Abstract：
With the global increase in life expectancy, there has been a rise in the incidence of cognitive impairments attributed to diverse etiologies. Notably, approximately 50% of individuals diagnosed with mild cognitive impairment (MCI) progress to dementia within 3 years. However, the precise mechanisms underlying MCI remain elusive. Therefore, this study aimed to elucidate potential mechanisms implicated in MCI utilizing Per2 knockout (KO) mice, which have previously been shown to have cognitive deficits. Behavioral (Y-maze, Barnes maze) and molecular (electrophysiology, RNA sequencing, western blot, and immunofluorescence) experiments were conducted in Per2 KO and wild-type (WT) mice. Per2 KO mice exhibited impaired spatial working memory in the Y-maze and Barnes maze. However, there were no significant group differences in hippocampal long-term potentiation (LTP) between Per2 KO and WT mice, whereas striatal LTP in Per2 KO mice was lower compared to WT mice. In RNA sequencing analysis, 58 genes were downregulated and 64 genes were upregulated in the striatum of Per2 KO mice compared to WT mice. Among the differentially expressed genes, four genes (Chrm2, EphB2, Htr1b, Oprm1) were identified. Optimal expression levels of EPHB2 and OPRM1 were found to significantly enhance cognitive performance in mice. Additionally, Per2 KO mice exhibited reduced EPHB2-NMDAR-LTP and OPRM-mTOR signaling, along with elevated amyloid beta (Aβ) levels, when compared to WT mice. However, these alterations were reversed upon administration of morphine treatment. Striatal OPRM1-mTOR signaling, EPHB2-NMDAR-LTP signaling, and Aβ expression levels may exert a combined effect on MCI under the control of Per2 expression.
摘要：
随着全球预期寿命的增加，由于不同的病因,认知障碍的发病率有所上升.值得注意的是,约50%的轻度认知障碍(MCI)患者在3年内进展为痴呆.然而,MCI背后的确切机制仍然难以捉摸。因此,本研究旨在阐明利用Per2敲除（KO）小鼠参与MCI的潜在机制，以前已经被证明有认知缺陷。行为(Y-迷宫，巴恩斯迷宫)和分子(电生理学，RNA测序，westernblot,和免疫荧光）实验在Per2KO和野生型（WT）小鼠中进行。Per2KO小鼠在Y迷宫和Barnes迷宫中表现出受损的空间工作记忆。然而,Per2KO和WT小鼠海马长时程增强(LTP)无显著组间差异,而Per2KO小鼠的纹状体LTP低于WT小鼠。在RNA测序分析中，与WT小鼠相比，Per2KO小鼠纹状体中58个基因下调，64个基因上调。在差异表达的基因中，四个基因(Chrm2,EphB2,Htr1b,Oprm1）已确定。发现EPHB2和OPRM1的最佳表达水平显着增强小鼠的认知表现。此外,Per2KO小鼠表现出降低的EPHB2-NMDAR-LTP和OPRM-mTOR信号,随着淀粉样蛋白β（Aβ）水平升高，与WT小鼠相比。然而,这些改变在给予吗啡治疗后被逆转.纹状体OPRM1-mTOR信号,EPHB2-NMDAR-LTP信号,和Aβ表达水平可能在Per2表达的控制下对MCI产生联合作用。
