Maternal high fat diet alters offspring epigenetic regulators, amygdala glutamatergic profile and anxiety

Maternal obesity during pregnancy can impact long-term health, predisposition to disease, and risk of neurological disorders in offspring. This may arise from disruption to epigenetic processes during offspring brain development. Using a maternal high fat diet (mHFD) mouse model, we investigated the expression of genes encoding epigenetic regulators in the brains of gestational day (GD) 17.5 mHFD offspring. We found significant, regionally unique changes in expression of epigenetic regulators in the developing brain of mHFD offspring compared to controls, with Gadd45b downregulated in medial prefrontal cortex, Mecp2 downregulated in amygdala, and sex-specific downregulation of Crebbp, Dnmt3b, and Mecp2 in male mHFD hippocampus. Decreased Mecp2 in the amygdala was associated with significant upregulation of the Mecp2-repressed gene, Tbr1, and an increased number of TBR1⁺ glutamatergic neurons in the basomedial nucleus of the amygdala. Tbr1 upregulation in amygdala was also observed in postnatal day 8 (P8) mHFD offspring, and levels of glutamate receptor gene Grin2b, and Fos, a marker for neuronal activity, were increased. Indications of heightened excitatory drive in mHFD offspring amygdala were associated with an anxiety-like phenotype, with mHFD offspring displaying altered ultrasonic vocalization characteristics at P8, and adult female mHFD offspring spending decreased time on the open arm of the Elevated Plus Maze. Together, this data provides insight into sex-specific offspring vulnerability to perinatal mHFD programming of anxiety-like behaviors.