Summary: Researchers published the first complete synapse-level wiring diagram, or connectome, of the entire central nervous system of an adult fruit fly (Drosophila melanogaster). The study integrates a newly mapped fruit fly spinal cord equivalent (the nerve cord) with the previously established brain map to achieve a holistic view of the nervous system.
By analyzing this structural data, investigators upended long-held neuroscientific theories of centralized command, proving instead that motor control for complex actions like walking and flying is highly distributed across localized neural modules situated directly within the body’s appendages.
Key Facts
- The Complete Central Nervous System Connectome: For the first time, researchers can follow the entire pipeline of biological information flow from sensory input to physical motor action across an intact, single adult invertebrate nervous system.
- The Brain and Nerve Cord (BANC) Dataset: Imaged via advanced electron microscopy at the Lee Lab, the project stitched together millions of high-resolution images of thousands of ultra-thin slices of a single fly using custom AI alignment and reconstruction tools.
- The Distributed Control Paradigm: Rather than relying on a central command hub in the fly brain to dictate physical tasks, structural analysis revealed that movement is managed at a local level. Neural circuits in individual legs handle their own local mechanics and simply network with neighboring limbs to coordinate complex gaits like walking.
- The FlyWire Legacy: The project expands upon the 2024 FlyWire Consortium brain map led by Princeton professors Mala Murthy and Sebastian Seung, successfully bridging the cerebral networks with the appendage-controlling motor systems of the nerve cord.
- Embodying the Map at Synapse Resolution: While the electron microscopy scans specifically targeted the central nervous system, the team utilized identifiable neurons and historic literature to map synapses directly out to sensory organs and physical appendages, effectively creating an “embodied” connectome.
- An Open-Source Research Foundation: Funded in part by the U.S. BRAIN Initiative, the NIH, and the NSF, the fully interactive dataset has been made freely available online to provide a global baseline, analogous to the Human Genome Project, for future computational neuroscience and mammalian comparative studies.
- Next-Generation Artificial Intelligence Applications: Beyond biology, the connectome’s decentralized wiring architecture offers concrete mathematical principles to help train advanced AI agents and robotics to navigate complex virtual and physical environments.
Source: Harvard
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: 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.
Key Questions Answered:
A: Because a brain map alone cannot explain how an organism physically moves through space. The nerve cord functions as the fly’s spinal cord, directly processing sensations and controlling limbs. Bridging the brain and the nerve cord allows scientists to track the complete flow of information from sensory perception to physical action for the first time.
A: Through a highly efficient, decentralized layout. The landmark study showed that instead of a central brain hub acting as a master controller, the fly uses independent, local neural modules located inside its appendages. The circuit in one leg controls that leg’s movement, communicating directly with adjacent legs to coordinate complex behaviors.
A: Fruit flies routinely execute complex behaviors, such as learning, navigating, and dodging threats—that modern robotics still struggle to replicate efficiently. The connectome provides a concrete biological blueprint showing how thousands of simple neurons assemble into decentralized networks, offering lessons on how to train AI agents with less computational overhead.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience research news
Author: Katie Brace
Source: Harvard
Contact: Katie Brace – Harvard
Image: The image is credited to Tyler Sloan
Original Research: Closed access.
“Distributed control circuits across a brain-and-cord connectome” by Alexander S. Bates, Jasper S. Phelps, Minsu Kim, Helen H. Yang, Arie Matsliah, 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, Justin Ellis-Joyce, Jiayi Zhang, 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, Fei Wang, 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, H. Sebastian Seung, Benjamin L. de Bivort, Mala Murthy, Jan Drugowitsch, Rachel I. Wilson & Wei-Chung Allen Lee. Nature
DOI:10.1038/s41586-026-10735-w
Abstract
Distributed control circuits across a brain-and-cord connectome
Just as genomes revolutionized molecular genetics, connectomes (maps of neurons and synapses) are transforming neuroscience. To date, the only organisms with complete connectomes are worms, sea squirts, and comb jellies (10–10 synapses). By contrast, the fruit fly is more complex (10 synaptic connections), with a brain that supports learning and spatial memory and an intricate ventral nerve cord analogous to the vertebrate spinal cord.
Here we report the first densely-reconstructed adult fly connectome that unites the brain and ventral nerve cord, and we leverage this resource to investigate principles of neural control. We show that effector neurons (motor neurons, endocrine cells, and efferent neurons targeting the viscera) are primarily influenced by sensory neurons in the same body part, forming local feedback loops.
These local loops are linked by long-range circuits involving ascending and descending neurons organized into behavior-centric modules. Single ascending and descending neurons are often positioned to influence the voluntary movements of multiple body parts, together with the endocrine cells or visceral organs that support those movements.
Brain regions involved in learning and navigation supervise these circuits. These results reveal an architecture that is distributed, parallelized, and embodied, reminiscent of distributed control architectures in engineered systems.
