Sonothermogenetic pulse controls mouse behavior

Science Highlights
September 22, 2021
Thomas M Johnson

Sound + heat + genetics = first test of non-invasive cell-specific brain therapy in mice

Neurological disorders such as Parkinson's disease and epilepsy have had some treatment success using deep brain stimulation devices, but those require invasive and expensive surgical implantation. Now engineers funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) have devised a system to control motor activity in the brain without surgical device implantation, a first step toward non-invasive cell-specific brain stimulation therapies.

The research team, led by Hong Chen, PhD, associate professor of biomedical engineering in the McKelvey School of Engineering and radiation oncology in the School of Medicine at Washington University in St. Louis have combined sound, heat, and genetics to create a non-invasive system able to stimulate specific cell types deep inside the brain. 

Illustration of activation of TRPV1 ion channel by focused ultrasound
Focused ultrasound (FUS) non-invasively activates the TRPV1 receptor to turn on specific mouse neurons. When FUS contacts TRPV1 on the surface of mouse brain cells the small heat increase causes the receptor to open allowing the influx of calcium ions that stimulates the neuron. Credit: Chen Ultrasound Lab, University of Washington in St. Louis.

 

They have named the approach sonothermogenetics.

“Sono” refers to the ultrasound part of the technology. It takes advantage of the ability of focused ultrasound to penetrate deep into the brain, but have an effect only on a small area of brain cells being targeted. “Thermo” refers to a tiny amount of heat that is created when the ultrasound hits its target. “Genetics” refers to the fact that the team uses genes that encode proteins that can be turned on and off by the small amount of heat generated by the focused ultrasound. 

“This engineering approach could help address the public health problem created by the growing number of individuals affected by neurological disorders worldwide by offering non-invasive treatment alternatives to patients,” said Randy King, PhD, director of the NIBIB program in Interventional Ultrasound. 

link to video about sonothermogenetics
Watch the video from the Chen Ultrasound Lab

The work was made possible by the combination of ultrasound and a heat sensitive cell surface ion channel called TRPV1. Tests in cell cultures confirmed that when TRPV1 is on the surface of cells, ultrasound treatment increases the temperature by only 4–5 degrees causing the TRPV1 ion channel to turn on. 

The group then tested their system in mice. They used a viral vector carrying the gene for TRPV1 to deliver the heat sensitive ion channel into the striatum in the brains of mice. The striatum was chosen because it is the area of the brain that controls motor movement.

Focused ultrasound was then delivered to the striatum. When the focused ultrasound was turned on the TRPV1 channel was activated, and the mice repeatedly turned in circles until the ultrasound was turned off. There was no change in movement in mice treated with the ultrasound that had not been infected with the viral vector and so did not have the TRPV1 gene in the neurons of the striatum. The results confirmed that infecting the desired neural cell type with the heat sensitive TRPV1 gene allowed the researchers to influence the activity of the desired brain cells with focused ultrasound.

The research team is now working to scale sonothermogenetics from mice to larger animal models. As proof of concept for potential use in humans, the team has begun work using the sonothermogenetic system to modulate eye movements in non-human primates.

“It is going to be a long way for us to move this technique to humans because it involves gene engineering to modify neurons in the brain,” explains Hong, on the potential of the sonothermogenetic technology. “But we're confident once we overcome all the hurdles and translate this technique to the clinic, it would play a transformative role in next-generation therapies for the treatment of central neural system diseases, such as Parkinson's, depression, and epilepsy.”

The study results were published in the journal Brain Stimulation [1].

The work was supported by the National Institutes of Health (NIH) BRAIN Initiative (R01MH116981) and NIBIB (R01EB027223 and R01EB030102), and the Hope Center Viral Vectors Core at Washington University School of Medicine.

1. Sonothermogenetics for noninvasive and cell-type specific deep brain neuromodulation. Yang Y, Pacia CP, Ye D, Zhu L, Baek H, Yue Y, Yuan J, Miller MJ, Cui J, Culver JP, Bruchas MR, Chen H. Brain Stimul. 2021 Jul-Aug;14(4):790-800. doi: 10.1016/j.brs.2021.04.021.

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