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Vagus Nerve And The Cholinergic System

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Updated on December 13, 2022
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Vagus Nere & The Cholinergic System

The cranial nerves in the body amount to twelve in which one of which is the cranial nerve. The nerves are in pairs and they serve as a connection between the brain and other parts of the body such as the torso, the neck, and the head; the nerves have both sensory and motor functions they serve. Some of the sensory functions include taste, smell, and sight, while the motor functions they perform depend on the group of muscles they serve (1).

Some of the nerves serve a single function of either sensory or motor while some serve both motor and sensory functions in which one of such is the vagus nerve, the tenth cranial nerve in the body, and the longest cranial nerve running from the brain stem to the colon. It provides both sensory and motor functions to different parts of the body.

The sensory functions of the vagus nerve

These include:

  • It supplies the root of the tongue to provide sensation for taste minimally
  • It supplies the digestive tract to provide sensation to its different organs such as the esophagus, the stomach, and the esophagus, as well as the trachea and larynx.
  • It provides a sensory effect to the posterior part of the ear, particularly the skin, and the exterior of the auditory canal.

The motor functions of the vagus nerve

These include:

  • It stimulates the muscles at the roof of the oral cavity, particularly that of the pharynx, the larynx, and the palate.
  • It helps to reduce the heart rate when it stimulates the muscles of the heart.
  • It enhances motility by involuntarily stimulating the digestive tract (1).

Overview Of The Cholinergic System

The cholinergic system of the central nervous system is made up of nerve cells which are the smallest unit of the central nervous system, that make use of acetylcholine, a neurotransmitter that helps to transduce action potential. The nerve cells involved are made up of acetylcholine, and they also release the neurotransmitter when there is an impulse for its use. The cholinergic system is traced to some cognitive functions which include emotions, memory, and selective attention (2).

Acetylcholine synthesis requires certain components which include: choline, a natural amine located in the double lipid layer of the cell membrane, an enzyme choline acetylcholinesterase which can only be seen in acetylcholinergic cells, a thioester acetyl coenzyme A, which can serve as a donor and an acceptor of the acetyl group. These components all coming together are used in the synthesis of the neurotransmitter acetylcholine (2).

The cholinergic system nerve fibers took their origin from the nucleus ambiguus (NA) located in the brainstem, after which it journeys down the cranial nerve ten, the vagus nerve, and meet at the parasympathetic ganglia usually seen at the wall of the airway. Right from the parasympathetic ganglia, short ganglionic fibers arise (postganglionic fibers), and they travel to the smooth muscles of the airway and the submucosal glands, thereafter releasing acetylcholine that will act on the muscarinic receptors (3).

Vagus And Cholinergic Control Of Metabolism

The vagus nerve is an inevitable intermediary that connects the brain and the nervous system in regulating metabolic processes. The vagus afferent fibers, which are sensory, alongside the cell bodies located at the nodose ganglia pass information to the brain when there is any metabolic alteration going on especially when it has to do with nutrients in the gastrointestinal tract, and the porta hepatic system (4).

The metabolic regulation process involves the communication of the neural synaptic transmission that takes place in a very short time amounting to milliseconds on a timescale, and a longer communication, which is the humoral communication that occurs within minutes. Once the signal is sent out, they decussate at the Nucleus tractus solitarius (NTS) located at the medulla oblongata of the brainstem, which has a direct link both structurally and functionally to the dorsal motor neuron (DMN).

The efferent arm of the vagus nerve, also the motor part of the vagus cholinergic neuron which took its origin from the dorsal motor neuron and the Nucleus ambiguus (NA) will provide the preganglionic nerve innervation to the body organs, and visceral, thereby regulating the important heart, gastrointestinal functions, as well as respiratory functions, and all are mediated via the muscarinic acetylcholine receptors (mAChRs), located on the smooth muscle cells of the heart muscles, cardiac myocytes, and glandular cells (4).

The efferent arm of the nerve, the vagus nerve is also involved in glucose regulation in the liver, otherwise known as hepatic gluconeogenesis, and secretion from the pancreatic gland, both exocrine and endocrine.

For example, the cholinergic signaling of the efferent arm of the vagus nerve is involved in stimulating the release of insulin from the pancreas via the M3 muscarinic acetylcholine receptors mediated pathway. In a study carried out on mice, a group of mice having a deficiency in the pancreatic beta cells in the M3 mAChRs all have insufficient insulin secretion and glucose intolerance.

The dorsal vagal complex which consists of the nucleus tractus solitarius, the dorsal motor neuron, and postrema, alongside neuronal connection with the hypothalamic nucleus and certain areas of the forebrain, all come together to form the complex brain network controlling metabolism (4).

The afferent arm of the vagus nerve is mainly responsible for controlling satiety and regulation of feeding. In a study conducted using rats as specimens, the stimulation of the afferent fibers of the vagus nerve helps in achieving weight loss in the chosen rats specimens as well as maintaining the weight loss. The study gave an eye-opener on how the afferent vagus nerve to the abdomen, when targeted by bio-medical devices can help in the medical management and treatment of obesity (4).

Vagus Nerve And Cholinergic System In Control Of Inflammation

Inflammation is a triggered physiological response of the body to harmful stimuli, which includes the destruction of tissues, pathogenic microorganism invasion, and this mechanism involves the activation of immune cells such as white blood cells and macrophages as well as the release of inflammatory mediators such as cytokines and chemokines. The inflammatory event however resolves once the body returns to its homeostatic state (4).

However, other types of persistent, exacerbating, or chronic inflammation results in secondary tissue damage and have a role in the pathophysiology of many illnesses, including sepsis, IBD, rheumatoid arthritis, and others (4).

As a result, reducing inflammation is crucial for illness prevention as well as a helpful therapeutic approach to disease therapy. Research conducted in the past 20 years has shown that neurological processes controlled by the vagus nerve play a significant role in modulating inflammation in addition to immunological and hormone modulation (4).

IL-1, TNF, and other inflammatory cytokines, as well as other inflammatory chemicals, have been proven in several studies to be able to activate sensory vagus neurons. These peripheral inflammatory changes are sent to the brainstem, which then produces vagus nerve cholinergic anti-inflammatory output as part of a reflex arc (4).

The vagus nerve is very inevitably important in regulating the body's metabolic processes, the efferent arm of the vagus nerve is well known for its cholinergic control of immune system function and proinflammatory responses usually through the inflammatory reflex. Metabolic regularization and alteration of the immune system in obese individuals is usually a result of chronic inflammation, a rate-limiting step in the aetiopathogenesis of insulin resistance and diabetes mellitus, especially type 2.

In the past two years, cholinergic processes within the inflammatory reflex have been linked to the reduction of inflammation and metabolic problems caused by obesity. This information has encouraged the investigation of cutting-edge therapeutic strategies for the management of illnesses linked to obesity (5).

Controlling inflammation necessitates efficient interactions between the immune response and the brain. The inflammation reflex is a centrally brought system that controls proinflammatory cytokine production and inflammation by regulating afferent vagus nerve transmission, which is triggered by cytokines or pathogen-derived products. Excessive innate immune responses and cytokine toxicity occur when this inflammatory reaction is absent as a result of brain lesions or genetically eliminating crucial components (5).

Findings that vagus nerve stimulation reduces local and serum levels of proinflammatory cytokines in rodents with endotoxemia and that acetylcholine prevents the release of TNF, IL-1, and IL-18 from lipopolysaccharide-stimulated macrophages revealed an essential role of efferent vagus nerve cholinergic signaling in brain-to-immune interaction a little more than ten years ago. Due to these discoveries, the cholinergic anti-inflammatory pathway was identified as the arm of the inflammatory reflex dependent on the efferent vagus nerve (5).

The inflammatory reflex was further understood after the reveal of the effective collaboration between the vagus nerve, and the splenic nerve, and the subsequent identification of the choline acetylcholinesterase enzyme as the circuit’s source of acetylcholine (4).

Research has also demonstrated that brain mAChR signaling can activate the inflammatory reflex and its efferent arm, the cholinergic anti-inflammatory system.
In rodent models of endotoxemia, IBD, hemorrhagic shock, lupus, and other diseases, the anti-inflammatory and metabolic benefits of systemically acting mAChR receptors and the AChE inhibitor galantamine have been shown and connected to the inflammatory reflex (1).

Cholinergic Control Of The Airway Through The Vagus Nerve

One of the main components of a sensory system that tracks changes in micronutrient and metabolic chemicals is the vagus nerve afferents that innervate the liver and gastrointestinal tract. These nerve fibers communicate to the brain data about cholecystokinin, leptin, peptide YY, insulin, and glucose that have been recognized by related mechanoreceptors, chemoreceptors, and particular metabolite receptors in the gut and hepatic portal system (5).

The cholinergic nerve fibers originated from the nucleus ambiguus located in the brain stem, and it travels through the vagus nerve the synapse occurs at the parasympathetic ganglia found at the wall of the airways, Small post-ganglionic fibers leave these ganglia and proceed to the submucosal glands and smooth muscle of the airways (3).

Animals undergoing electric impulses of the vagus nerve experience bronchoconstriction and mucus production as a result of the release of Acetylcholinesterase from cholinergic nerve terminals and stimulation of muscarinic cholinergic receptors on smooth muscle and gland cells. A muscarinic receptor antagonist, such as atropine, should be administered beforehand to avoid vagally induced bronchoconstriction (3).

Vagus nerve cholinergic control of the digestive system

Control and integration of vagus nerve-regulated physiological systems, such as metabolic and cardiovascular, gastrointestinal, and respiratory functions, are key functions of the brain (6). The vagus nerve regulates physiological processes such as metabolism and cardiovascular, gastrointestinal, and respiratory function, and these processes are largely controlled and integrated by the brain.

This modulation, which includes the control of hepatic and intestinal inflammation in experimental settings of APAP-induced liver damage, hemorrhagic shock, and colitis, has been demonstrated to be significantly influenced by brain cholinergic mAChR-mediated signaling (6).

Galantamine, a centrally acting AChE inhibitor, together with the central, intracerebroventricular injection of mAChR ligands reduces the inflammatory response of the mucosa in colitis-prone animals.

Because these effects are reversed in mice after vagotomy, splenic nerve transection, or splenectomy and depend on splenic CD11c+ cells and 7nAChR signaling, they are caused by brain-to-spleen neural circuitry in the inflammatory reflex. Central, intracerebroventricular injection significantly reduces the severity of murine colitis by activating the brain-to-spleen neural axis in the inflammatory response (6).

In addition, glucose in the lumen of the digestive tract causes neuronal activation in the vagus nerve afferents, the nucleus tractus solitarius, the arcuate hypothalamic nucleus, and the dorsal motor nucleus, focusing on the role of brain circuitry in the vagus nerve regulation of the gastrointestinal system and pancreatic secretion in addition to its intrinsic effects on the enteric nervous system (5).

The vagus nerve is an inevitable intermediary that connects the brain and the nervous system in regulating metabolic processes. The vagus afferent fibers, which are sensory, alongside the cell bodies located at the nodose ganglia pass information to the brain when there is any metabolic alteration going on especially when it has to do with nutrients in the gastrointestinal tract, and the porta hepatic system (4).

FrequentlyAsked Questions

What is the effect of acetylcholine on the vagus nerve?

The suppression of cytokine synthesis by vagus nerve stimulation depends on these T cells' ability to produce acetylcholine. Thus, T cells are controlled by action potentials that originate in the vagus nerve, which in turn create the neurotransmitter acetylcholine needed to regulate innate immune responses (7).

Does the vagus nerve emit acetylcholine?

Acetylcholine is released by parasympathetic neurons moving through the vagus nerve to act on M2 and M3 muscarinic receptors on the smooth muscle of the airways. Additionally, the nerve terminals have autoinhibitory M2 muscarinic receptors that react to acetylcholine produced and prevent the release of other neurotransmitters (8).

Is acetylcholine sympathetic or parasympathetic?

Acetylcholine is the main neurotransmitter used by the parasympathetic nervous system (9).

References

  1. https://www.healthline.com/human-body-maps/vagus-nerve
  2. https://link.springer.com/referenceworkentry/10.1007/978-0-387-79948-3_1113
  3. https://www.sciencedirect.com/topics/medicine-and-dentistry/cholinergic-nerve
  4. https://www.frontiersin.org/articles/10.3389/fnins.2019.00263/full#:~:text=Efferent%20(motor)%20vagus%20nerve%20cholinergic,muscle%20cells%2C%20and%20glandular%20cells
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082307/
  6. https://journals.physiology.org/doi/full/10.1152/ajpgi.00195.2018#:~:text=dysfunction%20and%20inflammation.-,VAGUS%20NERVE%20CHOLINERGIC%20CONTROL%20OF%20GASTROINTESTINAL%20IMMUNE%20RESPONSES%20AND%20INFLAMMATION,8%2C%2058%2C%2065).
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548937/
  8. https://www.sciencedirect.com/topics/medicine-and-dentistry/parasympathetic-nerve
  9. https://www.britannica.com/science/acetylcholine
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