Abstract Ultrasound has been used to non-invasively manipulate neuronal functions in humans and other animals 1–4 . However, this approach is limited as it has been challenging to target specific cells within the brain or body 5–8 . Here, we identify human Transient Receptor Potential A1 ( hs TRPA1) as a candidate that confers ultrasound sensitivity to mammalian cells. Ultrasound-evoked gating of hs TRPA1 specifically requires its N-terminal tip region and cholesterol interactions; and target cells with an intact actin cytoskeleton, revealing elements of the sonogenetic mechanism. Next, we use calcium imaging and electrophysiology to show that hs TRPA1 potentiates ultrasound-evoked responses in primary neurons. Furthermore, unilateral expression of hs TRPA1 in mouse layer V motor cortical neurons leads to c-fos expression and contralateral limb responses in response to ultrasound delivered through an intact skull. Collectively, we demonstrate that hs TRPA1-based sonogenetics can effectively manipulate neurons within the intact mammalian brain, a method that could be used across species.

Sonogenetic control of mammalian cells using exogenous Transient Receptor Potential A1 channels