The first map of every neuron in an adult brain was made for a fruit fly

The first wiring diagram of every neuron in an adult brain and the 50 million connections between them was made for a fruit fly.

This historic achievement was achieved by a large international collaboration of scientists, called the FlyWire Consortium, including researchers from the MRC Molecular Biology Laboratory (in Cambridge, UK), Princeton University, the University of Vermont and from the University of Cambridge.

It is published in two articles in Nature.

The diagram of the 139,255 neurons in the brain of an adult fly is the first of an entire brain for an animal capable of walking and seeing. Previous efforts have completed full brain diagrams of much smaller brains, such as that of a fruit fly larva, which has 3,016 neurons, and that of a nematode worm, which has 302 neurons.

Researchers say the complete fly brain map is a key first step to completing larger brains. Because the fruit fly is a common tool in research, its brain map can be used to advance our understanding of how neural circuits work.

Dr Gregory Jefferis, from the MRC Molecular Biology Laboratory and University of Cambridge, who was one of the co-leads of the research, said: “If we want to understand how the brain works, we need a mechanistic understanding of how all the neurons come together and allow you to think. For most brains, we have no idea how these networks work.

“Flies can do all sorts of complicated things like walk, fly, navigate, and males sing to females. Brain wiring diagrams are a first step toward understanding everything we care about: how we control our movements , answer the phone, or recognize a friend.

Dr Mala Murthy of Princeton University, who was one of the co-leads of the research, said: “We have made the entire database open and freely accessible 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 it will be possible to compare what happens when things go wrong in our brains, for example with mental health problems.”

Brains are not snowflakes

The scientists found that there were substantial similarities between the wiring of this map and previous smaller-scale efforts that had mapped parts of the fly’s brain. This led researchers to conclude that there are many similarities in the wiring between individual brains, that each brain is not a single structure like a snowflake.

Comparing their brain diagram to previous diagrams of small areas of the brain, the researchers also found that about 0.5 percent of neurons showed developmental variations that could lead to miswiring of connections between neurons. The researchers say this will be an important area for future research to understand whether these changes are linked to individuality or brain disorders.

Make the map

An entire fly brain is less than 1 millimeter wide. The researchers started with a female brain cut into seven thousand slices, each just 40 nanometers thick, which were previously scanned by high-resolution electron microscopy in the laboratory of project co-leader Davi Bock, then at Janelia Research Campus in the United States.

Analyzing more than 100 terabytes of image data (the equivalent of the storage in 100 typical laptop computers) to extract the shapes of approximately 140,000 neurons and 50 million connections between them is too big a challenge for humans to handle. carried out manually. The researchers relied on AI developed at Princeton University to identify and map neurons and their connections to each other.

However, AI still makes many errors in data sets of this size. The FlyWire Consortium, comprised of teams from more than 76 laboratories and 287 researchers from around the world, as well as volunteers from the general public, dedicated approximately 33 person-years to carefully reviewing all the data.

Dr Sebastian Seung, from Princeton University, who was one of the co-leads of the research, said: “Mapping the entire brain has been made possible thanks to advances in computer AI. It would not have been possible to reconstruct the entire wiring diagram. manually. This is a demonstration of how AI can advance neuroscience. The fly brain is an important step in our journey to reconstructing a wiring diagram of an entire mouse brain.

The researchers also annotated many details about the wiring diagram, such as the classification of more than 8,000 cell types in the brain. It also allows researchers to select particular systems in the brain for further study, such as neurons involved in vision or movement.

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

“Annotating neurons is like adding street and city names, business hours, phone numbers, reviews, etc. to the map: you need both to make it really useful.”

Simulation of brain functions

It is also the first whole-brain wiring map – often called a connectome – to predict the function of all connections between neurons.

Neurons use electrical signals to send messages. Each neuron can have hundreds of branches that connect it to other neurons. The points where these branches meet and transmit signals between neurons are called synapses. There are two main ways that neurons communicate across synapses: excitatory (which promotes the continuation of the electrical signal into the receiving neuron) or inhibitory (which reduces the likelihood that the next neuron will transmit signals).

The team’s researchers also used AI image scanning technology to predict whether each synapse was inhibitory or excitatory.

Dr. Jefferis added: “To begin to digitally simulate the brain, we need to know not only the structure of the brain, but also how neurons work to turn on and off. »

“Using our data, which was shared online as we worked, other scientists have already begun trying to simulate how the fly’s brain responds to the outside world. It’s an important start, but we will need to collect many different types of data to produce reliable simulations of how a brain works.

Associate Professor Davi Bock, who was one of the co-leads of the University of Vermont research, said: “The hyper-detail of electron microscopy data creates its own challenges, particularly at large scales. This team wrote sophisticated software algorithms to identify patterns of cellular structure and connectivity in all these details.

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

This research was conducted using a female fly brain. Since there are differences in neuronal structure between the brains of male and female flies, the researchers also plan to characterize a male brain in the future.