Hearing Loss In Humans Research Articles

Neuronal development in the cochlea of a nonhuman primate model, the common marmoset.

Precise cochlear neuronal development is vital to hearing ability. Understanding the developmental process of the spiral ganglion is useful for studying hearing loss aimed at aging or regenerative therapy. Although interspecies differences have been reported between rodents and humans, to date, most of our knowledge about the development of cochlear neuronal development has been obtained from rodent models because of the difficulty in using human fetal samples in this field. In this study, we investigated cochlear neuronal development in a small New World monkey species, the common marmoset (Callithrix jacchus). We examined more than 25 genes involved in the neuronal development of the cochlea and described the critical developmental steps of these neurons. We also revealed similarities and differences between previously reported rodent models and this primate animal model. Our results clarified that this animal model of cochlear neuronal development is more similar to humans than rodents and is suitable as an alternative for the analysis of human cochlear development. The time course established in this report will be a useful tool for studying primate‐specific neuronal biology of the inner ear, which could eventually lead to new treatment strategies for human hearing loss.

Oral D-methionine protects against cisplatin-induced hearing loss in humans: phase 2 randomized clinical trial in India

Objective: This exploratory Phase 2 clinical trial is the first determining safety and efficacy of oral D-methionine (D-met) in reducing cisplatin-induced ototoxicity. Design: Randomised parallel double-blind placebo-controlled exploratory Phase 2 study. Study samples: Fifty adult cancer patients received oral D-met or placebo before each cisplatin dose. Physical examination, blood collection and audiometry occurred at baseline and subsequent visits plus post-treatment audiometry. After attrition, final analysis included 27 patients. Results: Significant treatment group by ear and time (baseline vs. post-treatment) interactions occurred at 10 kHz and 11.2 kHz. Placebo and D-met groups differed in threshold shift for left ear at 11.2 kHz (mean difference = 22.97 dB [9.59, 36.35]). Averaging across ears, placebo group showed significant threshold shifts from baseline to post-treatment at 10 kHz (mean shift= −13.65 dB [−21.32,−5.98]), 11.2 kHz (−16.15 dB [−25.19,−7.12]), and 12.5 kHz (−11.46 dB [−19.18,−3.74]) but not 8 kHz (−8.65 dB [−17.86, 0.55]). The D-met group showed no significant threshold shifts (8 kHz: −1.25 dB [−7.75, 5.25]; 10 kHz:−3.93 dB [−8.89, 1.03]; 11.2 kHz:−4.82 dB [−11.21, 1.57]; 12.5 kHz:−3.68 dB [−11.57, 4.21]). Side effects did not significantly differ between groups. Conclusion: Oral D-met reduces cisplatin-induced ototoxicity in humans.

Inner hair cell dysfunction in Klhl18 mutant mice leads to low frequency progressive hearing loss.

Age-related hearing loss in humans (presbycusis) typically involves impairment of high frequency sensitivity before becoming progressively more severe at lower frequencies. Pathologies initially affecting lower frequency regions of hearing are less common. Here we describe a progressive, predominantly low-frequency recessive hearing impairment in two mutant mouse lines carrying different mutant alleles of the Klhl18 gene: a spontaneous missense mutation (Klhl18lowf) and a targeted mutation (Klhl18tm1a(KOMP)Wtsi). Both males and females were studied, and the two mutant lines showed similar phenotypes. Threshold for auditory brainstem responses (ABR; a measure of auditory nerve and brainstem neural activity) were normal at 3 weeks old but showed progressive increases from 4 weeks onwards. In contrast, distortion product otoacoustic emission (DPOAE) sensitivity and amplitudes (a reflection of cochlear outer hair cell function) remained normal in mutants. Electrophysiological recordings from the round window of Klhl18lowf mutants at 6 weeks old revealed 1) raised compound action potential thresholds that were similar to ABR thresholds, 2) cochlear microphonic potentials that were normal compared with wildtype and heterozygous control mice and 3) summating potentials that were reduced in amplitude compared to control mice. Scanning electron microscopy showed that Klhl18lowf mutant mice had abnormally tapering of the tips of inner hair cell stereocilia in the apical half of the cochlea while their synapses appeared normal. These results suggest that Klhl18 is necessary to maintain inner hair cell stereocilia and normal inner hair cell function at low frequencies.

Differential regulation of mammalian and avian ATOH1 by E2F1 and its implication for hair cell regeneration in the inner ear

The mammalian inner ear has a limited capacity to regenerate its mechanosensory hair cells. This lack of regenerative capacity underlies the high incidence of age-related hearing loss in humans. In contrast, non-mammalian vertebrates can form new hair cells when damage occurs, a mechanism that depends on re-activation of expression of the pro-hair cell transcription factor Atoh1. Here, we show that members of the E2F transcription factor family, known to play a key role in cell cycle progression, regulate the expression of Atoh1. E2F1 activates chicken Atoh1 by directly interacting with a cis-regulatory region distal to the avian Atoh1 gene. E2F does not activate mouse Atoh1 gene expression, since this regulatory element is absent in mammals. We also show that E2F1 expression changes dynamically in the chicken auditory epithelium during ototoxic damage and hair cell regeneration. Therefore, we propose a model in which the mitotic regeneration of non-mammalian hair cells is due to E2F1-mediated activation of Atoh1 expression, a mechanism which has been lost in mammals.

Insulin-like Growth Factor 1 Signaling in Mammalian Hearing

Insulin-like growth factor 1 (IGF-1) is a peptide hormone belonging to the insulin family of proteins. Almost all of the biological effects of IGF-1 are mediated through binding to its high-affinity tyrosine kinase receptor (IGF1R), a transmembrane receptor belonging to the insulin receptor family. Factors, receptors and IGF-binding proteins form the IGF system, which has multiple roles in mammalian development, adult tissue homeostasis, and aging. Consequently, mutations in genes of the IGF system, including downstream intracellular targets, underlie multiple common pathologies and are associated with multiple rare human diseases. Here we review the contribution of the IGF system to our understanding of the molecular and genetic basis of human hearing loss by describing, (i) the expression patterns of the IGF system in the mammalian inner ear; (ii) downstream signaling of IGF-1 in the hearing organ; (iii) mouse mutations in the IGF system, including upstream regulators and downstream targets of IGF-1 that inform cochlear pathophysiology; and (iv) human mutations in these genes causing hearing loss.

Mice heterozygous for the Serpinb6a null mutation show deficits in central auditory function after acoustic trauma.

Complete deficiency of the serine protease inhibitor gene, SERPINB6, is responsible for autosomal-recessive, nonsyndromic sensorineural hearing loss in humans. A mouse model of this deafness gene identifies Serpinb6a expression in the neurosensory epithelium and fibrocytes of the cochlea. Homozygous Serpinb6a mutant mice display an exaggerated hearing loss after exposure to moderate acoustic trauma. It is unknown if and how heterozygous Serpinb6a mice show increased vulnerability to acoustic trauma. We exposed Serpinb6a+/- and Serpinb6a+/+ mice to acoustic trauma and measured their hearing function prior to, 3 and 14 days postexposure, analysing shifts in hearing threshold and amplitudes of Wave I and II of the auditory brainstem-evoked response (ABR) to 4, 8, 16 and 32 kHz tones. Shifts in hearing threshold and Wave I amplitude of Serpinb6a+/- mice were not significantly different from Serpinb6a+/+ mice at both time points and all frequencies tested (P > 0.05, Mann-Whitney test). However, Wave II amplitudes at 16 and 32 kHz tones, were more severely diminished in Serpinb6a+/- mice (P < 0.05). To exclude any effects of ageing on auditory function in Serpinb6a+/- mice, hearing function of unexposed Serpinb6a+/- mice was measured at start and end of the experimental period. The shift in Wave II amplitude of exposed Serpinb6a+/- mice was significantly lower than unexposed Serpinb6a+/- mice only at 16 and 32 kHz (P < 0.01), confirming acoustic trauma as the main cause of hearing deficits in Serpinb6a+/- mice. These results suggest that heterozygous Serpinb6a humans may be vulnerable to noise.

Time-domain analysis of a three-dimensional numerical model of the human spiral cochlea at medium intensity.

For the processing and detection of speech and music, the human cochlea has an exquisite sensitivity and selectivity of frequency and a dynamic range. How the cochlea performs these remarkable functions has fascinated auditory scientists for decades. Because it is not possible to measure sound-induced vibrations within the cochlea in a living human being, mathematical modeling has played an important role in cochlear mechanics. For this study, a three-dimensional human cochlear model with a fluid‒structure coupling was constructed. Time-domain analysis was performed to calculate the displacement, velocity, and stress of the basilar membrane (BM) and osseous spiral lamina (OSL) at different times in response to a pure tone stimulus. The model reproduced the traveling-wave motion of the BM. The model also showed that the cochlea's spiral shape can induce asymmetrical mechanical behavior of the BM and cause cochlear fluid to move in a radial direction; this may contribute to human sound perception. The cochlea's spiral shape not only enhances a low-frequency vibration of the BM but also changes the maximization of the positions of vibration. Therefore, the spiral's characteristics play a key role in the cochlea's frequency selectivity for low-frequency sounds. And this suggests that the OSL can react to sound as quickly as the BM. Furthermore, the basal region of the BM tends to have more stress than its other regions, and this may explain the clinical observation that human sensorineural hearing loss often occurs at high frequencies.

Murine GRXCR1 Has a Different Function Than GRXCR2 in the Morphogenesis of Stereocilia.

Mutations in human glutaredoxin domain-containing cysteine-rich protein 1 (GRXCR1) and its paralog GRXCR2 have been linked to hearing loss in humans. Although both GRXCR1 and GRXCR2 are required for the morphogenesis of stereocilia in cochlear hair cells, a fundamental question that remains unclear is whether GRXCR1 and GRXCR2 have similar functions in hair cells. Previously, we found that GRXCR2 is critical for the stereocilia morphogenesis by regulating taperin localization at the base of stereocilia. Reducing taperin expression level rescues the morphological defects of stereocilia and hearing loss in Grxcr2-deficient mice. So far, functions of GRXCR1 in mammalian hair cells are still unclear. Grxcr1-deficient hair cells have very thin stereocilia with less F-actin content inside, which is different from Grxcr2-deficient hair cells. In contrast to GRXCR2, which is concentrated at the base of stereocilia, GRXCR1 is diffusely distributed throughout the stereocilia. Notably, GRXCR1 interacts with GRXCR2. In Grxcr1-deficient hair cells, the expression level of GRXCR2 and taperin is reduced. Remarkably, different from that in Grxcr2-deficient mice, reducing taperin expression level does not rescue the morphological defects of stereocilia or hearing loss in Grxcr1-deficient mice. Thus, our findings suggest that GRXCR1 has different functions than GRXCR2 during the morphogenesis of stereocilia.

Spontaneous otoacoustic emissions are biomarkers for mice with tectorial membrane defects

Cochlear function depends on the operation of a coupled feedback loop, incorporating outer hair cells (OHCs), and structured to assure that inner hair cells (IHCs) convey frequency specific acoustic information to the brain, even at very low sound levels. Although our knowledge of OHC function and its contribution to cochlear amplification has expanded, the importance of the tectorial membrane (TM) to the processing of mechanical inputs has not been fully elucidated. In addition, there are a surprising number of genetic mutations that affect TM structure and that produce hearing loss in humans. By synthesizing old and new results obtained on several mouse mutants, we learned that animals with abnormal TMs are prone to generate spontaneous otoacoustic emissions (SOAE), which are uncommon in most wildtype laboratory animals. Because SOAEs are not produced in TM mutants or in humans when threshold shifts exceed approximately 25 dB, some degree of cochlear amplification is required. However, amplification by itself is not sufficient because normal mice are rarely spontaneous emitters. Since SOAEs reflect active cochlear operation, TM mutants are valuable for studying the oscillatory nature of the amplification process and the structures associated with its stabilization. Inasmuch as the mouse models were selected to mirror human auditory disorders, using SOAEs as a noninvasive clinical tool may assist the classification of individuals with genetic defects that influence the active mechanisms responsible for sensitivity and frequency selectivity, the hallmarks of mammalian hearing.

Noise Exposure and Distortion Product Otoacoustic Emission Suprathreshold Amplitudes: A Genome-Wide Association Study

Background: Although several candidate-gene association studies have been conducted to investigate noise-induced hearing loss (NIHL) in humans, most are underpowered, unreplicated, and account for only a fraction of the genetic risk. Mouse genome-wide association studies (GWASs) have revolutionized the field of genetics and have led to the discovery of hundreds of genes involved in complex traits. The hybrid mouse diversity panel (HMDP) is a collection of classic inbred and recombinant inbred strains whose genomes have been either genotyped at high resolution or sequenced. To further investigate the genetics of NIHL, we report the first GWAS based on distortion product otoacoustic emission (DPOAE) measurements and the HMDP. Methods: A total of 102 strains (n = 635) from the HMDP were evaluated based on DPOAE suprathreshold amplitudes before and after noise exposure. DPOAE amplitude variation was set at 60 and 70 dB SPL of the primary tones for each frequency separately (8, 11.3, 16, 22.6, and 32 kHz). These values provided an indirect assessment of outer hair cell integrity. Six-week-old mice were exposed for 2 h to 10 kHz octave-band noise at 108 dB SPL. To perform local expression quantitative trait locus (eQTL) analysis, gene expression microarray profiles were generated using cochlear RNA from 64 hybrid mouse strains (n = 3 arrays per strain). Results: Several new loci were identified and positional candidate-genes associated with NIHL were prioritized, especially after noise exposure (1 locus at baseline and 5 loci after exposure). A total of 35 candidate genes in these 6 loci were identified with at least 1 probe whose expression was regulated by a significant cis-eQTL in the cochlea. After careful analysis of the candidate genes based on cochlear gene expression, 2 candidate genes were prioritized: Eya1 (baseline) and Efr3a (post-exposure). Discussion and Conclusion: For the first time, an association analysis with correction for population structure was used to map several loci for hearing traits in inbred strains of mice based on DPOAE suprathreshold amplitudes before and after noise exposure. Our results identified a number of novel loci and candidate genes for susceptibility to NIHL, especially the Eya1 and Efr3a genes. Our findings validate the power of the HMDP for detecting NIHL susceptibility genes.

Tinnitus development is associated with synaptopathy of inner hair cells in Mongolian gerbils.

Human hearing loss (HL) is often accompanied by comorbidities like tinnitus, which is affecting up to 15% of the adult population. Rodent animal studies could show that tinnitus may not only be a result of apparent HL due to cochlear hair cell damage but can also be a consequence of synaptopathy at the inner hair cells (IHCs) already induced by moderate sound traumata. Here, we investigate synaptopathy previously shown in mice in our animal model, the Mongolian gerbil, and relate it to behavioral signs of tinnitus. Tinnitus was induced by a mild monaural acoustic trauma leading to monaural noise induced HL in the animals, quantified by auditory brainstem response (ABR) audiometry. Behavioral signs of tinnitus percepts were detected by measurement of prepulse inhibition of the acoustic startle response in a gap-noise paradigm. Fourteen days after trauma, the cochleae of both ears were isolated, and IHC synapses were counted within several spectral regions of the cochlea. Behavioral signs of tinnitus were only found in animals with IHC synaptopathy, independent of type of HL. On the other hand, animals with apparent HL but without behavioral signs of tinnitus showed a reduction in amplitudes of ABR waves I&II but no significant changes in the number of synapses at the IHC. We conclude-in line with the literature-that HL is caused by damage to the IHC or by other reasons but that the development of tinnitus, at least in our animal model, is closely linked to synaptopathy at the IHC.

Experimental Investigation of Turbulence Effects on Aerodynamics Noise of Channeled NACA 0012 Airfoil

Abstract Wind power is rapidly growing worldwide as renewable and clean energy of choice due to its competitiveness in cost and technology advancement. However, as the wind turbines grow, the aerodynamic noise generated from the rotating blades is becoming a major concern that limits the use of wind turbines, especially near residential housing areas. Significant low sleep quality has been reported within 2 km of wind turbine locations that is becoming a problem for wider use of wind energy. Generally, continuous exposure to 85–90 dB noise causes permanent hearing loss in humans. To reduce the aerodynamic noise, channeled blades were implemented in this work to damp the airflow turbulence that causes the aerodynamic noise. Samples of different diameter sizes and angles of inclinations with respect to the cord have been tested and compared to a regular unchanneled blade. Noise measurements have been carried out using low-frequency microphones with frequencies ranging between 0 and 10,000 Hz. While turbulence measurements were performed using a hot-wire anemometer. The measured noise around the blades ranged between 20 and 70 dB up to 600 Hz has been proven to be directly related to turbulence intensity. The best low noise blade design was recommended based on noise measurement.

Inhalation of Molecular Hydrogen, a Rescue Treatment for Noise-Induced Hearing Loss.

Noise exposure is the most important external factor causing acquired hearing loss in humans, and it is strongly associated with the production of reactive oxygen species (ROS) in the cochlea. Several studies reported that the administration of various compounds with antioxidant effects can treat oxidative stress-induced hearing loss. However, traditional systemic drug administration to the human inner ear is problematic and has not been successful in a clinical setting. Thus, there is an urgent need to develop rescue treatment for patients with acute acoustic injuries. Hydrogen gas has antioxidant effects, rapid distribution, and distributes systemically after inhalation.The purpose of this study was to determine the protective efficacy of a single dose of molecular hydrogen (H2) on cochlear structures. Guinea pigs were divided into six groups and sacrificed immediately after or at 1 or 2 weeks. The animals were exposed to broadband noise for 2 h directly followed by 1-h inhalation of 2% H2 or room air. Electrophysiological hearing thresholds using frequency-specific auditory brainstem response (ABR) were measured prior to noise exposure and before sacrifice. ABR thresholds were significantly lower in H2-treated animals at 2 weeks after exposure, with significant preservation of outer hair cells in the entire cochlea. Quantification of synaptophysin immunoreactivity revealed that H2 inhalation protected the cochlear inner hair cell synaptic structures containing synaptophysin. The inflammatory response was greater in the stria vascularis, showing increased Iba1 due to H2 inhalation.Repeated administration of H2 inhalation may further improve the therapeutic effect. This animal model does not reproduce conditions in humans, highlighting the need for additional real-life studies in humans.

Missense variant in LOXHD1 is associated with canine nonsyndromic hearing loss

Hearing loss is a common sensory deficit in both humans and dogs. In canines, the genetic basis is largely unknown, as genetic variants have only been identified for a syndromic form of hearing impairment. We observed a congenital or early-onset sensorineural hearing loss in a Rottweiler litter. Assuming an autosomal recessive inheritance, we used a combined approach of homozygosity mapping and genome sequencing to dissect the genetic background of the disorder. We identified a fully segregating missense variant in LOXHD1, a gene that is known to be essential for cochlear hair cell function and associated with nonsyndromic hearing loss in humans and mice. The canine LOXHD1 variant was specific to the Rottweiler breed in our study cohorts of pure-bred dogs. However, it also was present in some mixed-breed dogs, of which the majority showed Rottweiler ancestry. Low allele frequencies in these populations, 2.6% and 0.04%, indicate a rare variant. To summarize, our study describes the first genetic variant for canine nonsyndromic hearing loss, which is clinically and genetically similar to human LOXHD1-related hearing disorder, and therefore, provides a new large animal model for hearing loss. Equally important, the affected breed will benefit from a genetic test to eradicate this LOXHD1-related hearing disorder from the population.

Loxhd1 Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells.

Sound detection happens in the inner ear via the mechanical deflection of the hair bundle of cochlear hair cells. The hair bundle is an apical specialization consisting of actin-filled membrane protrusions (called stereocilia) connected by tip links (TLs) that transfer the deflection force to gate the mechanotransduction channels. Here, we identified the hearing loss-associated Loxhd1/DFNB77 gene as being required for the mechanotransduction process. LOXHD1 consists of 15 polycystin lipoxygenase α-toxin (PLAT) repeats, which in other proteins can bind lipids and proteins. LOXHD1 was distributed along the length of the stereocilia. Two LOXHD1 mouse models with mutations in the 10th PLAT repeat exhibited mechanotransduction defects (in both sexes). While mechanotransduction currents in mutant inner hair cells (IHCs) were similar to wild-type levels in the first postnatal week, they were severely affected by postnatal day 11. The onset of the mechanotransduction phenotype was consistent with the temporal progression of postnatal LOXHD1 expression/localization in the hair bundle. The mechanotransduction defect observed in Loxhd1-mutant IHCs was not accompanied by a morphologic defect of the hair bundle or a reduction in TL number. Using immunolocalization, we found that two proteins of the upper and lower TL protein complexes (Harmonin and LHFPL5) were maintained in the mutants, suggesting that the mechanotransduction machinery was present but not activatable. This work identified a novel LOXHD1-dependent step in hair bundle development that is critical for mechanotransduction in mature hair cells as well as for normal hearing function in mice and humans.SIGNIFICANCE STATEMENT Hair cells detect sound-induced forces via the hair bundle, which consists of membrane protrusions connected by tip links. The mechanotransduction machinery forms protein complexes at the tip-link ends. The current study showed that LOXHD1, a multirepeat protein responsible for hearing loss in humans and mice when mutated, was required for hair-cell mechanotransduction, but only after the first postnatal week. Using immunochemistry, we demonstrated that this defect was not caused by the mislocalization of the tip-link complex proteins Harmonin or LHFPL5, suggesting that the mechanotransduction protein complexes were maintained. This work identified a new step in hair bundle development, which is critical for both hair-cell mechanotransduction and hearing.

Functional Role of Class III Myosins in Hair Cells.

Cytoskeletal motors produce force and motion using the energy from ATP hydrolysis and function in a variety of mechanical roles in cells including muscle contraction, cargo transport, and cell division. Actin-based myosin motors have been shown to play crucial roles in the development and function of the stereocilia of auditory and vestibular inner ear hair cells. Hair cells can contain hundreds of stereocilia, which rely on myosin motors to elongate, organize, and stabilize their structure. Mutations in many stereocilia-associated myosins have been shown to cause hearing loss in both humans and animal models suggesting that each myosin isoform has a specific function in these unique parallel actin bundle-based protrusions. Here we review what is known about the classes of myosins that function in the stereocilia, with a special focus on class III myosins that harbor point mutations associated with delayed onset hearing loss. Much has been learned about the role of the two class III myosin isoforms, MYO3A and MYO3B, in maintaining the precise stereocilia lengths required for normal hearing. We propose a model for how class III myosins play a key role in regulating stereocilia lengths and demonstrate how their motor and regulatory properties are particularly well suited for this function. We conclude that ongoing studies on class III myosins and other stereocilia-associated myosins are extremely important and may lead to novel therapeutic strategies for the treatment of hearing loss due to stereocilia degeneration.

Transient Delivery of aKCNQ2/3-Specific Channel Activator 1 Week After Noise Trauma Mitigates Noise-Induced Tinnitus.

Exposure to loud noise can cause hearing loss and tinnitus in mice and humans. In mice, one major underlying mechanism of noise-induced tinnitus is hyperactivity of auditory brainstem neurons, due at least in part, to decreased Kv7.2/3 (KCNQ2/3) potassium channel activity. In our previous studies, we used a reflex-based mouse model of tinnitus and showed that administration of a non-specific KCNQ channel activator, immediately after noise trauma, prevented the development of noise-induced tinnitus, assessed 1week after trauma. Subsequently, we developed RL-81, a very potent and highly specific activator of KCNQ2/3 channels. Here, to test the timing window within which RL-81 prevents tinnitus in mice, we modified and employed an operant animal model of tinnitus, where mice are trained to move in response to sound but not move in silence. Mice with behavioral evidence of tinnitus are expected to move in silence. We validated this mouse model by testing the effect of salicylate, which is known to induce tinnitus. We found that transient administration of RL-81 1week after noise exposure did not affect hearing loss but reduced significantly the percentage of mice with behavioral evidence of tinnitus, assessed 2weeks after noise exposure. Our results indicate that RL-81 is a promising drug candidate for further development for the treatment of noise-induced tinnitus.

Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss.

Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug–induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans.

ACTG1 regulates intervertebral disc degeneration via the NF-κB-p65 and Akt pathways

ACTG1 is a member of the actin family but is not a muscle actin gene. The ACTG1 mutation leads to hearing loss in humans, and the knockdown of ACTG1 suppresses the proliferation and migration of tumor cells; however, its role in intervertebral disc degeneration (IDD) is yet unclear. Bioinformatics methods revealed that ACTG1 might be a hub gene in IDD. Furthermore, the expression ACTG1 in severely degenerated nucleus pulposus (NP) tissues (Pfirrmann grade IV and V) was low as compared to that in mildly degenerated samples (Pfirrmann grade II and III). Moreover, the ACTG1 level was negatively correlated with human disc degeneration grades. The low expression of ACTG1 is also found in degenerated NP tissues in the rat. To further explore the function of ACTG1 in IDD, the gene expression was depleted in human NP cells via siRNA transfection. The ablation of ACTG1 increased MMP3 expression but decreased the level of collagen II. Excessive apoptosis was observed in ACTG1 knockdown groups, indicating that the absence of ACTG1 exacerbated IDD. GO function and pathway enrichment analysis for differentially expressed genes (DEGs) of two microarray datasets (GSE56081 and GSE42611) indicated that inflammatory response plays a crucial role in IDD. Interestingly, in the protein-protein interaction (PPI) network, ACTG1 is connected to the proteins of inflammation-related pathways. Furthermore, ACTG1 knockdown upregulated P–P65 level but suppressed P-Akt expression. These data collectively demonstrated that ACTG1 regulated the development of IDD through the NF-κB-p65 and Akt pathways, and ACTG1 may be a novel marker and therapeutic target of IDD in the future.

Mole-rats play evolution by ear

Scuttling around their burrows, mole-rats can kick up a bit of a racket, calling out in the dark to their extensive family. Surprisingly, naked mole-rats and their close relatives Damaraland mole-rats have terrible hearing, especially compared with other rodents. Mole-rats have no outer ears and the vibration-sensing hair cells in their inner ear are weirdly connected to their nerves, but neither feature totally explains why they are nearly deaf. Why they evolved bad hearing is a mystery too. They might have lost hearing over time like other subterranean animals lost sight. Alternatively, poor hearing could be an advantage, dampening echoes in noisy burrows. Sonja Pyott from the University of Groningen, The Netherlands, and colleagues investigated the physiological and evolutionary causes of mole-rats’ poor hearing.First, the authors did a mole-rat hearing test to see what sounds got their inner ear – the cochlea – talking to their brain and found that naked and Damaraland mole-rat ears respond to tones between 0.5 and 4 kHz or 2 kHz, respectively, a narrower and lower range than for other rodents. Next, the authors did a full auditory system workup, seeking a physiological mechanism to explain why mole-rats are hard of hearing. As hair cells vibrate in response to incoming sounds, they make noises called otoacoustic emissions. Typically, otoacoustic emissions increase with louder noises and they track how well the cochlea amplifies sounds. Yet, unlike all mammals studied to date, mole-rat otoacoustic emissions were similar across the range of sounds tested (∼70 dB, comparable to an alarm clock), meaning their cochleas didn't make quiet sounds louder.The researchers wondered why mole-rat inner ears didn't amplify sounds, focusing on the outer hair cells that convert soundwaves into brainwaves. As mutations in the hair cell protein prestin, which helps hair cells vibrate, cause hearing loss in humans, the team hypothesized that mole-rat prestin might be dysfunctional. But, when they checked, the mole-rats didn't have any problems with their prestin; they had the right amount in the right places and none of the usual mutations previously associated with hearing loss. Moreover, when they isolated hair cells from mole-rats, the sensors sent electrical signals just as well mouse hair cells, meaning that the lack of cochlear amplification in mole-rats wasn't caused by loss or dysfunction of prestin.Undeterred, the team turned their attention to stereocilia bundles, the ‘tufts’ attached to the hair cells that sway in response to sound. Scanning electron microscopy revealed that mole-rat stereocilia are a mess, jutting out at sharp angles and even missing in some places – a situation that probably makes they them less sensitive to sounds. The disorganization seemed to be caused by several mutations in the linker proteins that connect the tips of individual stereocilia like wires, causing all of the stereocilia to sway in unison, co-ordinating their auditory signals.Confident they had identified one mechanism for poor mole-rat hearing, the team tackled the ultimate question: why? Comparing mole-rat linker proteins with those of other rodents, they found far more amino acid sequence-altering mutations than expected in the mole-rat proteins; the probability of accumulating all those mutations randomly was infinitesimal, making it unlikely they had occurred by chance. The authors concluded that several of the linker protein mutations, and the poor hearing they caused, are likely advantageous for mole-rats.As you'd expect a noisy, sociable, subterranean rodent to have excellent hearing, hard of hearing mole-rats have long been a mystery. But now part of that mystery has been resolved and a key piece of the puzzle is a few mutations in proteins that connect a small, but mighty, part of their ears.