Ultrafast Multichannel Optogenetic Stimulation of the Auditory Pathway for Optical Cochlear Implants
by Daniel Keppeler
Date of Examination:2018-12-17
Date of issue:2019-01-14
Advisor:Prof. Dr. Tobias Moser
Referee:Prof. Dr. Dr. Oliver Schlüter
Referee:Dr. Katrin Willig
Referee:Prof. Dr. Thomas Dresbach
Referee:Prof. Dr. Ralf Heinrich
Referee:Ph.D. Camin Dean
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Description:Dissertation
Abstract
English
In case of profound sensorineural hearing loss and deafness, cochlear implants (CIs) partially restore hearing and provide missing auditory information to the brain. Electrical stimulation of the spiral ganglion neurons (SGNs) enables speech understanding in the majority of the approximately 500,000 CI users. However, the utility of current clinical CIs is limited by their wide current spread resulting in limited coding of spectral information. As light can be better confined in space, optical CIs (oCIs) promise lower spread of excitation in the cochlea which might enable better speech comprehension in noisy background as well as music appreciation. This thesis focuses on five key aspects for development of future CIs in research and clinical translation: (1) Characterizing a novel ultrafast optogenetic tool in the mouse cochlea: Chronos, a channelrhodopsin (ChR) supporting high temporal fidelity prerequisite for auditory coding. (2) Improving spiral ganglion neuron (SGN) expression levels and SGN targeting by the recently discovered adeno-associated virus (AAV)-PHP.B. (3) Enhancing ChR trafficking to the plasma membrane (Chronos—ES/TS). (4) Evaluating cochlear space for optical probes in common animal models employing phase-contrast X-ray tomography thereby providing a comprehensive library for morphological parameters relevant for CI development in rodents and non-human primates. (5) Establishing first multichannel oCIs based on microfabricated light-emitting diode (LED) arrays in channelrhodopsin-2 (ChR2)-expressing rats and their functional validation utilizing auditory brainstem responses (ABRs). Taken together, the thesis demonstrates feasibility of optogenetic cochlea stimulation by expressing the ultrafast ChR Chronos and LED-based multichannel oCIs.
Keywords: optogenetic; cochlea; implant; CI; channelrhodopsin; ChR2; Chronos; AAV; adeno-associated virus; CBCT; microCT; X-ray; optical; LED; microLED; auditory; opsin; tomography; ABR; auditory brainstem response; multichannel; optrode