The relation among hearing loss, sensory cell loss and tuning characteristics in the chinchilla

AbstractThe prevalence of noise-induced hearing loss (NIHL) continues to increase, with limited therapies available for individuals with cochlear damage. We have previously established that the transcription factor FOXO3 is necessary to preserve outer hair cells (OHCs) and hearing thresholds up to two weeks following mild noise exposure in mice. The mechanisms by which FOXO3 preserves cochlear cells and function are unknown. In this study, we analyzed the immediate effects of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo3+/−), and Foxo3 knock-out (Foxo3−/−) mice to better understand FOXO3’s role(s) in the mammalian cochlea. We used confocal and multiphoton microscopy to examine well-characterized components of noise-induced damage including calcium regulators, oxidative stress, necrosis, and caspase-dependent and caspase-independent apoptosis. Lower immunoreactivity of the calcium buffer Oncomodulin in Foxo3−/− OHCs correlated with cell loss beginning 4 h post-noise exposure. Using immunohistochemistry, we identified parthanatos as the cell death pathway for OHCs. Oxidative stress response pathways were not significantly altered in FOXO3’s absence. We used RNA sequencing to identify and RT-qPCR to confirm differentially expressed genes. We further investigated a gene downregulated in the unexposed Foxo3−/− mice that may contribute to OHC noise susceptibility. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), a possible endogenous source of lysophosphatidic acid (LPA), has not previously been described in the cochlea. As LPA reduces OHC loss after severe noise exposure, we treated noise-exposed Foxo3−/− mice with exogenous LPA. LPA treatment delayed immediate damage to OHCs but was insufficient to ultimately prevent their death or prevent hearing loss. These results suggest that FOXO3 acts prior to acoustic insult to maintain cochlear resilience, possibly through sustaining endogenous LPA levels.

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

F1000Research ◽

10.12688/f1000research.11310.1 ◽

2017 ◽

Vol 6 ◽

pp. 927 ◽

Cited By ~ 78

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.

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

10.31219/osf.io/spkxh ◽

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.

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Oral Antioxidant Vitamins and Magnesium Limit Noise-Induced Hearing Loss by Promoting Sensory Hair Cell Survival: Role of Antioxidant Enzymes and Apoptosis Genes

Antioxidants ◽

10.3390/antiox9121177 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1177

Author(s):

Juan C. Alvarado ◽

Verónica Fuentes-Santamaría ◽

Pedro Melgar-Rojas ◽

María C. Gabaldón-Ull ◽

José J. Cabanes-Sanchis ◽

...

Keyword(s):

Cell Death ◽

Hearing Loss ◽

Antioxidant Enzymes ◽

Oral Administration ◽

Hair Cell ◽

Cell Survival ◽

Sensory Cell ◽

Auditory Function ◽

Sensory Hair ◽

Sensory Hair Cell

Noise induces oxidative stress in the cochlea followed by sensory cell death and hearing loss. The proof of principle that injections of antioxidant vitamins and Mg2+ prevent noise-induced hearing loss (NIHL) has been established. However, effectiveness of oral administration remains controversial and otoprotection mechanisms are unclear. Using auditory evoked potentials, quantitative PCR, and immunocytochemistry, we explored effects of oral administration of vitamins A, C, E, and Mg2+ (ACEMg) on auditory function and sensory cell survival following NIHL in rats. Oral ACEMg reduced auditory thresholds shifts after NIHL. Improved auditory function correlated with increased survival of sensory outer hair cells. In parallel, oral ACEMg modulated the expression timeline of antioxidant enzymes in the cochlea after NIHL. There was increased expression of glutathione peroxidase-1 and catalase at 1 and 10 days, respectively. Also, pro-apoptotic caspase-3 and Bax levels were diminished in ACEMg-treated rats, at 10 and 30 days, respectively, following noise overstimulation, whereas, at day 10 after noise exposure, the levels of anti-apoptotic Bcl-2, were significantly increased. Therefore, oral ACEMg improves auditory function by limiting sensory hair cell death in the auditory receptor following NIHL. Regulation of the expression of antioxidant enzymes and apoptosis-related proteins in cochlear structures is involved in such an otoprotective mechanism.

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Mechanisms of hearing loss and cell death in the cochlea of connexin mutant mice

AJP Cell Physiology ◽

10.1152/ajpcell.00483.2019 ◽

2020 ◽

Vol 319 (3) ◽

pp. C569-C578

Author(s):

Bei Chen ◽

Hongen Xu ◽

Yanfang Mi ◽

Wei Jiang ◽

Dan Guo ◽

...

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

Hair Cell ◽

Stria Vascularis ◽

Reactive Oxygen Species Generation ◽

Cell Loss ◽

Outer Hair Cells ◽

Spiral Ligament ◽

Hair Cell Loss ◽

Auditory Brain Stem Response

Mutations in connexin 30 (Cx30) are known to cause severe congenital hearing impairment; however, the mechanism by which Cx30 mediates homeostasis of endocochlear gap junctions is unclear. We used a gene deletion mouse model to explore the mechanisms of Cx30 in preventing hearing loss. Our results suggest that despite severe loss of the auditory brain-stem response and endocochlear potential at postnatal day 18, Cx30−/− mice only show sporadic loss of the outer hair cells. This inconsistency in the time course and severity of hearing and hair cell losses in Cx30−/− mice might be explained, in part, by an increase in reactive oxygen species generation beginning at postnatal day 10. The expression of oxidative stress genes was increased in Cx30−/− mice in the stria vascularis, spiral ligament, and organ of Corti. Furthermore, Cx30 deficiency caused mitochondrial dysfunction at postnatal day 18, as assessed by decreased ATP levels and decreased expression of mitochondrial complex I proteins, especially in the stria vascularis. Proteomic analysis further identified 444 proteins that were dysregulated in Cx30−/− mice, including several that are involved in mitochondria electron transport, ATP synthesis, or ion transport. Additionally, proapoptotic proteins, including Bax, Bad, and caspase-3, were upregulated at postnatal day 18, providing a molecular basis to explain the loss of hearing that occurs before hair cell loss. Therefore, our results are consistent with an environment of oxidative stress and mitochondrial damage in the cochlea of Cx30−/− mice that is coincident with hearing loss but precedes hair cell loss.

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The quantitative relation between sensory cell loss and hearing thresholds

Hearing Research ◽

10.1016/0378-5955(89)90065-8 ◽

1989 ◽

Vol 38 (3) ◽

pp. 199-211 ◽

Cited By ~ 95

Author(s):

Roger P Hamernik ◽

James H Patterson ◽

George A Turrentine ◽

William A Ahroon

Keyword(s):

Sensory Cell ◽

Cell Loss ◽

Quantitative Relation ◽

Hearing Thresholds

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Relationship Between Hair Cell Loss and Hearing Loss in Fishes

The Effects of Noise on Aquatic Life II - Advances in Experimental Medicine and Biology ◽

10.1007/978-1-4939-2981-8_132 ◽

2016 ◽

pp. 1067-1074 ◽

Cited By ~ 3

Author(s):

Michael E. Smith

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Cell Loss ◽

Hair Cell Loss

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Novel QUEST MRI In Vivo Measurement of Noise-induced Oxidative Stress in the Cochlea

Scientific Reports ◽

10.1038/s41598-019-52439-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

André Kühl ◽

Angela Dixon ◽

Mirabela Hali ◽

Aaron K. Apawu ◽

Antonela Muca ◽

...

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

Cell Loss ◽

Hair Cell Loss ◽

Resonance Imaging ◽

In Vivo Measurement ◽

Anti Oxidant ◽

Individual Evaluation ◽

Excised Tissue

Abstract Effective personalized therapeutic treatment for hearing loss is currently not available. Cochlear oxidative stress is commonly identified in the pathogenesis of hearing loss based upon findings from excised tissue, thus suggesting a promising druggable etiology. However, the timing and site(s) to target for anti-oxidant treatment in vivo are not clear. Here, we address this long-standing problem with QUEnch-assiSTed Magnetic Resonance Imaging (QUEST MRI), which non-invasively measures excessive production of free radicals without an exogenous contrast agent. QUEST MRI is hypothesized to be sensitive to noise-evoked cochlear oxidative stress in vivo. Rats exposed to a loud noise event that resulted in hair cell loss and reduced hearing capability had a supra-normal MRI R1 value in their cochleae that could be corrected with anti-oxidants, thus non-invasively indicating cochlear oxidative stress. A gold-standard oxidative damage biomarker [heme oxidase 1 (HO-1)] supported the QUEST MRI result. The results from this study highlight QUEST MRI as a potentially transformative measurement of cochlear oxidative stress in vivo that can be used as a biomarker for improving individual evaluation of anti-oxidant treatment efficacy in currently incurable oxidative stress-based forms of hearing loss.

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Interaural correlations in normal and traumatized cochleas: Length and sensory cell loss

The Journal of the Acoustical Society of America ◽

10.1121/1.394285 ◽

1986 ◽

Vol 80 (6) ◽

pp. 1729-1736 ◽

Cited By ~ 26

Author(s):

Barbara A. Bohne ◽

Denyse G. Bozzay ◽

Gary W. Harding

Keyword(s):

Sensory Cell ◽

Cell Loss

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Loss of Myh14 Increases Susceptibility to Noise-Induced Hearing Loss in CBA/CaJ Mice

Neural Plasticity ◽

10.1155/2016/6720420 ◽

2016 ◽

Vol 2016 ◽

pp. 1-16 ◽

Cited By ~ 8

Author(s):

Xiaolong Fu ◽

Linqing Zhang ◽

Yecheng Jin ◽

Xiaoyang Sun ◽

Aizhen Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Outer Hair Cell ◽

Cell Loss ◽

Acoustic Trauma ◽

Noise Induced Hearing Loss ◽

Wild Type ◽

Auditory Function ◽

Susceptibility To Noise ◽

Susceptible Gene

MYH14 is a member of the myosin family, which has been implicated in many motile processes such as ion-channel gating, organelle translocation, and the cytoskeleton rearrangement. Mutations in MYH14 lead to a DFNA4-type hearing impairment. Further evidence also shows that MYH14 is a candidate noise-induced hearing loss (NIHL) susceptible gene. However, the specific roles of MYH14 in auditory function and NIHL are not fully understood. In the present study, we used CRISPR/Cas9 technology to establish a Myh14 knockout mice line in CBA/CaJ background (now referred to as Myh14−/−mice) and clarify the role of MYH14 in the cochlea and NIHL. We found that Myh14−/−mice did not exhibit significant hearing loss until five months of age. In addition, Myh14−/−mice were more vulnerable to high intensity noise compared to control mice. More significant outer hair cell loss was observed in Myh14−/−mice than in wild type controls after acoustic trauma. Our findings suggest that Myh14 may play a beneficial role in the protection of the cochlea after acoustic overstimulation in CBA/CaJ mice.

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