PROJECT SUMMARY/ABSTRACT Consumption of saturated fats and refined sugars has dramatically increased in the last century and, not surprisingly, obesity rates have risen concomitantly. Approximately 30% of older adults (65 and older) are obese, and this is alarming because obesity among this age group has been associated with cognitive impairments and dementia, such as Alzheimer’s Disease. There is growing evidence that obesity-related neuroinflammation may play a prominent role in Alzheimer’s disease initiation and/or progression. However, there is a fundamental gap in understanding the underlying mechanisms involved in this relationship. Preclinical data indicate that even short-term consumption of high-fat diets (HFD) triggers a potent neuroinflammatory response in the hippocampus and amygdala, causing profound spatial, contextual, and emotional memory deficits. The long- term goal is to develop effective interventions to prevent and reverse debilitating memory declines in the aged population caused by unhealthy diets or obesity. The objective of this application is to understand the mechanisms that underlie aging-associated HFD-induced hippocampal- and amygdalar-dependent memory impairments. Short-term HFD consumption will be used in this proposal to avoid having the many co-morbidities associated with obesity confound results and interpretations. The central hypothesis is that the interaction of aging and HFD causes profound memory impairments through neuroinflammation-evoked deterioration of synaptic plasticity, as measured by long-term potentiation, in both the hippocampus and the amygdala. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine the extent to which HFD consumption disrupts LTP in the hippocampus and amygdala, and 2) Determine the extent to which central IL-1b mediates HFD-induced LTP disruptions in aged rats. The approach is innovative, in the applicant’s opinion, because it will determine, for the first time, whether neuroinflammation, caused by HFD consumption, in the amygdala and hippocampus leads to impairments in LTP. The proposed research is significant because it is expected to advance and expand understanding of early mechanisms of hippocampal and amygdalar dysfunction in the aged population following HFD consumption. Ultimately, such knowledge will lead to novel approaches to slow or prevent further cognitive declines that could otherwise develop into Alzheimer’s disease.