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Biol Psychiatry. 2016 Dec 1;80(11):815-826. doi: 10.1016/j.biopsych.2016.01.009. Epub 2016 Jan 30.

Hippocampal Sirtuin 1 Signaling Mediates Depression-like Behavior.

Author information

1
Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi.
2
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. Electronic address: s-uchida@yamaguchi-u.ac.jp.
3
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.

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:

Anxiety; Chronic stress; Dendritic atrophy; Depression; Hippocampus; Sirtuin

Comment in

PMID:
27016384
DOI:
10.1016/j.biopsych.2016.01.009
[Indexed for MEDLINE]

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