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Focused ultrasound excites neurons via mechanosensitive calcium accumulation and ion channel amplification

Yoo, Sangjin and Mittelstein, David R. and Hurt, Robert and Lacroix, Jerome and Shapiro, Mikhail G. (2020) Focused ultrasound excites neurons via mechanosensitive calcium accumulation and ion channel amplification. . (Unpublished)

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Ultrasonic neuromodulation has the unique potential to provide non-invasive control of neural activity in deep brain regions with high spatial precision and without chemical or genetic modification. However, the biomolecular and cellular mechanisms by which focused ultrasound excites mammalian neurons have remained unclear, posing significant challenges for the use of this technology in research and potential clinical applications. Here, we show that focused ultrasound excites neurons through a primarily mechanical mechanism mediated by specific calcium-selective mechanosensitive ion channels. The activation of these channels results in a gradual build-up of calcium, which is amplified by calcium- and voltage-gated channels, generating a burst firing response. Cavitation, temperature changes, large-scale deformation, and synaptic transmission are not required for this excitation to occur. Pharmacological and genetic inhibition of specific ion channels leads to reduced responses to ultrasound, while over-expressing these channels results in stronger ultrasonic stimulation. These findings provide a critical missing explanation for the effect of ultrasound on neurons and facilitate the further development of ultrasonic neuromodulation and sonogenetics as unique tools for neuroscience research.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Yoo, Sangjin0000-0002-0449-4242
Mittelstein, David R.0000-0001-8747-0483
Hurt, Robert0000-0002-4347-6901
Lacroix, Jerome0000-0001-5687-0652
Shapiro, Mikhail G.0000-0002-0291-4215
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Posted May 22, 2020. The authors thank Minjee Jang for assistance with calcium image processing and helpful discussions, and Tomokasu Sato for assistance with initial experiments, and all members of the Shapiro lab for helpful discussions and assistance with experiments. This research was supported by NIH BRAIN Initiative grants R24MH106107, RF1MH117080 (to M.G.S.) and NARSAD Young Investigator Grant (28802) from the Brain & Behavior Research Foundation. Author Contributions: S.J.Y. and M.G.S. conceived this research. S.J.Y. and M.G.S. designed all experiments and S.J.Y. performed and analyzed the data. D.R.M. and S.J.Y. planned and performed the high-speed-imaging. R.H. and S.J.Y. planned and performed the gene construction. J.L. designed the initial optical setup for calcium imaging. S.J.Y. and M.G.S. wrote the manuscript with inputs from all authors. The authors declare no competing financial interests. Data and Materials Availability: Raw data and genetic constructs are available upon request to the authors.
Funding AgencyGrant Number
Brain and Behavior Research Foundation28802
Record Number:CaltechAUTHORS:20200526-071834189
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Official Citation:Focused ultrasound excites neurons via mechanosensitive calcium accumulation and ion channel amplification. Sangjin Yoo, David R. Mittelstein, Robert Hurt, Jerome Lacroix, Mikhail G. Shapiro. bioRxiv 2020.05.19.101196; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103433
Deposited By: Tony Diaz
Deposited On:26 May 2020 17:16
Last Modified:26 May 2020 17:16

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