Show simple item record

Sound Encoding in the Mouse Cochlea: Molecular Physiology and Optogenetic Stimulation

dc.contributor.advisorStrenzke, Nicola Dr.
dc.contributor.authorJing, Zhizi
dc.titleSound Encoding in the Mouse Cochlea: Molecular Physiology and Optogenetic Stimulationde
dc.contributor.refereeMoser, Tobias Prof. Dr.
dc.description.abstractengAfferent synapses between inner hair cells (IHCs) and spiral ganglion neurons in the cochlea translate sound information into a discrete spike code, providing us the opportunity to directly observe the output of the cochlea. The availability of mutant strains with genetic hearing impairment makes the mouse a valuable species to investigate the molecular mechanisms of cochlear function. In this thesis, mouse was used as a model species to study cochlear sound encoding by recording single unit activities from auditory nerve fibers (ANFs) in vivo. First, developmental changes of ANF responses before and after hearing onset were characterized as an introduction on how normal ANF responses mature during the early postnatal age. Spontaneous bursting activity from ANFs/cochlear nucleus neurons was observed before hearing onset. After hearing onset, the average spontaneous and evoked spike rates of single ANFs increased, while tuning threshold and frequency selectivity improved between p14-15 to p20-21. To gain insight into the role of synaptic organization in cochlear and ANF function, mice carrying targeted mutations of presynaptic scaffold protein Bassoon were analyzed. IHCs of mice that are deficient of the central portion of the presynaptic scaffold protein Bassoon (BSNΔEx4/5) were previously shown to mostly lack synaptic ribbons and to have a smaller readily releasable pool of synaptic vesicles and reduced exocytosis, resulting in lower firing rates of ANFs. To distinguish better between the effects of the Bassoon mutation and those of the loss of the synaptic ribbon, the BSNΔEx4/5 phenotype was compared with that of a newly generated gene trap mutant (BSNgt), which has an intermediate phenotype in terms of the fraction of ribbon occupied active zones, presumably due to leaky expression of a small amount of Bassoon protein. The mean distance between the remaining ribbons and the active zone was greater in BSNgt than in wildtype and the synaptic calcium channel clusters had reduced immunostaining reactivity. The BSNgt IHCs showed a slightly less severe reduction of peak Ca2+ currents and sustained exocytosis compared to BSNΔEx4/5. However, IHC fast exocytosis and single unit responses of ANFs showed almost identical response properties between the two mutants. These data suggest that it is not the physical presence or absence of a synaptic ribbon but rather the disruption of presynaptic ultrastructure (e.g. abnormal calcium channel clustering, looser ribbon anchorage) that mainly determines the synaptic phenotype of Bassoon mutants.  Next, the ANF responses of Black Swiss mice (BLSW) were characterized. BLSW mice have inherited early onset sensorineural hearing loss and susceptibility to audiogenic seizures due to a mutation in the Gipc3 gene. BLSW ANFs showed higher tuning thresholds and broader frequency selectivity, which is consistent with a previous report of OHC dysfunction. Interestingly, BLSW ANFs had elevated spontaneous discharge activity, indicating that Gipc3 is a key molecular player not only for normal OHC but also for IHC function.  Upon hearing loss due to HC dysfunction, the remaining ANFs can be electrically stimulated to restore the sense of hearing. The number of useful frequency channels using electrical stimulation is limited by the spread of current. Focused optical stimulation may allow for more selective activation of ANFs compared to electrical stimulation. In the last part of the thesis, spiking activity was measured in response to laser light stimulation in ANFs and cochlear nucleus neurons of mice with constitutive expression of the light-gated ion channel Channelrhodopsin-2 and virus-mediated expression of the faster ChR2 variant CatCh. de
dc.contributor.coRefereeWolf, Fred Prof. Dr.
dc.contributor.thirdRefereeGöpfert, Martin Prof. Dr.
dc.subject.engsound encodingde
dc.subject.engauditory nerve fiberde
dc.subject.engBassoon mutantsde
dc.subject.engBlack swiss micede
dc.subject.engoptogenetic stimulationde
dc.subject.engsensorineural hearing lossde
dc.subject.enginner hair cellde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

Files in this item


This item appears in the following Collection(s)

Show simple item record