Long-term high-fat diet consumption by mice throughout adulthood induces neurobehavioral alterations and hippocampal neuronal remodeling accompanied by augmented microglial lipid accumulation.

High-fat diet (HFD) consumption is generally associated with an increased risk of cognitive and emotional dysfunctions that constitute a sizeable worldwide health burden with profound social and economic consequences. Middle age is a critical time period that affects one's health later in life; pertinently, the prevalence of HFD consumption is increasing among mature adults. Given the growing health-related economic burden imposed globally by increasing rates of noncommunicable diseases in rapidly aging populations, along with the pervasive but insidious health impairments associated with HFD consumption, it is critically important to understand the effects of long-term HFD consumption on brain function and to gain insights into their potential underlying mechanisms. In the present study, adult male C57BL/6J mice were randomly assigned a control diet (CD, 10 kJ% from fat) or an HFD (60 kJ% from fat) for 6 months (6 M) or 9 months (9 M) followed by behavioral tests, serum biochemical analysis, and histological examinations of both the dorsal and ventral regions of the hippocampus. In both the 6 M and 9 M cohorts, mice that consumed an HFD exhibited poorer memory performance in the Morris water maze test (MWM) and greater depression- and anxiety-like behavior during the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST) than control mice. Compared with age-matched mice in the CD group, mice in the HFD group showed abnormal hippocampal neuronal morphology, which was particularly evident in the ventral hippocampus. Hippocampal microglia in mice in the HFD group generally had a more activated phenotype evidenced by a smaller microglial territory area and increased cluster of differentiation 68 (CD68, a marker of phagocytic activity) immunoreactivity, while the microglial density in the dentate gyrus (DG) was decreased, indicating microglial decline. The engulfment of postsynaptic density 95 (PSD95, a general postsynaptic marker) puncta by microglia was increased in the HFD groups. Histological analysis of neutral lipids using a fluorescent probe (BODIPY) revealed that the total neutral lipid content in regions of interests (ROIs) and the lipid load in microglia were increased in the HFD group relative to the age-matched CD group. In summary, our results demonstrated that chronic HFD consumption from young adulthood to middle age induced anxiety- and depression-like behavior as well as memory impairment. The negative influence of chronic HFD consumption on behavioral and hippocampal neuroplasticity appears to be linked to a change in microglial phenotype that is accompanied by a remarkable increase in cellular lipid accumulation. These observations highlighting the potential to target lipid metabolism deficits to reduce the risk of HFD-associated emotional dysfunctions.