Intermittent Fasting Improves Social Interaction and Decreases Inflammatory Markers in Cortex and Hippocampus

Autism spectrum disorder (ASD) is a psychiatric condition characterized by reduced social interaction, anxiety, and stereotypic behaviors related to neuroinflammation and microglia activation. We demonstrated that maternal exposure to Western diet (cafeteria diet or CAF) induced microglia activation, systemic proinflammatory profile, and ASD-like behavior in the offspring. Here, we aimed to identify the effect of alternate day fasting (ADF) as a non-pharmacologic strategy to modulate neuroinflammation and ASD-like behavior in the offspring prenatally exposed to CAF diet. We found that ADF increased plasma beta-hydroxybutyrate (BHB) levels in the offspring exposed to control and CAF diets but not in the cortex (Cx) and hippocampus (Hpp). We observed that ADF increased the CD45 + cells in Cx of both groups; In control individuals, ADF promoted accumulation of CD206 + microglia cells in choroid plexus (CP) and increased in CD45 + macrophages cells and lymphocytes in the Cx. Gestational exposure to CAF diet promoted defective sociability in the offspring; ADF improved social interaction and increased microglia CD206 + in the Hpp and microglia complexity in the dentate gyrus. Additionally, ADF led to attenuation of the ER stress markers (Bip/ATF6/p-JNK) in the Cx and Hpp. Finally, biological modeling showed that fasting promotes higher microglia complexity in Cx, which is related to improvement in social interaction, whereas in dentate gyrus sociability is correlated with less microglia complexity. These data suggest a contribution of intermittent fasting as a physiological stimulus capable of modulating microglia phenotype and complexity in the brain, and social interaction in male mice.