Enteric Nervous System Flashcards
GIT dual roles
-play a role in digestion and defense
>supplies the energy, nutrients, vitamins, fluids, electrolytes for survival
>protect against hostile micro-organisms, toxins, environmental contaminants
Stresses faced by gut
-digestive processes (acids, enzymes, bile acids, food antigens)
-mechanical stretch and strain
Phases of digestion
-cephalic-anticipation of eating
-oral
-gastric
-intestinal
-colonic
CNS vs. ENS
-ENS and CNS are separate
-If CNS cut, ENS will still have some function
Enteric Nervous System
-brain of the gut (collection of neurons)
-control function of muscle layers and sphincters over long distances (esophagus to anus)
-coordinated by inputs from endocrine or paracrine hormones (ex. stressed) which than can pass information on to CNS
Microbiome
-microbiota communicates with gut, which is then passed on to the brain
Two layers of nerve cell bodies in ENS
1.submucosal plexus (Meissner’s plexus)
2.Myenteric plexus (Auerbach’s plexus)
ENS sensory fibers
-extend to enteroendocrine cells lining the lumen of the gut and within the lamina propria, submucosa and muscle layers
Structure of ENS
-system of ganglia (cell bodies) within the gut wall that directly controls the GI system
second brain or mini brain
Cephalic phase of digestion
-anticipation of food (salivation etc.)
-initiated by CNS which interacts with ENS
**this bidirectional communication between CNS and ENS is essential (gut-brain axis) to control intestinal homeostasis
Myenteric plexus
-lies between the longitudinal and circular muscle layers
Submucosal plexus
-found within the connective tissues of the submucosa
>mammals have an inner and outer layer of ganglia
Esophagus and stomach neurons
-mostly found in myenteric plexus
Role of myenteric plexus
-control GI motility by regulating contractility in the longitudinal and circular muscles
-also integrates stimuli into the afferents with the sympathetic (splanchnic) and parasympathetic (vagal) pathways
Role of submucosal plexus
-controls secretory functions, absorption and blood flow
-also assists in longitudinal and circular muscle control
-integrates stimuli into the afferents with the sympathetic (splanchnic) and parasympathetic (vagal) pathways
Signal processing in ENS
1.Intrinsic sensory neurons (IPANS)
2.basic sensory neuron synapsing onto excitatory or inhibitory neuron
3.interneurons
Intrinsic sensory neurons (IPANS, intrinsic primary afferent neurons)
-have chemosensory and mechanosensory properties
-located in both submucosal and myenteric plexus
>only submucosal are sensitive to mechanical stimulation
-can also function as interneurons
Interneurons
-various subtypes, regional differences
-primary transmitter is acetylcholine. Others: 5-HT/serotonin, ATP, tachykinin, nitric oxide, somatostatins
Reflex neuron control components
1.IPANs that project into mucosa and activated by epithelial sensor
2. motor, vasomotor and/or secretory neurons
3.interneurons
Epithelial sensor
-enterochromaffin cells (enteroendocrine cell type) that release 5-HT in response to mechanical or chemical stimuli
>activated by mechanical movement of feces/food moving through GI. Also sensitive to chemo, pathogens, laxatives
ENS reflex
-reflex starts with sensory enterochromaffin cells detecting mechanical or chemical stimuli which results in them releasing 5-HT (serotonin) which binds to 5-HTp1 receptor of the afferent neurons (IPANS)
-Afferent neurons (IPANS) stimulate the interneurons or ganglia of the plexuses/mini brain
-Plexuses takes information and stimulates the correct efferent neurons
-Efferent neurons activated to get secretion, motility, and vasodilation. They do this by releasing acetylcholine and VIP onto effector cells of Cajal, smooth muscle of vessel, epithelial cells
***when initial enterochromaffin cell response is very large, interneurons will also stimulate extrinsic primary afferent pain/sensory pathways in vagal and CNS to cause vomiting
What does IPAN activate?
-IPAN activates either:
1.ascending interneurons that synapse with excitatory motor neurons (NT:acetylcholine) resulting on contraction if orally
2.descending interneurons resulting in excitation of inhibitory motors (NT: NO and purine nucleotides) and therefore relaxation
-This allows for pressure gradient that propels bolus anally
Enteric circuit activation of peristalic reflex
-intrinsic sensory nerons synapse with:
1.ascending interneurons and excitatory motor neurons=contraction cranially
2.descending interneurons and inhibitory motor neurons= relaxation caudally/aborally
Acetylcholine
-Increases motility and secretion
-released by neurons, bind to muscarinic or nicotinic
NO and purine transmitters
-used on inhibitory neurons
Serotonin (5-HT)
-increases motility and secretion, and pain and vomiting
-released by enterochromaffin cells and neurons
NE or Epi
-released by sympathetic neurons in the two plexuses and the adrenals
-targets enterochromaffin cells and neurons
-high levels decrease motility secretion whereas low levels increase motility
ENS and mucosal environment
-intestinal epithelium, immune cells and soluble neuroactive signals transfer stimuli from the intestinal microbiota to the ENS
3 options that signals passed from intestinal environment to the ENS:
- enteroendocrine cells detect luminal chemical changes and contact neurons with a synapse
- enteroendocrine cells take up metabolic stimuli and convert to hormones or neuroactive molecules which activate serotonin pathway
3.enteroendocrine cells release soluble hormones and neuroactive peptides that diffuse into enteric vascular system and act on CNS
Enteric glia
-distributed throughout GIT
-synaptic and non-synaptic specialization of cell membranes allows responses to neuronal activity (bidirectional communication)
-influence secretion, motility, barrier function
-involved in immune-related signaling molecules
Interstitial cells
-includes cells of Cajal and platelet growth factor receptor (PDGFR)alpha cells
-form gap junctions with smooth muscle cells which is important in the regulation of motility
Muscalaris macrophages
-most abundant immune cells in GIT
-can influence contractility
-modulate anti-inflammatory effects of vagal stimulation
Parasympathetic
-vagal and sacral nerves
-increase ENS reflex activity (motility/secretion/blood)
-innervates myenteric submucosal neurons/plexus (but not on muscles and epithelial cells themselves)
-more innervation in proximal (esophagus and stomach) than in distal (colon and anorectum)…less in proximal colon and Small intestine
Sympathetic
-splanchnic nerves
-adrenergic receptors
-fight or flight decreases GI activity (motility, secretion, blood flow) and fluid secretion caused by infectious pathogens such as cholera toxin
-innervates myenteric plexus and submucosal plexus
Ileal Brake
-Presence of glucose, proteins, and lipids in the ileum activates the distal to proximal feedback ileal brake
-The brake reduces gastric activation and prolongs small intestinal transit time
What mediates the ileal brake?
-mediated through neural (vagus nerve) and endocrine and paracrine mediators (GLP-1 and PYY) produced in L cells of the ileum and colon
»GLP-1 receptors have been found on ileal neurons
-also influenced by fibre intake
-can be disrupted by ileal or colon surgery
Control of mucosal growth and proliferation
-intestinal epithelial cells turn over every 2-4 days
-vagotomy alters gastric mucosa morphology
-serotonin is potential mediator
>Greater mucosal proliferation occurs when serotonin reuptake transporter is lacking
Control of secretion
-Duodenal submucosa glands (Brunner’s glands)-secrete bicarbonate secretion
>regulated by neurons in submucosa of inner submucosal plexus (NT: acetylcholine or VIP)
-Acid secretion is stomach controlled by vagal cholinergic and enteric neuronal pathways
Control of Barrier
-monolayer of polarized epithelial cells that form a continuous interface along the gut but it is not completely impermeable
>some antigen leakage occurs for immune education
>inhibits passage of luminal toxins, antigens, and pathogens
Tight junctions of protective barrier
-regulate paracellular transport using proteins located between epithelial cells
>occludin, claudin, junctional adhesion molecules and tricellulin
>ZO-1 is scaffolding protein
Neural control of protective barrier
-Enteric nervous system (cholinergic and adrenergic)
>impacted by VIP (which increases ZO-1) and potentially stress
IPAN and colitis
-chemical of mechanical stimulation increases serotonin, which activates IPAN
-IPAN activates secretory reflexes in the mucosal plexus
**colitis is linked to increased serotonin availability (which alters secretory activity)
Innervation of mucosa
-most digestive and defensive functions of the GIT occur in mucosa which is innervated by a dense network of nerve fibers derived from the submucosal and myenteric plexus AND extrinsic spinal and vagal primary afferent nerves and sympathetic postganglionic nerve fibers
Enteric nerves of GI mucosa
-they do not penetrate epithelial lining of GI tract
-enteric nerves and glia cells rely on signals from luminal sensors (specialized cells responding to chemical or mechanical stimuli)
Luminal sensors
- specialized cells responding to chemical or mechanical stimuli
>these cells are mostly enteroendocrine cells including enterochromaffin cells which secrete 5-HT and synapse with nerves and glia
-mechanoreceptors also present that express Piezo2 ion channel
Serotonin signaling
-Transmitter of CNS
-majority of serotonin from enterochromaffin cells in GIT that is released in response to chemical and mechanical stimuli
>Serotonin derived from tryptophan via TPH1 (rate limiting enzyme)
»short chain fatty acids can alter TPH1 expression and activity
Termination of serotonin signal
-needs serotonin reuptake transporter (SERT) which removes 5-HT from interstitial space
-then degraded by MAO-A
Indirect and direct serotonin mediation
1.gut microbiota can directly affect enterochromaffin cell to increase TPH1 expression
2. gut microbiota can indirectly effect through microbial metabolites
3.Short chain fatty acids stimulate serotonin synthesis and therefore release and motility
4. Tryptophan metabolism can be affected by microbes
5.Tryptamine is a ligand for the 5-HT4 receptor
6. secondary bile acids are formed from primary bile acids by gut microbiota
Microbiota impact on GIT
-microbiota can shape the phenotype of enteric neurons
-mostly through their impact on serotonin
Serotonin receptors
-many different serotonin receptors that all have different functions
-many different drugs/therapeutics that can target either the synthesis (through TPH1) or the breakdown (SERT) of serotonin and receptor functions
