Maternal high-fat diet modifies myelin organization, microglial interactions, and results in social memory and sensorimotor gating deficits in adolescent mouse offspring
Date
2021
Authors
Bordeleau, Maude
Fernández de Cossío, Lourdes
Lacabanne, Chloé
Savage, Julie C.
Vernoux, Nathalie
Chakravarty, Mallar
Tremblay, Marie-Ève
Journal Title
Journal ISSN
Volume Title
Publisher
Brain, Behavior, & Immunity - Health
Abstract
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 -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.
Description
We are grateful to Julie-Christine Lévesque for providing training and support at the Bioimaging platform of the Infectious Disease Research Axis funded by the Canadian Foundation Innovation (CFI). Special thanks to Katherine Picard who performed in part the imaging for the myelin assessment of the corpus callosum and entirely the confocal imaging for the morphological analyses of microglia. We wish to thank Dr. Vincent Pernet who provided the Nogo-A antibody. We also thank Iris Kim and J. Kasia Szyszkowicz for technical support. Lastly, we are grateful to Dr. Giamal N. Luheshi who helped us to initiate this project by guiding the development of our mouse model of maternal high-fat diet and the behavioral assessment.
Keywords
maternal high-fat diet, myelin, cytosolic channels, oligodendrocytes, microglia, adolescence, mouse
Citation
Bordeleau, M., Fernández de Cossío, L., Lacabanne, C., Savage, J. C., Vernoux, N., Chakravarty, M., & Tremblay, M-È. (2021). Maternal high-fat diet modifies myelin organization, microglial interactions, and results in social memory and sensorimotor gating deficits in adolescent mouse offspring. Brain, Behavior, & Immunity - Health, 15, 100281. https://doi.org/10.1016/j.bbih.2021.100281