Nonthermal and reversible control of neuronal signaling and behavior by midinfrared stimulation

Abstract

Significance Infrared neural stimulation (INS) is an emerging technology for neuromodulation and holds promise for clinical application. While most INS studies have been conducted at near-infrared wavelengths, whether midinfrared light with frequencies matching the chemical bond vibration of biomolecules can influence neuronal function remains unknown. We found that midinfrared light with low water absorption provides nonthermal and reversible modulation of neuronal spiking activity and sensorimotor behavior. Nonlinear resonance between light and chemical bond vibration at the selectivity sieve of the K+ channel directly enhances ion conductivity and thus regulates AP waveform and spiking activity. Together, our results reveal nonthermal effects of MIRS on functional biomolecules, neuronal signaling, and behavior state. Therefore, MIRS could serve as a form of physical neuromodulation. Various neuromodulation approaches have been employed to alter neuronal spiking activity and thus regulate brain functions and alleviate neurological disorders. Infrared neural stimulation (INS) could be a potential approach for neuromodulation because it requires no tissue contact and possesses a high spatial resolution. However, the risk of overheating and an unclear mechanism hamper its application. Here we show that midinfrared stimulation (MIRS) with a specific wavelength exerts nonthermal, long-distance, and reversible modulatory effects on ion channel activity, neuronal signaling, and sensorimotor behavior. Patch-clamp recording from mouse neocortical pyramidal cells revealed that MIRS readily provides gain control over spiking activities, inhibiting spiking responses to weak inputs but enhancing those to strong inputs. MIRS also shortens action potential (AP) waveforms by accelerating its repolarization, through an increase in voltage-gated K+ (but not Na+) currents. Molecular dynamics simulations further revealed that MIRS-induced resonance vibration of –C=O bonds at the K+ channel ion selectivity filter contributes to the K+ current increase. Importantly, these effects are readily reversible and independent of temperature increase. At the behavioral level in larval zebrafish, MIRS modulates startle responses by sharply increasing the slope of the sensorimotor input–output curve. Therefore, MIRS represents a promising neuromodulation approach suitable for clinical application.