Discovery of a master neuron that controls movement in worms has implications for human disease

Researchers at Sinai Health and the University of Toronto have uncovered a mechanism in the nervous system of the tiny roundworm C. elegans that could have significant implications for treating human diseases and advancing robotics.

The study, led by Mei Zhen and colleagues at the Lunenfeld-Tanenbaum Research Institute, was published in the journal Science Advances and reveals the crucial role of a specific neuron called AVA in controlling the worm’s ability to shift between forward and backward motion.

Crawling towards food sources and swiftly reversing from danger is a matter of life and death for the worms. This type of behavior, where two actions are mutually exclusive, is common in many animals including humans—we cannot sit and run at the same time, for example.

Scientists long believed that control of movements in worms was due to straightforward reciprocal actions between two neurons: AVA and AVB. The former was thought to promote backward motion while AVB facilitated forward motion, with each neuron inhibiting the other to control movement direction.

However, the new data from Zhen’s team challenge this notion, uncovering a more complex interaction where the AVA neuron plays a dual role. It not only instantly stops forward motion by inhibiting AVB, but also maintains a longer-term stimulation of AVB to ensure a smooth transition back to forward movement.

The discovery highlights the AVA neuron’s ability to finely control movement through distinct mechanisms, depending on different signals and across different time scales.

“In terms of engineering, this is a very economical design,” said Zhen, who is also a professor of molecular genetics in U of T’s Temerty Faculty of Medicine. “The strong, robust inhibition of the backward circuit allows the animals to respond to bad environments and escape. At the same time, the controller neuron continues to put in constitutive gas into the forward circuit to generate movement towards safer places.”

Jun Meng, a former Ph.D. student in the Zhen lab who led the research, said understanding how animals transition between such opposing motor states is crucial for insights into how animals move as well as neurological disorder research—and that the worms provide a unique window into basic neural wiring inside their simple, see-through bodies.

The discovery that the AVA neuron plays such a dominant role offers a major new insight into the neural circuit that scientists have studied since the inception of modern genetics over half a century ago. The Zhen lab successfully leveraged cutting-edge technology to precisely modulate the activity of individual neurons and record data from living worms in motion.

Zhen, who is also a professor of cell and systems biology at U of T’s Faculty of Arts & Science, emphasizes the importance of interdisciplinary collaboration in this research. Meng performed key experiments, while neuronal electrical recordings were conducted by Bin Yu, a Ph.D. student in Shangbang Gao’s lab at Huazhong University of Science and Technology in China.

Tosif Ahamed, a former post-doctoral researcher in the Zhen lab and now a Theory Fellow at the HHMI Janelia Research Campus in the United States, led mathematical modeling efforts that were crucial for testing hypotheses and gaining the new insights.

The findings provide a simplified model to study how neurons can manage multiple roles in movement control—a concept that might extend to human neurological conditions.

For example, AVA’s dual role depends on its electric potential, which is regulated by ion channels on its surface. Zhen is already exploring how similar mechanisms could be involved in a rare condition known as CLIFAHDD syndrome, caused by mutations in similar ion channels. Additionally, the new findings could inform the development of more adaptable and efficient robotic systems capable of complex movements.

“From the origin of modern science to the forefront of today’s research, model organisms like C. elegans have been instrumental in peeling back the layers of complexity in our biological systems,” said Anne-Claude Gingras, director of the Lunenfeld-Tanenbaum Research Institute, vice-president of research at Sinai Health and a professor of molecular genetics in U of T’s Temerity Faculty of Medicine.

“This research is a great example of how much we can learn from simple animals, to then think about applying this new knowledge to advancing medicine and technology.”