Using ultrasound to activate ion channels in brain cells
Oct. 19, 2021-- Researchers have discovered the mechanism that causes ion channels in brain cells to switch open after the cells are exposed to ultrasound waves. The discovery could have applications in the development of non-invasive, non-pharmacological treatments of neurological conditions.
The team, which is composed of researchers from the MADLab at University of California San Diego and the Chalasani lab at the Salk Institute for Biological Studies, presents its results in the Nov. 7 issue of the journal Advanced Science.
“No one has seen the cell membrane move like this before,” said James Friend, a professor in the UC San Diego Department of Mechanical and Aerospace Engineering.
The researchers discovered that the thin membranes of neuronal and fibroblast cells are deformed by incident ultrasound, which causes these membranes to stretch. This is surprising because the cell membranes are roughly 10 nanometers thick, or 10,000 times smaller than a human hair's width. In addition, the liquid on both sides of the membranes is roughly the same composition. Researchers observed that the stretch is caused by the reflection of a small portion of the ultrasound from the membrane, deforming and stretching it.
When the membrane stretches, its capacitance changes. Because there is already a voltage difference from the inside of the cell to the outside (due to chemical differences), a capacitance change in the presence of this voltage difference causes current to flow.
“This may prove effective in triggering specific ion channels, such as TRPA1, an ion channel often used in sonogenetics research,” said Aditya Vasan, the paper’s first author and a Ph.D. student in Friend’s research group.
This ion channel is already expressed in important cells in some organs, making this type of ultrasound intervention possible. As a result, this mechanism could also be used in treatments used on the heart, liver, pancreas, gall bladder and other organs that either have TRPA1 or could be added later.
A unique system
A unique high-speed, digital, holographic microscope allowed researchers to observe this stretching mechanism for the first time. Researchers were able to use the instrument to confirm the amplitude of the cell membrane's deformation and its dynamic response to ultrasound exposure.
The microscope marries a 1-million frame-per-second camera to a laser-driven microscope that uses holography — the interference between light passed through a measurement sample and light that goes around that sample. The holographic method produces a measurement of the deformation of a surface—whether a fluid-air surface or the surface of a cell membrane—without scanning.
Most models of cell membranes use static analyses, ignoring the dynamics of that model. The team’s results suggest ignoring the dynamics may be a mistake. Their model is dynamic, and includes mechanical and electrical information to form a complete picture. It is also nonlinear. The results are similar to what was observed in experiments for similar ultrasound exposure values. The nonlinearity and the dynamics are both important parts in modeling.
This work was completed in in vitro neurons and HEK cells. Next steps include investigating in mice whether TRPA1 and potentially other channels can be used to provide targeted actuation of cells in the brain of live, freely moving mice.
The research was funded by a SERF grant from the W.M. Keck Foundation, the National Institutes of Health and the National Science Foundation.
Jacobs School of Engineering