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Curr Biol. 2017 Sep 11;27(17):2623-2629.e2. doi: 10.1016/j.cub.2017.07.019. Epub 2017 Aug 17.

Differential Phase Arrangement of Cellular Clocks along the Tonotopic Axis of the Mouse Cochlea Ex Vivo.

Author information

1
Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Otolaryngology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea.
2
Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden.
3
Department of Molecular Cell Biology, Leiden University Medical Center, 2333 Leiden, the Netherlands.
4
Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden; Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
5
Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: barbara.canlon@ki.se.

Abstract

Topological distributions of individual cellular clocks have not been demonstrated in peripheral organs. The cochlea displays circadian patterns of core clock gene expression [1, 2]. PER2 protein is expressed in the hair cells and spiral ganglion neurons of the cochlea in the spiral ganglion neurons [1]. To investigate the topological organization of cellular oscillators in the cochlea, we recorded circadian rhythms from mouse cochlear explants using highly sensitive real-time tracking of PER2::LUC bioluminescence. Here, we show cell-autonomous and self-sustained oscillations originating from hair cells and spiral ganglion neurons. Multi-phased cellular clocks were arranged along the length of the cochlea with oscillations initiating at the apex (low-frequency region) and traveling toward the base (high-frequency region). Phase differences of 3 hr were found between cellular oscillators in the apical and middle regions and from isolated individual cochlear regions, indicating that cellular networks organize the rhythms along the tonotopic axis. This is the first demonstration of a spatiotemporal arrangement of circadian clocks at the cellular level in a peripheral organ. Cochlear rhythms were disrupted in the presence of either voltage-gated potassium channel blocker (TEA) or extracellular calcium chelator (BAPTA), demonstrating that multiple types of ion channels contribute to the maintenance of coherent rhythms. In contrast, preventing action potentials with tetrodotoxin (TTX) or interfering with cell-to-cell communication the broad-spectrum gap junction blocker (CBX [carbenoxolone]) had no influence on cochlear rhythms. These findings highlight a dynamic regulation and longitudinal distribution of cellular clocks in the cochlea.

KEYWORDS:

Period 2; auditory; bioluminescence imaging; cellular oscillators; circadian rhythm; cochlea; ion channels; spiral ganglion neurons; synchrony; tonotopy

PMID:
28823676
DOI:
10.1016/j.cub.2017.07.019
[Indexed for MEDLINE]
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