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.

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 Development of Tinnitus and Hyperacusis in a Mouse Model of Tobramycin Cochleotoxicity

2021 ◽  
Vol 14 ◽  
Author(s):  
Ryan J. Longenecker ◽  
Rende Gu ◽  
Jennifer Homan ◽  
Jonathan Kil
Keyword(s):  
Mouse Model ◽  
Recovery Period ◽  
Acoustic Startle ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Acoustic Startle Reflex ◽  
Spiral Ganglion Neuron ◽  
Brainstem Response ◽  
Group 2 ◽  
Behavioral Evidence

Aminoglycosides (AG) antibiotics are a common treatment for recurrent infections in cystic fibrosis (CF) patients. AGs are highly ototoxic, resulting in a range of auditory dysfunctions. It was recently shown that the acoustic startle reflex (ASR) can assess behavioral evidence of hyperacusis and tinnitus in an amikacin cochleotoxicity mouse model. The goal of this study was to establish if tobramycin treatment led to similar changes in ASR behavior and to establish whether ebselen can prevent the development of these maladaptive neuroplastic symptoms. CBA/Ca mice were divided into three groups: Group 1 served as a control and did not receive tobramycin or ebselen, Group 2 received tobramycin (200 mg/kg/s.c.) and the vehicle (DMSO/saline/i.p.) daily for 14 continuous days, and Group 3 received the same dose/schedule of tobramycin as Group 2 and ebselen at (20 mg/kg/i.p.). Auditory brainstem response (ABR) and ASR hearing assessments were collected at baseline and 2, 6, 10, 14, and 18 weeks from the start of treatment. ASR tests included input/output (I/O) functions which assess general hearing and hyperacusis, and Gap-induced prepulse inhibition of the acoustic startle (GPIAS) to assess tinnitus. At 18 weeks, histologic analysis showed predominantly normal appearing hair cells and spiral ganglion neuron (SGN) synapses. Following 14 days of tobramycin injections, 16 kHz thresholds increased from baseline and fluctuated over the 18-week recovery period. I/O functions revealed exaggerated startle response magnitudes in 50% of mice over the same period. Gap detection deficits, representing behavioral evidence of tinnitus, were observed in a smaller subset (36%) of animals. Interestingly, increases in ABR wave III/wave I amplitude ratios were observed. These tobramycin data corroborate previous findings that AGs can result in hearing dysfunctions. We show that a 14-day course of tobramycin treatment can cause similar levels of hearing loss and tinnitus, when compared to a 14-day course of amikacin, but less hyperacusis. Evidence suggests that tinnitus and hyperacusis might be common side effects of AG antibiotics.

scholarly journals Age-related decline in behavioral discrimination of amplitude modulation frequencies compared to envelope-following responses

2017 ◽  
Author(s):  
Jesyin Lai ◽  
Edward L. Bartlett
Keyword(s):  
Amplitude Modulation ◽  
Speech Intelligibility ◽  
Modulation Depth ◽  
Acoustic Startle ◽  
Hearing Threshold ◽  
Auditory Brainstem ◽  
Acoustic Startle Reflex ◽  
Neural Activation ◽  
Age Related ◽  
Brainstem Response

AbstractThe ability to discriminate modulation frequencies is important for speech intelligibility because speech has amplitude and frequency modulations. Neurophysiological responses assessed by envelope following responses (EFRs) significantly decline at faster amplitude modulation frequencies (AMF) in older subjects. A typical assumption is that a decline in EFRs will necessarily result in corresponding perceptual deficits. To test this assumption, we investigated young and aged Fischer-344 rats’ behavioral AMF discrimination abilities and compared to their EFRs. A modified version of prepulse inhibition (PPI) of acoustic startle reflex (ASR) was used to obtain behavioral performance. A PPI trial contains pulses of sinusoidal AM (SAM) at 128 Hz presented sequentially, a SAM prepulse with different AMF and a startle-eliciting-stimulus. To account for hearing threshold shift or age-related synaptopathy, stimulus levels were presented at 10-dB lower or match to the aged peripheral neural activation (using auditory brainstem response wave I amplitude). When AMF differences and modulation depths were large, young and aged animals’ behavioral performances were comparable. Aged animals’ AMF discrimination abilities declined as the AMF difference or the modulation depth reduced, even compared to the young with peripheral matching. Young animals showed smaller relative decreases in EFRs with reduced modulation depths. The correlation of EFRs and AM perception was identified to be more consistent in young animals. The overall results revealed larger age-related deficits in behavioral perception compared to EFRs, suggesting additional factors that affect perception despite smaller degradation in neural responses. Hence, behavioral and physiological measurements are critical in unveiling a more complete picture on the auditory function.

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.

Mechanical stress-induced reactive gliosis in the auditory nerve and cochlear nucleus

2011 ◽  
Vol 114 (2) ◽  
pp. 414-425 ◽  
Author(s):  
Tetsuji Sekiya ◽  
Masahiro Matsumoto ◽  
Ken Kojima ◽  
Kazuya Ono ◽  
Yayoi S. Kikkawa ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Cochlear Nucleus ◽  
Auditory Nerve ◽  
Auditory Brainstem ◽  
Reactive Gliosis ◽  
Auditory Pathways ◽  
Microsurgical Treatment ◽  
Auditory Nerves ◽  
Brainstem Response ◽  
Temporal Bones

Object Hearing levels following microsurgical treatment gradually deteriorate in a number of patients treated for vestibular schwannoma (VS), especially in the subacute postoperative stage. The cause of this late-onset deterioration of hearing is not completely understood. The aim of this study was to investigate the possibility that reactive gliosis is a contributory factor. Methods Mechanical damage to nerve tissue is a feature of complex surgical procedures. To explore this aspect of VS treatment, the authors compressed rat auditory nerves with 2 different degrees of injury while monitoring the compound action potentials of the auditory nerve and the auditory brainstem responses. In this experimental model, the axons of the auditory nerve were quantitatively and highly selectively damaged in the cerebellopontine angle without permanent compromise of the blood supply to the cochlea. The temporal bones were processed for immunohistochemical analysis at 1 week and at 8 weeks after compression. Results Reactive gliosis was induced not only in the auditory nerve but also in the cochlear nucleus following mechanical trauma in which the general shape of the auditory brainstem response was maintained. There was a substantial outgrowth of astrocytic processes from the transitional zone into the peripheral portion of the auditory nerve, leading to an invasion of dense gliotic tissue in the auditory nerve. The elongated astrocytic processes ran in parallel with the residual auditory neurons and entered much further into the cochlea. Confocal images disclosed fragments of neurons scattered in the gliotic tissue. In the cochlear nucleus, hypertrophic astrocytic processes were abundant around the soma of the neurons. The transverse diameter of the auditory nerve at and proximal to the compression site was considerably reduced, indicating atrophy, especially in rats in which the auditory nerve was profoundly compressed. Conclusions The authors found for the first time that mechanical stress to the auditory nerve causes substantial reactive gliosis in both the peripheral and central auditory pathways within 1–8 weeks. Progressive reactive gliosis following surgical stress may cause dysfunction in the auditory pathways and may be a primary cause of progressive hearing loss following microsurgical treatment for VS.

scholarly journals Pyroptosis Accelerates Spiral Ganglion Neuronal Degeneration Induced by Aminoglycosides in the Cochlea

2021 ◽  
Author(s):  
Yazhi Xing ◽  
Jia Fang ◽  
Zhuangzhuang Li ◽  
Mingxian Li ◽  
Chengqi Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Rna Sequencing ◽  
Hair Cells ◽  
Nlrp3 Inflammasome ◽  
Auditory Brainstem Response ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Response Threshold ◽  
Brainstem Response ◽  
Ganglion Neurons

Abstract Background In aminoglycoside-induced hearing loss, damage to spiral ganglion neurons (SGNs) accelerates gradually after the acute outer hair cell death, accompanied by macrophage infiltration and cytokine release. Pyroptosis plays a critical role in neurodegenerative diseases. Here, we explored the potential role of pyroptosis in SGN degeneration. Methods C57BL/6J mice were randomly divided into a kanamycin plus furosemide group and saline control group. Auditory functions were evaluated by auditory brainstem response tests conducted before treatment and at 1, 5, 15, and 30 days after treatment. HCs and SGNs were assessed for morphological alterations. SGNs were subjected to RNA sequencing and mRNA and protein analyses of NLRP3 inflammasome-related molecules. Macrophage activation was evaluated based on morphological and mRNA alterations. The effect of NLRP3 inhibition on SGN survival after kanamycin treatment was evaluated in organ explant cultures treated with Mcc950, a specific inhibitor of the NLRP3 inflammasome. Results Kanamycin and furosemide administration led to irreversible deterioration of the auditory brainstem response threshold, accompanied by acute loss of outer hair cells and gradually progressive loss of inner hair cells. SGNs showed a progressive decrease in quantity, as well as swelling and membrane rupture, at 15 and 30 days. RNA sequencing of SGNs showed that inflammation and immune-related responses were significantly upregulated, as was the expression of the inflammasome-related gene NLRP3. During 30 days of kanamycin exposure, the canonical pyroptosis pathway was constantly activated in SGNs. Activation and infiltration of microglia-like cells/macrophages, and increased production of cytokines, hallmarks of neuroinflammation, were also observed. Mcc950 significantly ameliorated SGN degeneration by inhibiting NLRP3 expression and promoting release of interleukins 1β and 18. Conclusions Pyroptosis causes cell death during aminoglycoside-induced SGN degeneration. Activation of the NLRP3 inflammasome leads to a cascade of inflammatory events in SGNs. Inhibition of the NLRP3 inflammasome significantly alleviates SGN damage, suggesting that it could serve as a new molecular target for the treatment of aminoglycoside-induced SGN degeneration.

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