Abstract
Sound conditioning (SC) is defined as “toughening” to lower levels of sound over time, which reduces a subsequent noise-induced threshold shift. Although the protective effect of SC in mammals is generally understood, the exact mechanisms involved have not yet been elucidated. To confirm the protective effect of SC against noise exposure (NE) and the stress-related signaling pathway of its rescue, we observed target molecule changes caused by SC of low frequency prior to NE as well as histology analysis in vivo and verified the suggested mechanisms in SGNs in vitro. Further, we investigated the potential role of Hsp70 and Bmi1 in SC by targeting SOD1 and SOD2 which are regulated by the FoxO1 signaling pathway based on mitochondrial function and reactive oxygen species (ROS) levels. Finally, we sought to identify the possible molecular mechanisms associated with the beneficial effects of SC against noise-induced trauma. Data from the rat model were evaluated by western blot, immunofluorescence, and RT-PCR. The results revealed that SC upregulated Hsp70, Bmi1, FoxO1, SOD1, and SOD2 expression in spiral ganglion neurons (SGNs). Moreover, the auditory brainstem responses (ABRs) and electron microscopy revealed that SC could protect against acute acoustic trauma (AAT) based on a significant reduction of hearing impairment and visible reduction in outer hair cell loss as well as ultrastructural changes in OHCs and SGNs. Collectively, these results suggested that the contribution of Bmi1 toward decreased sensitivity to noise-induced trauma following SC was triggered by Hsp70 induction and associated with enhancement of the antioxidant system and decreased mitochondrial superoxide accumulation. This contribution of Bmi1 was achieved by direct targeting of SOD1 and SOD2, which was regulated by FoxO1. Therefore, the Hsp70/Bmi1-FoxO1-SOD signaling pathway might contribute to the protective effect of SC against AAT in a rat model.
Highlights
Sound conditioning (SC), known as noise-induced “toughening,” is widely defined as acoustic stimulation at a low intensity for an extended period of time prior to an elevated noise exposure (NE), which reduces the permanent threshold shift caused by a high-intensity sound
We found that Hsp70, Bmi1, FoxO1, SOD1, and SOD2 were all involved in the SC-induced enhancement of the antioxidant system and reduced reactive oxygen species (ROS) accumulation in the spiral ganglion neurons (SGNs)
Our study in vivo and in vitro produced similar results to Chen et al the current study found that these functional and ultrastructural changes of mitochondria were accompanied by significant upregulation of Hsp70 and Bmi1 expression induced by SC and that overexpression of Hsp70 significantly enhanced Bmi1 expression in rat SGNs (Hsp70 might stabilize Bmi1 at the protein level rather than increase it at the transcriptional level) and clearly decreased mitochondrial superoxide accumulation, while Bmi1 inhibitor attenuated the effect of Hsp70 transfection
Summary
Sound conditioning (SC), known as noise-induced “toughening,” is widely defined as acoustic stimulation at a low intensity for an extended period of time prior to an elevated noise exposure (NE), which reduces the permanent threshold shift caused by a high-intensity sound. Another study confirmed that SC of the low frequency (a pure tone of 1 kHz) prior to a loud noise upregulated tyrosine hydroxylase in the lateral efferent to protect against acoustic trauma [4]. Recent research suggested that the beneficial mechanisms of SC which was prior to a loud noise initiate in the cochlea and eventually reach the central auditory system. This phenomenon might be in part related to an interplay between the calretinin and nitric oxide signaling pathways and increases in the cytosolic calcium buffering capacity induced by SC [6]. It has been widely accepted that preconditioning to sound, especially sound conditioning of low frequency prior to a loud noise (but not sound conditioning after acoustic trauma), is a well-documented strategy to provide protection against AAT and the underlying mechanisms behind the protective effect of SC largely might refer to cochlear tissue
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