CCR2-dependent recruitment of SPP1+ macrophages promoted noise-induced hearing loss via pyroptosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE346691 | GEO | 2026/09/14
REPOSITORIES: GEO
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Project description:Noise-induced hidden hearing loss (HHL) is a new type of hearing loss that has been identified in recent years and leads to insidious damage to the cochlea, unlike the well-known noise-induced hearing loss (NIHL). However, the cellular and molecular basis for it remains to be elucidated. Here, we established a single-cell transcriptome profile of the C57BL/6J mouse cochlea, in which we describe the transcriptome changes of individual cell types within the cochlea with HHL and NIHL. Mice in the HHL group were exposed to 110 dB of noise for 2 hours, and those in the NIHL group were exposed to 115 dB of noise for 4 hours for 3 days. The cochlea was taken 6 hours after the last noise exposure. The control group was not exposed to noise, with other conditions being the same as those in the noise-exposed group. The results of sequencing at the single-cell level help us gain a deeper understanding of the mechanisms of the development of HHL and NIHL.
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Project description:In the United States, roughly 10% of the population is exposed daily to hazardous levels of noise in the workplace. Twin studies estimate heritability for noise-induced hearing loss (NIHL) of approximately 36%, and strain specific variation in sensitivity has been demonstrated in mice. Based upon the difficulties inherent to the study of NIHL in humans, we have turned to the study of this complex trait in mice. We exposed 5 week-old mice from the Hybrid Mouse Diversity Panel (HMDP) to a 10 kHz octave band noise at 108 dB for 2 hours and assessed the permanent threshold shift 2 weeks post exposure using frequency specific stimuli. These data were then used in a genome-wide association study (GWAS) using the Efficient Mixed Model Analysis (EMMA) to control for population structure. In this manuscript we describe our GWAS, with an emphasis on a significant peak for susceptibility to NIHL on chromosome 17 within a haplotype block containing NADPH oxidase-3 (Nox3). Our peak was detected after an 8 kHz tone burst stimulus. Nox3 mutants and heterozygotes were then tested to validate our GWAS. The mutants and heterozygotes demonstrated a greater susceptibility to NIHL specifically at 8 kHz both on measures of distortion product otoacoustic emissions (DPOAE) and on auditory brainstem response (ABR). We demonstrate that this sensitivity resides within the synaptic ribbons of the cochlea in the mutant animals specifically at 8 kHz. Our work is the first GWAS for NIHL in mice and elucidates the power of our approach to identify tonotopic genetic susceptibility to NIHL.
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Project description:This project investigates proteomic changes associated with noise-induced hearing loss (NIHL) using a rat model. Sprague–Dawley rats were exposed to acute broadband noise (110 dB SPL for 1 hour), resulting in an approximately 40 dB auditory threshold shift measured by cochlear nerve compound action potential (CAP). Proteomic profiling was performed on perilymph, cochlear-sourced cerebrospinal fluid (CSF), whole blood, and plasma to identify molecular responses to acoustic trauma. Comparative analysis revealed significant protein alterations across local cochlear fluids and systemic samples, highlighting pathways related to metabolism, immune responses, complement/coagulation, and lipid regulation. The dataset provides a resource for exploring molecular mechanisms of NIHL and identifying potential systemic biomarkers associated with cochlear injury.
2026-03-20 | PXD075720 | JPOST Repository
Project description:Hearing loss often arises from impairments in multiple genes, complicating therapeutic development. MicroRNAs, as master regulators, offer promising targets for complex diseases. We explored miR-96’s roles in hair cell (HC) function and noise-induced hearing loss (NIHL), finding that miR-96-/-, not miR-96+/-, mice exhibited progressive hearing loss due to gene regulatory network dysregulation from miR-96 loss in HCs not spiral ganglion neurons (SGNs). Viral-mediated delivery of miR-96 into the inner ear partially rescued hearing of miR-96-/- mice. Tamoxifen-induced depletion of miR-96 in adult UBCCreERT2/+; miR-96fl/fl mice led to hearing loss, with Bach2, Gabra2, Gabra4, Grk1 up-regulation, and Tnn, Col11a1, Gjb3 and Hnf4a down-regulation. Furthermore, noise trauma reduced miR-96, altering Bach2, Bcl2l1, Slc26a9, Gabrb1, Grk1, Nos2 and Cyp1a1 expression, while miR-96 overexpression protected hearing against noise by reversing the expression of Bach2, Bcl2l1 and Cyp1a1. Our findings underscore miR-96’s essential role in adult hearing maintenance and NIHL prevention, presenting it as a promising therapeutic target.
2025-04-21 | GSE247473 | GEO
Project description:Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). However, effective treatments are completely lacking. We investigated cellular stress responses induced by loud noise in a mouse model of cochlear synaptopathy and tested whether selective activation of the dominant pathway identified could confer protection. RNA sequencing and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood–labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin–proteasome function in SGNs. Notably, TRC051384 treatment improved auditory brainstem response recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. These findings establish proteotoxic stress in SGNs as a central driver of NIHL and identify HSF1 activation as a promising therapeutic strategy.
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Project description:Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). However, effective treatments are completely lacking. We investigated cellular stress responses induced by loud noise in a mouse model of cochlear synaptopathy and tested whether selective activation of the dominant pathway identified could confer protection. RNA sequencing and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood–labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin–proteasome function in SGNs. Notably, TRC051384 treatment improved auditory brainstem response recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. These findings establish proteotoxic stress in SGNs as a central driver of NIHL and identify HSF1 activation as a promising therapeutic strategy.
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Project description:Hearing functions through the mechanical transduction of inner ear sensory cells, hair cells, and their connections to the auditory neurons, which convert the stimuli into electrical signals to be detected by the brain. Noise-induced hearing loss (NIHL) caused by exposure to excessively sounds cannot be medically corrected. Strategies to overcome the apparently irreversible noise-induced hearing loss (NIHL) in mammals become paramount for hearing treatment. The drug has been reported in attenuating inflammation in different species. Here, we tested the effect of the drug in acoustic trauma. We carried out single-cell RNA sequencing to examine the gene expression profiles comparing Drug group with Untreated group in response to the acoustic trauma.
2023-06-01 | GSE218326 | GEO
Project description:The molecular mechanisms underlying the great differences in susceptibility to noise-induced hearing loss (NIHL) exhibited by both humans and laboratory animals are unknown. Using microarray technology, the present study demonstrates that the effects of noise overexposure on the expression of molecules likely to be important to the development of NIHL differ among inbred mice that have distinctive susceptibilities to NIHL including B6.CAST, 129X1/SvJ, and 129S1/SvImJ. The noise-exposure protocol produced, on average, a permanent loss of about 40 dB in sensitivity for auditory brainstem responses in susceptible B6.CAST mice, but no threshold elevations for the two resistant 129S1/SvImJ and 129X1/SvJ substrains. Measurements of noise-induced gene expression changes 6 h after the noise exposure revealed significant alterations in the expression levels of 48 genes in the resistant mice, while by these same criteria, there were seven differentially expressed genes in the susceptible B6.CAST mice. Differentially expressed genes in both groups of mice included subsets of transcription factors. However, only in the resistant mice was there a significant induction of proteins involved in cell-survival pathways such as HSP70, HSP40, p21, GADD45ï¢, Ier3, and Nfï«ï¢iïº. Moreover, increased expression of three of these factors after noise was confirmed at the protein level. Drastically enhanced HSP70, GADD45ï¢, and p21 immunostaining were detected 6 h after the noise exposure in subsets of cells of the lateral wall, spiral limbus, and organ of Corti as well as in cochlear nerve fibers. Upregulation of these proteins after noise exposure likely contributes to the prevalence of survival cellular pathways and thus to the resistance to NIHL that is characteristic of the 129X1/SvJ mice. Experiment Overall Design: Female 10-wk-old mice of the B6.CAST and 129X1/SvJ strains were divided randomly into non-noise control and noise-exposure groups. The non-noise mice served as controls in the gene-profiling experiments to control for the stress induced by experimenter handling and/or confinement of the mice in the noise-exposure chamber that was not directly related to the noise. This mice were in the noise chamber for a sham exposure. In contrast, the ânoiseâ groups were exposed to a 105-dB SPL, 10-kHz octave band of noise for 1 h and sacrificed 6 h after the exposure. Of each of these major groups, eight mice were used for each of three 129X1/SvJ control and three noise-exposed 129X1/SvJ arrays and two B6.CAST control and two noise-exposed B6.CAST arrays. Consequently within each subgroup the arrays are biological replicates.
2008-10-25 | E-GEOD-8342 | biostudies-arrayexpress
Project description:The molecular mechanisms underlying the great differences in susceptibility to noise-induced hearing loss (NIHL) exhibited by both humans and laboratory animals are unknown. Using microarray technology, the present study demonstrates that the effects of noise overexposure on the expression of molecules likely to be important to the development of NIHL differ among inbred mice that have distinctive susceptibilities to NIHL including B6.CAST, 129X1/SvJ, and 129S1/SvImJ. The noise-exposure protocol produced, on average, a permanent loss of about 40 dB in sensitivity for auditory brainstem responses in susceptible B6.CAST mice, but no threshold elevations for the two resistant 129S1/SvImJ and 129X1/SvJ substrains. Measurements of noise-induced gene expression changes 6 h after the noise exposure revealed significant alterations in the expression levels of 48 genes in the resistant mice, while by these same criteria, there were seven differentially expressed genes in the susceptible B6.CAST mice. Differentially expressed genes in both groups of mice included subsets of transcription factors. However, only in the resistant mice was there a significant induction of proteins involved in cell-survival pathways such as HSP70, HSP40, p21, GADD45beta, Ier3, and Nf-kappaB. Moreover, increased expression of three of these factors after noise was confirmed at the protein level. Drastically enhanced HSP70, GADD45beta, and p21 immunostaining were detected 6 h after the noise exposure in subsets of cells of the lateral wall, spiral limbus, and organ of Corti as well as in cochlear nerve fibers. Upregulation of these proteins after noise exposure likely contributes to the prevalence of survival cellular pathways and thus to the resistance to NIHL that is characteristic of the 129X1/SvJ mice. Keywords: effects of noise exposure in distinct inbred mice
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