Vagus Nerve Drives Motivation and Reward in Surprising Ways 

New research maps a gut-brain superhighway of communication via the vagus nerve.

Posted Sep 21, 2018

These are exciting times when it comes to state-of-the-art research that advances our understanding of the vagus nerve and how it works. This week, two new studies were published that illuminate how the vagus nerve communicates messages directly from the gut to the brain as part of a reward and motivation system. The first study, by researchers from the Mount Sinai School of Medicine, “A Neural Circuit for Gut-Induced Reward,” was published September 20 in the journal Cell. The second study, by researchers from Duke University School of Medicine, “A Gut-Brain Neural Circuit for Nutrient Sensory Transduction,” appears in the September 21 issue of Science

 Wellcome Library/Public Domain
Early anatomical drawing of the vagus nerve. Vagus means "wandering" in Latin. Vagus is the longest nerve in the human body. Left and right vagal branches "wander" from the brainstem to the lowest viscera of the gut.
Source: Wellcome Library/Public Domain

As you can see by looking at this lengthy anatomical illustration of the vagus nerve, the “wandering” nerve is the longest in the human body; it travels in two multi-pronged branches from the brainstem to the lowest viscera of the gut.

In 1921, Otto Loewi isolated the first known neurotransmitter when he observed that the vagus nerve squirts an inhibitory substance onto the heart that helps calm the nervous system and counterbalance fight-or-flight responses. Today, we call this neurotransmitter “acetylcholine,” but Loewi originally coined the term “vagusstoff” (German for “vagus substance”) to describe this tranquilizer-like secretion. Every time you take a diaphragmatic belly breath, the cardiac branch of your vagus nerve squirts some vagusstoff onto your heart as you exhale, which is one reason why taking a deep breath is a fundamental aspect of the so-called “relaxation response.” (For more see, “Diaphragmatic Breathing Exercises and Your Vagus Nerve” and “Vagus Nerve Facilitates Guts-Wits-and-Grace Under Pressure.”) 

Now, almost a century after Loewi discovered vagusstoff, two pioneering studies significantly advance our understanding of how branches of the vagus nerve communicate gut-to-brain messages within milliseconds as part of a neural superhighway known as the gut-brain axis.

Historically, most experts believed that circulating hormones—as opposed to direct communication via the vagus nerve—conveyed reward signals from the gut to the brain as part of our motivation system. Together, these two September 2018 studies from different peer-reviewed journals pinpoint surprising ways that gut-to-brain circuitry creates a direct neural pathway of communication. 

In the first abovementioned study, researchers at Mount Sinai used optogenetics to illuminate how specific reward neurons in the right vagus link peripheral sensory cells to a population of reward neurons in the brain. Notably, the researchers were surprised to find that neurons of the left vagus nerve were tied to satiety but not reward. This groundbreaking research also reveals that the left and right branches of the vagus nerve ascend asymmetrically into the central nervous system. 

There are for four noteworthy highlights from this paper: (1) the researchers identify a critical role for the vagal gut-to-brain axis in motivation and reward, (2) Optogenetic stimulation of the vagal gut-to-brain axis produces reward behaviors, (3) Asymmetric brain pathways of vagal origin mediate motivation and dopamine activity, (4) Gut-innervating vagal sensory neurons are major components of the reward circuitry. 

"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," Ivan de Araujo of the Department of Neuroscience at the Icahn School of Medicine at Mount Sinai and senior author of the paper said in a statement. "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."

"We were surprised to learn that only the right vagal branch eventually contacts the dopamine-containing reward neurons in the brainstem," lead author Wenfei Han, who is currently at Yale University's John B. Pierce Laboratory, said in a statement.

Dopamine has long been known as a neural transmitter that drives reward and motivation. According to the researchers, identifying how right vagal neurons convey reward signals directly to the brain opens up the possibility for new and more specific vagus nerve stimulation (VNS) targets that may increase the efficacy of vagal nerve stimulation therapies—such as those used for treatment-resistant depression. (For more see, "Vagus Nerve Stimulation Offers New Hope for Major Depression." ) 

The Gut-Brain Axis May Be Hardwired (and Not Hormonal)

The second recent study on gut-to-brain communication via the vagus nerve suggests that because "gut feelings" travel at such lightning-fast speeds, they outpace hormonal diffusion. In fact, the Duke researchers were shocked to find that a signal going from the intestine to the brainstem in mice via the gut-brain axis moved across a single synapse in under 100 milliseconds. 

In 2015, senior author Diego Bohórquez of Duke University School of Medicine published a landmark paper in the Journal of Clinical Investigation showing that specific cells in the gut contained synapses that were linked to some type of neural tapestry. For their latest follow-up study (2018), Bohórquez and his Duke Neurobiology lab team set out to map this gut-to-brain neural circuitry.

 metamorworks/Shutterstock
Source: metamorworks/Shutterstock

When first author Maya Kaelberer tagged a rabies virus using a green fluorescent dye and injected it into the stomach of mice, she observed a direct vagus nerve circuit between the gut and brainstem. Kaelberer and colleagues were able to recreate this gut-brain neural circuitry by growing sensory gut cells of mice in the same petri dish side-by-side with vagal neurons. To her amazement, Kaelberer observed the vagus nerve neurons crawling along the surface of the dish and connecting to gut cells. Then, this neural engram began firing synaptic signals. If sugar was added to the mix, the firing rate of synapses got noticeably faster. When Kaelberer measured just how quickly this information was being communicated, she was surprised to find it was happening in milliseconds and suspected that glutamate was a key player in this process. She was right.

As the authors sum up, “This more direct circuit for gut-brain signaling uses glutamate as a neurotransmitter. Thus, sensory cues that stimulate the gut could potentially be manipulated to influence specific brain functions and behavior, including those linked to food choices.”

Although this study was on mice, Bohórquez and his team speculate that the structure and function of this neural circuitry will be the same in humans. "We think these findings are going to be the biological basis of a new sense," Bohórquez said in a statement. "One that serves as the entry point for how the brain knows when the stomach is full of food and calories. It brings legitimacy to the idea of 'gut feeling' as a sixth sense." (For more see, "How Does the Vagus Nerve Convey Gut Instincts to the Brain?") 

In future research, Bohórquez and his Duke team are eager to pinpoint how signals communicated from the gut-to-brain via the vagus nerve help us intuitively discern the caloric content and nutrition contained in what we eat and drink. 

References

Wenfei Han, Luis A. Tellez, Matthew H. Perkins, Isaac O. Perez, Taoran Qu, Jozelia Ferreira, Tatiana L. Ferreira, Daniele Quinn, Zhong-Wu Liu, Xiao-Bing Gao, Melanie M. Kaelberer, Diego V. Bohórquez, Sara J. Shammah-Lagnado, Guillaume de Lartigue, Ivan E. de Araujo. "A Neural Circuit for Gut-Induced Reward" Cell (First published: September 20, 2018) DOI: 10.1016/j.cell.2018.08.049

Melanie Maya Kaelberer, Kelly L. Buchanan, Marguerita E. Klein, Bradley B. Barth, Marcia M. Montoya, Xiling Shen, Diego V. Bohórquez. "A Gut-Brain Neural Circuit for Nutrient Sensory Transduction." Science (First published: September 21, 2018) DOI: 10.1126/science.aat5236