Zhonghua Yan Ke Za Zhi. 2023 Sep 11;59(9):730-739. doi: 10.3760/cma.j.cn112142-20221213-00633.
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.