Rankovic, Vladan

[["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Vogl, Christian"],["dc.contributor.author","Dörje, Nele M."],["dc.contributor.author","Bahader, Iman"],["dc.contributor.author","Duque-Afonso, Carlos J."],["dc.contributor.author","Thirumalai, Anupriya"],["dc.contributor.author","Weber, Thomas"],["dc.contributor.author","Kusch, Kathrin"],["dc.contributor.author","Strenzke, Nicola"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2021-04-14T08:29:50Z"],["dc.date.available","2021-04-14T08:29:50Z"],["dc.date.issued","2021"],["dc.description.abstract","Hearing impairment is the most common sensory disorder in humans. So far, rehabilitation of profoundly deaf subjects relies on direct stimulation of the auditory nerve through cochlear implants. However, in some forms of genetic hearing impairment, the organ of Corti is structurally intact and therapeutic replacement of the mutated gene could potentially restore near natural hearing. In the case of defects of the otoferlin gene (OTOF), such gene therapy is hindered by the size of the coding sequence (~6 kb) exceeding the cargo capacity (\\u0026lt;5 kb) of the preferred viral vector, adeno-associated virus (AAV). Recently, a dual-AAV approach was used to partially restore hearing in deaf otoferlin knock-out (Otof-KO) mice. Here, we employed in vitro and in vivo approaches to assess the gene-therapeutic potential of naturally-occurring and newly-developed synthetic AAVs overloaded with the full-length Otof coding sequence. Upon early postnatal injection into the cochlea of Otof-KO mice, overloaded AAVs drove specific expression of otoferlin in ~30% of all IHCs, as demonstrated by immunofluorescence labeling and polymerase chain reaction. Recordings of auditory brainstem responses and a behavioral assay demonstrated partial restoration of hearing. Together, our results suggest that viral gene therapy of DFNB9—using a single overloaded AAV vector—is indeed feasible, reducing the complexity of gene transfer compared to dual-AAV approaches."],["dc.identifier.doi","10.3389/fnmol.2020.600051"],["dc.identifier.pmid","33488357"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83002"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/123"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.publisher","Frontiers Media S.A."],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1662-5099"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","12191"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific reports"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Schidlitzki, Alina"],["dc.contributor.author","Twele, Friederike"],["dc.contributor.author","Klee, Rebecca"],["dc.contributor.author","Waltl, Inken"],["dc.contributor.author","Römermann, Kerstin"],["dc.contributor.author","Bröer, Sonja"],["dc.contributor.author","Meller, Sebastian"],["dc.contributor.author","Gerhauser, Ingo"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Li, Dandan"],["dc.contributor.author","Brandt, Claudia"],["dc.contributor.author","Bankstahl, Marion"],["dc.contributor.author","Töllner, Kathrin"],["dc.contributor.author","Löscher, Wolfgang"],["dc.date.accessioned","2019-07-09T11:44:52Z"],["dc.date.available","2019-07-09T11:44:52Z"],["dc.date.issued","2017-09-22"],["dc.description.abstract","Epilepsy may arise following acute brain insults, but no treatments exist that prevent epilepsy in patients at risk. Here we examined whether a combination of two glutamate receptor antagonists, NBQX and ifenprodil, acting at different receptor subtypes, exerts antiepileptogenic effects in the intrahippocampal kainate mouse model of epilepsy. These drugs were administered over 5 days following kainate. Spontaneous seizures were recorded by video/EEG at different intervals up to 3 months. Initial trials showed that drug treatment during the latent period led to higher mortality than treatment after onset of epilepsy, and further, that combined therapy with both drugs caused higher mortality at doses that appear safe when used singly. We therefore refined the combined-drug protocol, using lower doses. Two weeks after kainate, significantly less mice of the NBQX/ifenprodil group exhibited electroclinical seizures compared to vehicle controls, but this effect was lost at subsequent weeks. The disease modifying effect of the treatment was associated with a transient prevention of granule cell dispersion and less neuronal degeneration in the dentate hilus. These data substantiate the involvement of altered glutamatergic transmission in the early phase of epileptogenesis. Longer treatment with NBQX and ifenprodil may shed further light on the apparent temporal relationship between dentate gyrus reorganization and development of spontaneous seizures."],["dc.identifier.doi","10.1038/s41598-017-12368-6"],["dc.identifier.pmid","28939854"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14940"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59116"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/602102/EU//EPITARGET"],["dc.relation.issn","2045-2322"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","599"],["dc.title","A combination of NMDA and AMPA receptor antagonists retards granule cell dispersion and epileptogenesis in a model of acquired epilepsy."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e99649"],["dc.bibliographiccitation.issue","24"],["dc.bibliographiccitation.journal","The EMBO Journal"],["dc.bibliographiccitation.volume","37"],["dc.contributor.author","Keppeler, Daniel"],["dc.contributor.author","Merino, Ricardo Martins"],["dc.contributor.author","Lopez de la Morena, David"],["dc.contributor.author","Bali, Burak"],["dc.contributor.author","Huet, Antoine Tarquin"],["dc.contributor.author","Gehrt, Anna"],["dc.contributor.author","Wrobel, Christian"],["dc.contributor.author","Subramanian, Swati"],["dc.contributor.author","Dombrowski, Tobias"],["dc.contributor.author","Wolf, Fred"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Neef, Andreas"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2019-07-09T11:51:47Z"],["dc.date.available","2019-07-09T11:51:47Z"],["dc.date.issued","2018"],["dc.description.abstract","Optogenetic tools, providing non‐invasive control over selected cells, have the potential to revolutionize sensory prostheses for humans. Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in cochlear implants. However, most channelrhodopsins do not support the high temporal fidelity pertinent to auditory coding because they require milliseconds to close after light‐off. Here, we biophysically characterized the fast channelrhodopsin Chronos and revealed a deactivation time constant of less than a millisecond at body temperature. In order to enhance neural expression, we improved its trafficking to the plasma membrane (Chronos‐ES/TS). Following efficient transduction of SGNs using early postnatal injection of the adeno‐associated virus AAV‐PHP.B into the mouse cochlea, fiber‐based optical stimulation elicited optical auditory brainstem responses (oABR) with minimal latencies of 1 ms, thresholds of 5 μJ and 100 μs per pulse, and sizable amplitudes even at 1,000 Hz of stimulation. Recordings from single SGNs demonstrated good temporal precision of light‐evoked spiking. In conclusion, efficient virus‐mediated expression of targeting‐optimized Chronos‐ES/TS achieves ultrafast optogenetic control of neurons."],["dc.identifier.doi","10.15252/embj.201899649"],["dc.identifier.pmid","30396994"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16193"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/60011"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.title","Ultrafast optogenetic stimulation of the auditory pathway by targeting‐optimized Chronos"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","submitted_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","120"],["dc.bibliographiccitation.journal","Epilepsy & Behavior"],["dc.bibliographiccitation.lastpage","131"],["dc.bibliographiccitation.volume","61"],["dc.contributor.author","Brandt, Claudia"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Töllner, Kathrin"],["dc.contributor.author","Klee, Rebecca"],["dc.contributor.author","Bröer, Sonja"],["dc.contributor.author","Löscher, Wolfgang"],["dc.date.accessioned","2018-11-07T10:10:59Z"],["dc.date.available","2018-11-07T10:10:59Z"],["dc.date.issued","2016"],["dc.description.abstract","In rodent models in which status epilepticus (SE) is used to induce epilepsy, typically most animals develop spontaneous recurrent seizures (SRS). The SE duration for induction of epileptogenesis depends on the type of SE induction. In models with electrical SE induction, the minimum duration of SE to induce epileptogenesis in >90% of animals ranges from 3-4 h. A high incidence of epilepsy is an advantage in the search of antiepileptogenic treatments, whereas it is a disadvantage in the search for biomarkers of epileptogenesis, because it does not allow a comparison of potential biomarkers in animals that either develop or do not develop epilepsy. The aim of this project was the refinement of an established SE rat model so that only similar to 50% of the animals develop epilepsy. For this purpose, we used an electrical model of SE induction, in which a self-sustained SE develops after prolonged stimulation of the basolateral amygdala. Previous experiments had shown that the majority of rats develop SRS after 4-h SE in this model so that the SE reduced duration to 2.5 h by administering diazepam. This resulted in epilepsy development in only 50% of rats, thus reaching the goal of the project. The latent period to onset of SRS was >2 weeks in most rats. Development of epilepsy could be predicted in most rats by behavioral hyperexcitability, whereas seizure threshold did not differentiate rats that did and did not develop SRS. The refined SE model may offer a platform to identify and validate biomarkers of epileptogenesis. (C) 2016 Elsevier Inc. All rights reserved."],["dc.description.sponsorship","European Union's Seventh Framework Programme (EPITARGET) [602102]"],["dc.identifier.doi","10.1016/j.yebeh.2016.05.012"],["dc.identifier.isi","000381248000023"],["dc.identifier.pmid","27343814"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39960"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation.issn","1525-5069"],["dc.relation.issn","1525-5050"],["dc.title","Refinement of a model of acquired epilepsy for identification and validation of biomarkers of epileptogenesis in rats"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Zabelskii, Dmitrii"],["dc.contributor.author","Alekseev, Alexey"],["dc.contributor.author","Kovalev, Kirill"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Balandin, Taras"],["dc.contributor.author","Soloviov, Dmytro"],["dc.contributor.author","Bratanov, Dmitry"],["dc.contributor.author","Savelyeva, Ekaterina"],["dc.contributor.author","Podolyak, Elizaveta"],["dc.contributor.author","Volkov, Dmytro"],["dc.contributor.author","Vaganova, Svetlana"],["dc.contributor.author","Astashkin, Roman"],["dc.contributor.author","Chizhov, Igor"],["dc.contributor.author","Yutin, Natalia"],["dc.contributor.author","Rulev, Maksim"],["dc.contributor.author","Popov, Alexander"],["dc.contributor.author","Eria-Oliveira, Ana-Sofia"],["dc.contributor.author","Rokitskaya, Tatiana"],["dc.contributor.author","Mager, Thomas"],["dc.contributor.author","Antonenko, Yuri"],["dc.contributor.author","Rosselli, Riccardo"],["dc.contributor.author","Armeev, Grigoriy"],["dc.contributor.author","Shaitan, Konstantin"],["dc.contributor.author","Vivaudou, Michel"],["dc.contributor.author","Büldt, Georg"],["dc.contributor.author","Rogachev, Andrey"],["dc.contributor.author","Rodriguez-Valera, Francisco"],["dc.contributor.author","Kirpichnikov, Mikhail"],["dc.contributor.author","Moser, Tobias"],["dc.contributor.author","Offenhäusser, Andreas"],["dc.contributor.author","Willbold, Dieter"],["dc.contributor.author","Koonin, Eugene"],["dc.contributor.author","Bamberg, Ernst"],["dc.contributor.author","Gordeliy, Valentin"],["dc.date.accessioned","2021-04-14T08:31:48Z"],["dc.date.available","2021-04-14T08:31:48Z"],["dc.date.issued","2020"],["dc.description.abstract","Phytoplankton is the base of the marine food chain as well as oxygen and carbon cycles and thus plays a global role in climate and ecology. Nucleocytoplasmic Large DNA Viruses that infect phytoplankton organisms and regulate the phytoplankton dynamics encompass genes of rhodopsins of two distinct families. Here, we present a functional and structural characterization of two proteins of viral rhodopsin group 1, OLPVR1 and VirChR1. Functional analysis of VirChR1 shows that it is a highly selective, Na+/K+-conducting channel and, in contrast to known cation channelrhodopsins, it is impermeable to Ca2+ ions. We show that, upon illumination, VirChR1 is able to drive neural firing. The 1.4 Å resolution structure of OLPVR1 reveals remarkable differences from the known channelrhodopsins and a unique ion-conducting pathway. Thus, viral rhodopsins 1 represent a unique, large group of light-gated channels (viral channelrhodopsins, VirChR1s). In nature, VirChR1s likely mediate phototaxis of algae enhancing the host anabolic processes to support virus reproduction, and therefore, might play a major role in global phytoplankton dynamics. Moreover, VirChR1s have unique potential for optogenetics as they lack possibly noxious Ca2+ permeability."],["dc.identifier.doi","10.1038/s41467-020-19457-7"],["dc.identifier.pmid","33177509"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83717"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/91"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","2041-1723"],["dc.relation.workinggroup","RG Mager (Advanced Optogenes)"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.rights","CC BY 4.0"],["dc.title","Viral rhodopsins 1 are an unique family of light-gated cation channels"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Oestreicher, David"],["dc.contributor.author","Picher, Maria Magdalena"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Moser, Tobias"],["dc.contributor.author","Pangrsic, Tina"],["dc.date.accessioned","2021-10-01T09:58:18Z"],["dc.date.available","2021-10-01T09:58:18Z"],["dc.date.issued","2021"],["dc.description.abstract","Clinical management of auditory synaptopathies like other genetic hearing disorders is currently limited to the use of hearing aids or cochlear implants. However, future gene therapy promises restoration of hearing in selected forms of monogenic hearing impairment, in which cochlear morphology is preserved over a time window that enables intervention. This includes non-syndromic autosomal recessive hearing impairment DFNB93, caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels Ca V 1.3. Based on disease modeling in Cabp2 –/– mice, DFNB93 hearing impairment has been ascribed to enhanced steady-state inactivation of IHC Ca V 1.3 channels, effectively limiting their availability to trigger synaptic transmission. This, however, does not seem to interfere with cochlear development and does not cause early degeneration of hair cells or their synapses. Here, we studied the potential of a gene therapeutic approach for the treatment of DFNB93. We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2 –/– mice and assessed the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC Ca V 1.3 function resulting in improved hearing of Cabp2 –/– mice. These preclinical results prove the feasibility of DFNB93 gene therapy."],["dc.description.abstract","Clinical management of auditory synaptopathies like other genetic hearing disorders is currently limited to the use of hearing aids or cochlear implants. However, future gene therapy promises restoration of hearing in selected forms of monogenic hearing impairment, in which cochlear morphology is preserved over a time window that enables intervention. This includes non-syndromic autosomal recessive hearing impairment DFNB93, caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels Ca V 1.3. Based on disease modeling in Cabp2 –/– mice, DFNB93 hearing impairment has been ascribed to enhanced steady-state inactivation of IHC Ca V 1.3 channels, effectively limiting their availability to trigger synaptic transmission. This, however, does not seem to interfere with cochlear development and does not cause early degeneration of hair cells or their synapses. Here, we studied the potential of a gene therapeutic approach for the treatment of DFNB93. We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2 –/– mice and assessed the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC Ca V 1.3 function resulting in improved hearing of Cabp2 –/– mice. These preclinical results prove the feasibility of DFNB93 gene therapy."],["dc.identifier.doi","10.3389/fnmol.2021.689415"],["dc.identifier.pmid","34489639"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/90035"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/418"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.publisher","Frontiers Media S.A."],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1662-5099"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.relation.workinggroup","RG Pangršič Vilfan (Experimental Otology)"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e202101338"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Life Science Alliance"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Bali, Burak"],["dc.contributor.author","Gruber-Dujardin, Eva"],["dc.contributor.author","Kusch, Kathrin"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2022-06-01T09:39:47Z"],["dc.date.available","2022-06-01T09:39:47Z"],["dc.date.issued","2022"],["dc.description.abstract","AAV-mediated optogenetic neural stimulation has become a clinical approach for restoring function in sensory disorders and feasibility for hearing restoration has been indicated in rodents. Nonetheless, long-term stability and safety of AAV-mediated channelrhodopsin (ChR) expression in spiral ganglion neurons (SGNs) remained to be addressed. Here, we used longitudinal studies on mice subjected to early postnatal administration of AAV2/6 carrying fast gating ChR f-Chrimson under the control of the human synapsin promoter unilaterally to the cochlea. f-Chrimson expression in SGNs in both ears and the brain was probed in animals aged 1 mo to 2 yr. f-Chrimson was observed in SGNs at all ages indicating longevity of ChR-expression. SGN numbers in the AAV-injected cochleae declined with age faster than in controls. Investigations were extended to the brain in which viral transduction was observed across the organ at varying degrees irrespective of age without observing viral spread-related pathologies. No viral DNA or virus-related histopathological findings in visceral organs were encountered. In summary, our study demonstrates life-long (24 mo in mice) expression of f-Chrimson in SGNs upon single AAV-dosing of the cochlea."],["dc.description.sponsorship","European Research Council"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft"],["dc.description.sponsorship","Fondation Pour l’Audition"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft"],["dc.identifier.doi","10.26508/lsa.202101338"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/108563"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/481"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-572"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","2575-1077"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0/"],["dc.title","Analyzing efficacy, stability, and safety of AAV-mediated optogenetic hearing restoration in mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Huet, Antoine Tarquin"],["dc.contributor.author","Dombrowski, Tobias"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Thirumalai, Anupriya"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2021-04-14T08:27:59Z"],["dc.date.available","2021-04-14T08:27:59Z"],["dc.date.issued","2021"],["dc.description.abstract","Optogenetic stimulation of type I spiral ganglion neurons (SGNs) promises an alternative to the electrical stimulation by current cochlear implants (CIs) for improved hearing restoration by future optical CIs (oCIs). Most of the efforts in using optogenetic stimulation in the cochlea so far used early postnatal injection of viral vectors carrying blue-light activated channelrhodopsins (ChRs) into the cochlea of mice. However, preparing clinical translation of the oCI requires (i) reliable and safe transduction of mature SGNs of further species and (ii) use of long-wavelength light to avoid phototoxicity. Here, we employed a fast variant of the red-light activated channelrhodopsin Chrimson (f-Chrimson) and different AAV variants to implement optogenetic SGN stimulation in Mongolian gerbils. We compared early postnatal (p8) and adult (\\u0026gt;8 weeks) AAV administration, employing different protocols for injection of AAV-PHP.B and AAV2/6 into the adult cochlea. Success of the optogenetic manipulation was analyzed by optically evoked auditory brainstem response (oABR) and immunohistochemistry of mid-modiolar cryosections of the cochlea. In order to most efficiently evaluate the immunohistochemical results a semi-automatic procedure to identify transduced cells in confocal images was developed. Our results indicate that the rate of SGN transduction is significantly lower for AAV administration into the adult cochlea compared to early postnatal injection. SGN transduction upon AAV administration into the adult cochlea was largely independent of the chosen viral vector and injection approach. The higher the rate of SGN transduction, the lower were oABR thresholds and the larger were oABR amplitudes. Our results highlight the need to optimize viral vectors and virus administration for efficient optogenetic manipulation of SGNs in the adult cochlea for successful clinical translation of SGN-targeting gene therapy and of the oCI."],["dc.identifier.doi","10.3389/fnmol.2021.635897"],["dc.identifier.pmid","33776648"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/82465"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/305"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.publisher","Frontiers Media S.A."],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1662-5099"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Developing Fast, Red-Light Optogenetic Stimulation of Spiral Ganglion Neurons for Future Optical Cochlear Implants"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","EMBO Molecular Medicine"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Bali, Burak"],["dc.contributor.author","Lopez de la Morena, David"],["dc.contributor.author","Mittring, Artur"],["dc.contributor.author","Mager, Thomas"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Huet, Antoine Tarquin"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2021-06-01T09:42:20Z"],["dc.date.available","2021-06-01T09:42:20Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract 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."],["dc.description.abstract","Synopsis image Identifying suitable channelrhodopsins is crucial for future optogenetic restoration of sound encoding by optical cochlear implants. Here, fast and very fast light‐activated Chrimsons were compared for their utility to optogenetically encode timing and intensity information in the auditory nerve. Very fast Chrimson increases temporal fidelity but confers lower light sensitivity of optogenetic auditory nerve fiber stimulation compared with fast Chrimson. Adding trafficking sequences of the inwardly rectifying potassium channel 2.1 improved plasma membrane expression of very fast Chrimson enabling shorter stimulus durations The dynamic range, based on the discharge rate, of optogenetic auditory nerve fiber stimulation was narrower than that of acoustic stimulation. The dynamic range, based on temporal precision of spiking, of optogenetic auditory nerve fiber stimulation was broader than that based on discharge rate."],["dc.description.abstract","Identifying suitable channelrhodopsins is crucial for future optogenetic restoration of sound encoding by optical cochlear implants. Here, fast and very fast light‐activated Chrimson were compared for their utility to optogenetically encode timing and intensity information in the auditory nerve. image"],["dc.description.sponsorship","EC | H2020 | H2020 Priority Excellent Science | H2020 European Research Council (ERC)"],["dc.description.sponsorship","Cluster of Excellence; Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells; (MBExC) Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)"],["dc.description.sponsorship","Leibniz Program"],["dc.description.sponsorship","Göttingen Promotionkolleg für Medizinstudierende"],["dc.identifier.doi","10.15252/emmm.202013391"],["dc.identifier.pmid","33960685"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85221"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/255"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1757-4684"],["dc.relation.issn","1757-4676"],["dc.relation.workinggroup","RG Mager (Advanced Optogenes)"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.rights","This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited."],["dc.title","Utility of red‐light ultrafast optogenetic stimulation of the auditory pathway"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","EMBO Molecular Medicine"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Dieter, Alexander"],["dc.contributor.author","Klein, Eric"],["dc.contributor.author","Keppeler, Daniel"],["dc.contributor.author","Jablonski, Lukasz"],["dc.contributor.author","Harczos, Tamas"],["dc.contributor.author","Hoch, Gerhard"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Paul, Oliver"],["dc.contributor.author","Jeschke, Marcus"],["dc.contributor.author","Ruther, Patrick"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2021-04-14T08:25:11Z"],["dc.date.available","2021-04-14T08:25:11Z"],["dc.date.issued","2020"],["dc.description.abstract","Abstract Electrical cochlear implants (eCIs) partially restore hearing and enable speech comprehension to more than half a million users, thereby re‐connecting deaf patients to the auditory scene surrounding them. Yet, eCIs suffer from limited spectral selectivity, resulting from current spread around each electrode contact and causing poor speech recognition in the presence of background noise. Optogenetic stimulation of the auditory nerve might overcome this limitation as light can be conveniently confined in space. Here, we combined virus‐mediated optogenetic manipulation of cochlear spiral ganglion neurons (SGNs) and microsystems engineering to establish acute multi‐channel optical cochlear implant (oCI) stimulation in adult Mongolian gerbils. oCIs based on 16 microscale thin‐film light‐emitting diodes (μLEDs) evoked tonotopic activation of the auditory pathway with high spectral selectivity and modest power requirements in hearing and deaf gerbils. These results prove the feasibility of μLED‐based oCIs for spectrally selective activation of the auditory nerve."],["dc.description.abstract","Synopsis image Electrical cochlear implants effectiveness in individuals remains limited by the spread of the electric current in the cochlea. This study explores the potential of optogenetics for hearing restoration through combining optogenetic manipulation of the auditory nerve with microsystems engineering. μLED‐based optical cochlear implants (oCI) enable stimulation of the rodent auditory nerve. The strength of induced responses scales with the number of recruited emitters. μLED‐evoked neural responses are tonotopic and spectrally selective. The combination of gene therapy and microsystems engineering enables optical activation of the auditory nerve with higher spectral precision in gerbils."],["dc.description.abstract","Electrical cochlear implants effectiveness in individuals remains limited by the spread of the electric current in the cochlea. This study explores the potential of optogenetics for hearing restoration through combining optogenetic manipulation of the auditory nerve with microsystems engineering. image"],["dc.description.sponsorship","H2020 European Research Council (ERC) http://dx.doi.org/10.13039/100010663"],["dc.description.sponsorship","Bundesministerium für Bildung und Forschung (BMBF) http://dx.doi.org/10.13039/501100002347"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft (DFG) http://dx.doi.org/10.13039/501100001659"],["dc.identifier.doi","10.15252/emmm.202012387"],["dc.identifier.pmid","32596983"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81549"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/52"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1757-4684"],["dc.relation.issn","1757-4676"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.rights","This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited."],["dc.title","μLED‐based optical cochlear implants for spectrally selective activation of the auditory nerve"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]