Circadian Regulation of Cochlear Sensitivity to Noise by Circulating Glucocorticoids

Abstract

SUMMARY 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.

Circadian vulnerability of cisplatin‐induced ototoxicity in the cochlea

“…Cochlear explants from PER2::LUC reporter mice, cultured for a period of 6-9 days, were exposed for a duration of 3 days to six different doses of cisplatin (40,80,160, 400, 800, and 1600 nM), applied either at the trough of the oscillations at day 3 of the culture (day administration) or at the peak of the oscillations, at day 3.5 of the culture (night administration) in the absence of presynchronization. Day cisplatin treatment did not show any effect on PER2 rhythms on the amplitude (one-way ANOVA, F (6,27) = 0.794, P = .582), phase (one-way ANOVA, F (6,30) = 0.65, P = .69), and period (one-way ANOVA, F (6, 24) = 1.214, P = .333, Figure 5A-C). In contrast, night cisplatin administration caused a decrease in the amplitude (one-way ANOVA, F (6, 29) = 5.505, P = .0007) and delay in the phase (one-way ANOVA, F (6, 31) = 3.769, P = .006), and the period (one-way ANOVA, F (6, 29) = 3.793, P = .0065) ( Figure 5D-F).…”

“…27 At the cellular level, oscillatory patterns propagate from the apex toward middle turns and cellular synchronicity within the cochlea requires the function of voltage-gated potassium channel and extracellular calcium. 28 Two consequences from this auditory clock have been evidenced: first, the cochlea is more vulnerable at nighttime to noise damage, 29 a process that requires circulating glucocorticoids 30 ; second, the action of drugs (eg, dihydroxyflavone, a selective TrkB agonist, and dexamethasone) to protect from noise-damage depending on the time-of-the-day, the TrkB agonist is effective when administered at nighttime, and dexamethasone at daytime. 29,30 Thus, drugs may have a different impact depending on the time-of-the-day when administered.…”

“…28 Two consequences from this auditory clock have been evidenced: first, the cochlea is more vulnerable at nighttime to noise damage, 29 a process that requires circulating glucocorticoids 30 ; second, the action of drugs (eg, dihydroxyflavone, a selective TrkB agonist, and dexamethasone) to protect from noise-damage depending on the time-of-the-day, the TrkB agonist is effective when administered at nighttime, and dexamethasone at daytime. 29,30 Thus, drugs may have a different impact depending on the time-of-the-day when administered. Whether the ototoxic effects of cisplatin on the auditory system depend on the time-of-the-day is poorly known.…”

“…Since it is well established that cisplatin impacts the mitochondria, 3 and that mitochondrial function is an essential element of clock regulation, 55 cisplatin may impact clock function via altered mitochondrial metabolism at a specific times-of-the-day. Reversely, it could also be that the circadian expression of mitochondrial genes in the cochlea such as Sod2 and Lrp2, which peak at nighttime in the cochlea, 30 could render the cochlea more vulnerable at nighttime. Indeed, should the function of the hearing organ be already subjected to high metabolic demand during the active phase, there would not be enough capacity for triggering appropriate damage response mechanisms.…”

Endogenous SIRT3 activity is dispensable for normal hearing recovery after noise exposure in young adult mice

“…These loss-of-function studies also complement the already-published gain-of-function studies. Multiple labs have successfully used this method to identify genes [22] and conditions [23] that modulate susceptibility to noise damage. Noise exposure can eliminate high-frequency auditory synapses [21, 24] in a glutamine-dependent manner [25], and the restoration of auditory synapses was proposed to be the mechanism by which SIRT3 reduced NIHL [20].…”