Neuroscience breakthrough: A Princeton-led research team has mapped the entire brain of an adult fruit fly for the first time
Princeton-led FlyWire Consortium built a complete connectome of every neuron in a Drosophila brain
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For many heartbreaking diseases of the brain — dementia, Parkinson’s, Alzheimer’s and others — doctors can only treat the symptoms. Medical science does not have a cure.
Why? Because it’s confounding to cure what we don’t understand, and the human brain, with its millions of neurons connected by a hundred trillion synapses, is almost hopelessly complex.
A Princeton-led team of neuroscientists has now made a massive step toward understanding the human brain, by building a neuron-by-neuron and synapse-by-synapse roadmap — scientifically speaking, a “connectome” — through the brain of an adult fruit fly (Drosophila melanogaster).
This image is a video still showing the brain inside an adult fruit fly. The full video is available by request to flywire@princeton.edu.
view moreCredit: Amy Sterling / FlyWire / Princeton University
A Princeton-led team of scientists has built the first neuron-by-neuron and synapse-by-synapse roadmap through the brain of an adult fruit fly (Drosophila melanogaster), marking a major milestone in the study of brains. This research is the flagship article in the Oct. 2 special issue of Nature, which is devoted to the new fruit fly “connectome.”
Previous researchers mapped the brain of a C. elegans worm, with its 302 neurons, and the brain of a larval fruit fly, which had 3,000 neurons, but the adult fruit fly is several orders of magnitude more complex, with almost 140,000 neurons and roughly 50 million synapses connecting them.
Fruit flies share 60% of human DNA, and three in four human genetic diseases have a parallel in fruit flies. Understanding the brains of fruit flies is a steppingstone to understanding brains of larger more complex species, like humans.
“This is a major achievement,” said Mala Murthy, director of the Princeton Neuroscience Institute and, with Sebastian Seung, co-leader of the research team. “There is no other full brain connectome for an adult animal of this complexity.” Murthy is also Princeton’s Karol and Marnie Marcin ‘96 Professor of Neuroscience.
Princeton’s Seung and Murthy are co-senior authors on the flagship paper of the Nature issue, which includes a suite of nine related papers with overlapping sets of authors, led by researchers from Princeton University, the University of Vermont, the University of Cambridge, the University of California-Berkeley, UC-Santa Barbara, Freie Universität-Berlin, and the Max Planck Florida Institute for Neuroscience. The work was funded in part by the NIH’s BRAIN Initiative, the Princeton Neuroscience Institute’s Bezos Center for Neural Circuit Dynamics and McDonnell Center for Systems Neuroscience, and other public and private neuroscience institutes and funds, listed at the end of this document.
The map was developed by the FlyWire Consortium, which is based at Princeton University and made up of teams in more than 76 laboratories with 287 researchers around the world as well as volunteer gamers.
Sven Dorkenwald, the lead author on the flagship Nature paper, spearheaded the FlyWire Consortium.
“What we built is, in many ways, an atlas,” said Dorkenwald, a 2023 Ph.D. graduate of Princeton now at the University of Washington and the Allen Institute for Brain Science. “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.”
And just like a map that traces out every tiny alley as well as every superhighway, the fly connectome shows connections within the fruit fly brain at every scale.
The map was built from 21 million images taken of a female fruit fly brain by a team of scientists led by Davi Bock, then at the Howard Hughes Medical Institute’s Janelia Research Campus and now at the University of Vermont. Using an AI model built by researchers and software engineers working with Princeton’s Sebastian Seung, the lumps and blobs in those images were turned into a labeled, three-dimensional map. Instead of keeping their data confidential, the researchers opened their in-progress neural map to the scientific community from the beginning.
“Mapping the whole brain has been made possible by advances in AI computing. It would have not been possible to reconstruct the entire wiring diagram manually. This is a display of how AI can move neuroscience forward,’ said Prof. Sebastian Seung, one of the co-leaders of the research and Princeton’s Evnin Professor in Neuroscience and a professor of computer science.
“Now that we have this brain map, we can close the loop on which neurons relate to which behaviors,” said Dorkenwald.
The development could lead to tailored treatments to brain diseases.
“In many respects, it (the brain) is more powerful than any human-made computer, yet for the most part we still do not understand its underlying logic,” said John Ngai, director of the U.S. National Institutes of Health’s BRAIN Initiative, which provided partial funding for the FlyWire project. “Without a detailed understanding of how neurons connect with one another, we won’t have a basic understanding of what goes right in a healthy brain or what goes wrong in disease.”
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This research was supported by the National Institutes of Health (NIH) BRAIN Initiative (RF1 MH117815, RF1 MH129268, 1RF1MH120679-01 and U24 NS126935) and National Institute Of Neurological Disorders And Stroke (NINDS) (RF1NS121911); the Princeton Neuroscience Institute’s Bezos Center for Neural Circuit Dynamics and McDonnell Center for Systems Neuroscience; Google; the Allen Institute for Brain Science; the National Science Foundation (NSF Neuronex2 2014862, Neuronex2 MRC MC_EX_MR/T046279/1, MRC MC-U105188491, PHY-1734030); Wellcome Trust Collaborative Award (203261/Z/16/Z and 220343/Z/20/Z); a Marie Skłodowska-Curie postdoctoral fellowship (H2020-WF-01-2018-867459); the Portuguese Research Council (Grant PTDC/MED-NEU/4001/2021); and the Intelligence Advanced Research Projects Activity (IARPA) via the Department of Interior (DOI) (D16PC0005).
For brain video, high resolution images and copies of the papers, please view our press kit.
Author contacts:
Princeton University, USA: To arrange an interview the study authors Mala Murthy or Sebastian Seung, please contact Molly Seltzer at ms80@princeton.edu and Dan Vahaba at
MRC LMB in Cambridge, UK: To arrange an interview with study author Greg Jefferis, please contact Hilary Jones in the UKRI media team: +44 7892 770105, hilary.jones@ukri.org; out of hours press@ukri.org, 01793 298902.
University of Vermont, USA: To arrange an interview with study author Davi Bock, please contact Angela Ferrante, Public Relations Manager at the Larner College of Medicine at the University of Vermont by calling +1 516-458-0721 or emailing: Angela.Ferrante@med.uvm.edu
About FlyWire
The FlyWire Consortium includes researchers from at least 76 laboratories and 287 individuals around the world as well as a network of gamers and other volunteers — see: https://flywire.ai/consortium. The senior authors for the two papers describing and annotating the complete connectome are Mala Murthy and Sebastian Seung (Princeton University), Gregory Jefferis (MRC LMB and University of Cambridge), and Davi Bock (University of Vermont).
About Princeton University
Princeton University is a vibrant community of scholarship, research, and teaching that stands in the nation's service and the service of humanity. As a global research university with world-class excellence across the arts and humanities, the social sciences, the natural sciences, and engineering, the University is home to more than 1,250 faculty members who share a commitment to innovation, free inquiry, and the discovery and transmission of knowledge and new ideas. Princeton combines its strengths in research with a distinctive emphasis on undergraduate and doctoral education, preparing its 5,500 undergraduates and 3,200 graduate students for positions of leadership and lives of service.
About the National Institute of Mental Health (NIMH)
The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website. NIH’s The BRAIN Initiative, a multidisciplinary collaboration across 10 NIH Institutes and Centers, is uniquely positioned for cross-cutting discoveries in neuroscience to revolutionize our understanding of the human brain. By accelerating the development and application of innovative neurotechnologies, The BRAIN Initiative® is enabling researchers to understand the brain at unprecedented levels of detail in both health and disease, improving how we treat, prevent, and cure brain disorders. The BRAIN Initiative involves a multidisciplinary network of federal and non-federal partners whose missions and current research portfolios complement the goals of The BRAIN Initiative.
About the MRC Laboratory of Molecular Biology
The Medical Research Council (MRC) Laboratory of Molecular Biology (LMB) is one of the world's leading research institutes. Discoveries and inventions developed at the LMB, for example DNA sequencing and methods to determine the structure of proteins, have revolutionised all areas of biology. Its scientists work to advance understanding of biological processes at the molecular level. This information will help us to understand the workings of complex systems, such as the immune system and the brain, and solve key problems in human health. http://www2.mrc-lmb.cam.ac.uk/
About the University of Cambridge
The University of Cambridge is one of the world’s leading universities, with a rich history of radical thinking dating back to 1209. Its mission is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. Cambridge was second in the influential 2024 QS World University Rankings, the highest rated institution in the UK. The University comprises 31 autonomous Colleges and over 100 departments, faculties and institutions. Its 24,000 students include around 9,000 international students from 147 countries. In 2023, 73% of its new undergraduate students were from state schools and more than 25% from economically disadvantaged backgrounds. Cambridge research spans almost every discipline, from science, technology, engineering and medicine through to the arts, humanities and social sciences, with multi-disciplinary teams working to address major global challenges. In the Times Higher Education’s rankings based on the UK Research Excellence Framework, the University was rated as the highest scoring institution covering all the major disciplines. A 2023 report found that the University contributes nearly £30 billion to the UK economy annually and supports more than 86,000 jobs across the UK, including 52,000 in the East of England. For every £1 the University spends, it creates £11.70 of economic impact, and for every £1 million of publicly-funded research income it receives, it generates £12.65 million in economic impact across the UK. The University sits at the heart of the ‘Cambridge cluster’, in which more than 5,000 knowledge-intensive firms employ more than 71,000 people and generate £21 billion in turnover. Cambridge has the highest number of patent applications per 100,000 residents in the UK.
About the Larner College of Medicine at the University of Vermont
Founded in 1822, the Robert Larner, M.D., College of Medicine at the University of Vermont is dedicated to developing exceptional physicians and scientists by offering innovative curriculum designs, state-of-the-art research facilities, and clinical partnerships with leading health care institutions. The college’s commitment to excellence has earned national recognition, attracting talented students, trainees, physicians, and researchers from across the country. With a focus on diversity, equity, and inclusion, the Larner College of Medicine prides itself on cultivating an environment that uplifts and supports its faculty and student populations while advancing medical education, research, and patient care in Vermont and beyond.
Learn more at med.uvm.edu
Fruit fly connectome: All 139,255 neurons in an adult fruit fly brain (IMAGE)
This image shows the complete fruit fly connectome: all 139,255 brain cells in the brain of an adult fruit fly. Activity within these neurons drives an entire organism, from sensory perception to decision-making to flying. These neurons are connected by more than 50 million connections (synapses). A Princeton-led team of gamers, neuroscientists and professional tracers painstakingly mapped out the locations and connections of every brain cell, using 21 million images.
Credit
Tyler Sloan / FlyWire / Princeton University
The 50 largest neurons of the fly brain connectome
This map shows the precise location and arrangement of the 50 largest neurons of the fly brain connectome. These 50, along with another 139,205 brain cells in the brain of an adult fruit fly, were painstakingly mapped by a Princeton University-led team of neuroscientists, gamers and professional tracers. Activity within these neurons (brain cells) drives everything the organism does, from sensory perception to decision-making to controlling flight. The brain cells are connected by more than 50 million connections (synapses). Find more here: https://doi.org/10.1038/s41586-024-07558-y
Credit
Tyler Sloan and Amy Sterling / FlyWire / Princeton University
Journal
Nature
Method of Research
Imaging analysis
Subject of Research
Animals
Article Title
Neuronal wiring diagram of an adult brain
Article Publication Date
3-Oct-2024
Global effort to map the human brain releases first data
The BICAN Rapid Release Inventory provides early access to comprehensive single-cell data, aiming to accelerate brain research.
Allen Institute
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Brain slice being prepared for analysis and study
view moreCredit: Erik Dinnel / Allen Institute
Seattle, WA – October 1, 2024 – The BRAIN Initiative® Cell Atlas Network (BICAN) has launched its first major data release, marking a significant milestone in the ambitious effort to map the whole human brain.
The data, accessible through the BICAN Rapid Release Inventory, includes single-cell and single-nucleus transcriptomic and epigenomic profiles from humans, mice, and 10 other mammalian species. Sourced from multiple grants and labs within the consortium, including the Allen Institute, these data are from projects that aim to identify and define brain cell types based on molecular profiles.
“The tap is open, the data is flowing, and more is on the way,” said Carol Thompson, Ph.D., associate director of data management at the Allen Institute. “The hope is that if we can encourage data reuse and sharing by multiple labs, we can maximize the value of these datasets and really amplify the public investment into research.”
This effort is funded by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®. BICAN unites neuroscientists, computational biologists, and software engineers to create a comprehensive atlas of the human brain. This effort builds on earlier NIH BRAIN Initiative-funded projects at the Allen Institute and elsewhere, which mapped the cells of the entire mouse brain and parts of the human brain by studying the genes active in individual cells.
“This release represents a major step forward to this next frontier of neuroscience, where we finally will start to understand what sets the human brain apart,” said Fenna Krienen, Ph.D., an assistant professor at the Princeton Neuroscience Institute whose lab contributed data to today’s release.
“By bringing together experts across multiple specialties, the BICAN project is a model of open science,” said John Ngai, Ph.D., director of the NIH BRAIN Initiative. “The availability of this rapidly growing treasure trove of data will enable researchers around the world to propel the field toward a deeper understanding of the human brain in both health and disease, ultimately paving the way to more precise treatments and cures for devastating brain disorders.”
The open data release is designed to accelerate discoveries in neuroscience by providing unprecedented access to raw data from brain cells across species and developmental stages. Traditionally, it can take years between a scientist generating data and that information becoming available through a published paper.
This initiative marks a departure from that conventional approach, prioritizing early data sharing to foster collaboration and speed up research. “I hope this model becomes the norm, where we release data before it’s published and work together to create resources for the entire community,” Krienen said.
Researchers can now use this open dataset to map and define brain cell types, offering new insights into brain cellular diversity and function. “Neuroscience is a challenging field," Thompson said. "The more we can do to ensure the data we generate fuels more studies and helps the community, the better off we'll be.”
Learn more on portal.brain-bican.org.
About the Allen Institute
The Allen Institute is an independent, 501(c)(3) nonprofit research organization founded by philanthropist and visionary, the late Paul G. Allen. The Allen Institute is dedicated to answering some of the biggest questions in bioscience and accelerating research worldwide. The Institute is a recognized leader in large-scale research with a commitment to an open science model. Its research institutes and programs include the Allen Institute for Brain Science, launched in 2003; the Allen Institute for Cell Science, launched in 2014; the Allen Institute for Immunology, launched in 2018; and the Allen Institute for Neural Dynamics, launched in 2021. In 2016, the Allen Institute expanded its reach with the launch of The Paul G. Allen Frontiers Group, which identifies pioneers with new ideas to expand the boundaries of knowledge and make the world better. For more information, visit alleninstitute.org.
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