Targeted Mechanogenetics to Modulate Specific Deep Neural Circuits

ABSTRACT 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.