Impact of opsin kinetics on high-rate stimulation of the auditory nerve in mice

Abstract Optogenetic stimulation improves spectral resolution compared to electrical stimulation in preclinical cochlear implant studies but remains unreliable at the high stimulation rates needed for precise temporal resolution. Combined optogenetic-electrical stimulation has been shown to improve temporal resolution while maintaining good spectral resolution. However, the reliability of combined stimulation at clinically relevant stimulation rates (> 400 pulses per second (pps)) is yet to be tested, nor whether altering opsin channel kinetics impacts these findings. We investigated responses of the auditory nerve and inferior colliculus to electrical, optogenetic, and combined stimulation in mice virally transduced with one of three opsin variants with different opsin kinetics: ChR2-H134R, ChIEF, or ChR2-C128A. Robust optogenetic responses were elicited in ChR2-H134R and ChIEF mice but extended periods of stimulation led to severe and non-recoverable deterioration of optogenetic responses. Unlike previous studies, there was no consistent facilitation of electrical responses in combined stimulation trials. Although ChIEF responses outperformed ChR2-H134R at 100 pps, the temporal characteristics were similar at higher rates. Combined stimulation significantly improved response characteristics at 400 pps, shown here for the first time in mice virally transduced with the ChR2-H134R and ChIEF opsins. These results have significant implications for the translation of optogenetic-only and combined stimulation techniques for hearing loss.