Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden; Department of Otolaryngology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea.
Curr Biol. 2019 Aug 5;29(15):2477-2487.e6. doi: 10.1016/j.cub.2019.06.057. Epub 2019 Jul 25.
The cochlea possesses a robust circadian clock machinery that regulates auditory function. How the cochlear clock is influenced by the circadian system remains unknown. Here, we show that cochlear rhythms are system driven and require local Bmal1 as well as central input from the suprachiasmatic nuclei (SCN). SCN ablations disrupted the circadian expression of the core clock genes in the cochlea. Because the circadian secretion of glucocorticoids (GCs) is controlled by the SCN and GCs are known to modulate auditory function, we assessed their influence on circadian gene expression. Removal of circulating GCs by adrenalectomy (ADX) did not have a major impact on core clock gene expression in the cochlea. Rather it abolished the transcription of clock-controlled genes involved in inflammation. ADX abolished the known differential auditory sensitivity to day and night noise trauma and prevented the induction of GABA-ergic and glutamate receptors mRNA transcripts. However, these improvements were unrelated to changes at the synaptic level, suggesting other cochlear functions may be involved. Due to this circadian regulation of noise sensitivity by GCs, we evaluated the actions of the synthetic glucocorticoid dexamethasone (DEX) at different times of the day. DEX was effective in protecting from acute noise trauma only when administered during daytime, when circulating glucocorticoids are low, indicating that chronopharmacological approaches are important for obtaining optimal treatment strategies for hearing loss. GCs appear as a major regulator of the differential sensitivity to day or night noise trauma, a mechanism likely involving the circadian control of inflammatory responses.
耳蜗拥有强大的生物钟机制，调节听觉功能。耳蜗时钟如何受昼夜节律系统影响尚不清楚。本文中，作者显示耳蜗节律受系统驱动，需要局部 Bmal1 和来自视交叉上核（SCN）的中枢输入。SCN 消融破坏了耳蜗中核心时钟基因的昼夜节律表达。由于糖皮质激素（GCs）的昼夜分泌受 SCN 控制，且 GCs 已知可调节听觉功能，作者评估了它们对昼夜节律基因表达的影响。通过肾上腺切除术（ADX）去除循环 GCs 对耳蜗核心时钟基因表达没有重大影响。相反，它消除了参与炎症的时钟控制基因的转录。ADX 消除了对日夜噪声创伤的已知差异听觉敏感性，并阻止了 GABA 能和谷氨酸受体 mRNA 转录物的诱导。然而，这些改善与突触水平的变化无关，表明可能涉及其他耳蜗功能。由于 GCs 对噪声敏感性的这种昼夜调节，作者评估了合成糖皮质激素地塞米松（DEX）在一天中不同时间的作用。DEX 仅在白天（当循环 GCs 较低时）给药时对急性噪声创伤有效，表明时相药理学方法对于获得听力损失的最佳治疗策略很重要。GCs 似乎是对日夜噪声创伤差异敏感性的主要调节因子，该机制可能涉及炎症反应的昼夜节律控制。
