Most of us will experience nausea at some point, but the sensation remains poorly understood at the molecular and cellular level. Researchers at Harvard Medical School have now identified and characterized neurons that regulate nausea-like responses in mice. Their studies, reported in Neuron, demonstrated that when these neurons are experimentally turned on, nausea-like responses can be activated, regardless of exposure to nausea-triggering substances. And without these neurons, nausea-like responses to poisons were lost. The team claims the findings shed new light on the sensation of nausea, and point to potential targets for the design of improved, more precise anti-nausea medications.

“Everyone knows what nausea feels like, but it has been largely mysterious at a molecular and genetic level,” said Stephen Liberles, PhD, professor of cell biology in the Blavatnik Institute at HMS, and corresponding author of the team’s report. “By identifying neuron types at the heart of this phenomenon, we can now investigate how it works and design better ways to control it in the future.”

Led by study first author, Chuchu Zhang, PhD, research fellow in cell biology at HMS, the team reports the findings in a paper titled, “Area Postrema Cell Types that Mediate Nausea-Associated Behaviors.”

That familiar stomach-unsettling queasy sensation of nausea is a signal that something in the body isn’t quite right, and is commonly accompanied by vomiting. Nausea is generally a temporary sensation, but for some people, perhaps individuals on certain chemotherapy regimens, nausea can be severe, chronic and even life threatening if it prevents patients from adhering to treatment. However, the cellular basis of nausea has not been well understood, and so nausea still represents “a mysterious process,” the authors wrote. “Sensory pathways leading to nausea have remained enigmatic …”.

In fact, nausea is the most common reason for cancer patients having to stop their treatments, but current anti-nausea drugs display very variable success across different patient populations, the authors continued. A better understanding of nausea-related biology could help in the development of new treatments. “Understanding the diversity of molecular and cellular pathways capable of evoking nausea should allow for more effective nausea intervention,” they commented.

Liberles, Zhang, and colleagues began their investigation of nausea by looking at a region of the brain called the area postrema, which is located in the brain stem, and has long been implicated in nausea and vomiting responses to some stimuli. The area postrema is one of the rare parts of the brain outside the blood-brain barrier that can monitor blood-borne chemicals. This is thought to allow the area postrema to detect harmful substances or danger signals in the bloodstream and act as an alarm bell in response.

Until now, the different types and functions of cells within the area postrema remained unclear. In their study, the researchers used single-nucleus RNA sequencing technology to characterize gene expression in thousands of individual area postrema cells from mice, and build an atlas of cell types. The resulting atlas revealed that there were only a handful of different neuron types in the area postrema. “Here, we used single-nucleus RNA sequencing to investigate area postrema cell diversity, finding that it contains only a few neuron types,” they wrote. “We identified four excitatory and three inhibitory neuron types and assembled genetic tools to map, image, and control several of them. Chemogenetics revealed two subpopulations of excitatory GLP1R neurons that provide aversive teaching signals …”

Of particular interest were neurons that expressed GLP1R, a receptor protein on the cell surface that previous studies have linked to blood sugar and appetite control. To probe whether these neurons play a role in nausea, the researchers had to first assess if mice were actually experiencing the sensation of nausea. They did so by adding cherry or grape flavoring to the animals’ drinking water. Then they gave the mice either an innocuous substance or one known to induce nausea. If a mouse felt malaise, it would quickly associate a fruit flavor with the negative sensation and so avoid it, similar to how humans develop food aversions after eating something disagreeable.

GLP1R neurons (red) play a critical role in detecting toxins in blood vessels (green) and initiating the nausea response. [Chuchu Zhang, Stephen Liberles]

The researchers tested several different substances, including lithium chloride and lipopolysaccharide, a toxin produced by bacteria associated with food poisoning. As expected, all the tested substances led to strong flavor aversion in mice.

However, mice from which GLP1R neurons were experimentally removed stopped developing flavor aversions for most of the substances. This observation suggested that they no longer experienced malaise as normal. “Ablating area posotrema GLP1R neurons eliminated flavor avoidance conditioned to multiple stimuli …” the investigators stated.

The team also experimentally turned GLP1R neurons on. They found that mice with activated GLP1R neurons would acquire strong flavor aversions even when they had not been exposed to a nausea-inducing substance. “We used a technique to activate these neurons, essentially tricking them into thinking there was a toxin present,” Zhang said. “This led to conditioned flavor avoidance, which was strong evidence for a connection between these neurons and the nausea response.”

Additional analyses revealed that GLP1R neurons connect to many other regions of the brain, including one called the parabrachial nucleus, which has been recognized as a hub for pain and aversion. This may be how area postrema neurons help induce conditioned flavor-aversion memories, Zhang noted. The team also found that GLP1R neurons expressed numerous other cell-surface receptors, such as the receptor GFRAL. Interestingly, removing this subset of neurons caused mice to stop developing flavor aversions for only lithium chloride and lipopolysaccharide. This indicated a “division of labor” between area postrema neurons, with different neuron types responsible for detecting and raising the alarm for different substances.

The study findings present a wealth of data to help scientists better understand nausea, how toxins or medicines trigger the sensation, and how it can be controlled to benefit patients, the authors said. “Revealing area postrema cell types and receptors that sense signals of visceral malaise may help in the identification of new therapies for nausea, a major clinical need,” they wrote. “These studies reveal the basic organization of area postrema nausea circuitry and provide a framework toward understanding and therapeutically controlling nausea.”

For example, the team found that certain neurons expressed a calcium-sensing receptor called CaSR. This receptor is a target for the drug cinacalcet, which is used to treat a hormonal imbalance in patients with chronic kidney disease and other conditions. Nausea is a main side effect of this drug, and so the research team tested whether area postrema neurons were involved. Giving cinacalcet to mice led to flavor-aversion behaviors, which could be averted when GLP1R neurons were removed. This suggested that CaSR receptors may also play a role in nausea-like responses in area postrema neurons.

“Nausea is a very unpleasant sensation, and current anti-nausea drugs are not perfect,” Zhang said. “Many people still experience nausea during cancer treatment, pregnancy and more, and so better understanding and treating nausea is a very important clinical need.”

The authors acknowledged that numerous questions about these neurons and their role in nausea remain. For example, it is still unclear to which signals in the bloodstream the area postrema neurons respond. The team’s current working model is that toxins or medicines damage the body, triggering the release of chemicals into the bloodstream, which receptors on area postrema neurons detect.

In addition, the researchers note that their reported work focused on excitatory neurons, which, when activated, go on to activate other neurons. Their atlas of area postrema cells identified many other cell types, including inhibitory neurons, which dampen the activity of other neurons. The team is now investigating the function of these other cell types in the nausea response.

“Some of the most exciting and important discoveries in neuroscience have involved the identification of sensory receptors, both external and internal,” said Liberles, who is a Howard Hughes Medical Institute Investigator. “While there has been a great deal of progress in understanding the neurons important for sensations like hunger, thirst and satiety, the neurons relevant for nausea have remained ill-defined. We still have a lot to do to understand how the sensation of nausea arises at the molecular, neural, and cellular levels. There are many next-generation questions enabled by these findings.”

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