scholarly journals Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss

2021 ◽  
Vol 8 ◽  
Author(s):  
Melanie Holmgren ◽  
Lavinia Sheets
Keyword(s):  
Cell Death ◽  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Lateral Line ◽  
Hair Cells ◽  
High Energy ◽  
Sensorineural Hearing ◽  
Mitochondrial Activity ◽  
Ototoxic Drugs

Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug–induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans.

scholarly journals Noise-induced and age-related hearing loss:  new perspectives and potential therapies

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 927 ◽  
Author(s):  
M Charles Liberman
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Auditory Nerve ◽  
Cell Loss ◽  
Sensorineural Hearing ◽  
Hair Cell Loss ◽  
Age Related ◽  
Age Related Hearing Loss

The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a “hidden hearing loss” for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

scholarly journals Research Progress on the Mechanism of Cochlear Hair Cell Regeneration

2021 ◽  
Vol 15 ◽  
Author(s):  
Shan Xu ◽  
Ning Yang
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Molecular Mechanisms ◽  
Sensorineural Hearing ◽  
Research Progress ◽  
Cell Regeneration ◽  
Hair Cell Regeneration ◽  
Auditory Hair Cells

Mammalian inner ear hair cells do not have the ability to spontaneously regenerate, so their irreversible damage is the main cause of sensorineural hearing loss. The damage and loss of hair cells are mainly caused by factors such as aging, infection, genetic factors, hypoxia, autoimmune diseases, ototoxic drugs, or noise exposure. In recent years, research on the regeneration and functional recovery of mammalian auditory hair cells has attracted more and more attention in the field of auditory research. How to regenerate and protect hair cells or auditory neurons through biological methods and rebuild auditory circuits and functions are key scientific issues that need to be resolved in this field. This review mainly summarizes and discusses the recent research progress in gene therapy and molecular mechanisms related to hair cell regeneration in the field of sensorineural hearing loss.

scholarly journals Deletion of Clusterin Protects Cochlear Hair Cells against Hair Cell Aging and Ototoxicity

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Xiaochang Zhao ◽  
Heidi J. Henderson ◽  
Tianying Wang ◽  
Bo Liu ◽  
Yi Li
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Sensorineural Hearing ◽  
Cell Aging ◽  
Supporting Cells ◽  
Drug Induced ◽  
Cochlear Hair Cells ◽  
Age Related

Hearing loss is a debilitating disease that affects 10% of adults worldwide. Most sensorineural hearing loss is caused by the loss of mechanosensitive hair cells in the cochlea, often due to aging, noise, and ototoxic drugs. The identification of genes that can be targeted to slow aging and reduce the vulnerability of hair cells to insults is critical for the prevention of sensorineural hearing loss. Our previous cell-specific transcriptome analysis of adult cochlear hair cells and supporting cells showed that Clu, encoding a secreted chaperone that is involved in several basic biological events, such as cell death, tumor progression, and neurodegenerative disorders, is expressed in hair cells and supporting cells. We generated Clu-null mice (C57BL/6) to investigate its role in the organ of Corti, the sensory epithelium responsible for hearing in the mammalian cochlea. We showed that the deletion of Clu did not affect the development of hair cells and supporting cells; hair cells and supporting cells appeared normal at 1 month of age. Auditory function tests showed that Clu-null mice had hearing thresholds comparable to those of wild-type littermates before 3 months of age. Interestingly, Clu-null mice displayed less hair cell and hearing loss compared to their wildtype littermates after 3 months. Furthermore, the deletion of Clu is protected against aminoglycoside-induced hair cell loss in both in vivo and in vitro models. Our findings suggested that the inhibition of Clu expression could represent a potential therapeutic strategy for the alleviation of age-related and ototoxic drug-induced hearing loss.

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 Sensorineural Hearing Loss Due to Exposure of Noisy Trains on Populations Around Turirejo Train Railroad Cross

2020 ◽  
Vol 12 (1) ◽  
pp. 59
Author(s):  
Diana Kusuma Wardhani ◽  
Jojok Mukono Mukono
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Noise Intensity ◽  
Noise Exposure ◽  
Sound Level ◽  
Sensorineural Hearing ◽  
High Noise ◽  
Railroad Tracks ◽  
The Government

Introduction: As one of the preferred modes of land transportation, the frequency of train services was very high. One of the negative impacts arising from train activity was noise. The high noise intensity of the train causes hearing loss. Method: This study aims to analyze the differences in the incidence of hearing loss in 2 groups of residents in Turirejo Lawang Malang. This research used the observational method and the data were analyzed descriptive qualitative. A total of 20 people were selected as respondents by purposive sampling. Noise intensity was measured by Sound Level Meter and audiometric measurements were examined at SIMA Malang Laboratory. Result and Discussion: The prevalence of sensorineural hearing loss was more common in residents whose homes at 3-7 m away from the railroad tracks. In addition, residents who lived at least 15 years at a distance of 3-7 m also experienced more hearing loss. One cause of hearing loss is due to exposure to high noise and for a long time and will damage the hair cells in the cochlea, causing hearing loss. If noise exposure continues and for a long period of time damage to hair cells will be permanent and cannot return to normal. Conclusion: There needs to be a policy from the government in determining the minimum limit of the distance of the house to the railroad tracks. In addition, it is necessary to install a barrier near people’s homes to reduce noise.

scholarly journals Enhancing the sensitivity of the envelope-following response for cochlear synaptopathy screening in humans: the role of stimulus envelope

2020 ◽  
Author(s):  
Viacheslav Vasilkov ◽  
Markus Garrett ◽  
Manfred Mauermann ◽  
Sarah Verhulst
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Auditory Nerve ◽  
Outer Hair Cell ◽  
Cell Damage ◽  
Modulation Depth ◽  
Auditory Evoked Potential ◽  
Sensorineural Hearing ◽  
Age Related

AbstractAuditory de-afferentation, a permanent reduction in the number of innerhair-cells and auditory-nerve synapses due to cochlear damage or synaptopathy, can reliably be quantified using temporal bone histology and immunostaining. However, there is an urgent need for non-invasive markers of synaptopathy to study its perceptual consequences in live humans and to develop effective therapeutic interventions. While animal studies have identified candidate auditory-evoked-potential (AEP) markers for synaptopathy, their interpretation in humans has suffered from translational issues related to neural generator differences, unknown hearing-damage histopathologies or lack of measurement sensitivity. To render AEP-based markers of synaptopathy more sensitive and differential to the synaptopathy aspect of sensorineural hearing loss, we followed a combined computational and experimental approach. Starting from the known characteristics of auditory-nerve physiology, we optimized the stimulus envelope to stimulate the available auditory-nerve population optimally and synchronously to generate strong envelope-following-responses (EFRs). We further used model simulations to explore which stimuli evoked a response that was sensitive to synaptopathy, while being maximally insensitive to possible co-existing outer-hair-cell pathologies. We compared the model-predicted trends to AEPs recorded in younger and older listeners (N=44, 24f) who had normal or impaired audiograms with suspected age-related synaptopathy in the older cohort. We conclude that optimal stimulation paradigms for EFR-based quantification of synaptopathy should have sharply rising envelope shapes, a minimal plateau duration of 1.7-2.1 ms for a 120-Hz modulation rate, and inter-peak intervals which contain near-zero amplitudes. From our recordings, the optimal EFR-evoking stimulus had a rectangular envelope shape with a 25% duty cycle and a 95% modulation depth. Older listeners with normal or impaired audiometric thresholds showed significantly reduced EFRs, which were consistent with how (age-induced) synaptopathy affected these responses in the model.Significance StatementCochlear synaptopathy was in 2009 identified as a new form of sensorineural hearing loss (SNHL) that also affects primates and humans. However, clinical practice does not routinely screen for synaptopathy, and hence its consequences for degraded sound and speech perception remain unclear. Cochlear synaptopathy may thus remain undiagnosed and untreated in the aging population who often report self-reported hearing difficulties. To enable an EEG-based differential diagnosis of synaptopathy in humans, it is crucial to develop a recording method that evokes a robust response and emphasizes inter-individual differences. These differences should reflect the synaptopathy aspect of SNHL, while being insensitive to other aspects of SNHL (e.g. outer-hair-cell damage). This study uniquely combines computational modeling with experiments in normal and hearing-impaired listeners to design an EFR stimulation and recording paradigm that can be used for the diagnosis of synaptopathy in humans.

scholarly journals Autophagy Regulates the Survival of Hair Cells and Spiral Ganglion Neurons in Cases of Noise, Ototoxic Drug, and Age-Induced Sensorineural Hearing Loss

2021 ◽  
Vol 15 ◽  
Author(s):  
Lingna Guo ◽  
Wei Cao ◽  
Yuguang Niu ◽  
Shuangba He ◽  
Renjie Chai ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Noise Exposure ◽  
Spiral Ganglion ◽  
Sensorineural Hearing ◽  
Spiral Ganglion Neurons ◽  
Core Components ◽  
Spontaneous Regeneration ◽  
Ganglion Neurons

Inner ear hair cells (HCs) and spiral ganglion neurons (SGNs) are the core components of the auditory system. However, they are vulnerable to genetic defects, noise exposure, ototoxic drugs and aging, and loss or damage of HCs and SGNs results in permanent hearing loss due to their limited capacity for spontaneous regeneration in mammals. Many efforts have been made to combat hearing loss including cochlear implants, HC regeneration, gene therapy, and antioxidant drugs. Here we review the role of autophagy in sensorineural hearing loss and the potential targets related to autophagy for the treatment of hearing loss.

scholarly journals Isolation of sensory hair cell specific exosomes in human perilymph

2021 ◽  
Author(s):  
Pei Zhuang ◽  
Suiching Phung ◽  
Athanasia Warnecke ◽  
Alexandra Arambula ◽  
Madeleine St. Peter ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Inner Ear ◽  
Molecular Characterization ◽  
Sensorineural Hearing ◽  
Alternative Methods ◽  
Sensory Hair ◽  
Sensory Hair Cell ◽  
Human Inner Ear

AbstractEvaluation of hearing loss patients using clinical audiometry has been unable to give a definitive cellular or molecular diagnosis, hampering the development of treatments of sensorineural hearing loss. However, biopsy of inner ear tissue without losing residual hearing function for pathologic diagnosis is extremely challenging. In a clinical setting, perilymph can be accessed, so alternative methods for molecular characterization of the inner ear may be developed. Recent approaches to improving inner ear diagnostics have been focusing on the evaluation of the proteomic or miRNA profiles of perilymph. Inspired by recent characterization and classification of many neurodegenerative diseases using exosomes which not only are produced in locally in diseased tissue but are transported beyond the blood brain barrier, we demonstrate the isolation of human inner ear specific exosomes using a novel ultrasensitive immunomagnetic nano pom-poms capture-release approach. Using perilymph samples harvested from surgical procedures, we were able to isolate exosomes from sensorineural hearing loss patients in only 2-5 μL of perilymph. By isolating sensory hair cell derived exosomes through their expression level of myosin VII, we for the first time sample material from hair cells in the living human inner ear. This work sets up the first demonstration of immunomagnetic capture-release nano pom-pom isolated exosomes for liquid biopsy diagnosis of sensorineural hearing loss. With the ability to isolate exosomes derived from different cell types for molecular characterization, this method also can be developed for analyzing exosomal biomarkers from more accessible patient tissue fluids such as plasma.

scholarly journals Towards personalized auditory models: predicting individual sensorineural-hearing-loss profiles from recorded human auditory physiology

2020 ◽  
Author(s):  
Sarineh Keshishzadeh ◽  
Markus Garrett ◽  
Sarah Verhulst
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Auditory Processing ◽  
Auditory Evoked Potential ◽  
Sensorineural Hearing ◽  
Model Parameters ◽  
Non Invasive ◽  
Auditory Models ◽  
Auditory Physiology

AbstractOver the past decades, different types of auditory models have been developed to study the functioning of normal and impaired auditory processing. Several models can simulate frequency-dependent sensorineural hearing loss (SNHL), and can in this way be used to develop personalized audio-signal processing for hearing aids. However, to determine individualized SNHL profiles, we rely on indirect and non-invasive markers of cochlear and auditory-nerve (AN) damage. Our progressive knowledge of the functional aspects of different SNHL subtypes stresses the importance of incorporating them into the simulated SNHL profile, but has at the same time complicated the task of accomplishing this on the basis of non-invasive markers. In particular, different auditory evoked potential (AEP) types can show a different sensitivity to outer-hair-cell (OHC), inner-hair-cell (IHC) or AN damage, but it is not clear which AEP-derived metric is best suited to develop personalized auditory models. This study investigates how simulated and recorded AEPs can be used to derive individual AN- or OHC-damage patterns and personalize auditory processing models. First, we individualized the cochlear-model parameters using common methods of frequency-specific OHC-damage quantification, after which we simulated AEPs for different degrees of AN-damage. Using a classification technique, we determined the recorded AEP metric that best predicted the simulated individualized CS profiles. We cross-validated our method using the dataset at hand, but also applied the trained classifier to recorded AEPs from a new cohort to illustrate the generalisability of the method.

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