Cochlin Deficiency Protects Against Noise-Induced Hearing Loss

Abstract

Cochlin is the most abundant protein in the inner ear. To study its function in response to noise trauma, we exposed adolescent wild-type (Coch+/+) and cochlin knock-out (Coch–/–) mice to noise (8–16 kHz, 103 dB SPL, 2 h) that causes a permanent threshold shift and hair cell loss. Two weeks after noise exposure, Coch–/– mice had substantially less elevation in noise-induced auditory thresholds and hair cell loss than Coch+/+ mice, consistent with cochlin deficiency providing protection from noise trauma. Comparison of pre-noise exposure thresholds of auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) in Coch–/– mice and Coch+/+ littermates revealed a small and significant elevation in thresholds of Coch–/– mice, overall consistent with a small conductive hearing loss in Coch–/– mice. We show quantitatively that the pro-inflammatory component of cochlin, LCCL, is upregulated after noise exposure in perilymph of wild-type mice compared to unexposed mice, as is the enzyme catalyzing LCCL release, aggrecanase1, encoded by Adamts4. We further show that upregulation of pro-inflammatory cytokines in perilymph and cochlear soft-tissue after noise exposure is lower in cochlin knock-out than wild-type mice. Taken together, our data demonstrate for the first time that cochlin deficiency results in conductive hearing loss that protects against physiologic and molecular effects of noise trauma.

Cochlin Deficiency Protects Aged Mice from Noise-Induced Hearing Loss

“…A similar observation can be drawn from ABR measurements where thresholds of Coch −/− mice recovered to baseline values one week after noise exposure except at 16 kHz while ABR thresholds of Coch +/+ mice remained elevated at all frequencies. Similar to our study, Seist et al discovered that Coch −/− mice had significantly lower DPOAE-and ABR thresholds shifts when compared to Coch +/+ mice following exposure to 103 dB of broadband noise (8–16 kHz) for 2 h [ 18 ]. Threshold shifts recovered after one week are considered as TTS.…”

“…To assess whether cochlin could be responsible for the difference in hearing thresholds that was observed between Coch +/+ and Coch −/− mice after noise exposure, Coch expression in wildtype mice was assessed using an anti -COCH antibody. We found that Coch expression was significantly decreased in Coch +/+ mice after noise exposure, which could be explained by the observation of Seist et al that cleaved cochlin is upregulated in Coch +/+ mice following noise exposure [ 18 ].…”

“…Staining revealed that there was no loss of hair cells and neurons in both groups indicating another mechanism is responsible for the difference in response to noise exposure that is observed between Coch +/+ and Coch −/− mice. In contrast, Seist et al observed OHC loss in both Coch −/− and Coch +/+ mice after noise exposure where the number of surviving OHC was significantly higher in Coch −/− mice when compared to wildtype animals [ 18 ]. It is important to note that the mice that were used in their study were only 6 weeks old and NIHL vulnerability varies with age at exposure.…”

“…Seist et al observed an increased expression of the Adamts4 gene which is responsible for the cleavage of the LCCL domain of cochlin initiating immune response. In addition, the expression of genes encoding for the proinflammatory cytokines IL6 and CXCL1 was upregulated in the perilymph of Coch +/+ mice 6 h post noise exposure when compared to Coch −/− mice [ 18 ]. These results suggest that cochlin may be involved in the immune response after noise exposure in young mice, but this upregulation does not lead to an increase of macrophages in the inner ear of older mice as indicated by our findings.…”

“…Seist et al concluded that the difference in threshold shifts after noise exposure in Coch −/− mice is due to a small conductive hearing loss observed at the age of 6 weeks in these mice attenuating the amount of noise carried in the cochlea and thereby preventing some of the noise-induced damage [ 18 ]. In our study, we followed up Coch +/+ and Coch −/− mice until the age of two years to assess hearing function with six months being the first timepoint where measurements were performed.…”