By tangling up bitter– and sweet–sensing cells on the tongues of mice, researchers have teased apart how the taste system wires itself. The results, from Howard Hughes Medical Institute (HHMI) Investigator Charles Zuker at Columbia University and colleagues, reveal how cells constantly reconnect to keep taste abilities running smoothly, allowing flavor information to flow from tongue to brain.

The ability to sense sweet, bitter, salty, sour, and savory is innate, explained Hojoon Lee, a postdoctoral researcher in Zuker’s lab who led the study, published August 9 in the journal Nature. “We are born to be averse to sour or bitter tastes and attracted to sweet things,” he says.

Although it may seem like taste is merely a matter of pleasure (or mild disgust), those responses can be key to survival, especially for other animals. Sweet tastes can signal nutrient–dense fare, whereas bitter tastes can mark a deadly poison.

For doing such an important job, the taste system has unexpectedly high turnover. Taste receptor cells on the tongue are constantly dying and being replaced. These cells are nestled in the taste buds and live for only about two weeks – which means that stem cells continually need to churn out new ones.

Amid such high turnover, how does the taste system do its job reliably? Connections between cells in the taste buds and neurons must be re–wired correctly each time for the taste system to work. “If you don’t connect properly, you’re going to be triggering the wrong behavioral responses,” Zuker says. But just how the taste system pulled off this feat was a mystery.

“Essentially, very little was known about the wiring of the taste system,” Lee said. Each taste receptor cell is tuned to detect one of the five flavors. When the cell recognizes a chemical taste, it jumps into action. This activity is picked up by a bundle of nerves originating in ganglion neurons located just behind the mice’s ears. Most ganglion neurons hook up with receptor cells that all sense the same flavor; e.g., bitter connects to bitter and sweet to sweet. The neurons then send taste messages from the tongue to the brain.

To figure out how ganglion neurons find and reconnect to the correct newly–born taste receptor cells, Zuker, Lee, and colleagues genetically engineered mice to have mixed–up taste systems. Then, the researchers watched how the miswiring linked bitter taste receptor cells to sweet neurons or sweet receptor cells to bitter neurons.

Using a method called RNA sequencing, Zuker’s team identified two molecules that may function as critical signals. Bitter–sensing taste receptor cells produce a molecule called Semaphorin 3A, while sweet–sensing taste receptor cells produce a different one – Semaphorin 7A. Both molecules are known to help neural circuits wire up correctly.

Next, the researchers tested mice with bitter–sensing taste receptor cells that lacked Semaphorin 3A. Without Semaphorin 3A, previously bitter–associated ganglion neurons expanded their repertoire and reached out to other kinds of taste receptor cells – nearly half also responded to sweet, umami, and salty flavors, the researchers found.

More mix–ups followed. When mice produced Semaphorin 3A in their sweet and umami taste receptor cells, the neurons that normally respond to bitter now responded to sweet tastes, too. The mice’s behavior reflected this confusion.

Similar results came from experiments in which Semaphorin 7A, the sweet signal, was produced in bitter–sensing taste receptor cells. Ganglion cells that usually respond to sweet flavors now began detecting bitter ones, too.

The results show that specific molecular signals in newborn taste receptor cells can pull the right nerve cell connections toward them, creating cellular links that lead to proper taste sensation.