Journal
STEM CELLS
Volume 34, Issue 2, Pages 470-482Publisher
WILEY
DOI: 10.1002/stem.2246
Keywords
Neural stem cells; Arachidonic acid; Docosahexaenoic acid; Epoxides; Anxiety; Metabolomics
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Funding
- Japan Society for the Promotion of Science for Young Scientists from the Japan Science and Technology Agency
- Mishima Kaiun Memorial Foundation
- MEXT [21300115]
- Asahi Glass Foundation
- Grants-in-Aid for Scientific Research [26670447, 25253067, 26291046, 21300115, 16K16280, 15H04648] Funding Source: KAKEN
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Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are essential nutrients. Although several studies have suggested that a balanced dietary n-6:n-3 ratio is essential for brain development, the underlying cellular and molecular mechanism is poorly understood. Here, we found that feeding pregnant mice an n-6 excess/n-3 deficient diet, which reflects modern human diets, impairsed neocortical neurogenesis in the offspring. This impaired neurodevelopment occurs through a precocious fate transition of neural stem cells from the neurogenic to gliogenic lineage. A comprehensive mediator lipidomics screen revealed key mediators, epoxy metabolites, which were confirmed functionally using a neurosphere assay. Importantly, although the offspring were raised on a well-balanced n-6: n-3 diet, they exhibited increased anxiety-related behavior in adulthood. These findings provide compelling evidence that excess maternal consumption of n-6 PUFAs combined with insufficient intake of n-3 PUFAs causes abnormal brain development that can have long-lasting effects on the offspring's mental state.
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