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Astonishing complete map of fruit fly brain achieved by scientists




It is less than one millimetre wide and was sliced into seven thousand pieces.

Then scientists proceeded to map all 139,255 neurons in the brain of a fruit fly - and all 50 million connections between them.

Professor Gregory Jefferis. Picture: MRC LMB
Professor Gregory Jefferis. Picture: MRC LMB

The result is the first wiring diagram of the entire brain of an animal that can walk and see.

The astonishing achievement, which could shed light on the workings of human brains, is the work of the international FlyWire Consortium, including researchers from the University of Cambridge, the MRC Laboratory of Molecular Biology (LMB) in Cambridge, Princeton University, and the University of Vermont.

Dr Gregory Jefferis, from the University of Cambridge and the LMB, one of the co-leaders of the research, said: “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. For most brains we have no idea how these networks function.

“Flies can do all kinds of complicated things like walk, fly, navigate and the males sing to the females. Brain wiring diagrams are a first step towards understanding everything we’re interested in – how we control our movement, answer the telephone or recognise a friend.”

The study, published in a pair of papers in the journal Nature, represents a huge step forward from previous work, which delivered whole brain diagrams for much smaller brains, such as a fruit fly larva, with 3,016 neurons, and a nematode worm, which has 302 neurons.

3D rendering of all 139,255 neurons in the fruit fly brain. Data source: FlyWire.ai. Rendering: Philipp Schlegel, University of Cambridge/MRC LMB
3D rendering of all 139,255 neurons in the fruit fly brain. Data source: FlyWire.ai. Rendering: Philipp Schlegel, University of Cambridge/MRC LMB

And it represents a key step towards mapping larger brains. The fruit fly is commonly used in research so its brain map will also advance our understanding of how neural circuits operate.

Dr Marta Costa from the University of Cambridge’s Department of Zoology, who was also involved in the research, said “This brain map, the biggest so far, has only been possible thanks to technical advances that didn’t seem possible 10 years ago. It is a true testament to the way that innovation can drive research forward. The next steps will be to generate even bigger maps, such as a mouse brain, and ultimately, a human one.”

The researchers found substantial similarities between the wiring in this map and previous smaller-scale efforts to map out parts of the fly brain, leading them to conclude that there are many similarities in wiring between individual brains, meaning each brain is not a unique structure.

The cells in the fruit fly brain are connected by more than 50 million synapses. Image: Tyler Sloan and Amy Sterling/FlyWire/Princeton University
The cells in the fruit fly brain are connected by more than 50 million synapses. Image: Tyler Sloan and Amy Sterling/FlyWire/Princeton University

Comparing their brain diagram to the previous ones of small areas revealed that about 0.5 per cent of neurons have developmental variations that could cause connections between neurons to be miswired.

Future research could help us understand if these changes are linked to individuality or brain disorders.

Dr Mala Murthy, from Princeton University, one of the co-leaders of the research, said: “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. 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.”

How it was done

3D rendering of the 75k neurons in the fly’s visual system. Data source: FlyWire.ai. Rendering: Philipp Schlegel, University of Cambridge/MRC LMB.
3D rendering of the 75k neurons in the fly’s visual system. Data source: FlyWire.ai. Rendering: Philipp Schlegel, University of Cambridge/MRC LMB.

To create the brain wiring diagram - also known as a connectome - the researchers took one female brain, less than a millimetre in size and cut it into 7,000 slices, each only 40 nanometres thick.

These were scanned using high resolution electron microscopy in the laboratory of project co-leader Davi Bock, at Janelia Research Campus in the US.

More than 100 terabytes of image data was generated - about the same amount of storage you might in 100 typical laptops.

Extracting the shapes of 139,255 neurons and all 50 million connections between them was too big a task to be completed manually. Instead, the researchers built on artificial intelligence developed at Princeton University to identify and map neurons and their connections to each other.

But the AI still makes many errors in datasets of this size so the Princeton University researchers established the FlyWire Consortium, featuring teams in more than 76 laboratories and 287 researchers around the world, as well as volunteers from the general public.

They spent the equivalent of what would be about 33 years for one person painstakingly proofreading all the data.

Dr Sebastian Seung, from Princeton University, a co-leader of the research, said: “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. The fly brain is a milestone on our way to reconstructing a wiring diagram of a whole mouse brain.”

The researchers annotated many details, such as classifying more than 8,000 cell types, enabling them to select particular systems within the brain for further study, such as the neurons involved in sight or movement.

Dr Philipp Schlegel, the first author of one of the studies, from the MRC Laboratory of Molecular Biology, said: “This dataset is a bit like Google Maps but for brains: the raw wiring diagram between neurons is like knowing which structures on satellite images of the Earth correspond to streets and buildings.

“Annotating neurons is like adding the names for streets and towns, business opening times, phone numbers and reviews to the map – you need both for it to be really useful.”

Simulating brain function

3D rendering of the around 100 motor neurons of the fruit fly brain. These neurons control the fly’s mouth parts. The colours correspond to the nerve they project through. Data source: FlyWire.ai. Rendering: Philipp Schlegel, University of Cambridge/MRC LMB
3D rendering of the around 100 motor neurons of the fruit fly brain. These neurons control the fly’s mouth parts. The colours correspond to the nerve they project through. Data source: FlyWire.ai. Rendering: Philipp Schlegel, University of Cambridge/MRC LMB

This is the first whole brain wiring map to predict the function of all the connections between neurons, which use electrical signals to send messages.

Each neuron can have hundreds of branches connecting it to other neurons. They meet and transmit signals between neurons at points called synapses.

There are two primary ways that neurons communicate across synapses, known as excitatory, which promotes the continuation of the electrical signal in the receiving neuron, and inhibitory, which reduces the likelihood that the next neuron will transmit signals.

The scientists used AI image scanning technology to predict whether each synapse was inhibitory or excitatory.

Dr Jefferis said: “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.

“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.”

Associate Professor Davi Bock, one of the co-leaders of the research from the University of Vermont, said: “The hyper-detail of electron microscopy data creates its own challenges, especially at scale. This team wrote sophisticated software algorithms to identify patterns of cell structure and connectivity within all that detail.

“We now can make precise synaptic level maps and use these to better understand cell types and circuit structure at whole-brain scale. This will inevitably lead to a deeper understanding of how nervous systems process, store and recall information. I think this approach points the way forward for the analysis of future whole-brain connectomes, in the fly as well as in other species."

There are differences in neuronal structure between male and female fly brains, so the researchers also plan to characterise a male brain in the future.

The principal funders of the work were the National Institutes of Health BRAIN Initiative, Wellcome, Medical Research Council, Princeton University and National Science Foundation.



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