SEX- AND AGE-DEPENDENT WESTERN-DIET INDUCED BLOOD-BRAIN BARRIER DYSREGULATION AND RELATIONSHIP TO BEHAVIOR, HYPERGLYCEMIA, BODY WEIGHT, AND MICROGLIA

There has been a rapid shift in food environment of Western cultures that has increased consumption of diets high in fat and sugar, which have imparted negative effects on metabolic and neurocognitive health. There is also building evidence that the adverse effects of Western diet

(WD) are different in males and females, such that males are impacted more at an earlier age and females are impacted later in life. The underlying biological mechanisms linking WD and neurocognitive health are often associated with energy dysregulation or neuroinflammation. WD

disrupts glucose homeostasis and causes low grade inflammation in the body, and these can impact

the brain by disrupting the blood-brain barrier (BBB). The BBB is the microvasculature found throughout the entire brain that tightly regulates what compounds get into the brain to ensure optimal neuronal function. WD disrupts the BBB, however, the effects of WD on BBB integrity

in females and younger individuals remain largely unknown. Based on the metabolic and behavioral effects of WD, we hypothesized that the effects are age- and sex- specific. To test this, we gave male and female rats access to a WD for 8-10 weeks starting in juvenile period (post-natal

day 21) or in adulthood (post-natal day 75), then measured body weight, behavior, glucose tolerance, the density of two different markers of BBB integrity. We also measured density of resident immune cells (microglia) to assess the relationship between inflammation and BBB integrity. First, we focused on the impact of hyperglycemia on the BBB since elevated glucose alters glucose transporter 1 (GLUT1). We found sex- and age- specific decreases in GLUT1 density in the prefrontal cortex and hippocampus—two brain regions commonly associated with neurocognitive impairments associated with WD. Correlational comparisons between WD and chow (CH) animals also found that the typically relationship between glucose tolerance and

GLUT1 in the PFC and hippocampus were overall disrupted in WD animals. Second, we measured the leakage of albumin, a blood protein, since WD depletes the tight junctions that would typically prevent albumin from entering the brain and triggering a neuroinflammatory response. We did not find an increase in albumin density in WD animals, however, we found a main effect of age which

offers insight to differential susceptibilities to BBB leakage. Third, we focused on inflammation and found that WD did not impact microglia density in our experiments, nor did it correlate with GLUT1, albumin, or behavior. Collectively, our findings support the hypothesis that the impact of

WD on the BBB is sex- and age- specific, suggest that WD does not increase leakage of compounds such as albumin, and highlights the nuanced relationships between WD, metabolic disruption, behavioral deficits, and neuroinflammation.