How to train your worm to explore the circuits involved in learning

Angelina Sylvain

Angelina Sylvain, a graduate student in the Princeton Neuroscience Institute, trains C. elegans roundworms to associate food with the smell of butterscotch for her studies of the neural circuits involved in learning and memory. (Photo by Molly Sharlach)

AS AN UNDERGRADUATE, Angelina Sylvain was fascinated to learn that devastating declines in cognition and muscle coordination could be caused by changes in a single gene — the cause of Huntington’s disease. She was intrigued by the fact that brain surgery on an epileptic patient cured him of seizures, but wiped out his ability to form short-term memories.

These remarkable discoveries first drew Sylvain to the field of neuroscience, though she never imagined that her own efforts to understand the human brain would involve training tiny worms.

A fourth-year graduate student in the Princeton Neuroscience Institute, Sylvain seeks to understand how the activities of neurons in the brain lead to particular behaviors and memories.

“The problem with studying the human brain is that we have 86 billion neurons,” she said. “But worms have only 302. And they’re transparent, so you can use imaging techniques to indirectly observe the activities of neurons.”

The millimeter-long roundworms, known by the scientific name Caenorhabditis elegans, can be found squirming underfoot in temperate environments. In the lab, they swim in petri dishes and feast on E. coli bacteria. Working with Coleen Murphy, an associate professor of molecular biology and the Lewis-Sigler Institute for Integrative Genomics, Sylvain teaches the worms to associate food with the scent of butanone, a chemical that smells like butterscotch.

During the training process, Sylvain tracks the activation of individual neurons as the worms learn to identify and move toward the alluring odor. She uses specially engineered worms in which specific neurons glow green in response to calcium ions, hallmarks of neuron activation. At first, only a sensory neuron lights up when the worms smell butanone. But after the worms learn to associate butanone with a meal, Sylvain can detect the activation of an entire neural circuit — a sensory neuron, an interneuron and a motor neuron. The motor neuron leads the worm to swim toward the scent.

By training the worms, Sylvain hopes to answer basic questions about how long-term memories are formed. She plans to examine the numbers and combinations of neurons required to establish memories, as well as the adaptability of memory-forming pathways. By eliminating specific neurons, she can test whether the worms can still form memories, and how the circuits change.

Sylvain relishes both the challenges and the rewards of academic research. “Academia offers a fantastic combination of the ability to teach and mentor, and also to ask awesome research questions,” she said. “It’s always a struggle when experiments fail. But when things finally work out, there’s a great sense of satisfaction that you’ve uncovered something nobody else knows.”

Coleen Murphy’s research group is funded by the National Institute on Aging of the National Institutes of Health.

–By Molly Sharlach