A subset of neurons in the central nervous system (brain and ventral nerve cord) of the male Drosophila fruit fly. This wiring diagram of the central nervous system of an adult male fruit fly will help researchers better understand how the brain enables complex action, from sensory perception to behavior. Credit: Data acquired and analyzed by the FlyEM Project Team at HHMI’s Janelia Research Campus, the Cambridge Connectomics Group, and Google Research. Image by Philip Hubbard/HHMI Janelia Research Campus
When Janelia researchers set out in 2008 to map every neuron in the fly brain, many scientists thought the effort was doomed. It had taken more than a decade to map the connectome of the roundworm C. elegans, which has just 302 neurons. Most researchers assumed mapping a fly brain, with well over 100,000 neurons, would take too long, cost too much and reveal too little about how brains actually work.
But those skeptics didn’t deter Janelia’s founding Executive Director Gerry Rubin and today, after almost 20 years, the vision has come to fruition. Rubin and team have now published 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.”
A complete nervous system, mapped
The newly completed connectome, published in Cell, covers the brain, both optic lobes and the ventral nerve cord of a male fruit fly. The map will allow scientists to trace complete neural circuits linking sensory input to behavior, such as how a fly navigates toward a goal, and compare male and female brains to understand sex-linked behaviors like mating and aggression.
Using the new map, Janelia researchers and collaborators have already begun uncovering new findings about differences between male and female fly brains and about the insect's visual and taste systems. For example, the researchers discovered that while sex-differentiated neurons cluster in higher brain regions, the circuits underlying basic sensation and movement are largely shared between males and females, with circuit "switches" that reroute sensory signals into different behavioral pathways depending on sex.
Tracing signals from the eye through the full connectome also showed that visual processing engages more than half of the brain's neuron types—far more widespread than previously appreciated.
Additionally, a complete map of the fly taste system showed how taste neurons carrying attractive signals and those carrying repulsive signals connect to circuits that control feeding, locomotion, hormone release and courtship. The map could help scientists understand how internal states can shape taste-driven decisions.
What comes next
Janelia is now applying what it learned mapping the fly brain to vertebrate models. This includes a whole-brain connectome of the larval zebrafish to create predictive models of brain function, as well as an emerging effort to map the nervous system of Danionella, a fish that stays transparent into adulthood.
The ultimate goal is a mechanistic account of how a vertebrate brain generates complex behavior—insight researchers hope could eventually help explain how conditions like Alzheimer's, autism and depression arise in humans.
For Rubin, these projects are the next logical step for Janelia. In fewer than 20 years, the research campus and its collaborators proved that creating a connectome for a complex brain is within the realm of possibility and can provide unprecedented insights into how the brain works.