At a glance:
In a first, a large, international team led by multiple labs at Harvard Medical School and Princeton University has published a complete wiring diagram of all the connections between neurons in the central nervous system of an adult fruit fly.
The work allows researchers to begin to study how the brain and body interact to carry out complex behaviors such as walking and flying. It also empowers deeper investigations into the basic principles of how nervous systems work.
“We can see all of the neurons and their connections as a complete unit for the first time and ask, ‘What do we learn from that?’” said study co-senior author Rachel Wilson , the Joseph B. Martin Professor of Basic Research in the Field of Neurobiology in the Blavatnik Institute at HMS.
The highly detailed diagram of neural connections — known as a connectome — adds a map of the fruit fly’s spinal cord equivalent, called a nerve cord, to a previously published connectome of the fly brain.
“It is really important to have a central nervous system connectome that is as complete as possible so we can link up the brain and body and start thinking about behavior holistically,” said study co-senior author Wei-Chung Allen Lee , associate professor of neurobiology at HMS and HMS professor of neurology at Boston Children’s Hospital.
In analyzing the connectome, the team found that many fruit fly behaviors are controlled by local neural circuits in the body parts that are involved, rather than by a central hub in the brain.
The entire connectome is now freely available online so that other scientists can use it to propel neuroscience research.
The work, published June 8 in Nature , was supported in part by U.S. federal funding, including the BRAIN Initiative (Brain Research Through Advancing Innovative Neurotechnologies), National Institutes of Health, and National Science Foundation.
Creating a complex connectome
How neurons in the brain and body connect to one another and work together to produce behavior is an important open question in neuroscience. The fruit fly Drosophila melanogaster offers an effective model for studying this question. Fruit flies are easy to breed and maintain in the lab, and despite having a relatively simple nervous system made up of around 160,000 neurons, they exhibit complex behaviors such as navigation, social interaction, learning, and responding to sensory cues. They also come with what Lee describes as an incredibly sophisticated genetic toolkit, meaning researchers can access, control, and record activity from individual neurons or populations of neurons.
In 2024, the FlyWire Consortium — led by Mala Murthy and Sebastian Seung at Princeton, who are also co-authors of the new study — published a complete connectome of a fruit fly brain . Meanwhile, Lee and colleagues were developing a connectome of a fruit fly nerve cord, which controls its legs, wings, and other appendages and processes sensory information.
“The brain and nerve cord connectomes are each useful on their own, but until you can bridge the two, it’s hard to understand how information moves between the brain and the body,” said co-first author Helen Yang , a research fellow in neurobiology in the Wilson Lab.
Co-first author Alexander Bates , also a research fellow in neurobiology in the Wilson Lab, added that while the brain contains the majority of the neurons, the neurons in the nerve cord are “some of the most useful” because they’re involved in things like sensation and movement and are easier to interpret.
The FlyWire team was excited to pivot to work on the brain and neural cord, or BANC, dataset imaged in the Lee Lab, said co-senior author Murthy, the Karol and Marnie Marcin ’96 Professor of Neuroscience at Princeton and director of the Princeton Neuroscience Institute (PNI).
“The new connectome represents a major advance for the field, with the ability to understand how circuits in the brain receive feedback from and control the actions of the body,” she said.
“For the first time, we can follow information flow from sensation to action across an entire nervous system,” added co-author Arie Matsliah of the PNI.
A powerful tool emerges
To build the connectome, the team created thousands of thin, serial sections of a single fruit fly, which they imaged with electron microscopy to produce millions of images of neurons and neural connections. They then used AI tools to align the images and stitch them into a cohesive 3D map.
The connectome shows how each individual neuron connects to every other neuron in the brain and nerve cord at the synapse level. Although the map doesn’t span the fly’s entire body, the team was able to use identifiable neurons and the scientific literature to connect the neurons in the central nervous system to those in many of its appendages and sensory organs, effectively “embodying” the connectome.
Researchers can use the connectome to form new hypotheses to test in the lab, Lee said. He likens it to having access to the comprehensive information in Google Maps when planning a new route.
“The connectome has shown us that most of our hypotheses are too simple. Now, we can develop more complex hypotheses and move forward with experiments to test them,” Lee said.
The authors have already used the connectome to explore motor control — specifically, how a fly moves its legs and other body parts.
One longstanding idea in neuroscience, they said, is that a centralized controller in the brain is responsible for making decisions about the actions an animal will perform.
However, that is not what they found.
Instead, they discovered that motor control in the fruit fly mostly happens at a local level — for example, movement of a fly’s leg is primarily controlled by the neural circuits for that leg. The local circuits for one leg then communicate with circuits for other legs to carry out complex coordinated movements like walking.
The same was true for neural circuits for a fly’s wings, mouth, and other body parts. Moreover, the team found that these motor circuits interface with other types of circuits — such as those in the visual or endocrine systems — that provide additional information needed to shape behavior.
“Our findings suggest that control for actions is highly distributed in local modules that link up and work together in different ways,” Bates said.
Future directions
The researchers see endless future directions for research using their connectome. Yang draws an analogy to the Human Genome Project, another large-scale, open-source resource that has had a wide range of applications.
In the near future, the researchers plan to add more information to the connectome, including about neuropeptides, the small, protein-like molecules that neurons use to communicate.
Insights from the connectome may reveal fundamental principles about how nervous systems operate across species, including in humans.
Plenty of neuroscientific discoveries in fruit flies have translated from invertebrates to mammals, Bates said, including in navigation, olfaction, and memory.
Another goal is “to bring full-connectome mapping to much more complex organisms,” said Matsliah. Advances in AI, computation, and open collaborative science are making it easier to conduct such work, he said.
A big question, the researchers agree, is whether the distributed control of neural circuits they saw in the flies occurs in other species — something that Lee is now investigating in mice.
“I would be shocked if this is unique to the fly,” Yang said. “We don't have this level of resolution in other animals, but we know that they have a lot of these local circuits.”
The work may also have applications in artificial intelligence. For example, the connectome provides concrete, biological information that could inform the design of artificial agents navigating virtual worlds — systems increasingly used to study intelligence and refine and train AI.
“One thing that always amazes me is that this tiny little fly does a hell of a lot; even our best AI agents and robots can’t do everything that a fly does,” Yang said. “There may be lessons for AI in how the nervous system is organized.”
Authorship, funding, disclosures
Jasper S. Phelps and Minsu Kim are also co-first authors of the study. Jan Drugowitsch is co-senior author. Additional authors include Zaki Ajabi, Eric Perlman, Kevin M. Delgado, Mohammed Abdal Monium Osman, Christopher K. Salmon, Jay Gager, Benjamin Silverman, Sophia Renauld, Farzaan Salman, Janki Patel, Matthew F. Collie, Jingxuan Fan, Diego A. Pacheco, Yunzhi Zhao, Wenyi Zhang, Laia Serratosa Capdevila, Ruairí J.V. Roberts, Eva J. Munnelly, Nina Griggs, Helen Langley, Borja Moya-Llamas, Zuoyu Zhang, Ryan T. Maloney, Szi-chieh Yu, Amy R. Sterling, Marissa Sorek, Krzysztof Kruk, Nikitas Serafetinidis, Serene Dhawan, Finja Klemm, Paul Brooks, Ellen Lesser, Jessica M. Jones, Sara E. Pierce-Lundgren, Su-Yee Lee, Yichen Luo, Andrew P. Cook, Theresa H. McKim, Dimitrios Stasi Giakoumas, Benjamin Gorko, Emily C. Kophs, Tjalda Falt, Alexa M. Negron-Morales, Austin Burke, James Hebditch, Kyle P. Willie, Ryan Willie, Sergiy Popovych, Nico Kemnitz, Dodam Ih, Kisuk Lee, Ran Lu, Akhilesh Halageri, J. Alexander Bae, Ben Jourdan, Gregory Schwartzman, Damian D. Demarest, Emily Behnke, Doug Bland, Anne Kristiansen, Jaime Skelton, Tom Stocks, Dustin Garner, Anthony Hernandez, Sandeep Kumar, The BANC-FlyWire Consortium, Kevin C. Daly, Sven Dorkenwald, Forrest Collman, Marie P. Suver, Lisa M. Fenk, Michael J. Pankratz, Zepeng Yao, Stephen J. Huston, Tomke Stürner, Gregory S.X.E. Jefferis, Katharina Eichler, Andrew M. Seeds, Stefanie Hampel, Sweta Agrawal, Tatsuo S. Okubo, Meet Zandawala, Thomas Macrina, Diane-Yayra Adjavon, Jan Funke, John C. Tuthill, Anthony Azevedo, and Benjamin L. de Bivort.
Funding was provided by the National Institutes of Health (grants R01NS121874; RF1MH117808; U19NS118246; U24NS126935; RF1MH117815; K99NS129759; R00NS117657; R01NS102333; RF1NS128785; R01NS140174; UM1NS132253; U24NS13992; RF1MH128840; R01NS121911; T32GM144273; R01DK139131; R25NS080687), a Sir Henry Wellcome Postdoctoral Fellowship (222782/Z/21/Z), a Smith Family Foundation Odyssey Award, a Harvard/MIT Joint Research Grant, an HHMI Life Sciences Research Foundation Postdoctoral Fellowship (PJ100000343), a New York Stem Cell Foundation Robertson Neuroscience Investigator Award, the Deutsche Forschungsgemeinschaft (ZA1296/1-1; EXC2151-390873048; PA787/7-3; PA787/9-3), the Nevada IDeA Network of Biomedical Research Excellence (GM103440), the National Science Foundation (2127379; 2014862), the Japan Society for the Promotion of Science (KAKENHI 25K00370), the Japan Science and Technology Agency (ASPIRE JPMJAP2302; CRONOS JPMJCS24K2), an HHMI Gilliam Fellowship (GT15790), the Max Planck Society, the Shanahan Family Foundation, a Kempner Graduate Fellowship, the Medical Research Council (MC_EX_MR/T046279/1), the Alice and Joseph Brooks Fund, and the Beijing Natural Science Foundation (IS23084). The authors also acknowledge that the work benefited from the O2 High-Performance Compute Cluster, supported by the Research Computing Group at HMS.
Harvard University filed a patent application for GridTape (WO2017184621A1) on behalf of the inventors, including W. Lee, and negotiated licensing agreements with interested partners. Macrina, Popovych, Kemnitz, Ih, K. Lee, Lu, Halageri, Bae, and Seung declare financial interest in Zetta AI. Seung declares financial interest in Memazing, Inc. Capdevila, Roberts, Langley, Munnelly, Griggs, and Moya-Llamas declare financial interest in Aelysia Ltd. Perlman is a principal of Yikes LLC.
Nature
Distributed control circuits across a brain-and-cord connectome
8-Jun-2026