Current concepts in age-related hearing loss: epidemiology and mechanistic pathways.
ABSTRACT: Age-related hearing loss (AHL), also known as presbycusis, is a universal feature of mammalian aging and is characterized by a decline of auditory function, such as increased hearing thresholds and poor frequency resolution. The primary pathology of AHL includes the hair cells, stria vascularis, and afferent spiral ganglion neurons as well as the central auditory pathways. A growing body of evidence in animal studies has suggested that cumulative effect of oxidative stress could induce damage to macromolecules such as mitochondrial DNA (mtDNA) and that the resulting accumulation of mtDNA mutations/deletions and decline of mitochondrial function play an important role in inducing apoptosis of the cochlear cells, thereby the development of AHL. Epidemiological studies have demonstrated four categories of risk factors of AHL in humans: cochlear aging, environment such as noise exposure, genetic predisposition, and health co-morbidities such as cigarette smoking and atherosclerosis. Genetic investigation has identified several putative associating genes, including those related to antioxidant defense and atherosclerosis. Exposure to noise is known to induce excess generation of reactive oxygen species (ROS) in the cochlea, and cumulative oxidative stress can be enhanced by relatively hypoxic situations resulting from the impaired homeostasis of cochlear blood supply due to atherosclerosis, which could be accelerated by genetic and co-morbidity factors. Antioxidant defense system may also be influenced by genetic backgrounds. These may explain the large variations of the onset and extent of AHL among elderly subjects. This article is part of a Special Issue entitled "Annual Reviews 2013".
Project description:BACKGROUND:Cochlear implantation for single-sided deafness (SSD) is the only treatment option with the potential to restore binaural hearing cues. Significant binaural benefit has been measured in adults by speech in noise and localisation tests, who receive a cochlear implant for SSD, however, little is known on the cortical changes that help provide this benefit. In the present study, detection of sound in the auditory cortex, speech testing and localisation was used to investigate the ability of a cochlear implant (CI) to restore auditory cortical latencies and improve binaural benefit in the adult SSD population. METHODS:Twenty-nine adults with acquired single-sided deafness who received a CI in adulthood were studied. Speech perception in noise was tested using the Bamford-Kowal-Bench speech-in-noise test, localisation ability was measured using the auditory speech sounds evaluation (A?E) localisation test and cortical auditory evoked responses, comparing N1-P2 latencies recorded from the normal hearing ear and cochlear implant were used to investigate the synchrony of the cortical pathway from the CI and normal hearing ear (NHe) with binaural hearing function. RESULTS:There was a significant improvement in speech perception in noise in all spatial configurations S0/N0 (Z = -3.066, p<0.002), S0/NHE (Z = -4.031, p<0.001), SCI/NHE (Z = -3.851, p<0.001). Localization significantly improved when tested with the cochlear implant on (p<0.001) with a shorter duration of deafness correlating to a greater improvement in localisation ability F(1:18) = 6.854; p = 0.017). There was no significant difference in N1-P2 latency recorded from the normal hearing ear and the CI. CONCLUSION:Cortical auditory evoked response latencies recorded from the CI and NHe showed no significant difference, indicating that the detection of sound in the auditory cortex occurred simultaneously, providing the cortex with auditory information for binaural hearing.
Project description:We have previously identified neurons tuned to spectral contrast of wideband sounds in auditory cortex of awake marmoset monkeys. Because additive noise alters the spectral contrast of speech, contrast-tuned neurons, if present in human auditory cortex, may aid in extracting speech from noise. Given that this cortical function may be underdeveloped in individuals with sensorineural hearing loss, incorporating biologically-inspired algorithms into external signal processing devices could provide speech enhancement benefits to cochlear implantees. In this study we first constructed a computational signal processing algorithm to mimic auditory cortex contrast tuning. We then manipulated the shape of contrast channels and evaluated the intelligibility of reconstructed noisy speech using a metric to predict cochlear implant user perception. Candidate speech enhancement strategies were then tested in cochlear implantees with a hearing-in-noise test. Accentuation of intermediate contrast values or all contrast values improved computed intelligibility. Cochlear implant subjects showed significant improvement in noisy speech intelligibility with a contrast shaping procedure.
Project description:Cochlear neuropathy resulting from unsafe noise exposure is a life altering condition that affects many people. This hearing dysfunction follows a conserved mechanism where inner hair cell synapses are lost, termed cochlear synaptopathy. Here we investigate cochlear synaptopathy in the FVB/nJ mouse strain as a prelude for the investigation of candidate genetic mutations for noise damage susceptibility. We used measurements of auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to assess hearing recovery in FVB/nJ mice exposed to two different noise levels. We also utilized confocal fluorescence microscopy in mapped whole mount cochlear tissue, in conjunction with deconvolution and three-dimensional modeling, to analyze numbers, volumes and positions of paired synaptic components. We find evidence for significant synapse reorganization in response to both synaptopathic and sub-synaptopathic noise exposures in FVB/nJ. Specifically, we find that the modulation in volume of very small synaptic ribbons correlates with the presence of reduced ABR peak one amplitudes in both levels of noise exposures. These experiments define the use of FVB/nJ mice for further genetic investigations into the mechanisms of noise damage. They further suggest that in the cochlea, neuronal-inner hair cell connections may dynamically reshape as part of the noise response.
Project description:A deficiency of pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of deafness. Pejvakin-deficient (Pjvk-/-) mice also exhibited variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggested a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation showed that the cochlear sensory hair cells and auditory pathway neurons of Pjvk-/- mice and patients were exceptionally vulnerable to sound. Pjvk-/- cochleas displayed features of marked oxidative stress and impaired anti-oxidant defenses. We showed that pejvakin is associated with peroxisomes, and is required for the oxidative stress-induced proliferation of these organelles. In Pjvk-/- hair cells, peroxisomes displayed structural abnormalities after the onset of hearing. Noise-exposure of wild-type mice rapidly upregulated Pjvk cochlear transcription, and triggered peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the anti-oxidant activity of peroxisomes protects the auditory system against noise-induced damage. Three RNA samples was extracted from dissected organ of Corti (OC) for each genotype (Pjvk-/- and Pjvk+/+ mice) and analyzed (triplicate OCmm-1, OCmm-2, and OCmm-3 for Pjvk-/-, and triplicate OCpp-1, OCpp-2, and OCpp-3 for Pjvk+/+).
Project description:Age-related hearing loss (AHL) is the progressive loss of auditory function with aging. The DBA/2J (DBA) mice have been used as a model of AHL and undergoes progressive, age-related hearing loss by 12 weeks of age. Here we analyzed cochlear gene expression of 7-week-old and 36-week-old DBA mice using microarrays. Auditory brainstem response (ABR) analysis confrimed that severe age-related hearing loss occured in 36-week-old mice, whereas moderate hearing loss occured in 7-week-old mice. Comprehensive gene expression analysis identified genes correlated with AHL and revealeed that 15 mitochondrial process categories, including “mitochondrial electron transport chain”, “oxidative phosphorylation”, “respiratory chain complex I”, “respiratory chain complex IV”, and “respiratory chain complex V”, were statistically associated with AHL-correlated genes in the cochlea of 36-week-old DBA mice, and that 25 genes encoding components of the mitochondrial respiratory chain (respiratory chain complex I, IV, and V) were significantly down-regulated in the cochlea. These observations provide evidence that AHL is associated with down-regulation of genes involved in the mitochondrial respiratory chain in the cochlea of DBA mice, and suggest that mitochondrial respiratory chain dysfunction may be a key feature of AHL in mammalian cochlea. Experiment Overall Design: To determine the effects of age-related hearing loss, each 7-week-old sample (n = 3) was compared to each 36-week-old sample (n = 3), generating a total of nine pairwise comparisons. Using DAVIS and EASE, the identified genes were assign to “GO: Biological Process” categories of Gene Ontology Consortium. Furthermore, we used EASE to determine the total number of genes that were assigned to each biological process category, and to perform Fisher exact test. Quality control measures were not used. No replicates were done. Dye swap was not used.
Project description:Excessive exposure to noise damages the principal cochlear structures leading to hearing impairment. Inflammatory and immune responses are central mechanisms in cochlear defensive response to noise but, if unregulated, they contribute to inner ear damage and hearing loss. Transforming growth factor ? (TGF-?) is a key regulator of both responses and high levels of this factor have been associated with cochlear injury in hearing loss animal models. To evaluate the potential of targeting TGF-? as a therapeutic strategy for preventing or ameliorating noise-induced hearing loss (NIHL), we studied the auditory function, cochlear morphology, gene expression and oxidative stress markers in mice exposed to noise and treated with TGF-?1 peptidic inhibitors P17 and P144, just before or immediately after noise insult. Our results indicate that systemic administration of both peptides significantly improved both the evolution of hearing thresholds and the degenerative changes induced by noise-exposure in lateral wall structures. Moreover, treatments ameliorated the inflammatory state and redox balance. These therapeutic effects were dose-dependent and more effective if the TGF-?1 inhibitors were administered prior to inducing the injury. In conclusion, inhibition of TGF-?1 actions with antagonistic peptides represents a new, promising therapeutic strategy for the prevention and repair of noise-induced cochlear damage.
Project description:Betaine-homocysteine S-methyltransferases (BHMTs) are methionine cycle enzymes that remethylate homocysteine; hence, their malfunction leads to hyperhomocysteinemia. Epidemiologic and experimental studies have revealed a correlation between hyperhomocysteinemia and hearing loss. Here, we have studied the expression of methionine cycle genes in the mouse cochlea and the impact of knocking out the Bhmt gene in the auditory receptor. We evaluated age-related changes in mouse hearing by recording auditory brainstem responses before and following exposure to noise. Also, we measured cochlear cytoarchitecture, gene expression by RNA-arrays and quantitative RT-PCR, and metabolite levels in liver and plasma by HPLC. Our results indicate that there is an age-dependent strain-specific expression of methionine cycle genes in the mouse cochlea and a further regulation during the response to noise damage. Loss of Bhmt did not cause an evident impact in the hearing acuity of young mice, but it produced higher threshold shifts and poorer recovery following noise challenge. Hearing loss was associated with increased cochlear injury, outer hair cell loss, altered expression of cochlear methionine cycle genes, and hyperhomocysteinemia. Our results suggest that BHMT plays a central role in the homeostasis of cochlear methionine metabolism and that Bhmt2 up-regulation could carry out a compensatory role in cochlear protection against noise injury in the absence of BHMT.-Partearroyo, T., Murillo-Cuesta, S., Vallecillo, N., Bermúdez-Muñoz, J. M., Rodríguez-de la Rosa, L., Mandruzzato, G., Celaya, A. M., Zeisel, S. H., Pajares, M. A., Varela-Moreiras, G., Varela-Nieto, I. Betaine-homocysteine S-methyltransferase deficiency causes increased susceptibility to noise-induced hearing loss associated with plasma hyperhomocysteinemia.
Project description:BACKGROUND:For patients with single-sided deafness (SSD), restoration of binaural function via cochlear implant (CI) has been shown to improve speech understanding in noise. The objective of this study was to investigate changes in behavioral performance and cortical auditory responses following cochlear implantation. DESIGN:Prospective longitudinal study. SETTING:Tertiary referral center. METHODS:Six adults with SSD were tested before and 12 months post-activation of the CI. Six normal hearing (NH) participants served as experimental controls. Speech understanding in noise was evaluated for various spatial conditions. Cortical auditory evoked potentials were recorded with /ba/ stimuli in quiet and in noise. Global field power and responses at Cz were analyzed. RESULTS:Speech understanding in noise significantly improved with the CI when speech was presented to the CI ear and noise to the normal ear (p<0.05), but remained poorer than that of NH controls (p<0.05). N1 peak amplitude measure in noise significantly increased after CI activation (p<0.05), but remained lower than that of NH controls (p<0.05) at 12 months. After 12 months of CI experience, cortical responses in noise became more comparable between groups. CONCLUSION:Binaural restoration in SSD patients via cochlear implantation improved speech performance noise and cortical responses. While behavioral performance and cortical auditory responses improved, SSD-CI outcomes remained poorer than that of NH controls in most cases, suggesting only partial restoration of binaural hearing.
Project description:Regular exercise significantly slowed age-related hearing loss (AHL) and cochlear degeneration in a well- established murine model. Overall design: We examined the effects of long-term voluntary wheel running on age-related hearing loss in CBA/CaJ mice, a well-established model of AHL. The CBA/CaJ mouse strain displays late-onset age-related hearing loss by 18-20 months of age and is a widely used model of AHL
Project description:Noise exposure causes auditory nerve (AN) degeneration and hearing deficiency, though the proximal biological consequences are not entirely understood. Most AN fibers and spiral ganglion neurons are ensheathed by myelinating glia that provide insulation and ensure rapid transmission of nerve impulses from the cochlea to the brain. Here we show that noise exposure administered to mice of either sex rapidly affects myelinating glial cells, causing molecular and cellular consequences that precede nerve degeneration. This response is characterized by demyelination, inflammation, and widespread expression changes in myelin-related genes, including the RNA splicing regulator Quaking (QKI) and numerous QKI target genes. Analysis of mice deficient in QKI revealed that QKI production in cochlear glial cells is essential for proper myelination of spiral ganglion neurons and AN fibers, and for normal hearing. Our findings implicate QKI dysregulation as a critical early component in the noise response, influencing cochlear glia function that leads to AN demyelination and, ultimately, to hearing deficiency.SIGNIFICANCE STATEMENT Auditory glia cells ensheath a majority of spiral ganglion neurons with myelin, protect auditory neurons, and allow for fast conduction of electrical impulses along the auditory nerve. Here we show that noise exposure causes glial dysfunction leading to myelin abnormality and altered expression of numerous genes in the auditory nerve, including QKI, a gene implicated in regulating myelination. Study of a conditional mouse model that specifically depleted QKI in glia showed that QKI deficiency alone was sufficient to elicit myelin-related abnormality and auditory functional declines. These results establish QKI as a key molecular target in the noise response and a causative agent in hearing loss.