果蝇味觉连接组图谱揭示从感知到行为的神经通路

For fruit flies, taste is a full-body experience. Taste-sensing neurons scattered along their tongue, throat, legs and wings provide a sophisticated palate for sweetness, bitterness, salt, water, carbonation, lipids and amino acids.

A new wiring map shows how those tastebuds connect to the brain and back out to neurons that control responses such as walking, swallowing and secreting insulin for digestion. This detailed blueprint, published last month in Cell, transforms the fly into a test bed for understanding precisely how taste is processed and drives behavior.

“We think we know a lot about taste, but we know so little,” says Jan Pielage, professor of neurobiology and zoology at RPTU University Kaiserslautern, who was not involved in the new work. Now “we can use Drosophila, the power of Drosophila genetics, to really test individual hypotheses [about taste].” 

Because taste-sensing neurons are specialized, the relationship between perception and behavior is simpler for taste than it is for vision or hearing, says study investigator Carlos Ribeiro, senior group leader of the Behavior and Metabolism Lab at the Champalimaud Centre for the Unknown. Responses to a given visual stimulus can vary greatly, but flies generally gravitate toward sweet-tasting things and avoid bitter ones, so “how the behavior is driven is inbuilt in the neurons,” he says. 

Ribeiro and his team used light microscopy to identify all of the taste-sensing neurons in the tongue, throat, legs and wings of male and female flies, and determined what taste each neuron perceives based on its shape and gene expression. They then used the full male nervous system connectome, which was published in the same issue of Cell as the taste connectome, and the female fruit fly brain connectome to trace the axons that extend from the taste neurons and project into the brain.

Sweet-sensing neurons, no matter where they are found on the fly’s body, converge on similar downstream neurons, the team found. But those pathways preserved the information about which body part sensed the sweetness. 

“This is a very cool architecture,” Ribeiro says, because it allows the fly to react with the same type of behavior—acceptance—while tailoring it to the situation: “Because obviously if [the food] is touched by the leg, the fly should stop, but if it’s touched by the tongue, it should then be swallowed.”

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he fly pharynx contains a “huge family” of different types of taste-sensing neurons that seem to be “controlling very specific aspects of behavior,” including swallowing and the release of insulin, Ribeiro says, and the fly tongue sports at least two newly identified types of taste-sensing neurons.

In general, taste-sensing neurons are more diverse than what their gene expression would suggest, Ribeiro adds. “Yes, there might be many neurons which all detect sugar, so they are molecularly similar, but they have different roles to play.”

Also, taste was thought to be a purely feed-forward mechanism, but the team found that “feeding neurons are inhibited constantly, and then what taste actually does is it releases this brake,” which might be nature’s strategy to avoid runaway behavior and keep processes under control, Ribeiro says. 

Like all connectomes, this taste connectome has to be tested and validated, Pielage says. To create it, Ribeiro and his colleagues used artificial intelligence to predict what neurotransmitter individual neurons expressed and whether those neurons excited or inhibited others. They also constructed circuits based on mathematical estimates of connectivity between neurons separated by multiple synapses, which “potentially underrepresents pathways built from numerous but weak connections,” Pielage says. 

And just as a genome doesn’t solve biology, having a connectome is a “really valuable tool” but doesn’t solve the brain, says Juan Sánchez-Alcañiz, a tenured researcher at CSIC, the Spanish  National Research Council, who was not involved in the new work.

“It’s like a road map,” he says. But if there’s a traffic jam, he adds, a map can’t tell you how things are going to flow. Overlaying single-cell RNA sequencing data to see which genes neurons express in particular states of activation or inhibition is where the connectomics field is headed to “try to decipher how a nervous system is actually working,” he says. 

Connectomes, because they show how individual neurons fit into behavioral circuits, empower scientists to probe the function of individual neurons, using neurogenetics, Pielage says. 

“The beauty is that in the fly, we can now activate or silence any neuron if we have genetic access [and] then see how this changes the behavior,” he says. “It’s basically a platform now upon which we can play.” 

That makes connectome-mapping worth the Herculean, two-decade effort, Ribeiro says. “This lays, really, the ground for many, many future discoveries for us, and many other people.”

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