Key Takeaways:
- Janelia researchers and collaborators at the MRC Laboratory of Molecular Biology, the University of Cambridge and Google Research have completed a map of the more than 166,000 neurons in the brain and ventral nerve cord of the fruit fly. The wiring diagram will help researchers better understand how the brain enables complex action, from sensory perception to behavior.
- The achievement marks nearly two decades of connectomics research at Janelia, an effort involving hundreds of researchers that has accelerated the field of connectomics and led to advances in neuroscience, imaging, AI, and biology.
- Janelia is now applying lessons learned in fly connectomics to building connectomes of two transparent vertebrate fish — the larval zebrafish and adult Danionella. The ultimate goal is to provide a mechanistic account of how a vertebrate brain generates complex behavior — information that could help scientists unravel the logic of brain function and potentially reveal how diseases like Alzheimer's, autism, and depression arise.
When researchers at HHMI's Janelia Research Campus set out to create a map of all the neurons in the fruit fly brain in 2008, many in the scientific community thought they were out of their minds.
It had been 20 years since scientists had unveiled the wiring diagram — or connectome — of the 302 neurons in the tiny worm C. elegans, an effort that took more than a decade. Most scientists thought mapping the fly brain, with more than 100,000 neurons, would take too long and cost too much — and they didn't think it would tell neuroscientists much about how the brain worked.
But those skeptics didn't deter Janelia's founding Executive Director Gerry Rubin . Instead, it fueled his bet that through the development of better imaging and computational techniques, the research campus could bring down the cost and the time to map all the neurons of a complex animal, creating a wiring diagram that would yield unprecedented insights about how the brain enables sophisticated behavior.
Today, that vision has come to fruition with the publication of the connectome of the full central nervous system of a fruit fly: a wiring diagram of more than 166,000 neurons that make up the fly's brain and ventral nerve cord and the millions of connections between them.
Along the way, Janelia's pursuit of the fly connectome has transformed scientific research, revealing new insights into how the brain enables behavior, pioneering new technologies to empower biological discoveries, and helping to launch the thriving field of connectomics.
Now, Janelia is applying lessons learned in creating the fruit fly connectome to new animal models, with the ultimate goal of providing the first mechanistic account of how a vertebrate brain generates behavior.
"None of those things would've happened if we hadn't done the fly," says Rubin, now the head of Biology and a senior group leader at Janelia. "It was us having the leap of faith that we could assemble an interdisciplinary team who would develop ways to increase the efficiency of generating connectomes by more than 1,000-fold. That was our key contribution and without that, we could still be waiting."
Choosing to Complete the Fly Connectome
Soon after Janelia opened its doors, it became apparent that making a detailed map of a wiring diagram of the fly brain lay at the intersection of its two areas of focus at the time: neuroscience and advanced imaging.
"We felt, which wasn't a universally accepted idea, that we wouldn't be able to understand the brain at a satisfying level without having a wiring diagram," Rubin says. "We knew it was possible; it was a well-defined problem. We just had to figure out how to do it."
The team estimated that, with the technology available when they started, creating the fly connectome would take 500 people working for 10 years — a time and cost that needed to be reduced through technological improvements.
Researchers, led by Senior Group Leader Harald Hess , spent years optimizing and scaling up a pioneering microscopy technique to get sharper and more detailed images of individual neurons, while other teams working with collaborators at Google Research developed computational methods to speed up image interpretation, eventually reaching the point where the connectome was feasible.
"Janelia was just ideally set up to have the patience for developing these technologies, and I think it's been transformative not only for the fly connectome, but also many, many other applications," says Hess.
Making Milestones and Changing Science
The road to the full connectome started with mapping small, biologically interesting parts of the brain. Then, in 2020, the researchers unveiled the hemibrain . With 25,000 neurons, the map of half of the fly brain was the biggest and most detailed connectome ever created, proving the feasibility and utility of a fly brain map.
The hemibrain connectome enabled hundreds of research findings throughout the scientific community, revealing insights about how the brain works. It also made it easier for other scientific teams to enter the field, with research teams around the world now pursuing wiring diagrams of increasingly complex brains.
"There's a point where people lack imagination, but they finally see something and say, 'I got it.' This is why this is going to be really important," Rubin says. "That's what the hemibrain did for neuroscientists by showing what you could learn from a connectome. It just changed the attitude of people about what was going to be possible."
Completing the CNS Connectome
The newly completed connectome is the first map of an entire male fruit fly central nervous system, comprising all the neurons in the brain, both optic lobes, and ventral nerve cord.
It will allow scientists to trace the complete neuronal circuits that link sensory perception to behavior, enabling researchers to determine how flies carry out key actions, like navigating to a goal.
It is also allowing researchers to compare male and female brains and understand complex social behaviors — like mating and aggression — that can vary by sex.
In addition to providing a resource for the entire scientific community, Janelia researchers and collaborators have already started to uncover new biological insights about the differences between male and female fly brains, and the insect's visual and taste systems. (see sidebar)
Continuing to Push the Boundaries
Connectomics will remain an important component of Janelia's new research effort to understand how a vertebrate brain produces complex behavior.
