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A fruit fly’s brain is the size of a poppy seed and is easy to miss.
“Most people don’t even think that the fly has a brain,” said Vivek Jayaraman, a neuroscientist at Howard Hughes Medical Institute’s Janelia Research Campus in Virginia. “But of course, flies lead pretty rich lives.”
Flies can engage in complex behaviors, including navigating a variety of landscapes. grapple with rivals and serenading potential spouses. And their speckle-sized brain is extremely complex, containing about 100,000 neurons. tens of millions of connections or synapses between them.
Since 2014, in collaboration with a team of scientists at Janelia researchers at Googleare mapping these neurons and synapses to create a comprehensive wiring diagram of the fruit fly brain, also known as a junction.
The work in progress is time-consuming and expensive, even with the help of state-of-the-art machine learning algorithms. But the data they have published so far are striking in their detail, creating an atlas of tens of thousands of knotty neurons in many key areas of the fly brain.
And now, in a great new paperPublished Tuesday in the journal eLife, neuroscientists have set out to show what they can do with it.
Dr. By analyzing the connectors of only a small part of the fly brain, the central complex that plays an important role in navigation, Jayaraman and colleagues identified dozens of new neuron types and precisely defined neural circuits that help flies find their way. over the world. The study could ultimately help provide insight into how animal brains of all kinds, including ours, process a stream of sensory information and turn it into appropriate action.
It is also a proof of principle for the young modern field of contecomics, built on the promise that creating detailed diagrams of the brain’s wiring will yield scientific returns.
A senior investigator at the Allen Institute for Brain Sciences in Seattle, Dr. “It’s really extraordinary,” said Clay Reid of the new article. “I think anyone who looks at it will tell you that connectomics is a tool we need in neuroscience – just stop.”
‘Your fly brain is cooked’
The only complete link in the animal kingdom belongs to the humble roundworm C. elegans. Pioneering biologist Sydney Brenner, who would later win the Nobel Prize, began the project in the 1960s. His small team spent years using colored pencils to manually trace all 302 neurons.
“Brenner understood that to understand the nervous system, you need to know its structure,” said Scott Emmons, a neuroscientist and geneticist at the Albert Einstein College of Medicine. create new C. elegans ports. “And that goes for biology. Structure is very important.”
Brenner and colleagues published their milestone paperreaching 340 pages in 1986.
But the field of modern conectomy didn’t rise until the 2000s, when advances in imaging and computation finally made it possible to map connections in larger brains. In recent years, research teams around the world have begun to connect links of zebrafish, songbirds, mice, humans, and more.
When the Janelia Research Campus opened in 2006, its founding director Gerald Rubin had his eye on the fruit fly. Dr. “I don’t want to offend any of my worm colleagues, but I think flies are the simplest brain that exhibits really interesting, complex behaviors,” said Rubin.
Several different teams at Janelia have embarked on fly-link projects since then, but the work that led to the new paper began in 2014. The brain of a single five-day-old female fruit fly.
The researchers cut the fly brain into slices and then used a technique known as focused ion beam scanning electron microscopy to carefully image them layer by layer. The microscope essentially functioned like a very small, very precise nail file, filing an extremely thin layer of the brain, taking a picture of the exposed tissue, and then repeating the process until there was nothing left.
Dr. “You view and cut small slices of the fly brain at the same time, so they won’t exist after you’re done,” Jayaraman said. “So if you screw something up, you’re done. Your goose is cooked – or your fly brain is cooked.”
The team then used computer vision software to combine the resulting millions of images into a single, three-dimensional volume and sent it to Google. There, the researchers used advanced machine learning algorithms to identify each neuron and trace its twisting branches.
Finally, the Janelia team used additional computational tools to pinpoint synapses, and human researchers tweaked the operation of computers, corrected errors, and developed wiring diagrams.
Researchers last year Published Connectome for what they call “hemibrain” A large part of the central fly’s brain containing regions and structures crucial for sleep, learning, and navigation.
Accessible for free online, the connector contains approximately 25,000 neurons and 20 million synapses; this is much more than the C. elegans conjunction.
“This is dramatic growth,” said Cori Bargmann, a neuroscientist at Rockefeller University in New York. “This is a tremendous step towards the goal of unraveling the brain’s connectivity.”
welcome to orientation
When the half-brain connection is ready, Dr., an expert in the neuroscience of flight navigation. Jayaraman was eager to dive into the data in the central complex.
The brain region, containing about 3,000 neurons and found in all insects, helps flies build an internal model of their spatial relationship to the world and then select and execute behaviors appropriate to their situation, such as foraging for food when they are hungry.
“You mean you can give me the wiring diagram for something like this?” Dr. Jayaraman said. “This is better industrial espionage than you can get by learning about the Apple iPhone.”
He and his colleagues studied connectivity data by examining how the region’s neural circuits are put together.
For example, Dr. Hannah Haberkern, a postdoctoral fellow in Jayaraman’s lab, analyzed neurons that send sensory information to the ellipsoid body. fly’s internal compass.
Dr. Haberkern found that neurons known to transmit information about the polarization of light (a spherical environmental marker many animals use for navigation) make more connections with compass neurons than neurons that relay information about other neurons. visual features and signs.
Neurons dedicated to the polarization of light also bind to brain cells that provide information about other navigational cues and have the ability to strongly inhibit.
The researchers hypothesize that flying brains may be wired to prioritize information about the global environment while navigating – but these circuits are flexible so they can pay more attention to local features of the landscape when such information is insufficient. Dr. “They have all these comeback strategies,” Haberkern said.
fruit fly phone home
Other members of the research team identified specific neural pathways that seemed well-suited to help the fly follow its head and body orientation, predict its future orientation and direction of travel, calculate its current orientation to another desired location, and then move in that direction. .
For example, imagine a hungry fly temporarily abandons a rotting banana to see if it can do anything better. But after a few (literally) fruitless minutes of exploration, he wants to return to his previous meal.
The connectivity data shows that certain brain cells, technically known as PFL3 neurons, help the fly perform this maneuver. These neurons receive two critical inputs: They receive signals from neurons that follow the direction the fly is facing, and from neurons that follow the direction of the banana.
After receiving these signals, the PFL3 neurons then send their own message to a series of rotating neurons, which in turn makes the fly deviate in the right direction. Dinner is served again.
Dr. “It’s really amazing to be able to track this activity through this circuit – from sensory to motor, through this complex intermediate circuit,” said research scientist Brad Hulse, who led this part of the analysis in Jayaraman’s lab. Binder added, “It showed us a lot more than we thought.”
And the group’s article – a draft with 75 figures and stretching to 360 pages – is just the beginning.
“It really provides this fundamental truth for further exploration of this brain region,” said Stanley Heinze, an insect neuroscientist at Lund University in Sweden. “It’s just extremely impressive.”
And it’s just plain enormous. Dr. “I would really treat it as a book rather than a paper,” Heinze said.
In fact, the paper is so large that the front print server bioRxiv At first, perhaps the admins refused to publish it because they — understandably — thought it actually happened. a book, said Dr. jayaraman (The server eventually published the work, after a few days of extra processing, he saved it.)
Dr. Jayaraman added that the publication of the article in eLife was “mutually required with some special permissions and editorial staff.”
flying lessons
There are limitations to what a snapshot of a single brain can reveal at a single moment in time, and connectomes don’t capture everything interesting in an animal brain. (Janelia’s hemibrain context bypasses glial cells that perform all sorts of important tasks in the brain, for example.)
Jayaraman and colleagues stressed that they wouldn’t have drawn so much from the connection had it not been for the research done decades ago by many other scientists on fruit fly behavior and basic neuron physiology and function, as well as theoretical neuroscience. Business.
But connection diagrams can help researchers explore existing theories and form better hypotheses, figuring out what questions to ask and what experiments to perform.
Dr. “What we’re really excited about now is to take the connectome-inspired ideas and go back to the microscope, get back to our electrodes, and actually record the brain and see if those ideas are true,” Hulse said.
Of course, one might ask, and some may ask why a fruit fly’s brain circuitry is important.
Dr. “This is what I get asked a lot during the holidays,” Hulse said.
Flies are not mice, chimpanzees or humans, but their brains perform some of the same basic tasks.. Understanding basic neural circuits in an insect could provide important clues to how other animal brains approach similar problems, said neuroscientist David Van Essen of the University of Washington in St.
Gaining a deep understanding of the fly brain “also gives us insights that are very relevant to our understanding of the brains and behavior of mammals and even humans,” he said.
Building the connections for larger, more complex brains will be extremely difficult. The mouse brain contains about 70 million neurons, while the human brain contains 86 billion neurons.
But the central complex paper is certainly not a one-off; Dr. Detailed studies of territorial mouse and human conjugates are currently in preparation, Reid said: “There’s a lot to come.”
Journal editors, consider yourself warned.
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