Tetherless Optical Neuromodulation: Wavelength from Orange-red to Mid-infrared

 Chao Sun1,2 · Qi Fan1,2 · Rougang Xie3  · Ceng Luo3  · Bingliang Hu2  · Quan Wang1,2
1 Key Laboratory of Spectral Imaging Technology, Xi’an Institute of Optics and Precision Mechanics (XIOPM), Chinese Academy of Sciences, Xi’an 710119, China 
2 Key Laboratory of Biomedical Spectroscopy of Xi’an, Key Laboratory of Spectral Imaging Technology, XIOPM, Chinese Academy of Sciences, Xi’an 710119, China 
3 Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China

Abstract
Optogenetics, a technique that employs light for neuromodulation, has revolutionized the study of neural mechanisms and the treatment of neurological disorders due to its high spatiotemporal resolution and cell-type specificity. However, visible light, particularly blue and green light, commonly used in conventional optogenetics, has limited penetration in biological tissue. This limitation necessitates the implantation of optical fibers for light delivery, especially in deep brain regions, leading to tissue damage and experimental constraints. To overcome these challenges, the use of orange-red and infrared light with greater tissue penetration has emerged as a promising approach for tetherless optical neuromodulation. In this review, we provide an overview of the development and applications of tetherless optical neuromodulation methods with long wavelengths. We first discuss the exploration of orange-red wavelength-responsive rhodopsins and their performance in tetherless optical neuromodulation. Then, we summarize two novel tetherless neuromodulation methods using near-infrared light: upconversion nanoparticle-mediated optogenetics and photothermal neuromodulation. In addition, we discuss recent advances in mid-infrared optical neuromodulation.

Keywords
Optical neuromodulation; Tetherless; Orange-red wavelength responding rhodopsins; Upconversion nanoparticle-mediated optogenetics; Photothermal neuromodulation