| dc.description.abstracteng | Cochlear implants (CIs) constitute the interface between the sound-deprived brain of patients suffering from sensorineural hearing loss and the auditory scene surrounding them. By electrically stimulating the auditory nerve (AN), CIs mimic coding principles of the cochlea and provide the user with auditory information, enabling speech comprehension in half a million implantees. Unfortunately, current is hard to steer in the cochlear fluids, limiting the spatial selectivity and thus the spectral resolution of electrical hearing restoration. As light can be conveniently confined in space, optogenetic stimulation of the genetically modified AN might overcome this limitation. Indeed, cochlear optogenetics with high temporal fidelity was demonstrated upon viral gene transfer of ultrafast Channelrhodopsins in early postnatal mice, and field potentials in the auditory midbrain of transgenic mice indicated increased spectral selectivity of cochlear optogenetics. Furthermore, optical cochlear implants (oCIs) based on light emitting diodes have been developed for multi-site illumination of the AN. However, a long way remains to be gone before considering clinical translation. Working with adult Mongolian gerbils whose AN has been virally transduced with the Channelrhodopsin-variant CatCh, this thesis addresses three milestones towards the development of cochlear optogenetics: First, perception of optogenetic AN activation has been demonstrated on the behavioral level, which is essential when considering that oCIs must convey behaviorally relevant information to future users. Second, cochlear optogenetics has been demonstrated to activate the auditory pathway in a tonotopic manner and with increased spectral selectivity as compared to mono- and bipolar electrical stimulation. This finding is of uppermost importance, since clinical translation of cochlear optogenetics is only justified if a substantial advantage of optogenetic over electric sound encoding is to be expected. Third, virus-mediated gene transfer in adult gerbils has been combined with microsystems technology to facilitate multi-channel optogenetic AN activation. 16-channel oCIs based on microscale light emitting diodes enabled AN activation with higher spectral selectivity as compared to electrical stimulation, and hence demonstrate the feasibility of a translational oCI approach. Furthermore, functional activation of the AN by optogenetics has been demonstrated in a gerbil model of sensorineural hearing loss, both on the physiological and behavioral level. These results suggest that optogenetic hearing restoration is behaviorally relevant and might indeed overcome the major bottleneck of electrical CIs, raising hope that the quality of artificial sound encoding for future patients might be improved by optical cochlear implants. | de |