Age-Related Cochlear Synaptopathy: An Early-Onset Contributor to Auditory Functional Decline

Sergeyenko, Y.; Lall, Kumud; Liberman, M. Charles; Kujawa, Sharon G.

doi:10.1523/jneurosci.1783-13.2013

Cited by 665 publications

(844 citation statements)

References 72 publications

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“…We then fixed the tissue and stained for myosin VIIA, a commonly used immunochemical marker that is specifically expressed in HCs. [28][29][30][31][32] We consistently observed tdTomato-negative (dead) HCs that showed immunoreactivity for myosin VIIA ( Figure 6a). As our data indicate that loss of tdTomato is a reliable indicator of HC death, these tdTomato-negative/ myosin VIIA-positive HCs are corpses.…”

Section: Scs Constrict and Remove Hcs Killed By Neomycinmentioning

confidence: 77%

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

et al. 2015

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Hearing loss and balance disorders affect millions of people worldwide. Sensory transduction in the inner ear requires both mechanosensory hair cells (HCs) and surrounding glia-like supporting cells (SCs). HCs are susceptible to death from aging, noise overexposure, and treatment with therapeutic drugs that have ototoxic side effects; these ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic drug cisplatin. Although both classes of drugs are known to kill HCs, their effects on SCs are less well understood. Recent data indicate that SCs sense and respond to HC stress, and that their responses can influence HC death, survival, and phagocytosis. These responses to HC stress and death are critical to the health of the inner ear. Here we have used live confocal imaging of the adult mouse utricle, to examine the SC responses to HC death caused by aminoglycosides or cisplatin. Our data indicate that when HCs are killed by aminoglycosides, SCs efficiently remove HC corpses from the sensory epithelium in a process that includes constricting the apical portion of the HC after loss of membrane integrity. SCs then form a phagosome, which can completely engulf the remaining HC body, a phenomenon not previously reported in mammals. In contrast, cisplatin treatment results in accumulation of dead HCs in the sensory epithelium, accompanied by an increase in SC death. The surviving SCs constrict fewer HCs and display impaired phagocytosis. These data are supported by in vivo experiments, in which cochlear SCs show reduced capacity for scar formation in cisplatin-treated mice compared with those treated with aminoglycosides. Together, these data point to a broader defect in the ability of the cisplatin-treated SCs, to preserve tissue health in the mature mammalian inner ear. . 4 SCs perform many functions, including providing critical trophic factors, preventing excitotoxicity, and mediating regeneration in those systems (non-mammalian vertebrates) capable of replacing lost HCs. 5-11 When HCs die, SCs also preserve the integrity and function of the remaining tissue by forming scars and clearing dead HCs. 2,12-17 Maintaining a fluid barrier at the surface of the sensory epithelium after damage is necessary to preserve the electro-chemical gradient that drives HC depolarization and therefore sensory transduction after the onset of hearing (reviewed in Wangemann). 18 Several major stressors cause HC death, 19-22 including aging, noise trauma, and exposure to therapeutic drugs with ototoxic side effects. When a HC is killed by noise or aminoglycoside antibiotics, surrounding SCs form a filamentous actin (F-actin) cable that constricts the HC at its apex. 2,[12][13][14][15][16][17] This process separates the apical portion of the cell, including the stereocilia bundle, from the HC body and preserves a sealed reticular lamina. 23 In the chick utricle, following the apical constriction of dead HCs, the SCs engulf and phagocytose the remaining HC corpse. 15 Additional data from the chick indicate that the ototoxi...

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Section: Scs Constrict and Remove Hcs Killed By Neomycinmentioning

confidence: 77%

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

et al. 2015

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“…This suggests that ABR thresholds are largely independent of wave amplitudes and reflect only the minimum response rather than predicting the maximum capacity to respond. A recent study has also shown the reduction in ABR wave amplitudes with age, corresponding to the loss of synaptic strength in the auditory nerve and the number of spiral ganglion cells, much prior to changes seen in hearing thresholds (Sergeyenko et al 2013). Hence, the thresholds, which measure the lowest detectable level of activity, seem to be indicative of the sensitivity of level coding and detection of sound, while the ABR wave amplitudes, especially at peak response level, seem to be indicative of the number and synchronicity of the neurons in effectively representing these phasic stimuli at their highest capacity.…”

Section: Discussionmentioning

confidence: 93%

“…The ABR thresholds are an indicator of sound sensitivity, outer hair cell function, and the presence of a minimal number of functional auditory nerve synapses (Boettcher 2002;Kujawa and Liberman 2009;KonradMartin et al 2012). The ABR wave amplitudes are an indicator of overall auditory neuronal number and short-term synchrony of each generator and are a better predictor of peripheral synaptic function than ABR thresholds (Kujawa and Liberman 2009;Sergeyenko et al 2013). The FFRs and EFRs are an indicator of sustained temporal processing, emphasizing the functions of more central generators (Kuwada et al 2002;Parthasarathy and Bartlett 2012), given a normal or altered number of hair cells and ribbon synapses, and have been observed to be better predictors of speech perception in quiet and in noise (Anderson et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…In the periphery there is an observed decrease in the number and function of the hair cells in the cochlea leading to increased hearing thresholds (CHABA 1988) and widened auditory filters (CHABA 1988;Buckiova et al 2007;Chen et al 2009;Syka 2010) as well as a reduction in the endocochlear potential of the scala media (Mills et al 2006) and cochlear synaptic loss (Sergeyenko et. al 2013).…”

Section: Introductionmentioning

confidence: 99%

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Age-Related Changes in the Relationship Between Auditory Brainstem Responses and Envelope-Following Responses

Parthasarathy

Datta

Torres

et al. 2014

JARO

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Hearing thresholds and wave amplitudes measured using auditory brainstem responses (ABRs) to brief sounds are the predominantly used clinical measures to objectively assess auditory function. However, frequency-following responses (FFRs) to tonal carriers and to the modulation envelope (envelope-following responses or EFRs) to longer and spectro-temporally modulated stimuli are rapidly gaining prominence as a measure of complex sound processing in the brainstem and midbrain. In spite of numerous studies reporting changes in hearing thresholds, ABR wave amplitudes, and the FFRs and EFRs under neurodegenerative conditions, including aging, the relationships between these metrics are not clearly understood. In this study, the relationships between ABR thresholds, ABR wave amplitudes, and EFRs are explored in a rodent model of aging. ABRs to broadband click stimuli and EFRs to sinusoidally amplitude-modulated noise carriers were measured in young (3-6 months) and aged (22-25 months) Fischer-344 rats. ABR thresholds and amplitudes of the different waves as well as phase-locking amplitudes of EFRs were calculated. Age-related differences were observed in all these measures, primarily as increases in ABR thresholds and decreases in ABR wave amplitudes and EFR phaselocking capacity. There were no observed correlations between the ABR thresholds and the ABR wave amplitudes. Significant correlations between the EFR amplitudes and ABR wave amplitudes were observed across a range of modulation frequencies in the young. However, no such significant correlations were found in the aged. The aged click ABR amplitudes were found to be lower than would be predicted using a linear regression model of the young, suggesting altered gain mechanisms in the relationship between ABRs and FFRs with age. These results suggest that ABR thresholds, ABR wave amplitudes, and EFRs measure complementary aspects of overlapping neurophysiological processes and the relationships between these measurements changes asymmetrically with age. Hence, measuring all three metrics provides a more complete assessment of auditory function, especially under pathological conditions like aging.

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“…However, even in healthy animals reared in silence, presbycusis is still observed (Sergeyenko et al 2013;Yan et al 2013).…”

Section: Hearing Neuronsmentioning

confidence: 99%

Aging of perennial cells and organ parts according to the programmed aging paradigm

Libertini

Ferrara

2016

AGE

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If aging is a physiological phenomenon-as maintained by the programmed aging paradigm-it must be caused by specific genetically determined and regulated mechanisms, which must be confirmed by evidence. Within the programmed aging paradigm, a complete proposal starts from the observation that cells, tissues, and organs show continuous turnover: As telomere shortening determines both limits to cell replication and a progressive impairment of cellular functions, a progressive decline in age-related fitness decline (i.e., aging) is a clear consequence. Against this hypothesis, a critic might argue that there are cells (most types of neurons) and organ parts (crystalline core and tooth enamel) that have no turnover and are subject to wear or manifest alterations similar to those of cells with turnover. In this review, it is shown how cell types without turnover appear to be strictly dependent on cells subjected to turnover. The loss or weakening of the functions fulfilled by these cells with turnover, due to telomere shortening and turnover slowing, compromises the vitality of the served cells without turnover. This determines well-known clinical manifestations, which in their early forms are described as distinct diseases (e.g., Alzheimer's disease, Parkinson's disease, age-related macular degeneration, etc.). Moreover, for the two organ parts (crystalline core and tooth enamel) without viable cells or any cell turnover, it is discussed how this is entirely compatible with the programmed aging paradigm.

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Age-Related Cochlear Synaptopathy: An Early-Onset Contributor to Auditory Functional Decline

Cited by 665 publications

References 72 publications

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

Age-Related Changes in the Relationship Between Auditory Brainstem Responses and Envelope-Following Responses

Aging of perennial cells and organ parts according to the programmed aging paradigm

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