A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma

Cell Reports, Journal Year: 2021, Volume and Issue: 36(13), P. 109758 - 109758

Published: Sept. 1, 2021

Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells inner ear, dysfunction its lateral wall, axonal retraction type 1C spiral ganglion neurons, and activation immune response. We use RiboTag single-cell RNA sequencing survey cell-type-specific molecular landscape mouse ear before after noise trauma. identify induction transcription factors STAT3 IRF7 immune-related genes across all cell-types. Yet, transcriptomic changes dominate The ATF3/ATF4 stress-response pathway is robustly induced in 1A noise-resilient potassium transport are downregulated mRNA metabolism outer hair cells, deafness-associated most cell types. This resource available via Gene Expression Analysis Resource (gEAR; https://umgear.org/NIHL) provides blueprint for rational development drugs prevent treat NIHL.

Language: Английский

---

Protection of cochlear synapses from noise-induced excitotoxic trauma by blockade of Ca ²⁺ -permeable AMPA receptors

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(7), P. 3828 - 3838

Published: Feb. 3, 2020

Exposure to loud sound damages the postsynaptic terminals of spiral ganglion neurons (SGNs) on cochlear inner hair cells (IHCs), resulting in loss synapses, a process termed synaptopathy. Glutamatergic neurotransmission via α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type receptors is required for synaptopathy, and here we identify possible involvement GluA2-lacking Ca2+-permeable AMPA (CP-AMPARs) using IEM-1460, which has been shown block AMPARs. In CBA/CaJ mice, 2-h exposure 100-dB pressure level octave band (8 16 kHz) noise results no permanent threshold shift but does cause significant synaptopathy reduction auditory brainstem response (ABR) wave-I amplitude. Chronic intracochlear perfusion IEM-1460 artificial perilymph (AP) into adult mice prevented decrease ABR amplitude relative AP alone. Interestingly, itself did not affect threshold, presumably because GluA2-containing AMPARs can sustain sufficient synaptic transmission evoke low-threshold responses during blockade On individual densities, observed nanodomains alongside regions with robust GluA2 expression, consistent idea that synapses have both CP-AMPARs Ca2+-impermeable SGNs innervating same IHC differ their vulnerability noise. We found local heterogeneity among abundance subunits may underlie such differences vulnerability. propose role noise-induced whereby account excitotoxic susceptibility. These data suggest means maintaining normal hearing thresholds while protecting against selective CP-AMPARs.

Language: Английский

---

Macrophages Promote Repair of Inner Hair Cell Ribbon Synapses following Noise-Induced Cochlear Synaptopathy

Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 43(12), P. 2075 - 2089

Published: Feb. 21, 2023

Resident cochlear macrophages rapidly migrate into the inner hair cell synaptic region and directly contact damaged connections after noise-induced synaptopathy. Eventually, such synapses are spontaneously repaired, but precise role of in degeneration repair remains unknown. To address this, were eliminated using colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Sustained treatment with PLX5622 CX 3 CR1 GFP /+ mice both sexes led to robust elimination resident (∼94%) without significant adverse effects on peripheral leukocytes, function, structure. At day (d) post noise exposure 93 or 90 dB SPL for 2 hours, degree hearing loss synapse comparable presence absence macrophages. 30 d exposure, appeared repaired However, macrophages, was significantly reduced. Remarkably, cessation treatment, repopulated cochlea, leading enhanced repair. Elevated auditory brainstem response thresholds reduced Peak amplitudes showed limited recovery recovered similarly Cochlear neuron augmented preservation exposure. While central microglia depletion remain be investigated, these data demonstrate that do not affect necessary sufficient restore function SIGNIFICANCE STATEMENT The between cells spiral ganglion neurons can lost because over biological aging. This may represent most common causes sensorineural also known as hidden loss. Synaptic results degradation information, difficulty listening noisy environments other perceptual disorders. We cochlea following synaptopathic Our work reveals a novel innate-immune cells, repair, could harnessed regenerate ribbon noise- age-linked synaptopathy, loss, associated anomalies.

Language: Английский

---

Hidden hearing loss: Fifteen years at a glance

Hearing Research, Journal Year: 2024, Volume and Issue: 443, P. 108967 - 108967

Published: Jan. 30, 2024

Hearing loss affects approximately 18% of the population worldwide. difficulties in noisy environments without accompanying audiometric threshold shifts likely affect an even larger percentage global population. One potential causes hidden hearing is cochlear synaptopathy, synapses between inner hair cells (IHC) and auditory nerve fibers (ANF). These are most vulnerable structures cochlea to noise exposure or aging. The deafferentation, i.e., afferent information, whose downstream effect information that sent higher-order processing stages. Understanding physiological perceptual effects this early deafferentation might inform interventions prevent later, more severe loss. In past decade, a large body work has been devoted better understand loss, including their corresponding impact on pathway, use measures for clinical diagnosis deafferentation. This review synthesizes findings from studies humans animals answer some key questions field, it points gaps knowledge warrant investigation. Specifically, recent suggest electrophysiological have function as indicators humans, but research needed these be included part test battery.

Language: Английский

---

Spatial patterns of noise-induced inner hair cell ribbon loss in the mouse mid-cochlea

iScience, Journal Year: 2024, Volume and Issue: 27(2), P. 108825 - 108825

Published: Jan. 8, 2024

In the mammalian cochlea, moderate acoustic overexposure leads to loss of ribbon-type synapse between inner hair cell (IHC) and its postsynaptic spiral ganglion neuron (SGN), causing a reduced dynamic range hearing but not permanent threshold elevation. A prevailing view is that such ribbon (known as synaptopathy) selectively impacts low-spontaneous-rate high-threshold SGN fibers contacting predominantly modiolar IHC face. However, spatial pattern synaptopathy remains scarcely characterized in most sensitive mid-cochlear region, where two morphological subtypes with distinct size gradients coexist. Here, we used volume electron microscopy investigate noise exposure-related changes mouse IHCs without loss. Our quantifications reveal differ worst-hit area synaptopathy. Moreover, show relative enrichment mitochondria surviving terminals, providing key experimental evidence for long-proposed role SGN-terminal synaptic vulnerability.

Language: Английский

---

Lack of Fractalkine Receptor on Macrophages Impairs Spontaneous Recovery of Ribbon Synapses After Moderate Noise Trauma in C57BL/6 Mice

Frontiers in Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: June 13, 2019

Noise trauma causes loss of synaptic connections between cochlear inner hair cells (IHCs) and the spiral ganglion neurons (SGNs). Such can trigger slow progressive degeneration SGNs. Macrophage fractalkine signaling is critical for neuron survival in injured cochlea, but its role synaptopathy unknown. Fractalkine, a chemokine, constitutively expressed by SGNs signals via receptor CX3CR1 that on macrophages. The present study characterized immune response examined function repair synapses following noise trauma. Adult mice wild type, heterozygous knockout C57BL/6 background were exposed 2 h to an octave band at 90 dB SPL. exposure caused temporary shifts hearing thresholds without any evident have intact signaling. Enhanced macrophage migration toward IHC-synaptic region was observed immediately after all genotypes. Synaptic immunolabeling revealed rapid ribbon throughout basal turn cochlea damaged spontaneously recovered with CX3CR1. However, (KO) animals displayed enhanced correlated attenuated suprathreshold neural responses higher frequencies. Exposed KO also exhibited increased IHCs SGN cell bodies compared mice. These results indicate macrophages promote moderate requires

Language: Английский

---

Synaptic migration and reorganization after noise exposure suggests regeneration in a mature mammalian cochlea

Scientific Reports, Journal Year: 2020, Volume and Issue: 10(1)

Published: Nov. 17, 2020

Abstract Overexposure to intense noise can destroy the synapses between auditory nerve fibers and their hair cell targets without destroying cells themselves. In adult mice, this synaptopathy is immediate largely irreversible, whereas, in guinea pigs, counts of immunostained synaptic puncta recover with increasing post-exposure survival. Here, we asked whether recovery simply reflects changes immunostaining, or there actual retraction extension neurites and/or synaptogenesis. Analysis numbers, sizes spatial distribution pre- post-synaptic markers on cochlear inner cells, pigs surviving from 1 day 6 months after a synaptopathic exposure, shows dramatic re-organization during period which synapse 16 91% normal most affected regions. Synaptic move all over membrane recovery, translocating far positions at basolateral pole, auditory-nerve terminals extend towards cell’s apical end re-establish contact them. These observations provide stronger evidence for spontaneous neural regeneration mature mammalian cochlea than be inferred alone.

Language: Английский

---

Noise-Induced Hearing Loss: Updates on Molecular Targets and Potential Interventions

Neural Plasticity, Journal Year: 2021, Volume and Issue: 2021, P. 1 - 16

Published: July 6, 2021

Noise overexposure leads to hair cell loss, synaptic ribbon reduction, and auditory nerve deterioration, resulting in transient or permanent hearing loss depending on the exposure severity. Oxidative stress, inflammation, calcium overload, glutamate excitotoxicity, energy metabolism disturbance are main contributors noise-induced (NIHL) up now. Gene variations also identified as NIHL related. Glucocorticoid is only approved medication for treatment. New pharmaceuticals targeting oxidative neuropathy emerging, highlighted by nanoparticle-based drug delivery system. Given complexity of pathogenesis behind NIHL, deeper more comprehensive studies still need be fulfilled.

Language: Английский

---

Auditory-nerve responses in mice with noise-induced cochlear synaptopathy

Journal of Neurophysiology, Journal Year: 2021, Volume and Issue: 126(6), P. 2027 - 2038

Published: Nov. 17, 2021

Noise-induced damage to synapses between inner hair cells and auditory-nerve fibers (ANFs) can occur without permanent cell damage, resulting in pathophysiology that “hides” behind normal thresholds. Prior single-fiber neurophysiology guinea pig suggested noise selectively targets high-threshold ANFs. Here, we show the lingering differs mouse, with both ANF groups affected a paradoxical gain-of-function surviving low-threshold fibers, including increased onset rate, decreased jitter, reduced maskability.

Language: Английский

---

Intrinsic mechanism and pharmacologic treatments of noise-induced hearing loss

Theranostics, Journal Year: 2023, Volume and Issue: 13(11), P. 3524 - 3549

Published: Jan. 1, 2023

Noise accounts for one-third of hearing loss worldwide.Regretfully, noise-induced (NIHL) is deemed to be irreversible due the elusive pathogenic mechanisms that have not been fully elucidated.The complex interaction between genetic and environmental factors, which influences numerous downstream molecular cellular events, contributes NIHL.In clinical settings, there are no effective therapeutic drugs other than steroids, only treatment option patients with NIHL.Therefore, need NIHL currently unmet, along recent progress in our understanding underlying regulatory mechanisms, has led a lot new literatures focusing on this field.The emergence novel technologies modify local drug delivery inner ear development promising approaches, under investigation.In comprehensive review, we focus outlining analyzing basics potential therapeutics NIHL, as well application biomaterials nanomedicines delivery.The objective review provide an incentive NIHL's fundamental research future translation.

Language: Английский

---