A Drosophila single-cell resource for brain metabolism research

一个健康的人类胎儿在母亲的子宫内发育时，其生长速度令人印象深刻。然而，在大约5%的孕妇中，营养和氧气不能从母亲有效地供应给胎儿。当这种代谢压力发生时，胎儿身体并不总是可能继续以正常的速度生长。然而，在许多这样的案例中，胎儿大脑的生长仍然显著地不受干扰。我们的研究旨在确定目前尚不为人所知的保护过程，使大脑比身体更容易发育。为了实现这一目标，我们之前的工作已经在果蝇身上模拟了大脑节制的某些方面，果蝇与人类有许多共同的基因，包括大约四分之三与人类疾病有关的基因。尽管果蝇的大脑比人类小得多，也没有人类那么复杂，但它们都含有非常相似的细胞类型--神经干细胞、神经元和神经胶质细胞。因此，我们建议，拥有相对简单的神经系统的果蝇，可以用来取代在小鼠或其他动物身上进行的部分大脑节约实验。我们的研究计划有三个主要目标。在第一个目标中，我们将使用一种名为单细胞测序的技术来制作一张地图或图谱，展示正常果蝇大脑中数以万计的细胞与代谢应激的果蝇大脑中每一个细胞中活跃的基因。通过这种方式，我们将确定哪些基因在果蝇大脑备用期间最活跃，并预计一些相同的基因在哺乳动物大脑备用期间也将活跃。在第二个目标中，我们将使用果蝇中可能的复杂遗传学来测试哪些高度活跃的基因对驱动大脑节制的生长过程最关键。在第三个也是最后一个目标中，我们将使用测序和遗传方法的结果来精确定位大脑中不同类型的细胞如何在大脑备用期间使用基因进行交流。该项目的一个持久遗产将是果蝇脑图谱，这是一个开放获取的网络资源，可供所有对大脑备用和脑研究感兴趣的科学家使用。这份图谱还可能帮助研究人员弄清楚哺乳动物大脑的新陈代谢是如何与健康和疾病联系在一起的。

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.