Complete wiring map of an adult fruit fly brain

Scientists built a neuron-by-neuron and synapse-by-synapse roadmap, called a connectome, of the entire brain of an adult fruit fly. Amy Sterling / FlyWire / Princeton University

Understanding how the brain works requires mapping the connections between the neurons within it. In recent years, this has been done for parts of brains from various model organisms, such as the fruit fly Drosophila melanogaster. But understanding brain function more globally requires mapping the entire brain.

FlyWire, a consortium of dozens of research labs from around the world, set out to produce a neuronal wiring diagram of a whole adult fruit fly brain. Fruit flies are ideal for brain studies because they show a range of behaviors, yet their brains are small compared to people’s. A description of the work, which was partly funded by NIH, and various related findings appeared in a nine-paper package in Nature on October 2, 2024.

The researchers identified connections between individual neurons from electron microscope images. The resulting wiring diagram, or connectome, consists of nearly 140,000 neurons and the more than 50 million synapses (where neurons connect) between them. This is the largest and most complex connectome produced to date.

About 85% of neurons in the fruit fly connectome are intrinsic to the brain, meaning that they synapse only with other brain neurons. Thus, the brain communicates primarily with itself. Intrinsic neurons varied in length from less than 0.2 mm to almost 20 mm, and in volume from 16 to more than 3,000 μm³.

3D rendering of all ~140,000 neurons in the fruit fly brain. Data source: FlyWire.ai; Rendering by Philipp Schlegel, University of Cambridge / MRC LMB

Most individual neurons have synapses in only a few regions of the brain, even though each region may be connected to many others. The researchers used the connectome to compute a projectome, or a map of neurons that link different brain regions.

The projectome provided important new insight into the role of a brain region called the subesophageal zone (SEZ). This region has been poorly covered in previous fly connectomes. The team found that it interacts with almost all parts of the brain. It receives a large fraction of the signals transmitted into the brain. And it sends many of the signals that go out of the brain, including nearly all the signals to motor neurons. Thus, the SEZ is important for information flow to and from the brain.

The projectome also revealed that most projections occurred between regions on the same side of the brain. But certain categories of neurons were more likely to project to the opposite hemisphere than others.

The connectome allows the analysis of information flow from various inputs through the brain. As an example, the researchers traced information flow through the ocellar circuit, which helps orient the fly’s body during flight in response to visual stimuli. The analysis suggests a mechanism for how it works.

FlyWire researchers also classified and annotated more than 8,400 types of cells found in the connectome. Cells were classified based on their location in the brain, connections, developmental origin, and shape. More than 3,600 cell types in the FlyWire connectome corresponded to those from an already-published partial fly connectome. The numbers of cells and connectivity of each type were similar between connectomes.

Since 2019, FlyWire has been available to other researchers online. The papers published in the collection demonstrate how the data can be used to gain new insights. The researchers hope that the data will help others to better understand how neural circuits work. Tools developed for FlyWire could also be used to analyze more complex brains in the same way.

“What we built is, in many ways, an atlas,” says co-author Dr. Sven Dorkenwald of Princeton University. “Just like you wouldn’t want to drive to a new place without Google Maps, you don’t want to explore the brain without a map. What we have done is build an atlas of the brain, and added annotations for all the businesses, the buildings, the street names. With this, researchers are now equipped to thoughtfully navigate the brain as we try to understand it.”

—by Brian Doctrow, Ph.D.