Unraveling the Complexity of Action Potential Propagation in Unmyelinated Axons

Axons are tiny parts of nerve cells that carry electrical signals. To send signals quickly and reliably, some axons are wrapped by myelin and insulated, much like electrical cables. However, many axons in our brain are not myelinated, and scientists still do not fully understand how nerve signals can move so quickly and reliably in those axons. Recent work suggests that unmyelinated axons are not just cables with a constant diameter like electrical cables; instead, they have repeating narrow and wider sections. The project will ask whether important sodium and potassium channels are found mainly in the wider sections, and whether the shape of the axon membrane controls where these channels insert and how well they work. By learning how the shape of a nerve cell helps control electrical signaling, this research could improve our basic understanding of how the brain works and help scientists build better models of nerve function. This project will have broad educational impacts as it will provide scientific training for high-school and undergraduate students, in addition to outreach events aimed at K-12 students and their families. This project advances NSF’s priorities in Biotechnology and Artificial Intelligence. The project will test the idea that sodium and potassium channels are concentrated in the wider parts of unmyelinated axons because membrane shape and local lipid composition create conditions that favor channel placement and activity. To do this, we will use live-cell labeling, electrophysiology, voltage imaging, and electron microscopy to map where these channels are located and how they function. They will also use computer simulations to study how membrane curvature affects lipid distribution, channel localization, and channel behavior at both coarse-grained and atomic levels. These results will then be added to models of action potential propagation in single axons and small networks of neurons. Finally, the team will experimentally test the model’s predictions by changing axon shape, reducing ankyrin and spectrin proteins that help organize channels, and measuring whether membrane tension affects channel function in cells grown in the lab. Together, these studies will show how axon shape, membrane organization, and ion channels work together to control nerve signaling in unmyelinated neurons This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.