Mouse Model Of Age-related Hearing Loss Research Articles

Transcriptomic analysis highlights cochlear inflammation associated with age-related hearing loss in C57BL/6 mice using next generation sequencing.

BackgroundIn our aging society, age-related hearing loss (AHL) is the most common sensory disorder in old people. Much progress has been made in understanding the pathological process of AHL over the past few decades. However, the mechanism of cochlear degeneration during aging is still not fully understood.MethodsNext generation sequencing technique was used to sequence the whole transcriptome of the cochlea of C57BL/6 mice, a mouse model of AHL. Differentially expressed genes (DEGs) were identified using the Cuffdiff software. GO and KEGG pathway enrichment analyses of the DEGs were implemented by using the GOseq R package and KOBAS software, respectively.ResultsA total of 731 genes (379 up- and 352 down-regulated) were revealed to be differentially expressed in the cochlea of aged mice compared to the young. Many genes associated with aging, apoptosis, necroptosis and particularly, inflammation were identified as being significantly modulated in the aged cochlea. GO and KEGG analyses of the upregulated DEGs revealed that the most enriched terms were associated with immune responses and inflammatory pathways, whereas many of the downregulated genes are involved in ion channel function and neuronal signaling. Real-time qPCR showed that H2O2 treatment significantly induced the expression of multiple inflammation and necroptosis-related genes in HEI-OC1 cells.ConclusionUsing next generation sequencing, our transcriptomic analysis revealed the differences of gene expression pattern with age in the cochlea of C57BL/6 mice. Our study also revealed multiple immune and inflammatory transcriptomic changes during cochlear aging and provides new insights into the molecular mechanisms underlying cochlear inflammation in AHL.

Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea

Pathologies of senescence, in particular those of neurosensory organs represent an important health problem. The improvement of the life expectation entails the fast increase of the frequency of the age-related hearing loss (ARHL) in the population. There are numerous factors that contribute to this process, which include altered vascular characteristics, hypoxia/ischemia, genetic mutations and production of reactive oxygen species. We were interested in understanding the mechanisms involved in the cochlear degeneration in a mouse model of ARHL, the cd/1 mice. Since in human, hypoxia/ischemia is an important pathogenetic factor for inner ear disease, the regulation of HIF-1 activity in the cochlea, the presence of radical oxygen species in the cochlea and its subsequent disturbances of cellular signaling cascades were investigated. In this study, we explored auditory function of cd/1 mice at the age of 4, 12 and 24 weeks and correlated it with the presence of oxidative damage in the cochlea, and cochlear HIF-1 responsive target genes regulation, involved in pathways promoting inflammation such as tumor necrosis factor (TNF-α), or cell death with the p53 protein, Bax protein and surviving factors with insulin-like growth factor-1 (IGF-1). After implantation of electrodes for auditory nerve acoustic thresholds measurements, we analyzed every cochlea. First, we confirmed that the cd/1 mice presented a characteristic profile of ARHL starting at 12 weeks of age. Then, according to our previous report [Riva, C., Longuet, M., Lucciano, M., Magnan, J., Lavieille, J.P., 2005. Implication of mitochondrial apoptosis in neural degeneration in a murin model for presbyacusis. Rev. Laryngol. Otol. Rhinol. 126 (2), 67–74], we noticed many alterations in the cochlea. Histologically, at 4 weeks, intensive HIF-1 α expression was detected in the cochlea followed by ROS formation at 12 weeks, which may lead to cochlear degeneration and induction the onset of ARHL in the cd/1 mice model. In the cochlea, while the inner and the outer hair cells remained intact at 4 and 12 weeks, the spiral ganglion was more altered. Moreover, the Schwann cells of the spiral ganglion seemed to be more vulnerable to free radical damage than the neurons and degenerated more rapidly. The mechanisms of degeneration in the spiral ganglion involved a caspase-3 and Bax mediated-apoptosis via p53 protein accumulation. Since oxygen radicals are required for the post-translational stabilization of HIF-1 α during hypoxia, the tandem “ HIF-ROS ” induced multiple reactions within the cochlea, like a strong inflammatory response with increased expression of TNF- α, and inhibition of neuronal protection mechanisms with repression of IGF-1.