Stephen Liberles, AB ’94, AM ’96, PhD ’00, professor of cell biology
Our brain is the command center of the body. In addition to crafting decisions, emotions, and movements, the brain also maintains essential autonomic functions, such as breathing, heart rhythm, and digestion. My lab studies the vagus nerve, the principal information highway connecting the brain with many peripheral organs, such as the lungs, heart, and gastrointestinal (GI) tract. The vagus nerve is a pair of large nerve bundles, each containing approximately 2,300 sensory neurons (in mouse) that provide critical information about our vital functions.
Surprisingly, despite the clear medical importance of controlling autonomic physiology, little is known about how the vagus nerve works. What are the anatomical connections between the vagus nerve, the periphery, and the brain? Do all vagal sensory neurons respond uniformly to distinct kinds of information, such as nutrients in food or stomach stretch, or are there specialized neuron types with discrete properties? Do different neuron types specifically control feeding, breathing, and heart rate? What receptors does the vagus nerve use to detect internal organ stimuli? Focusing on gut-to-brain signals, what types of vagal sensory neurons connect with the GI tract?
My lab has found that different subsets of neurons constitute the vagus nerve bundle and carry unique types of information to the brain. We used genetic approaches in mice to map neuron anatomy and to image neuron responses. One subpopulation of vagal sensory neurons contains a seldom-studied receptor called GPR65. GPR65 neurons form terminals in the intestinal villi, the finger-like folded surface of the intestine, where they respond to the presence of ingested nutrients, such as glucose. Different neurons, distinguished by expression of a receptor (GLP1R), connect with GI muscle and detect stretch of the stomach and intestine. Thus, we could genetically define different neuron types that respond to nutrients and GI stretch, signals long appreciated to impact feeding behavior and metabolism.
We also observed that subsets of vagal neurons have specific targeting patterns in the brain. Genetically guided anatomical tracing revealed that vagal GPR65 and GLP1R neurons target immediately adjacent, but distinct, brainstem regions. These and related findings in neurons that regulate respiration indicate the existence of a map in the brainstem, where a particular region of the brain is connected to a particular organ in the periphery. The presence of a brainstem map is similar to the map in the somatosensory cortex, which has a spatial map representing tactile input from fingers, toes, and other somatosensory regions. These findings also suggest that different vagal sensory neuron types engage particular higher-order neural circuits for specific control of autonomic physiology and behavior.
Next, we interrogated the roles of GPR65 and GLP1R neurons in GI physiology. We first asked whether activation of either neuron type impacts gut motility, a key function of the GI tract which helps propel digested food through the gut. Using a powerful technique called optogenetics, we activated specific subsets of vagal neurons by shining light on the nerve trunk in gene-targeted mice. Activating GPR65 neurons strikingly inhibited gastric contractions but did not impact breathing or heart rate, which are also under vagal control, while activating GLP1R neurons instead caused an increase of gastric contractility. These findings indicated that individual vagal sensory neurons can impact whole-body physiological systems with high selectivity. The vagus nerve should not be considered simply as one uniform structure, as is often done in the clinic. Moreover, these optogenetic approaches presumably can trick the brain, creating false sensations of fullness, even in the absence of ingested food.
Moving forward, my lab will continue to use molecular and genetic approaches to deconstruct vagus nerve function. A major focus will be the identification of sensory receptors. In another project, we, together with Ardem Patapoutian, PhD, at The Scripps Research Institute, identified an essential role for the mechanosensitive ion channel Piezo2 in the sensation of airway stretch, a stimulus that evokes a powerful reflexive blockade of breathing. There are many more vagal sensations to unravel and sensory receptors to identify. We hope that a basic understanding of vagus nerve sensory biology will provide new ways to control autonomic physiology in health and disease.