高脂饮食对空间学习记忆功能的影响及齿状回N-甲基-D-天冬氨酸受体的调节作用  

Effect of High-Fat Diet on Spatial Learning and Memory and Regulatory Role of N-Methyl-D-Aspartate Receptors in the Dentate Gyrus

作　　者：刘桦映 董薇 张子涵 李英顺 金清华 LIU Huaying;DONG Wei;ZHANG Zihan;LI Yingshun;JIN Qinghua(Department of Physiology and Pathophysiology,College of Medicine,Yanbian University,Yanji 133002,China)

机构地区：[1]延边大学医学院生理学与病理生理学教研室,吉林延吉133002

出　　处：《食品科学》2024年第23期123-130,共8页Food Science

基　　金：国家自然科学基金地区科学基金项目(32160195,81760158)。

摘　　要：以刚断奶的大鼠为实验对象,进行长达12周的高脂饮食(high fat diet,HFD)(45%脂肪),观察大鼠的体质量及血脂和血糖水平,通过Morris水迷宫检测大鼠的空间学习和记忆能力;蛋白免疫印迹法检测海马齿状回(dentate gyrus,DG)区磷酸化的钙/钙调素依赖性蛋白激酶II(phosphorylated Ca^(2+)/calmodulin dependent protein kinase Ⅱ,p-CaMKⅡ)和环磷腺苷效应元件结合蛋白(phosphorylated cAMP-response element binding protein,p-CREB)以及神经炎症因子的表达;用蛋白免疫印迹法和免疫组织化学染色法观察DG区小胶质细胞标志物的表达,并通过往海马DG区注射N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体阻断剂MK-801,观察DG区NMDA受体在上述改变中的作用。结果表明,与对照(control,CON)组比较,长期HFD诱发大鼠出现肥胖体态,即食源性肥胖(diet-induced obesity,DIO);与CON组比较,DIO组大鼠及DG区注射MK-801(DIO+MK)组的体质量及血清中的甘油三酯、总胆固醇和低密度脂蛋白的水平均显著增加;Morris水迷宫训练结果显示,与CON组比较,DIO组大鼠空间学习记忆功能损伤,而DG区微量注射MK-801可缓解上述损伤;与CON组比较,DIO组大鼠DG区p-CaMKII和p-CREB的表达显著降低,而离子钙结合衔接分子1、白介素-6(interleukin-6,IL-6)和IL-1β的表达却显著增加,但向海马DG区微量注射MK-801可反转上述变化。综上所述,长期HFD诱发大鼠的肥胖体态及神经炎症反应,并造成空间学习记忆功能损伤,而阻断海马DG区的NMDA受体可以提高CaMKII-CREB通路活性和减少神经炎症反应,改善DIO大鼠的空间学习和记忆损伤。本研究可为合理膳食及探明不良饮食习惯诱发的DIO影响记忆功能的机制提供理论依据。Newly weaned rats were fed with high-fat diet(HFD)(containing 45%fat)for 12 weeks,and body mass,serum lipid and glucose levels were observed.The Morris water maze(MWM)test was used to evaluate the spatial learning and memory capacity of the rats;Western blot was used to detect the expression of phosphorylated Ca^(2+)/calmodulin dependent protein kinase Ⅱ(p-CaMKⅡ)and cAMP-response element binding protein(p-CREB),pro-inflammatory cytokines,including interleukin-6(IL-6)and IL-1βin the hippocampal dentate gyrus(DG);the expression of ionized calcium binding adapter molecule 1(Iba1)in the DG were observed by Western blot and immunohistochemistry.Furthermore,the role of N-methyl-D-aspartate(NMDA)receptors in the above changes was examined by microinjection of the NMDA receptor blocker MK-801 into the DG.Our results showed that the rats developed diet-induced obesity(DIO)after long-term HFD consumption compared with the control(CON)group.Body mass and the levels of serum triglyceride,total cholesterol,and low-density lipoprotein were significantly increased in the DIO and DIO+MK-801 injection groups.In the MWM test,compared with the CON group,spatial learning and memory capacity was impaired in the DIO group,and microinjection of MK-801 into the DG rescued these impairments.Compared with the CON group,the expression of p-CaMKII and p-CREB was significantly decreased and the expression of Iba1,IL-6 and IL-1βin the DG was significantly increased in the DIO group;however,these changes were reversed by microinjection of MK-801 into the DG of DIO rats.Our results suggest that longterm HFD consumption induces DIO and neuroinflammatory responses,and impairs spatial learning and memory.Moreover,blocking of NMDA receptors in the DG rescues spatial learning and memory impairments in DIO rats by activating the CaMKII-CREB signaling pathway and decreasing neuroinflammatory responses.This study provides a theoretical basis for rational diet and understanding the mechanism of HFD-induced impairments in learning and memory.

关 键 词：高脂饮食 食源性肥胖 空间学习和记忆 齿状回 N-甲基-D-天冬氨酸受体 

分 类 号：R151[医药卫生—营养与食品卫生学]