Sonogenetics 2.0

PROJECT SUMMARY/ABSTRACT Achieving noninvasive, cell-type-specific, and spatially precise neuromodulation remains to be a major challenge in the development of neuromodulation technologies. The objective of this project is to develop Sonogenetics 2.0, the next-generation sonogenetic technique for cell-type-specific, spatially precise neuromodulation in the whole brain of freely behaving animals without intracranial surgery. Sonogenetics 2.0 employs low-intensity focused ultrasound (FUS) combined with microbubbles to deliver intranasally administered adeno-associated viruses (AAVs) to the FUS-targeted brain region with minimal systemic exposure. It then utilizes FUS sonication to remotely activate the expressed ultrasound-sensitive ion channels encoded by the AAVs and thereby controls the activity of AAV-transduced neurons. Sonogenetics 2.0 addresses three critical barriers to developing sonogenetics: the lacks molecular probes with optimized ultrasound sensitivity (Aim 1), requires surgical injection of viral vectors to express the probes (Aim 2), and has a low spatial resolution in delivering ultrasound in the mouse brain (Aim 3). Sonogenetics 2.0 will be independently validated by neuroscience laboratories and benchmarked with optogenetics (Aim 4). The proposed Sonogenetics 2.0 is significant because technological breakthroughs are urgently needed to fulfill the great potential of sonogenetics. Sonogenetics 2.0 provides a complementary tool to existing neuromodulation techniques with the potential to be translated to large animals and humans. A multidisciplinary team with combined expertise in ultrasound device design, ion channel engineering, neuromodulation, and neuroscience is well suited to this project. This project is innovative because Sonogenetics 2.0 is the first-in-class ultrasound tool for completely noninvasive and cell-type-specific neuromodulation by combining noninvasive genetic construct delivery with noninvasive activation of transduced neurons. The proposed research is expected to have a sustained, powerful impact in the research field of sonogenetics and provide the neuroscience community with a transformative tool that can be widely used to advance our current capabilities in investigating cell-type-specific processes in intact mammalian brains.