Circadian Regulation of Cochlear Sensitivity to Noise by Circulating Glucocorticoids

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • Circadian Clocks / physiology*
  • Cochlea / physiology*
  • Dexamethasone / administration & dosage*
  • Dexamethasone / metabolism
  • Glucocorticoids / administration & dosage*
  • Glucocorticoids / metabolism
  • Male
  • Mice
  • Noise*
  • Suprachiasmatic Nucleus / physiology
  • Suprachiasmatic Nucleus / surgery

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Glucocorticoids
  • Dexamethasone