Noninvasive and cell-type specific neuromodulation by integrating ultrasound and genetics

Abstract

The investigation of brain functions and treatment of brain disorders requires modulation of selected neurons in a noninvasive manner in the deep brain. To achieve this goal, sonogenetics has been developed that involves the use of focused ultrasound (FUS) to selectively control a specific type of neurons that have been genetically modified to express ultrasound-sensitive ion channels. Existing sonogenetic techniques utilize ultrasound mechanical effect to activate mechanosensitive ion channels. Different from existing approaches, we aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and cell-type-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with FUS-induced brief, non-noxious thermal effect. FUS sonication at the mouse brain in vivo selectively activated neurons that were genetically modified to express TRPV1. Temporally precise activation of TRPV1-expressing neurons was achieved with its success rate linearly correlated with the peak average temperature within the FUS-targeted brain region as measured by in vivo magnetic resonance thermometry. FUS stimulation of TRPV1-expressing neurons of the Parkinsonian circuit at the striatum repeatedly evoked rotating locomotor behavior in freely moving mice. FUS sonication was confirmed to be safe based on inspection of neuronal integrity, inflammation, and apoptosis markers. In summary, our study demonstrated that sonothermogenetics is a noninvasive and cell-type-specific neuromodulation technique.