scholarly journals Toward Cochlear Therapies

2018 ◽  
Vol 98 (4) ◽  
pp. 2477-2522 ◽  
Author(s):  
Jing Wang ◽  
Jean-Luc Puel
Keyword(s):  
Spiral Ganglion ◽  
Industrialized Countries ◽  
Cell Degeneration ◽  
Age Related ◽  
Causative Factors ◽  
Sensorineural Hearing Impairment ◽  
Endogenous Protection ◽  
Mechanosensory Hair Cells ◽  
Ganglion Neurons ◽  
Age Related Hearing Loss

Sensorineural hearing impairment is the most common sensory disorder and a major health and socio-economic issue in industrialized countries. It is primarily due to the degeneration of mechanosensory hair cells and spiral ganglion neurons in the cochlea via complex pathophysiological mechanisms. These occur following acute and/or chronic exposure to harmful extrinsic (e.g., ototoxic drugs, noise...) and intrinsic (e.g., aging, genetic) causative factors. No clinical therapies currently exist to rescue the dying sensorineural cells or regenerate these cells once lost. Recent studies have, however, provided renewed hope, with insights into the therapeutic targets allowing the prevention and treatment of ototoxic drug- and noise-induced, age-related hearing loss as well as cochlear cell degeneration. Moreover, genetic routes involving the replacement or corrective editing of mutant sequences or defected genes are showing promise, as are cell-replacement therapies to repair damaged cells for the future restoration of hearing in deaf people. This review begins by recapitulating our current understanding of the molecular pathways that underlie cochlear sensorineural damage, as well as the survival signaling pathways that can provide endogenous protection and tissue rescue. It then guides the reader through to the recent discoveries in pharmacological, gene and cell therapy research towards hearing protection and restoration as well as their potential clinical application.

scholarly journals Oxidative Stresses and Mitochondrial Dysfunction in Age-Related Hearing Loss

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Chisato Fujimoto ◽  
Tatsuya Yamasoba
Keyword(s):  
Hearing Loss ◽  
Mitochondrial Dysfunction ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
The Elderly ◽  
Laboratory Animals ◽  
Age Related ◽  
Ganglion Neurons ◽  
Age Related Hearing Loss

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.

scholarly journals Biased Auditory Nerve Central Synaptopathy Exacerbates Age-related Hearing Loss

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.

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

Aging ◽  
2016 ◽  
Vol 8 (9) ◽  
pp. 2081-2099 ◽  
Author(s):  
Robert D. Frisina ◽  
Bo Ding ◽  
Xiaoxia Zhu ◽  
Joseph P. Walton
Keyword(s):  
Hearing Loss ◽  
Spiral Ganglion ◽  
Cell Loss ◽  
Spiral Ganglion Neurons ◽  
Loss Prevention ◽  
Age Related ◽  
Ganglion Neurons ◽  
Age Related Hearing Loss

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

BMC Biology ◽  
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.

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

2016 ◽  
Vol 21 (5) ◽  
pp. 326-332 ◽  
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.

Acid Phosphatase Activity in Spiral Ganglion Neurons of C57BL/6 Mice

1998 ◽  
Vol 4 (S2) ◽  
pp. 1104-1105
Author(s):  
Glenn M. Cohen
Keyword(s):  
Acid Phosphatase ◽  
Spiral Ganglion ◽  
Distribution Patterns ◽  
Electron Microscopic ◽  
Age Related ◽  
Sensory Hair Cells ◽  
Dense Deposits ◽  
Underlying Mechanisms ◽  
Ganglion Neurons ◽  
Marker Molecule

C57BL/6 mice, along with several other mouse genotypes, have served as models for human presbycusis (age-related hearing losses). C57BL/6 mice and their genetic substrain C57/M6 show progressively severe hearing losses, starting as early as 30 days postnatally. The hearing losses result from sweeping degeneration of sensory (hair) cells and neurons that begins in the basal end of the cochlea and advances apically. Although the underlying mechanisms orchestrating sensory and neural degeneration are not known, it is possible to correlate degenerative events with the cytoplasmic levels and distribution patterns of a marker molecule, such as acid phosphatase (AP). AP, a representative lysosomal enzyme, plays a role in both normal cellular metabolism and degenerative changes (trauma and senescence). AP activity is visualized histochemically at the light and electron microscopic levels by the presence of dense deposits within lysosomes.

scholarly journals Auditory responses evoked by optical stimulation on the optogenetic-infected cochlear neurons in the guinea pigs

2020 ◽  
Author(s):  
Chen Liu ◽  
Shu Fang ◽  
Da-xiong Ding ◽  
Han-dai Qin ◽  
Shuo-long Yuan ◽  
...  
Keyword(s):  
Cochlear Implants ◽  
Guinea Pigs ◽  
Spiral Ganglion ◽  
Acoustic Stimulation ◽  
Electrophysiological Recording ◽  
Gene Encoding ◽  
Auditory Responses ◽  
Sensorineural Hearing Impairment ◽  
Cochlear Neurons ◽  
Ganglion Neurons

AbstractCochlear implants (CIs) are by far the optimal option to partially restore hearing for the patients of sensorineural hearing impairment (HI) by electrically stimulating spiral ganglion neurons (SGNs). However, wide current spread from each electrode constitute an interface which restricts precision and quality of the electrical CIs. Recently, optogenetic stimulation of the cochlea has been proved as a more optimized approach via adeno-associated virus (AAV) carrying the gene encoding the light-sensitive channelrhodopsin-2. Here, we focus on summarizing recent work on stable and accurate ChR2 expression and compare the electrophysiological recording of optogenetic and acoustic stimulation in adult guinea pigs. Light stimulation generated auditory responses that was similar to that of acoustic stimulation. Moreover, normal hearing adult guinea pigs responded with a rise in amplitudes with increasing light intensity. In conclusion, optogenetic cochlear stimulation achieved good spectral selectivity of artificial sound encoding in a new adult rodent model, suggesting that the capabilities of optogenetics might be applied to improve cochlear implants in the future.

scholarly journals Local Macrophage-Related Immune Response Is Involved in Cochlear Epithelial Damage in Distinct Gjb2-Related Hereditary Deafness Models

2021 ◽  
Vol 8 ◽  
Author(s):  
Kai Xu ◽  
Sen Chen ◽  
Le Xie ◽  
Yue Qiu ◽  
Xue Bai ◽  
...  
Keyword(s):  
Immune Response ◽  
Spiral Ganglion ◽  
Null Model ◽  
Outer Hair Cells ◽  
Inflammatory Factors ◽  
Null Mouse ◽  
Cell Degeneration ◽  
Hereditary Deafness ◽  
Macrophage Recruitment ◽  
Ganglion Neurons

The macrophage-related immune response is an important component of the cochlear response to different exogenous stresses, including noise, ototoxic antibiotics, toxins, or viral infection. However, the role of the immune response in hereditary deafness caused by genetic mutations is rarely explored. GJB2, encoding connexin 26 (Cx26), is the most common deafness gene of hereditary deafness. In this study, two distinct Cx26-null mouse models were established to investigate the types and underlying mechanisms of immune responses. In a systemic Cx26-null model, macrophage recruitment was observed, associated with extensive cell degeneration of the cochlear epithelium. In a targeted-cell Cx26-null model, knockout of Cx26 was restricted to specific supporting cells (SCs), which led to preferential loss of local outer hair cells (OHCs). This local OHC loss can also induce a macrophage-related immune response. Common inflammatory factors, including TNF-α, IL-1β, Icam-1, Mif, Cx3cr1, Tlr4, Ccl2, and Ccr2, did not change significantly, while mRNA of Cx3cl1 was upregulated. Quantitative immunofluorescence showed that the protein expression of CX3CL1 in Deiters cells, a type of SC coupled with OHCs, increased significantly after OHC death. OHC loss caused the secondary death of spiral ganglion neurons (SGNs), while the remaining SGNs expressed high levels of CX3CL1 with infiltrated macrophages. Taken together, our results indicate that CX3CL1 signaling regulates macrophage recruitment and that enhancement of macrophage antigen-presenting function is associated with cell degeneration in Cx26-null mice.

scholarly journals No dramatic age-related loss of hair cells and spiral ganglion neurons in Bcl-2 over-expression mice or Bax null mice

2010 ◽  
Vol 5 (1) ◽  
pp. 28 ◽  
Author(s):  
Haiyan Shen ◽  
Jonathan I Matsui ◽  
Debin Lei ◽  
Lirong Han ◽  
Kevin K Ohlemiller ◽  
...  
Keyword(s):  
Hair Cells ◽  
Spiral Ganglion ◽  
Spiral Ganglion Neurons ◽  
Over Expression ◽  
Age Related ◽  
Ganglion Neurons
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