scholarly journals The integrity of cochlear hair cells is established and maintained through the localization of Dia1 at apical junctional complexes and stereocilia

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Yuzuru Ninoyu ◽  
Hirofumi Sakaguchi ◽  
Chen Lin ◽  
Toshiaki Suzuki ◽  
Shigeru Hirano ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Noise Exposure ◽  
Spiral Ganglion ◽  
Cell Junctions ◽  
Ultrastructural Changes ◽  
Apical Surface ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Junctional Complexes

AbstractDia1, which belongs to the diaphanous-related formin family, influences a variety of cellular processes through straight actin elongation activity. Recently, novel DIA1 mutants such as p.R1213X (p.R1204X) and p.A265S, have been reported to cause an autosomal dominant sensorineural hearing loss (DFNA1). Additionally, active DIA1 mutants induce progressive hearing loss in a gain-of-function manner. However, the subcellular localization and pathological function of DIA1(R1213X/R1204X) remains unknown. In the present study, we demonstrated the localization of endogenous Dia1 and the constitutively active DIA1 mutant in the cochlea, using transgenic mice expressing FLAG-tagged DIA1(R1204X) (DIA1-TG). Endogenous Dia1 and the DIA1 mutant were regionally expressed at the organ of Corti and the spiral ganglion from early life; alongside cochlear maturation, they became localized at the apical junctional complexes (AJCs) between hair cells (HCs) and supporting cells (SCs). To investigate HC vulnerability in the DIA1-TG mice, we exposed 4-week-old mice to moderate noise, which induced temporary threshold shifts with cochlear synaptopathy and ultrastructural changes in stereocilia 4 weeks post noise exposure. Furthermore, we established a knock-in (KI) mouse line expressing AcGFP-tagged DIA1(R1213X) (DIA1-KI) and confirmed mutant localization at AJCs and the tips of stereocilia in HCs. In MDCKAcGFP-DIA1(R1213X) cells with stable expression of AcGFP-DIA1(R1213X), AcGFP-DIA1(R1213X) revealed marked localization at microvilli on the apical surface of cells and decreased localization at cell-cell junctions. The DIA1-TG mice demonstrated hazy and ruffled circumferential actin belts at AJCs and abnormal stereocilia accompanied with HC loss at 5 months of age. In conclusion, Dia1 plays a pivotal role in the development and maintenance of AJCs and stereocilia, ensuring cochlear and HC integrity. Subclinical/latent vulnerability of HCs may be the cause of progressive hearing loss in DFNA1 patients, thus suggesting new therapeutic targets for preventing HC degeneration and progressive hearing loss associated with DFNA1.

scholarly journals Effects of cochlear hair cell ablation on spatial learning/memory

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Z. Jason Qian ◽  
Anthony J. Ricci
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Spatial Learning ◽  
Hair Cells ◽  
Noise Exposure ◽  
Memory Errors ◽  
Cochlear Hair Cells ◽  
Cochlear Hair Cell ◽  
Cell Ablation ◽  
Spatial Learning Memory

AbstractCurrent clinical interest lies in the relationship between hearing loss and cognitive impairment. Previous work demonstrated that noise exposure, a common cause of sensorineural hearing loss (SNHL), leads to cognitive impairments in mice. However, in noise-induced models, it is difficult to distinguish the effects of noise trauma from subsequent SNHL on central processes. Here, we use cochlear hair cell ablation to isolate the effects of SNHL. Cochlear hair cells were conditionally and selectively ablated in mature, transgenic mice where the human diphtheria toxin (DT) receptor was expressed behind the hair-cell specific Pou4f3 promoter. Due to higher Pou4f3 expression in cochlear hair cells than vestibular hair cells, administration of a low dose of DT caused profound SNHL without vestibular dysfunction and had no effect on wild-type (WT) littermates. Spatial learning/memory was assayed using an automated radial 8-arm maze (RAM), where mice were trained to find food rewards over a 14-day period. The number of working memory errors (WME) and reference memory errors (RME) per training day were recorded. All animals were injected with DT during P30–60 and underwent the RAM assay during P90–120. SNHL animals committed more WME and RME than WT animals, demonstrating that isolated SNHL affected cognitive function. Duration of SNHL (60 versus 90 days post DT injection) had no effect on RAM performance. However, younger age of acquired SNHL (DT on P30 versus P60) was associated with fewer WME. This describes the previously undocumented effect of isolated SNHL on cognitive processes that do not directly rely on auditory sensory input.

scholarly journals Deletion of Tricellulin Causes Progressive Hearing Loss Associated with Degeneration of Cochlear Hair Cells

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Toru Kamitani ◽  
Hirofumi Sakaguchi ◽  
Atsushi Tamura ◽  
Takenori Miyashita ◽  
Yuji Yamazaki ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells

scholarly journals Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Pengcheng Xu ◽  
Longhao Wang ◽  
Hu Peng ◽  
Huihui Liu ◽  
Hongchao Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Mitochondrial Dysfunction ◽  
Hair Cells ◽  
Cell Loss ◽  
Outer Hair Cells ◽  
Hair Cell Loss ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Inner Hair Cells

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

scholarly journals Autophagy Regulates the Survival of Hair Cells and Spiral Ganglion Neurons in Cases of Noise, Ototoxic Drug, and Age-Induced Sensorineural Hearing Loss

2021 ◽  
Vol 15 ◽  
Author(s):  
Lingna Guo ◽  
Wei Cao ◽  
Yuguang Niu ◽  
Shuangba He ◽  
Renjie Chai ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Noise Exposure ◽  
Spiral Ganglion ◽  
Sensorineural Hearing ◽  
Spiral Ganglion Neurons ◽  
Core Components ◽  
Spontaneous Regeneration ◽  
Ganglion Neurons

Inner ear hair cells (HCs) and spiral ganglion neurons (SGNs) are the core components of the auditory system. However, they are vulnerable to genetic defects, noise exposure, ototoxic drugs and aging, and loss or damage of HCs and SGNs results in permanent hearing loss due to their limited capacity for spontaneous regeneration in mammals. Many efforts have been made to combat hearing loss including cochlear implants, HC regeneration, gene therapy, and antioxidant drugs. Here we review the role of autophagy in sensorineural hearing loss and the potential targets related to autophagy for the treatment of hearing loss.

scholarly journals Transcription Co-Factor LBH Is Necessary for Maintenance of Stereocilia Bundles and Survival of Cochlear Hair Cells

2020 ◽  
Author(s):  
Huizhan Liu ◽  
Kimberlee P. Giffen ◽  
Grati M’Hamed ◽  
Seth W. Morrill ◽  
Yi Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Molecular Mechanisms ◽  
Notch Pathway ◽  
Outer Hair Cells ◽  
Limb Bud ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Significant Gene ◽  
Critical Requirement

AbstractHearing loss affects ~10% of adults worldwide and is irreversible. Most sensorineural hearing loss is caused by progressive loss of mechanosensitive hair cells (HCs) in the cochlea of the inner ear. The molecular mechanisms underlying HC maintenance and loss are largely unknown. Our previous cell-specific transcriptome analysis showed that Limb-Bud-and-Heart (LBH), a transcription co-factor implicated in development, is abundantly expressed in outer hair cells (OHCs). We used Lbh-null mice to identify its role. Surprisingly, Lbh deletion did not affect differentiation and early development of HCs, as nascent HCs in Lbh knockout mice had normal looking stereocilia bundles. Whole-cell recording showed that the stereocilia bundle was mechanosensitive and OHCs exhibited the characteristic electromotility. However, Lbh-null mice displayed progressive hearing loss, with stereocilia bundle degeneration and OHC loss as early as postnatal day 12. Cell-specific RNA-seq and bioinformatic analyses identified Spp1, Six2, Gps2, Ercc6, Snx6 as well as Plscr1, Rarb, Per2, Gmnn and Map3k5 among the top five transcription factors up- or down-regulated in Lbh-null OHCs. Furthermore, this analysis showed significant gene enrichment of biological processes related to transcriptional regulation, cell cycle, DNA damage/repair and autophagy. In addition, Wnt and Notch pathway-related genes were found to be dysregulated in Lbh-deficient OHCs. We speculate that LBH may promote maintenance of HCs and stereocilia bundles by regulating Notch and Wnt signaling activity. Our study implicates, for the first time, loss of LBH function in progressive hearing loss, and demonstrates a critical requirement of LBH in promoting HC survival.

scholarly journals Transcription co-factor LBH is necessary for the survival of cochlear hair cells

2021 ◽  
Vol 134 (7) ◽  
Author(s):  
Huizhan Liu ◽  
Kimberlee P. Giffen ◽  
M'Hamed Grati ◽  
Seth W. Morrill ◽  
Yi Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Molecular Mechanisms ◽  
Notch Pathway ◽  
Outer Hair Cells ◽  
Progressive Hearing Loss ◽  
Cochlear Hair Cells ◽  
Adult Mice ◽  
Significant Gene ◽  
Critical Requirement

ABSTRACT Hearing loss affects ∼10% of adults worldwide. Most sensorineural hearing loss is caused by the progressive loss of mechanosensitive hair cells (HCs) in the cochlea. The molecular mechanisms underlying HC maintenance and loss remain poorly understood. LBH, a transcription co-factor implicated in development, is abundantly expressed in outer hair cells (OHCs). We used Lbh-null mice to identify its role in HCs. Surprisingly, Lbh deletion did not affect differentiation and the early development of HCs, as nascent HCs in Lbh knockout mice had normal looking stereocilia. The stereocilia bundle was mechanosensitive and OHCs exhibited the characteristic electromotility. However, Lbh-null mice displayed progressive hearing loss, with stereocilia bundle degeneration and OHC loss as early as postnatal day 12. RNA-seq analysis showed significant gene enrichment of biological processes related to transcriptional regulation, cell cycle, DNA damage/repair and autophagy in Lbh-null OHCs. In addition, Wnt and Notch pathway-related genes were found to be dysregulated in Lbh-deficient OHCs. Our study implicates, for the first time, loss of LBH function in progressive hearing loss, and demonstrates a critical requirement of LBH in promoting HC survival in adult mice.

scholarly journals Age-Related Hearing Loss and Degeneration of Cochlear Hair Cells in Mice Lacking Thyroid Hormone Receptor β1

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3853-3865 ◽  
Author(s):  
Lily Ng ◽  
Emily Cordas ◽  
Xuefeng Wu ◽  
Kristen R. Vella ◽  
Anthony N. Hollenberg ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Thyroid Hormone ◽  
Hair Cells ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Spiral Ganglion ◽  
Spiral Ligament ◽  
Root Cells ◽  
Cochlear Hair Cells ◽  
Age Related

A key function of the thyroid hormone receptor β (Thrb) gene is in the development of auditory function. However, the roles of the 2 receptor isoforms, TRβ1 and TRβ2, expressed by the Thrb gene are unclear, and it is unknown whether these isoforms promote the maintenance as well as development of hearing. We investigated the function of TRβ1 in mice with a Thrbb1 reporter allele that expresses β-galactosidase instead of TRβ1. In the immature cochlea, β-galactosidase was detected in the greater epithelial ridge, sensory hair cells, spiral ligament, and spiral ganglion and in adulthood, at low levels in the hair cells, support cells and root cells of the outer sulcus. Although deletion of all TRβ isoforms causes severe, early-onset deafness, deletion of TRβ1 or TRβ2 individually caused no obvious hearing loss in juvenile mice. However, over subsequent months, TRβ1 deficiency resulted in progressive loss of hearing and loss of hair cells. TRβ1-deficient mice had minimal changes in serum thyroid hormone and thyrotropin levels, indicating that hormonal imbalances were unlikely to cause hearing loss. The results suggest mutually shared roles for TRβ1 and TRβ2 in cochlear development and an unexpected requirement for TRβ1 in the maintenance of hearing in adulthood.

Fluorocitrate Neural Dystrophy of the Guinea Pig Cochlea

1975 ◽  
Vol 33 ◽  
pp. 368-369
Author(s):  
G.J. Spector ◽  
C.D. Carr ◽  
I. Kaufman Arenberg ◽  
R.H. Maisel
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Sodium Phosphate ◽  
Sensory Cells ◽  
Barium Salt ◽  
Perfusion Medium ◽  
Cochlear Hair Cells ◽  
Neural Degeneration ◽  
Sodium Phosphate Buffer ◽  
Cochlear Neurons

All studies on primary neural degeneration in the cochlea have evaluated the end stages of degeneration or the indiscriminate destruction of both sensory cells and cochlear neurons. We have developed a model which selectively simulates the dystrophic changes denoting cochlear neural degeneration while sparing the cochlear hair cells. Such a model can be used to define more precisely the mechanism of presbycusis or the hearing loss in aging man.Twenty-two pigmented guinea pigs (200-250 gm) were perfused by the perilymphatic route as live preparations using fluorocitrate in various concentrations (15-250 ug/cc) and at different incubation times (5-150 minutes). The barium salt of DL fluorocitrate, (C6H4O7F)2Ba3, was reacted with 1.0N sulfuric acid to precipitate the barium as a sulfate. The perfusion medium was prepared, just prior to use, as follows: sodium phosphate buffer 0.2M, pH 7.4 = 9cc; fluorocitrate = 15-200 mg/cc; and sucrose = 0.2M.

scholarly journals Temporal Alterations to Central Auditory Processing without Synaptopathy after Lifetime Exposure to Environmental Noise

2021 ◽  
Author(s):  
Florian Occelli ◽  
Florian Hasselmann ◽  
Jérôme Bourien ◽  
Jean-Luc Puel ◽  
Nathalie Desvignes ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Auditory Cortex ◽  
Auditory Processing ◽  
Noise Exposure ◽  
Sound Intensity ◽  
Environmental Noise ◽  
Central Auditory Processing ◽  
Adult Rats ◽  
Cochlear Hair Cells ◽  
Lifetime Exposure

Abstract People are increasingly exposed to environmental noise through the cumulation of occupational and recreational activities, which is considered harmless to the auditory system, if the sound intensity remains <80 dB. However, recent evidence of noise-induced peripheral synaptic damage and central reorganizations in the auditory cortex, despite normal audiometry results, has cast doubt on the innocuousness of lifetime exposure to environmental noise. We addressed this issue by exposing adult rats to realistic and nontraumatic environmental noise, within the daily permissible noise exposure limit for humans (80 dB sound pressure level, 8 h/day) for between 3 and 18 months. We found that temporary hearing loss could be detected after 6 months of daily exposure, without leading to permanent hearing loss or to missing synaptic ribbons in cochlear hair cells. The degraded temporal representation of sounds in the auditory cortex after 18 months of exposure was very different from the effects observed after only 3 months of exposure, suggesting that modifications to the neural code continue throughout a lifetime of exposure to noise.

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