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Light micrograph of human brain tissue showing neurons and glial cells. Dr_Microbe/Getty Images
  • Glial cells modulate the communication between neurons in the brain and play an active role in specific brain circuits.
  • These cells perform a similar role in the enteric nervous system, which regulates how food travels through the gut.
  • Until now, scientists did not know whether these glial cells belonged to specific circuits in the enteric nervous system of the gut or whether they played a more general role.
  • A new study reports that glial cells do belong to specific circuits, interacting with particular neurons to produce a defined functional outcome.
  • The results may ultimately lead to the development of treatments for conditions that affect the gut, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).

The nervous system consists of two primary cell types: neurons and glia. Neurons transmit messages using electrical or chemical signals. Historically, scientists considered glial cells to play only a supportive and protective role.

However, recent evidence suggests that glial cells can communicate directly with neurons and can actively influence or modulate the transmission of signals between neurons.

Studies have shown that glial cells play a specific role in brain circuits, interacting with certain types of neurons to modulate the transmission of specific information.

Dr. Brian Gulbransen, lead author of the recent study and a professor at Michigan State University in East Lansing, explains the role of glial cells using the analogy of notes produced by an electric guitar.

He says, “[G]lia aren’t carrying the notes played on an electric guitar; they’re the pedals and amplifiers modulating the tone and volume of those notes.”

The digestive system has its own local nervous system known as the enteric nervous system. The enteric nervous system contains at least as many neurons as the spinal cord, which is why scientists sometimes call it the “second brain.”

Notably, the enteric nervous system can still control gut motility even when the nerve connections with the brain and spinal cord are severed.

Scientists know that glial cells in the enteric nervous system actively communicate with neurons and impact gut function.

However, they did not know whether enteric glial cells were a part of a specific network. In other words, they did not know whether glial cells in the enteric nervous system exclusively communicated with specific neurons to modulate the response to specific stimuli or generate specific outputs.

A new study that appears in the journal Proceedings of the National Academy of Sciences shows that glial cells in the enteric nervous system indeed belong to specific networks.

Describing the study results, Dr. Gulbransen said, “The main finding of this study is that there are distinct subsets of enteric glia that ‘listen’ to specific neural pathways and that these subsets of glia play specialized roles in modifying those, and the surrounding pathways.”

He explained that this is interesting “because it highlights a new mechanism whereby neural circuits in the gut are ‘tuned’ by enteric glia. […] This finding highlights a new layer of complexity in how enteric neurocircuits work, and this is important in understanding how gut motility is controlled.”

Understanding gut motility is of importance, because changes in motility play a part in a number of conditions, including gastroesophageal reflux disorder, IBD, and IBS.

Food is propelled through the digestive system by a process called peristalsis, which involves involuntary rhythmic contractions of the smooth muscle wall of the digestive tract.

During peristalsis, the gut segment directly above the lump of swallowed food contracts. At the same time, muscles in the segment below the food relax. This forces food through the digestive tract.

Peristalsis is controlled by three enteric nervous system pathways: the ascending, descending, and circumferential pathways.

As food passes through, the circular muscles in the gut stretch, which activates these pathways. The ascending pathway causes contraction of the segment above the food, and the descending pathway causes relaxation of the gut segment below the food.

The ascending pathway consists of excitatory neurons that mostly release the neurotransmitter acetylcholine. Neurons in the descending pathway generally release nitric oxide or purines to communicate with other neurons.

The circumferential pathway consists of neurons that encircle the wall of the digestive tract and relays changes in the smooth muscle wall to neurons in the ascending and descending pathways.

In the recent study, the researchers used tissue dissected from the gastrointestinal (GI) tract of male and female mice to understand how the cells of the enteric nervous system work together in a network.

The researchers first determined whether some glial cells selectively responded to the activation of the three major enteric nervous system pathways.

They individually stimulated the ascending, descending, and circumferential pathways and measured the activation of glia in response to the stimulation of each pathway.

The researchers found that a majority of glia responded upon the activation of all three pathways. Significantly, over 10% of glia selectively responded to the stimulation of only the ascending (13%) or descending (12%) pathway.

These results show that subpopulations of glial cells exclusively belong to either the ascending or descending pathway.

The study authors observed similar results with the response of neurons to the stimulation of the ascending and descending pathways.

Interestingly, they also found that the magnitude of glial cell responses in the ascending and descending pathways of female mice was greater than it was in male mice.

Purines are one of the neurotransmitters that neurons use in the descending pathway to communicate with each other. In contrast, acetylcholine is mostly released by neurons to communicate with other neurons in the excitatory ascending pathway.

To investigate whether these neurotransmitters produce a specific response in glial cells, the researchers used inhibitors for acetylcholine and purine receptors. These inhibitors selectively blocked the action of neurotransmitters on glia but did not impact signaling between neurons.

The researchers found that stimulation of the descending or ascending pathway in the presence of either one of the neurotransmitter inhibitors activated a distinct population of neurons and glia, compared with the untreated control group.

For instance, the glial purine receptor blocker increased the proportion of neurons solely activated upon stimulation of the descending pathway while reducing the proportion of neurons activated by both pathways.

Similarly, the acetylcholine receptor blocker increased the proportion of glia that were activated upon stimulation of both the descending and ascending pathways.

Blocking the action of these neurotransmitters on glial cells also influenced the activity in each pathway. The purine receptor blocker reduced the activation of the ascending pathway but not the descending pathway. By contrast, the acetylcholine receptor blocker increased neuronal response in the descending pathway but not in the ascending pathway.

These experiments show that glial cells respond to purines and acetylcholine released by neurons, resulting in a change in the population of neurons and glia associated with each pathway, subsequently modulating the activity of each pathway.

The study authors then investigated the role of glial cells in regulating specific motor pathways using chemogenetics.

Chemogenetics is a technique that allows for the selective activation or inhibition of a specific subset of cells, such as glial cells, by using an engineered protein synthesized in the laboratory.

The researchers used this approach to selectively activate the glial cells. The activation inhibited both ascending and descending pathways, showing that glial cells could influence downstream neurons.

Moreover, the stimulation of glial cells reduced the response of neurons in both the descending and ascending pathways in female mice and only in the descending pathway in male mice.

The results from the previous experiment using the glial receptor blockers alone and the use of these blockers in combination with the chemogenetic approach helped the researchers elucidate how neurotransmitters activated glial cells to modulate the response of neurons in the ascending and descending pathways.

These experiments showed that the activation of glial cells by acetylcholine played an important role in inhibiting the descending pathway. However, glial cells activated by acetylcholine also seemed to inhibit the ascending pathway to a certain extent.

Moreover, purine neurotransmitter-induced activation of glial cells stimulated the ascending excitatory pathway.

In sum, the results of these experiments showed that the release of purines and acetylcholine activate glial cells to result in the recruitment of neurons to either the ascending or descending pathway, leading to specific changes in gut motility.

Dr. Keith Sharkey, a professor at the University of Calgary in Canada, explained to Medical News Today how these results show that “the neural networks of the enteric nervous system that control all gut function are very finely regulated in a directional and sex-specific manner by enteric glial cells.”

Dr. Sharkey was not involved in the study.

MNT spoke with Dr. Nick Spencer, a professor at Flinders University in Australia, who was not involved in the study.

He said the study shows that “enteric glial cells actually interact with certain types of enteric neurons in a highly specific and network-specific manner. Until now, it had remained mysterious whether enteric glia communicate in any ordered pattern with the known, highly polarized ascending excitatory and descending inhibitory enteric neural pathways in the gut wall.”

“These findings open the way for a new level of scientific enquiry in glial cell neurobiology in the [GI] tract.”

– Dr. Nick Spencer

Dr. Sharkey noted that the findings of the study “allow for a completely new understanding of gut dysmotility, which are common and highly debilitating disorders of gut function, such as [IBS], to be reframed as diseases of neural network connections — that is, conditions in which network-level [perturbations] drive disease and the symptoms experienced by patients.”

“These findings will therefore allow for the development of better diagnostics and treatment, as well as novel therapies, etc. This work will allow for more personalized approaches to treatment as well — as opposed to the one-size-fits-all model that is common in much of medicine.”

“Moreover, by showing that the glial control is sex-specific, these authors help us understand why so many [GI] diseases occur in a sex-specific manner. And beyond these more practical implications, the work also has a lot of biological and physiological implications for understanding neural control mechanisms,” Dr. Sharkey continued.

Describing future research directions, Dr. Gulbransen noted: “We have ongoing studies that are addressing how glia and enteric motor neurocircuits are affected following inflammation. This is important, since neuroplasticity following acute inflammation is thought to produce [GI] dysmotility in common diseases, such as [IBS] and [IBD].”

“The hope is that by understanding how the glial control over motor neurocircuits is changed during inflammation, we will identify ways in which this mechanism can be harnessed to improve gut motility.”