High-energy diet consumption predisposes rats to cognitive impairments, neuroinflammation, and neurovascular damage

Sara Louise Hargrave, Purdue University

Abstract

We have previously demonstrated that diet-induced obese (DIO) rats fed a high-fat, high-dextrose (HFD) diet are impaired at hippocampal-dependent tasks following 10d and 90d (but not 40d) access to diet. The goals of the present studies were to characterize the progression of molecular and functional brain changes following access to high-energy diets and to assess whether any pathological changes observed were correlated with cognitive deficits. In Experiment 1, rats were fed either CHOW, HFD, a high-fat/sucrose diet, or a ketogenic diet for 10d, 40d, or 90d, at which point they were tested for performance on the Spontaneous Alternation (SA) task. The hypothalamus and hippocampus were then analyzed for the expression of genes associated with glucose (GLUT1) and monocarboxylate (MCT1) transport, platelet endothelial cell adhesion (CD31), neurogenesis (BDNF), and inflammation (IL- 1-beta;, IL-6, and TNF-alpha). Experiment 2 analyzed the effect of 10d, 40d, or 90d HFD or CHOW exposure on spatial learning and assessed whether animals used a hippocampal- or striatal-dependent strategy to solve the learning task. To counteract the early HFD-induced hyperphagia, a group of rats was pair-fed HFD (HFD-PF) to the calories consumed by CHOW rats for the first 10d and assessed on the same learning paradigm. Following behavioral testing, regional BBB permeability was analyzed throughout the brain in order to determine the regional and sub-regional specificity of HFD-induced neurovascular damage. After 10 days, HFD-DIO rats from Experiment 1 were hyperglycemic, impaired at SA performance, and had decreased hippocampal and hypothalamic GLUT1 and MCT1 expression, suggesting 10d HFD-induced cognitive impairments may be due to decreased influx of nutrients to the brain. HFD-DIO rats from Experiment 2 were hyperglycemic, impaired at spatial navigation, and relied less on a hippocampal strategy. HFD-PF rats were not hyperglycemic but still exhibited spatial deficits and a preference for a non- hippocampal-dependent strategy, suggesting that HFD exposure provoked learning and memory impairments even when consumed in moderation. There were no differences in BBB permeability at this time. Blood glucose and performance on the behavioral assays in both Experiments 1 and 2 normalized by the 40d time point. At this time, BBB permeability did not differ between treatments. However, hippocampal MCT1 remained low in HFD-DIO rats, suggesting that HFD has sustained effects on monocarboxylate transport that were independent of SA performance deficits. By 90d, there were significant learning impairments in HFD rats from Experiment 2. HFD-DIO rats were also less likely to use a hippocampal- dependent strategy to solve this task. However, HFD-DIO rats from Experiment 1 were not impaired at SA performance. This suggests that HFD induces deficits specific to the hippocampus and related structures, which may not be easily observed by more general assessments. HFD-DIO rats showed several markers of pathology, including reductions in BDNF, increases in inflammation in the hippocampus and hypothalamus, and low CD31 in the hippocampus. Further, HFD-DIO rats had elevated BBB permeability to the hippocampus, hypothalamus, substantia nigra, dorsal striatum, and hindbrain. The region most associated with altered cognitive performance was the ventral hippocampus, which has been shown to be involved in learning about reward and inhibiting unnecessary or counterproductive responses to appetitive stimuli. These data suggest that maintenance on HFD can damage structures associated with both ingestive behavior and cognition. This, in turn, has the potential to increase responding to food cues. An improved understanding of the molecular and cellular processes involved in HFD-induced inflammation and neurovascular damage could yield options for the treatment or prevention of obesity and cognitive dementia. (Abstract shortened by UMI.)

Degree

Ph.D.

Advisors

Kinzig, Purdue University.

Subject Area

Neurosciences|Nutrition|Physiological psychology

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