Running from the brain to the large intestine, the vagus nerve is the body’s longest cranial nerve, encoding sensory information from the visceral organs. It plays a key role in respiratory, gastrointestinal, cardiovascular, endocrine and immune system functions.

Interoception—the body’s ability to sense its internal state in a timely and precise manner—is facilitated by the vagus sensory neurons, which independently code the three critical features of a body signal: the involved visceral organ, the tissue layer where the signal originates, and the type of sensory modality.

This was just discovered by Qiancheng Zhao, assistant professor in medicine-endocrinology and McNair Scholar at Baylor University School of Medicine, and Department of Medicine-Endocrinology, Baylor College of Medicine, and Department of Neuroscience, School of Medicine, Yale University.

Clinical applications

Zhao said his findings could provide potential new vagal targets, so future researchers might use this genetic information to help them access different visceral organs precisely.

The more detailed map also could help clarify the vagus nerve’s role in interception (the body’s ability to sense its internal state in a timely and precise manner) and find whether there might be neural modulatory applications for treating interoceptive disorders in respiratory, gastrointestinal, cardiovascular, endocrine and immune system functions.

Encoding sensory information

However, it has not been clear how the body’s longest cranial nerve, running from the brain to the large intestine, encodes sensory information from the visceral organs.

Applying a variety of techniques, Zhao discovered that vagal sensory neurons independently code the three critical features of a body signal: the involved visceral organ; the tissue layer where the signal originates; and the type of sensory modality.

Decoding vagal sensory nerve traffic

The vagal highway is crowded with traffic, with sensory and motor pathways intermingling in the nerve bundle. One of the potential challenges of expanding vagal nerve stimulation (VNS) is finding ways to identify and target specific vagal signals, instead of broadly stimulating the nerve—potentially creating unwanted side effects.

“We know that vagal sensory neurons can project to the visceral organs,” said Zhao. “So our question was: what signals from those visceral organs need to be sensed by vagal sensory neurons?”

To decipher the complexity of VNS traffic, Zhao and his colleagues focused on three aspects: the visceral organ sending the signal, the tissue layer in the organ where the signal originates and the kind of sensory stimulus.

To identify organ-projecting neurons, they have combined a viral tracing approach with single-cell RNA sequencing The analysis revealed that vagal sensory neurons use different gene modules to code specific visceral organs. They also traced neuronal projections in transparent, whole-mounted mouse organs to determine how vagal sensory neurons innervate the layers of specific tissues.

Zhao and his colleague Chuyue Yu at Yale University also developed an in vivo calcium imaging technique. It allowed them to identify the molecular features of vagal sensory neurons responding to different types of stimuli, such as mechanical inflation in the lung and chemical stimuli of nutrients from a protein shake in the mouse GI tract.

“When we have the anatomical map together with the molecular information and the inputs from functional imaging, then we can really have a full picture to understand the sensory logic,” Zhao said.

Clinical applications

Zhao’s research could inform future therapies that stimulate the vagus nerve to treat a variety of physical and psychiatric disorders, using VNS through an implantable electrical pulse generator (which has been approved by the U.S. Food and Drug Administration to treat drug-resistant epilepsy and depression).

Zhao said his findings could provide potential new vagal targets, so future researchers might use this genetic information to help them access different visceral organs precisely. The more detailed map also could help clarify the vagus nerve’s role in interoception and whether there might be neural modulatory applications for treating interoceptive disorders.

Aging

Zhao is also interested in discovering more about how vagal sensory neurons might behave differently across the lifespan and under different disease conditions. “We know that our physiological parameters, such as heart rate and blood pressure will change during aging so we might want to look, for example, at how the aging state changes the interaction between the sensory nerve and different organs.”

For his work investigating and mapping this internal information highway, Zhao is the 2024 grand prize winner of the Science & PINS Prize for Neuromodulation.

Citation: Zhao, Q. (2024). Navigating internal senses: A road map for the vagal interoceptive system. Science. https://www.science.org/doi/10.1126/science.adq8578 (open access)

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