Researchers have mapped the first complete wiring diagram of neural connections in the brain, known as a connectome map, of the common fruit fly. The study details over 50 million connections between more than 130,000 neurons and appears as part of a package of nine papers in the journal Nature. It is the largest and most complete connectome of an adult animal brain created and provides critical information about how brains are wired, and the signals and connections needed for healthy brain function. In 1986, Sydney Brenner and colleagues published the first complete connectome: a map of all 302 neurons in the nervous system of the microscopic roundworm C. elegans, as well as all the 7,000 connections, or synapses, between those neurons. The relatively simple worm wiring diagram has informed efforts to understand the basis of animal behaviors for almost 40 years. This new research on the fruit fly connectome, supported by the NIH Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, or The BRAIN Initiative®, is exciting news for all of us in the neuroscience community.
The new connectome has the potential to transform and extend our understanding of the cellular and molecular regulation of behavior as it takes advantage of the surprisingly advanced cognition and behavior in the fruit fly—features that make the fly such a great model organism. Fruit flies can navigate vast distances, form long-term memories, and engage in social interactions—making them an ideal candidate for this initial connectome project. Further, because the fruit fly genome can be manipulated, it has been a useful model of many neurogenetic disorders. For instance, the NINDS-led program known as the Undiagnosed Disease Network often finds genetic variants of unknown significance in persons being investigated for mysterious medical illnesses and will utilize the fruit fly model to investigate the functional impacts of candidate genes and variants. In many cases, neurogenetic diseases modeled in the fruit fly are used to screen for drugs that might have beneficial effects.
This fruit fly connectome study is a prime example of fulfilling NINDS’s aim to advance neuroscience research that will ultimately improve neurological health for all people. Research on the development, structure, and function of the normal nervous system, or fundamental neuroscience, is the foundation for achieving our mission. Last year, the Fundamental Neuroscience Working Group of the National Advisory Neurological Disorders and Stroke (NANDS) Council presented their report(pdf, 915 KB) on advancing fundamental neuroscience research to NANDS Council. One recommendation included the promotion of interdisciplinary team science and collaboration with technical experts across diverse disciplines. The BRAIN Initiative supports large-scale, multidisciplinary, multimodal research that generates technologies and resources that benefit the entire neuroscience community and people with lived experience of neurological disorders. NINDS and the National Institute of Mental Health (NIMH) are the lead Institutes among the 10 NIH Institutes and Centers that participate in the BRAIN Initiative.
I am proud of and excited by how the neuroscience research community came together to complete the fruit fly brain connectome. This groundbreaking accomplishment is a shared success and a testament to the power of collaborative research. To create the connectome, researchers used electron microscopes to image thousands of slices through the fly brain. AI and other algorithms were used to stitch the images together and trace the neurons and their long processes in 3D. However, the software can be susceptible to error, and it benefits from adding a trained human eye to ensure accuracy. So, the researchers developed open-source tools that allowed a large online community to proofread them for accuracy. This collaboration, called FlyWire, included scientists from around the world, and their involvement significantly accelerated the completion of this connectome. The flagship paper presenting this research was led by Mala Murthy, Ph.D., and Sebastian Seung, Ph.D., at Princeton University, and the companion paper was led by Greg Jefferis, Ph.D. at the University of Cambridge and Davi Bock, Ph.D. at the University of Vermont.
The map identifies the full set of neuronal cell classes in the fruit fly brain, including different types of neurons and their synapses, or connections between them, as well as the types of neurotransmitters (brain signaling chemicals) secreted by each neuron. The researchers also created a map of projections between fruit fly brain regions, known as a projectome, that tracks the organization of the brain’s hemispheres and behavioral circuits. The projectome allows for the detailed mapping of specific brain circuits that control behavior, such as the ocellar brain circuit, which takes in visual stimuli and outputs behavioral changes that orient the fly’s body during flight.
This connectome project provides an important new resource for understanding how the circuits in the brain drive behavior and is a substantial addition to prior research on cells and cell circuits supported by the BRAIN Initiative. For example, last year, scientists unveiled a landmark atlas cataloging the location and type of every cell in the adult mouse brain and provided information on the connectivity between these cells. Of the 10 studies included in the collection of that research, seven were funded through the BRAIN Initiative Cell Census Network (BICCN) and two were funded through the larger BRAIN Initiative. Also last year, the BICCN published a set of 24 papers detailing the exceptionally complex diversity of cells in the human brain and non-human brain. Earlier this year, in a study supported in part by the BRAIN Initiative, researchers created the most detailed 3D reconstruction of a section of human brain tissue ever produced. Now that we have established the fruit fly brain connectome, the same methodology could help support the development of connectome maps for other larger species, such as mice. The lessons learned will also inform the ongoing BICCN and BRAIN Initiative Cell Atlas Network (BICAN) projects that are being built off of light-microscopy data and have an emphasis on mapping the human brain. Researchers can find data analysis tools for the complete fruit fly connectome on the FlyWire website and interact with the connectome data online.
FlyWire will be featured during the 2024 BRAIN Initiative Alliance Toolmakers Satellite Event at the upcoming Society for Neuroscience meeting. Comprising federal and non-federal members and affiliates, the BRAIN Initiative Alliance's mission is to coordinate and facilitate U.S. BRAIN Initiative-related communications from its BRAIN Initiative Alliance members to diverse audiences, including the public, Congress and policymakers, and the scientific community. On Sunday, October 6, 2024, the BRAIN Initiative Alliance will host Building Tools & Tech for an Innovative Future: A BRAIN Initiative Alliance Social at the Society for Neuroscience meeting. Researchers will share their tools and discuss topics including software, optics and microscopy, genetic and cell engineering, and electrophysiology and probes. Visit the event page for the full list of tools and toolmakers to be showcased at this year’s event. Events like these serve as opportunities to foster networking among researchers in the neuroscience community and disseminate the incredible tools and technology being produced by BRAIN Initiative investigators.
Studies like FlyWire show how the BRAIN Initiative is helping to fuel transformative neuroscience research. Through the BRAIN Initiative and other programs that promote fundamental neuroscience and team science, we are accelerating progress toward a deeper understanding of the human brain that will seed new possibilities for treating neurological disorders.
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