期刊
BIOLOGICAL PSYCHIATRY
卷 80, 期 11, 页码 815-826出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2016.01.009
关键词
Anxiety; Chronic stress; Dendritic atrophy; Depression; Hippocampus; Sirtuin
资金
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Agency for Medical Research and Development
- SENSHIN Medical Research Foundation
- Uehara Memorial Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [25893152, 26860481, 15K09807, 26670542, 15H04895] Funding Source: KAKEN
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.
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