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Optogenetic stimulation of neurons, driven by the development of light-gated rhodopsins, has revolutionized the experimental interrogation of neural circuits and holds promise for next-generation treatment of neurological disorders. However, it is limited by the inability of visible light to penetrate deep inside brain tissue. Optical stimulation of deep brain neurons, for example, has hitherto required the insertion of invasive optical fibers because the activating blue-green wavelengths are strongly scattered and absorbed by endogenous chromophores. Red-shifted variants of rhodopsins have been developed, but their action spectra still fall out of the near-infrared (NIR) optical window (650-1350 nm) where light has its maximal depth of penetration in brain tissue. Here, we developed a novel approach for NIR optogenetics, where lanthanide-doped upconversion nanocrystals (UCNPs) were used to absorb tissue-penetrating 980 nm NIR and emit visible light for rhodopsin activation. Due to lanthanides’ ladder-like electronic energy structure, the emission of UCNPs can be precisely tuned to a particular wavelength by control of energy transfer via selective lanthanide-ion doping. For instance, incorporation of Tm3+ into Yb3+ doped host lattices leads to blue emission (~470 nm) that matches the maximum absorption of channelrhodopsin-2 (ChR2) for neuronal activation, while the Yb3+/Er3+ couple emits green light (~540 nm) compatible with activation of halorhodopsin (NpHR) or archaerhodopsin (Arch) for neuronal inhibition. We demonstrated that molecularly tailored UCNPs could serve as optogenetic actuators of transcranial NIR to functionally stimulate deep brain neurons in mice. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations via activation of inhibitory neurons in the medial septum, silenced seizure via inhibition of excitatory cells in the hippocampus, and triggered memory recall via excitation of a hippocampal engram. UCNP technology would open the door to less-invasive optical neuronal activity manipulation with the potential for remote therapy.
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