SIK3–HDAC4 in the suprachiasmatic nucleus regulates the timing of arousal at the dark onset and circadian period in mice

Fuyuki Asano, Staci J. Kim, Tomoyuki Fujiyama, Chika Miyoshi, Noriko Hotta-Hirashima, Nodoka Asama, Kanako Iwasaki, Miyo Kakizaki, Seiya Mizuno, Michihiro Mieda, Fumihiro Sugiyama, Satoru Takahashi, Shoi Shi, Arisa Hirano, Hiromasa Funato, Masashi Yanagisawa

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Mammals exhibit circadian cycles of sleep and wakefulness under the control of the suprachiasmatic nucleus (SCN), such as the strong arousal phase-locked to the beginning of the dark phase in laboratory mice. Here, we demonstrate that salt-inducible kinase 3 (SIK3) deficiency in gamma-aminobutyric acid (GABA)-ergic neurons or neuromedin S (NMS)–producing neurons delayed the arousal peak phase and lengthened the behavioral circadian cycle under both 12-h light:12-h dark condition (LD) and constant dark condition (DD) without changing daily sleep amounts. In contrast, the induction of a gain-of-function mutant allele of Sik3 in GABAergic neurons exhibited advanced activity onset and a shorter circadian period. Loss of SIK3 in arginine vasopressin (AVP)–producing neurons lengthened the circadian cycle, but the arousal peak phase was similar to that in control mice. Heterozygous deficiency of histone deacetylase (HDAC) 4, a SIK3 substrate, shortened the circadian cycle, whereas mice with HDAC4 S245A, which is resistant to phosphorylation by SIK3, delayed the arousal peak phase. Phase-delayed core clock gene expressions were detected in the liver of mice lacking SIK3 in GABAergic neurons. These results suggest that the SIK3–HDAC4 pathway regulates the circadian period length and the timing of arousal through NMS-positive neurons in the SCN.

Original languageEnglish (US)
Article numbere2218209120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number11
DOIs
StatePublished - Mar 10 2023

Keywords

  • HDAC4
  • SIK3
  • arousal timing
  • circadian period
  • circadian rhythms

ASJC Scopus subject areas

  • General

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