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

Abstract

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.

Update on neurobiological mechanisms of fear: illuminating the direction of mechanism exploration and treatment development of trauma and fear-related disorders

“…In addition, acoustic and magnetic thermal genetics, as a minimally invasive neuromodulation technique with high spatial and temporal resolution, can achieve precise control of specific brain regions and has application prospects in the clinical treatment of trauma and fear-related diseases. Relative research has laid a solid foundation for achieving the regulation of brain regions associated with fear extinction (Munshi et al, 2017;Duque et al, 2022;Xian et al, 2023;Yang et al, 2023). It can be seen that the application of the above neuromodulation techniques for the treatment of stress-related disorders such as PTSD in humans is becoming possible.…”

Nanotransducer-Enabled Deep-Brain Neuromodulation with NIR-II Light

“…The use of an acoustic interface enables through-scalp optogenetics neuromodulation in live mice without any brain implants or scalp incision, but also necessitates close contact between the ultrasound transducer and the animal’s head, since acoustic waves transmit poorly across the air–tissue interface. At the current stage, sono-optogenetics has only been demonstrated in head-fixed animals, but the development of wearable ultrasound transducers may enable sono-opto­genetics neuromodulation in freely moving subjects. − …”

Sonogenetics: Recent advances and future directions

“…D) MscL-G22s sonogenetic stimulation of visual cortex showed millisecond resolution as measured by µEcoGarray [64]. E) Given the high spatiotemporal resolution of MscL-G22s sonogeneitcs, it is feasible for controlling place preference behavior [42].…”

“…More recently, a follow-up study by the same research group showed that MscL-G22s used fiber photometry to show that sonogenetic stimulation can effectively induce neural activation in deeper brain regions [42]. Ultrasound triggered activity in MscL-expressing neurons in the dorsal striatum without increased activation in the neighboring regions and increased locomotion in freely-moving mice.…”

“…In the following section, we will discuss the challenges and future directions for sonogenetics. The latency is around 200 ms [42].…”