Transient Sleep Deprivation Induces Persistent Auditory Neuropathy via ROS-Initiated Neuroinflammation and BK Channel Suppression

The link between sleep disorders and sensorineural hearing loss (SNHL) is a critical clinical issue, yet the underlying mechanisms remain elusive. Here, we first establish a strong, dose-dependent association between the severity of sleep disturbance and the degree of hearing loss in a clinical cohort of patients with sudden SNHL. To dissect causal mechanisms, we employ a mouse model of acute sleep deprivation (SD), demonstrating that SD causes a long-lasting, high-frequency hearing loss that, unlike restraint stress, cannot be attributed to generalized systemic stress. The core pathology is a tonotopically restricted cochlear synaptopathy, characterized by loss of hair cell ribbon synapses, initiated by transient oxidative stress and maintained by a chronic, self-sustaining neuroinflammatory program, that drives persistent transcriptional suppression of large-conductance calcium-activated potassium (BK) channels. Tonotopic BK channels suppression is functionally validated by single-cell electrophysiology and closely tracks frequency-specific hearing loss. Critically, pharmacological intervention with the antioxidant N-Acetyl-L-cysteine (NAC) or the BK channel opener NS1619 during the acute phase prevents auditory and synaptic deficits, establishing causal necessity for each pathway node. Together, these findings delineate a causally validated cascade from sleep loss to cochlear pathology, identifying a putative neuroinflammatory memory and BK channels as a therapeutic target for stress-induced sensory neuropathy.