Age-related hearing loss: prevention of threshold declines, cell loss and apoptosis in spiral ganglion neurons

Age-related hearing loss (ARHL), the progressive loss of hearing associated with aging, is the most common sensory disorder in the elderly population. The pathology of ARHL includes the hair cells of the organ of Corti, stria vascularis, and afferent spiral ganglion neurons as well as the central auditory pathways. Many studies have suggested that the accumulation of mitochondrial DNA damage, the production of reactive oxygen species, and decreased antioxidant function are associated with subsequent cochlear senescence in response to aging stress. Mitochondria play a crucial role in the induction of intrinsic apoptosis in cochlear cells. ARHL can be prevented in laboratory animals by certain interventions, such as caloric restriction and supplementation with antioxidants. In this review, we will focus on previous research concerning the role of the oxidative stress and mitochondrial dysfunction in the pathology of ARHL in both animal models and humans and introduce concepts that have recently emerged regarding the mechanisms of the development of ARHL.

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Biased Auditory Nerve Central Synaptopathy Exacerbates Age-related Hearing Loss

10.1101/2020.06.09.142737 ◽

2020 ◽

Author(s):

Meijian Wang ◽

Chuangeng Zhang ◽

Shengyin Lin ◽

Yong Wang ◽

Benjamin J. Seicol ◽

...

Keyword(s):

Hearing Loss ◽

Auditory Processing ◽

Auditory Nerve ◽

Spiral Ganglion ◽

Central Auditory Processing ◽

Endbulb Of Held ◽

Age Related ◽

Central Synapses ◽

Ganglion Neurons ◽

Age Related Hearing Loss

SUMMARYSound information is transmitted from the cochlea to the brain by different subtypes of spiral ganglion neurons (SGN), which show varying degrees of vulnerbility under pathological conditions. It remains unclear how information from these SGNs reassemble among target neurons in the cochlear nucleus (CN) at the auditory nerve (AN) central synapses, and how different synapses change during hearing loss. Combining immunohistochemistry with electrophysiology, we investigated the giant endbulb of Held synapses and their postsynaptic bushy neurons in mice under normal hearing and age-related hearing loss (ARHL). We found that calretinin-expressing and non-calretinin-expressing endbulbs converge at continuously different ratios onto bushy neurons with varying physiological properties. Endbulbs degenerate during ARHL, and the degeneration is more severe in non-calretinin-expressing synapses, which correlates with a gradual decrease in neuronal subpopulation predominantly innervated by these inputs. Our findings suggest that biased AN central synaptopathy and shifted CN neuronal composition underlie reduced auditory input and altered central auditory processing during ARHL.

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Age-Related Hearing Loss in Mn-SOD Heterozygous Knockout Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/325702 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 22

Author(s):

Makoto Kinoshita ◽

Takashi Sakamoto ◽

Akinori Kashio ◽

Takahiko Shimizu ◽

Tatsuya Yamasoba

Keyword(s):

Hearing Loss ◽

Manganese Superoxide Dismutase ◽

Stria Vascularis ◽

Spiral Ganglion ◽

Cell Loss ◽

Auditory Brainstem ◽

Spiral Ganglion Cell ◽

Age Related ◽

Brainstem Response ◽

Age Related Hearing Loss

Age-related hearing loss (AHL) reduces the quality of life for many elderly individuals. Manganese superoxide dismutase (Mn-SOD), one of the antioxidant enzymes acting within the mitochondria, plays a crucial role in scavenging reactive oxygen species (ROS). To determine whether reduction in Mn-SOD accelerates AHL, we evaluated auditory function in Mn-SOD heterozygous knockout (HET) mice and their littermate wild-type (WT) C57BL/6 mice by means of auditory brainstem response (ABR). Mean ABR thresholds were significantly increased at 16 months when compared to those at 4 months in both WT and HET mice, but they did not significantly differ between them at either age. The extent of hair cell loss, spiral ganglion cell density, and thickness of the stria vascularis also did not differ between WT and HET mice at either age. At 16 months, immunoreactivity of 8-hydroxydeoxyguanosine was significantly greater in the SGC and SV in HET mice compared to WT mice, but that of 4-hydroxynonenal did not differ between them. These findings suggest that, although decrease of Mn-SOD by half may increase oxidative stress in the cochlea to some extent, it may not be sufficient to accelerate age-related cochlear damage under physiological aging process.

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Exacerbated age-related hearing loss in mice lacking the p43 mitochondrial T3 receptor

BMC Biology ◽

10.1186/s12915-021-00953-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Corentin Affortit ◽

François Casas ◽

Sabine Ladrech ◽

Jean-Charles Ceccato ◽

Jérôme Bourien ◽

...

Keyword(s):

Hearing Loss ◽

Spiral Ganglion ◽

Electrophysiological Recording ◽

Mitochondrial Activity ◽

P53 Expression ◽

Age Related ◽

Hearing Function ◽

Ganglion Neurons ◽

Age Related Hearing Loss

Abstract Background Age-related hearing loss (ARHL), also known as presbycusis, is the most common sensory impairment seen in elderly people. However, the cochlear aging process does not affect people uniformly, suggesting that both genetic and environmental (e.g., noise, ototoxic drugs) factors and their interaction may influence the onset and severity of ARHL. Considering the potential links between thyroid hormone, mitochondrial activity, and hearing, here, we probed the role of p43, a N-terminally truncated and ligand-binding form of the nuclear receptor TRα1, in hearing function and in the maintenance of hearing during aging in p43−/− mice through complementary approaches, including in vivo electrophysiological recording, ultrastructural assessments, biochemistry, and molecular biology. Results We found that the p43−/− mice exhibit no obvious hearing loss in juvenile stages, but that these mice developed a premature, and more severe, ARHL resulting from the loss of cochlear sensory outer and inner hair cells and degeneration of spiral ganglion neurons. Exacerbated ARHL in p43−/− mice was associated with the early occurrence of a drastic fall of SIRT1 expression, together with an imbalance between pro-apoptotic Bax, p53 expression, and anti-apoptotic Bcl2 expression, as well as an increase in mitochondrial dysfunction, oxidative stress, and inflammatory process. Finally, p43−/− mice were also more vulnerable to noise-induced hearing loss. Conclusions These results demonstrate for the first time a requirement for p43 in the maintenance of hearing during aging and highlight the need to probe the potential link between human THRA gene polymorphisms and/or mutations and accelerated age-related deafness or some adult-onset syndromic deafness.

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Differential Expression of Bcl-2 in the Cochlea and Auditory Cortex of a Mouse Model of Age-Related Hearing Loss

Audiology and Neurotology ◽

10.1159/000450937 ◽

2016 ◽

Vol 21 (5) ◽

pp. 326-332 ◽

Cited By ~ 5

Author(s):

Qiuhong Huang ◽

Hao Xiong ◽

Haidi Yang ◽

Yongkang Ou ◽

Zhigang Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Mouse Model ◽

Auditory Cortex ◽

Hair Cells ◽

Spiral Ganglion ◽

Outer Hair Cells ◽

Protective Effects ◽

Age Related ◽

Ganglion Neurons ◽

Age Related Hearing Loss

Bcl-2, the first gene shown to be involved in apoptosis, is a potent regulator of cell survival and known to have protective effects against a variety of age-related diseases. However, the possible relationship between hearing and Bcl-2 expression in the cochlea or auditory cortex of C57BL/6 mice, a mouse model of age-related hearing loss, is still unknown. Using RT-PCR, immunohistochemistry, and Western blot analysis, our results show that Bcl-2 is strongly expressed in the inner hair cells and spiral ganglion neurons of young mice. In addition, moderate Bcl-2 expression is also detected in the outer hair cells and in the neurons of the auditory cortex. A significant reduction of Bcl-2 expression in the cochlea or auditory cortex is also associated with elevated hearing thresholds and hair cell loss during aging. The expression pattern of Bcl-2 in the peripheral and central auditory systems suggests that Bcl-2 may play an important role in auditory function serving as a protective molecule against age-related hearing loss.

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MCMV triggers ROS/NLRP3-associated inflammasome activation in the inner ear of mice and cultured spiral ganglion neurons, contributing to sensorineural hearing loss

International Journal of Molecular Medicine ◽

10.3892/ijmm.2018.3539 ◽

2018 ◽

Cited By ~ 5

Author(s):

Wei Zhuang ◽

Caiji Wang ◽

Xi Shi ◽

Shiwei Qiu ◽

Shili Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Inner Ear ◽

Spiral Ganglion ◽

Sensorineural Hearing ◽

Inflammasome Activation ◽

Spiral Ganglion Neurons ◽

Ganglion Neurons

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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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Spatiotemporal Developmental Upregulation of Prestin Correlates With the Severity and Location of Cyclodextrin-Induced Outer Hair Cell Loss and Hearing Loss

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.643709 ◽

2021 ◽

Vol 9 ◽

Author(s):

Dalian Ding ◽

Haiyan Jiang ◽

Senthilvelan Manohar ◽

Xiaopeng Liu ◽

Li Li ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cells ◽

Auditory Nerve ◽

High Frequency ◽

Spiral Ganglion ◽

Low Frequency ◽

Nerve Fibers ◽

Spiral Ganglion Neurons ◽

Auditory Nerve Fibers ◽

Ganglion Neurons

2-Hyroxypropyl-beta-cyclodextrin (HPβCD) is being used to treat Niemann-Pick C1, a fatal neurodegenerative disease caused by abnormal cholesterol metabolism. HPβCD slows disease progression, but unfortunately causes severe, rapid onset hearing loss by destroying the outer hair cells (OHC). HPβCD-induced damage is believed to be related to the expression of prestin in OHCs. Because prestin is postnatally upregulated from the cochlear base toward the apex, we hypothesized that HPβCD ototoxicity would spread from the high-frequency base toward the low-frequency apex of the cochlea. Consistent with this hypothesis, cochlear hearing impairments and OHC loss rapidly spread from the high-frequency base toward the low-frequency apex of the cochlea when HPβCD administration shifted from postnatal day 3 (P3) to P28. HPβCD-induced histopathologies were initially confined to the OHCs, but between 4- and 6-weeks post-treatment, there was an unexpected, rapid and massive expansion of the lesion to include most inner hair cells (IHC), pillar cells (PC), peripheral auditory nerve fibers, and spiral ganglion neurons at location where OHCs were missing. The magnitude and spatial extent of HPβCD-induced OHC death was tightly correlated with the postnatal day when HPβCD was administered which coincided with the spatiotemporal upregulation of prestin in OHCs. A second, massive wave of degeneration involving IHCs, PC, auditory nerve fibers and spiral ganglion neurons abruptly emerged 4–6 weeks post-HPβCD treatment. This secondary wave of degeneration combined with the initial OHC loss results in a profound, irreversible hearing loss.

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Caffeine Induces Autophagy and Apoptosis in Auditory Hair Cells via the SGK1/HIF-1α Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.751012 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xiaomin Tang ◽

Yuxuan Sun ◽

Chenyu Xu ◽

Xiaotao Guo ◽

Jiaqiang Sun ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cells ◽

Stria Vascularis ◽

Spiral Ganglion ◽

Organ Of Corti ◽

Spiral Ganglion Neurons ◽

Auditory Hair Cells ◽

Qrt Pcr ◽

Ganglion Neurons

Caffeine is being increasingly used in daily life, such as in drinks, cosmetics, and medicine. Caffeine is known as a mild stimulant of the central nervous system, which is also closely related to neurologic disease. However, it is unknown whether caffeine causes hearing loss, and there is great interest in determining the effect of caffeine in cochlear hair cells. First, we explored the difference in auditory brainstem response (ABR), organ of Corti, stria vascularis, and spiral ganglion neurons between the control and caffeine-treated groups of C57BL/6 mice. RNA sequencing was conducted to profile mRNA expression differences in the cochlea of control and caffeine-treated mice. A CCK-8 assay was used to evaluate the approximate concentration of caffeine. Flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting were performed to detect the effects of SGK1 in HEI-OC1 cells and basilar membranes. In vivo research showed that 120 mg/ kg caffeine injection caused hearing loss by damaging the organ of Corti, stria vascularis, and spiral ganglion neurons. RNA-seq results suggested that SGK1 might play a vital role in ototoxicity. To confirm our observations in vitro, we used the HEI-OC1 cell line, a cochlear hair cell-like cell line, to investigate the role of caffeine in hearing loss. The results of flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting showed that caffeine caused autophagy and apoptosis via SGK1 pathway. We verified the interaction between SGK1 and HIF-1α by co-IP. To confirm the role of SGK1 and HIF-1α, GSK650394 was used as an inhibitor of SGK1 and CoCl2 was used as an inducer of HIF-1α. Western blot analysis suggested that GSK650394 and CoCl2 relieved the caffeine-induced apoptosis and autophagy. Together, these results indicated that caffeine induces autophagy and apoptosis in auditory hair cells via the SGK1/HIF-1α pathway, suggesting that caffeine may cause hearing loss. Additionally, our findings provided new insights into ototoxic drugs, demonstrating that SGK1 and its downstream pathways may be potential therapeutic targets for hearing research at the molecular level.

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