Ji Xiao, Zhao Zhenwu
The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.
Emergency Department, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China.
Brain Res Bull. 2023 Apr;195:14-24. doi: 10.1016/j.brainresbull.2023.01.002. Epub 2023 Jan 10.
Silencing of miR-92a-3p may be beneficial in relieving depression of chronically stressed rats. The level of kruppel-like factor 2 (KLF2) was increased in the striatum of depressed rats after ketamine treatment. Enriched environment (EE) ameliorated depression-like behaviors in rats. However, the specific mechanism of EE treatment on depression induced by chronic unpredictable mild stress (CUMS) remains unclear.
After CUMS-induced male Sprague Dawley rats were treated under EE or/and Adeno-Associated Virus (AAV)-miR-92a-3p, depression-like behaviors, cognitive ability, dendritic spine density, as well as levels of miR-92a-3p and KLF2 were detected by the behavioral tests, morris water maze test, Golgi staining, and quantitative real-time polymerase chain reaction (qRT-PCR) as needed. The body weight of rats was also measured. Next, primary hippocampal neurons were cultivated. The targeting relationship between miR-92a-3p and KLF2 was analyzed by TargetScan v7.2 and dual-luciferase reporter assay. After hippocampal neurons were transfected with miR-92a-3p mimic or/and overexpressed KLF2 vector, the cell viability, and apoptosis, together with the levels of KLF2, brain-derived neurotrophic factor (BDNF), phosphorylated (p)-tropomysin related kinase B (p-TrkB) and TrkB were determined by MTT assay, flow cytometry, qRT-PCR, and western blot as needed.
EE ameliorated CUMS-induced depression-like behaviors and cognitive ability, and elevated the neuronal dendritic spine density and KLF2 level, but reduced miR-92a-3p level in hippocampal tissues, while the above effects were reversed by AAV-miR-92a-3p. MiR-92a-3p mimic restrained cell viability, along with p-TrkB/ TrkB and BDNF levels, but promoted apoptosis in hippocampal neurons, which were reversed by overexpressed KLF2.
EE ameliorates CUMS-induced depression-like symptoms in rats via regulating the miR-92a-3p/KLF2 pathway.
沉默miR-92a-3p可能有助于缓解慢性应激大鼠的抑郁症状。氯胺酮治疗后，抑郁大鼠纹状体中 kruppel样因子2（KLF2）水平升高。丰富环境（EE）可改善大鼠的抑郁样行为。然而，EE治疗慢性不可预测轻度应激（CUMS）所致抑郁的具体机制仍不清楚。
对CUMS诱导的雄性Sprague Dawley大鼠进行EE或/和腺相关病毒（AAV）-miR-92a-3p处理后，根据需要通过行为测试、莫里斯水迷宫试验、高尔基染色和定量实时聚合酶链反应（qRT-PCR）检测抑郁样行为、认知能力、树突棘密度以及miR-92a-3p和KLF2水平。还测量了大鼠的体重。接下来，培养原代海马神经元。通过TargetScan v7.2和双荧光素酶报告基因检测分析miR-92a-3p与KLF2之间的靶向关系。用miR-92a-3p模拟物或/和过表达KLF2载体转染海马神经元后，根据需要通过MTT法、流式细胞术、qRT-PCR和蛋白质免疫印迹法测定细胞活力、凋亡情况以及KLF2、脑源性神经营养因子（BDNF）、磷酸化（p）-原肌球蛋白相关激酶B（p-TrkB）和TrkB的水平。
EE改善了CUMS诱导的抑郁样行为和认知能力，提高了神经元树突棘密度和海马组织中KLF2水平，但降低了miR-92a-3p水平，而AAV-miR-92a-3p可逆转上述作用。miR-92a-3p模拟物抑制了细胞活力以及p-TrkB/TrkB和BDNF水平，但促进了海马神经元凋亡，而过表达KLF2可逆转这些作用。
EE通过调节miR-92a-3p/KLF2通路改善CUMS诱导的大鼠抑郁样症状。
