Why did we fund this project?
This award aims to develop a single-cell atlas of brain metabolism in Drosophila, in both healthy and metabolically stressed conditions, replacing the use of mice in some studies.
Nutrient restriction in pregnancy can lead to restricted foetal growth, but in many cases the brain is ‘spared’ and less affected than the rest of the body. The protective processes that allow this to happen are not well understood but can potentially result in neural disorders later in life. In vivo studies in mice are the gold standard experimental model for inducing foetal growth restriction. Metabolic stresses are induced during the animals’ pregnancy either through diet restrictions or inducing hypoxia using surgical interventions or hypoxic chambers. Dr Alex Gould and colleagues have previously established a replacement model for mechanistic studies of brain sparing using Drosophila, which possess the three main types of cells found in the human brain. Drosophila are not currently considered capable of suffering and so can be used as an alternative for mammalian models.
With NC3Rs funding, Alex will work with Dr Adrien Franchet, a postdoctoral fellow, to use single-cell sequencing to produce the first atlas of Drosophila brain metabolism. They will combine RNAi and gene expression data to compare normal and metabolically stressed Drosophila. The Drosophila CNS Stressome Atlas will be made available to all researchers as an open-access resource to generate new hypotheses about brain sparing and metabolic interactions in the brain, without the need for initial exploratory studies to be performed in genetically modified mouse models.
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.