Rapid rescue of despair behaviors by sonogenetic neuromodulation of the mPFC-DRN pathway

Sonogenetics combines genetic tools and low-intensity ultrasound to non-invasively modulate specific neuronal populations and circuits, exhibiting potential for treating brain diseases. This study examines sonogenetics' potential in a mouse depression model, targeting excitatory medial prefrontal cortex (mPFC) neurons projecting to the dorsal raphe nucleus (DRN). Projecting neurons were induced to express a mechanosensitive ion channel (MscL-G22S), and alterations in patterns of neuronal activation and despair-like behaviors upon sonication were evaluated. Sonogenetics selectively activated targeted excitatory mPFC neurons projecting to the DRN, enhancing real-time DRN neuronal activity and serotonin release, with no observed tissue damage or astrocytic/microglial activation. Tail suspension and forced swim tests revealed that sonogenetically activating this pathway rapidly reversed despair-like behaviors in stressed mice, whereas effects observed upon mPFC sonication were abrogated by functionally silencing downstream DRN neurons, and this effect is fully recapitulated by selective inhibition of DRN serotonergic neurons alone. Collectively, this study constitutes the first demonstration of the potential for a circuit-targeted sonogenetic therapeutic approach for relieving despair behaviors.