Epigenetic programming for cortical architecture throughout life. The evolution of diets has led to a preference for polyunsaturated fats (PUFA), with Western diets being rich in o-6-PUFAs. Evidence is mounting that o-6-PUFAs are limiting the metabolic and cognitive processes in humans. Choosing a ‘Western diet’ rich in o-6-PUFAs during pregnancy can reprogram the maternal metabolism, with the maternal nutrient intake triggering the imprinting of cellular and molecular adaptations on the unborn child. Although adverse neurological outcomes are one of the most common consequences of intrauterine o-6-PUFA excesses, the cellular basis of long-term changes to brain architecture is still unknown. We show here that nutritional o-6 PUFAs-derived endocannabinoids depress CB1 cannabinoid receptive receptors and induce epigenetic repression to transcriptional regulatory networks controlling neural differentiation. Cortical neurons in mouse fetuses exposed to excessive o-6-PUFAs during pregnancy lose their positional identity as well as axonal specificity. The conversion of o-6 polyunsaturated fatty acids into endocannabinoids disrupted signaling at CB1 cannabinoid neuronal receptors. This disruption was primarily due to Stat3-dependent transcriptional pathways that are required for neuronal differentiation. Global proteomics identified immunoglobulins as direct substrates. DNA methylation profiling and chromatin accessibility profiling revealed epigenetic reprogramming in 1400 neurons following prolonged cannabinoid treatment. Our findings suggest that anxiety and depression-like traits manifest in adult offspring. This is consistent with genetic models for reduced IgCAM levels, suggesting causality. Our data reveal a regulatory system whose disruption could affect an offspring’s brain function throughout their life. Immediate Communication Published: 18 November 2019 Valentina Cinquina 1, Daniela Calvigioni 1,
Source:
https://www.nature.com/articles/s41380-019-0580-4
