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Sound-level coding in the auditory nerve is achieved through the progressive recruitment of auditory nerve fibers (ANFs) that differ in threshold of activation and in the stimulus level at which the spike rate saturates. To investigate the functional state of the ANFs, the electrophysiological tests routinely used in clinics only capture the first action potentials firing in synchrony at the onset of the acoustic stimulation. Assessment of other properties (e.g., spontaneous rate and adaptation time constants) requires single-fiber recordings directly from the nerve, which for ethical reasons is not allowed in humans. By combining neuronal activity measurements at the round window and signal-processing algorithms, we constructed a peristimulus time response (PSTR), with a waveform similar to the peristimulus time histograms (PSTHs) derived from single-fiber recordings in young adult female gerbils. Simultaneous recordings of round-window PSTR and single-fiber PSTH provided models to predict the adaptation kinetics and spontaneous rate of the ANFs tuned at the PSTR probe frequency. The predictive model derived from gerbils was then validated in female mice and finally applied to humans by recording PSTRs from the auditory nerve in normal-hearing patients who underwent cerebellopontine angle surgeries. A rapid adaptation time constant of ∼3 ms and a mean spontaneous rate of ∼22 spikes/s in the 4 kHz frequency range were found. This study offers a promising diagnostic tool to map the human auditory nerve, thus opening new avenues to better understanding auditory neuropathies, tinnitus, and hyperacusis.SIGNIFICANCE STATEMENTNeural adaptation in auditory nerve fibers corresponds to the reduction in the neuronal activity to prolonged or repeated sound stimulation. For obvious ethical reasons, single-fiber recordings from the auditory nerve are not feasible in humans, creating a critical gap in extending data obtained using animal models to humans. Using electrocochleography in rodents, we inferred adaptation kinetics and spontaneous discharge rates of the auditory nerve fibers in humans. Routinely used in basic and clinical laboratories, this tool will provide a better understanding of auditory disorders such as neuropathies, tinnitus, and hyperacusis, and will help to improve hearing-aid fittings.

Wolfram syndrome (WS) is a rare neurodegenerative disease encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) and neurological disorders. None of the animal models of the pathology are presenting with an early onset HL, impeding the understanding of the role of Wolframin (WFS1), the protein responsible for WS, in the auditory pathway. We generated a knock-in mouse, the Wfs1E864K line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, associated with a decrease of the endocochlear potential (EP) and a devastating alteration of the stria vascularis and neurosensory epithelium. The mutant protein prevented the localization to the cell surface of the Na+/K+ATPase-β1 subunit, a key protein for the maintenance of the EP. Overall, our data support an important role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na+/K+ATPase β1-subunit.

The temporal structure of sensory inputs contains essential information for their interpretation by the brain1–9. Sensory systems represent these temporal cues through two codes: the temporal sequences of neuronal activity and the spatial patterns of neuronal firing rate3,7,10–20. However, it is still unknown which of these two coexisting codes causally drives sensory decisions3,10,20,21. To separate their contributions, we designed an optogenetic stimulation paradigm in the mouse auditory cortex to generate neuronal activity patterns differing exclusively along their temporal or spatial dimensions. Training mice to discriminate these patterns shows that they efficiently learn to discriminate spatial but not temporal patterns, indicating that spatial representations are necessary for sensory learning. In line with this result, we observed, based on large-scale neuronal recordings of the auditory system, that the auditory cortex is the first region in which spatial patterns efficiently represent temporal auditory cues varying over several hundred milliseconds. This feature is shared by the deep layers of neural networks trained to categorise time-varying sounds. Therefore, the emergence of a spatial code for temporal sensory cues is a necessary condition to associate temporally structured stimuli to decisions. We expect this constraint to be crucial for re-engineering perception by cortical stimulation.

Objectives Otitis media with effusion (OME) is a common pathology in children. Effusions contain Metalloproteinases (MMPs), which can lead to atrophy of the tympanic membrane (TM) due to destructive effect on the lamina propria. Not all cases of OME are complicated with atrophy, maybe explained by an inter-individual variation of MMP concentration in effusions. The purpose of this study was to determine the correlation between concentration of MMPs and existence of TM atrophy in children. Participants - Main outcome measures The effusion from thirty middle ears were collected during insertion of VT in children aged 15 months to 10 years, including 11 eardrums with tympanic atrophy and 19 without tympanic atrophy. ELISA tests were used to measure concentrations of MMP-2, MMP-7, MMP-9 and TIMP-2 in the effusions. Correlations between MMP levels and atrophy of eardrum was investigated, as well as correlation with age, gender, number of previous ventilation tube insertion, and viscosity of the glue. Results The mean concentration of MMP-2 was higher in the atrophic group than in effusions without TM atrophy (0.6 ng/mg versus 0.5 ng/mg total protein respectively), while the TIMP-2 concentration was lower in this group. The level of MMP-2 decreased with the age. Finally, a significantly higher concentration of MMP-9 and TIMP-2 was found in high-viscosity effusions. Conclusion This study suggests that MMP-2 activity could play an important role in destruction of the eardrum during OME in infancy. MMP-2 level assessment could be interesting for determining children with risk of lamina propria destruction.

The apex or apical region of the cochlear spiral within the inner ear encodes for low-frequency sounds. The disposition of sensory hair cells on the organ of Corti is largely variable in the apical region of mammals, and it does not necessarily follow the typical three-row pattern of outer hair cells (OHCs). As most underwater noise sources contain low-frequency components, we expect to find most lesions in the apical region of the cochlea of toothed whales, in cases of permanent noise-induced hearing loss. To further understand how man-made noise might affect cetacean hearing, there is a need to describe normal morphological features of the apex and document interspecific anatomic variations in cetaceans. However, distinguishing between apical normal variability and hair cell death is challenging. We describe anatomical features of the organ of Corti of the apex in 23 ears from five species of toothed whales (harbor porpoise Phocoena phocoena, spinner dolphin Stenella longirostris, pantropical spotted dolphin Stenella attenuata, pygmy sperm whale Kogia breviceps, and beluga whale Delphinapterus leucas) by scanning electron microscopy and immunofluorescence. Our results showed an initial region where the lowest frequencies are encoded with two or three rows of OHCs, followed by the typical configuration of three OHC rows and three rows of supporting Deiters' cells. Whenever two rows of OHCs were detected, there were usually only two corresponding rows of supporting Deiters' cells, suggesting that the number of rows of Deiters' cells is a good indicator to distinguish between normal and pathological features.

Type I spiral ganglion neurons (I-SGNs) of the mammalian cochlea convey all acoustic information from the sensory hair cells to second order neurons in the brainstem. Despite evidence supporting physiological diversity of I-SGNs and of its importance for encoding the various features of sounds, knowledge of their molecular diversity is only emerging. In this review, we outline the recent efforts in the identification of mammalian I-SGN types and summarize how genetic and anatomical features of each individual neuron type relate to functional aspects that characterize sound information processing in the primary auditory afferent system.

Riassunto Gli acufeni soggettivi sono delle percezioni uditive che non rispondono a una stimolazione sonora registrabile. Sono generalmente sintomatici di una lesione attiva o sequenziale del sistema uditivo periferico. Tuttavia, i meccanismi fisiopatologici multipli e intricati che spiegano sia la loro emergenza che la loro connotazione spiacevole, persino insopportabile, implicano piu probabilmente delle disfunzioni centrali. Cio rifletterebbe un’anomala di plasticita cerebrale generalmente indotta dalla perdita dell’udito. Un’analisi clinica rigorosa che evidenzia i fattori organici e psicologici coinvolti, nonche ulteriori esami prescritti in modo ragionato, consentono di orientare e guidare efficacemente i pazienti. Allo stato attuale delle conoscenze, non esiste un trattamento curativo, in particolare un trattamento farmacologico, sistematicamente applicabile a tutti i pazienti. Tuttavia, varie terapie palliative volte a migliorare la tolleranza del sintomo si sono dimostrate efficaci: come le terapie cognitivo- comportamentali e diversi metodi di rieducazione sonora. Questo vale anche per gli interventi di riabilitazione dell’udito con apparecchi acustici o impianti cocleari. La prospettiva di un ripristino ad integrum della funzione cocleare, grazie agli strumenti emergenti della farmacologia intracocleare e della terapia genica, nonche alle tecniche innovative per la modulazione dell’attivita cerebrale costituiscono una speranza per tutti i pazienti che soffrono di acufeni.

International audience; Recent studies demonstrated that reversible continuous noise exposure may induce a temporary threshold shift (TTS) with a permanent degeneration of auditory nerve fibers, although hair cells remain intact. To probe the impact of TTS-inducing impulse noise exposure on hearing, CBA/J Mice were exposed to noise impulses with peak pressures of 145 dB SPL. We found that 30 min after exposure, the noise caused a mean elevation of ABR thresholds of ~30 dB and a reduction in DPOAE amplitude. Four weeks later, ABR thresholds and DPOAE amplitude were back to normal in the higher frequency region (8–32 kHz). At lower frequencies, a small degree of PTS remained. Morphological evaluations revealed a disturbance of the stereociliary bundle of outer hair cells, mainly located in the apical regions. On the other hand, the reduced suprathreshold ABR amplitudes remained until 4 weeks later. A loss of synapse numbers was observed 24 h after exposure, with full recovery two weeks later. Transmission electron microscopy revealed morphological changes at the ribbon synapses by two weeks post exposure. In addition, increased levels of oxidative stress were observed immediately after exposure, and maintained for a further 2 weeks. These results clarify the pathology underlying impulse noise-induced sensory dysfunction, and suggest possible links between impulse-noise injury, cochlear cell morphology, metabolic changes, and hidden hearing loss.

People are increasingly exposed to environmental noise through the cumulation of occupational and recreational activities, which is considered harmless to the auditory system, if the sound intensity remains

In our aging society, age-related hearing loss (ARHL) has become a major socioeconomic issue. Reactive oxygen species (ROS) may be one of the main causal factors of age-related cochlear cell degeneration. We examined whether ROS-induced DNA damage response drives cochlear cell senescence and contributes to ARHL from the cellular up to the system level. Our results revealed that sublethal concentrations of hydrogen peroxide (H2O2) exposure initiated a DNA damage response illustrated by increased γH2AX and 53BP1 expression and foci formation mainly in sensory hair cells, together with increased levels of p-Chk2 and p53. Interestingly, postmitotic cochlear cells exposed to H2O2 displayed key hallmarks of senescent cells, including dramatically increased levels of p21, p38, and p-p38 expression, concomitant with decreased p19 and BubR1 expression and positive senescence-associated β-galactosidase labeling. Importantly, the synthetic superoxide dismutase/catalase mimetic EUK-207 attenuated H2O2-induced DNA damage and senescence phenotypes in cochlear cells in vitro. Furthermore, systemic administration of EUK-207 reduced age-related loss of hearing and hair cell degeneration in senescence-accelerated mouse-prone 8 (SAMP8) mice. Altogether, these findings highlight that ROS-induced DNA damage responses drive cochlear cell senescence and contribute to accelerated ARHL. EUK-207 and likely other antioxidants with similar mechanisms of action could potentially postpone cochlear aging and prevent ARHL in humans.

Knowledge of the refractory properties of auditory-nerve fibers (ANFs) is required for understanding the transduction of the graded membrane potential of the receptor cells into spike trains. The refractory properties inferred when ANFs are excited by electrical stimulation might differ from those present when ANFs are excited naturally by transmitter release from receptor cells. As a proxy for the latter, we investigated the recovery of spike amplitude with time since the previous spike in long extracellular recordings of the activity of individual ANFs from anesthetized Mongolian gerbils. Voltage traces were filtered minimally to avoid distortions of spike amplitude and timing. The amplitude of each spike was defined as the difference between its peak voltage and an extrapolated instantaneous reference voltage at the time of the peak. Spike amplitude was normalized to that of the previous spike to exclude effects of long-term changes in recording conditions. To ensure that the amplitude of the first spike in each pair was fully recovered, each spike pair was used only when preceded by an interspike interval of at least 5 ms. We find that the recovery of spike amplitude is well described by a short dead time followed by a double-exponential recovery function. Total recovery times were short (median: 0.85 ms; interquartile range: 0.74–1.00 ms) and independent of the ANF's characteristic frequency and spontaneous rate, but they increased weakly with increasing mean rate. We emphasize the differences between the recovery of spike amplitude, the recovery of spike probability from postsynaptic refractoriness, and the recovery of spike probability as reflected in the hazard-rate function. Our findings are inconsistent with the long refractory periods assumed in some models, but are consistent with the brief refractoriness assumed in the synapse model of Peterson and Heil (2018), which reproduces the stochastic properties of stationary spontaneous and sound-driven ANF spike trains.

Information in sound stimuli is conveyed from sensory hair cells to the cochlear nuclei by the firing of auditory nerve fibers (ANFs). For obvious ethical reasons, single unit recordings from the cochlear nerve have never been performed in human, thus functional hallmarks of ANFs are unknown. By filtering and rectifying the electrical signal recorded at the round window of gerbil cochleae, we reconstructed a peri-stimulus time response (PSTR), with a waveform similar to the peri-stimulus time histograms (PSTHs) recorded from single ANFs. Pair-by-pair analysis of simultaneous PSTR and PSTH recordings in gerbil provided a model to predict the rapid adaptation and spontaneous discharge rates (SR) in a population of ANFs according to their location in the cochlea. We then probed the model in the mouse, in which the SR-based distribution of ANFs differs from the gerbil. We show that the PSTR-based predictions of the rapid adaptation time constant and mean SR across frequency again matched those obtained by recordings from single ANFs. Using PSTR recorded from the human cochlear nerve in 8 normal-hearing patients who underwent cerebellopontine angle surgeries for a functional cranial-nerve disorders (trigeminal neuralgia or hemifacial spasm), we predicted a rapid adaptation of about 3 milliseconds and a mean SR of 23 spikes/s in the 4 kHz frequency range in human ANFs. Together, our results support the use of PSTR as a promising diagnostic tool to map the auditory nerve in humans, thus opening new avenues to better understanding neuropathies, tinnitus, and hyperacusis.

DFNA25 is an autosomal-dominant and progressive form of human deafness caused by mutations in the SLC17A8 gene, which encodes the vesicular glutamate transporter type 3 (VGLUT3). To resolve the mechanisms underlying DFNA25, we studied the phenotype of the mouse harboring the p.A221V mutation in human (corresponding to p.A224V in mouse). Using auditory brainstem response and distortion products of otoacoustic emissions, we showed that VGLUT3A224V/A224V mouse replicates the DFNA25 progressive hearing loss with intact cochlear amplification. Scanning electron microscopy examinations demonstrated fused stereocilia bundle of the inner hair cells (IHCs) as the primary cause for DFNA25. In addition, the IHC ribbon synapses undergo structural and functional modifications at later stages. Using super-resolution microscopy, we observed oversized synaptic ribbons associated with an increase in the rate of the sustained releasable pool of exocytosis. These results indicate that the primary defect in DFNA25 stems from a failure in the mechano-transduction followed by a change in synaptic transfer. The VGLUT3A224V/A224V mouse model opens the way to a deeper understanding and to a potential treatment of DFNA25.

International audience; Over the last decade, pioneering molecular gene therapy for inner-ear disorders have achieved experimental hearing improvements after a single local or systemic injection of adeno-associated, virus-derived vectors (rAAV for recombinant AAV) encoding an extra copy of a normal gene, or ribozymes used to modify a genome. These results hold promise for treating congenital or later-onset hearing loss resulting from monogenic disorders with gene therapy approaches in patients. In this review, we summarize the current state of rAAV-mediated inner-ear gene therapies including the choice of vectors and delivery routes, and discuss the prospects and obstacles for the future development of efficient clinical rAAV-mediated cochlear gene medicine therapy.

Introduction Current literature does not provide strong evidence that remote programming of hearing aids is effective, despite its increasing use by audiologists. We tested speech perception outcomes, real-ear insertion gain, and changes in self-perceived hearing impairment after face-to-face and remote programming of hearing aids in a randomized multicentre, single-blind crossover study. Methods Adult experienced hearing aid users were enrolled during routine follow-up visits to audiology clinics. Hearing aids were programmed both face to face and remotely, then participants randomly received either the face-to-face or remote settings in a blinded manner and were evaluated 5 weeks later. Participants then received the other settings and were evaluated 5 weeks later. Results Data from 52 out of 60 participants were analysed. We found excellent concordance in performance of hearing aids programmed face to face and remotely for speech understanding in quiet (phonetically balanced kindergarten test – intraclass correlation coefficient of 0.92 (95% confidence interval: 0.87–0.95)), and good concordance in performance for speech understanding in noise (phonetically balanced kindergarten +5 dB signal-to-noise ratio – intraclass correlation coefficient of 0.71 (95% confidence interval: 0.55–0.82)). Face-to-face and remote programming took 10 minutes (±2.9) and 10 minutes (±2.8), respectively. Real-ear insertion gains were highly correlated for input sound at 50, 65 and 80 dB sound pressure levels. The programming type did not affect the abbreviated profile of hearing aid questionnaire scores. Conclusions In experienced hearing aid users, face-to-face and remote programming of hearing aids give similar results in terms of speech perception, with no increase in the time spent on patients’ care and no difference in self-reported hearing benefit. ClinicalTrials.gov Identifier NCT02589561

Il 16% della popolazione adulta e una persona su due oltre i 75 anni soffrono di disturbi uditivi (sordita, acufeni). Visto l’aumento della speranza di vita e l’esposizione al rumore che accelera l’invecchiamento, molte persone avranno dei benefici nell’uso di apparecchi. Oggi, praticamente tutti gli apparecchi acustici sono digitali e connessi. Questi dispositivi si presentano come retroauricolari indossati sul padiglione o come intrauricolari piu o meno nascosti nel condotto uditivo esterno. Il principio di questi apparecchi e di amplificare l’informazione pertinente (in particolare il discorso) per avviarla vicino al timpano. Questo articolo descrive il funzionamento e le strategie di elaborazione del segnale per adattarsi alle diverse situazioni di ascolto dei pazienti. Certamente, l’adattamento protesico si basa su un approccio scientifico, soprattutto perche si basa su un bilancio audiologico completo e su dei software di trattamento del segnale sofisticati. Tuttavia, il successo di un apparecchio si basa anche su una gestione rieducativa del paziente, cosi come su un supporto personalizzato e regolare per arrivare a una regolazione adeguata alla sordita, all’ambiente, alla vita e alle aspettative dell’ipoudente.

El 16% de la poblacion adulta y un 50% de las personas mayores de 75 anos presentan trastornos auditivos (sorderas, acufenos). Debido al aumento de la esperanza de vida y a la exposicion al ruido, que acelera el envejecimiento, muchas personas mejorarian su audicion con una adaptacion audioprotesica. En la actualidad, casi todas las audioprotesis son digitales y con conexion inalambrica. Estos dispositivos pueden ser retroauriculares, que se colocan sobre el pabellon, o intraauriculares, disimulados mas o menos en el conducto auditivo externo. El fundamento de estos aparatos es amplificar la informacion pertinente (en particular el habla) para dirigirla hacia el timpano. En este articulo, se describe el funcionamiento y las estrategias de tratamiento de la senal para adaptarse a las diversas situaciones auditivas de los pacientes. Sin duda, la adaptacion protesica se basa en un proceso cientifico, en particular porque se apoya en un estudio audiologico completo y en programas informaticos de tratamiento de la senal sofisticados. Sin embargo, el exito de la adaptacion audioprotesica requiere tambien una rehabilitacion del paciente, asi como un acompanamiento personalizado y frecuente para lograr un ajuste adaptado a la sordera, al entorno, a la vida y a las expectativas de la persona con sordera.

Auditory nerve fibers (ANFs) convey acoustic information from the sensory cells to the brainstem using an elaborated neural code based on both spike timing and rate. As the stimulus tone frequency increases, time coding fades and ceases, resulting in high-frequency tone encoding that relies mostly on the spike discharge rate. Here, we recapitulated our recent single-unit data from gerbil’s auditory nerve to highlight the most relevant mode of coding (spike timing versus spike rate) in tone-in-noise. We report that high-spontaneous rate (SR) fibers driven by low-frequency tones in noise are able to phase lock ∼30 dB below the level that evoked a significant elevation of the discharge rate, whereas medium- and low-SR fibers switch their preferential mode of coding from rate coding in quiet, to time coding in noise. For high-frequency tone, the low-threshold/high-SR fibers reach their maximum discharge rate in noise and do not respond to tones, whereas medium- and low-SR fibers are still able to respond to tones making them more resistant to background noise. Based on these findings, we first discuss the ecological function of the ANF distribution according to their spontaneous discharge rate. Then, we point out the poor synchronization of the low-SR ANFs, accounting for the discrepancy between ANF number and the amplitude of the compound action potential of the of the auditory nerve. Finally, we proposed a new diagnostic tool to assess low-SR fibers, which does not rely on the onset response of the ANFs.

International audience; Aging is often considered to affect both the peripheral (i.e. the cochlea) and central (brainstem and thalamus-cortex) auditory systems. We investigated the effects of aging on the cochlea, brainstem and cortex of female Sprague-Dawley rats. The auditory nerve threshold remained stable between the ages of nine and 21 months, as did distortion product otoa-coustic emissions and the number of ribbon synapses between inner hair cells and nerve fibers. The first clear signs of aging appeared in the brainstem, in which response amplitude decreased, with thresholds remaining stable until the age of 15 months, and increasing slightly thereafter. The responses of primary auditory cortex neurons revealed specific effects of aging: at 21 months, receptive fields were spectrally narrower and the temporal reliability of responses to communication sounds was lower. However, aging had a null or even positive effect on neuronal responses in the presence of background noise, responses to amplitude-modulated sounds, and responses in gap-detection protocols. Overall, inter-animal variability remained high relative to the variability across groups of different ages, for all parameters tested. Beha-vioral performance for the modulation depth of amplitude modulation noise was worse in 21-month old animals than in other animals. Age-related alterations of cortical and behavioral responses were thus observed in animals displaying no signs of aging at the peripheral level. These results suggest that intrinsic, central aging effects can affect the perception of acoustic stimuli independently of the effects of aging on peripheral receptors.

International audience; Chronic subjective tinnitus is a widespread disorder. This perceptual anomaly is assumed to result from a dysbalance of excitatory and inhibitory mechanisms on different levels of the auditory pathways. However, the brain areas involved are still under discussion. Using resting-state functional magnetic resonance imaging, we investigate differences in cerebral regional homogeneity (ReHo) between patients with unilateral chronic tinnitus and nontinnitus control subjects. To our knowledge, our study is the first to investigate the intraregional connectivity of patients with unilateral tinnitus in relation to hearing loss. Our analyses, based on strict recruitment and characterization of the participants, showed reduced ReHo in the primary auditory cortex contralateral to the side of the perceived tinnitus percept in patients. Reduced ReHo in this same region was also correlated with increased Tinnitus Handicap Inventory and Visual Analogue Scale for loudness scores, reflecting an alteration of synchronization in this region related to the perceived loudness of the tinnitus and the related distress. Furthermore, increased ReHo in the supramarginal and angular gyri ipsilateral to the tinnitus side was correlated with increased tinnitus duration and hearing threshold at the tinnitus pitch. The correlations observed in these brain areas, which are normally related to the nontinnitus ear, could highlight compensatory mechanisms in these secondary auditory regions.

International audience; Vesicular glutamate transporters (VGLUT1-3) mediate the uptake of glutamate into synaptic vesicles. VGLUTs are pivotal actors of excitatory transmission and of almost all brain functions. Their implication in various pathologies has been clearly documented. Despite their functional importance, the pharmacology of VGLUTs is limited to a few dyes such as Trypan Blue, Rose Bengal or Brilliant Yellow type. Here, we report the design and evaluation of new potent analogs based on Trypan Blue scaffold. Our best compound, named LSP5-2157, has an EC50 of 50 nM on glutamate vesicular uptake. Using a 3D homology model of VGLUT1 and docking experiments, we determined its putative binding subdomains within vesicular glutamate transporters and validated the structural requirement for VGLUT inhibition. To better estimate the specificity and potency of LSP5-2157, we also investigated its ability to block glutamatergic transmission in autaptic hippocampal cells. Neither glutamate receptors nor GABAergic transmission or transmission machinery were affected by LSP5-2157. Low doses of compound reversibly reduce glutamatergic neurotransmission in hippocampal autpases. LSP5-2157 had a low and depressing effect on synaptic efficacy in hippocampal slice. Furthermore, LSP5-2157 had no effect on NMDA-R- mediated fEPSP but reduce synaptic plasticity induced by 3 trains of 100 Hz. Finally, LSP5-2157 had the capacity to inhibit VGLUT3-dependent auditory synaptic transmission in the guinea pig cochlea. In this model, it abolished the compound action potential of auditory nerve at high concentration showing the limited permeation of LSP5-2157 in an in-vivo model. In summary, the new ligand LSP5-2157, has a high affinity and specificity for VGLUTs and shows some permeability in isolated neuron, tissue preparations or in vivo in the auditory system. These findings broaden the field of VGLUTs inhibitors and open the way to their use to assess glutamatergic functions in vitro and in vivo.

Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin‐induced ototoxicity remains unclear, and hearing preservation during cisplatin‐based chemotherapy in patients is lacking. We found activation of the ATM‐Chk2‐p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin‐induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer hair cell death and inner hair cell survival. Encouragingly, however, genetic or pharmacological ablation of p53 substantially attenuated cochlear cell apoptosis, thus preserving hearing. Importantly, systemic administration of a p53 inhibitor in mice bearing patient‐derived triple‐negative breast cancer protected auditory function, without compromising the anti‐tumor efficacy of cisplatin. Altogether, these findings highlight a novel and effective strategy for hearing protection in cisplatin‐based chemotherapy.

High mobility group box 1 (HMGB1) is a DNA-binding protein that facilitates gene transcription and may act extracellularly as a late mediator of inflammation. The roles of HMGB1 in the pathogenesis of the spiral ganglion neurons (SGNs) of the cochlea are currently unknown. In the present study, we tested the hypothesis that early phenotypical changes in the SGNs of the amikacin-poisoned rat cochlea are mediated by HMGB1. Our results showed that a marked downregulation of HMGB1 had occurred by completion of amikacin treatment, coinciding with acute damage at the dendrite extremities of the SGNs. A few days later, during the recovery of the SGN dendrites, the protein was re-expressed and transiently accumulated within the nuclei of the SGNs. The phosphorylated form of the transcription factor c-Jun (p-c-Jun) was concomitantly detected in the nuclei of the SGNs where it often co-localized with HMGB1, while the anti-apoptotic protein BCL2 was over-expressed in the cytoplasm. In animals co-treated with amikacin and the histone deacetylase inhibitor trichostatin A, both HMGB1 and p-c-Jun were exclusively found within the cytoplasm. The initial disappearance of HMGB1 from the affected SGNs may be due to its release into the external medium, where it may have a cytokine-like function. Once re-expressed and translocated into the nucleus, HMGB1 may facilitate the transcriptional activity of p-c-Jun, which in turn may promote repair mechanisms. Our study therefore suggests that HMGB1 can positively influence the survival of SGNs following ototoxic exposure via both its extracellular and intranuclear functions.

Gerbils possess a very specialized cochlea in which the low-frequency inner hair cells (IHCs) are contacted by auditory nerve fibers (ANFs) having a high spontaneous rate (SR), whereas high frequency IHCs are innervated by ANFs with a greater SR-based diversity. This specificity makes this animal a unique model to investigate, in the same cochlea, the functional role of different pools of ANFs. The distribution of the characteristic frequencies of fibers shows a clear bimodal shape (with a first mode around 1.5 kHz and a second around 12 kHz) and a notch in the histogram near 3.5 kHz. Whereas the mean thresholds did not significantly differ in the two frequency regions, the shape of the rate-intensity functions does vary significantly with the fiber characteristic frequency. Above 3.5 kHz, the sound-driven rate is greater and the slope of the rate-intensity function is steeper. Interestingly, high-SR fibers show a very good synchronized onset response in quiet (small first-spike latency jitter) but a weak response under noisy conditions. The low-SR fibers exhibit the opposite behavior, with poor onset synchronization in quiet but a robust response in noise. Finally, the greater vulnerability of low-SR fibers to various injuries including noise- and age-related hearing loss is discussed with regard to patients with poor speech intelligibility in noisy environments. Together, these results emphasize the need to perform relevant clinical tests to probe the distribution of ANFs in humans, and develop appropriate techniques of rehabilitation. This article is part of a Special Issue entitledAnnual Reviews 2016.

Resume Objectifs Valider une nouvelle methode d’audiometrie vocale utilisant des listes personnalisees, enregistrees par le sujet a tester, et beneficiant d’une notation automatique. Patients et methodes L’effet de l’utilisation de sa propre voix a ete etudie par la comparaison des tests de logatomes CVC pre-enregistres ou enregistres par le sujet a tester. Ensuite, des listes personnalisees de 3 phonemes ont ete etablies avec le logiciel OTOSPEECH, et leur score a ete compare aux listes de references. Enfin, les scores de listes personnalisees ont ete compares apres notation automatique (score DTW) ou notation manuelle. Resultats L’utilisation de sa propre voix ne modifie pas les scores de perception de logatomes a 10, 20 et 30 dB (Anova > 0,05). Il existe une correlation entre les scores obtenus avec les listes pre-enregistrees et les listes enregistrees par les sujets (n = 10, r2 = 0,76, p Conclusions Une notation automatisee de listes personnalisees d’audiometrie vocale, enregistrees par le sujet a tester, donne des resultats similaires aux techniques classiques d’audiometrie.

Sensorineural hearing impairment is the most common sensory disorder and a major health and socio-economic issue in industrialized countries. It is primarily due to the degeneration of mechanosensory hair cells and spiral ganglion neurons in the cochlea via complex pathophysiological mechanisms. These occur following acute and/or chronic exposure to harmful extrinsic (e.g., ototoxic drugs, noise...) and intrinsic (e.g., aging, genetic) causative factors. No clinical therapies currently exist to rescue the dying sensorineural cells or regenerate these cells once lost. Recent studies have, however, provided renewed hope, with insights into the therapeutic targets allowing the prevention and treatment of ototoxic drug- and noise-induced, age-related hearing loss as well as cochlear cell degeneration. Moreover, genetic routes involving the replacement or corrective editing of mutant sequences or defected genes are showing promise, as are cell-replacement therapies to repair damaged cells for the future restoration of hearing in deaf people. This review begins by recapitulating our current understanding of the molecular pathways that underlie cochlear sensorineural damage, as well as the survival signaling pathways that can provide endogenous protection and tissue rescue. It then guides the reader through to the recent discoveries in pharmacological, gene and cell therapy research towards hearing protection and restoration as well as their potential clinical application.

Auditory nerve fibers (ANFs) encode pure tones through two modes of coding, spike time and spike rate, depending on the tone frequency. In response to a low-frequency tone, ANF firing is phase locked to the sinusoidal waveform. Because time coding vanishes with an increase in the tone frequency, high-frequency tone coding relies on the spike rate of the ANFs. Adding a continuous broadband noise to a tone compresses the rate intensity function of ANFs and shifts its dynamic range toward higher intensities. Therefore, the ANFs with high-threshold/low-spontaneous rate (SR) are thought to contribute to behavioral tone detection in noise. However, this theory relies on the discharge rate of the ANFs. The direct comparison with the masking threshold through spike timing, irrespective of the spontaneous rate, has not so far been investigated. Taking advantage of a unique proxy to quantify the spike synchrony (i.e., the shuffle autocorrelogram), we show in female gerbils that high-SR ANFs are more adapted to encode low-frequency thresholds through temporal code, giving them a strong robustness in noise. By comparing behavioral thresholds measured using prepulse inhibition of the acoustical startle reflex with population thresholds calculated from ANFs pooled per octave band, we show that threshold-based spike timing provides a better estimate of behavioral thresholds in the low-frequency range, whereas the high-frequency behavioral thresholds rely on the spiking rate, particularly in noise. This emphasizes the complementarity of temporal and rate modes to code tone-in-noise thresholds over a large range of frequencies. SIGNIFICANCE STATEMENT There is a general agreement that high-threshold/low-spontaneous rate (SR) auditory nerve fibers (ANFs) are of prime importance for tone detection in noise. However, this theory is based on the discharge rate of the fibers. Comparing the behavioral thresholds and single ANF thresholds shows that this is only true in the high-frequency range of tone stimulations. In the low-frequency range of tones (up to 2.7 kHz in the gerbil), the most sensitive ANFs (high-SR fibers) carry neural information through a spike-timing mode, even for noise in which tones do not induce a noticeable increment in the spike rate. This emphasizes the interplay between spike-time and spike-rate modes in the auditory nerve to encode tone-in-noise threshold over a large range of tone frequencies.

International audience; HYPOTHESIS: Evaluate the benefit of preoperative surgical planning using computed tomography (CT) for atraumatic cochlear implantation. BACKGROUND: The surgical technique has a direct impact on hearing and structure preservation. Much interest has been given to depth of electrode insertion. We focused on electrode diameter depending on exposure of round window membrane (RWM) as calculated on preoperative CT. METHODS: Measurements were calculated radiologically and anatomically on 10 temporal bones. Results were compared with CT scans of a control population. Thereafter, preoperative CT scan measurements were applied to seven additional temporal bones that underwent cochlear implantation with the insertion of two electrodes of different diameters (14 implantations) to validate radiological analysis. RESULTS: RWM size was 1.5?\textpm?0.2?mm on CT and 1.2?\textpm?0.2?mm during dissection; posterosuperior bony overhang of round window niche was 1.1?\textpm?0.1?mm on CT and 1.3?\textpm?0.2?mm during dissection. There was no statistically significant difference between radiological and anatomical measurements and between radiological measurements of cadaveric temporal bones and control population (p?\textgreater?0.05 for both). Also, preoperative surgical planning was reliable in the seven temporal bones implanted with two electrode types (accuracy 93%, sensitivity 85.7%, specificity 100%) yielding no damage to intracochlear structures. CONCLUSION: Difficulties to access RWM could be predicted on preoperative CT of temporal bones and control population, which correlated well with anatomical dissections and surgical findings during cochlear implantation. According to CT planning, electrode insertion through RWM was feasible in most patients, with or without drilling posterosuperior bony overhang of round window niche. Promontory cochleostomy could be recommended when electrode apical diameter exceeded maximal RWM exposure. There was no case of intracochlear trauma on microdissections.

International audience; OBJECTIVE:Teleotoscopy requires the assistance of telehealth facilitators; but their training requirements remain to be determined. We evaluated the use of an otoscopy simulator to train facilitators to remote otoscopies sent via the Internet using a teleaudiology platform.DESIGN:Neurotologists experts were asked to identify images using the otoscopy simulator and to perform an identification task of significant anatomical landmarks. The experts were asked to repeat those tasks remotely, with the help of facilitators who either received basic training, or no training prior to the experiment.STUDY SAMPLE:Three experts, three trained facilitators and three untrained facilitators participated in this study.RESULTS:The use of an otoscopy simulator in addition to remote otoscopy yielded a good inter- and intrarater agreement (κ between 0.81-1, and 0.80-0.87, respectively). The accuracy of diagnosis was high on-site (11.7% error) and remotely (0% error). The time required for landmark identification task was not increased when performed remotely with a trained facilitator versus on-site otoscopy (9.3 versus 9.2 s/landmark). Conversely, the lack of training of facilitators increased significantly this time (15.6 s/landmark, p

International audience; Previous experimental data indicates the hyperpolarization-activated cation (Ih ) current, in the inner ear, consists of two components [different hyperpolarization-activated cyclic nucleotide-gated (HCN) subunits] which are impossible to pharmacologically isolate. To confirm the presence of these two components in vestibular ganglion neurons we have applied a parameter identification algorithm which is able to discriminate the parameters of the two components from experimental data. Using simulated data we have shown that this algorithm is able to identify the parameters of two populations of non-inactivated ionic channels more accurately than a classical method. Moreover, the algorithm was demonstrated to be insensitive to the key parameter variations. We then applied this algorithm to Ih current recordings from mouse vestibular ganglion neurons. The algorithm revealed the presence of a high-voltage-activated slow component and a low-voltage-activated fast component. Finally, the electrophysiological significance of these two Ih components was tested individually in computational vestibular ganglion neuron models (sustained and transient), in the control case and in the presence of cAMP, an intracellular cyclic nucleotide that modulates HCN channel activity. The results suggest that, first, the fast and slow components modulate differently the action potential excitability and the excitatory postsynaptic potentials in both sustained and transient vestibular neurons and, second, the fast and slow components, in the control case, provide different information about characteristics of the stimulation and this information is significantly modified after modulation by cAMP.

Damaging effects on the cochlea of high-intensity acoustic overexposures have been extensively documented, but only few works have focused on the danger of moderate noise levels. Using scanning and transmission electron microscopy, we explored the noise-induced neuroepithelial changes that occur in the cochlea of rats subjected to moderate intensities, 70 and 85 dB SPL, for an extended period of time (6 hr/day over 3 months). Although the full quota of outer and inner sensory hair cells remained present, we detected discrete abnormalities, likely resulting from metabolic impairment, in both types of hair cell within the basal region of the cochlea. In contrast, important noise-dependent losses of spiral ganglion neurons had occurred. In addition, we found cytoplasmic accumulations of lipofuscin-like aggregates in most of the surviving cochlear neurons. These results strongly suggest that noise levels comparable to those of certain working environments, with sufficient exposure duration, pose a severe risk to the cochlea. Moreover, our data support the notion that long-duration exposure to moderate noise is a causative factor of presbycusis.

Characterizing the microenvironment of a damaged organ of Corti and identifying the basic mechanisms involved in subsequent epithelial reorganization are critical for improving the outcome of clinical therapies. In this context, we studied the expression of a variety of cell markers related to cell shape, cell adhesion and cell plasticity in the rat organ of Corti poisoned with amikacin. Our results indicate that, after severe outer hair cell losses, the cytoarchitectural reorganization of the organ of Corti implicates epithelial-mesenchymal transition mechanisms and involves both collective and individual cell migratory processes. The results also suggest that both root cells and infiltrated fibroblasts participate in the homeostasis of the damaged epithelium, and that the flat epithelium that may emerge offers biological opportunities for late regenerative therapies.