The aim of this study was to examine if nicotine was able to improve cognition deficits in a mouse model of chronic mild stress. Twenty-four male C57BL/6 mice were divided into three groups: control, stress, and stress with nicotine treatment. The animal model was established by combining chronic unpredictable mild stress (CUMS) and isolated feeding. Mice were exposed to CUMS continued for 28 days, while nicotine (0.2 mg/kg) was also administrated for 28 days. Weight and sucrose consumption were measured during model establishing period. The anxiety and behavioral despair were analyzed using the forced swim test (FST) and open-field test (OFT). Spatial cognition was evaluated using Morris water maze (MWM) test. Following behavioral assessment, both long-term potentiation (LTP) and depotentiation (DEP) were recorded in the hippocampal dentate gyrus (DG) region. Both synaptic and Notch1 proteins were measured by Western. Nicotine increased stressed mouse's sucrose consumption. The MWM test showed that spatial learning and reversal learning in stressed animals were remarkably affected relative to controls, whereas nicotine partially rescued cognitive functions. Additionally, nicotine considerably alleviated the level of anxiety and the degree of behavioral despair in stressed mice. It effectively mitigated the depression-induced impairment of hippocampal synaptic plasticity, in which both the LTP and DEP were significantly inhibited in stressed mice. Moreover, nicotine enhanced the expression of synaptic and Notch1 proteins in stressed animals. The results suggest that nicotine ameliorates the depression-like symptoms and improves the hippocampal synaptic plasticity closely associated with activating transmembrane ion channel receptors and Notch signaling components. Graphical Abstract ᅟ.
U1 small nuclear RNA (U1 snRNA), as one of the most abundant noncoding RNA in eukaryotic cells plays an important role in splicing of pre-mRNAs. Compared to other studies which have focused on the primary function of U1 snRNA and the neurodegenerative diseases caused by the abnormalities of U1 snRNA, this study is to investigate how the U1 snRNA over-expression affects the expression of genes on a genome-wide scale. In this study, we built a model of U1 snRNA over-expression in a rat cell line. By comparing the gene expression profiles of U1 snRNA over-expressed cells with those of their controls using the microarray experiments, 916 genes or loci were identified significantly differentially expressed. These 595 up-regulated genes and 321 down-regulated genes were further analyzed using the annotations from the GO terms and the KEGG database. As a result, three of 12 enriched pathways are well-known cancer pathways, while nine of them were associated to cancers in previous studies. The further analysis of 73 genes involved in 12 pathways suggests that U1 snRNA regulates cancer gene expression. The microarray data with ID GSE84304 is available in the NCBI GEO database.
We recently reported that presenilin-1 (PS1) induced an increase of U1 snRNA expression accompanied with the change of amyloid precursor protein expression, β-amyloid level and cell death. In the present study, our data showed that both overexpression and knockdown of U1 snRNA could cause the loss in the function of U1 snRNA and resulted in PCPA as well as the same downstream phenomena including the expression changes of genes specific to AD, tau hyperphosphorylation on the site of Thr212, the decrease of acetylated α-tubulin, the reduction of cell viability and upregulation of RIPK1, RIPK3 and caspase8. These findings not only helped researchers better understand the functions of U1 snRNA, but also paved the way to reveal the mechanisms of AD from a different point of view and may find a new therapeutic target for the disease.
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