A Drosophila single-cell resource for brain metabolism research

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A healthy human fetus grows at an impressive rate as it develops inside the mother's uterus. In about 5% of pregnancies, however, nutrients and oxygen cannot be efficiently supplied from mother to fetus. When this metabolic stress occurs, it is not always possible for the fetal body to continue to grow at the normal rate. Nevertheless, in many of these cases, the growth of the fetal brain remains remarkably unperturbed. Our research aims to identify, as yet unknown, protective processes that spare the growth of the brain over that of the body. Towards this goal, our previous work has modelled some aspects of brain sparing in the fruit fly Drosophila, which shares many genes with humans - including about three-quarters of those linked to human diseases. Although the brain of Drosophila is much smaller and less complex than that of humans, they both contain very similar cell types - neural stem cells, neurons and glia. We therefore propose that Drosophila, with its relatively simple nervous system, can be used to replace a proportion of the brain sparing experiments that would otherwise be carried out in mice or other animals. Our research plan has three main aims. In the first aim, we will use a technology called single-cell sequencing to produce a map or atlas of the genes active in every one of the tens of thousands of cells in the normal versus the metabolically stressed Drosophila brain. In this way, we will identify which genes are most active during Drosophila brain sparing, anticipating that some of the equivalent genes will also be active during mammalian brain sparing. In the second aim, we will use the sophisticated genetics possible in Drosophila to test which of the highly active genes are the most essential for the growth processes that drive brain sparing. In the third and final aim, we will use the results of the sequencing and genetic approaches to pinpoint how the different cell types in the brain use genes to communicate with each during brain sparing. An enduring legacy of this project will be a Drosophila brain atlas, an open-access web resource that can be used by all scientists interested in brain sparing and brain research. This atlas may also help researchers to work out how metabolism in the mammalian brain is linked to health and disease.