Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats

Abstract

Overall dietary energy intake, particularly the consumption of simple sugars such as fructose, has been increasing steadily in Western societies, but the effects of such diets on the brain are poorly understood. Here, we used functional and structural assays to characterize the effects of excessive caloric intake on the hippocampus, a brain region important for learning and memory. Rats fed with a high-fat, high-glucose diet supplemented with high-fructose corn syrup showed alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for 8 months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation at Schaffer collateral--CA1 synapses. These changes occurred concurrently with reductions in levels of brain-derived neurotrophic factor in the hippocampus. We conclude that a high-calorie diet reduces hippocampal synaptic plasticity and impairs cognitive function, possibly through BDNF-mediated effects on dendritic spines.

Figure 1. A high calorie diet impairs hippocampus-dependent learning and synaptic plasticity, with correlated decreases in CA1 dendritic spine density

A, Rats maintained on a high-calorie diet (HCD) took more time to find a hidden platform in the hippocampus-dependent water maze. B, Rats on the HCD also took a more circuitous route to the platform. C, Rats fed the HCD exhibited less LTP following stimulation of the Schaffer collateral pathway. D, The HCD reduced dendritic spine density on secondary and tertiary dendrites from both the apical and basal dendritic arbors of CA1 pyramidal neurons. E, There was no change in total dendritic length in rats fed the HCD compared to rats on the control diet. F, There were no significant differences in the complexity of the dendritic arbor, measured by counting the number of bifurcations. Asterisk (*) indicates significance at p<0.05 following repeated-measures ANOVA (A–C) or t-tests (D–F).

Figure 2. Excessive calorie intake reduces dendritic spine density and synaptic marker immunofluorescence, and increases the number of pyknotic nuclei in the CA1 region of the hippocampus

A, Representative example of a CA1 neuron visualized with Golgi impregnation. Scale bar = 20 µm. Top right panel shows dendritic segments from the basal arbor of an animal on the control diet or the high-calorie diet (HCD), where indicated. Scale bar applies to all dendritic segments; length = 5 µm. Bottom right panel shows segments from apical oblique dendrites in animals fed the control diet or HCD, as indicated. B, Anatomical regions for analysis of synaptophysin labeling. Scale bar = 20 µm. C, Confocal micrograph showing synaptophysin labeling at the resolution and scale used for analysis. Scale bar = 2 µm. D, Low-magnification view of Nissl staining in hippocampal area CA1. Scale bar=20 µm. E, Examples of cells with condensed and/or fragmented nuclei. Scale bar=10 µm.