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 PromBERA: A preoperative eABR: An update

2018 ◽  
Vol 4 (1) ◽  
pp. 563-565 ◽  
Author(s):  
Daniel Polterauer ◽  
Maike Neuling ◽  
Joachim Müller ◽  
John-Martin Hempel ◽  
Giacomo Mandruzzato ◽  
...  
Keyword(s):  
Cochlear Implantation ◽  
Auditory Nerve ◽  
Round Window ◽  
Electrode Array ◽  
Auditory Brainstem ◽  
Auditory Brainstem Responses ◽  
Speech Comprehension ◽  
Testing Procedures ◽  
Brainstem Response ◽  
Round Window Niche

AbstractPrior to cochlear implantation, audiological tests are performed to determine candidacy in subjects with a hearing loss. This is usually done by measuring the acoustic auditory brainstem response (ABR). Unfortunately, for some subjects, a reproducible ABR recording cannot be obtained, even at high acoustic levels. Having a healthy stimulating auditory nerve is required for cochlear implantation in order to benefit from the electrical pulses that are generated by the implant and to improve speech comprehension. In some subjects, this prerequisite cannot be measured using routine audiological tests. In this study, the feasibility of recording electrically evoked auditory brainstem responses (eABR) using a stimulating transtympanic electrode, placed on the round window niche, together with MED-EL clinical system is investigated. The results show that it is possible to record reproducible eABR measurements using PromBERA. The response was also confirmed with intraoperative eABR measurements that were stimulated using the implanted CI electrode array. Similarities between the intraoperative measurements and the preoperative recorded waveforms were observed. In summary, the integrity and excitability of the auditory nerve can be objectively measured using the PromBERA in subjects where standard clinical testing procedures are unable to provide the information required.

scholarly journals N-Methyl-D-Aspartate Receptors Involvement in the Gentamicin-Induced Hearing Loss and Pathological Changes of Ribbon Synapse in the Mouse Cochlear Inner Hair Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Juan Hong ◽  
Yan Chen ◽  
Yanping Zhang ◽  
Jieying Li ◽  
Liujie Ren ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Auditory Brainstem ◽  
Ribbon Synapse ◽  
Synaptic Ribbons ◽  
Pathological Changes ◽  
Inner Hair Cell ◽  
Ribbon Synapses ◽  
Brainstem Response ◽  
Mature Mouse ◽  
Response Thresholds

Cochlear inner hair cell (IHC) ribbon synapses play an important role in sound encoding and neurotransmitter release. Previous reports show that both noise and aminoglycoside exposures lead to reduced numbers and morphologic changes of synaptic ribbons. In this work, we determined the distribution of N-methyl-D-aspartate receptors (NMDARs) and their role in the gentamicin-induced pathological changes of cochlear IHC ribbon synaptic elements. In normal mature mouse cochleae, the majority of NMDARs were distributed on the modiolar side of IHCs and close to the IHC nuclei region, while most of synaptic ribbons and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) were located on neural terminals closer to the IHC basal poles. After gentamicin exposure, the NMDARs increased and moved towards the IHC basal poles. At the same time, synaptic ribbons and AMPARs moved toward the IHC bundle poles on the afferent dendrites. The number of ribbon synapse decreased, and this was accompanied by increased auditory brainstem response thresholds and reduced wave I amplitudes. NMDAR antagonist MK801 treatment reduced the gentamicin-induced hearing loss and the pathological changes of IHC ribbon synapse, suggesting that NMDARs were involved in gentamicin-induced ototoxicity by regulating the number and distribution of IHC ribbon synapses.

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 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 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 Tinnitus and Auditory Perception After a History of Noise Exposure: Relationship to Auditory Brainstem Response Measures

2017 ◽  
Author(s):  
Naomi Bramhall
Keyword(s):  
Speech Perception ◽  
Confidence Interval ◽  
Hair Cell ◽  
Auditory Nerve ◽  
Auditory Brainstem Response ◽  
Auditory Perception ◽  
Noise Exposure ◽  
Auditory Brainstem ◽  
Distortion Product ◽  
Brainstem Response

ObjectivesDetermine whether auditory brainstem response (ABR) wave I amplitude is associated with measures of auditory perception in young people with normal distortion product otoacoustic emissions (DPOAEs) and varying levels of noise exposure history.DesignTinnitus, loudness tolerance, and speech perception ability were measured in 31 young military Veterans and 43 non-Veterans (19-35 years of age) with normal pure tone thresholds and DPOAEs. Speech perception was evaluated in quiet using NU-6 word lists and in background noise using the words in noise (WIN) test. Loudness discomfort levels were measured using 1, 3, 4, and 6 kHz pulsed pure tones. DPOAEs and ABRs were collected in each participant to assess outer hair cell (OHC) and auditory nerve function. ResultsThe probability of reporting tinnitus in this sample increased by a factor of 2.0 per 0.1 µV decrease in ABR wave I amplitude (90% Bayesian confidence interval = 1.2 to 4.2) for males and by a factor of 2.2 (90% confidence interval = 1.1 to 5.1) for females after adjusting for sex and DPOAE level. No apparent relationship was found between wave I amplitude and either loudness tolerance or speech perception in quiet or noise.ConclusionsReduced ABR wave I amplitude was associated with a markedly increased risk of tinnitus, even after adjusting for DPOAEs and sex. In contrast, wave III and V amplitudes had little effect on tinnitus risk. This suggests that changes in peripheral input at the level of the inner hair cell (IHC) or auditory nerve may lead to increases in central gain that give rise to the perception of tinnitus. Although the extent of synaptopathy in the study participants cannot be measured directly, these findings are consistent with the prediction that tinnitus may be a perceptual consequence of cochlear 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.

Effects of noise exposure on neonatal auditory brainstem response thresholds in pregnant guinea pigs at different gestational periods

2016 ◽  
Vol 43 (1) ◽  
pp. 78-86
Author(s):  
Chihiro Morimoto ◽  
Kazuhiko Nario ◽  
Tadashi Nishimura ◽  
Ryota Shimokura ◽  
Hiroshi Hosoi ◽  
...  
Keyword(s):  
Auditory Brainstem Response ◽  
Guinea Pigs ◽  
Noise Exposure ◽  
Auditory Brainstem ◽  
Brainstem Response ◽  
Response Thresholds

Excitatory transmission in the basolateral amygdala

1991 ◽  
Vol 66 (3) ◽  
pp. 986-998 ◽  
Author(s):  
D. G. Rainnie ◽  
E. K. Asprodini ◽  
P. Shinnick-Gallagher
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Nmda Antagonist ◽  
Receptor Activation ◽  
Nmda Receptor Antagonist ◽  
Current Injection ◽  
Membrane Hyperpolarization ◽  
Postsynaptic Potentials ◽  
The Mean ◽  
Stimulation Of

1. Intracellular current-clamp recordings obtained from neurons of the basolateral nucleus of the amygdala (BLA) were used to characterize postsynaptic potentials elicited through stimulation of the stria terminalis (ST) or the lateral amygdala (LA). The contribution of glutamatergic receptor subtypes to excitatory postsynaptic potentials (EPSPs) were analyzed by the use of the non N-methyl-D-aspartate (non-NMDA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the NMDA antagonist, (DL)-2-amino-5-phosphonovaleric acid (APV). 2. Basic membrane properties of BLA neurons determined from membrane responses to transient current injection showed that at the mean resting membrane potential (RMP; -67.2 mV) the input resistance (RN) and time constant for membrane charging (tau) were near maximal, and that both values were reduced with membrane hyperpolarization, suggesting an intrinsic regulation of synaptic efficacy. 3. Responses to stimulation of the ST or LA consisted of an EPSP followed by either a fast inhibitory postsynaptic potential (f-IPSP) only, or by a fast- and subsequent slow-IPSP (s-IPSP). The EPSP was graded in nature, increasing in amplitude with increased stimulus intensity, and with membrane hyperpolarization after DC current injection. Spontaneous EPSPs were also observed either as discrete events or as EPSP/IPSP waveforms. 4. In physiological Mg2+ concentrations (1.2 mM), at the mean RMP, the EPSP consisted of dual, fast and slow, glutamatergic components. The fast-EPSP (f-EPSP) possessed characteristics of kainate/quisqualate receptor activation, namely, the EPSP increased in amplitude with membrane hyperpolarization, was insensitive to the NMDA receptor antagonist, APV (50 microM), and was blocked by the non-NMDA receptor antagonist, CNQX (10 microM). In contrast, the slow-EPSP (s-EPSP) decreased in amplitude with membrane hyperpolarization, was insensitive to CNQX (10 microM), and was blocked by APV (50 microM), indicating mediation by NMDA receptor activation. 5. In the presence of CNQX (10 microM), ST stimulation evoked an APV-sensitive s-EPSP. In contrast, LA stimulation evoked a f-IPSP, which when blocked by subsequent addition of bicuculline methiodide (BMI; 30 microM) revealed a temporally overlapping APV-sensitive s-EPSP. These data suggest that EPSP amplitude and duration are determined, in part, by the shunting of membrane conductance caused by a concomitant IPSP. 6. Superfusion of either CNQX or APV in BLA neurons caused membrane hyperpolarization and blockade of spontaneous EPSPs and IPSPs, suggesting that these compounds may act to block tonic excitatory amino acid (EAA) release within the nucleus, and that a degree of feed-forward inhibition occurs within the nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

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