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

Abstract

Background Maternal 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. Methods We used an integrative approach combining molecular techniques, confocal and scanning electron microscopy, to investigate the effects of mHFD vs control diet on inflammatory priming, as well as microglial density, distribution, morphology, and ultrastructure in mice. These analyses were performed on the mothers, and/or their adolescent offspring at postnatal day (P) 30. Results Our 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. Conclusions Here, 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.

High fat diet consumption and social instability stress impair stress adaptation and maternal care in C57Bl/6 mice

“…Although we could not quantify weekly food intake due to group housing conditions, we noted significant fluctuations in weight gain during SIS exposure, supporting our hypothesis that the social stress may have influenced eating patterns and energy expenditure. In regard to other maternal HF diet models in mice, several groups have observed consistent trends in increased body weight gain and an increase in various fat depots leading up to breeding (Bellisario et al, 2015(Bellisario et al, , 2014Bordeleau et al, 2020). The broad consensus from these studies is that the body weight increase may stem from increased daily consumption of the HF diet, due to its higher caloric content.…”

Shedding light on the role of CX3CR1 in the pathogenesis of schizophrenia

“…MIA with Poly I:C in mice caused dendritic spine loss, impairments in learning-dependent dendritic spine formation and deficits in learning tasks which were mediated by CX3CR1-highly expressing monocytes via TNF-α-dependent mechanisms. Recently, Bordeleau et al [ 183 ] reported a different approach in inducing MIA and showed that exposure to a high-fat diet resulted in maternal systemic inflammation and simultaneously decreased the mRNA expression of Cx3cr1 in the hippocampus of male offspring mice.…”

“…Recently, Bordeleau et al [ 183 ] reported a different approach in inducing MIA and showed that exposure to a high-fat diet resulted in maternal systemic inflammation and simultaneously decreased the mRNA expression of Cx3cr1 in the hippocampus of male offspring mice.…”