Exposure to enriched environment ameliorated chronic unpredictable mild stress-induced depression-like symptoms in rats via regulating the miR-92a-3p/kruppel-like factor 2 (KLF2) pathway

• Published in: Brain research bulletin 2023-04, Vol.195, p.14-24
• Main Authors: Ji, Xiao, Zhao, Zhenwu
• Format: Article
• Language: English
• Subjects: Animals; Brain-Derived Neurotrophic Factor - metabolism; Chronic unpredictable mild stress; Depression; Enriched environment; Kruppel-like factor 2; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Male; MicroRNAs - genetics; MicroRNAs - metabolism; MiR-92a-3p; Rats; Rats, Sprague-Dawley; Transcription Factors
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2023.01.002

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. •EE ameliorated CUMS-induced depression-like symptoms in rats.•MiR-92a-3p reversed the effect of EE on CUMS-induced depression-like symptoms in rats.•MiR-92a-3p reduced p-TrkB level, but induced neurons’ apoptosis by targeting KLF2.