Non-invasive, opsin-free mid-infrared modulation activates cortical neurons and accelerates associative learning

Abstract Boosting learning capability represents a long-sought dream of mankind. Neurostimulant drugs or magnetic/electrical stimulation techniques can overcome attention deficits, but these drugs or techniques are weakly beneficial in boosting the learning capabilities of healthy subjects. Here, we report a stimulation technique, mid-infrared modulation (MIM), that delivers mid-infrared light energy through opened skull or even non-invasively through thinned intact skull and can activate brain neurons in vivo without introducing any exogeneous gene. Using c-Fos immunohistochemistry, in vivo single-cell electrophysiology and two-photon Ca2+ imaging in mice, we demonstrate that MIM significantly induces firing activities of neurons in the targeted cortical area. Moreover, mice that receive MIM targeting to the auditory cortex during an auditory associative learning task exhibit a strikingly faster learning speed (~ 50% faster) than control mice. Together, this non-invasive, opsin-free MIM technique is demonstrated with a great translational potential for activating brain neurons and boosting brain learning capability.