The worm returns

The wiring diagram of the male nematode’s nervous system is only a beginning.

When scientists seemed to have completed the map of the nervous system of a tiny male worm in 2012 (T. A. Jarrell et al. Science 337, 437–444; 2012), some researchers were already questioning whether the whole effort, originating some 40 years before, was truly worth it. The construction of the wiring diagram for the nervous system of the male of the nematode species Caenorhabditis elegans built on the wiring diagram for the hermaphrodite, established more than 25 years earlier, and required painstaking tracing of how the male worm’s extra neurons connected to each other.

Stephen Hawking was talking metaphorically when he famously wrote that to unravel the laws of nature would be to know the mind of God. The C. elegans project was quite literal: as Sydney Brenner, the originator of the project, jokingly entitled the manuscript of a landmark 1986 paper, the scientists really did want to know ‘the mind of the worm’. And in doing so, they argued, they could learn more about how brains create behaviour in higher organisms all the way up to humans.

Can we really know the mind of a worm? Three years on we have an answer of sorts: possibly. In fact, it turns out that we did not even find all the neurons that comprise the male worm’s mind. For on page 385, researchers including two of the 2012 team publish an appendix to the wiring diagram of the male C. elegans. As well as the 383 neurons already identified, they describe the discovery of neurons number 384 and 385, which they found in the worm’s head.

There is much to admire about the new work, not least that the researchers chose to call the new cells — mystery cells found in the male worms — MCMs. No metaphor there either. It stands for mystery cells of the male.

What’s on a male nematode’s MCMs? Not so much of a mystery as it turns out: sex. The new neurons have an old role, and help the worms to learn to prioritize the search for a mate over the need for food. When these neurons are put out of action, the male worms never discover the facts of life. The findings offer much more than a completion of the neural map of the male worm. In most organisms, sex-specific differences in behaviour extend to cognitive-like processes such as learning, which can aid reproductive success, but the underlying neural mechanisms are mostly unclear.

The discovery of the MCMs, and the subsequent experiments with them, link developmental and anatomical sex differences in high-order processing areas of the brain to sex-specific behaviour during learning. In doing so, they help to shed light on the neural basis of sex differences in behaviour. And they show that these neurons arise upon sexual maturation from specialized cells called glia — unlike other neurons in C. elegans and other invertebrates, which arise from epithelial or undifferentiated blast cells.

Was the effort to trace out the connections between the male nematode’s neurons worth it? Like all good maps, the wiring diagram of the C. elegansis best viewed as a starting point. The final destination is sure to surprise us.

Artificial worm starts to wriggle

C elegans
The project to create the C. elegans nematode in code should unlock more secrets of how it lives

A project to create artificial life has hit a key milestone – the simulated creature can now wriggle.

The Open Worm project aims to build a lifelike copy of a nematode roundworm entirely out of computer code.

This week the creature’s creators added code that gets the virtual worm wriggling like the real thing.

The next step is to hook the body up to a simulation of the worm’s brain to help understand more about how and why it moves.

Swim speed

The Open Worm project started in May 2013 and is slowly working towards creating a virtual copy of the Caenorhabditis elegans nematode. This worm is one of the most widely studied creatures on Earth and was the first multicelled organism to have its entire genome mapped.

The simulated worm slowly being built out of code aims to replicate C. elegans in exquisite detail with each of its 1,000 cells being modelled on computer.

Early work on the worm involved making a few muscle segments twitch but now the team has a complete worm to work with. The code governing how the creature’s muscles move has been refined so its swaying motion and speed matches that of its real life counterpart. The tiny C. elegans manages to move around in water at a rate of about 1mm per second.

“Its movement closely resembles published literature on how C. elegans swims,” project leader John Hurliman told the New World Notes blog.

The immediate next step for the project is to plug in the system used to model how nerve fibres in the worm fire to get muscle segments twitching and propelling the whole creature forward.

Soon the Open Worm creators hope to make a virtual version of C. elegans available online so people can interact with it via a web browser.

Using Precisely-Targeted Lasers, Researchers Manipulate Neurons in Worms’ Brains and Take Control of Their Behavior.

In the quest to understand how the brain turns sensory input into behavior, Harvard scientists have crossed a major threshold. Using precisely-targeted lasers, researchers have been able to take over an animal’s brain, instruct it to turn in any direction they choose, and even to implant false sensory information, fooling the animal into thinking food was nearby.

As described in a September 23 paper published in Nature, a team made up of Sharad Ramanathan, an Assistant Professor of Molecular and Cellular Biology, and of Applied Physics, Askin Kocabas, a Post-Doctoral Fellow in Molecular and Cellular Biology, Ching-Han Shen, a Research Assistant in Molecular and Cellular Biology, and Zengcai V. Guo, from the Howard Hughes Medical Institute were able to take control of Caenorhabditis elegans — tiny, transparent worms — by manipulating neurons in the worms’ “brain.”

The work, Ramanathan said, is important because, by taking control of complex behaviors in a relatively simple animal — C. elegans have just 302 neurons -we can understand how its nervous system functions..

“If we can understand simple nervous systems to the point of completely controlling them, then it may be a possibility that we can gain a comprehensive understanding of more complex systems,” Ramanathan said. “This gives us a framework to think about neural circuits, how to manipulate them, which circuit to manipulate and what activity patterns to produce in them .”

“Extremely important work in the literature has focused on ablating neurons, or studying mutants that affect neuronal function and mapping out the connectivity of the entire nervous system. ” he added. “Most of these approaches have discovered neurons necessary for specific behavior by destroying them. The question we were trying to answer was: Instead of breaking the system to understand it, can we essentially hijack the key neurons that are sufficient to control behavior and use these neurons to force the animal to do what we want?”

Before Ramanathan and his team could begin to answer that question, however, they needed to overcome a number of technical challenges.

Using genetic tools, researchers engineered worms whose neurons gave off fluorescent light, allowing them to be tracked during experiments. Researchers also altered genes in the worms which made neurons sensitive to light, meaning they could be activated with pulses of laser light.

The largest challenges, though, came in developing the hardware necessary to track the worms and target the correct neuron in a fraction of a second.

“The goal is to activate only one neuron,” he explained. “That’s challenging because the animal is moving, and the neurons are densely packed near its head, so the challenge is to acquire an image of the animal, process that image, identify the neuron, track the animal, position your laser and shoot the particularly neuron — and do it all in 20 milliseconds, or about 50 times a second. The engineering challenges involved seemed insurmountable when we started. But Askin Kocabas found ways to overcome these challenges”

The system researchers eventually developed uses a movable table to keep the crawling worm centered beneath a camera and laser. They also custom-built computer hardware and software, Ramanathan said, to ensure the system works at the split-second speeds they need.

The end result, he said, was a system capable of not only controlling the worms’ behavior, but their senses as well. In one test described in the paper, researchers were able to use the system to trick a worm’s brain into believing food was nearby, causing it to make a beeline toward the imaginary meal.

Going forward, Ramanathan and his team plan to explore what other behaviors the system can control in C. elegans. Other efforts include designing new cameras and computer hardware with the goal of speeding up the system from 20 milliseconds to one. The increased speed would allow them to test the system in more complex animals, like zebrafish.

“By manipulating the neural system of this animal, we can make it turn left, we can make it turn right, we can make it go in a loop, we can make it think there is food nearby,” Ramanathan said. “We want to understand the brain of this animal, which has only a few hundred neurons, completely and essentially turn it into a video game, where we can control all of its behaviors.”



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