School of Life Science, Nanchang University, Nanchang, China.
Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, China.
CNS Neurosci Ther. 2024 Feb;30(2):e14627. doi: 10.1111/cns.14627.
Systemic inflammation in which lipopolysaccharide (LPS) is released into circulation can cause cognitive dysfunction and we have previously shown that LPS impaired working memory (WM) which refers to the ability to guide incoming behavior by retrieving recently acquired information. However, the mechanism is not very clear, and currently, there is no approved strategy to improve inflammation-induced WM deficit. Notably, epidemiological studies have demonstrated a lower occurrence rate of inflammatory-related diseases in smoking patients, suggesting that inflammation-induced WM impairment may be improved by nicotine treatment. Here, our object is to investigate the effect and potential mechanisms of acute and chronic nicotine treatment on LPS-produced WM deficiency.
Delayed alternation T-maze task (DAT) was applied for evaluating WM which includes both the short-term information storage and the ability to correct errors in adult male mice. Immunofluorescence staining and immunoblotting were used for assessing the levels and distribution of CREB-regulated transcription coactivator 1 (CRTC1) and hyperpolarization-activated cation channels 2 (HCN2) in the medial prefrontal cortex (mPFC) and hippocampus. Quantitative PCR and ELISA were employed for analyzing the mRNA and protein levels of TNF-α and IL-1β.
Our results revealed that administration of LPS (i.p.) at a dose of 0.5 mg/kg significantly produced WM impairment in the DAT task accompanied by an increase in IL-1β and TNF-α expression in the mPFC. Moreover, intra-mPFC infusion of IL-1Ra, an IL-1 antagonist, markedly alleviated LPS-induced WM deficiency. More important, chronic (2 weeks) but not acute nicotine (0.2 mg/kg, subcutaneous) treatment significantly alleviated LPS-induced WM deficiency by upregulating CRTC1 and HCN2. Of note, intra-mPFC infusion of HCN blocker ZD7288 produced significant WM deficiency.
In summary, in this study, we show that chronic nicotine treatment ameliorates acute inflammation-induced working memory deficiency by increasing CRTC1 and HCN2 in adult male mice.
脂多糖（LPS）释放到循环系统中会引起全身炎症，从而导致认知功能障碍，我们之前的研究表明 LPS 会损害工作记忆（WM），WM 是指通过检索最近获得的信息来指导传入行为的能力。然而，其机制尚不清楚，目前尚无改善炎症引起的 WM 缺陷的批准策略。值得注意的是，流行病学研究表明，吸烟患者炎症相关疾病的发生率较低，这表明尼古丁治疗可能改善炎症引起的 WM 损伤。在这里，我们的目的是研究急性和慢性尼古丁处理对 LPS 引起的 WM 缺陷的影响及其潜在机制。
延迟交替 T 迷宫任务（DAT）用于评估 WM，包括短期信息存储和纠正成年雄性小鼠错误的能力。免疫荧光染色和免疫印迹用于评估内侧前额叶皮层（mPFC）和海马中 CREB 调节转录共激活因子 1（CRTC1）和超极化激活阳离子通道 2（HCN2）的水平和分布。定量 PCR 和 ELISA 用于分析 TNF-α 和 IL-1β 的 mRNA 和蛋白水平。
我们的结果表明，腹腔内注射 LPS（0.5mg/kg）剂量显著导致 DAT 任务中的 WM 损伤，同时 mPFC 中 IL-1β 和 TNF-α 的表达增加。此外，mPFC 内注射 IL-1 拮抗剂 IL-1Ra 可显著减轻 LPS 诱导的 WM 缺陷。更重要的是，慢性（2 周）而不是急性尼古丁（0.2mg/kg，皮下）治疗通过上调 CRTC1 和 HCN2 显著减轻 LPS 诱导的 WM 缺陷。值得注意的是，mPFC 内注射 HCN 阻滞剂 ZD7288 会导致明显的 WM 缺陷。
总之，在这项研究中，我们表明慢性尼古丁治疗通过增加成年雄性小鼠 mPFC 中的 CRTC1 和 HCN2 来改善急性炎症引起的工作记忆缺陷。
