Hippocampal Sirtuin 1 Signaling Mediates Depression-like Behavior
Hippocampal Sirtuin 1 Signaling Mediates Depression-like Behavior
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DOI：
10.1016/j.biopsych.2016.01.009
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发表时间：
2016-12-01
影响因子：
10.6
通讯作者：
Watanabe, Yoshifumi
中科院分区：
文献类型：
--
作者：
Abe-Higuchi, Naoko;Uchida, Shusaku;Watanabe, Yoshifumi
背景：尽管抑郁症是全世界残疾的主要原因，但其病理生理学却知之甚少。最近的证据表明去乙酰化酶（SIRT）在认知和突触可塑性中发挥着关键作用，但它们在情绪调节中的作用仍然存在争议。在这里，我们的目的是研究 SIRT 功能是否与慢性压力引起的抑郁样行为和神经元萎缩有关。方法：我们测量了小鼠抑郁模型中 SIRT 的表达和活性。我们给小鼠注射了 SIRT1 激活剂或抑制剂，并测量了它们的抑郁样行为和树突棘形态。为了直接评估 SIRT1 的作用，我们使用病毒介导的基因转移来过表达野生型 SIRT1 或显性失活 SIRT1，并评估它们的抑郁样行为。最后，我们研究了细胞外信号调节蛋白激酶 1 和 2（SIRT1 的潜在下游靶标）在抑郁样行为中的作用。 结果：我们发现慢性压力会降低海马齿状回的 SIRT1 活性。海马 SIRT1 功能的药物和遗传抑制导致抑郁样行为的增加。相反，SIRT1 激活可阻止抑郁相关表型的发展以及慢性压力暴露引起的异常树突结构。此外，在应激条件下，海马 SIRT1 激活增加了细胞外信号调节蛋白激酶 1 和 2 的磷酸化水平，病毒介导的海马细胞外信号调节蛋白激酶 2 的激活和抑制分别导致抗抑郁和促抑郁行为。 结论：我们的结果表明，海马 SIRT1 通路有助于慢性应激引发的抑郁相关表型和异常树突。萎缩。
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.