Enteric Nervous System

What is the enteric nervous system?

• The ENS is a network of neurons located in the wall of the gastrointestinal tract, making it the largest part of the autonomic nervous system.

  • Consists of more neuron cell bodies than the spinal cord

  • Includes axons and terminals of visceral sensory neurons, sympathetic neurons and parasympathetic neurons that innervate the GI tract

  • Innervates all layers of GI tract including smooth muscle, mucosal epithelium and endocrine cells

What is the basic structure of the ENS and wall of the GI tract?

Longitudinal Muscle:

• The outer layer of muscle that runs along the length of the GI tract, facilitating the shortening of segments for peristalsis.

Myenteric Plexus:

• Located between the circular and longitudinal muscle layers.

• Primarily facilitates gastrointestinal motility by regulating the contraction and relaxation of smooth muscle layers.

• The main neural supply for the gut

• Has much larger ganglia (100-200 neurons)

Circular Muscle:

• Forms the inner layer of muscle in the gastrointestinal wall, responsible for segmental contractions to mix and propel contents.

Submucous Plexus:

• Located in the submucosa, primarily regulating digestive secretions and blood flow within the GI tract.

• Smaller ganglia

Submucous Artery:

• Supplies blood to the submucosal area, helping to nourish the plexuses (including the submucous plexus) and maintain intestinal health.

Mucosa:

• The innermost layer of the GI tract, composed of epithelial cells and connective tissue, responsible for nutrient absorption and secretion.

What is a plexus in terms of the ENS?

• A network or braid of nerve fibers, often involving complicated interconnections between nerve cells.

• In the enteric nervous system, plexuses such as the myenteric and submucous plexuses coordinate various functions such as motility, secretions, and local reflexes in the GI tract.

• Plexuses allow for localized control and modulation of gastrointestinal functions independent of the central nervous system.

  • The primary plexus consists of interganglionic connective nerve trunks that run between myenteric ganglia.

  • The secondary plexus is the nerve trunks that run into circular muscles.

  • The tertiary plexus supply the longitudinal muscles.

• Submucosal plexus present in stomach, but not ganglionated.

  • Ganglionated submucosal plexus begins at pylorus

• Ganglionated myenteric plexus begins at upper oesophageal sphincter

• Several non-ganglionated plexuses

  • Innervate muscle, mucosa, blood vessels

What are ganglia in terms of the ENS?

• Clusters of neuronal cell bodies located outside the central nervous system.

• Function as relay stations for transmitting nerve signals and integrating information from different parts of the nervous system.

• In the context of the enteric nervous system, ganglia are associated with both sensory and motor functions throughout the gastrointestinal tract.

  • Not all plexuses are ganglionated, some are just nerve trunks that innervate different layers of the GI tract wall.

  • Myenteric ganglia are typically larger than submucosal ganglia.

Describe an example of an enteric neural circuit

Example of peristaltic circuit:

• The intrinsic sensory neurons sense the presence of a stimulus in the gut lumen and communicate with interneurons going in both directions along the gut

• The inhibitory motor neurons cause a relaxation of the gut muscle (anal to the site of stimulation)

• The excitatory motor neurons cause a contraction on the oral side of stimulation

There is no distinct location in the gut that is responsible for one neural circuit, these circuits are mixed throughout the gut and the overall gut function is determined by these circuits

What are the four steps of intestinal motility?

• Segmentation: Mixing through local constrictions alternating with relaxations.

• Peristalsis: Propulsion involving strong contractions that move contents towards the anus, preceded by a relaxation phase.

• Retropulsion: Similar to peristalsis but moves content in the oral direction, predominantly in the duodenum and proximal colon.

• Receptive Relaxation: Relaxation of smooth muscle to prepare for content arrival, significant in the stomach and intestines.

What is the migrating motor complex and what are the three phases?

Migrating Motor Complex (MMC): Occurs 4-6 hours post-meal, involved in clearing debris from the small intestine.

• Still uses the same neurons, muscles and pathways but the pattern of activity is different

• MMC clears debris and bacteria from small intestinal lumen

• Repeats every 90 – 120 min

• Abolished by feeding

• At least 3 phases that appear to propagate from either gastric antrum or the proximal duodenum to the ileo-caecal junction

  • Phase 1: Quiescence for about an hour.

  • Phase 2: Irregular contractions build.

  • Phase 3: Strong, rhythmic contractions lasting 10-15 minutes.

What is the role of interneurons in the ENS?

Ascending and descending interneurons facilitate coordinated contraction and inhibition pathways, enabling effective motility control (these are immunoreactive to different compounds) throughout the enteric nervous system, interconnecting sensory and motor neurons.

Describe the basic neural circuit that controls intestinal motility?

The basic neural circuit controlling intestinal motility consists of sensory neurons detecting luminal changes, interneurons processing this information, and motor neurons that modulate smooth muscle contraction for effective motility. This circuitry enables coordinated peristaltic and segmental movements.

The basic neural circuit involved in the law of intestine is initiated by activation of intrinsic sensory neurons (ISNs) at one site.

• Activation of ISNs can stimulate local interneurons and motor neurons whose projections are polarised.

• Excitatory motor neurons project orally to mediate contractions above the stimulation. Inhibitory motor neurons project anally to mediate relaxations below the stimulation. Motor neurons alone do not allow for propagation of the motor patterns.

• Interneurons extend the range of this polarisation by contacting other interneurons. Ascending interneurons project orally. At least three classes of descending interneurons have been identified and they all project anally. Some descending interneurons are connected to ascending interneurons and excitatory motor neurons and this allows anally directed constriction to follow relaxation, hence allowing propagation of motor patterns.

What are the main factors altering gut function?

Gut function depends on the luminal content

• The ongoing motor activity in any region of the gut moves the content around and responds to it to change the motor activity

Key factors altering gut behaviour:

• Chemical Composition: High nutrients favour segmentation over propulsion, as they go slower to take up more nutrients

• Volume: Large volumes trigger propulsive contractile patterns and receptive relaxation ahead of that activity, increasing speed but reducing segmentation thus the uptake of nutrients

• Mechanical Properties: Viscosity and texture influence movement speeds; rapid for low viscosity, slow and stimulating for high viscosity. low viscosity content impacts mucosal movement and stimulation.

There must be chemoreceptive ISNs and mechanoreceptive ISNs

How does the enteric system change activity when intrinsic sensory neuron terminals do not penetrate the mucosal epithelium

The ability to sense the state of the gut environment is important for the ENS to coordinate gut function. Intrinsic sensory neurons must have chemosensitive and mechanosensitive properties

• Enterochromaffin Cells:

  • These are the key to sensing luminal content changes despite terminal ISN not penetrating mucosal epithelium.

  • Produces Serotonin (5-HT); 90% of body’s serotonin is synthesized in these cells.

What are the main functions of the enteric nervous system?

• Controls movement of intestinal content

• Regulation of water and electrolyte transport across the mucosa:

  • Movement of water and salt into the body from intestinal lumen – absorption

  • Movement of water and salt from body into lumen – secretion

  • Whole body homeostasis

• Contributes to control of acid secretion in stomach, mucus secretion along length and bicarbonate secretion in duodenum

What are two extrinsic primary afferents that supply the gastrointestinal tract?

Extrinsic primary afferents that supply the GI tract includes:

• Vagal primary afferents with cell bodies located in the nodose ganglia

• Dorsal root afferents that run in splanchnic and pelvic nerves (often thought to be nociceptive)

These afferents have distinct terminations in central processing centres because their functions are different and lead to different overall outcomes for their activity

What makes up the extrinsic nerve supply of the ENS and what is the role of each?

• Sympathetic Nerves: Modulate ENS function throughout the whole GI tract.

  •  but have little direct effect on the muscle or mucosa

• Parasympathetic Nerves: innervate upper and lower parts of the GI tract, affecting motility and secretion.

  • Come either by the vagus nerve (to innervate the oesophagus, stomach and duodenum) or the via the pelvic nerves (to innervate the colon, rectum and anus)

• Extrinsic sensory neurons: Supply sensory neurons, with 90% being vagal afferents, playing crucial roles in reflex actions and sensory feedback.

  • Innervate the whole length of the GI tract

What do we know about Neuromuscular Contractions?

• In vitro studies show contractions are not solely brain-dependent; can occur even when the nervous system is chemically inhibited.

• Contractions only seen if there are nutrients in the lumen

• Contractions blocked by antagonists of nicotinic or muscarinic acetylcholine receptors

  • Both receptors are required for normal functioning of the system

• Contractions abolished by tetrodotoxin, which blocks nerve action potentials, but not those of smooth muscle

• Contractions of intestinal smooth muscle do not depend on the brain or spinal cord

• Contractions can be confined to a local region or sequentially cover long segments

• Some contractions apparently move along the segment – propagate

• Jejunum contains entire circuit for generation of a complex behaviour

  • Circuit involves two types of cholinergic neurons

What intrinsic sensory neurons in the ENS?

• Intrinsic Sensory Neurons: Responsible for detecting physical distension and chemical signals in the lumen.

  • Sensitive to distension

  • Sensitive to mucosal deformation

  • Sensitive to luminal nutrients

What are motor neurons in the ENS?

• Motor Neurons: Can be excitatory (project orally) or inhibitory (project anally) affecting smooth muscle activity.

  • To circular muscle

  • To longitudinal muscle

What are interneurons in the ENS?

• Interneurons: Connect excitatory and inhibitory motor neurons, playing a role in coordinating muscle contractions.

  • Running orally, ascending

  • Running anally, descending

What are secretomotor neurons in the ENS?

• Secretomotor neurons: regulate the secretion of digestive enzymes and fluids in the gastrointestinal tract, stimulating glands to produce necessary substances for digestion

What are vasodilator neurons in the ENS?

• Vasodilator neurons: modulate blood flow within the GI tract by inducing vasodilation

What are Intestinofugal neurons in the ENS?

• Intestinofugal neurons: send signals from the intestine back to the central nervous system, facilitating reflexes and feedback mechanisms that help regulate gastrointestinal motility and secretion based on the state of the gut

What are interplexus interneurons in the ENS?

• Interplexus interneurons: provide connections and communication between different plexuses within the enteric nervous system, integrating information and coordinating responses for smooth muscle control and secretion in the GI tract.

What is the law of the intestine?

A law that explain propulsion via peristalsis

• Physiological stimulus-induced contractions in the intestine occur with ascending excitation above and descending inhibition below the stimulus point.

  • A “physiological” stimulus applied to the intestinal wall will cause a contraction above the stimulus and a relaxation below.

    • Ascending excitation and descending inhibition

  • If a neuron sends an axon orally, then it is likely to be in an excitatory pathway, if its axon has terminals in the muscle then it may be an excitatory motor neuron

  • If a neuron sends an axon anally (aborally), then it is likely to be in an inhibitory pathway and if it has terminals in the muscle it may be an inhibitory motor neuron

• This principle helps identify specific neuronal types and their behavioural contributions in GI motility.

What are the main neurotransmitters in the ENS and how can these be blocked?

• Acetylcholine (ACh) and Substance P (SP) are key excitatory neurotransmitters.

• Nitric oxide (NO) plays a crucial role in mediating inhibition in smooth muscle cells.

The addition of tetrodotoxin, which blocks nerve action potentials, abolishes the contractile activities, therefore intestinal contractions must be neurally mediated. Nicotinic and muscarinic receptor antagonists also block the contractions. From this, we can deduce that there are cholinergic neurons that contact neurons with nicotinic receptors and cholinergic motor neurons that activate muscarinic receptors found on smooth muscles.

What is immunohistochemistry and what is its purpose?

Immunohistochemistry is a technique that can label for specific neurochemical markers in the ENS, allowing us to differentiate between different neurochemical subtypes that correlate with certain functional enteric neuronal classes. Each ganglion may contain more than twenty different neuronal subtypes which are intermingled. Some markers also label varicosities on nerve fibre trunks that run into the circular muscles and these may be motor neurons