Sex-Specific Neurobehavioral Programming in Offspring by a Maternal High-Fat, Plant-Based Diet: A Central Role of the Hippocampus

INTRODUCTION: Long-term maternal high-fat diets (mHFDs) and obesity have been associated with an increased risk of neurodevelopmental and neuropsychiatric disorders in offspring, likely due to altered neural circuit programming. This study aimed to investigate the effect of plant-based mHFD on activity, mood regulation, and cognition in offspring of both sexes. METHODS: Female rats were assigned to an HFD or a control diet (CD) (45 vs. 4% fat) for 4 weeks before mating, and throughout gestation and lactation. The offspring were weaned to CD and assigned to either mHFD groups (FH-female HFD, MH-male HFD) or CD groups (FC-female CD, MC-male CD). Behavioral assessment included the open field test (OFT), elevated plus maze (EPM), novel object recognition test (NORT), sucrose preference test (SPT), and the forced swimming test (FST). Immunochistochemical staining was performed to evaluate Ki67+, DCX+, and PV+, while serum hormone levels were measured by ELISA. RESULTS: The mHFD induced hyperactivity in the OFT and impaired learning and memory in the NORT in both sexes. In females, it reduced anxiety-like behavior in the OFT, but increased depression-like behavior in both SPT and FST. These effects were accompanied by decreased neurogenesis in females, as observed in both Ki67+ and DCX+ cells. The mHFD also decreased estradiol and increased corticosterone in females, and decreased testosterone in mHFD males. CONCLUSION: A long-term plant-based mHFD exerts sex-specific effects on offspring activity levels, mood regulation and cognition, which may be attributed to impaired hippocampal neurogenesis and hormonal regulation.