Chronic stress affects PERIOD2 expression through glycogen synthase kinase-3β phosphorylation in the central clock

Neuroreport. 2012 Jan 25;23(2):98-102. doi: 10.1097/WNR.0b013e32834e7ec2.


Mood disorders are considered to be associated with altered circadian rhythms, but the correlation between them has remained obscure. The mood stabilizer, lithium, is an inhibitor of glycogen synthase kinase-3β (GSK-3β), which is a modulator of the circadian clock system. Here, we show that chronic restraint (CR) stress diminishes behavioral activity and rhythmicity in mice. CR stress elevated GSK-3β phosphorylation and blunted the rhythmic expression of PERIOD2 (PER2) in the brain. Moreover, lithium, when administered to the stress-imposed mice, reduced GSK-3β phosphorylation and restored PER2 expression in the suprachiasmatic nucleus in a nighttime-specific manner. These data suggest that CR stress altered the circadian behavioral rhythm through a change in circadian gene expression of PER2 and GSK-3β phosphorylation in the suprachiasmatic nucleus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Brain / drug effects
  • Brain / metabolism*
  • Circadian Clocks / physiology*
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Lithium Compounds / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Period Circadian Proteins / biosynthesis*
  • Phosphorylation
  • Stress, Psychological / metabolism*


  • Antidepressive Agents
  • Lithium Compounds
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3