scholarly journals SMPX Deficiency Causes Stereocilia Degeneration and Progressive Hearing Loss in CBA/CaJ Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Hailong Tu ◽  
Aizhen Zhang ◽  
Xiaolong Fu ◽  
Shiqi Xu ◽  
Xiaohui Bai ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Noise Exposure ◽  
Muscle Protein ◽  
Auditory Brainstem ◽  
Null Mouse ◽  
Suitable Model ◽  
Human Beings ◽  
Progressive Hearing Loss ◽  
Brainstem Response

The small muscle protein, x-linked (SMPX) encodes a small protein containing 88 amino acids. Malfunction of this protein can cause a sex-linked non-syndromic hearing loss, named X-linked deafness 4 (DFNX4). Herein, we reported a point mutation and a frameshift mutation in two Chinese families who developed gradual hearing loss with age. To explore the impaired sites in the hearing system and the mechanism of DFNX4, we established and validated an Smpx null mouse model using CRISPR-Cas9. By analyzing auditory brainstem response (ABR), male Smpx null mice showed a progressive hearing loss starting from high frequency at the 3rd month. Hearing loss in female mice was milder and occurred later compared to male mice, which was very similar to human beings. Through morphological analyses of mice cochleas, we found the hair cell bundles progressively degenerated from the shortest row. Cellular edema occurred at the end phase of stereocilia degeneration, followed by cell death. By transfecting exogenous fluorescent Smpx into living hair cells, Smpx was observed to be expressed in stereocilia. Through noise exposure, it was shown that Smpx might participate in maintaining hair cell bundles. This Smpx knock-out mouse might be used as a suitable model to explore the pathology of DFNX4.

scholarly journals Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xi Gu ◽  
Daqi Wang ◽  
Zhijiao Xu ◽  
Jinghan Wang ◽  
Luo Guo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Protective Effect ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Auditory Brainstem Response ◽  
Gene Editing ◽  
Auditory Brainstem ◽  
Sensorineural Hearing ◽  
Brainstem Response

Abstract Background Aging, noise, infection, and ototoxic drugs are the major causes of human acquired sensorineural hearing loss, but treatment options are limited. CRISPR/Cas9 technology has tremendous potential to become a new therapeutic modality for acquired non-inherited sensorineural hearing loss. Here, we develop CRISPR/Cas9 strategies to prevent aminoglycoside-induced deafness, a common type of acquired non-inherited sensorineural hearing loss, via disrupting the Htra2 gene in the inner ear which is involved in apoptosis but has not been investigated in cochlear hair cell protection. Results The results indicate that adeno-associated virus (AAV)-mediated delivery of CRISPR/SpCas9 system ameliorates neomycin-induced apoptosis, promotes hair cell survival, and significantly improves hearing function in neomycin-treated mice. The protective effect of the AAV–CRISPR/Cas9 system in vivo is sustained up to 8 weeks after neomycin exposure. For more efficient delivery of the whole CRISPR/Cas9 system, we also explore the AAV–CRISPR/SaCas9 system to prevent neomycin-induced deafness. The in vivo editing efficiency of the SaCas9 system is 1.73% on average. We observed significant improvement in auditory brainstem response thresholds in the injected ears compared with the non-injected ears. At 4 weeks after neomycin exposure, the protective effect of the AAV–CRISPR/SaCas9 system is still obvious, with the improvement in auditory brainstem response threshold up to 50 dB at 8 kHz. Conclusions These findings demonstrate the safe and effective prevention of aminoglycoside-induced deafness via Htra2 gene editing and support further development of the CRISPR/Cas9 technology in the treatment of non-inherited hearing loss as well as other non-inherited diseases.

scholarly journals Effect of Phlorofucofuroeckol A and Dieckol Extracted from Ecklonia cava on Noise-induced Hearing Loss in a Mouse Model

Marine Drugs ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. 443
Author(s):  
Hyunjun Woo ◽  
Min-Kyung Kim ◽  
Sohyeon Park ◽  
Seung-Hee Han ◽  
Hyeon-Cheol Shin ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Noise Exposure ◽  
Radical Scavenging ◽  
Threshold Shift ◽  
Ecklonia Cava ◽  
Control Group ◽  
Noise Induced Hearing Loss ◽  
Antioxidant Agents ◽  
Brainstem Response

One of the well-known causes of hearing loss is noise. Approximately 31.1% of Americans between the ages of 20 and 69 years (61.1 million people) have high-frequency hearing loss associated with noise exposure. In addition, recurrent noise exposure can accelerate age-related hearing loss. Phlorofucofuroeckol A (PFF-A) and dieckol, polyphenols extracted from the brown alga Ecklonia cava, are potent antioxidant agents. In this study, we investigated the effect of PFF-A and dieckol on the consequences of noise exposure in mice. In 1,1-diphenyl-2-picrylhydrazyl assay, dieckol and PFF-A both showed significant radical-scavenging activity. The mice were exposed to 115 dB SPL of noise one single time for 2 h. Auditory brainstem response(ABR) threshold shifts 4 h after 4 kHz noise exposure in mice that received dieckol were significantly lower than those in the saline with noise group. The high-PFF-A group showed a lower threshold shift at click and 16 kHz 1 day after noise exposure than the control group. The high-PFF-A group also showed higher hair cell survival than in the control at 3 days after exposure in the apical turn. These results suggest that noise-induced hair cell damage in cochlear and the ABR threshold shift can be alleviated by dieckol and PFF-A in the mouse. Derivatives of these compounds may be applied to individuals who are inevitably exposed to noise, contributing to the prevention of noise-induced hearing loss with a low probability of adverse effects.

scholarly journals Auditory Brainstem Response Altered in Humans With Noise Exposure Despite Normal Outer Hair Cell Function

2017 ◽  
Vol 38 (1) ◽  
pp. e1-e12 ◽  
Author(s):  
Naomi F. Bramhall ◽  
Dawn Konrad-Martin ◽  
Garnett P. McMillan ◽  
Susan E. Griest
Keyword(s):  
Hair Cell ◽  
Auditory Brainstem Response ◽  
Noise Exposure ◽  
Outer Hair Cell ◽  
Cell Function ◽  
Auditory Brainstem ◽  
Brainstem Response

scholarly journals Oncomodulin Delays Age-Related Hearing Loss in C57 and CBA Mice

2021 ◽  
Author(s):  
Leslie K Climer ◽  
Aubrey J Hornak ◽  
Kaitlin Murtha ◽  
Yang Yang ◽  
Andrew M Cox ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cell Function ◽  
Otoacoustic Emission ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Distortion Product Otoacoustic Emission ◽  
Progressive Hearing Loss ◽  
Distortion Product ◽  
Age Related ◽  
Brainstem Response

Ca2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca2+ binding protein preferentially expressed in outer hair cells of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM prevents early progressive hearing loss in mice of two different genetic backgrounds: CBA/CaJ and C57Bl/6J. In both backgrounds, genetic disruption of Ocm leads to early progressive hearing loss as measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). In both strains, loss of Ocm reduced hearing across lifetime (hearing span) by more than 50% relative to wild type (WT). Even though the two WT strains have very different hearing spans, OCM plays a considerable and similar role within their genetic environment to regulate hearing function. The accelerated ARHL of the Ocm KO illustrates the importance of Ca2+ signaling in maintaining hearing health.

scholarly journals Hidden hearing loss is associated with loss of ribbon synapses of cochlea inner hair cells

2021 ◽  
Author(s):  
Feng Song ◽  
Bin Gan ◽  
Na Wang ◽  
Zhe Wang ◽  
An-ting Xu
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Noise Exposure ◽  
Repeated Exposure ◽  
Ribbon Synapse ◽  
Intensity Noise ◽  
Auditory Function ◽  
Ribbon Synapses ◽  
Brainstem Response ◽  
Hidden Hearing Loss

This study aimed to observe the changes in the cochlea ribbon synapses after repeated exposure to moderate-to-high intensity noise. Guinea pigs received 95 dB SPL white noise exposure 4 hours a day for consecutive 7 days (we regarded it a medium-term and moderate-intensity noise, or MTMI noise). Animals were divided into 4 groups: Control, 1DPN (1-day post noise), 1WPN (1-week post noise), and 1MPN (1-month post noise). Auditory function analysis by ABR and CAP recordings, as well as ribbon synapse morphological analyses by immunohistochemistry (Ctbp2 and PSD95 staining) were performed one day, one week, and one month after noise exposure. After MTMI noise exposure, the amplitudes of auditory brainstem response (ABR) I and III waves were suppressed. The compound action potential (CAP) threshold was elevated, and CAP amplitude was reduced in the 1DPN group. No apparent changes in hair cell shape, arrangement or number were observed, but the number of ribbon synapse was reduced. The 1WPN and 1MPN groups showed that part of ABR and CAP changes recovered, as well as the synapse number. The defects in cochlea auditory function and synapse changes were observed mainly in the high-frequency region. Together, repeated exposure in MTMI noise can cause hidden hearing loss, which is partially reversible after leaving the noise environment; and MTMI noise induced hidden hearing loss is associated with inner hair cell ribbon synapses.

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.

Differential effects of pannexins on noise-induced hearing loss

2016 ◽  
Vol 473 (24) ◽  
pp. 4665-4680 ◽  
Author(s):  
Julia M. Abitbol ◽  
John J. Kelly ◽  
Kevin Barr ◽  
Ashley L. Schormans ◽  
Dale W. Laird ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Noise Exposure ◽  
Morphological Changes ◽  
Cell Types ◽  
Auditory Pathway ◽  
Auditory Brainstem ◽  
Vital Role ◽  
Noise Induced Hearing Loss ◽  
Loud Noise ◽  
Brainstem Response

Hearing loss, including noise-induced hearing loss, is highly prevalent and severely hinders an individual's quality of life, yet many of the mechanisms that cause hearing loss are unknown. The pannexin (Panx) channel proteins, Panx1 and Panx3, are regionally expressed in many cell types along the auditory pathway, and mice lacking Panx1 in specific cells of the inner ear exhibit hearing loss, suggesting a vital role for Panxs in hearing. We proposed that Panx1 and/or Panx3 null mice would exhibit severe hearing loss and increased susceptibility to noise-induced hearing loss. Using the auditory brainstem response, we surprisingly found that Panx1−/− and Panx3−/− mice did not harbor hearing or cochlear nerve deficits. Furthermore, while Panx1−/− mice displayed no protection against loud noise-induced hearing loss, Panx3−/− mice exhibited enhanced 16- and 24-kHz hearing recovery 7 days after a loud noise exposure (NE; 12 kHz tone, 115 dB sound pressure level, 1 h). Interestingly, Cx26, Cx30, Cx43, and Panx2 were up-regulated in Panx3−/− mice compared with wild-type and/or Panx1−/− mice, and assessment of the auditory tract revealed morphological changes in the middle ear bones of Panx3−/− mice. It is unclear if these changes alone are sufficient to provide protection against loud noise-induced hearing loss. Contrary to what we expected, these data suggest that Panx1 and Panx3 are not essential for baseline hearing in mice tested, but the therapeutic targeting of Panx3 may prove protective against mid-high-frequency hearing loss caused by loud NE.

Methionine Sulfoxide Reductase A Knockout Mice Show Progressive Hearing Loss and Sensitivity to Acoustic Trauma

2018 ◽  
Vol 23 (1) ◽  
pp. 20-31 ◽  
Author(s):  
Safa Alqudah ◽  
Mark Chertoff ◽  
Dianne Durham ◽  
Jackob Moskovitz ◽  
Hinrich Staecker ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Knockout Mice ◽  
Noise Exposure ◽  
Methionine Sulfoxide ◽  
Auditory Brainstem ◽  
Acoustic Trauma ◽  
Methionine Sulfoxide Reductase ◽  
Distortion Product Otoacoustic Emission ◽  
Distortion Product ◽  
Brainstem Response

Methionine sulfoxide reductases (MsrA and MsrB) protect the biological activity of proteins from oxidative modifications to methionine residues and are important for protecting against the pathological effects of neurodegenerative diseases. In the current study, we characterized the auditory phenotype of the MsrA knockout mouse. Young MsrA knockout mice showed small high-frequency threshold elevations for auditory brainstem response and distortion product otoacoustic emission compared to those of wild-type mice, which progressively worsened in older MsrA knockout mice. MsrA knockout mice showed an increased sensitivity to noise at young and older ages, suggesting that MsrA is part of a mechanism that protects the cochlea from acoustic damage. MsrA mRNA in the cochlea was increased following acoustic stimulation. Finally, expression of mRNA MsrB1 was compromised at 6 months old, but not in younger MsrA knockout mice (compared to controls). The identification of MsrA in the cochlea as a protective mediator from both early onset hearing loss and acoustic trauma expands our understanding of the pathways that may induce protection from acoustic trauma and foster further studies on how to prevent the damaging effect of noise exposure through Msr-based therapy.

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.

Sign in / Sign up

Export Citation Format

Share Document