Targeted Mechanogenetics to Modulate Specific Deep Neural Circuits

Sonogenetics utilizes ultrasound for targeted, cell-type-specific modulation of neuronal activity. However, manipulating specific circuits within complex brain areas poses significant challenges due to heterogenous cell types with varying inherent sonosensitivity. Building on previous gas-vesicle-assisted ultrasound neuromodulation studies, we investigate an in vivo nanobubble-enhanced sonogenetic strategy, termed mechanogenetics, for circuit-level neural modulation. Application of this approach to distinct brain regions increased electromyography responses following motor-cortex stimulation and enhanced neural activity in deep-brain regions. Importantly, mechanogenetics enables us to modulate neural circuits controlling feeding behavior by specifically stimulating the mouse lateral hypothalamus (LH), with minimal disturbance in adjacent areas. The observed mechanogenetically-induced decreases in feeding behavior were further found to be mediated by LH-glutamatergic inputs to the ventral tegmental area. Furthermore, assessments of neural integrity, inflammation, and apoptosis support biosafety under the tested conditions. These findings demonstrate the feasibility of applying mechanogenetics to a behaviorally relevant deep neural circuit and provide a framework for localized, genetically targeted ultrasound neuromodulation.