Tuning curves derived from auditory brainstem responses point to a defect in outer hair cells of hypothyroid mice

AbstractDamage to the cochlear sensory epithelium is a key contributor to noise-induced sensorineural hearing loss (SNHL). KCNQ4 plays an important role in the cochlear potassium circulation and outer hair cells survival. As miR-153 can target and regulate KCNQ4, we sought to study the role of miR-153 in SNHL. 12-week-old male CBA/J mice were exposed to 2–20 kHz broadband noise at 96 dB SPL to induce temporary threshold shifts and 101 dB SPL to induce permanent threshold shifts. Hearing loss was determined by auditory brainstem responses (ABR). Relative expression of miR-153 and KCNQ4 in mice cochlea were determined by Real-Time quantitative PCR. miR-153 mimics were co-transfected with wild type or mutated KCNQ4 into HEK293 cells. Luciferase reporter assay was used to validate the binding between miR-153 and KCNQ4. AAV-sp-153 was constructed and administrated intra-peritoneally 24- and 2-h prior and immediately after noise exposure to knockdown miR-153. The KCNQ4 is mainly expressed in outer hair cells (OHCs). We showed that the expression of KCNQ4 in mice cochlea was reduced and miR-153 expression was significantly increased after noise exposure compared to control. miR-153 bound to 3′UTR of KNCQ4, and the knockdown of miR-153 with the AAV-sp-153 administration restored KCNQ4 mRNA and protein expression. In addition, the knockdown of miR-153 reduced ABR threshold shifts at 8, 16, and 32 kHz after permanent threshold shifts (PTS) noise exposure. Correspondingly, OHC losses were attenuated with inhibition of miR-153. This study demonstrates that miR-153 inhibition significantly restores KNCQ4 in cochlea after noise exposure, which attenuates SNHL. Our study provides a new potential therapeutic target in the prevention and treatment of SNHL.

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R448 – Phex Mutation Causes Sensorineural Deafness in Mice

Otolaryngology ◽

10.1016/j.otohns.2008.05.604 ◽

2008 ◽

Vol 139 (2_suppl) ◽

pp. P194-P195

Author(s):

Gao Xia

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Hair Cells ◽

Sensorineural Deafness ◽

Organ Of Corti ◽

Auditory Brainstem ◽

Outer Hair Cells ◽

Auditory Brainstem Responses ◽

Phex Gene ◽

Scanning Electron

Problem Pug is an ENU mutated mouse model for X-linked dominant hypophosphatemic rickets (XLH) in human. Mapping and sequence analysis revealed that Pug mutation is a unique Phe-to-Ser transition at amino acid 80 of PHEX protein leading to the loss of Phex function. Patients with XLH and Pug mutant mice exhibit abnormal phenotypes including growth retardation, hypophosphatemia and osteomalacia. In addition, hearing impairment was also found in some hypophosphatemic mouse models and patients. Here, we used the Pug mutant mice to study the role of Phex gene in the pathology of hearing impairment. Methods Auditory brainstem responses(ABR) to click and 8,16,32kHz stimuli were employed to measure pug mice of 1–8 months old. Serial sections were used to detect the abnormalities involving the temporal bone, stria vascularis, the organ of Corti, spiral ganglion cells, and scanning electron microscopy was performed to exam the basilar membrane of pug mice. Results Auditory brainstem responses test showed that Pug mice have elevated hearing thresholds. Histology analysis demonstrated a thickened temporal bone with many interspersed areas of nonmineralization surrounding the mutant cochlea and decreased numbers of neuronal processes in the organ of Corti, mostly in basal turns. Furthermore, abnormal stereocilia of inner and outer hair cells of the Corti organ were identified by scanning electron microscopy. Inner and outer hair cells were also greatly reduced in Pug mice. Conclusion The impaired hearing function and the morphological abnormalities of inner ears are induced by the mutation of Phex gene. Significance Pug mice have structural and functional defects in the inner ear and may serve as a new disease model of sensorineural deafness. Support This work was supported by the ground of JiangSu Province Femouse Doctor Project(RC2007010).

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Neuroplastin expression is essential for hearing and hair cell PMCA expression

Brain Structure and Function ◽

10.1007/s00429-021-02269-w ◽

2021 ◽

Author(s):

Xiao Lin ◽

Michael G. K. Brunk ◽

Pingan Yuanxiang ◽

Andrew W. Curran ◽

Enqi Zhang ◽

...

Keyword(s):

Hair Cell ◽

White Noise ◽

Hair Cells ◽

Normal Development ◽

Single Photon ◽

Photon Emission ◽

Auditory Brainstem ◽

Outer Hair Cells ◽

Emission Computed Tomography ◽

Cell Degeneration

AbstractHearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice (Nptn−/−) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn−/− mice. Adult Nptn−/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn−/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn−/− mice. Conditional ablation of neuroplastin in Nptnlox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult NptnΔlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

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R449 – The Role of DPZF in Inner Ear Development and Function

Otolaryngology ◽

10.1016/j.otohns.2008.05.605 ◽

2008 ◽

Vol 139 (2_suppl) ◽

pp. P195-P195

Author(s):

Gao Xia

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Inner Ear ◽

Hair Cells ◽

Otoacoustic Emissions ◽

Auditory Brainstem ◽

Auditory Brainstem Responses ◽

Inner Ear Development ◽

Scanning Electron

Problem The dendritic cell-derived BTB/POZ zinc finger (DPZF) protein belongs to the C2H2 zinc finger protein transcription factor family. It is localized on chromosome 3 and widely expressed in hematopoietic tissues, including human dendritic cells (DC), monocytes, B cells and T cells. DPZF null mice (DPZF-/-) exhibit a circling phenotype, suggestive of an inner ear defect. Here, we present our work on the role of DPZF in hearing defects. Methods We used auditory brainstem responses (ABR) and distortion production otoacoustic emissions (DPOAEs) to test the hearing function of DPZF-/- mice, then gross observation and histopathology analysis including serial sections and scanning electron microscopy were performed to exam the cochlea of DPZF-/- mice. Results Auditory brainstem responses (ABR) and distortion production otoacoustic emissions (DPOAEs) showed that DPZF-/-mice were completely deaf. Disorganized and fewer hair cells of the Corti organ in DPZF-/- mice were identified by scanning electron microscopy. Besides, although the hair cells of the utricle and saccule were grossly normal, the stereocilia were greatly reduced in number. Further more, lipofuscin was seen in the stria vascularis with the amount of which increased with age. Conclusion The impaired hearing and balance function and the morphological abnormalities of inner ears are caused by the deletion of DPZF gene. Significance DPZF gene may participates in regulating inner ear development and the DPZF null mice may serve as a new disease model of hearing loss. Support This work was supported by the ground of Jiangsu Province Famous Doctor Project(RC2007010).

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Compound Action-Potential Tuning Curves in Normal and Acoustically Traumatized Cats

Annals of Otology Rhinology & Laryngology ◽

10.1177/000348948309200518 ◽

1983 ◽

Vol 92 (5) ◽

pp. 496-503 ◽

Cited By ~ 4

Author(s):

Neil T. Shepard ◽

Paul J. Abbas

Keyword(s):

Action Potential ◽

Hair Cells ◽

Tuning Curve ◽

Compound Action Potential ◽

Outer Hair Cells ◽

Signal Frequency ◽

Control Group ◽

Tail Region ◽

Tuning Curves ◽

Compound Action

Compound action-potential tuning curves, using a forward-masking paradigm, were developed on both a control group and a group of acoustically traumatized cats. Differences observed between the two populations included a decrease in the sharpness of the tip, in the sensitivity of the tip, and/or in the sensitivity of the tail region. Phase-contrast light microscopy was performed on all exposed ears using a celloidin-embedding technique with horizontal sectioning. Whenever an abnormality in an action-potential tuning curve was seen, histological evidence of damage to the organ of Corti in an appropriate region corresponding to the signal frequency was observed. However, several cases of damage to the cochlea were observed with normal tuning curves. Whenever the tip region of the tuning curve was elevated, evidence of damage to all three rows of outer hair cells and to the inner hair cells was seen.

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Neuroprotective Effect of Near-Infrared Light in an Animal Model of CI Surgery

Audiology and Neurotology ◽

10.1159/000508619 ◽

2020 ◽

pp. 1-7

Author(s):

Ira Strübing ◽

Moritz Gröschel ◽

Susanne Schwitzer ◽

Arne Ernst ◽

Felix Fröhlich ◽

...

Keyword(s):

Animal Model ◽

Hearing Loss ◽

Hair Cells ◽

Cochlear Implantation ◽

Near Infrared ◽

Outer Hair Cells ◽

Auditory Brainstem Responses ◽

Infrared Light ◽

Residual Hearing ◽

Significant Difference

Introduction: The preservation of residual hearing has become an important consideration in cochlear implant (CI) recipients in recent years. It was the aim of the present animal experimental study to investigate the influence of a pretreatment with near-infrared (NIR) light on preservation of sensory hair cells and residual hearing after cochlear implantation. Methods: NIR was applied unilaterally (15 min, 808 nm, 120 mW) to 8 guinea pigs, immediately before a bilateral scala tympani CI electrode insertion was performed. The nonirradiated (contralateral) side served as control. Twenty-eight days postoperatively, auditory brainstem responses (ABRs) were registered from both ears to screen for hearing loss. Thereafter, the animals were sacrificed and inner hair cells (IHCs) and outer hair cells (OHCs) were counted and compared between NIR-pretreated and control (contralateral) cochleae. Results: There was no IHC loss upon cochlear implantation. OHC loss was most prominent on both sides at the apical part of the cochlea. NIR pretreatment led to a statistically significant reduction in OHC loss (by 39.8%). ABR recordings (across the frequencies 4–32 kHz) showed a statistically significant difference between the 2 groups and corresponds well with the apical structural damage. Hearing loss was reduced by about 20 dB on average for the NIR-pretreated group (p ≤ 0.05). Discussion/Conclusion: A single NIR pretreatment in this animal model of CI surgery appears to be neuroprotective for residual hearing. This is in line with other studies where several NIR posttreatments have protected cochlear and other neural tissues. NIR pretreatment is an inexpensive, effective, and noninvasive approach that can complement other ways of preserving residual hearing and, hence, should deserve further clinical evaluation in CI patients.

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Expression of a membrane-targeted fluorescent reporter disrupts auditory hair cell mechanoelectrical transduction and causes profound deafness

10.1101/2020.09.18.303743 ◽

2020 ◽

Author(s):

Angela Ballesteros ◽

Tracy S. Fitzgerald ◽

Kenton J. Swartz

Keyword(s):

Hair Cells ◽

Otoacoustic Emissions ◽

Fluorescent Protein ◽

Super Resolution ◽

Auditory Brainstem ◽

Auditory Brainstem Responses ◽

Fluorescent Reporter ◽

Auditory Hair Cells ◽

Mechanoelectrical Transduction ◽

Distortion Product

AbstractThe reporter mT/mG mice expressing a membrane-targeted fluorescent protein are becoming widely used to study the auditory and vestibular system due to its versatility. Here we show that high expression levels of the fluorescent mtdTomato reporter affect the function of the sensory hair cells and the auditory performance of mT/mG transgenic mice. Auditory brainstem responses and distortion product otoacoustic emissions revealed that adult mT/mG homozygous mice are profoundly deaf, whereas heterozygous mice present high frequency loss. We explore whether this line would be useful for studying and visualizing the membrane of auditory hair cells by airyscan super-resolution confocal microscopy. Membrane localization of the reporter was observed in hair cells of the cochlea, facilitating imaging of both cell bodies and stereocilia bundles without altering cellular architecture or the expression of the integral membrane motor protein prestin. Remarkably, hair cells from mT/mG homozygous mice failed to uptake the FM1-43 dye and to locate TMC1 at the stereocilia, indicating defective mechanoelectrical transduction machinery. Our work emphasizes that precautions must be considered when working with reporter mice and highlights the potential role of the cellular membrane in maintaining functional hair cells and ensuring proper hearing.

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Spirulina Prevent Caspase-Independent Apoptosis in the Cochlea and Brainstem of Senescence-Accelerated Prone-8 Mice

10.21203/rs.3.rs-61504/v1 ◽

2020 ◽

Author(s):

Yin-Ching Chan ◽

Mei-Hsiao Lin ◽

Juen-Haur Hwang

Keyword(s):

Water Extract ◽

Auditory Brainstem ◽

Normal Diet ◽

Outer Hair Cells ◽

Auditory Brainstem Responses ◽

Spiral Ganglion Neuron ◽

Control Group ◽

Sound Stimulation ◽

Samp8 Mice ◽

Parp 1

Abstract Background: Spirulina platensis water extract (SP) could decrease hearing degeneration via reducing oxidative stress damages in the auditory system of senescence-accelerated prone-8 (SAMP8) mice. This study aimed to investigate the effects of SP on the caspase-independent apoptosis in the cochlea and brainstem of SAMP8 mice.Methods: Twelve 11-month-old SAMP8 mice were randomly divided into two groups: control group (SAMP8 mice was fed a normal diet) and spirulina group (SAMP8 mice was fed a normal diet with oral supplementation SP for 6 weeks. Auditory brainstem responses (ABRs) were measured in the beginning and at the end of the study. Cochlear histology and immunochemistry and Western blotting of brainstem were performed at the end of the study.Results: Compared with control group, spirulina group had significantly lower ABR thresholds using click sound stimulation at the end of this study. The spirulina group had significantly higher counts of outer hair cells (OHC) and spiral ganglion neuron (SGN) density in the middle turn of the cochlea. The spirulina group had significantly lower expressions of poly (ADP-ribose) polymerase-1 (PARP-1) and apoptosis-inducing factor (AIF) in the cochlea. Also, the spirulina group had significantly lower expression of PARP-1, but not the AIF, in the brainstem.Conclusions: SP could decrease hearing degeneration in SAMP8 mice possibly via reducing caspase-independent apoptosis signal pathway in the cochlea and brainstem.

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Auditory neuropathy in a patient with mitochondrial myopathy and multiple mtDNA deletions

The Journal of Laryngology & Otology ◽

10.1017/s0022215106001472 ◽

2006 ◽

Vol 120 (10) ◽

pp. 888-891 ◽

Cited By ~ 9

Author(s):

F Forli ◽

M Mancuso ◽

A Santoro ◽

M T Dotti ◽

G Siciliano ◽

...

Keyword(s):

Hair Cells ◽

Otoacoustic Emissions ◽

Mitochondrial Myopathy ◽

Spiral Ganglion ◽

Mitochondrial Diseases ◽

Auditory Brainstem ◽

Auditory Neuropathy ◽

Auditory Brainstem Responses ◽

Common Symptom ◽

First Case

Auditory neuropathy (AN) is a hearing disorder characterized by the absence or severe distortion of the auditory brainstem responses, in the presence of preserved otoacoustic emissions. This peculiar combination suggests the presence of a defect impinging upon the functional complex formed by inner hair cells, the primary afferents (spiral ganglion neurones) and the first order synapses between hair cells and the cochlear nerve. Typically, AN patients show a severe speech perception impairment, which appears reduced out of proportion to pure tone threshold, but the clinical presentation of AN is quite complex.Hearing loss is a common symptom associated with mitochondrial diseases; however, AN has only rarely been reported in these disorders.Here we report a rare association, the first case observed in Italy, in a patient with autosomal recessive mitochondrial myopathy and mitochondrial DNA multiple deletions, and a hearing deficit with the audiological and electrophysiological features of AN.

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Preventing presbycusis in mice with enhanced medial olivocochlear feedback

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2000760117 ◽

2020 ◽

Vol 117 (21) ◽

pp. 11811-11819 ◽

Cited By ~ 3

Author(s):

Luis E. Boero ◽

Valeria C. Castagna ◽

Gonzalo Terreros ◽

Marcelo J. Moglie ◽

Sebastián Silva ◽

...

Keyword(s):

Hearing Loss ◽

Hair Cells ◽

Outer Hair Cells ◽

Auditory Brainstem Responses ◽

Cochlear Function ◽

Gain Of Function ◽

Distortion Product ◽

Age Related ◽

Medial Olivocochlear ◽

Age Related Hearing Loss

“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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