Graded optogenetic activation of the auditory pathway for hearing restoration.

Optogenetic control of neural activity enables innovative approaches to improve functional restoration of diseased sensory and motor systems. For clinical translation to succeed, optogenetic stimulation needs to closely match the coding properties of the targeted neuronal population and employ optimally operating emitters. This requires the customization of channelrhodopsins, emitters and coding strategies. Here, we provide a framework to parametrize optogenetic neural control and apply it to the auditory pathway that requires high temporal fidelity of stimulation. We used a viral gene transfer of ultrafast targeting-optimized Chronos into spiral ganglion neurons (SGNs) of the cochlea of mice. We characterized the light-evoked response by in vivo recordings from individual SGNs and neurons of the anteroventral cochlear nucleus (AVCN) that detect coincident SGN inputs. Our recordings from single SGNs demonstrated that their spike probability can be graded by adjusting the duration of light pulses at constant intensity, which optimally serves efficient laser diode operation. We identified an effective pulse width of 1.6 ms to maximize encoding in SGNs at the maximal light intensity employed here (∼35 mW). Alternatively, SGNs were activated at lower energy thresholds using short light pulses (<1 ms). An upper boundary of optical stimulation rates was identified at 316 Hz, inducing a robust spike rate adaptation that required a few tens of milliseconds to recover. We developed a semi-stochastic stimulation paradigm to rapidly (within minutes) estimate the input/output function from light to SGN firing and approximate the time constant of neuronal integration in the AVCN. By that, our data pave the way to design the sound coding strategies of future optical cochlear implants.

Utility of red-light ultrafast optogenetic stimulation of the auditory pathway.

Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in current cochlear implants. Here, we employed fast and very fast variants of the red-light-activated channelrhodopsin (ChR) Chrimson (f-Chrimson and vf-Chrimson) to study their utility for optogenetic stimulation of SGNs in mice. The light requirements were higher for vf-Chrimson than for f-Chrimson, even when optimizing membrane expression of vf-Chrimson by adding potassium channel trafficking sequences. Optogenetic time and intensity coding by single putative SGNs were compared with coding of acoustic clicks. vf-Chrimson enabled putative SGNs to fire at near-physiological rates with good temporal precision up to 250 Hz of stimulation. The dynamic range of SGN spike rate coding upon optogenetic stimulation was narrower than for acoustic clicks but larger than reported for electrical stimulation. The dynamic range of spike timing, on the other hand, was more comparable for optogenetic and acoustic stimulation. In conclusion, f-Chrimson and vf-Chrimson are promising candidates for optogenetic stimulation of SGNs in auditory research and future cochlear implants.