Fruit fly larvae: Explain how neurons connect to networks and how brain circuits create behavior.

Marta Zlatic has one of the longest and most tedious film libraries.
at her lab at the Janelia Research Campus at the Howard Hughes Medical Institute in Virginia, the neuroscientist stored more than 20,000 hours of black-and-white short films starring fruit fly larvae.
the protagonists of these films are doing everyday things, such as wriggles and crawls, but they can help answer one of the most important questions in modern neuroscience: how brain circuits create behavior.
This is an important goal throughout the field of neuroscience: to clarify how neurons connect to networks, how signals move across networks, and how they collaborate to guide animals around, make decisions, or, for humans, express emotions and create consciousness.
the simplest "wiring map" of the brain that scientists have in focused fruit flies comes from the beautiful crypto-nebule -- just over 300 neurons.
its connectivity (a map of each individual neural connection) was drawn in the 1980s.
, however, it is difficult to look closely at the connections in these activities.
neuroscientist suspects that the worm's brain works in the same way as the larger brain.
is why many scientists like Zlatic rely on another invertebrate, fruit flies.
the larvae of fruit flies are complex enough to show some interesting behavior, but have enough neurons to make it feasible to map brain circuits.
, Zlatic and colleagues have mastered a range of related techniques, such as photogenetics.
the technique, photosensitive proteins are used to control or monitor neuron activity when fruit flies are active.
Zlatic and her husband Albert Cardona, who also work at the Jania Research Park, are developing ways to collect high-resolution cross-sectional images of the larvae' brains and automate the painstaking process of tracking all connections between the parts.
then, by matching the larvae' behavior and activity patterns to the map, the team was able to discover which loops brought about the corresponding behavior.
, for example, is how the brain chooses between two competing behaviors.
last year, Cardona, Zlatic and their team tracked a brain circuit in fruit fly larvae.
when larvae face nasty airflow, the researchers asked them to choose between curling their heads up and bending them.
the second encounter with airflow, the same larvae may first choose to bend their heads and then curl their heads.
team identified which neurons were responding to the air coming out and activated them in turn using photogenetics.
they observed that the brain circuit was inhibited when they were crouching, and the brain circuit was enhanced when the head was bent.
all of this happens in milliseconds.
, the researchers built computer models to predict how larvae respond when stimulated in a specific way.
"wiring map" if studying neural circuits can be a revelation, it is that no network is too small to surprise, and attempts to understand them have been repeatedly thwarted.
30 years ago, Eve Marder, a neuroscientman at Brandis University in Massachusetts, has been studying simple circuits of 30 neurons in a crab's gastrointestinal system.
its role is simple, and the "wiring map" was drawn decades ago.
, however, this simple loop still provides some puzzles.
, for example, Marder found that while the circuits of individual animals may look similar and produce the same output, they vary widely in signal strength and synth conductivity.
, she is now focusing on how loops maintain their identity over time, as things like ion channels and receptors are replaced.
there are rules for replacing all components but still maintaining loops? All of these challenges apply equally to larger networks, says Marder.
"we still have a long way to go in figuring out how to deal with the information we get from animals performing various behaviors and performing complex tasks.
scientists are preparing for this challenge.
this effort requires a number of new methods of data collection and analysis, many of which have become widespread over the past five years or so.
Zlatic team worked with other scientists at the Jania Research Park to adapt the photogenetics tool.
to analyze video of fruit fly larvae, Zlatic brings in statisticians and computer experts who specialize in machine learning to design methods for classifying larvae movements.
, in Cardona's lab, scientists edited thousands of images of brain slices taken using electron microscopes and did their best to track connections between neurons to map the larvae' brains.
the map as a starting point for their other work, including mapping brain circuits, manipulating brain circuits, and observing larvae' behavior.
, however, cardona says the drawing process is a major obstacle in the field for now.
160 neurons that reconstructed the fruit fly odor detection circuit took the Cardona team more than 1,100 hours.
an estimate extrapolated from previous fruit fly studies shows that mapping the entire brain of adult fruit flies takes hundreds of people a year to complete.
it helps to automate this process, the algorithm may add false connections or miss some connections although it is possible.
who work on larger circuits often break down problems -- starting with a list of cell types.
is being used by the Allen Institute for Brain Sciences in Seattle, the Mouse Brain Connection Map project.
study published in 2014, the team identified 49 cells in the visual cortical system of mice alone.
these cells vary in size and shape, discharge speed, and expression of genes.
researchers predict that there are several orders of magnitude more cell types in the brain as a whole.
"I guess there could be up to 10,000 neurons.
," said Hongkui Zeng, a researcher from the project.
task of providing information about medical problems on many neuroscientists' wish lists is to record the activity of multiple neurons at the same time.
, the researchers were able to stimulate a neuron and observe which other neurons were stimulated, and then build dynamic images of the chains of control that contribute to various behaviors.
" is the next big challenge in mapping more complex brains.
," Says Zeng.
that even in a circuit of 30 cells favored by Mader, this is still hypothetical.
Marder can insert electrodes into several cells at the same time.
other scientists who study small circuits use a variety of techniques to find indicators of which cells are discharge and when.
, for example, the researchers were able to measure calcium ions released by neuron discharge, or to observe fluorescent reactions that responded to changes in voltage around cell membranes.
, however, it's like measuring the speed of a car by using the force of the wind it generates as it passes: the speed of the indicator can't keep up with the discharge rate itself.
now, you can record the activity of all neurons, but it's a little slow, only once in two seconds.
," Zlatic says, "but in the time you missed it, it happened."
"to more accurately grasp the dynamics of brain circuits or to provide information to solve medical problems."
spent 25 years teaching students about brain networks, including those drawn up by experts working on Parkinson's disease.
admits that if the treatment works, the details of the brain circuit don't really matter, but they may help figure out why the drug works for some but not for others, or which factors are linked to the drug's efficacy.
clinical evidence suggests that different Parkinson's patients have different potential abnormalities in specific brain regions and circuits.
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