Circadian regulation of auditory function

Abstract

The circadian system integrates environmental cues to regulate physiological functions in a temporal fashion. The suprachiasmatic nucleus, located in the hypothalamus, is the master clock that synchronizes central and peripheral organ clocks to orchestrate physiological functions. Recently, molecular clock machinery has been identified in the cochlea unravelling the potential involvement in the circadian regulation of auditory functions. Here, we present background information on the circadian system and review the recent findings that introduce circadian rhythms to the auditory field. Understanding the mechanisms by which circadian rhythms regulate auditory function will provide fundamental knowledge on the signalling networks that control vulnerability and resilience to auditory insults.

Fig. 1. The molecular clock machinery

A) Core loop: CLOCK (C) and BMAL1 (B) bind to E-box DNA motifs and induce the transcription of Per and Cry genes (Per1, Per2, Cry1 and Cry2). Accumulation of PER/CRY complexes inhibit the transactivation potential of C and B, thereby repressing their own transcription. As a consequence, PER and CRY levels decline, allowing C and B to initiate a new cycle of gene expression. Per1 and Per2 transcription can be additionally induced by systemically regulated transcriptional factors: Heat shock factor (HSF) binding to heat shock elements (HSE), cAMP responsive element (CRE)-binding protein (CREB) and glucocorticoid receptor (GR) binding to glucocorticoid responsive elements (GRE). B) Interlocking loop: CLOCK and BMAL1 activate the orphan nuclear receptor genes Ror (Rorα, Rorβ and Rorγ) and Rev-Erb (Rev-Erbα and Rev-Erbβ). The transcription of Bmal1 and Clock is then regulated through competition between REV-ERB repressors and ROR activators, acting on retinoid-related orphan receptor response elements (RORE). C) Regulation of clock-controlled genes (CCGs): CLOCK and BMAL1 can regulate the transcription of CCGs by binding to E-box elements on their promoter area. These genes are then translated into CCG protein products and regulate physiological processes in a temporal way.

Fig. 2. Organization of the circadian system

The suprachiasmatic nucleus (SCN) is the major pacemaker of the circadian system that receives photic information directly from the retina and synchronizes peripheral oscillators found in other brain areas and peripheral tissues (entrainment). This is mediated through autonomic innervation, humoral signals, hormones and the regulation of body temperature and feeding.

Fig. 3. Diurnal variation of auditory function

A) Acoustic startle response (ASR) in CBA mice is greater in the morning (ZT 3–6, red) compared to night (ZT 14–16, blue). B) Auditory brainstem response (ABR) of CBA mice exposed to noise in the morning (ZT 3–5, red) or at night (ZT 14–16, blue) show similar levels of hearing damage when measured 24 h post exposure. However, 2 weeks later the morning group shows complete recovery of their threshold shifts, whereas the night group still shows high threshold shifts, thereby permanent hearing damage. Modified with permission from Cell Press (Melster et. al., 2014).

Fig. 4. Circadian PER2::LUC rhythms in the adult cochlea

Representative bioluminescence recordings of circadian PER2::LUC expression from cultured cochlea, liver and SCN explants. In the adult cochlea PER2 is mainly expressed in inner hair cells, outer hair cells and in the spiral ganglion neurons. Modified with permission from Cell Press (Melster et. al., 2014).

Fig. 5. Effects of noise exposure on the cochlear clock

A) Cochlear PER2::LUC rhythm amplitude after exposure to a morning (ZT 3–5, red) or a night (ZT14–16, blue) noise trauma. Night noise significantly reduces the rhythm amplitude of the PER2::LUC oscillation, whereas day noise does not. B) Temporal expression of Per2, Per1, Rev-Erbα, and Bmal1 mRNAs in cochlea from non-exposed mice (white circles) or exposed to a morning (ZT 3, red circles) or night (ZT 15, blue circles) noise trauma. Night noise supresses the amplitude of Per2, Per1 and Rev-Erbα rhythms and increases the amplitude of Bmal1 rhythms. Modified with permission from Cell Press (Melster et. al., 2014).

Fig. 6. Regulation of diurnal noise sensitivity by Bdnf

A) Bdnf mRNA expression in the cochlea after a noise exposure in the morning (ZT 3–5, red) or at night (ZT 14–16, blue). Day noise trauma increases Bdnf mRNA by 35-fold. B) ABR threshold shifts from mice exposed to noise in the morning (ZT 3–5, red) or at night (ZT 14–16, blue), measured 24 hr post (left panel) and 2 weeks post (right panel). DMSO-treated animals (white circles) and DHF-treated animals (filled circles). DHF administration prevents from permanent hearing loss in the night exposed group, as hearing thresholds return to normal levels 2 weeks after noise exposure. The lack of Bdnf induction after night noise and the hearing threshold rescue by DHF suggest that BDNF signalling contributes to the diurnal sensitivity to noise damage. Modified with permission from Cell Press (Melster et. al., 2014).