Sleep Deprivation Causes Cochlear Synaptopathy via TLR4 Pathway

Background: Sleep deprivation (SD) is linked to auditory system damage and reversible hearing loss. The American Academy of Sleep Medicine recommends adults sleep at least 7 hours nightly, but SD is prevalent due to modern lifestyles, affecting many, including over 61.8% of sudden deafness patients. Understanding the mechanisms behind SD-induced auditory impairment is essential.

Method: This study employed a prolonged SD paradigm through curling prevention by water (CPW) in a mouse model, keeping mice awake for approximately 96% of the time. We analyzed auditory function using auditory brainstem response (ABR) testing immediately after 72-hour SD and assessed auditory thresholds, protein expression levels, and inflammatory responses. Proteomics and gene expression analysis were conducted to identify differentially expressed proteins (DEPs) related to oxidative stress and inflammation.

Result: After 72 hours of SD, ABR thresholds increased significantly across frequencies: 13 dB (click), 14 dB (4 kHz), and 31 dB (32 kHz), indicating temporary auditory impairment. A total of 898 DEPs were identified, with 245 proteins upregulated and 653 downregulated, primarily associated with oxidative stress and inflammatory responses. Notably, TLR4/NF-κB/NLRP3 pathway activation was observed, leading to significant increases in inflammatory markers (IL-1β, IL-6, IL-17A) in the serum.

Conclusion: Prolonged SD activates the TLR4/NF-κB/NLRP3 signaling pathway, inducing cochlear inflammation and oxidative stress, which culminates in temporary threshold shifts and cochlear synaptopathy. These findings urge clinicians to monitor auditory health in patients with sleep disorders. Further research is needed to explore the chronic effects of SD on auditory function and identify deeper molecular mechanisms, as the study primarily focused on acute exposure.

Original citation address: https://www.besjournal.com/en/article/doi/10.3967/bes2026.022