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Published January 25, 2022 | public
Journal Article Open

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


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 primary murine cortical neurons in culture 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 mechanistic explanation for the effect of ultrasound on neurons to facilitate the further development of ultrasonic neuromodulation and sonogenetics as tools for neuroscience research.

Additional Information

© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 09 June 2021; Accepted 05 January 2022; Published 25 January 2022. The authors thank Minjee Jang for assistance with calcium image processing and helpful discussions, Tomokazu 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. Related research in the Shapiro Lab is supported by the Packard Fellowship. Data availability: Genetic constructs will be made available through Addgene. Source data are provided with this paper. Code availability: Processing code is available upon request to the authors. 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 the experiments and analyzed the data. D.R.M. and S.J.Y. planned and performed the high-speed-imaging. R.C.H. and S.J.Y. designed and built the genetic constructs. J.L. designed the initial optical setup for calcium imaging. S.J.Y. and M.G.S. wrote the manuscript with input from all authors. The authors declare no competing interests. Peer review information: Nature Communications thanks Jacob Robinson and the other anonymous reviewer(s) for their contribution to the peer review this work. Peer reviewer reports are available.

Attached Files

Submitted - 2020.05.19.101196v1.full.pdf

Supplemental Material - 41467_2022_28040_MOESM1_ESM.pdf

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August 22, 2023
September 11, 2023