Mapping the Mind: Worm's Brain Activity Fully Decoded

Using new technologies and methodologies, they have developed a comprehensive atlas that shows how most of the worm's neurons code for its various actions.

This study provides a complex look at how an animal's nervous system controls behavior. The team's findings, data and models are available on the "WormWideWeb".

Highlights:

The study used a new microscope and software system that tracked nearly every behavior of the worm and the activity of every neuron in its head.

The research found that neurons encode both current and past behaviors, allowing the worm to understand the impact of its past actions on its current situation.

An important finding was that 30% of neurons that code behavior can remap their behavior coding, adapting their functions to changing circumstances.

Source: Picower Institute for Learning and Memory

To understand the full relationship between brain activity and behavior, scientists needed a way to map this relationship for all neurons in an entire brain, a challenge so far insurmountable.

But after inventing new technologies and methods for this purpose, a team of scientists from MIT's Picower Institute for Learning and Memory have produced a rigorous accounting of neurons in the tiny brain of a lowly worm C. elegans , mapping how his brain cells encode nearly all of his essential behaviors, such as movement and eating.

In the journal Cell, the team presents new brain-scale recordings and a mathematical model that accurately predicts the various ways in which neurons represent the worm's behaviors.

By applying this model specifically to each cell, the team produced an atlas of how most cells and the circuits in which they participate encode the animal's actions. The atlas therefore reveals the underlying "logic" of how the worm's brain produces a sophisticated and flexible repertoire of behaviors, even when its environmental circumstances change.

"This study provides a global map of how the animal's nervous system is organized to control behavior," said lead author Steven Flavell, associate professor in MIT's Department of Brain and Cognitive Sciences.

"It shows how the many defined nodes that make up the animal's nervous system encode precise behavioral characteristics, and how this depends on factors such as recent experience and the animal's current condition."

Graduate students Jungsoo Kim and Adam Atanas, who each earned their PhDs this spring for the research, are co-lead authors on the study. They also made all of their data, along with the results of their model and atlas, freely available to fellow researchers on a website called WormWideWeb.

Microscopes to models

To perform the measurements needed to develop their model, Flavell's lab invented a new microscope and a software system that automatically tracks nearly all of the worm's behaviors (moving, feeding, sleeping, egg-laying, etc.) and worm activity. each neuron in its head (the cells are designed to flash as calcium ions build up).

Distinguishing and reliably tracking separate neurons as the worm wiggles and bends required writing custom software, using the latest tools in machine learning. It was found to be 99.7% accurate in sampling the activities of individual neurons with a significantly improved signal-to-noise ratio compared to previous systems, the scientists report.

The team used the system to simultaneously record the behavior and neural data of more than 60 worms as they scoured their dishes, doing whatever they wanted.

Analysis of the data revealed three new observations about neural activity in the worm: neurons track behavior not only of the present moment but also of the recent past; they adapt their encoding of behaviors, such as movement, based on a surprising variety of factors; and many neurons encode multiple behaviors simultaneously.

For example, while wiggling around your little lab box might seem like a very simple act, neurons represent factors like speed, direction, and whether or not the worm is eating. In some cases, they represented the movement of the animal going back in time for about a minute.

By encoding recent movements rather than current movements, these neurons could help the worm calculate how its past actions influenced its current outcome. Many neurons also combined behavioral information to perform more complex maneuvers.

Just as a human driver must remember to steer the car in the opposite direction when backing up rather than forward, certain neurons in the worm's brain have integrated the direction of movement and the direction of the animal's steering.

By carefully analyzing these types of correlation patterns between neural activity and behaviors, scientists developed the probabilistic neural coding model of C. elegans.

The model, encapsulated in a single equation, explains how each neuron represents various factors to accurately predict if and how neural activity reflects behavior. Nearly 60% of the neurons in the worm's head represented at least one behavior.

To fit the model, the research team used a probabilistic modeling approach that allowed them to understand how certain they were of each parameter in the fitting model, an approach pioneered by co-author Vikash Mansinghka, a principal investigator who leads the Probabilistic Computation Project at MIT.

make an atlas

By creating a model that could quantify and predict how any brain cell would represent behavior, the team first collected data from neurons without tracking the specific identity of the cells. But a key goal of studying worms is to understand how each cell and circuit contributes to behavior.

So, to apply the model's ability to each of the worm's specific neurons, all of which were previously mapped, the team's next step was to link the neural activity and behavior of each cell on the map.

To do this, each neuron had to be labeled with a unique color so that its activity could be associated with its identity. The team did this on dozens of free-moving animals, which gave them insight into how nearly every defined neuron in the worm's head related to the animal's behavior.

The atlas resulting from this work revealed a great deal of information, mapping more completely the neural circuits that control each of the animal's behaviors. These new findings will allow for a more holistic understanding of how these behaviors are controlled, Flavell said.

"It allowed us to come full circle," he said. “Our hope is that as our colleagues study aspects of neural circuit function, they can refer to this atlas to get a fairly comprehensive view of the major neurons involved.

Designed for flexibility

Another major result of the team's work was the discovery that while most neurons still obeyed the model's predictions, a smaller set of neurons in the worm's brain - about 30% of those that code behavior - were able to flexibly remap their behavior coding, essentially new jobs.

Neurons in this group were reliably similar across animals and were well connected to each other in the worm's synaptic wiring diagram.

Theoretically, these remapping events could occur for a number of reasons. So the team conducted further experiments to see if they could cause neurons to remap. As the worms squirmed around their dishes, the researchers applied a rapid laser zap that heated the agar around the worm's head.

The heat was harmless but sufficient to annoy the worms for some time, inducing a change in the animal's behavioral state that lasted a few minutes. From these recordings, the team could see that many neurons remapped their behavioral coding as the animals changed behavioral states.