Prenatal immune challenge and perinatal high-fat/high-sugar diet: a double-hit model of neurodevelopmental...

Early-life environmental insults such as maternal immune activation (MIA) and Western diets are major risk factors for neurodevelopmental disorders. However, little is known about how these factors interact to shape brain metabolism and behavior in adulthood. This study examined the independent and combined effects of prenatal immune challenge (MIA) and perinatal exposure to a high-fat/high-sugar (HFS) diet on emotion-like behavior, cognitive performance, and regional brain oxidative metabolism in male Wistar rats. A 2 × 2 factorial design was used, with prenatal treatment (lipopolysaccharide [LPS] or saline) and diet maintained from gestation to adulthood (HFS or standard diet [SD]) as between-subject factors. Behavioral assessment included testing the animals in the elevated zero maze, forced swimming test, and Morris water maze. Brain cytochrome c oxidase (CCO) activity was quantified as a marker of regional brain oxidative metabolic capacity in the prefrontal, hippocampal, amygdalar, and accumbal regions. Both MIA and HFS diet independently increased anxiety- and depression-like behaviors, whereas their combination produced the most pronounced impairments in emotional regulation and cognitive flexibility. These behavioral alterations were paralleled by specific elevations in CCO activity, particularly within prefrontal, amygdalar, and hippocampal regions. The findings suggest that MIA and a perinatal obesogenic diet could converge on shared neurobiological mechanisms promoting a maladaptive brain hypermetabolic state across functionally related prefrontal, hippocampal, and amygdalar regions. In conclusion, the results support a "double-hit" model of neurodevelopmental vulnerability, in which MIA and sustained exposure to an obesogenic diet act synergistically to promote neural and behavioral vulnerability.