scholarly journals Autophagy: A Novel Horizon for Hair Cell Protection

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Chang Liu ◽  
Zhiwei Zheng ◽  
Pengjun Wang ◽  
Shuangba He ◽  
Yingzi He
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Auditory System ◽  
Hair Cells ◽  
Acoustic Trauma ◽  
Hearing Protection ◽  
Cellular Reaction ◽  
Cell Protection ◽  
Ototoxic Drugs ◽  
Potential Measure

As a general sensory disorder, hearing loss was a major concern worldwide. Autophagy is a common cellular reaction to stress that degrades cytoplasmic waste through the lysosome pathway. Autophagy not only plays major roles in maintaining intracellular homeostasis but is also involved in the development and pathogenesis of many diseases. In the auditory system, several studies revealed the link between autophagy and hearing protection. In this review, we aimed to establish the correlation between autophagy and hair cells (HCs) from the aspects of ototoxic drugs, aging, and acoustic trauma and discussed whether autophagy could serve as a potential measure in the protection of HCs.

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 Inner Ear Hair Cell Protection in Mammals against the Noise-Induced Cochlear Damage

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Muhammad Waqas ◽  
Song Gao ◽  
Iram-us-Salam ◽  
Muhammad Kazim Ali ◽  
Yongming Ma ◽  
...  
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Structural Integrity ◽  
Acoustic Trauma ◽  
Outer Hair Cells ◽  
Cell Protection ◽  
Protection Strategies ◽  
Deterioration Process ◽  
Intense Noise

Inner ear hair cells are mechanosensory receptors that perceive mechanical sound and help to decode the sound in order to understand spoken language. Exposure to intense noise may result in the damage to the inner ear hair cells, causing noise-induced hearing loss (NIHL). Particularly, the outer hair cells are the first and the most affected cells in NIHL. After acoustic trauma, hair cells lose their structural integrity and initiate a self-deterioration process due to the oxidative stress. The activation of different cellular death pathways leads to complete hair cell death. This review specifically presents the current understanding of the mechanism exists behind the loss of inner ear hair cell in the auditory portion after noise-induced trauma. The article also explains the recent hair cell protection strategies to prevent the damage and restore hearing function in mammals.

scholarly journals Research Progress of Hair Cell Protection Mechanism

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Yurong Mu ◽  
Hongguo Su ◽  
Fan Wu ◽  
Jianming Yang ◽  
Dan Li
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Research Progress ◽  
Cell Protection ◽  
Protection Mechanism ◽  
Hearing Research

How to prevent and treat hearing-related diseases through the protection of hair cells (HCs) is the focus in the field of hearing in recent years. Hearing loss caused by dysfunction or loss of HCs is the main cause of hearing diseases. Therefore, clarifying the related mechanisms of HC development, apoptosis, protection, and regeneration is the main goal of current hearing research. This review introduces the latest research on mechanism of HC protection and regeneration.

scholarly journals Assessment of cochlear toxicity in response to chronic 3,3′-iminodipropionitrile in mice reveals early and reversible functional loss that precedes overt histopathology

2021 ◽  
Vol 95 (3) ◽  
pp. 1003-1021
Author(s):  
Erin A. Greguske ◽  
Jordi Llorens ◽  
Sonja J. Pyott
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Auditory System ◽  
Hair Cells ◽  
Time Course ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Hair Cell Loss ◽  
Brainstem Response ◽  
Peripheral Auditory System

AbstractThe peripheral auditory and vestibular systems rely on sensorineural structures that are vulnerable to ototoxic agents that cause hearing loss and/or equilibrium deficits. Although attention has focused on hair cell loss as the primary pathology underlying ototoxicity, evidence from the peripheral vestibular system indicates that hair cell loss during chronic exposure is preceded by synaptic uncoupling from the neurons and is potentially reversible. To determine if synaptic pathology also occurs in the peripheral auditory system, we examined the extent, time course, and reversibility of functional and morphological alterations in cochleae from mice exposed to 3,3′-iminodipropionitrile (IDPN) in drinking water for 2, 4 or 6 weeks. Functionally, IDPN exposure caused progressive high- to low-frequency hearing loss assessed by measurement of auditory brainstem response wave I absolute thresholds and amplitudes. The extent of hearing loss scaled with the magnitude of vestibular dysfunction assessed behaviorally. Morphologically, IDPN exposure caused progressive loss of outer hair cells (OHCs) and synapses between the inner hair cells (IHCs) and primary auditory neurons. In contrast, IHCs were spared from ototoxic damage. Importantly, hearing loss consistent with cochlear synaptopathy preceded loss of OHCs and synapses and, moreover, recovered if IDPN exposure was stopped before morphological pathology occurred. Our observations suggest that synaptic uncoupling, perhaps as an early phase of cochlear synaptopathy, also occurs in the peripheral auditory system in response to IDPN exposure. These findings identify novel mechanisms that contribute to the earliest stages of hearing loss in response to ototoxic agents and possibly other forms of acquired hearing loss.

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 Effects of cochlear hair cell ablation on spatial learning/memory

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Z. Jason Qian ◽  
Anthony J. Ricci
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Spatial Learning ◽  
Hair Cells ◽  
Noise Exposure ◽  
Memory Errors ◽  
Cochlear Hair Cells ◽  
Cochlear Hair Cell ◽  
Cell Ablation ◽  
Spatial Learning Memory

AbstractCurrent clinical interest lies in the relationship between hearing loss and cognitive impairment. Previous work demonstrated that noise exposure, a common cause of sensorineural hearing loss (SNHL), leads to cognitive impairments in mice. However, in noise-induced models, it is difficult to distinguish the effects of noise trauma from subsequent SNHL on central processes. Here, we use cochlear hair cell ablation to isolate the effects of SNHL. Cochlear hair cells were conditionally and selectively ablated in mature, transgenic mice where the human diphtheria toxin (DT) receptor was expressed behind the hair-cell specific Pou4f3 promoter. Due to higher Pou4f3 expression in cochlear hair cells than vestibular hair cells, administration of a low dose of DT caused profound SNHL without vestibular dysfunction and had no effect on wild-type (WT) littermates. Spatial learning/memory was assayed using an automated radial 8-arm maze (RAM), where mice were trained to find food rewards over a 14-day period. The number of working memory errors (WME) and reference memory errors (RME) per training day were recorded. All animals were injected with DT during P30–60 and underwent the RAM assay during P90–120. SNHL animals committed more WME and RME than WT animals, demonstrating that isolated SNHL affected cognitive function. Duration of SNHL (60 versus 90 days post DT injection) had no effect on RAM performance. However, younger age of acquired SNHL (DT on P30 versus P60) was associated with fewer WME. This describes the previously undocumented effect of isolated SNHL on cognitive processes that do not directly rely on auditory sensory input.

Neurotrophin gene therapy may be able to treat individuals with noise-induced hearing loss or neural presbyacusis

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Cell Loss ◽  
Cell Populations ◽  
Noise Induced Hearing Loss ◽  
Hair Cell Loss ◽  
Functional Impairments ◽  
Peripheral Axon

Neurotrophin (NT) cochlear gene therapy might perhaps give a single treatment that might greatly enhance neuronal survival, resulting in CI patients, provided the many challenges described above can be adequately addressed and safety concerns allayed by more animal model investigations. This is particularly crucial for juvenile CI patients, who have to rely on electrical hearing for the remainder of their lives, and whose outcomes are quite different. In addition, NT gene therapy may have the potential to treat patients with noise-induced hearing loss or neural presbyacusis (e.g., age-related cochlear synaptopathy), where primary neuronal loss is a key cause of hearing loss. Animal research into noise-induced hearing loss has shown that even exposures that generate only reversible threshold alterations and no hair cell loss can lead to permanent loss of SGN synapses on hair cells, resulting in functional impairments and ultimately SGN degeneration. Cochlear synapses frequently precede both hair cell loss and threshold increases in human ears, according to current studies. Cochlear synaptopathy is characterized by ears with intact hair cell populations and normal audiograms as "hidden" hearing loss. Many frequent perceptual abnormalities, including speech-in-noise difficulties, tinnitus, and hyperacusis, are likely produced by suppressing affected neurons, which radically alters information processing. Thus, in the future, NT gene therapy may be successful in inducing SGN peripheral axon resprouting and synaptic regeneration into residual (or even regenerated) hair cell populations. We have demonstrated compelling evidence that, in this investigation, BDNF gene therapy can boost SGN survival and enhance peripheral axon maintenance or rerouting. NT-3 has been found in adult animals exposed to acoustic damage to induce synaptic regeneration of these fibers, reconnecting them to hair cells and their ribbon synapses, and restoring hearing function. Combining BDNF and NT-3 gene therapy may be the most effective way to maintain/restore a more normal cochlear neuronal substrate.

Carboplatin ototoxicity: an animal model

1993 ◽  
Vol 107 (7) ◽  
pp. 585-589 ◽  
Author(s):  
Mark Wake ◽  
Sachio Takeno ◽  
Danyl Ibrahim ◽  
Robert Harrison ◽  
Richard Mount
Keyword(s):  
Animal Model ◽  
Light Microscopy ◽  
Hair Cell ◽  
Brain Stem ◽  
Auditory System ◽  
Hair Cells ◽  
Afferent Input ◽  
Evoked Responses ◽  
Auditory Thresholds ◽  
Scanning Electronmicroscopy

A new animal model of ototoxicity is presented using intravenous carboplatin in adult chinchillas. A range of physiological and morphological effects was produced using doses calculated from the recommended therapeutic range (200–400 mg/m2). Auditory thresholds to tone pips stimuli were monitored using brain stem evoked responses (ABR). Cochlear histopathology was studied by light microscopy (LM) and ultrstructural hair cell abnormalities investigated with scanning electronmicroscopy (SEM). Carboplatin in this animal model predominantly affected the inner hair cells. This may provide an important model for the study of selective loss of the main afferent input in the auditory system.

scholarly journals The challenge of hair cell regeneration

2010 ◽  
Vol 235 (4) ◽  
pp. 434-446 ◽  
Author(s):  
Andrew K Groves
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Electrical Energy ◽  
Cell Regeneration ◽  
Hair Cell Regeneration ◽  
Therapeutic Approaches ◽  
Auditory Hair Cells ◽  
Sensory Hair Cells ◽  
Ototoxic Drugs ◽  
Effects Of Aging

Sensory hair cells of the inner ear are responsible for translating auditory or vestibular stimuli into electrical energy that can be perceived by the nervous system. Although hair cells are exquisitely mechanically sensitive, they can be easily damaged by excessive stimulation by ototoxic drugs and by the effects of aging. In mammals, auditory hair cells are never replaced, such that cumulative damage to the ear causes progressive and permanent deafness. In contrast, non-mammalian vertebrates are capable of replacing lost hair cells, which has led to efforts to understand the molecular and cellular basis of regenerative responses in different vertebrate species. In this review, we describe recent progress in understanding the limits to hair cell regeneration in mammals and discuss the obstacles that currently exist for therapeutic approaches to hair cell replacement.

scholarly journals Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Pengcheng Xu ◽  
Longhao Wang ◽  
Hu Peng ◽  
Huihui Liu ◽  
Hongchao Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Mitochondrial Dysfunction ◽  
Hair Cells ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Hair Cell Loss ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Inner Hair Cells

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

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