Noise induces Ca2+ signaling waves and Chop/S-Xbp1 expression in the hearing cochlea
Yesai Park, Jiang Li, Noura Ismail Mohamad, Ian R. Matthews, Peu Santra, Elliott H. Sherr, Dylan K. Chan
Yesai Park, Jiang Li, Noura Ismail Mohamad, Ian R. Matthews, Peu Santra, Elliott H. Sherr, Dylan K. Chan
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Research Article Otology

Noise induces Ca2+ signaling waves and Chop/S-Xbp1 expression in the hearing cochlea

Abstract

Exposure to loud noise is a common cause of acquired hearing loss. Disruption of subcellular calcium homeostasis and downstream stress pathways in the endoplasmic reticulum and mitochondria, including the unfolded protein response (UPR), have been implicated in the pathophysiology of noise-induced hearing loss. However, studies on the association between calcium homeostasis and stress pathways have been limited due to limited ability to measure calcium dynamics in mature-hearing, noise-exposed mice. We used a genetically encoded calcium indicator mouse model in which GCaMP6f is expressed specifically in hair cells or supporting cells under control of Myo15Cre or Sox2Cre, respectively. We performed live calcium imaging and UPR gene expression analysis in 8-week-old mice exposed to levels of noise that cause cochlear synaptopathy (98 db sound pressure level [SPL]) or permanent hearing loss (106 dB SPL). UPR activation occurred immediately after noise exposure, and the pattern of UPR activation was dependent on noise level, with the proapoptotic pathway upregulated only after 106 dB noise exposure. Spontaneous calcium transients in hair cells and intercellular calcium waves in supporting cells, which are present in neonatal cochleae, were quiescent in mature-hearing cochleae but reactivated upon noise exposure. Noise exposure of 106 dB was associated with more persistent and expansive intercellular Ca2+ signaling wave activity. These findings demonstrate a strong and dose-dependent association between noise exposure, UPR activation, and changes in calcium homeostasis in hair cells and supporting cells, suggesting that targeting these pathways may be effective to develop treatments for noise-induced hearing loss.

Authors

Yesai Park, Jiang Li, Noura Ismail Mohamad, Ian R. Matthews, Peu Santra, Elliott H. Sherr, Dylan K. Chan

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Figure 6

Ca2+ activity in adult cochlear supporting cells.

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Ca2+ activity in adult cochlear supporting cells. (A) Live imaging of no...
(A) Live imaging of noise-exposed Sox2Cre-GCaMP6f adult cochlea. Preexposure to 98 dB SPL noise induces ICS wave activity in supporting cells of the adult cochlea, including pillar cells (PC) and Dieters’ cells (DC). Time interval between successive images is 8 seconds. Scale bar: 20 μm. Representative video also shown in Supplemental Video 5. (B and C) Effect of noise exposure on Ca2+ peak and ICS wave activity. Compared with control unexposed cochleae, cochleae from mice exposed to 98 dB as well as 106 dB noise showed increased number of Ca2+ peaks (B) and ICS waves (C) 1 hour after beginning of noise exposure. Twenty-four hours after completion of noise exposure, 98 dB–exposed mice had no significant increase in either Ca2+ peaks or ICS waves compared with control, whereas 106 dB–exposed mice had persistent elevation in both Ca2+ peak activity and ICS waves. (D and E) Effect of noise exposure on Ca2+ peak decay time. Ca2+ peak decay time is compared under the indicated conditions at the individual peak (D) or cochlea (E) level. (F and G) Effect of noise exposure on ICS wave propagation distance. Distance traveled for ICS waves, compared at the individual wave (F) and cochlea (G) level was increased after 106 dB but not 98 dB noise exposure. (B, C, E, and G) Data are shown as mean ± SEM, with individual values in gray. Sample size refers to the number of individual cochleae. (D and F) Tukey plots (box: first quartile/median/third quartile; whiskers: 10th and 90th percentile; dots: individual points outside the whiskers) are shown. Sample size refers to the number of individual cochleae (B, C, E, and G), peaks (D), or waves (F) analyzed. Groups were compared with 1-way ANOVA with Dunnett’s test for multiple comparisons against control for each condition, with P values as indicated underneath each graph. Additionally, 2-tailed unpaired Student’s t test was performed to compare values at the 24-hour time point after noise exposure, as indicated in brackets with associated P values.