Auditory sensitivity and the outer hair cell system in the CBA mouse model of age-related hearing loss

Age-related hearing loss (ARHL) is the most common sensory deficit in aging society, which is accompanied by increased speech discrimination difficulties in noisy environments, social isolation, and cognitive decline. The audiometric degree of ARHL is largely correlated with sensory hair cell loss in addition to age-related factors not captured by histopathological analysis of the human cochlea. Previous studies have identified the senescence-accelerated mouse prone strain 8 (SAMP8) as a model for studying ARHL and age-related modifications of the cochlear redox environment. However, the SAMP8 population exhibits a large variability in auditory function decline over age, whose underlying cause remains unknown. In this study, we analyzed auditory function of SAMP8 mice by measuring auditory brainstem response (ABR) thresholds at the age of 6 weeks (juvenile), 12 weeks (young adult), and 24 weeks (adult). Consistent with previous studies, SAMP8 mice exhibit an early progressive, age-related decline of hearing acuity. However, a spatiotemporal cytohistological analysis showed that the significant increase in threshold variability was not concurrently reflected in outer hair cell (OHC) loss observed in the lower and upper quartiles of the ABR threshold distributions over age. This functional loss was found to precede OHC loss suggesting that age-related phenotypic changes may be contributing factors not represented in cytohistological analysis. The expression of potassium channels KCNQ4 (KV7.4), which mediates the current IK,n crucial for the maintenance of OHC membrane potential, and KCNQ1 (KV7.1), which is an essential component in potassium circulation and secretion into the endolymph generating the endocochlear potential, showed differences between these quartiles and age groups. This suggests that phenotypic changes in OHCs or the stria vascularis due to variable oxidative deficiencies in individual mice may be predictors of the observed threshold variability in SAMP8 mice and their progressive ARHL. In future studies, further phenotypic predictors affected by accumulated metabolic challenges over age need to be investigated as potentially underlying causes of ARHL preceding irreversible OHC loss in the SAMP8 mouse model.

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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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Inhibition of DRP-1-Dependent Mitophagy Promotes Cochlea Hair Cell Senescence and Exacerbates Age-Related Hearing Loss

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2019.00550 ◽

2019 ◽

Vol 13 ◽

Cited By ~ 4

Author(s):

Hanqing Lin ◽

Hao Xiong ◽

Zhongwu Su ◽

Jiaqi Pang ◽

Lan Lai ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Cell Senescence ◽

Age Related ◽

Age Related Hearing Loss

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

10.1101/2020.06.05.136184 ◽

2020 ◽

Cited By ~ 2

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.

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N-acetylcysteine Treatment Reduces Age-related Hearing Loss and Memory Impairment in the Senescence-Accelerated Prone 8 (SAMP8) Mouse Model

Aging and Disease ◽

10.14336/ad.2017.0930 ◽

2018 ◽

Vol 9 (4) ◽

pp. 664 ◽

Cited By ~ 7

Author(s):

Aurore Marie ◽

Johann Meunier ◽

Emilie Brun ◽

Susanna Malmstrom ◽

Veronique Baudoux ◽

...

Keyword(s):

Hearing Loss ◽

Mouse Model ◽

Memory Impairment ◽

Samp8 Mouse ◽

Age Related ◽

Age Related Hearing Loss

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Hair Cell Damage Tied to Age-Related Hearing Loss

Leader Mag Digital Object Group ◽

10.1044/leader.rib2.25102020.17 ◽

2020 ◽

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Cell Damage ◽

Age Related ◽

Hair Cell Damage ◽

Age Related Hearing Loss

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miR-29b overexpression induces cochlear hair cell apoptosis through the regulation of SIRT1/PGC-1α signaling: Implications for age-related hearing loss

International Journal of Molecular Medicine ◽

10.3892/ijmm.2016.2735 ◽

2016 ◽

Vol 38 (5) ◽

pp. 1387-1394 ◽

Cited By ~ 18

Author(s):

Tao Xue ◽

Li Wei ◽

Ding-Jun Zha ◽

Jian-Hua Qiu ◽

Fu-Quan Chen ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Cell Apoptosis ◽

Cochlear Hair Cell ◽

Age Related ◽

Age Related Hearing Loss

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Rapamycin Added to Diet in Late Mid-Life Delays Age-Related Hearing Loss in UMHET4 Mice

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.658972 ◽

2021 ◽

Vol 15 ◽

Author(s):

Richard A. Altschuler ◽

Lisa Kabara ◽

Catherine Martin ◽

Ariane Kanicki ◽

Courtney E. Stewart ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Outer Hair Cell ◽

Control Diet ◽

Cell Loss ◽

Diet Group ◽

Age Related ◽

Significant Difference ◽

Basal Half ◽

And Control

Our previous study demonstrated rapamycin added to diet at 4 months of age had significantly less age-related outer hair cell loss in the basal half of the cochlea at 22 months of age compared to mice without rapamycin. The present study tested adding rapamycin to diet later in life, at 14 months of age, and added a longitudinal assessment of auditory brain stem response (ABR). The present study used UMHET4 mice, a 4 way cross in which all grandparental strains lack the Cdh23753A allele that predisposes to early onset, progressive hearing loss. UMHET4 mice typically have normal hearing until 16–17 months, then exhibit threshold shifts at low frequencies/apical cochlea and later in more basal high frequency regions. ABR thresholds at 4, 12, 24, and 48 kHz were assessed at 12, 18, and 24 months of age and compared to baseline ABR thresholds acquired at 5 months of age to determine threshold shifts (TS). There was no TS at 12 months of age at any frequency tested. At 18 months of age mice with rapamycin added to diet at 14 months had a significantly lower mean TS at 4 and 12 kHz compared to mice on control diet with no significant difference at 24 and 48 kHz. At 24 months of age, the mean 4 kHz TS in rapamycin diet group was no longer significantly lower than the control diet group, while the 12 kHz mean remained significantly lower. Mean TS at 24 and 48 kHz in the rapamycin diet group became significantly lower than in the control diet group at 24 months. Hair cell counts at 24 months showed large loss in the apical half of most rapamycin and control diet mice cochleae with no significant difference between groups. There was only mild outer hair cell loss in the basal half of rapamycin and control diet mice cochleae with no significant difference between groups. The results show that a later life addition of rapamycin can decrease age-related hearing loss in the mouse model, however, it also suggests that this decrease is a delay/deceleration rather than a complete prevention.

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