短暂睡眠剥夺通过ROS启动的神经炎症和BK通道抑制诱导持续性听觉神经病。

文献信息

中文摘要

睡眠障碍与感音神经性听力损失（SNHL）之间的联系是一个关键的临床问题，但其潜在机制仍不清楚。在此，我们首先在突发性感音神经性听力损失患者的临床队列中，建立了睡眠障碍严重程度与听力损失程度之间强烈的剂量依赖性关联。为了剖析因果机制，我们采用了急性睡眠剥夺（SD）小鼠模型，证明SD会导致持久的高频听力损失，与束缚应激不同，这种听力损失不能归因于全身性应激。核心病理是音调定位受限的耳蜗突触病，其特征是毛细胞带状突触丢失，由短暂氧化应激启动，并由慢性、自我维持的神经炎症程序维持，该程序驱动大电导钙激活钾（BK）通道的持续性转录抑制。音调定位的BK通道抑制通过单细胞电生理学得到功能验证，并与频率特异性听力损失密切相关。关键的是，在急性期使用抗氧化剂N-乙酰-L-半胱氨酸（NAC）或BK通道开放剂NS1619进行药物干预，可预防听觉和突触缺陷，确立了每个通路节点的因果必要性。总之，这些发现描绘了从睡眠丧失到耳蜗病理的因果验证级联，确定了推定的神经炎症记忆和BK通道作为应激诱导的感觉神经病的治疗靶点。

英文摘要

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.