
activated during a swallow by signals in efferent vagal nerves traveling from the brainstem to the esophageal ENS. It can be triggered
also by mechanical distension of the esophagus by a luminal blockage. In the small and large intestine, the reflex circuit can be
activated by at least two kinds of stimuli. One is luminal distension and activation of intramural mechanoreceptors and the other
is by serotonin released as a paracrine signal from mucosal enterochromaffin cells by shearing forces at the luminal surface of the
intestine. When the circuit is triggered to its on-state, excitatory motor neurons in the longitudinal muscle coat are activated to
configure the receiving segment and inactivation of inhibitory motor neurons to the circular muscle coat takes place in the
propulsive segment.
ENS microcircuits, which include the polysynaptic propulsive reflex (Fig. 8), can be organized for propulsion in the oral or
aboral direction in the same length of small or large intestine. When a segment of large intestine is obstructed, reverse propulsion
moves the luminal contents in the oral direction away from the obstruction. Retro-propulsion then stops and forward propulsion
propels the contents in the direction of the obstruction. During the act of vomiting, powerful retro-propulsion starts in the middle of
the small intestine and rapidly propels the luminal contents in the direction of the opened gastric pylorus. In both cases the
polysynaptic propulsive reflex circuit is polarized in a direction opposite to that of the circuit responsible for propulsion in the
aboral direction. During emesis, ENS function near the top level of neural organization generates linked propulsive and receiving
segments that start in the mid-jejunum and travel in the oral direction. Reverse propulsion does not occur in the human esophagus,
but becomes a significant motility event for regurgitation of indigestible materials (e.g., hair, bone, insect exoskeletons, etc.) in
raptorial birds such as owls and hawks.

Figure 8 A ‘hardwired’ polysynaptic reflex circuit in the ENS underlies intestinal propulsive motility. Two kinds of input activate the circuit. One is
distension of the intestinal wall. The second is stimulation of release of 5-hydroxytryptamine from enterochromaffin cells by mechanical stimulation
of the mucosa. When the reflex circuit is active, excitatory motor neurons to the longitudinal muscle coat and inhibitory motor neurons to the circular
muscle coat are activated to form the receiving segment below the point of stimulation (Fig. 8). At the same time, activation of excitatory motor neurons
to the circular muscle coat and inactivation of inhibitory motor neurons to the circular muscle coat occurs in the propulsive segment above the point of
stimulation.
 Enteric Nervous System: Physiology 9

Figure 9 ENS reflex control of the longitudinal and circular muscle coats configures propulsive and receiving segments that underlie multiple patterns
of intestinal propulsive behavior. (A) The intestinal muscle coats behave in a stereotypical pattern during propulsive motility. A ‘hardwired’ polysynaptic
reflex circuit in the ENS determines the stereotypical pattern of behavior. The longitudinal muscle coat in the segment ahead of the advancing luminal
contents contracts while the circumferential muscle coat relaxes simultaneously. Shortening of the longitudinal intestinal axis and circular muscle relaxation
in the same segment expands the lumen, which becomes a receiving segment for the forward moving contents. A linked component of the polysynaptic
reflex contracts the circular muscle in the segment behind the advancing intraluminal contents. The longitudinal muscle layer in the same segment relaxes
simultaneously with contraction of the circular muscle, which results in conversion of this region to a propulsive segment that propels the luminal contents
ahead into the receiving segment. Activity of inhibitory musculomotor neurons maintains physiological ileus behind the advancing propulsive segment and
prevents excitation of the circular muscle from spreading backward in the smooth muscle, which behaves as a functional electrical syncytium. (B) Motor
behavior of the intestinal wall during the peristaltic reflex in a segment of guinea-pig ileum in response to distension by infusion of saline at time ¼ xs.
Shortening of the longitudinal axis and expansion of the lumen is seen in the receiving segment and contraction of the circular muscle and reduction in the
diameter of the receiving segment is apparent at time ¼ 3xs as propulsion proceeds to empty the lumen through the outlet. Wall behavior was redrawn
from video images gifted to the author by Prof. M. Takaki, Dept. of Physiol., Nara Medical Univ. Nara University, Japan.

Level 3: Central Pattern Generators

Central pattern generators (CPGs) are known as circuits that generate repetitive patterns of motor behavior independent of any
sensory input. They are a property of most independent integrative nervous systems. CPGs are known to underlie fifty or more
rhythmic motor behaviors including walking, chewing, swimming, feeding, flying and respiration in vertebrates and invertebrates.
Rhythmic and cyclical motor and secretory behaviors in the intestinal tract reflect functioning of CPGs at an upper level of
hierarchical ENS organization.
CPGs have three common properties: 1) the motor output patterns consist of rhythmically timed bursts of action potentials that
arise either from an ensemble of neurons, not traceable to any individual neuron in the system, or are generated by endogenous
firing of a single neuron; 2) stereotypic sequences of repetitive behavior (e.g., walking) are evoked by activation of single command
neurons or by exposure of the CPG circuit to a paracrine neuromodulator; 3) motor behavior can be initiated and modified by
sensory feedback, but the stereotyped sequence of motor events continues in the absence of sensory input.
CPGs in the ENS have endogenous neuronal oscillators that determine the timing of recurring firing of ENS musculomotor and
secretomotor neurons. Recurrent timing of firing is evident for a subset of musculomotor neurons in stretched intestinal whole-
mount preparations in vitro. The CPG neurons in the ENS fire bursts of action potentials repeatedly over prolonged periods with
the spike bursts fired precisely at 6-sec intervals or at exact multiples of 6 sec (i.e., 12, 18, or 24 sec) in the cat small intestine
(Fig. 10). Blockade of synaptic transmission does not change the timing of the discharge, as would be expected if the CPGs
were indeed endogenous clocks.
Recurring responses to paracrine release of histamine from enteric mast cells illustrates how a paracrine neuromodulator
influences a CPG in the ENS to generate a rhythmic pattern of glandular secretion linked with motility. Application of exogenous
histamine to simulate degranulation of enteric mast cells, or degranulation of mast cells and release of endogenous histamine in
the intestine of animal models after sensitization to food antigens or intestinal parasites, evokes rhythmic cycles of chloride
secretion with the peak of each cycle linked to a contraction of the circular muscle coat. Secretory cycles occur at about 1/min in
the guinea pig colon (Fig. 11). As each secretory cycle peaks, contraction of the circular muscle coat occurs. Activation of the
CPG in this case is independent of the concentration of the neuromodulator with the exception of a requirement for a threshold
concentration. The integrated neural network at this level of organization behaves like it incorporates a ‘switch’ that activates the
ENS app, which includes the CPG, in an on-off manner.
10 Enteric Nervous System: Physiology

Figure 10 Central pattern generator discharge. Putative central pattern generator in the myenteric plexus of the cat small intestine spontaneously
fires recurrent bursts of action potentials at precisely timed intervals. (A) Bursts of action potentials recorded extracellularly on a slow time base.
(B) Action potentials in a single burst recorded on an expanded time base. (C) Burst interval histogram. This neuron fired with negligible variability
at 6 sec intervals. When a 6 sec interval was missed, discharge resumed at an interval that was a multiple of 6 sec.

Figure 11 Example of a central pattern generator in the ENS, which generates a repetitive pattern of linked secretomotor and musculomotor behavior
in guinea-pig colon. The full thickness preparation of intestinal wall was placed in an Ussing chamber for recording chloride secretion as a surrogate for
glandular secretion of H2O and electrolytes. Contractile activity in the muscularis externa was detected by a small strain gage attached to the serosal
surface.

The paracrine action of histamine to activate an ENS behavioral program that incorporates a CPG is reminiscent of similar
neuromodulatory actions of the hormone, cholecystokinin. Application of cholecystokinin, to mimic enteroendocrine release in
the cat small intestine activates, in an all-or-none manner, an app incorporating a CPG for repetitive cycling of the hardwired
propulsive reflex circuit associated with mixing motility (see Fig. 8). A comparable repetitive patterning of activation of the
hardwired propulsive reflex circuit, at the same hierarchical level of ENS organization, occurs when flat sheet preparations from
guinea pig colon remain tightly stretched for periods of minutes in vitro.

Level 4: Plasticity
Earlier heuristic models for neural somatomotor networks suggested that each pattern of skeletal motor behavior required a different
hardwired circuit. Current concepts suggest that this is not the case. Evidence supports a hypothesis that neural networks can be
polymorphic with the same circuit being capable of generating a variety of different motor behavioral patterns. Circuits of this
nature are viewed as defined anatomical networks consisting of a library of components that can be reconfigured in different
ways to form a variety of different functional outputs to the same effector system. Input of neuromodulatory signals to the network
determines the configuration and thereby the kind of output emanating from the network. Reconfiguration of the output from the
network is determined through the selective release of a neuromodulatory substance that overlays the entire network and acts to
alter the electrical and synaptic behavior of the neural elements in the microcircuits of the network. A neuromodulatory substance
in these cases might alter the input–output relations for a single neuron or for an entire integrated synaptic circuit.
The digestive tract of the spiny lobster was one of the earliest models for neuromodulatory reconfiguration of the output of
a neural network. The stomatogastric ganglion, which controls behavior of the lobster’s foregut, has 14 neurons. All synaptic
connections of each of the 14 neurons with neighboring neurons in the network are known. Output of the network controls for
different patterns of rhythmic movements as digestion progresses in the foregut. Exposure of the 14-neuron circuit to neuromodu-
lators reconfigures it for different motility patterns by changing the strengths of synapses in the network and altering intrinsic
neuronal excitability. An overlay of serotonin evokes a specific pattern of motor behavior and an exposure to dopamine evokes
 Enteric Nervous System: Physiology 11

Figure 12 The enteric nervous system (ENS) can be viewed as a ‘minibrain’ with a library of applications (‘apps’) for multiple patterns of small or
large intestinal behavior. The ENS stores a library of apps for specific patterns of intestinal motor behavior that are adaptive for one or the other of the
intestinal digestive states. In the postprandial state, the ENS ‘runs’ the motor app for mixing movements while other programs are inoperative. At the
completion of digestion and absorption of the nutrients of a meal, the postprandial program is terminated and the system calls up the interdigestive
app, which, when ‘running’, programs for motor behavior described as the migrating motor complex. The specialized motility pattern that occurs in the
upper one-third of the small intestine during emesis reflects output of another of the apps in the library. During emesis, propulsive motility in the upper
one-third of the small intestine is reversed for rapid movement of the luminal contents towards and into the stomach. The emetic app can be called-up
from the library either by commands from the brain or by local sensory detection of threatening substances in the lumen. Still another app, referred to
as power propulsion is ‘called-up’ for defense against infectious invaders, enterotoxins or food allergens, as well as being the app for reverse propulsion
during emesis.

another. Signaling by serotonin and dopamine is mediated by metabotropic neuronal receptors. Comparable neuromodulatory
changes in circuit configuration and output appears to be operational for the library of programs (i.e., apps) that are stored at
the uppermost levels of organization in the mammalian ENS. The ENS networks, which store the apps, are exposed to a variety
of different chemical mediators following their release from sources such as neurons, enteroendocrine cells and immune/
inflammatory cells. As mentioned earlier, the ENS library in the small intestine behaves as if it contains programs or apps for at
least five different patterns of motility namely: 1) interdigestive; 2) postprandial; 3) aboral power propulsion; 4) emetic oral power
propulsion; 5) physiological ileus (Fig. 12).

Interdigestive App
The migrating motor complex (MMC) is the ENS-programmed small intestinal motility pattern of the interdigestive state. It starts
when digestion and absorption is complete and the intestine is empty of nutrients 2–3 h after a meal. Contractile behavior of the
musculature during running of the MMC app is routinely monitored experimentally by sensors attached to the serosal surface of the
stomach or small intestine or by fluoroscopic imagining of contrast material in the lumen. The MMC starts as large-amplitude
propulsive contractions starting in the gastric antrum and propagating in the aboral direction into the duodenum and on through
the small intestine to the ileum.
When the app is ‘running’ the MMC occupies a limited length of intestine called the activity front, which has an upper and
a lower boundary. The activity front slowly advances, and ‘migrates’ down the intestine at a rate that progressively slows as it
approaches the ileum. Propulsion of luminal contents in the aboral direction occurs between the oral and aboral boundaries of
the activity front. The circular muscle contractions seen in the activity front are a reflection of the formation of the propulsive
segment formed by the hard-wired propulsive reflex circuit in the ENS organizational hierarchy. Each propulsive wave that traveling
aborally within the activity front consists of a propulsive and receiving segment, formed by the propulsive reflex circuit. Successive
propulsive waves start at the oral boundary and propagate to the aboral boundary of the activity front and stop. Successive
propulsive complexes start on average a short distance further in the aboral direction and propagate on average slightly beyond
the boundary where the previous one stopped. Thus, the entire activity front slowly migrates down the intestine, ‘sweeping’ the
lumen clean as it moves toward the junction with the colon. Physiological ileus is in effect along the bowel orally and aborally
to the upper and lower boundaries of the migrating activity front. Neither MMCs nor physiological ileus can be found in the small
intestine, in the absence of a functional ENS.

Postprandial App
Intake of a meal immediately halts running of the MMC app and starts the postprandial app, which programs for a mixing pattern of
motor behavior. The mixing movements are rhythmic with the frequency determined by a CPG in the ENS networks. The frequency
12 Enteric Nervous System: Physiology

at which the mixing movements occur is regionally specific, with the fastest frequency localized to the duodenum and progressive
slowing to the lowest frequency in the ileum. Propulsive contractions of the circular muscle, which propagate for only short
distances, account for the segmentation appearance of the mixing pattern in fluoroscopic images. Circular muscle contractions
in short propulsive segments are separated on either side by receiving segments with relaxed circular muscle and contracting
longitudinal muscle, each of which reflect activation of short ‘blocks’ of the ENS hardwired polysynaptic peristaltic reflex circuit.
Each propulsive segment jets the chyme in oral and anal directions into relaxed receiving segments where stirring and mixing occur.
This takes place continuously at closely spaced sites along most of the length of the small intestine in the postprandial digestive
state.

Power Propulsion App

Power propulsion is characterized by strong, long-lasting contractions of the circular muscle that travel over long distances along the
small and large intestine. The contractions, when recorded by force transducers on or in the intestine, reflect formation of the
propulsive segment of the hard-wired ENS propulsive reflex and are sometimes referred to as ‘giant migrating contractions’ because
they are considerably stronger than the phasic contractions of the circular muscle coat that appear in the activity front of the MMC or
in the mixing motility pattern. Giant migrating contractions have long durations in the range of 18–20 sec in dogs. They are
a component of efficient propulsive motility that quickly strips the lumen clean as they travel at speeds approaching 1 cm/sec
over long lengths of the intestine.
Power propulsion apps differ from propulsive motility in the activity front of the MMC and in the short-segmental mixing seen
when the postprandial app is running. The circular contractions in the propulsive segment are much stronger and propagation takes
place over much longer stretches of intestine. Enhanced release of ACh and/or substance P from excitatory musculomotor neurons
accounts for the large amplitude of the circular muscle contractions.

Aboral Power Propulsion App

The aboral power propulsion app rapidly moves the luminal contents of the distal small intestine or the large intestine towards the
anus. Noxious mucosal stimulation is a major trigger for calling-up this app and closing any other app that might be running.
Abdominal cramping pain, and sometimes fecal urgency and acute watery diarrhea, are associated with this motor behavior.
Exposure of the mucosa to irritants, introduction of luminal parasites, enterotoxins from pathogenic bacteria, allergic reactions,
and exposure to ionizing radiation are sufficient triggers for starting the aboral power propulsion app. These characteristics suggest
that this app is a defensive adaptation for rapid clearance of threats from the intestinal lumen. A power propulsion app also
underlies mass movements of intraluminal contents in normal states, especially in the distal ileum and large intestine. A power
propulsion app empties the colon of large quantities of feces during defecation.
The microcircuitry for aboral power propulsion is part of a more extensive defensive lower gut app that is called-up by exposure
to neuromodulators released during degranulation of enteric mast cells and other inflammatory/immune cells. Reconfiguration of
the synaptic networks by an overlay of these neuromodulators integrates stimulation of copious secretion of H2O and electrolytes
with power propulsion in a timed sequence. Secretion is activated initially and flushes threats (e.g., microorganisms, allergens,
noxious substances, etc.) into the lumen and holds them in suspension. Aborally directed power propulsion closely follows the
secretomotor response. Power propulsion rapidly propels the large volume of luminal liquid and suspended contents toward
the anus. Arrival of the large volume in the recto-sigmoid region causes rapid distension, which triggers the ENS recto-anal reflex
circuit to relax the smooth muscle and open the internal anal sphincter. Opening of the internal sphincter, in this situation,
underlies sensations of fecal urgency and emotional anxiety because the only remaining protection against incontinence is
spinally-evoked reflex contraction of the skeletal muscle of the puborectalis and external anal sphincter. Cramping abdominal
pain accompanies the large amplitude propulsive contractions during power propulsion. Symptoms of acute, explosive watery
diarrhea are self-explanatory at this point in the running of the defensive app.
Effects associated with the defense app are reminiscent of the hallmarks of several digestive disorders. Cramping abdominal
pain, fecal urgency and acute watery diarrhea are common symptoms for: 1) postprandial irritable bowel syndrome; 2) enteritis,
both infectious and radiation-induced; 3) ulcerative colitis; 4) Crohn’s disease; 5) microscopic colitis; 6) collagenous colitis; 7)
psychogenic stress.

Emesis App
The specialized motility pattern that occurs in the upper one-third of the small intestine during emesis reflects the ‘running’ of
another of the apps in the ENS library. During emesis, the direction of power propulsion in the upper one-third of the small
intestine is reversed for rapid propulsion of the luminal contents toward and into the stomach. The emetic app is ‘called-up’
from the library by commands either from the brain or by local sensory detection of a threatening agent in the lumen. Like the
aboral power propulsive app in the distal small intestine and in the large intestine, the adaptive significance of the emesis app is
rapid removal of a threat from the lumen of the upper small bowel.

Physiological Ileus App

Ileus is described clinically as mechanical, dynamic or adynamic obstruction of the bowel. Adynamic ileus is pathological
obstruction of the bowel due to failure of the smooth muscle to contract. Dynamic ileus is pathological intestinal obstruction
 Enteric Nervous System: Physiology 13

due to spastic contraction (i.e., failure to relax) of the circular musculature in a segment of bowel. Mechanical obstruction and
adynamic and dynamic ileus are accompanied by severe colicky pain, abdominal distension, vomiting and constipation.
In view of the characteristics of pathological ileus, physiological ileus was coined as a useful term for referencing the non-
pathological absence of motility in the small and large intestine. It is a normal state of the bowel in which the ENS programs
quiescence of motor function. Quiescence reflects ‘running’ of an app in which most of the synaptic connections in the propulsive
reflex circuits are in a closed state while a subset of inhibitory musculomotor neurons are continuously firing. Ongoing release of
inhibitory neurotransmitters at the neuromuscular junctions clamps the musculature in an inactive state. The physiological ileus
app runs for varying periods of time in different intestinal regions depending on factors such as the time after a meal and input
from the sympathetic nervous system during exercise. When the interdigestive app is running in the small intestine, physiological
ileus is ongoing in the regions of the intestine on either side of the upper and lower boundaries of the propagating activity front of
the MMC.

Summary

The ENS, like all other independent integrative nervous systems, whether in vertebrates or invertebrates, is organized in a hierarchy
of structures and functions ranging from the cellular-molecular at lower levels to preprogrammed synaptic networks (‘apps’) at the
uppermost levels. Behavioral properties emerge at the uppermost levels that cannot be predicted by a complete knowledge of a lower
level. A normally functioning ENS is essential for a healthy bowel and freedom from gut-related symptoms. Any neuropathic change
in the ENS will most likely result in an irritable-angry bowel.

Further Reading

Furness, J.B., 2006. The Enteric Nervous System. Blackwell, Oxford.

Gershon, M.D., 1998. The Second Brain. Harper-Collins, New York.
Liu, S., Wood, J.D., 2012. Enteric neurobiology of stress. In: Johnson, L.R., Kaunitz, J.D., Ghishan, F.K., Merchant, J.L., Said, H.M., Wood, J.D. (Eds.), Physiology of the
Gastrointestinal Tract, fifth ed. Elsevier, San Diego, pp. 2001–2018.
Wingate, D., Grundy, D., 2000. Neurogastroenterology and motility: at last, an equal partnership. Neurogastroenterol. Motil. 12, 1.
Wood, J.D., 2008. Enteric nervous system: reflexes, pattern generators and motility. Curr. Opin. Gastroenterol. 24, 149–158.
Wood, J.D., Alpers, D.H., Andrews, P.L., 1999. Fundamentals of neurogastroenterology. Gut 45 (Suppl. 2), II6–II16.
Wood, J.D., 2012a. Cellular neurophysiology of enteric neurons. In: Johnson, L.R., Kaunitz, J.D., Ghishan, F.K., Merchant, J.L., Said, H.M., Wood, J.D. (Eds.), Physiology of the
Gastrointestinal Tract, fifth ed. Elsevier, San Diego, pp. 629–669.
Wood, J.D., 2011. Enteric Nervous System: The Brain-in-the-Gut. Morgan & Claypool Life Sciences, New Jersey, USA.
Wood, J.D., 2012b. Pathophysiology underlying the irritable bowel syndrome. In: Johnson, L.R., Kaunitz, J.D., Ghishan, F.K., Merchant, J.L., Said, H.M., Wood, J.D. (Eds.),
Physiology of the Gastrointestinal Tract, fifth ed. Elsevier, San Diego, pp. 2157–2181.

q
Change History: December 2015. JD Wood updated the article, added a section on ‘neurogastroenterology’, updated the ‘further reading section’, and added
a new Fig. 7.