| dc.contributor.advisor | Moser, Tobias Prof. Dr. | |
| dc.contributor.author | López de la Morena, David | |
| dc.date.accessioned | 2019-07-15T09:34:44Z | |
| dc.date.available | 2019-07-15T09:34:44Z | |
| dc.date.issued | 2019-07-15 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0003-C167-F | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7546 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Optogenetic stimulation of the cochlea | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Rizzoli, Silvio O. Prof. Dr. | |
| dc.date.examination | 2018-12-18 | |
| dc.description.abstracteng | Optogenetic stimulation of the auditory nerve is a promising alternative to restore hearing. Since light can be focused on the target tissue, the optical cochlear implant (oCI) might support a major improvement in frequency resolution compared to current electrical CIs (eCIs). However, the slow kinetics of the first generation of optogenetic actuators hindered controlling the fast-spiking spiral ganglion neurons (SGNs) with high temporal fidelity.
In this work, I evaluated the ability of two fast-gating opsins (Chronos-ES/TS and f-Chrimson) to improve temporal fidelity of optogenetic stimulation of murine SGNs in vivo. Following postnatal injections of adeno-associated virus (AAV) via the round window, channelrhodopsin expression under the human synapsin promoter rendered SGNs light-sensitive without detrimental effects in neuronal survival.
Improved plasmalemmal expression of Chronos-ES/TS in SGNs ensued from the usage of the potent AAV.PHP.B capsid and the addition of endoplasmic reticulum export signals (ES) and plasma membrane trafficking signals (TS) to the Chronos transgene. High and homogeneous expression levels of Chronos-ES/TS in SGNs throughout the cochlea (~70%) allowed high spike probability and temporal precision of spiking up to 1 kHz with moderate energy thresholds assessed by optically-evoked auditory brainstem responses (oABR) (~7 µJ per pulse).
On the other hand, the fast-gating opsin f-Chrimson opened up the new avenue of fast red-shifted cochlear optogenetics. AAV2/6-mediated expression of f-Chrimson was high and homogeneous in the injected ear (~80%), allowing optical activation of the auditory pathway with low oABR energy thresholds (down to a minimum of 0.5 µJ per pulse) and restoring auditory activity at pulse rates up to 250 Hz in hearing-impaired mice 9 months post-injection. Further characterization at the single-neuron level revealed sub-millisecond temporal jitter of spiking up to pulse rates of 400 Hz and improved average dynamic range of optogenetic coding compared to electrical stimulation (~4 dB vs ~1 dB) that rose up to ~8 dB at the population level.
Therefore, these preclinical results pave the way for an increased frequency and intensity resolution in cochlear prosthetics and advance cochlear optogenetics by overcoming major obstacles that had so far hampered clinical translation of the oCI: enabling physiological stimulation rates with low light intensities in postnatally transduced animals. | de |
| dc.contributor.coReferee | Gollisch, Tim Prof. Dr. | |
| dc.contributor.thirdReferee | Strenzke, Nicola Dr. | |
| dc.contributor.thirdReferee | Dean, Camin Dr. | |
| dc.contributor.thirdReferee | Schmidt, Manuela Dr. | |
| dc.subject.eng | Optogenetics | de |
| dc.subject.eng | Cochlear implants | de |
| dc.subject.eng | Cochlea | de |
| dc.subject.eng | In vivo electrophysiology | de |
| dc.subject.eng | Adeno-associated virus | de |
| dc.subject.eng | Single-unit recordings | de |
| dc.subject.eng | Dynamic range | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0003-C167-F-1 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1672306582 | |