A novel gut-to-brain neural circuit establishes the vagus nerve as an essential component of the brain system that regulates reward and motivation, according to research conducted at the Icahn School of Medicine at Mount Sinai and published September 20 in the journal Cell. The study provides a concrete link between visceral organs and brain function, especially in regards to reward, and may help to inform novel targets for vagal stimulation therapy, particularly for eating and emotional disorders.
Previous research established the gut as a major regulator of motivational and emotional states but until now, the relevant gut-brain neuronal circuitry remained elusive. The vagus nerve, the longest of the cranial nerves, contains motor and sensory fibers and passes through the neck and thorax to the abdomen. Traditionally, scientists believed that the nerve exclusively mediated suppressive functions such as fullness and nausea; in contrast, circulating hormones, rather than vagal transmission, were thought to convey reward signals from the gut to the brain.
"Our study reveals, for the first time, the existence of a neuronal population of 'reward neurons' amid the sensory cells of the right branch of the vagus nerve," says Ivan de Araujo, DPhil, Senior Faculty in the Department of Neuroscience at the Icahn School of Medicine at Mount Sinai and senior author of the paper. "We focused on challenging the traditional view that the vagus nerve is unrelated to motivation and pleasure and we found that stimulation of the nerve, specifically its upper gut branch, is sufficient to strongly excite reward neurons lying deep inside the brain."
The branches of the vagus nerve are intricately intermingled, making it extremely difficult to manipulate each organ separately. To address this challenge, the research team employed a combination of virally delivered molecular tools that allowed them to exclusively target the vagal sensory neurons connected to the stomach and upper intestine.
Specifically, researchers combined different viruses carrying molecular tools in a way that allowed them to optically activate vagal neurons connected to the gut while vagal neurons leading to other organs remained mute. The approach, a state-of-the-art technique known as "optogenetics," allows investigators to use light to manipulate the activity of a prespecified set of neurons.
The study revealed that the newly identified reward neurons of the right vagus nerve operate under the same constraints attributed to reward neurons of the central nervous system, meaning they link peripheral sensory cells to the previously mapped populations of reward neurons in the brain. Strikingly, neurons of the left vagus were associated with satiety, but not with reward. The research team's anatomical studies also revealed, for the first time, that the right and left vagal branches ascend asymmetrically into the central nervous system.
"We were surprised to learn that only the right vagal branch eventually contacts the dopamine-containing reward neurons in the brainstem," explained Wenfei Han, MD, PhD, Assistant Professor of Neuroscience at the Icahn School of Medicine at Mount Sinai and lead author of the study. Dopamine is a neural transmitter known to be essential for reward and motivation.
The uncovering of right gastrointestinal vagal neurons as conveyors of reward signals to the brain opens opportunities for novel, more specific stimulation targets that may increase the efficacy of vagal nerve stimulation therapy, a treatment that involves delivering electrical impulses to the vagus nerve, for patients suffering from emotional and eating disorders.
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Researchers from The John B. Pierce Laboratory, Yale University School of Medicine, Duke University, and University of São Paulo contributed to this study.
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The Mount Sinai Health System is New York City's largest integrated delivery system encompassing seven hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The System includes approximately 6,600 primary and specialty care physicians; 10 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, it is ranked as a leading medical school for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat, while Mount Sinai Beth Israel, Mount Sinai St. Luke's and Mount Sinai West are ranked regionally. For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube.
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http://dx.doi.org/10.1016/j.cell.2018.08.049
