Translating animal models to human therapeutics in noise-induced and age-related hearing loss

Kujawa, Sharon G.; Liberman, M. Charles

doi:10.1016/j.heares.2019.03.003

Cited by 87 publications

(54 citation statements)

References 95 publications

(134 reference statements)

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“…It has been shown in humans that the longitudinal gradients of age-related OHC loss are complementary to those of the cochlear projections from the MOC system (82). Several reports have described that the density of MOC terminals on OHCs peaks at the middle region of the cochlea (83)(84)(85) and that there is an age-related decline during aging (46)(47)(48)(49)(50). Moreover, as the mouse ages, there are significant changes in the efficiency of the MOC suppression mechanism as elicited by contralateral narrowband stimuli, reinforcing the idea that age-related changes in the MOC or the operating points of OHCs might play a role in the progression of presbycusis in mammals (46)(47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Preventing presbycusis in mice with enhanced medial olivocochlear feedback

Boero

Castagna

Terreros

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“Growing old” is the most common cause of hearing loss. Age-related hearing loss (ARHL) (presbycusis) first affects the ability to understand speech in background noise, even when auditory thresholds in quiet are normal. It has been suggested that cochlear denervation (“synaptopathy”) is an early contributor to age-related auditory decline. In the present work, we characterized age-related cochlear synaptic degeneration and hair cell loss in mice with enhanced α9α10 cholinergic nicotinic receptors gating kinetics (“gain of function” nAChRs). These mediate inhibitory olivocochlear feedback through the activation of associated calcium-gated potassium channels. Cochlear function was assessed via distortion product otoacoustic emissions and auditory brainstem responses. Cochlear structure was characterized in immunolabeled organ of Corti whole mounts using confocal microscopy to quantify hair cells, auditory neurons, presynaptic ribbons, and postsynaptic glutamate receptors. Aged wild-type mice had elevated acoustic thresholds and synaptic loss. Afferent synapses were lost from inner hair cells throughout the aged cochlea, together with some loss of outer hair cells. In contrast, cochlear structure and function were preserved in aged mice with gain-of-function nAChRs that provide enhanced olivocochlear inhibition, suggesting that efferent feedback is important for long-term maintenance of inner ear function. Our work provides evidence that olivocochlear-mediated resistance to presbycusis-ARHL occurs via the α9α10 nAChR complexes on outer hair cells. Thus, enhancement of the medial olivocochlear system could be a viable strategy to prevent age-related hearing loss.

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Section: Discussionmentioning

confidence: 99%

Preventing presbycusis in mice with enhanced medial olivocochlear feedback

Boero

Castagna

Terreros

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…It is possible that the type of noise exposure would affect the impact of noise exposure on fMRI responses, but there is limited information at present about what spectrotemporal features of a sound exposure have the greatest damaging impact on high-threshold auditory nerve fibers. There is relatively recent animal data strongly suggesting that equal energy exposure produces similar synapse loss across different exposure durations (Kujawa, 2019). Therefore, total energy of exposure is thought to be key to inducing a given level of synaptopathy, i.e.…”

Section: Discussionmentioning

confidence: 99%

The association between subcortical and cortical fMRI and lifetime noise exposure in listeners with normal hearing thresholds

et al. 2020

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In animal models, exposure to high noise levels can cause permanent damage to hair-cell synapses (cochlear synaptopathy) for high-threshold auditory nerve fibers without affecting sensitivity to quiet sounds. This has been confirmed in several mammalian species, but the hypothesis that lifetime noise exposure affects auditory function in humans with normal audiometric thresholds remains unconfirmed and current evidence from human electrophysiology is contradictory. Here we report the auditory brainstem response (ABR), and both transient (stimulus onset and offset) and sustained functional magnetic resonance imaging (fMRI) responses throughout the human central auditory pathway across lifetime noise exposure. Healthy young individuals aged 25–40 years were recruited into high (n = 32) and low (n = 30) lifetime noise exposure groups, stratified for age, and balanced for audiometric threshold up to 16 kHz fMRI demonstrated robust broadband noise-related activity throughout the auditory pathway (cochlear nucleus, superior olivary complex, nucleus of the lateral lemniscus, inferior colliculus, medial geniculate body and auditory cortex). fMRI responses in the auditory pathway to broadband noise onset were significantly enhanced in the high noise exposure group relative to the low exposure group, differences in sustained fMRI responses did not reach significance, and no significant group differences were found in the click-evoked ABR. Exploratory analyses found no significant relationships between the neural responses and self-reported tinnitus or reduced sound-level tolerance (symptoms associated with synaptopathy). In summary, although a small effect, these fMRI results suggest that lifetime noise exposure may be associated with central hyperactivity in young adults with normal hearing thresholds.

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“…Recent work in animal models has clearly established the concept of hidden hearing loss, at least for noise-induced hearing loss, whereby animals with normal hearing thresholds have widespread cochlear synaptopathy of small SGN afferent fibers with intact hair cell populations (Kujawa & Liberman, 2019). Interestingly, the use of high-frequency audiograms (up to 16 kHz) may be useful to monitor hidden hearing loss in humans (Liberman, Epstein, Cleveland, Wang, & Maison, 2016).…”

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confidence: 99%

Evidence for independent peripheral and central age‐related hearing impairment

Bao

et al. 2020

J of Neuroscience Research

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Deleterious age‐related changes in the central auditory nervous system have been referred to as central age‐related hearing impairment (ARHI) or central presbycusis. Central ARHI is often assumed to be the consequence of peripheral ARHI. However, it is possible that certain aspects of central ARHI are independent from peripheral ARHI. A confirmation of this possibility could lead to significant improvements in current rehabilitation practices. The major difficulty in addressing this issue arises from confounding factors, such as other age‐related changes in both the cochlea and central non‐auditory brain structures. Because gap detection is a common measure of central auditory temporal processing, and gap detection thresholds are less influenced by changes in other brain functions such as learning and memory, we investigated the potential relationship between age‐related peripheral hearing loss (i.e., audiograms) and age‐related changes in gap detection. Consistent with previous studies, a significant difference was found for gap detection thresholds between young and older adults. However, among older adults, no significant associations were observed between gap detection ability and several other independent variables including the pure tone audiogram average, the Wechsler Adult Intelligence Scale‐Vocabulary score, gender, and age. Statistical analyses showed little or no contributions from these independent variables to gap detection thresholds. Thus, our data indicate that age‐related decline in central temporal processing is largely independent of peripheral ARHI.

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Translating animal models to human therapeutics in noise-induced and age-related hearing loss

Cited by 87 publications

References 95 publications

Preventing presbycusis in mice with enhanced medial olivocochlear feedback

Preventing presbycusis in mice with enhanced medial olivocochlear feedback

The association between subcortical and cortical fMRI and lifetime noise exposure in listeners with normal hearing thresholds

Evidence for independent peripheral and central age‐related hearing impairment

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