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Title: [Long-term high-fat diet's impact on synaptic plasticity in the visual cortex and hippocampus neurons: an experimental study].
Author: Ji XJ, Guo YT, Zhang W.
Journal: Zhonghua Yan Ke Za Zhi; 2023 Sep 11; 59(9):730-739. PubMed ID: 37670656.
Abstract:
Objective: To investigate the effects and mechanisms of long-term high-fat diet on synaptic plasticity in the visual cortex and hippocampus neurons of juvenile mice. Methods: This was an experimental study. Twenty-four 4-week-old male C57BL/6J mice were randomly divided into two groups, using a randomized numerical table, with 12 mice in each group. The ND group was fed a normal diet, while the HFD group was fed a high-fat diet. After 12 weeks of feeding, mouse body weight, body fat percentage, glucose tolerance, and blood lipid levels were recorded. Six mice from each group were randomly selected using a randomized numerical table, and long-term potentiation (LTP) in the lateral geniculate nucleus (LGN)-primary visual cortex binocular zone (V1B area) and hippocampus CA3-CA1 were recorded in vitro. Field excitatory postsynaptic potentials (fEPSPs) were measured, and the normalized fEPSP slope was calculated to evaluate changes in cortical synaptic plasticity. Subsequently, brain tissue was collected for Golgi staining to observe the development of pyramidal neurons in layers Ⅱ-Ⅲ of the primary visual cortex and CA1 region of the hippocampus, and changes in dendritic spine morphology and quantity were compared. The remaining six mice from each group were euthanized, and brain tissue was collected for transmission electron microscopy to observe ultrastructural changes in the visual cortex V1B area and hippocampus CA1 region neurons. Independent samples t-test was used for statistical analysis. Results: After 12 weeks of feeding, the body weight of mice in the HFD group was (29.17±1.63) g, significantly lower than the ND group which was (37.99±6.87) g (t=4.33, P<0.001). The body fat percentage in the HFD group was 1.09%±0.22%, which was higher than the ND group with 0.85%±0.09% (t=2.50, P=0.032). HFD mice showed a significant increase in blood glucose level 30 minutes after glucose injection, reaching (17.80±3.94) mmol/L, compared to the ND group with (23.10±1.48) mmol/L (t=3.07, P=0.013). At 60 minutes after glucose injection, the difference in blood glucose levels between the ND group [(13.58±2.39) mmol/L] and the HFD group [(23.70±3.56) mmol/L] was statistically significant (t=5.40, P<0.001). Subsequently, both groups showed a decline in blood glucose levels, and at 120 minutes after glucose injection, the blood glucose level in the ND group decreased to (8.50±1.05) mmol/L, while the HFD group remained at a higher level of (16.03±4.17) mmol/L, showing a statistically significant difference (t=3.91, P=0.004). The serum total cholesterol levels in the ND and HFD groups were (4.08±0.35) mmol/L and (10.80±0.90) mmol/L, respectively, with the HFD group higher than the ND group (t=15.23, P<0.001). However, there was no significant difference in triglyceride levels (P>0.05). The high-density lipoprotein cholesterol level in the ND group was (2.12±0.57) mmol/L, while in the HFD group, it was (1.28±0.15) mmol/L, with the HFD group lower than the ND group (t=3.15, P=0.014). Non-high-density lipoprotein cholesterol level in the HFD group was (11.06±1.46) mmol/L, significantly higher than the ND group with (2.28±0.43) mmol/L (t=12.88, P<0.001). In the hippocampal CA3-CA1 pathway, the fEPSP slope increased by 239.1%±88.8% of baseline in the ND group, while in the HFD group, it was only 147.6%±31.6% of baseline, indicating lower LTP compared to the ND group (t=7.20, P<0.001). For the LGN-V1 pathway, the fEPSP slope increased by 204.8%±67.0% of baseline in the ND group, while in the HFD group, it was 121.1%±15.7% of baseline, showing reduced LTP compared to the ND group (t=9.11, P<0.001). Regarding the visual cortex, in the V1B area of the ND group, the number of dendritic spines per 10 μm was (1.31±1.14), while in the HFD group, it was (0.77±0.43), demonstrating a significant decrease in dendritic spine density (t=3.45, P<0.001). The proportion of mature dendritic spines in the ND group was 69.98%, while non-mature dendritic spines accounted for 30.02%. In contrast, the HFD group had 45.76% mature dendritic spines and 54.24% non-mature dendritic spines. Regarding changes in hippocampal CA1 pyramidal neurons, the cell bodies and axons were not damaged, but HFD group neurons exhibited simplified dendritic structures with reduced branching. The number of dendritic spines per 10 μm was (10.25±3.84) in the HFD group and (25.22±8.21) in the ND group, indicating significantly lower dendritic spine density in the HFD group (t=12.42, P<0.001). The proportion of mature dendritic spines in the ND group was 70.88%, while non-mature dendritic spines accounted for 29.12%. In contrast, the HFD group had 47.37% mature dendritic spines and 52.63% non-mature dendritic spines. Moreover, the ultrastructure of neurons in the visual cortex V1B area and hippocampus CA1 region of HFD mice showed evident damage, with disrupted cell structures, swollen and vacuolated mitochondria, reduced or even disappeared mitochondrial cristae, and decreased synaptic quantity with damaged structure. Conclusions: Long-term high-fat diet in juvenile mice leads to abnormal development and functional maturation of synapses in the visual cortex and hippocampal regions. Dendrites, as the foundation of synaptic structures, undergo abnormal development, which can cause alterations in synaptic plasticity of related neural circuits. 目的： 探讨长期高脂饮食对幼年小鼠视皮质和海马神经元突触可塑性的影响及其机制。 方法： 实验研究。24只4周龄雄性C57BL/6J小鼠按随机数字表法分为两组，每组12只。正常饮食（ND）组采用正常饮食喂养，高脂饮食（HFD）组采用高脂饮食喂养。喂养12周，记录小鼠体重和体脂比，进行葡萄糖耐量试验和血脂水平测定。采用随机数字表法每组选择6只小鼠，对丘脑视皮质外侧膝状体（LGN）-初级视皮质双眼区（V1B区）和海马CA3-CA1的长时程增强作用进行在体记录，测量场兴奋性突触后电位（fEPSP）并计算标准化的fEPSP斜率，以评估小鼠皮质突触可塑性变化，之后取脑组织进行高尔基染色，观察初级视皮质双眼区Ⅱ-Ⅲ层和海马CA1区锥体神经元胞体、轴突、树突发育情况，比较树突棘形态与数量的变化。处死每组其余6只小鼠，取脑组织，采用透射电镜观察视皮质V1B区和海马CA1区神经元超微结构变化。采用独立样本t检验进行统计学分析。 结果： 喂养12周后，HFD组小鼠体重为（29.17±1.63）g，HFD组体重为（37.99±6.87）g，差异有统计学意义（t=4.33，P<0.001）。ND组体脂比为0.85%±0.09%，HFD组体脂比为1.09%±0.22%，差异有统计学意义（t=2.50，P=0.032）。HFD组小鼠在注射葡萄糖后30 min血糖水平升高显著，为（17.80±3.94）mmol/L，高于ND组的（23.10±1.48）mmol/L（t=3.07，P=0.013）。HFD组血糖水平下降缓慢，在注射葡萄糖后60 min，ND组与HFD组血糖水平差异最大，分别为（13.58±2.39）mmol/L和（23.70±3.56）mmol/L，差异有统计学意义（t=5.40，P<0.001）。之后两组血糖水平均开始下降，在注射葡萄糖后120 min，ND组血糖水平降至（8.50±1.05）mmol/L，而HFD组仍处于较高水平，为（16.03±4.17）mmol/L，差异有统计学意义（t=3.91，P=0.004）。ND组与HFD组小鼠血清总胆固醇水平分别为（4.08±0.35）和（10.80±0.90）mmol/L，HFD组高于ND组（t=15.23，P<0.001）；甘油三酯水平差异无统计学意义（P>0.05）。ND组高密度脂蛋白胆固醇水平为（2.12±0.57）mmol/L，HFD组为（1.28±0.15）mmol/L，HFD组低于ND组（t=3.15，P=0.014）。HFD组非高密度脂蛋白胆固醇水平为（11.06±1.46）mmol/L，ND组为（2.28±0.43）mmol/L，HFD组高于ND组（t=12.88，P<0.001）。海马CA3-CA1区通路，ND组fEPSP斜率增加为基线的239.1%±88.8%，而HFD组为基线的147.6%±31.6%，HFD组低于ND组（t=7.20，P<0.001）。LGN-V1通路，ND组fEPSP斜率增加为基线的204.8%±67.0%，HFD组为121.1%±15.7%，低于ND组（t=9.11，P<0.001）。对于视皮质，ND组V1B区Ⅱ-Ⅲ层的锥体神经元每10 μm树突上的树突棘数量为（1.31±1.14）个，而HFD组为（0.77±0.43）个，树突棘密度下降，差异有统计学意义（t=3.45，P<0.001）。ND组成熟型树突棘占比69.98%，非成熟型树突棘占比30.02%；HFD组成熟型树突棘占比45.76%，非成熟型树突棘占比54.24%。对于小鼠海马CA1区锥体神经元的变化，锥体细胞胞体及轴突未见损伤，HFD组神经元树突结构简单，分支减少。每10 μm树突上的树突棘数量HFD组为（10.25±3.84）个，ND组为（25.22±8.21）个，差异有统计学意义（t=12.42，P<0.001）。ND组成熟型树突棘占比70.88%，非成熟型占比29.12%，HFD组成熟型树突棘占比47.37%，非成熟型占比52.63%。HFD组小鼠视皮质V1B区和海马CA1区神经元超微结构明显受损，细胞结构紊乱，线粒体肿胀、空泡化，线粒体嵴减少甚至消失，同时突触数量减少且结构受损。 结论： 长期高脂饮食幼年小鼠的视皮质和海马区突触的发育和功能成熟异常。树突作为突触结构的基础，发育异常可引起相关区域神经元突触可塑性改变。.

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