Largest brain map ever reveals fruit fly’s neurons in exquisite detail

A fruit fly might not be the smartest organism, but scientists can still learn a lot from its brain. Researchers are hoping to do that now that they have a new map — the most complete for any organism so far — of the brain of a single fruit fly (Drosophila melanogaster). The wiring diagram, or ‘connectome’, includes nearly 140,000 neurons and captures more than 54.5 million synapses, which are the connections between nerve cells.
“This is a huge deal,” says Clay Reid, a neurobiologist at the Allen Institute for Brain Science in Seattle, Washington, who was not involved in the project but has worked with one of the team members who was. “It’s something that the world has been anxiously waiting for, for a long time.”
The map1 is described in a package of nine papers about the data published in Nature today. Its creators are part of a consortium known as FlyWire, co-led by neuroscientists Mala Murthy and Sebastian Seung at Princeton University in New Jersey.
Seung and Murthy say that they’ve been developing the FlyWire map for more than four years, using electron microscopy images of slices of the fly’s brain. The researchers and their colleagues stitched the data together to form a full map of the brain with the help of artificial-intelligence (AI) tools.
But these tools aren’t perfect, and the wiring diagram needed to be checked for errors. The scientists spent a great deal of time manually proofreading the data — so much time that they invited volunteers to help. In all, the consortium members and the volunteers made more than three million manual edits, according to co-author Gregory Jefferis, a neuroscientist at the University of Cambridge, UK. (He notes that much of this work took place in 2020, when fly researchers were at loose ends and working from home during the COVID-19 pandemic.)

But the work wasn’t finished: the map still had to be annotated, a process in which the researchers and volunteers labelled each neuron as a particular cell type. Jefferis compares the task to assessing satellite images: AI software might be trained to recognize lakes or roads in such images, but humans would have to check the results and name the specific lakes or roads themselves. All told, the researchers identified 8,453 types of neuron — much more than anyone had expected. Of these, 4,581 were newly discovered, which will create new research directions, Seung says. “Every one of those cell types is a question,” he adds.
The team was surprised by some of the ways in which the various cells connect to one another, too. For instance, neurons that were thought to be involved in just one sensory wiring circuit, such as a visual pathway, tended to receive cues from multiple senses, including hearing and touch1. “It’s astounding how interconnected the brain is,” Murthy says.
The FlyWire map data have been available for the past few years for researchers to explore. This has enabled scientists to learn more about the brain and about fruit flies — findings that are captured in some of the papers published in Nature today.

Cubic millimetre of brain mapped in spectacular detail

In one paper2, for example, researchers used the connectome to create a computer model of the entire fruit-fly brain, including all the connections between neurons. They tested it by activating neurons that they knew either sense sweet or bitter tastes. These neurons then launched a cascade of signals through the virtual fly’s brain, ultimately triggering motor neurons tied to the fly’s proboscis — the equivalent of the mammalian tongue. When the sweet circuit was activated, a signal for extending the proboscis was transmitted, as if the insect was preparing to feed; when the bitter circuit was activated, this signal was inhibited. To validate these findings, the team activated the same neurons in a real fruit fly. The researchers learnt that the simulation was more than 90% accurate at predicting which neurons would respond and therefore how the fly would behave.
In another study3, researchers describe two wiring circuits that signal a fly to stop walking. One of these contains two neurons that are responsible for halting ‘walk’ signals sent from the brain when the fly wants to stop and feed. The other circuit includes neurons in the nerve cord, which receives and processes signals from the brain. These cells create resistance in the fly’s leg joints, allowing the insect to stop while it grooms itself.
One limitation of the new connectome is that it was created from a single female fruit fly. Although fruit-fly brains are similar to each other, they are not identical. Until now, the most complete connectome for a fruit-fly brain was a map of a ‘hemibrain’ — a portion of a fly’s brain containing around 25,000 neurons. In one of the Nature papers out today4, Jefferis, Davi Bock, a neurobiologist at the University of Vermont in Burlington, and their colleagues compared the FlyWire brain with the hemibrain.
Some of the differences were striking. The FlyWire fly had almost twice as many neurons in a brain structure called the mushroom body, which is involved in smell, compared with the fly used in the hemibrain-mapping project. Bock thinks the discrepancy could be because the hemibrain fly might have starved while it was still growing, which harmed its brain development.
The FlyWire researchers say that much work remains to be done to fully understand the fruit-fly brain. For instance, the latest connectome shows only how neurons connect through chemical synapses, across which molecules called neurotransmitters send information. It doesn’t offer any information about electrical connectivity between neurons or about how neurons chemically communicate outside synapses. And Murthy hopes to eventually have a male fly connectome, too, which would allow researchers to study male-specific behaviours such as singing. “We’re not done, but it’s a big step,” Bock says.