Constant Light Dysregulates Cochlear Circadian Clock and Exacerbates Noise-Induced Hearing Loss (original) (raw)
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TrkB-Mediated Protection against Circadian Sensitivity to Noise Trauma in the Murine Cochlea
Current Biology, 2014
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 , and no effective drugs are available . 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 . 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 selfsustained 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, tropomyosinrelated 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.
The Journal of Neuroscience, 2016
Circadian rhythms regulate bodily functions within 24 h and long-term disruptions in these rhythms can cause various diseases. Recently, the peripheral auditory organ, the cochlea, has been shown to contain a self-sustained circadian clock that regulates differential sensitivity to noise exposure throughout the day. Animals exposed to noise during the night are more vulnerable than when exposed during the day. However, whether other structures throughout the auditory pathway also possess a circadian clock remains unknown. Here, we focus on the inferior colliculus (IC), which plays an important role in noise-induced pathologies such as tinnitus, hyperacusis, and audiogenic seizures. Using PER2::LUC transgenic mice and real-time bioluminescence recordings, we revealed circadian oscillations of Period 2 protein in IC explants for up to 1 week. Clock genes (Cry1,Bmal1,Per1,Per2,Rev-erbα, andDbp) displayed circadian molecular oscillations in the IC. Averaged expression levels of early-in...
Circadian regulation of auditory function
Hearing Research, 2017
Biological clocks evolved under the influence of rhythmic environmental cues, in order to provide an internal representation of time and allow organisms to exploit temporal niches (light/dark, cold/warm, wet/dry, etc.) with all the subsequent consequences. The environmental factors that influence the function of these clocks are called zeitgebers (German for ''time-giver''). Among these factors are the light-dark cycle, temperature, feeding and social interactions. The light-dark cycle is considered a major zeitgeber and probably the most significant in evolution because it is an explicit predictor of the daily cycle, as well as the seasonal cycle (length of day fluctuations). However, the biological clock being an endogenous timing system is capable of generating biological rhythms even in the absence of environmental cues. This ability ensures that the physiological functions of an organism will continue even in temporal isolation. When zeitgebers are not present, the biological clock sustains a rhythm of about 24h which is called circadian rhythm (from the Latin words ''circa'' and ''diem'', meaning approximately one day), with a corresponding circadian time (CT). In order to produce an accurate 24h period, the clock adjusts its rhythm on a daily basis. This adjustment is mediated mainly through entrainment to the daily light-dark cycle, meaning synchronization of the circadian time to the external time (Box 1). Consequently, the clock time relies on the rhythm of the zeitgeber and is referred as a zeitgeber time (ZT). 1.1 The molecular clock: How clocks tell time Circadian rhythms are innate and are governed by genetically programmed mechanisms. The discovery of genes encoding circadian behavioral rhythms in Drosophila melanogaster (Konopka et al., 1971) initiated an intense scientific effort to identify genes that regulate the
Medicine, 2015
The cause of sudden sensorineural hearing loss (SSNHL) remains unclear and therefore it is often considered as idiopathic. Sleep disturbance has been linked to SSNHL and circadian rhythm disruption, but the link between circadian rhythm disruption and SSNHL has never been investigated.In this study, we surveyed the sleep quality of 38 patients with SSNHL using a simple insomnia sleep questionnaire. The expression of circadian clock genes in peripheral blood (PB) leukocytes from 38 patients with SSNHL and 71 healthy subjects was accessed using real-time quantitative reverse transcriptase-polymerase chain reaction and validated using immunocytochemical staining.We found that 61.8% of patients with SSNHL suffered from insomnia before the insult of hearing loss. Besides, significantly decreased expression of PER1, CRY1, CRY2, CLOCK, BMAL1, and CKlε was found in PB leukocytes of patients with SSNHL when compared with healthy subjects. SSNHL patients with vertigo had significantly lower e...
Restoration of Circadian Rhythmicity in Circadian Clock-Deficient Mice in Constant Light
Journal of Biological Rhythms, 2006
In mammals, circadian rhythms in behavior and physiology are controlled by a central pacemaker, the SCN, and subordinated clocks throughout the body. On the molecular level, these clocks are based on transcriptional/ translational feedback loops involving a set of clock genes that regulate their own transcription. Among the components driving the mammalian circadian clock are the Period 1 and 2 (Per1 and Per2) and Cryptochrome 1 and 2 (Cry1 and Cry2) genes. In the present study, the authors characterize the behavioral and molecular rhythms of Per2/Cry1 double mutant mice under 3 different lighting conditions. In an LD cycle, the activity of these animals is masked by light, while in DD, the mutants lose circadian rhythmicity but exhibit strong ultradian rhythms. In LL of higher intensity, circadian rhythms are restored on the behavioral level with a drastically shortened endogenous period. Furthermore, both in the SCN and in the periphery, clock gene rhythms are restored. Based on these observations and also on the fact that light-mediated induction of Per gene expression is preserved in these mutants, the authors propose a mechanism by which endogenous ultradian rhythms may relay timed light exposure to the SCN, leading to a reinitiation of self-sustained circadian rhythms in LL.
Auditory deprivation modifies biological rhythms in the golden hamster
Archives italiennes de biologie
To assess to what extent auditory sensory deprivation affects biological rhythmicity, sleep/wakefulness cycle and 24 h rhythm in locomotor activity were examined in golden hamsters after bilateral cochlear lesion. An increase in total sleep time as well as a decrease in wakefulness (W) were associated to an augmented number of W episodes, as well as of slow wave sleep (SWS) and paradoxical sleep (PS) episodes in deaf hamsters. The number of episodes of the three behavioural states and the percent duration of W and SWS increased significantly during the light phase of daily photoperiod only. Lower amplitudes of locomotor activity rhythm and a different phase angle as far as light off were found in deaf hamsters kept either under light-dark photoperiod or in constant darkness. Period of locomotor activity remained unchanged after cochlear lesions. The results indicate that auditory deprivation disturbs photic synchronization of rhythms with little effect on the clock timing mechanism ...
bioRxiv (Cold Spring Harbor Laboratory), 2023
Arrhythmia is considered the most disrupted state of the biological circadian clock, and usually occurs when circadian regulatory genes are rendered non-functional, or the master clock (Suprachiasmatic Nucleus) is ablated. Since clock gene expression is aligned by the external solar day-night cycle to exhibit a 24-hour rhythm, we hypothesized that ill-timed light and dark exposure could negatively impact endogenous circadian clock function in mice. In this study, we present an environmentally driven approach to induce arrhythmia in mice that is also reversible. Using the previously characterized fragmented day-night cycle (FDN) where the 8-hour night is split into four 2-hour fragments and equally distributed across the 24-hour day, we show that mice gradually exposed to the FDN for 1 month lose their circadian rhythmicity. Furthermore, subsequent exposure to constant light or constant dark conditions does not yield typical circadian rhythms, but instead, reveals circadian arrhythmia. Finally, we show that the arrhythmic locomotion phenotype is reversible with one week of reintroduction to a 12 hr day-12 hr night cycle. This is the first study to show how the light-dark environment induces arrhythmia of an intact circadian clock and how it can be reversed.
Hearing Research, 2011
The molecular mechanisms underlying the vast differences between individuals in their susceptibility to noise-induced hearing loss (NIHL) are unknown. The present study demonstrated that the effects of noise over-exposure on the expression of molecules likely to be important in the development of NIHL differ among inbred mouse strains having distinct susceptibilities to NIHL including B6 (B6.CAST) and 129 (129X1/SvJ and 129S1/SvImJ) mice. The noise-exposure protocol produced a loss of 40 dB in hearing sensitivity in susceptible B6 mice, but no loss for the two resistant 129 substrains. Analysis of gene expression in the membranous labyrinth 6 h following noise exposure revealed up-regulation of transcription factors in both the susceptible and resistant strains. However, a significant induction of genes involved in cell-survival pathways such as the heat shock proteins HSP70 and HSP40, growth arrest and DNA damage inducible protein 45β (GADD45β), and CDK-interacting protein 1 (p21 cip1) was detected only in the resistant mice. Moreover, in 129 mice significant upregulation of HSP70, GADD45β, and p21 cip1 was confirmed at the protein level. Since the functions of these proteins include roles in potent antiapoptotic cellular pathways, their upregulation may contribute to protection from NIHL in the resistant 129 mice.
Acute Light Exposure Suppresses Circadian Rhythms in Clock Gene Expression
Journal of Biological Rhythms, 2011
Circadian arrhythmia can be induced in mammals by several weeks of constant light (Daan and Pittendrigh, 1976) or by a brief light stimulus given at the transition point of the phase response curve (i.e., the singularity point) (Winfree, 1980). More recently, some laboratories have employed novel light treatments that induce circadian arrhythmia in the Siberian hamster (Phodopus sungorus). In these studies, circadian arrhythmia was induced by using a phaseadv ancing light pulse on one night followed by a phase-delaying signal on the next night (Steinlechner et al., 2002; Ruby et al., 2004). Arrhythmia was reported for locomotor activity, body temperature, sleep/ wake cycles, and melatonin levels (Ruby et al., 2004; Steinlechner et al., 2002). The light treatment consistently caused a marked shortening of the active phase (i.e., alpha compression), resulting in arrhythmia within 2 to 5 circadian cycles that persisted despite the continued presence of the light-dark (LD) cycle. We hypothesized that the loss of overt rhythms was due to light-induced arrhythmia in the suprachiasmatic nucleus (SCN) because it is the central circadian LETTER