Award details

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

Reference	BB/W007347/1
Principal Investigator / Supervisor	Dr Vincent Croset
Co-Investigators / Co-Supervisors
Institution	Durham University
Department	Biosciences
Funding type	Research
Value (£)	493,358
Status	Current
Type	Research Grant
Start date	01/07/2022
End date	30/06/2025
Duration	36 months

Abstract

Brain control of state-dependent behaviour ensures appropriate nutrient intake for health, reproduction and survival. Multiple brain functions rely on a balanced diet, and deficiency of essential nutrients can drastically impair healthy ageing. The fruit fly (Drosophila melanogaster) provides an optimal platform for nutrition research. Hunger signalling is highly conserved between insects and mammals, and powerful genetic tools enable neuronal circuit dissection with unmatched accuracy. Whereas specific groups of neurons regulate feeding behaviour, a systems description of the mechanisms underlying state-dependent adaptations is lacking. How nutrient deficiency affects brain function over the life course also remains poorly understood. We will address how interactions between diet, transcription and ageing influence behaviour. Using the brain of Drosophila as a model, we will describe the effects of nutrient deficiency on transcription with single-cell resolution. This will help characterise the molecular control of food choice and consumption and explain the role of nutrition in cognitive decline. Peptidergic and dopaminergic neurons are central for regulating state-dependent behaviour. Using the latest single-cell RNA-sequencing technologies, we will reveal transcriptional correlates of nutrient deprivation across sub-populations of these neurons and provide a thorough depiction of molecular mechanisms underlying food selection. Amino acids are crucial for neurotransmission and for maintaining cognitive abilities in aged animals. We will use single-cell transcriptomics to identify how diets lacking amino acids affect the ageing brain. These experiments will establish new models to explain the interplay between nutrition, gene expression and behaviour, and open new research areas into eating disorders and healthy brain ageing.

Summary

BACKGROUND The 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 OBJECTIVES We 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. METHODOLOGY We 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 BENEFITS This 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.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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