LAUSR

Significance Since the invention of optogenetics, using light to control the activity of individual neurons and dissect the complex neural circuits has been a powerful tool for neuroscience owing to the high temporal precision and neuron-type specificity. However, one of the major challenges of optogenetics is the invasive delivery of light sources such as fiber optics inside the brain of live animals due to limited tissue penetration of photons. Here, we report a method termed “sono-optogenetics,” which provides minimally invasive optogenetic neuromodulation in the brain without any scalp incision, craniotomy, or brain implant. Sono-optogenetics delivers nanoscopic light sources via the endogenous blood circulation and provides millisecond-timescale switching of light emission for optogenetic neuromodulation via brain-penetrant focused ultrasound. Optogenetics, which uses visible light to control the cells genetically modified with light-gated ion channels, is a powerful tool for precise deconstruction of neural circuitry with neuron-subtype specificity. However, due to limited tissue penetration of visible light, invasive craniotomy and intracranial implantation of tethered optical fibers are usually required for in vivo optogenetic modulation. Here we report mechanoluminescent nanoparticles that can act as local light sources in the brain when triggered by brain-penetrant focused ultrasound (FUS) through intact scalp and skull. Mechanoluminescent nanoparticles can be delivered into the blood circulation via i.v. injection, recharged by 400-nm photoexcitation light in superficial blood vessels during circulation, and turned on by FUS to emit 470-nm light repetitively in the intact brain for optogenetic stimulation. Unlike the conventional “outside-in” approaches of optogenetics with fiber implantation, our method provides an “inside-out” approach to deliver nanoscopic light emitters via the intrinsic circulatory system and switch them on and off at any time and location of interest in the brain without extravasation through a minimally invasive ultrasound interface.