Chronic Stress Induces Brain Region-Specific Alterations of Molecular Rhythms that Correlate with Depression-like Behavior in Mice

  • Author Footnotes
    1 Authors RWL and NE are joint first authors.
    Ryan W. Logan
    1 Authors RWL and NE are joint first authors.
    Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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  • Author Footnotes
    1 Authors RWL and NE are joint first authors.
    Nicole Edgar
    1 Authors RWL and NE are joint first authors.
    Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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  • Andrea G. Gillman
    Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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  • Daniel Hoffman
    Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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  • Xiyu Zhu
    Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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  • Colleen A. McClung
    Address correspondence to Colleen A. McClung, Ph.D., University of Pittsburgh School of Medicine, Department of Psychiatry and Translational Neuroscience Program, 450 Technology Drive, Suite 223, Pittsburgh, PA 15219.
    Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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  • Author Footnotes
    1 Authors RWL and NE are joint first authors.
Published:February 04, 2015DOI:



      Emerging evidence implicates circadian abnormalities as a component of the pathophysiology of major depressive disorder (MDD). The suprachiasmatic nucleus (SCN) of the hypothalamus coordinates rhythms throughout the brain and body. On a cellular level, rhythms are generated by transcriptional, translational, and posttranslational feedback loops of core circadian genes and proteins. In patients with MDD, recent evidence suggests reduced amplitude of molecular rhythms in extra-SCN brain regions. We investigated whether unpredictable chronic mild stress (UCMS), an animal model that induces a depression-like physiological and behavioral phenotype, induces circadian disruptions similar to those seen with MDD.


      Activity and temperature rhythms were recorded in C57BL/6J mice before, during, and after exposure to UCMS, and brain tissue explants were collected from Period2 luciferase mice following UCMS to assess cellular rhythmicity.


      UCMS significantly decreased circadian amplitude of activity and body temperature in mice, similar to findings in MDD patients, and these changes directly correlated with depression-related behavior. While amplitude of molecular rhythms in the SCN was decreased following UCMS, surprisingly, rhythms in the nucleus accumbens (NAc) were amplified with no changes seen in the prefrontal cortex or amygdala. These molecular rhythm changes in the SCN and the NAc also directly correlated with mood-related behavior.


      These studies found that circadian rhythm abnormalities directly correlate with depression-related behavior following UCMS and suggest a desynchronization of rhythms in the brain with an independent enhancement of rhythms in the NAc.


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      Linked Article

      • Circadian Rhythms and Psychopathology: From Models of Depression to Rhythms in Clock Gene Expression and Back Again
        Biological PsychiatryVol. 78Issue 4
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          Unpredictable chronic mild stress (UCMS) in rodents induces several changes in behavior and physiology that are similar to major depressive disorder (MDD) in humans. Although the specific brain areas, hormones, and genes that mediate this complex response to UCMS are important points for research and discussion, potential circadian mechanisms have also been considered for some time. Logan et al. (1) describe a compelling correlation between behavioral assays that are relevant to depression and the amplitude of daily locomotion and temperature rhythms in mice.
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