Date of Award
Doctor of Philosophy (PhD)
Psychology & Neuroscience
Steven F. Maier
Ruth M. Barrientos
Angela D. Bryan
Benjamin N. Greenwood
The purpose of this dissertation is to establish a link between high-fat diet (HFD) and neuroinflammation, and to evaluate both the nature and mechanisms by which HFD influences neuroinflammatory processes. HFD-induced obese adipose tissue fosters a peripheral inflammatory environment, which contributes to the development of metabolic disease associated with obesity. In addition, HFD consumption is associated with disruptions in cognition, and hippocampal function appears to be particularly vulnerable to HFD. It is likely that HFD induces alterations in neuroinflammatory processes, which negatively influence hippocampal function and mediate cognitive decline. However, specific mechanisms by which HFD mediates neuroinflammatory processing are poorly understood.
Consumption of HFD (60% fat) was evaluated in wistar rats. With prolonged (2-5 months) HFD, rats developed obesity and hippocampal disruption, as measured by a contextual pre-exposure fear-conditioning (CPE-FC) paradigm. HFD-induced memory impairments were mediated by increased interleukin-1 beta (IL-1β) protein in hippocampus that occurred in response to a footshock during CPE-FC, as central IL-1 receptor antagonism with hIL-1RA prior to the footshock prevented the HFD-induced memory impairment. A 4-week dietary reversal (DR) in HFD rats eliminated hippocampal IL-1β increase to footshock and restored memory function, yet DR animals were still obese. Therefore, HFD, not obesity, mediated the alterations in neuroinflammation.
To assess the impact of HFD, independent of obesity, we evaluated the neuroinflammatory phenotype following 3 days of HFD and observed a primed neuroinflammatory environment and potentiated neuroinflammatory response to a subsequent inflammatory challenge. The influence of HFD was observed most prominently in hippocampus. HFD-induced elevations of corticosterone (CORT) and HMGB1 are implicated in mediating the effects of HFD on neuroinflammatory processes through observations of CORT and HMGB1 blockade with RU486 and BoxA, respectively.
The evidence presented herein demonstrates: prolonged HFD mediates hippocampal memory by altering neuroinflammatory responding, evidence of a primed neuroinflammatory environment is observed following 3 days HFD, and HFD mediates primed and potentiated neuroinflammation through induction of hippocampal CORT and HMGB1.
Sobesky, Julia Lillian, "Mind What You Eat: Implications and Mechanisms of High-Fat Diet-Induced Neuroinflammatory Priming" (2015). Psychology and Neuroscience Graduate Theses & Dissertations. 94.