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Curr Biol. 2019 Aug 5;29(15):2477-2487.e6. doi: 10.1016/j.cub.2019.06.057. Epub 2019 Jul 25.

Circadian Regulation of Cochlear Sensitivity to Noise by Circulating Glucocorticoids.

Author information

1
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden. Electronic address: christopher.cederroth@ki.se.
2
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden; Department of Otolaryngology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea.
3
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden.
4
Department of Diabetes and Circadian Rhythms, Nestlé Institute of Health Sciences, 1015 Lausanne, Switzerland.
5
Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm 17177, Sweden.
6
Department of Laboratory Medicine, Karolinska Institutet, Stockholm 17177, Sweden.
7
Department of Diabetes and Circadian Rhythms, Nestlé Institute of Health Sciences, 1015 Lausanne, Switzerland; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.

Abstract

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.

KEYWORDS:

CtBP2; PER2::LUC; Pax2-Cre; chronopharmacology; corticosterone; entrainment; excitotoxicity; glucocorticoid receptors; synaptic ribbon

PMID:
31353184
DOI:
10.1016/j.cub.2019.06.057
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