Dataset Information

Noise-Induced Dysregulation of Quaking RNA Binding Proteins Contributes to Auditory Nerve Demyelination and Hearing Loss.

ABSTRACT: 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.

SUBMITTER: Panganiban CH

PROVIDER: S-EPMC5858596 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Noise-Induced Dysregulation of <i>Quaking</i> RNA Binding Proteins Contributes to Auditory Nerve Demyelination and Hearing Loss.

Panganiban Clarisse H CH Barth Jeremy L JL Darbelli Lama L Xing Yazhi Y Zhang Jianning J Li Hui H Noble Kenyaria V KV Liu Ting T Brown LaShardai N LN Schulte Bradley A BA Richard Stéphane S Lang Hainan H

The Journal of neuroscience : the official journal of the Society for Neuroscience 20180206 10

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 n ...[more]

PMID: 29437856

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Project description:Although hippocampal changes due to noise-induced hearing loss have been suggested, little is known about the miRNA levels due to these hippocampal changes. Three-week-old Sprague-Dawley rats were divided into noise and control groups (n = 20 per group). The noise group rats were exposed to white Gaussian noise (115 dB SPL, 4 hours per day) for three days. One day after noise exposure, the hippocampi of rats were harvested and miRNA expressions were analyzed using the Affymetrix miRNA 4.0 microarray (n = 6 per group). The predicted target genes of each miRNA were retrieved, and the pathways related to the predicted target genes were analyzed. miR-758-5p, miR-210-5p, miR-370-5p, miR-652-5p, miR-3544, miR-128-1-5p, miR-665, miR-188-5p, and miR-874-5p expression increased in the hippocampal tissue of the noise group compared to that in the control group. The overlapping predicted target genes included Bend4, Creb1, Adcy6, Creb5, Kcnj9, and Pten. The pathways related to these genes were the estrogen signaling pathway, vasopressin-regulated water reabsorption, thyroid hormone synthesis, aldosterone synthesis and secretion, insulin secretion, circadian entrainment, insulin resistance, cholinergic synapse, dopaminergic synapse, cGMP-PKG signaling pathway, cAMP signaling pathway, PI3K-Akt signaling pathway, TNF signaling pathway, and AMPK signaling pathway. miR-448-3p, miR204-5p, and miR-204-3p expression decreased in the hippocampal tissue of the noise group compared to that in the control group. The overlapping predicted target genes of these three miRNAs were Rps6kas, Nfactc3, Rictor, Spred1, Cdh4, Cdh6, Dvl3, and Rcyt1b. Pathway analysis suggested that the Wnt signaling pathway is related to Dvl3 and Nfactc3. Noise-induced hearing loss dysregulates miR-758-5p, miR210-5p, miR370-5p, miR-652-5p, miR-3544, miR-128-1-5p, miR-665, miR-188-5p, miR-874-5p, miR-448-3p, miR-204-5p, miR-204-3p, and miR-140-5p expression in the hippocampus. These miRNAs have been predicted to be associated with hormonal, inflammatory, and synaptic pathways.

Project description:Key pointsSound information is transmitted by different subtypes of spiral ganglion neurons (SGN) from the ear to the brain. Selective damage of SGN peripheral synapses (cochlear synaptopathy) is widely recognized as one of the primary mechanisms of hearing loss, whereas the mechanisms at the SGN central synapses remain unclear. We report that different subtypes of SGN central synapses converge at different ratios onto individual target cochlear nucleus neurons with distinct physiological properties, and show biased morphological and physiological changes during age-related hearing loss (ARHL). The results reveal a new dimension in cochlear nucleus neural circuitry that systematically reassembles and processes auditory information from different SGN subtypes, which is altered during ageing and probably contributes to the development of ARHL. In addition to known cochlear synaptopathy, the present study shows that SGN central synapses are also pathologically changed during ageing, which collectively helps us better understand the structure and function of SGNs during ARHL.AbstractSound information is transmitted from the cochlea to the brain by different subtypes of spiral ganglion neurons (SGN), which show varying degrees of vulnerability under pathological conditions. Selective cochlear synaptopathy, the preferential damage of certain subtypes of SGN peripheral synapses, has been recognized as one of the main mechanisms of hearing loss. The organization and function of the auditory nerve (AN) central synapses from different subtypes of SGNs remain unclear, including how different AN synapses reassemble onto individual neurons in the cochlear nucleus, as well as how they differentially change during hearing loss. Combining immunohistochemistry with electrophysiology, we investigated the convergence pattern and subtype-specific synaptopathy of AN synapses at the endbulb of Held, as well as the response properties of their postsynaptic bushy neurons in CBA/CaJ mice of either sex under normal hearing and age-related hearing loss (ARHL). We found that calretinin-expressing (type Ia ) and non-calretinin-expressing (type Ib /Ic ) endbulbs converged along a continuum of different ratios onto individual bushy neurons with varying physiological properties. Endbulbs degenerated during ageing in parallel with ARHL. Furthermore, the degeneration was more severe in non-calretinin-expressing synapses, which correlated with a gradual decrease in bushy neuron subpopulation predominantly innervated by these inputs. These synaptic and cellular changes were profound in middle-aged mice when their hearing thresholds were still relatively normal and prior to severe ARHL. Our findings suggest that biased AN central synaptopathy and the correlated shift in cochlear nucleus neuronal composition play significant roles in weakened auditory input and altered central auditory processing during ARHL.

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Dataset Information

Noise-Induced Dysregulation of Quaking RNA Binding Proteins Contributes to Auditory Nerve Demyelination and Hearing Loss.

Publications

Noise-Induced Dysregulation of <i>Quaking</i> RNA Binding Proteins Contributes to Auditory Nerve Demyelination and Hearing Loss.

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