Bless You: Mouse Model Reveals Molecular Pathway Behind Sneezing

EDITOR’S CHOICE IN NEUROSCIENCE

The paper
F. Li et al., “Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem,” Cell, 184:3762–73, 2021.

Qin Liu studies sneezing for a personal reason: her entire family suffers from seasonal allergies. “Until you experience something chronically, it is really hard to appreciate how disruptive it can be,” says Liu, a neuroscientist at Washington University in St. Louis. And given the role of sneezing in pathogen transmission, a better understanding of the molecular underpinnings of the phenomenon could one day help scientists mitigate or treat infectious diseases.

When Liu first started looking into the mechanisms governing sneezing, she found that scientists know surprisingly little about how this process works. While prior research had identified a region in the brains of cats and humans that is active during sneezing, the exact pathways involved in turning a stimulus like pollen or spicy food into a sneeze remained unknown.

To study sneezing in more detail, Liu and her team developed a new model by exposing mice to irritants such as histamine and capsaicin—a chemical in spicy peppers—and characterizing the physical properties of their resulting sneezes. Then, focusing on that previously discovered sneeze center, located in the brain’s ventromedial spinal trigeminal nucleus (SpV), Liu attempted to map the neural pathway.

SNEEZE TRIGGER: When exposed to allergens such as histamine or chemical irritants such as capsaicin (1), sensory neurons in the noses of mice produce a peptide called neuromedin B (NMB). This signaling molecule binds to neurons in a region of the brainstem known as the ventromedial spinal trigeminal nucleus (SpV), which is known to be active during sneezing (2). These neurons send electrical signals (3) to neurons in another brainstem region called the caudal ventral respiratory group (cVRG), which controls exhalation, thus driving the initiation and propagation of sneezing (4). Ablating the nasal neurons or disrupting NMB signaling led to a significantly reduced sneezing reflex in the mice. WEB | PDF

Using a pain-relieving drug, the researchers desensitized nasal sensory fibers in mice known to be triggered by capsaicin. As a result, the animals stopped sneezing in response to irritants, implicating the neurons that make up these fibers in the sneeze pathway. Next, the team screened those neurons for the signaling molecules they released, revealing that a peptide called neuromedin B (NMB) binds to and activates neurons in the SpV, prompting them to fire electrical impulses to the caudal ventral respiratory group (cVRG), a region that controls exhalation. This pathway, the authors concluded, is necessary for sneezing. Mice engineered without NMB or without the complementary receptor in the SpV had a significantly reduced sneezing reflex.

“Overall, I thought it was a really beautiful paper, and the science in it was really well done,” says Sarina Elmariah, a skin neuroscientist at Harvard Medical School and Massachusetts General Hospital who was not involved in the study. These experiments build on a growing interest in sensory biology over the last decade, she says, adding that “the interactions between the immune system and the nervous system really set the stage” for the current work.

Liu and her colleagues are now interested in other sneezes—such as the light-induced sneeze reflex—and are also studying sneezes as a defense mechanism against viruses. They recently infected mice lacking the ability to sneeze with influenza and saw that, compared with wildtype mice, the modified mice had more-severe symptoms. How such findings will translate to humans remains unknown, but Liu says that developing better control over sneezing could one day have clinical relevance. “Instead of using antihistamines, we would have other options.”