Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.14.338699v1?rss=1 Authors: Duque, M., Lee-Kubli, C., Tufail, Y., Magaram, U., Lopez, J. M., Edsinger, E., Vasan, A., Shiao, R., Weiss, C., Friend, J., Chalasani, S. H. Abstract: Our understanding of the nervous system has been fundamentally advanced by light- and small molecule-sensitive proteins that can be used to modify neuronal excitability. However, optogenetics requires invasive instrumentation while chemogenetics lacks temporal control. Here, we identify a candidate channel that confers sensitivity to non-invasive ultrasound on millisecond timescales. Using a functional screen, we find that human Transient Receptor Potential A1 (hsTRPA1) increases ultrasound-evoked intracellular calcium levels and membrane potentials. Ultrasound, but not agonist, -evoked, gating of hsTRPA1, requires the N-terminal tip region, intact actin cytoskeleton, and cholesterol, implicating these features in the sonogenetic mechanism. We then use calcium imaging and electrophysiology to confirm that ultrasound-evoked responses of primary neurons are potentiated by hsTRPA1. We also show that unilateral expression of hsTRPA1 in mouse layer V motor cortical neurons leads to ultrasound-evoked contralateral limb responses to ultrasound delivered through an intact skull. Finally, ultrasound induces c-fos in hsTRPA1-expressing neurons, suggesting that our approach can be used for targeted activation of neural circuits. Together, our results demonstrate that hsTRPA1-based sonogenetics can effectively and non-invasively modulate neurons within the intact mammalian brain, a method that could be extended to other cell types across species. Copy rights belong to original authors. Visit the link for more info