Sono-optogenetics facilitated by a circulation-delivered rechargeable light source for minimally invasive optogenetics

Abstract

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.

Through-scalp deep-brain stimulation in tether-free, naturally-behaving mice with widefield NIR-II illumination

“…A fiber-tethered interface is also incompatible with social behavioral studies that involve multiple mice in the same cage (e.g., the IntelliCage) due to potential tangling and biting of the fibers 48 . A similar head-fixed or head-tethered setup is required for sonogenetic 49 and sono-optogenetic 22 neuromodulation. In contrast, NIR-II neuromodulation enables free motion and interaction of the subjects via an implant-free and tether-free stimulation interface, since distant 1064-nm light sources can target each animal from ~1 m above.…”

“…Furthermore, tethering the animal to an electrical wire or light source during behavioral studies leads to various deleterious consequences, especially for socially interacting animals ( Supplementary Table 1) 3,12 . To mitigate these challenges, several novel methods have been demonstrated, including wireless optogenetic interfaces 3,13 , red-shifted opsins [14][15][16][17][18] , ultrasensitive opsins [18][19][20] , optogenetic antennas based on upconversion nanoparticles 21 , and sono-optogenetics based on mechanoluminescent nanoparticles 22 . Despite these recent advances, none of the existing optogenetic interfaces are able to altogether eliminate both the head tethering/fixing and the brain implants for deep-brain neural modulation in freely moving animals 13,21 .…”

The bright side of sound: perspectives on the biomedical application of sonoluminescence

“…22 Recently some researchers have suggested US as a new tool to overcome certain drawbacks and improve the light delivery, mainly in the field of PDT and optogenetics. 5,[23][24][25][26][27] Light from sound…”

Mechanoluminescence materials for advanced artificial skin

“…The ZnS:Ag + , Co 2+ @ZnS core-shell ML nanoparticles with uniform size and morphology synthesized via the solvothermal method are demonstrated recently, in which the undoped ZnS shell enables a 9.2-fold increase of ML compared to the original ZnS:Ag + , Co 2+ by inhibiting the luminescence quenching effect caused by the solvent or ligand molecules, endowing the minimally invasive optogenetic activation when triggered by the focused ultrasound (Fig. 1a) [8]. This work also encourages the attempts to ML materials with customized luminescence properties such as color, intensity, and multistimuli-response by adjusting the component, thickness, number, and permutation of the shell layer.…”