Mapping Global Causal Responses to Noninvasive Modulation of Genetically and Spatially Targeted Neural Populations with Sonogenetic-fPET

Despite significant progress in brain circuit mapping over recent decades, a major challenge remains: no method currently allows for the noninvasive modulation of genetically and spatially defined neural populations while simultaneously monitoring their global effects throughout the brain and body. Here, we present sonogenetic-fPET, a technique that integrates sonogenetics with [18F]-2-fluoro-2-deoxy-D-glucose functional positron emission tomography (FDG-fPET) to overcome this challenge. Sonogenetics enables noninvasive, spatially targeted modulation of neurons genetically engineered to express the ultrasound-sensitive ion channel TRPV1, while FDG-fPET captures glucose metabolic changes triggered by this stimulation across the brain and body. We demonstrate the effectiveness of this technique by targeting neurons in the dorsal striatum, showcasing its capability to map global network responses to specific neuronal activation. Incorporating an acoustic hologram for sonogenetics further enables flexible modulation of different brain regions within a single mouse while concurrently mapping the resulting network activity. In summary, sonogenetic-fPET offers a tool for dissecting the global responses of the brain and body to the noninvasive modulation of genetically and spatially defined neuronal populations.