Endogenous glucocorticoid rhythms regulate the circadian sensitivity to noise

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. Since the circadian secretion of glucocorticoids (GCs) is controlled by the SCN and that 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. To explore the influence of GCs on time-dependent auditory function, we exposed animals to noise (6-12 kHz, 100 dB SPL for 1 h) during daytime (ZT3)  or nighttime (ZT15). on whole cochleae collected 2 hours post-day or night noise trauma

耳蜗具备一套强健的生物钟调控机制，可对听觉功能进行调节。目前学界对于昼夜节律系统如何调控耳蜗生物钟仍不明晰。本研究证实，耳蜗节律由整体系统驱动，既需要局部Bmal1的参与，也依赖于视交叉上核（suprachiasmatic nuclei, SCN）的中枢输入。切除视交叉上核会破坏耳蜗核心时钟基因的昼夜节律性表达。鉴于糖皮质激素（glucocorticoids, GCs）的昼夜分泌受视交叉上核调控，且已知GCs可调节听觉功能，我们评估了其对昼夜节律基因表达的影响。通过肾上腺切除术（adrenalectomy, ADX）清除循环中的GCs，并未对耳蜗核心时钟基因的表达产生显著影响，反而会抑制炎症相关时钟调控基因的转录。肾上腺切除术消除了已知的昼夜噪声创伤所致听觉敏感性差异，并阻断了γ-氨基丁酸能与谷氨酸受体mRNA转录本的诱导表达。然而，此类改善与突触层面的变化并无关联，提示可能存在其他耳蜗功能参与了该调控过程。鉴于GCs对噪声敏感性的上述昼夜调控作用，我们评估了合成糖皮质激素地塞米松（dexamethasone, DEX）在一日不同时段的作用效果。研究发现，仅在日间循环糖皮质激素水平较低时给药，地塞米松才能有效抵御急性噪声创伤，这表明时间药理学策略对于制定最优的听力损失治疗方案至关重要。GCs似乎是昼夜噪声创伤敏感性差异的核心调控因子，其潜在机制可能涉及炎症反应的昼夜节律调控。为探究GCs对时间依赖性听觉功能的影响，我们分别在日间（ZT3）与夜间（ZT15）对动物施加噪声刺激（6-12 kHz，100 dB SPL，持续1小时），并于日间或夜间噪声创伤后2小时收集完整耳蜗组织。