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Hippocampal Sirtuin 1 Signaling Mediates Depression-like Behavior

  • Naoko Abe-Higuchi
    Affiliations
    Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi
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  • Shusaku Uchida
    Correspondence
    Address correspondence to: Shusaku Uchida, Ph.D., Department of Neuroscience, Division of Neuropsychiatry, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
    Affiliations
    Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi

    Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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  • Hirotaka Yamagata
    Affiliations
    Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi

    Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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  • Fumihiro Higuchi
    Affiliations
    Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi

    Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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  • Teruyuki Hobara
    Affiliations
    Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi
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  • Kumiko Hara
    Affiliations
    Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi
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  • Ayumi Kobayashi
    Affiliations
    Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi
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  • Yoshifumi Watanabe
    Affiliations
    Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi
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      Abstract

      Background

      Although depression is the leading cause of disability worldwide, its pathophysiology is poorly understood. Recent evidence has suggested that sirtuins (SIRTs) play a key role in cognition and synaptic plasticity, yet their role in mood regulation remains controversial. Here, we aimed to investigate whether SIRT function is associated with chronic stress-elicited depression-like behaviors and neuronal atrophy.

      Methods

      We measured SIRT expression and activity in a mouse model of depression. We injected mice with a SIRT1 activator or inhibitor and measured their depression-like behaviors and dendritic spine morphology. To assess the role of SIRT1 directly, we used a viral-mediated gene transfer to overexpress the wild-type SIRT1 or dominant negative SIRT1 and evaluated their depression-like behaviors. Finally, we examined the role of extracellular signal-regulated protein kinases 1 and 2, a potential downstream target of SIRT1, in depression-like behavior.

      Results

      We found that chronic stress reduced SIRT1 activity in the dentate gyrus of the hippocampus. Pharmacologic and genetic inhibition of hippocampal SIRT1 function led to an increase in depression-like behaviors. Conversely, SIRT1 activation blocked both the development of depression-related phenotypes and aberrant dendritic structures elicited by chronic stress exposure. Furthermore, hippocampal SIRT1 activation increased the phosphorylation level of extracellular signal-regulated protein kinases 1 and 2 in the stressed condition, and viral-mediated activation and inhibition of hippocampal extracellular signal-regulated protein kinase 2 led to antidepressive and prodepressive behaviors, respectively.

      Conclusions

      Our results suggest that the hippocampal SIRT1 pathway contributes to the chronic stress-elicited depression-related phenotype and aberrant dendritic atrophy.

      Keywords

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      Linked Article

      • To Stay Happy, Keep Your SIRT1 Active
        Biological PsychiatryVol. 80Issue 11
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          Depression is one of the most common psychiatric disorders and a major cause of disability that affects almost 350 million people worldwide. Common symptoms include depressed mood, persistent anxiety, loss of interest or pleasure in hobbies, feelings of hopelessness, suicidal thoughts, and reduced motivation. Antidepressant drugs often take weeks or even months to reach therapeutic levels and may result in exacerbated symptoms. The pathophysiological cause of depression has not been clearly identified; however, researchers are actively investigating the molecular pathways that contribute to major depressive disorder in human subjects and examining the basis of stress sensitivity and resilience in rodent subjects.
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