An Orthogonal Near-Infrared Optical Switch for Wireless Neuromodulation in Freely Behaving Mice

Modulating neuronal activity with light is a powerful tool for neuroscience research. However, currently available technologies often require invasive fibers for the delivery of visible light, causing tissue damage and limiting behavioral studies. Although near-infrared (NIR) neuronal modulation improves tissue penetration depth, sustained NIR illumination during neuromodulation raises significant concerns about photothermal effects. Here, we introduce a dual-wavelength near-infrared switch (Dual-NIR Switch) that uses two transcranial NIR inputs to initiate and terminate neuronal activation, enabling tether-free neuromodulation in freely moving mice. The Dual-NIR Switch employs orthogonal dichromatic upconversion nanoparticles that emit blue and green light under 980 and 808 nm NIR excitation, respectively, to activate and inactivate the step-function opsin SOUL. Therefore, transient 980 nm NIR illumination initiates neuronal excitation that persists without further stimulation and can be rapidly terminated on demand by subsequent 808 nm NIR illumination. Upon sequential transcranial 980 and 808 nm NIR illumination in freely moving mice, we achieve on-demand control of behavioral paradigms across tunable time scales, ranging from seconds to minutes and even extending to subhour durations. By eliminating the need for sustained NIR irradiation, the Dual-NIR Switch offers an on-demand, duration-tunable neuromodulation tool for both basic neuroscience and potential therapeutic applications in treating brain diseases.