Sonogenetics – Controlling the Brain with Sound

My neuroscience colleagues have long been proponents of the technique known as optogenetics, a procedure that was named the scientific “Method of the Year” in 2010. For this method, brain cells are genetically engineered to respond to a specific wavelength of light. Typically this involves using a virus or other delivery system to augment brain cells with a new gene expressing a light-sensitive protein. Depending on how the cells are engineered they can either be activated or inhibited by the proper light exposure. This approach is used to target defined subsets of cells within an animal’s brain. By exposing these cells to the light source they will be turned on or off and their function can be examined in the absence of other confounding brain stimulation. This incredibly powerful approach has been instrumental in dissecting and understanding the precise role of different anatomical regions of the brain. Ideally, this method could even be used therapeutically, for example by using light to turn off cells involved in chronic pain. However, the one caveat of this method is that light must be delivered to the relevant brain region. Typically this involves the permanent insertion of optical fibers through the skull and into the targeted portion of the brain. While not an issue for animal studies, this surgical requirement makes optogenetics less amenable for application to human patients. A newly published study in the Journal “Nature Communications” presents a method that avoids surgical implantation for light delivery by instead utilizing ultrasound to modulate modified brain cells, a process dubbed sonogenetics. Ultrasound is already widely used in medical imaging as it is safe and easily penetrates through tissues. The problem solved in this new study was how to make brain cells react to sound waves. For optogenetics, scientists were able to use naturally occurring light-sensitive proteins found in some bacteria and algae to make brain cells responsive, but functionally similar proteins stimulated by sound were less explored. As sound is essentially mechanical energy, the research team focused on mechanosensitive proteins that would be activated by high-frequency ultrasound. It took six years and the testing of 300 candidate proteins, but eventually they found a protein called the TRPA1 receptor (also known as the wasabi receptor) that displayed the needed properties. To test the functional ability of TRPA1 its gene was incorporated into motor cortex neurons of live mice. Exposing the modified mice to ultrasound caused movement in the front and back legs, demonstrating that these neurons were now reactive to this sound frequency. This proof-of-principle study confirms that sound modulation of brain responses in mammals is feasible which should open the door to a flood of studies improving and refining this methodology. Being able to stimulate the brain with noninvasive sound is an exciting advance that removes the light delivery constraint of optogenetics. If sonogenetics turns out to be as functional as optogenetics, this could be a real boon not only for neuroscience research but also for human therapeutics.