Maternal high-fat diet modifies myelin organization, microglial interactions, and results in social memory and sensorimotor gating deficits in adolescent mouse offspring

Prenatal exposure to maternal high-fat diet (mHFD) acts as a risk factor for various neurodevelopmental alterations in the progeny. Recent studies in mice revealed that mHFD results in both neuroinflammation and hypomyelination in the exposed offspring. Microglia, the brain-resident macrophages, play crucial roles during brain development, notably by modulating oligodendrocyte populations and performing phagocytosis of myelin sheaths. Previously, we reported that mHFD modifies microglial phenotype (i.e., morphology, interactions with their microenvironment, transcripts) in the hippocampus of male and female offspring. In the current study, we further explored whether mHFD may induce myelination changes among the hippocampal-corpus callosum-prefrontal cortex pathway, and result in behavioral outcomes in adolescent offspring of the two sexes. To this end, female mice were fed with control chow or HFD for 4 weeks before mating, during gestation, and until weaning of their litter. Histological and ultrastructural analyses revealed an increased density of myelin associated with a reduced area of cytosolic myelin channels in the corpus callosum of mHFD-exposed male compared to female offspring. Transcripts of myelination-associated genes including Igf1 –a growth factor released by microglia– were also lower, specifically in the hippocampus (without changes in the prefrontal cortex) of adolescent male mouse offspring. These changes in myelin were not related to an altered density, distribution, or maturation of oligodendrocytes, instead we found that microglia within the corpus callosum of mHFD-exposed offspring showed reduced numbers of mature lysosomes and increased synaptic contacts, suggesting microglial implication in the modified myelination. At the behavioral level, both male and female mHFD-exposed adolescent offspring presented loss of social memory and sensorimotor gating deficits. These results together highlight the importance of studying oligodendrocyte-microglia crosstalk and its involvement in the long-term brain alterations that result from prenatal mHFD in offspring across sexes.