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Fructose consumption in adolescents is accompanied by increased incidence of childhood diabetes, metabolic disorder, and obesity that can last into adulthood. Adult male rats that consumed a high fructose diet (HFD) in adolescence have dysregulated emotional processing and upregulated gene expression of neuroinflammatory markers, yet downstream consequences on cognitive function in both sexes remain unknown. The current study aimed to determine the extent to which a HFD altered neural and microglial structure and function that may contribute to cognitive changes in males and females. Wistar rats were fed either chow or a HFD (55% fructose) beginning on postnatal day (PND) 23 and for the duration of the study. As adults, fructose-fed males, but not females, displayed impaired cognitive flexibility on the Barnes maze task and had more reactive microglia and altered neuronal morphology throughout the dentate gyrus (DG) and CA3 regions of the hippocampus. These findings suggest that, in males, a HFD activates microglia which may contribute to functional deficits, possibly through altering dendritic structure making them disproportionally vulnerable to fructose compared to females.

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Background: Repeated exposures to chronic stress can lead to long lasting negative behavioral and metabolic outcomes. Here, we aim to determine the impact of chronic stress and chronic low-level inflammation on behavior and synaptosomal metabolism.Methods: Male (n = 31) and female (n = 32) C57Bl/6 mice underwent chronic repeated predation stress or daily handling for two rounds of 15 consecutive days of exposure during the adolescent and early adult timeframes. Subsequently, mice were exposed to repeated lipopolysaccharide (LPS; 7.5 x 10 5 EU/kg) or saline injections every third day for eight weeks.Exploratory and social behaviors were assessed in the open field and social interaction tests prior to examination of learning and memory with the Barnes Maze. Mitochondrial function and morphology were assessed in synaptosomes post-mortem. In addition, expression of TNF-α, IL-1ß, and ROMO1 were examined in the hippocampus and prefrontal cortex. Circulating pro-and anti-inflammatory cytokines in the periphery were assessed following the first and last LPS injection as well as at the time of tissue collection. Circulating ROMO1 was assessed in terminal samples.Results: Exposure to repeated predatory stress increased time spent in the corners of the open field, suggestive of anxiety-like behavior, in both males and females. There were no significant group differences in the social interaction test and minimal effects were evident in the Barnes maze. A history of chronic stress interacted with chronic LPS in male mice to lead to a deficit in synaptosomal respiration. Female mice were more sensitive to both chronic stress and chronic LPS such that either a history of chronic stress or a history of chronic LPS was sufficient to disrupt synaptosomal respiration in females. Both stress and chronic LPS were sufficient to increase inflammation and reactive oxygen in males in the periphery and centrally. Females had increased markers of peripheral inflammation following acute LPS but no evidence of peripheral or central increases in inflammatory factors or reactive oxygen following chronic exposures. Conclusion:Collectively, these data suggest that while metrics of inflammation and reactive oxygen are disrupted in males following chronic stress and chronic LPS, only the combined condition is sufficient to alter synaptosomal respiration. Conversely, although evidence of chronic inflammation or chronic elevation in reactive oxygen is absent, females demonstrate profound shifts in synaptosomal mitochondrial function with either a history of chronic stress or a history of chronic inflammation. These data highlight that differential mechanisms are likely in play between the sexes and suggest that female sensitivity to neurogenerative conditions may be precipitated by influence of life experiences on mitochondrial function in the synapses.