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Microglial and peripheral immune priming is partially sexually dimorphic in adolescent mouse offspring exposed to maternal high-fat diet

Authors
  • Bordeleau, Maude1, 2, 3
  • Lacabanne, Chloé1
  • Fernández de Cossío, Lourdes4
  • Vernoux, Nathalie2
  • Savage, Julie C.2, 5
  • González-Ibáñez, Fernando2, 5
  • Tremblay, Marie-Ève2, 5, 3, 6, 7
  • 1 McGill University, Montreal, QC, Canada , Montreal (Canada)
  • 2 Centre de recherche du CHU de Québec–Université Laval, Québec, QC, Canada , Québec (Canada)
  • 3 McGill University, Montréal, QC, Canada , Montréal (Canada)
  • 4 University of California, La Jolla, San Diego, CA, USA , San Diego (United States)
  • 5 Université Laval, Québec, QC, Canada , Québec (Canada)
  • 6 University of Victoria, Victoria, BC, Canada , Victoria (Canada)
  • 7 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada , Vancouver (Canada)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Sep 05, 2020
Volume
17
Issue
1
Identifiers
DOI: 10.1186/s12974-020-01914-1
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundMaternal nutrition is critical for proper fetal development. While increased nutrient intake is essential during pregnancy, an excessive consumption of certain nutrients, like fat, can lead to long-lasting detrimental consequences on the offspring. Animal work investigating the consequences of maternal high-fat diet (mHFD) revealed in the offspring a maternal immune activation (MIA) phenotype associated with increased inflammatory signals. This inflammation was proposed as one of the mechanisms causing neuronal circuit dysfunction, notably in the hippocampus, by altering the brain-resident macrophages—microglia. However, the understanding of mechanisms linking inflammation and microglial activities to pathological brain development remains limited. We hypothesized that mHFD-induced inflammation could prime microglia by altering their specific gene expression signature, population density, and/or functions.MethodsWe used an integrative approach combining molecular (i.e., multiplex-ELISA, rt-qPCR) and cellular (i.e., histochemistry, electron microscopy) techniques to investigate the effects of mHFD (saturated and unsaturated fats) vs control diet on inflammatory priming, as well as microglial transcriptomic signature, density, distribution, morphology, and ultrastructure in mice. These analyses were performed on the mothers and/or their adolescent offspring at postnatal day 30.ResultsOur study revealed that mHFD results in MIA defined by increased circulating levels of interleukin (IL)-6 in the mothers. This phenotype was associated with an exacerbated inflammatory response to peripheral lipopolysaccharide in mHFD-exposed offspring of both sexes. Microglial morphology was also altered, and there were increased microglial interactions with astrocytes in the hippocampus CA1 of mHFD-exposed male offspring, as well as decreased microglia-associated extracellular space pockets in the same region of mHFD-exposed offspring of the two sexes. A decreased mRNA expression of the inflammatory-regulating cytokine Tgfb1 and microglial receptors Tmem119, Trem2, and Cx3cr1 was additionally measured in the hippocampus of mHFD-exposed offspring, especially in males.ConclusionsHere, we described how dietary habits during pregnancy and nurturing, particularly the consumption of an enriched fat diet, can influence peripheral immune priming in the offspring. We also found that microglia are affected in terms of gene expression signature, morphology, and interactions with the hippocampal parenchyma, in a partially sexually dimorphic manner, which may contribute to the adverse neurodevelopmental outcomes on the offspring.

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