Zhao Yan, Wang Shuang, Chu Zheng, Dang Yonghui, Zhu Juanxia, Su Xingli
Institute of Basic Medicine Science, Xi'an Medical University, Xi'an 70021, China.
College of Forensic Science, Xi'an Jiaotong University, Xi'an 70061, China.
Brain Res. 2017 Aug 15;1669:55-62. doi: 10.1016/j.brainres.2017.05.020. Epub 2017 May 24.
Long-term exposure to stress plays a key role in the pathogenesis of major depression. Recently, the ventrolateral orbital cortex (VLO) has received considerable attention for its role in the antidepressant response. However, the mechanisms underlying stress response in the VLO remain largely elusive. MiR-101 has been implicated in regulating multiple neurological processes. The present study used the chronic unpredictable mild stress (CUMS) rat model to investigate the expression of miR-101 in the VLOs of rat brains and the possible relevance of miR-101 to depression. Furthermore, an intra-VLO administration of a miR-101 mimic was performed to provide insights into the miR-101-mediated dysregulation mechanisms associated with depression. The results showed that chronic stress induced typical depressive-like behaviors in rats and decreased miR-101 levels in the VLOs of rat brains. Moreover, the dual specificity phosphatase 1 (DUSP1) protein levels were increased in the VLOs in CUMS rats, whereas the ERK phosphorylation and BDNF levels in the CUMS rats were decreased. Enhancing miR-101 expression via an intro-VLO microinjection of its mimic reversed the depressive-like behaviors in CUMS rats. Intra-VLO treatment with the miR-101 mimic also attenuated the upregulation of CUMS-induced DUSP1 expression and inhibited the downstream ERK phosphorylation and BDNF expression. These results suggest that miR-101 has functional significance in the pathophysiology of stress-induced dysfunctions in the VLO. MiR-101 may directly regulate DUSP1 expression, and the mechanism underlying the antidepressant effects of miR-101 may involve the negative regulation of DUSP1 expression, which in turn promotes downstream ERK/BDNF signaling.
长期暴露于应激在重度抑郁症的发病机制中起关键作用。最近，腹外侧眶额皮质（VLO）因其在抗抑郁反应中的作用而受到广泛关注。然而，VLO中应激反应的潜在机制仍 largely难以捉摸。MiR-101已被证明参与调节多种神经过程。本研究使用慢性不可预测轻度应激（CUMS）大鼠模型来研究miR-101在大鼠脑VLO中的表达以及miR-101与抑郁症的可能相关性。此外，通过向VLO内注射miR-101模拟物来深入了解与抑郁症相关的miR-101介导的失调机制。结果表明，慢性应激诱导大鼠出现典型的抑郁样行为，并降低大鼠脑VLO中miR-101的水平。此外，CUMS大鼠VLO中的双特异性磷酸酶1（DUSP1）蛋白水平升高，而CUMS大鼠中的ERK磷酸化和BDNF水平降低。通过向VLO内微量注射miR-101模拟物增强miR-101表达可逆转CUMS大鼠的抑郁样行为。向VLO内注射miR-101模拟物还可减弱CUMS诱导DUSP1表达的上调，并抑制下游ERK磷酸化和BDNF表达。这些结果表明，miR-101在VLO应激诱导功能障碍的病理生理学中具有功能意义。MiR-101可能直接调节DUSP1表达，miR-101抗抑郁作用的潜在机制可能涉及对DUSP1表达的负调节，进而促进下游ERK/BDNF信号传导。
