Transcriptional profiling of nutritional deficiency in single neurons: insights for state-dependent behaviour and healthy ageing

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BACKGROUNDThe function of our nervous system is intimately connected to our diet. Our brain constantly evaluates energy and nutrient levels in our bodies to make us eat when hungry and stop once sated. The brain also consumes much more energy than other organs and is therefore highly dependent on nutrient supply. However, appropriate nutrients are not always available, and some deficiencies can cause a variety of illnesses. For example, low levels of protein intake have been linked with depression and dementia, especially in aged individuals. Amino acids that constitute proteins are crucial for making the chemicals used by neurons to communicate. However, how amino acids contribute to maintaining brain health and why consuming them in sufficient amount is especially relevant in old age remains unclear.Fruit flies are an outstanding model organism to study brain and nutrition. They have a short life cycle and are inexpensive to culture in laboratories. Despite their small brain, they display many complex behaviours that can be artificially manipulated using a large selection of genetic tools. Notably, mechanisms regulating hunger and feeding in flies are very similar to those in humans. Neurons controlling feeding behaviour change their activity depending on nutritional needs. However, little is known about how these neurons sense whether the animal is hungry or not, or how they communicate with other brain regions. Discovering mechanisms regulating the activity of these neurons would help explain how animals choose their diet. AIMS AND OBJECTIVESWe will use fruit flies as a model to answer two questions. First, we will determine how specific genes in the brain control food preference and consumption, depending on the most needed nutrients. Second, we will explain how the lack of amino acids affects memory and other behaviours in aged individuals. METHODOLOGYWe will use state-of-the-art methods and computational tools to identify genes whose activity is influenced by a diet without sugars or proteins. Single-neuron resolution will precisely identify where in the brain these genes are important. We will artificially change the activity of candidate genes to determine how they regulate food choice and consumption. We will also measure how a diet lacking amino acids influences memory, to reveal their importance for healthy brain ageing. Using similar methods to those described above, we will find genes that change their activity in aged animals fed on a diet lacking proteins. This will help explain why protein deficiency has a more significant impact on the brains of aged animals.OUTCOMES AND BENEFITSThis project will shed light on essential mechanisms connecting nutrition with brain function. Identifying novel mechanisms to switch behaviour towards consuming missing nutrients will provide elements to understand how eating disorders develop. By measuring the long-term consequences of protein deprivation, we will explore the links between diet and the loss of cognitive abilities in aged individuals. Understanding dietary causes of neurodegeneration could help develop preventative strategies for patients at risk.