Nanobubble-actuated ultrasound neuromodulation for selectively shaping behavior in mice

Abstract

Ultrasound is an acoustic wave which can noninvasively penetrate the skull to deep brain regions, enabling neuromodulation. However, conventional ultrasound’s spatial resolution is diffraction-limited and low-precision. Here, we report acoustic nanobubble-mediated ultrasound stimulation capable of localizing ultrasound’s effects to only the desired brain region in male mice. By varying the delivery site of nanobubbles, ultrasound could activate specific regions of the mouse motor cortex, evoking EMG signaling and limb movement, and could also, separately, activate one of two nearby deep brain regions to elicit distinct behaviors (freezing or rotation). Sonicated neurons displayed reversible, low-latency calcium responses and increased c-Fos expression in the sub-millimeter-scale region with nanobubbles present. Ultrasound stimulation of the relevant region also modified depression-like behavior in a mouse model. We also provide evidence of a role for mechanosensitive ion channels. Altogether, our treatment scheme allows spatially-targetable, repeatable and temporally-precise activation of deep brain circuits for neuromodulation without needing genetic modification.

An Investigation of Parameter-Dependent Cell-Type Specific Effects of Transcranial Focused Ultrasound Stimulation Using an Awake Head-Fixed Rodent Model

“…Ultrasound has been tested in awake rodents before, but most commonly it is delivered under anesthesia and effects tested after awakening, which only allows for testing of long-term effects (M. G. Kim et al, 2022). Wearable transducers for rodents have been developed, but generally only allow for EEG recordings to be taken due to the higher noise levels from movement, and these transducers are not capable of as high precision or as wide a range of parameters (Di Ianni et al, 2023;Hou et al, 2024;Jo et al, 2022;Piech et al, 2017). To target the brain with tFUS precisely in an awake animal while taking high frequency recordings, head-fixation is required to keep the animal still.…”