Circuit-specific sonogenetic stimulation of the deep brain elicits distinct signaling and behaviors in freely moving mice

Sonogenetics uses heterologously-expressed proteins to sensitize neurons to ultrasound, enabling selective, non-invasive, and deep brain stimulation. However, its ability to modulate specific circuits or induce behavioral changes remains to be studied and characterized. Here, we demonstrate that sonogenetics enables efficient activation of well-defined neural circuits by transcranial low-intensity, low-frequency ultrasonic stimulation with high spatiotemporal resolution. Targeted neurons in subcortical regions were made to express a mechanosensitive ion channel (MscL-G22S). Ultrasound could trigger activity in MscL-expressing neurons in the dorsal striatum without increased activation in neighboring regions, and increase locomotion in freely-moving mice. Ultrasound stimulation of MscL-expressing neurons in the ventral tegmental area could activate the mesolimbic pathway to trigger dopamine release in the nucleus accumbens and modulate appetitive conditioning. In MscL-expressing cells, neuronal responses to ultrasound pulses were rapid, reversible and repeatable. Altogether, we show that sonogenetics can selectively manipulate targeted cells to activate defined neural pathways and affect behaviors.