A team of scientists supported by the National Institutes of Health (NIH)’s The BRAIN Initiative®, including Davi Bock, Ph.D., Associate Professor of Neurological Sciences at UVM’s Robert Larner, M.D. College of Medicine, recently made a substantial advancement in neurobiological research by successfully mapping the entire brain of Drosophila melanogaster, more commonly known as the fruit fly.
The study, titled “Whole-brain annotation and multi-connectome cell typing of Drosophila,” recently published in Nature, established a “consensus cell type atlas,” or a comprehensive guide, for understanding the different types of cells in the fruit fly brain. The fruit fly’s brain contains around 130,000 neurons (a human’s brain contains 86 billion; mice, which often stand-in for humans in scientific research and testing, have 100 million neurons). The electron microscopy dataset underlying the whole-brain connectome (known as FAFB, or “Full Adult Fly Brain”) uses the detailed shapes of every neuron in the fly’s brain as well as all the synaptic connections between them to identify and catalogue all cell types in the brain. This complete map will help researchers to identify how different circuits work together to control behaviors like motor control, courtship, decision-making, memory, learning, and navigation.
“If we want to understand how the brain works, we need a mechanistic understanding of how all the neurons fit together and let you think,” remarked study co-lead Gregory Jefferis, Ph.D. “For most brains we have no idea how these networks function. Now for the fly we have this complete wiring diagram, a key step in understanding complex brain functions. In fact, using our data, shared online as we worked, other scientists have already started trying to simulate how the fly brain responds to the outside world.”
“To begin to simulate the brain digitally, we need to know not only the structure of the brain, but also how the neurons function to turn each other on and off,” remarked study co-lead Gregory Jefferis, Ph.D. “Using our data, which has been shared online as we worked, other scientists have already started trying to simulate how the fly brain responds to the outside world. This is an important start, but we will need to collect many different kinds of data to produce reliable simulations of how a brain functions.”
While similar studies have been done with simpler organisms, such as the nematode worm C. elegans and the larval stage of the fruit fly, the adult fruit fly offers more intricate behaviors to study. Though the fruit fly’s brain is clearly less complex than that of a human, or even a mouse, the implications of the study are profound. There are tremendous commonalities in how neural circuits in all species process information; this work allows principles of information processing to be identified in a simpler model organism and then sought in larger brains. Bock notes that scientists are currently incapable of scaling up this approach to a human brain, but states that this achievement represents a noteworthy step toward complete connectome of a mouse brain.
“This type of work [being done across this field of connectomics] advances the state of the art in a once-in-a-century fashion, allowing us to both map the shapes and connections of every individual neuron in the complete brain of a fairly sophisticated animal, the adult fruit fly, and to annotate and mine the resulting connectome with cutting-edge software analytics. Neither light microscopy—even with multi-color fluorescence—nor the classical Golgi method and its allied approaches has provided this capability,” said Bock. “To achieve this feat at the scale of the entire brain of an important genetic model organism such as the fruit fly represents a remarkable advancement in the field.”
This study leverages tools and data generated by the FlyWire Consortium, which includes study leads such as UVM’s Bock; Gregory Jefferis, Ph.D., and Philipp Schlegel, Ph.D., from the MRC Laboratory of Molecular Biology and University of Cambridge; and Sebastian Seung, Ph.D. and Mala Murthy, Ph.D., of Princeton University. The consortium used electron microscopic brain images generated previously in Bock’s lab to create a detailed map of connections between neurons in the entire adult brain of a female fruit fly. This map includes around 50 million chemical synapses between the fly’s aforementioned 139,255 neurons. Researchers also added information about different types of cells, nerves, developmental lineages, and predictions about the neurotransmitters used by neurons. FlyWire’s Connectome Data Explorer open-access data analysis tool is accessible and available for download, and can be browsed interactively—all done in the spirit of encouraging team science. This work is detailed in an accompanying Nature paper, “Neuronal wiring diagram of an adult brain.”
“We have made the entire database open and freely available to all researchers. We hope this will be transformative for neuroscientists trying to better understand how a healthy brain works,” stated Murthy. “In the future we hope that it will be possible to compare what happens when things go wrong in our brains, for example in mental health conditions.”
By tracing connections from sensory cells to motor neurons, researchers can uncover potential circuit mechanisms that control behaviors in fruit flies, marking a crucial step toward understanding the complexities of human cognition and behavior.
“The diminutive fruit fly is surprisingly sophisticated and has long served as a powerful model for understanding the biological underpinnings of behavior,” said John Ngai, Ph.D., director of the study’s funding party, NIH’s The BRAIN Initiative®. “This milestone not only provides researchers a new set of tools for understanding how the circuits in the brain drive behavior, but importantly serves as a forerunner to ongoing BRAIN-funded efforts to map the connections of larger mammalian and human brains.”
The FlyWire Paper Package
The finished flywire connectome is reported by two papers, in which Dorkenwald et. Al. and Schlegel et. Al. jointly describe the resource:
The "flagship" paper, an overview of the connectome: Neuronal wiring diagram of an adult brain (Dorkenwald et. al.)
Annotations and cell typing: Whole-brain annotation and multi-connectome cell typing quantifies circuit stereotypy in Drosophila (Schlegel et. al.)
Seven additional papers enrich and analyze the connectome:
Visual system and cell types in the optic lobes: Neuronal “parts list” and wiring diagram for a visual system (Matsliah et. al.)
Connectome network analysis: Network Statistics of the Whole-Brain Connectome of Drosophila (Lin et. al.)
Virtual fly simulation: A Drosophila computational brain model reveals sensorimotor processing (Shiu et. al.)
Connectomic reconstruction predicts the functional organization of visual inputs to the navigation center of the Drosophila brain (Garner et. al.)
Neural circuit mechanisms for context specific halting in Drosophila (Sapkal et. al.)
The fly connectome reveals a path to the effectome (Pospisil et. al.)
Predicting visual function by interpreting a neuronal wiring diagram (Seung)
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The FlyWire consortium includes researchers from at least 76 laboratories and 287 individuals around the world - see: https://flywire.ai/consortium. The senior authors for the two papers describing 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 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
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. www.cam.ac.uk
About the NIH
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 National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.
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.
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