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 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.

scholarly journals Inner ear pathology and loss of hearing in estrogen receptor-β deficient mice

2009 ◽  
Vol 201 (3) ◽  
pp. 397-406 ◽  
Author(s):  
Rusana Simonoska ◽  
Annika E Stenberg ◽  
Maoli Duan ◽  
Konstantin Yakimchuk ◽  
Anders Fridberger ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Inner Ear ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Auditory Brainstem ◽  
Estrogen Receptor Β ◽  
Knock Out ◽  
Age Related ◽  
Brainstem Response ◽  
Knock Out Mice

There are well known differences between males and females in hearing. In the present study, the role of estrogen receptor-β (ER-β; listed as ESR2 in the MGI Database) in hearing was investigated by comparing hearing and morphology of the inner ear in ER-β knock-out mice (ER-β−/−) with that of wild-type (WT) littermates. Hearing was analyzed with auditory brainstem response audiometry at 3 and 12 months. The ER-β−/− mice were deaf at 1 year of age, and the morphological analysis showed absence of hair cells and loss of the whole organ of Corti initiated in the basal turn of the cochlea. Furthermore, in ER-β−/−, but not in WT mice, the spiral ganglion was lacking many of its neurons. Immunostaining showed the presence of both ER-α (listed as ESR1 in the MGI Database) and ER-β in the nuclei of some neurons in the inner ear in WT mice, but no ER-β was found in the ER-β−/− mice as expected. ER-α staining was predominant in the nuclei of large neurons and ER-β in nuclei of small neurons and fibroblasts. These results reveal that both ERs are present in the inner ear at specific localizations suggesting subtype-specific functions. It is concluded that ER-β is important for the prevention of age-related hearing loss. These findings strengthen the hypothesis that estrogen has a direct effect on hearing functions.

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.

scholarly journals Synaptic Release Potentiation at Aging Auditory Ribbon Synapses

2021 ◽  
Vol 13 ◽  
Author(s):  
Thibault Peineau ◽  
Séverin Belleudy ◽  
Susanna Pietropaolo ◽  
Yohan Bouleau ◽  
Didier Dulon
Keyword(s):  
Hearing Loss ◽  
Acoustic Startle ◽  
Auditory Brainstem ◽  
Bk Channels ◽  
Acoustic Startle Reflex ◽  
Inner Hair Cell ◽  
Functional Changes ◽  
Ribbon Synapses ◽  
Age Related ◽  
Cadherin 23

Age-related hidden hearing loss is often described as a cochlear synaptopathy that results from a progressive degeneration of the inner hair cell (IHC) ribbon synapses. The functional changes occurring at these synapses during aging are not fully understood. Here, we characterized this aging process in IHCs of C57BL/6J mice, a strain which is known to carry a cadherin-23 mutation and experiences early hearing loss with age. These mice, while displaying a large increase in auditory brainstem thresholds due to 50% loss of IHC synaptic ribbons at middle age (postnatal day 365), paradoxically showed enhanced acoustic startle reflex suggesting a hyperacusis-like response. The auditory defect was associated with a large shrinkage of the IHCs' cell body and a drastic enlargement of their remaining presynaptic ribbons which were facing enlarged postsynaptic AMPAR clusters. Presynaptic Ca2+ microdomains and the capacity of IHCs to sustain high rates of exocytosis were largely increased, while on the contrary the expression of the fast-repolarizing BK channels, known to negatively control transmitter release, was decreased. This age-related synaptic plasticity in IHCs suggested a functional potentiation of synaptic transmission at the surviving synapses, a process that could partially compensate the decrease in synapse number and underlie hyperacusis.

scholarly journals Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca2+-permeable AMPA receptors

2020 ◽  
Vol 117 (7) ◽  
pp. 3828-3838 ◽  
Author(s):  
Ning Hu ◽  
Mark A. Rutherford ◽  
Steven H. Green
Keyword(s):  
Ampa Receptors ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Spiral Ganglion Neurons ◽  
Loud Sound ◽  
Selective Blockade ◽  
Hearing Thresholds ◽  
Brainstem Response ◽  
Low Threshold ◽  
Ganglion Neurons

Exposure to loud sound damages the postsynaptic terminals of spiral ganglion neurons (SGNs) on cochlear inner hair cells (IHCs), resulting in loss of synapses, a process termed synaptopathy. Glutamatergic neurotransmission via α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type receptors is required for synaptopathy, and here we identify a possible involvement of GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) using IEM-1460, which has been shown to block GluA2-lacking AMPARs. In CBA/CaJ mice, a 2-h exposure to 100-dB sound pressure level octave band (8 to 16 kHz) noise results in no permanent threshold shift but does cause significant synaptopathy and a reduction in auditory brainstem response (ABR) wave-I amplitude. Chronic intracochlear perfusion of IEM-1460 in artificial perilymph (AP) into adult CBA/CaJ mice prevented the decrease in ABR wave-I amplitude and the synaptopathy relative to intracochlear perfusion of AP alone. Interestingly, IEM-1460 itself did not affect the ABR threshold, presumably because GluA2-containing AMPARs can sustain sufficient synaptic transmission to evoke low-threshold responses during blockade of GluA2-lacking AMPARs. On individual postsynaptic densities, we observed GluA2-lacking nanodomains alongside regions with robust GluA2 expression, consistent with the idea that individual synapses have both CP-AMPARs and Ca2+-impermeable AMPARs. SGNs innervating the same IHC differ in their relative vulnerability to noise. We found local heterogeneity among synapses in the relative abundance of GluA2 subunits that may underlie such differences in vulnerability. We propose a role for GluA2-lacking CP-AMPARs in noise-induced cochlear synaptopathy whereby differences among synapses account for differences in excitotoxic susceptibility. These data suggest a means of maintaining normal hearing thresholds while protecting against noise-induced synaptopathy, via selective blockade of CP-AMPARs.

Cisplatin Toxicology: The Role of Pro-inflammatory Cytokines and GABA Transporters in Cochlear Spiral Ganglion

2020 ◽  
Vol 25 (45) ◽  
pp. 4820-4826 ◽  
Author(s):  
Dongmei Gao ◽  
Hong Yu ◽  
Bo Li ◽  
Li Chen ◽  
Xiaoyu Li ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Spiral Ganglion ◽  
Auditory Brainstem ◽  
Protein Levels ◽  
Gaba Transporters ◽  
Tnf Α ◽  
Neuronal Tissues ◽  
Brainstem Response ◽  
Cochlear Spiral Ganglion ◽  
Pro Inflammatory Cytokines

Background: The current study was conducted to examine the specific activation of pro-inflammatory cytokines (PICs), namely IL-1β, IL-6 and TNF-α in the cochlear spiral ganglion of rats after ototoxicity induced by cisplatin. Since γ-aminobutyric acid (GABA) and its receptors are involved in pathophysiological processes of ototoxicity, we further examined the role played by PICs in regulating expression of GABA transporter type 1 and 3 (GAT-1 and GAT-3), as two essential subtypes of GATs responsible for the regulation of extracellular GABA levels in the neuronal tissues. Methods: ELISA and western blot analysis were employed to examine the levels of PICs and GATs; and auditory brainstem response was used to assess ototoxicity induced by cisplatin. Results: IL-1β, IL-6 and TNF-α as well as their receptors were significantly increased in the spiral ganglion of ototoxic rats as compared with sham control animals (P<0.05, ototoxic rats vs. control rats). Cisplatin-ototoxicity also induced upregulation of the protein levels of GAT-1 and GAT-3 in the spiral ganglion (P<0.05 vs. controls). In addition, administration of inhibitors to IL-1β, IL-6 and TNF-α attenuated amplification of GAT-1 and GAT-3 and improved hearing impairment induced by cisplatin. Conclusion: Our data indicate that PIC signals are activated in the spiral ganglion during cisplatin-ototoxicity which thereby leads to upregulation of GABA transporters. As a result, it is likely that de-inhibition of GABA system is enhanced in the cochlear spiral ganglion. This supports a role for PICs in engagement of the signal mechanisms associated with cisplatin-ototoxicity, and has pharmacological implications to target specific PICs for GABAergic dysfunction and vulnerability related to cisplatin-ototoxicity.

Thymoquinone treatment for inner-ear acoustic trauma in rats

2015 ◽  
Vol 129 (1) ◽  
pp. 38-45 ◽  
Author(s):  
F Aksoy ◽  
R Dogan ◽  
A Yenigun ◽  
B Veyseller ◽  
O Ozturan ◽  
...  
Keyword(s):  
Otoacoustic Emission ◽  
Auditory Brainstem ◽  
Acoustic Trauma ◽  
Control Group ◽  
Distortion Product Otoacoustic Emission ◽  
Distortion Product ◽  
Brainstem Response ◽  
Group 3 ◽  
Group 2 ◽  
Trauma Group

AbstractObjective:To investigate whether thymoquinone has any eliminative effects against inner-ear damage caused by acoustic trauma.Methods:Thirty-two male rats were divided into four groups. Group 1 was only exposed to acoustic trauma. Group 2 was given thymoquinone 24 hours before acoustic trauma and continued to receive it for 10 days after the trauma. Group 3 was only treated with thymoquinone, for 10 days. Group 4, the control group, suffered no trauma and received saline instead of thymoquinone. Groups 1 and 2 were exposed to acoustic trauma using 105 dB SPL white noise for 4 hours.Results:There was a significant decrease in distortion product otoacoustic emission values and an increase in auditory brainstem response thresholds in group 1 on days 1, 5 and 10, compared with baseline measurements. In group 2, a decrease in distortion product otoacoustic emission values and an increase in auditory brainstem response threshold were observed on day 1 after acoustic trauma, but measurements were comparable to baseline values on days 5 and 10. In group 3, thymoquinone had no detrimental effects on hearing. Similarly, the control group showed stable results.Conclusion:Thymoquinone was demonstrated to be a reparative rather than preventive treatment that could be used to relieve acoustic trauma.

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