Abstract
Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of next generations is still unclear. Here, we demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. HFD downregulates BDNF and insulin signaling in maternal tissues and epigenetically inhibits BDNF expression in both germline and hippocampus of progeny. Notably, exposure of the HFD offspring to novel enriched environment restores Bdnf epigenetic activation in the male germline and counteracts the transmission of cognitive impairment to the next generations. BDNF administration to HFD-fed mothers or preserved insulin sensitivity in HFD-fed p66Shc KO mice also prevents the intergenerational transmission of brain damage to the progeny. Collectively, our data suggest that maternal diet multigenerationally impacts on descendants’ brain health via gametic mechanisms susceptible to lifestyle.
Highlights
Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of generations is still unclear
We recently reported that increased GluA1 S-palmitoylation underlies hippocampal synaptic plasticity impairment and cognitive decline observed in experimental models of metabolic diseases[14]
Previous studies reported that maternal high fat diet (HFD) affected hippocampal plasticity of the offspring by impairing adult neurogenesis, dendritic spine formation, and cognitive functions[15,16,17]
Summary
Metabolic diseases harm brain health and cognitive functions, but whether maternal metabolic unbalance may affect brain plasticity of generations is still unclear. We demonstrate that maternal high fat diet (HFD)-dependent insulin resistance multigenerationally impairs synaptic plasticity, learning and memory. In experimental models HFD has been reported to transgenerationally predispose to obesity and metabolic syndrome until the third generation via an epigenetic inheritance[6] This probably occurs because genes can retain memory of the early-life metabolic stress via epigenetic changes that include posttranslational modifications of histone proteins and DNA methylation[7]. In this regard, early-life stress may induce long-term neurobiological modifications affecting synaptic function and structural plasticity[8,9]. BDNF administration or lack of pro-insulin resistance gene p66Shc in mothers abolishes the HFD-dependent transmission of cognitive impairment to the offspring
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