Impact of endogenous sonosensation on in vivo sonogenetics

Sonogenetics is a promising paradigm that uses non-invasive ultrasound to modulate neurons expressing sonosensitive proteins. However, the brain's varying endogenous sonosensitivity presents a challenge for its precise application. We first mapped this intrinsic sensitivity, identifying the somatosensory cortex as particularly responsive. Using an MscL-G22S-based approach in the somatosensory cortex, we found that ultrasound non-specifically activated both excitatory and inhibitory neurons in control mice, preventing behavioral output. In contrast, in MscL-expressing mice, ultrasound selectively activated excitatory neurons while suppressing inhibitory ones, thereby shifting the net neural response to successfully drive whisker movement. This effect was independent of auditory confounds or astrocytic involvement. Our study highlights that accounting for endogenous sonosensitivity is critical and demonstrates that optimized sonogenetic tools can achieve precise neuromodulation despite this inherent challenge.