Optogenetic Stimulation of the Auditory Nerve

Direct electrical stimulation of spiral ganglion neurons (SGNs) by cochlear implants (CIs) enables open speech comprehension in the majority of implanted deaf subjects(1-)(6). Nonetheless, sound coding with current CIs has poor frequency and intensity resolution due to broad current spread from each electrode contact activating a large number of SGNs along the tonotopic axis of the cochlea(7-)(9). Optical stimulation is proposed as an alternative to electrical stimulation that promises spatially more confined activation of SGNs and, hence, higher frequency resolution of coding. In recent years, direct infrared illumination of the cochlea has been used to evoke responses in the auditory nerve(10). Nevertheless it requires higher energies than electrical stimulation(10,11) and uncertainty remains as to the underlying mechanism(12). Here we describe a method based on optogenetics to stimulate SGNs with low intensity blue light, using transgenic mice with neuronal expression of channelrhodopsin 2 (ChR2)(13) or virus-mediated expression of the ChR2-variant CatCh(14). We used micro-light emitting diodes (µLEDs) and fiber-coupled lasers to stimulate ChR2-expressing SGNs through a small artificial opening (cochleostomy) or the round window. We assayed the responses by scalp recordings of light-evoked potentials (optogenetic auditory brainstem response: oABR) or by microelectrode recordings from the auditory pathway and compared them with acoustic and electrical stimulation

The connexin26 S17F mouse mutant represents a model for the human hereditary keratitis-ichthyosis-deafness syndrome

Mutations in the GJB2 gene coding for connexin26 (Cx26) can cause a variety of deafness and hereditary hyperproliferative skin disorders in humans. In this study, we investigated the Cx26S17F mutation in mice, which had been identified to cause the keratitis-ichthyosis-deafness (KID) syndrome in humans. The KID syndrome is characterized by keratitis and chronic progressive corneal neovascularization, skin hyperplasia, sensorineural hearing loss and increased carcinogenic potential. We have generated a conditional mouse mutant, in which the floxed wild-type Cx26-coding DNA can be deleted and the Cx26S17F mutation is expressed under control of the endogenous Cx26 promoter. Homozygous mutants are not viable, whereas the surviving heterozygous mice show hyperplasia of tail and foot epidermis, wounded tails and annular tail restrictions, and are smaller than their wild-type littermates. Analyses of auditory brainstem responses (ABRs) indicate an similar to 35 dB increased hearing threshold in these mice, which is likely due to the reduction of the endocochlear potential by 20-40%. Our results indicate that the Cx26S17F protein, which does not form functional gap junction channels or hemichannels, alters epidermal proliferation and differentiation in the heterozygous state. In the inner ear, reduced intercellular coupling by heteromeric channels composed of Cx26S17F and Cx30 could contribute to hearing impairment in heterozygous mice, while remaining wild-type Cx26 may be sufficient to stabilize Cx30 and partially maintain cochlear homeostasis. The phenotype of heterozygous mice resembles many of the symptoms of the human KID syndrome. Thus, these mice represent an appropriate model to further investigate the disease mechanism

Ca 2+

Ca2+ channels mediate excitation-secretion coupling and show little inactivation at sensory ribbon synapses, enabling reliable synaptic information transfer during sustained stimulation. Studies of Ca2+-channel complexes in HEK293 cells indicated that Ca2+-binding proteins (CaBPs) antagonize their calmodulin-dependent inactivation. Although human mutations affecting CABP2 were shown to cause hearing impairment, the role of CaBP2 in auditory function and the precise disease mechanism remained enigmatic. Here, we disrupted CaBP2 in mice and showed that CaBP2 is required for sound encoding at inner hair cell synapses, likely by suppressing Ca2+-channel inactivation. We propose that the number of activatable Ca2+ channels at the active zone is reduced when CaBP2 is lacking, as is likely the case with the newly described human CABP2 mutation

Evaluation study of the European Framework Programmes for Research and Innovation for a Resilient Europe: Final Report Phase 1:Evaluation study feeding into the Commission’s ex-post evaluation of Horizon 2020

This final report provides the results of the ‘Resilient Europe study’ implemented in the period between December 2021 and January 2023.The study was completed by a consortium consisting of PPMI Group, Prognos, VTT and Maastricht University. Using a wide range of qualitative and quantitative methods, the study covers Horizon 2020 activities that contribute to building a more resilient Europe in terms of addressing the following challenges: Societal Challenge 1; Societal Challenge 6; Societal Challenge 7. In parallel, the study also assesses four institutional partnerships, namely the AAL2, EDCTP2, IMI2 and EIT Health

Evaluation study of the European Framework Programmes for Research and Innovation for a Resilient Europe: Final Report Phase 1 - Annexes:Evaluation study feeding into the Commission’s ex-post evaluation of Horizon 2020

The annex is a complementary input into the study supporting the European Commission’s (EC) ex-post evaluation of the Societal Challenges 1, 6 and 7 of the EU Research and Innovation Framework Programme Horizon 2020. It provides a comprehensive analysis of the evaluation questions listed under tender specifications (see Table 1), supplementing the syntax analysis provided in the Final Report. Under this study, the term ‘Resilient Europe’ is understood as encompassing activities that contribute to building a more resilient Europe in terms of addressing the societal challenges: 1) Societal Challenge 1 (SC1): Health, demographic change and wellbeing; 2) Societal Challenge 6: Building more innovative, inclusive, resilient societies; 3) Societal Challenge 7: More secure societies. Additionally, the answers focus on specific public-public and public-private partnerships. The document is divided according to each Societal Challenge (SC1, SC6, SC7) and organised by the Better Regulation (BR) criteria. The exception applies to the Efficiency analysis, which was complemented as one chapter for all assessed programme parts upon the agreement with the EC. The table below presents short descriptions of each of the evaluation criteria. In addition, the 2 partnership-specific evaluation criteria – additionality and transparency and openness - apply to all partnerships assessed under this study