Non-invasive optical control of endogenous Ca²⁺ channels in awake mice

Optogenetic approaches for controlling Ca²⁺ channels provide powerful means for modulating diverse Ca²⁺-specific biological events in space and time. However, blue light-responsive photoreceptors are, in principle, considered inadequate for deep tissue stimulation unless accompanied by optic fiber insertion. Here, we present an ultra-light-sensitive optogenetic Ca²⁺ modulator, named monSTIM1 encompassing engineered cryptochrome2 for manipulating Ca²⁺ signaling in the brain of awake mice through non-invasive light delivery. Activation of monSTIM1 in either excitatory neurons or astrocytes of mice brain is able to induce Ca²⁺-dependent gene expression without any mechanical damage in the brain. Furthermore, we demonstrate that non-invasive Ca²⁺ modulation in neurons can be sufficiently and effectively translated into changes in behavioral phenotypes of awake mice.