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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., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Topological distributions of individual cellular clocks have not been demonstrated in peripheral organs. The cochlea displays circadian patterns of core clock gene expression [1, 2]. PER2 protein is expressed in the hair cells and spiral ganglion neurons of the cochlea in the spiral ganglion neurons [1]. To investigate the topological organization of cellular oscillators in the cochlea, we recorded circadian rhythms from mouse cochlear explants using highly sensitive real-time tracking of PER2::LUC bioluminescence. Here, we show cell-autonomous and self-sustained oscillations originating from hair cells and spiral ganglion neurons. Multi-phased cellular clocks were arranged along the length of the cochlea with oscillations initiating at the apex (low-frequency region) and traveling toward the base (high-frequency region). Phase differences of 3 hr were found between cellular oscillators in the apical and middle regions and from isolated individual cochlear regions, indicating that cellular networks organize the rhythms along the tonotopic axis. This is the first demonstration of a spatiotemporal arrangement of circadian clocks at the cellular level in a peripheral organ. Cochlear rhythms were disrupted in the presence of either voltage-gated potassium channel blocker (TEA) or extracellular calcium chelator (BAPTA), demonstrating that multiple types of ion channels contribute to the maintenance of coherent rhythms. In contrast, preventing action potentials with tetrodotoxin (TTX) or interfering with cell-to-cell communication the broad-spectrum gap junction blocker (CBX [carbenoxolone]) had no influence on cochlear rhythms. These findings highlight a dynamic regulation and longitudinal distribution of cellular clocks in the cochlea., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Noise-induced hearing loss (NIHL) is a debilitating sensory impairment affecting 10%-15% of the population, caused primarily through damage to the sensory hair cells or to the auditory neurons. Once lost, these never regenerate [1], and no effective drugs are available [2, 3]. Emerging evidence points toward an important contribution of synaptic ribbons in the long-term coupling of the inner hair cell and afferent neuron synapse to maintain hearing [4]. Here we show in nocturnal mice that night noise overexposure triggers permanent hearing loss, whereas mice overexposed during the day recover to normal auditory thresholds. In view of this time-dependent sensitivity, we identified a self-sustained circadian rhythm in the isolated cochlea, as evidenced by circadian expression of clock genes and ample PERIOD2::LUCIFERASE oscillations, originating mainly from the primary auditory neurons and hair cells. The transcripts of the otoprotecting brain-derived neurotrophic factor (BDNF) showed higher levels in response to day noise versus night noise, suggesting that BDNF-mediated signaling regulates noise sensitivity throughout the day. Administration of a selective BDNF receptor, tropomyosin-related kinase type B (TrkB), in the night protected the inner hair cell's synaptic ribbons and subsequent full recovery of hearing thresholds after night noise overexposure. The TrkB agonist shifted the phase and boosted the amplitude of circadian rhythms in the isolated cochlea. These findings highlight the coupling of circadian rhythmicity and the TrkB receptor for the successful prevention and treatment of NIHL., (Copyright © 2014 Elsevier Ltd. All rights reserved.)