Abstract
The transcriptomic landscape of mice with primary auditory neurons degeneration (PAND) indicates key pathways in its pathogenesis, including complement cascades, immune responses, tumor necrosis factor (TNF) signaling pathway, and cytokine-cytokine receptor interaction. Toll-like receptors (TLRs) are important immune and inflammatory molecules that have been shown to disrupt the disease network of PAND. In a PAND model involving administration of kanamycin combined with furosemide to destroy cochlear hair cells, Tlr 2/4 double knockout (DKO) mice had auditory preservation advantages, which were mainly manifested at 4–16 kHz. DKO mice and wild type (WT) mice had completely damaged cochlear hair cells on the 30th day, but the density of spiral ganglion neurons (SGN) in the Rosenthal canal was significantly higher in the DKO group than in the WT group. The results of immunohistochemistry for p38 and p65 showed that the attenuation of SGN degeneration in DKO mice may not be mediated by canonical Tlr signaling pathways. The SGN transcriptome of DKO and WT mice indicated that there was an inverted gene set enrichment relationship between their different transcriptomes and the SGN degeneration transcriptome, which is consistent with the morphology results. Core module analysis suggested that DKO mice may modulate SGN degeneration by activating two clusters, and the involved molecules include EGF, STAT3, CALB2, LOX, SNAP25, CAV2, SDC4, MYL1, NCS1, PVALB, TPM4, and TMOD4.
Highlights
Sensorineural hearing loss (SNHL), the most common sensory deficit in the world, affects nearly 300 million individuals and costs 980 billion USD annually
spiral ganglion neurons (SGN) degeneration was successfully induced by the destruction of cochlear hair cells, which is consistent with the results of previous studies (Hu et al, 2017; Ye et al, 2019)
The structure of the organ of Corti was almost completely collapsed and destroyed, and nearly no sensory epithelial cells remained in the middle turn on the 30th day after kanamycin and furosemide injection, while almost only a continuous layer of flattened cubic epithelial cells remained on the basilar membrane (Figure 2B)
Summary
Sensorineural hearing loss (SNHL), the most common sensory deficit in the world, affects nearly 300 million individuals and costs 980 billion USD annually. SNHL mainly arises from the damage or death of auditory hair cells Researchers have confirmed that many environmental insults immediately and directly damage hair cells, but the resulting SGN degeneration is chronic because of a lack of neurotrophic factors and peripheral stimuli (Kujawa and Liberman, 2009; Makary et al, 2011; Wu et al, 2021). Spiral ganglion neurons would mainly have Ic subtype loss if the loss of peripheral stimulus occurs, which is similar to SGN aging (Shrestha et al, 2018). Histology of 12 temporal bones from 6 subjects indicated that higher residual SGNs could predict better performance after implantation in a given patient (Riss et al, 2008; Cusumano et al, 2017)
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