scholarly journals An antibody to RGMa promotes regeneration of cochlear synapses after noise exposure

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jerome Nevoux ◽  
Mihaela Alexandru ◽  
Thomas Bellocq ◽  
Lei Tanaka ◽  
Yushi Hayashi ◽  
...  
Keyword(s):  
Hair Cells ◽  
Noise Exposure ◽  
Auditory Brainstem ◽  
Afferent Input ◽  
Nerve Fibers ◽  
Auditory Neuropathy ◽  
Axonal Guidance ◽  
Inner Hair Cell ◽  
Inner Hair Cells ◽  
Brainstem Response

AbstractAuditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion. Recent work has identified the synapse between cochlear primary afferent neurons and sensory hair cells as a particularly vulnerable component of this pathway. Loss of these synapses due to noise exposure or aging results in the pathology identified as hidden hearing loss, an initial stage of cochlear dysfunction that goes undetected in standard hearing tests. We show here that repulsive axonal guidance molecule a (RGMa) acts to prevent regrowth and synaptogenesis of peripheral auditory nerve fibers with inner hair cells. Treatment of noise-exposed animals with an anti-RGMa blocking antibody regenerated inner hair cell synapses and resulted in recovery of wave-I amplitude of the auditory brainstem response, indicating effective reversal of synaptopathy.

scholarly journals An Antibody to RGMa Promotes Regeneration of Cochlear Synapses after Noise Exposure

2020 ◽  
Author(s):  
Jerome Nevoux ◽  
Mihaela Alexandru ◽  
Thomas Bellocq ◽  
Lei Tanaka ◽  
Yushi Hayashi ◽  
...  
Keyword(s):  
Hair Cells ◽  
Noise Exposure ◽  
Auditory Brainstem ◽  
Afferent Input ◽  
Nerve Fibers ◽  
Auditory Neuropathy ◽  
Axonal Guidance ◽  
Inner Hair Cell ◽  
Inner Hair Cells ◽  
Brainstem Response

SUMMARYAuditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion. Recent work has identified the synapse between cochlear primary afferent neurons and sensory hair cells as a particularly vulnerable component of this pathway. Loss of these synapses due to noise exposure or aging results in the pathology identified as hidden hearing loss, an initial stage of cochlear dysfunction that goes undetected in standard hearing tests. We show here that repulsive axonal guidance molecule a (RGMa) acts to prevent regrowth and synaptogenesis of peripheral auditory nerve fibers with inner hair cells. Treatment of noise-exposed animals with an anti-RGMa blocking antibody regenerated inner hair cell synapses and resulted in recovery of wave-I amplitude of the auditory brainstem response, indicating effective reversal of synaptopathy.

scholarly journals The Impacts of Noise Exposure on the Middle Ear Muscle Reflex in a Veteran Population

2021 ◽  
Author(s):  
Naomi Bramhall ◽  
Kelly M. Reavis ◽  
M. Patrick Feeney ◽  
Sean Kampel
Keyword(s):  
Animal Models ◽  
Middle Ear ◽  
Noise Exposure ◽  
Outer Hair Cell ◽  
Auditory Brainstem ◽  
Nerve Fibers ◽  
Intensity Level ◽  
Physiological Indicators ◽  
Brainstem Response ◽  
Muscle Reflex

Noise-induced cochlear synaptopathy, the loss of the synaptic connections between inner hair cells and afferent auditory nerve fibers, has been demonstrated in multiple animal models, including non-human primates. However, given that synaptopathy can only be confirmed with post-mortem temporal bone analysis, it has been difficult to determine whether noise-induced synaptopathy occurs in humans. Human studies of noise-induced synaptopathy using physiological indicators identified in animal models (auditory brainstem response [ABR] wave I amplitude, the envelope following response [EFR], and the middle ear muscle reflex [MEMR]) have yielded mixed findings. Differences in the population studied may have contributed to the differing results. For example, due to differences in the intensity level of the noise exposure, noise-induced synaptopathy may be easier to detect in a military Veteran population than in populations with recreational noise exposure. We previously demonstrated a reduction in ABR wave I amplitude and EFR magnitude for young Veterans with normal audiograms reporting high levels of noise exposure compared to non-Veteran controls. In this report, we expand on the previous analysis in the same population to determine if MEMR magnitude is similarly reduced. The results of the statistical analysis, although not conventionally statistically significant, suggest a reduction in mean MEMR magnitude for Veterans reporting high noise exposure compared with non-Veteran controls. In addition, the MEMR appears relatively insensitive to subclinical outer hair cell dysfunction and is not well correlated with ABR and EFR measurements. When combined with our previous ABR and EFR findings in the same population, these results suggest that noise-induced synaptopathy occurs in humans. In addition, the findings indicate that the MEMR may be a good candidate for non-invasive diagnosis of cochlear synaptopathy/deafferentation and that the MEMR may reflect the integrity of different neural populations than the ABR and EFR.

scholarly journals Cochlear NMDA Receptors as a Therapeutic Target of Noise-Induced Tinnitus

2015 ◽  
Vol 35 (5) ◽  
pp. 1905-1923 ◽  
Author(s):  
Dan Bing ◽  
Sze Chim Lee ◽  
Dario Campanelli ◽  
Hao Xiong ◽  
Masahiro Matsumoto ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Auditory Nerve ◽  
Noise Exposure ◽  
Round Window ◽  
Receptor Activation ◽  
Auditory Brainstem ◽  
Nmda Receptor Antagonist ◽  
Inner Hair Cell ◽  
Ribbon Synapses ◽  
Brainstem Response

Background: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. Methods: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. Results: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. Conclusion: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.

scholarly journals Differences in Calcium Clearance at Inner Hair Cell Active Zones May Underlie the Difference in Susceptibility to Noise-Induced Cochlea Synaptopathy of C57BL/6J and CBA/CaJ Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Hongchao Liu ◽  
Hu Peng ◽  
Longhao Wang ◽  
Pengcheng Xu ◽  
Zhaoyan Wang ◽  
...  
Keyword(s):  
Hair Cell ◽  
Clearance Rate ◽  
Noise Exposure ◽  
Auditory Brainstem ◽  
Response Threshold ◽  
Inner Hair Cell ◽  
Cba Mice ◽  
Calcium Clearance ◽  
Brainstem Response ◽  
Susceptibility To Noise

Noise exposure of a short period at a moderate level can produce permanent cochlear synaptopathy without seeing lasting changes in audiometric threshold. However, due to the species differences in inner hair cell (IHC) calcium current that we have recently discovered, the susceptibility to noise exposure may vary, thereby impact outcomes of noise exposure. In this study, we investigate the consequences of noise exposure in the two commonly used animal models in hearing research, CBA/CaJ (CBA) and C57BL/6J (B6) mice, focusing on the functional changes of cochlear IHCs. In the CBA mice, moderate noise exposure resulted in a typical fully recovered audiometric threshold but a reduced wave I amplitude of auditory brainstem responses. In contrast, both auditory brainstem response threshold and wave I amplitude fully recovered in B6 mice at 2 weeks after noise exposure. Confocal microscopy observations found that ribbon synapses of IHCs recovered in B6 mice but not in CBA mice. To further characterize the molecular mechanism underlying these different phenotypes in synaptopathy, we compared the ratio of Bax/Bcl-2 with the expression of cytochrome-C and found increased activity in CBA mice after noise exposure. Under whole-cell patch clamped IHCs, we acquired two-photon calcium imaging around the active zone to evaluate the Ca2+ clearance rate and found that CBA mice have a slower calcium clearance rate. Our results indicated that excessive accumulation of calcium due to acoustic overexposure and slow clearance around the presynaptic ribbon might lead to disruption of calcium homeostasis, followed by mitochondrial dysfunction of IHCs that cause susceptibility of noise-induced cochlear synaptopathy in CBA mice.

scholarly journals Endogenous SIRT3 activity is dispensable for normal hearing recovery after noise exposure in young adult mice

2020 ◽  
Author(s):  
Sally Patel ◽  
Lisa Shah ◽  
Natalie Dang ◽  
Xiaodong Tan ◽  
Anthony Almudevar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Hair Cells ◽  
Noise Exposure ◽  
Oxidative Stress Response ◽  
Outer Hair Cells ◽  
Mitochondrial Oxidative Stress ◽  
Inner Hair Cells ◽  
Hearing Recovery ◽  
Brainstem Response

ABSTRACTOccupational noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large social and personal burden. Some genetic variants in the mitochondrial oxidative stress response correlate strongly with susceptibility to NIHL in both humans and mice. Here we test the hypothesis that SIRT3, a regulator of the mitochondrial oxidative stress response, is required in mice for endogenous recovery of auditory thresholds after a sub-traumatic noise exposure. We expose homozygous Sirt3-KO mice and their wild-type littermates to a noise dose that confers a temporary threshold shift, but is not sufficient to permanently reduce cochlear function, compromise cell survival, or damage synaptic structures. We find no difference in hearing function after recovery from noise exposure between the two genotypes, when measured by either auditory brainstem response (ABR) or distortion product otoacoustic emissions (DPOAE). We show that SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner hair cells, and faintly within inner hair cells. Nonetheless, outer hair cells and auditory synapses show no increase in loss after noise exposure in the homozygous Sirt3-KO mouse. These data show that SIRT3-dependent processes are not necessary for endogenous hearing recovery after a single, sub-traumatic noise exposure. They demonstrate the existence of cellular mechanisms of cochlear homeostasis in addition to the mitochondrial oxidative stress response. We also present a novel statistical analysis for identifying differences between peak 1 amplitude progressions in ABR waveforms.

scholarly journals Auditory Brainstem Response to Paired Click Stimulation as an Indicator of Peripheral Synaptic Health in Noise-Induced Cochlear Synaptopathy

2021 ◽  
Vol 14 ◽  
Author(s):  
Jae-Hun Lee ◽  
Min Young Lee ◽  
Ji Eun Choi ◽  
Jae Yun Jung
Keyword(s):  
Evoked Potentials ◽  
Hair Cells ◽  
Temporal Processing ◽  
Auditory Brainstem Response ◽  
Animal Studies ◽  
Auditory Evoked Potentials ◽  
Noise Exposure ◽  
Auditory Brainstem ◽  
Ribbon Synapses ◽  
Brainstem Response

IntroductionA defect in the cochlear afferent synapse between the inner hair cells and spiral ganglion neurons, after noise exposure, without changes in the hearing threshold has been reported. Animal studies on auditory evoked potentials demonstrated changes in the auditory brainstem response (ABR) measurements of peak I amplitude and the loss of synapses, which affect the temporal resolution of complex sounds. Human studies of auditory evoked potential have reported ambiguous results regarding the relationship between peak I amplitude and noise exposure. Paired click stimuli have been used to investigate the temporal processing abilities of humans and animals. In this study, we investigated the utility of measuring auditory evoked potentials in response to paired click stimuli to assess the temporal processing function of ribbon synapses in noise-induced cochlear synaptopathy.Materials and MethodsTwenty-two Sprague Dawley rats were used in this study, and synaptopathy was induced by narrow-band noise exposure (16 kHz with 1 kHz bandwidth, 105 dB sound pressure level for 2 h). ABRs to tone and paired click stimuli were measured before and 1, 3, 7, and 14 days after noise exposure. For histological analyses, hair cells and ribbon synapses were immunostained and the synapses quantified. The relationships among ABR peak I amplitude, number of synapses, and ABR to paired click stimuli were examined.ResultsOur results showed that ABR thresholds increase 1 day after noise exposure but fully recover to baseline levels after 14 days. Further, we demonstrated test frequency-dependent decreases in peak I amplitude and the number of synapses after noise exposure. These decreases were statistically significant at frequencies of 16 and 32 kHz. However, the ABR recovery threshold to paired click stimuli increased, which represent deterioration in the ability of temporal auditory processing. Our results indicate that the ABR recovery threshold is highly correlated with ABR peak I amplitude after noise exposure. We also established a direct correlation between the ABR recovery threshold and histological findings.ConclusionThe result from this study suggests that in animal studies, the ABR to paired click stimuli along with peak I amplitude has potential as an assessment tool for hidden hearing loss.

scholarly journals Dose-Dependent Pattern of Cochlear Synaptic Degeneration in C57BL/6J Mice Induced by Repeated Noise Exposure

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Minfei Qian ◽  
Qixuan Wang ◽  
Zhongying Wang ◽  
Qingping Ma ◽  
Xueling Wang ◽  
...  
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Noise Exposure ◽  
Moderate Intensity ◽  
Intensity Noise ◽  
Inner Hair Cell ◽  
Ribbon Synapses ◽  
Synaptic Degeneration ◽  
Brainstem Response ◽  
Dose Dependent

It is widely accepted that even a single acute noise exposure at moderate intensity that induces temporary threshold shift (TTS) can result in permanent loss of ribbon synapses between inner hair cells and afferents. However, effects of repeated or chronic noise exposures on the cochlear synapses especially medial olivocochlear (MOC) efferent synapses remain elusive. Based on a weeklong repeated exposure model of bandwidth noise over 2-20 kHz for 2 hours at seven intensities (88 to 106 dB SPL with 3 dB increment per gradient) on C57BL/6J mice, we attempted to explore the dose-response mechanism of prolonged noise-induced audiological dysfunction and cochlear synaptic degeneration. In our results, mice repeatedly exposed to relatively low-intensity noise (88, 91, and 94 dB SPL) showed few changes on auditory brainstem response (ABR), ribbon synapses, or MOC efferent synapses. Notably, repeated moderate-intensity noise exposures (97 and 100 dB SPL) not only caused hearing threshold shifts and the inner hair cell ribbon synaptopathy but also impaired MOC efferent synapses, which might contribute to complex patterns of damages on cochlear function and morphology. However, repeated high-intensity (103 and 106 dB SPL) noise exposures induced PTSs mainly accompanied by damages on cochlear amplifier function of outer hair cells and the inner hair cell ribbon synaptopathy, rather than the MOC efferent synaptic degeneration. Moreover, we observed a frequency-dependent vulnerability of the repeated acoustic trauma-induced cochlear synaptic degeneration. This study provides a sight into the hypothesis that noise-induced cochlear synaptic degeneration involves both afferent (ribbon synapses) and efferent (MOC terminals) pathology. The pattern of dose-dependent pathological changes induced by repeated noise exposure at various intensities provides a possible explanation for the complicated cochlear synaptic degeneration in humans. The underlying mechanisms remain to be studied in the future.

scholarly journals Noise Exposure Potentiates Exocytosis From Cochlear Inner Hair Cells

2021 ◽  
Vol 13 ◽  
Author(s):  
Luis E. Boero ◽  
Shelby Payne ◽  
Maria Eugenia Gómez-Casati ◽  
Mark A. Rutherford ◽  
Juan D. Goutman
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Synaptic Vesicles ◽  
Noise Exposure ◽  
Synaptic Function ◽  
Inner Hair Cells ◽  
Distortion Product ◽  
Brainstem Response ◽  
Ganglion Neurons ◽  
Bell Shaped Curve

Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15–16 were exposed to 1–12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured by tracking changes in membrane capacitance (ΔCm) from IHCs of the apical cochlea. Upon IHC depolarization to different membrane potentials, ΔCm showed the typical bell-shaped curve that mirrors the voltage dependence of Ca2+ influx, in both exposed and unexposed cells. Surprisingly, from IHCs at 1-day after exposure (d.a.e.), we found potentiation of exocytosis at the peak of the bell-shaped curve. The increase in exocytosis was not accompanied by changes in whole-cell Ca2+ influx, suggesting a modification in coupling between Ca2+ channels and synaptic vesicles. Consistent with this notion, noise exposure also changed the Ca2+-dependence of exocytosis from linear to supralinear. Noise exposure did not cause loss of IHCs, but did result in a small reduction in the number of IHC-SGN synapses at 1-d.a.e. which recovered by 14-d.a.e. In contrast, a strong reduction in auditory brainstem response wave-I amplitude (representing synchronous firing of SGNs) and distortion product otoacoustic emissions (reflecting outer hair cell function) indicated a profound hearing loss at 1- and 14-d.a.e. To determine the role of glutamate release in the noise-induced potentiation of exocytosis, we evaluated vesicular glutamate transporter-3 (Vglut3) knock-out (KO) mice. Unlike WT, IHCs from Vglut3KO mice showed a noise-induced reduction in ΔCm and Ca2+ influx with no change in the Ca2+-dependence of exocytosis. Together, these results indicate that traumatic noise exposure triggers changes of IHC synaptic function including a Vglut3-dependent potentiation of exocytosis.

Tinnitus development is associated with synaptopathy of inner hair cells in Mongolian gerbils

2018 ◽  
Author(s):  
Konstantin Tziridis ◽  
Jan Forster ◽  
Isabelle Buchheidt-Dörfler ◽  
Patrick Krauss ◽  
Achim Schilling ◽  
...  
Keyword(s):  
Animal Model ◽  
Hair Cells ◽  
Cell Damage ◽  
Adult Population ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Auditory Brainstem ◽  
Mongolian Gerbils ◽  
Inner Hair Cells ◽  
Brainstem Response

AbstractHuman hearing loss (HL) is often accompanied by comorbidities like tinnitus which is affecting up to 15% of the adult population. Rodent animal studies could show that tinnitus may not only be a result of apparent HL due to cochlear hair cell damage but can also be a consequence of synaptopathy at the inner hair cells (IHC) already induced by moderate sound traumata. Here we investigate synaptopathy previously shown in mice in our animal model, the Mongolian gerbil, and relate it to behavioral signs of tinnitus. Tinnitus was induced by a mild monaural acoustic trauma leading to monaural noise induced HL in the animals, quantified by auditory brainstem response (ABR) audiometry. Behavioral signs of tinnitus percepts were detected by measurement of prepulse inhibition of the acoustic startle response in a gap-noise paradigm. 14 days after trauma, the cochleae of both ears were isolated and IHC synapses were counted within several spectral regions of the cochlea. Behavioral signs of tinnitus were only found in animals with IHC synaptopathy, independent of type of HL. On the other hand, animals with apparent HL but without behavioral signs of tinnitus showed a reduction in amplitudes of ABR waves I&II but no significant changes in the number of synapses at the IHC. We conclude – in line with the literature – that HL is caused by damage to the IHC or by other reasons but that the development of tinnitus, at least in our animal model, is closely linked to synaptopathy at the IHC.

scholarly journals Exposure to Sodium Salicylate Disrupts VGLUT3 Expression in Cochlear Inner Hair Cells and Contributes to Tinnitus

2020 ◽  
pp. 181-190 ◽  
Author(s):  
W. ZHANG ◽  
Z. PENG ◽  
S. YU ◽  
Q.-L. SONG ◽  
T.-F. QU ◽  
...  
Keyword(s):  
Hair Cells ◽  
Cochlear Nucleus ◽  
Sodium Salicylate ◽  
Acoustic Startle ◽  
Auditory Brainstem ◽  
Acoustic Startle Reflex ◽  
Saline Control ◽  
Inner Hair Cells ◽  
Increased Risk ◽  
Brainstem Response

To examine whether exposure to sodium salicylate disrupts expression of vesicular glutamate transporter 3 (VGLUT3) and whether the alteration in expression corresponds to increased risk for tinnitus. Rats were treated with saline (control) or sodium salicylate (treated) Rats were examined for tinnitus by monitoring gap-pre-pulse inhibition of the acoustic startle reflex (GPIAS). Auditory brainstem response (ABR) was applied to evaluate hearing function after treatment. Rats were sacrificed after injection to obtain the cochlea, cochlear nucleus (CN), and inferior colliculus (IC) for examination of VGLUT3 expression. No significant differences in hearing thresholds between groups were identified (p>0.05). Tinnitus in sodium salicylate-treated rats was confirmed by GPIAS. VGLUT3 encoded by solute carrier family 17 members 8 (SLC17a8) expression was significantly increased in inner hair cells (IHCs) of the cochlea in treated animals, compared with controls (p<0.01). No significant differences in VGLUT3 expression between groups were found for the cochlear nucleus (CN) or IC (p>0.05). Exposure to sodium salicylate may disrupt SLC17a8 expression in IHCs, leading to alterations that correspond to tinnitus in rats. However, the CN and IC are unaffected by exposure to sodium salicylate, suggesting that enhancement of VGLUT3 expression in IHCs may contribute to the pathogenesis of tinnitus.

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