Optogenetic stimulation of preBötzinger complex reveals novel circuit interactions in swallow-breathing coordination

Online publication date: July 14, 2022

How does the brain coordinate swallowing and breathing?

In the first study of its kind to explore the neural pathways involved in swallow-breathing coordination, researchers at Seattle Children’s Research Institute’s Center for Integrative Brain Research found that the rhythm generator in the brainstem called the preBötzinger complex that controls the ability to take a breath also affects the ability to swallow in tandem.

The findings, led Alyssa Huff, PhD, in the Ramirez Lab, and Nino Ramirez, PhD, principal investigator and professor of neurological surgery at the University of Washington School of Medicine, were published in Proceedings of the National Academy of Science. Their work provides new insights into how the brain tightly controls and coordinates breathing and swallowing and how this control is lost in certain disorders impacting children and adults.

“Most people are not aware how important swallowing is,” Nino said. “Swallowing and breathing must be coordinated. Dysphagia [disordered swallow] affects children with congenital heart disease and premature infants, as well as adults with Parkinson’s disease and Alzheimer’s disease. If you don’t swallow properly, food or fluids can get into the lungs, causing aspiration pneumonia and possible death.”

Using optogenetic methods—akin to putting on/off light switches in nerve cells—in a mouse model of obstructive sleep apnea, they found overstimulating the preBötzinger complex led to a discoordinated swallow, keeping the airway open and unprotected, and increasing the risk for water to enter the lungs instead of the esophagus.

Patients with obstructive sleep apnea also often have dysphagia, but the mechanisms behind this were unknown. This study points to an overactive preBötzinger complex as a possible reason why the two conditions can coexist in sleep apnea patients.

The researchers found the parts of the nervous system that control swallowing and control breathing share the same pathway but they’re not hard-wired, making the system both flexible and vulnerable. Since the processes share common structures, one must be switched off to allow the other. This coordination is very sensitive to an intermittent lack of oxygen [hypoxia], a major problem in premature babies and congenital heart disease patients.

“This finding shows training might help the coordination,” said Alyssa, pointing to success using muscle-resistance training to strengthen swallowing, as well as diaphragm-strengthening exercises to increase lung volume.

“My goal is to understand where the neurocircuitry for swallow is located and how it coordinates with breathing, while keeping in mind all the muscles, lungs, upper airway and other involved structures,” Alyssa said. “If we can understand the mechanisms behind dysphagia in various diseases, then there is great potential for pharmaceutical therapies.”

In addition to paving the way for medications to help with dysphagia, Alyssa is working with the Center for Integrative Brain Research’s Dr. Franck Kalume, using the same modeling techniques to investigate Leigh Syndrome, a pediatric neurometabolic disease that affects children’s ability to swallow.

The Ramirez Lab’s Marlusa Karlen-Amarante, PhD, also contributed to the paper. The research was funded by the National Institutes of Health.

— Colleen Steelquist