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January/February 2024
Research: Promising Research May Spur New Treatments for Dysphagia A University of Virginia study has uncovered the “genetic fingerprint” of nerve cells controlling swallowing. Aging is associated with a number of health conditions affecting various parts of the body. Among those common conditions of older age, dysphagia—difficulty swallowing—is said to affect from 10% to 33% of older adults. Dysphagia occurs when there’s a problem with the neural control or structural process of swallowing and can turn the simple enjoyment of a meal into a stressful situation with every bite. Over time, dysphagia can lead to malnutrition, dehydration, pneumonia, choking, and more. While this condition hasn’t been well understood, there’s a growing body of research beginning to shed light on its mechanisms. Recently, a study published in the journal Cell Reports has identified the unique genetic fingerprint of the nerve cells governing the motor function of the esophagus. The study, led by a team of scientists from the University of Virginia’s (UVA) College and Graduate School of Arts & Sciences and UVA’s School of Medicine, has found there’s a genetically defined circuit for motor control of the esophagus. This opens the door for a new treatment approach to esophageal motility disorders. According to lead author Tatiana Coverdell, a clinical chemistry fellow at the National Institutes of Health in Bethesda, Maryland, the research began as an attempt to identify the neural pathways from the brain that control heart rate. The complexity of the neural pathways connecting the brain to various organs is still not well understood. In looking at the neural pathway to the heart, Coverdell says, they discovered a particular neuron subtype that controls axons that lead to the esophagus. When activated, this neuron causes esophageal contractions. Previously, Coverdell says, many studies focusing on the neural component of dysphagia have looked more broadly at entire nerves, such as the vagus nerve, or at brain regions such as the nucleus ambiguus, rather than identify specific subtypes of neurons within these regions. “While this has been very advantageous in understanding dysphagia, treatment options are still limited due to lack of more targeted therapeutics for disorders of swallowing,” Coverdell explains. A key treatment option for dysphagia involves vagal nerve stimulation. However, because the vagus nerve pathway controls a wide range of functions (including cardiorespiratory and digestive functions), this therapeutic approach can be accompanied by undesired side effects. “The vagus nerve is a superhighway of information between all of your visceral organs and your brain, and these motor neuron axons are found within that,” says coauthor John Campbell, PhD, a molecular neuroscientist and biology professor at UVA. “But when you stimulate that, you’re activating everything—all of these different pathways between the brain and other connected organs. Having a more targeted approach to affect just the esophageal motor function would allow these therapies to be more precise.” Campbell is also principal investigator at the Campbell Lab, which continues research in mapping neurocircuits for resting and digesting. But in cataloging the various cells that make up different regions of the brain and then looking at where each cell type sends its axons, the research team discovered the neuron subtype controlling the esophagus. Their approach, Coverdell says, is how they begin all research. “Our research into this topic and many other projects in the lab typically begins with a focus on generating a ‘parts list’ for a particular area of the brain—in this case, the nucleus ambiguus,” she says. “We are interested in figuring out what different types of cells make up that region and what they do. To understand this, we profile gene expression to identify cell types and then look at where each cell type sends its axons. We can then turn these cell types on or off and observe what happens with these organs.” Understanding the Unique Genetic Code “Any of these could be potential targets for treating dysphagia,” she adds. In other words, this research brings the field closer to more targeted treatment options, including potential pharmacological targeting. “Our study provided a few major advances in understanding the neural control of esophageal function,” Coverdell says. “First, we identified primary motor neurons for the esophagus on a molecular, anatomical, and functional level. Second, we revealed a genetic logic for the functional organization of the nucleus ambiguus and uncovered multiple other nucleus ambiguous subtypes, some of which may also have implications in esophageal control and swallowing. Lastly, we comprehensively characterized the gene expression profile of esophageal motor neurons, which can be mined for potential drug targets to treat swallowing disorders.” Campbell agrees that the research has made important strides toward better treatment options. “Our work has provided a complete ‘parts list’ for the motor neurons, which we believe control swallowing,” he explains. “This includes receptors, neuropeptides, and other signaling molecules which could be targeted by drugs to, as an example, improve the sensitivity of the swallowing reflex.” Coverdell says that targeting the esophagus more specifically (as opposed to the entire region, as occurs with vagus nerve treatments) can prevent unwanted effects of other treatments. “We now have a complete gene expression profile for these esophageal motor neurons,” Campbell adds. “It also gives us access to the whole neural circuitry that controls swallowing. So, we can work backward from these neurons that control the contractions of the esophagus and that will give us a complete picture of how the swallowing program is represented in the brain.” Looking to the Future “One question we are interested in is what is the physiological role of these Crhr2 nucleus ambiguus neurons?” she says. “Our study showed that these neurons are able to contract esophageal muscle, but we are further interested in the physiological role that this plays in swallowing. We are also interested in whether there are additional vagal neurons that may be involved in esophageal control and what the neural connection is between swallowing and heart rate.” The Campbell Lab has continued to explore the role of the nucleus ambiguus subtypes and has uncovered a few other subtypes that are likely involved in heart rate control. “Interestingly,” Coverdell says, “many previous studies have pointed to the connection between swallowing and heart rate, showing that there is a transient increase in heart rate during a swallow.” Campbell adds that another potential direction for the work includes looking at how these swallowing neurons are affected during neurodegenerative diseases such as Alzheimer’s and Parkinson’s, which are also associated with dysphagia. “Now that we can identify the neurons, we can study whether their function is impaired in models of neurodegenerative diseases,” he says. “We also want to know if these neurons stop working normally in other esophageal disorders, such as achalasia.” Coverdell says they are excited about the possibilities that could come from their work. “Our research has many implications for possible dysphagia treatment, but it also opens the door for more targeted therapeutics in other disorders,” she continues. “Research in our lab and others has revealed more about the organization of the vagus nerve and how it controls heart and digestive functions. Here in the Campbell Lab, we’ve found that genetically distinct subtypes of neurons in the brainstem send their axons to different visceral organs—like the esophagus, heart, and pancreas—through the vagus nerve to control these different organ functions. Due to the vast diversity of organs that the vagus nerve controls, this has potential implications for more targeted treatment of diabetes, cardiovascular diseases, and digestive disorders.” — Lindsey Getz is an award-winning freelance writer in Royersford, Pennsylvania. |
