脑室注射脂多糖建立小鼠认知行为障碍模型

Intracerebroventricular injection of lipopolysaccharide induces cognitive decline in mice

目的探讨脂多糖（lipopolysaccharide,LPS）单次脑室注射对C57小鼠认知功能的影响,以期建立中枢炎症的认知功能障碍小鼠模型。方法将40只C57小鼠分为空白对照组、LPS 10 ng组、LPS 100 ng组与LPS 2 000 ng组,进行Morris水迷宫空间获得性训练后分别对脑室单次给予LPS 0 ng、10 ng、100 ng、2 000 ng,给药后1 d进行空间探索实验,1~3 d进行工作记忆检测;另将40只C57小鼠分为空白对照组、LPS 10 ng组、LPS 100 ng组与LPS 2 000 ng组,进行新物体识别实验,适应并受训后进行脑室给药,给药后1 d行新物体识别测试;取10只C57小鼠分为两组,分别对脑室给予人工脑脊液、LPS 2 000 ng,6 h后取材检测海马IL-1β、TNF-α含量。结果与空白对照组相比,脂多糖给药组均引起小鼠在Morris水迷宫和新物体识别实验中认知功能下降,其中2 000 ng LPS给药组分别引起水迷宫空间探索实验中小鼠穿台次数、平台周边距离、目标象限停留路程百分比均分别减少72%、46%、32%,工作记忆检测中登台潜伏期延长2倍;新物体识别实验中新物体探索时间、探索次数百分比分别降低22%、21%;ELISA结果显示,2 000 ng LPS脑室注射导致海马IL-1β、TNF-α含量分别升高55%、41%。结论单次LPS（2μg）脑室注射可引起C57小鼠认知功能障碍,提示LPS导致炎性损伤可以作为小鼠认知功能障碍的候选模型。

Objective To investigate the effect of intracerebroventricular injection of lipopolysaccharide （LPS） on cognitive function and establish inflammation-induced cognitive dysfunction model in mice.Methods Forty C57 mice were randomly divided into four groups： control group, 10 ng group, 100 ng group, 2 000 ng group. Intracerebroventricular injection of LPS at dose of 0, 10, 100, 2 000 ng was performed after 5 days of acquisition training in a Morris water maze （MWM）. The probe test was conducted 1 day after LPS injection, and working memory was tested on day 1 to 3. The other 40 C57 mice were divided as the same way and used for novel object recognition test. Intracerebroventricular injection of LPS at the same doses was performed after acquaintance and training and mice were tested 1 day after injection. Ten more mice were injected with LPS at dose of 0, 2μg for IL-1β and TNF-α examination in hippocampus.Results The Morris water maze and novel object recognition test indicated that cognitive declined in all LPS groups, while 2 000 ng LPS group showed decrease of platform-site crossovers （72%）, distance around platform （46%）, percentage of distance travelled in the target quadrant （32%） during probe testing, increase of latency to the platform by twice during the working memory test in Morris water maze. Percentage of time and counts for novel object exploration in novel object recognition test were decreased by 22% and 21%, respectively. The ELISA test showed an increase of IL-1β （55%） and TNF-α （41%） levels in the hippocampus of mice in 2 000 ng LPS group.Conclusion Intracerebroventricular administration of lipopolysaccharide at dose of 2μg induces cognitive decline in C57 mice, which suggests that LPS-induced CNS inflammation can contribute to establish a cognitive dysfunction model in mice.