In developing humans and other mammals, malnourishment and placental insufficiency alter fetal metabolism, leading to growth restriction. In many cases, however, the growth of the brain is less affected than that of the body. This brain sparing response helps to safeguard cognitive development but it is imperfect - in some cases leading to adult offspring that are prone to neural disorders. To understand fetal brain sparing at the molecular level, we need to determine how environmental stresses change metabolic gene expression and function at the level of single cells, especially neural stem cells. The gold standard for mechanistic studies of brain sparing are mouse models, where animals are bred with complex genetic backgrounds and then subjected to metabolic stresses. We previously established an alternative model for brain sparing that harnesses the powerful genetics of the invertebrate species Drosophila. We now propose to build upon this foundational work to generate the first Drosophila single-cell atlas of brain metabolism. Importantly, our open-access web resource (the Drosophila CNS Stressome Atlas) will combine gene expression data with functional information from an RNAi screen of evolutionarily conserved metabolic genes. It will be designed to be used by the mammalian neurobiology community, in conjunction with existing mouse brain atlases of "unstressed" gene expression. This in silico evolutionary conservation approach will not provide an alternative to all mice brain sparing experiments but it will replace some of those at the early "trial-and-error" phase of hypothesis generation. As a proof-of-principle, preliminary data from the Drosophila atlas was used to generate two novel hypotheses involving metabolic interactions between neural stem cells and their niche. The Drosophila atlas promises to shed new light on how metabolism in the mammalian CNS is linked to health and disease.
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