Co-ordination of allostatic sickness responses through integrated brain circuits

"Sickness" is the response of animals and humans to illness and disease, to protect well-being and the functioning of vital organs. We and others have shown that the brain is responsible for the coordination of behaviour, metabolism and the immune system - though how it achieves this is largely unknown. Counterintuitively, when energy is required to fight disease, sickness results in a reduction of appetite, foraging, ingestion and digestion of food. This allows for recovery, reducing unnecessary energy expenditure and keeping the individual safe from possible harm while it is vulnerable. It also prevents further consumption of pathogens or poisons, which may have been the primary cause of illness. Instead, energy is partitioned away from movement and digestion to vital organs: glucose is required for the brain, while the heart, muscles, liver and kidneys increase the metabolism of fats. Furthermore, some of the drugs we take to combat disease will also make us feel sick; perhaps the most obvious example being cancer therapies. When cells become injured, they send out emergency signals, one of which is a messenger called GDF15. For example, GDF15 is secreted by cancer cells, but also by otherwise healthy tissues following cancer treatments. If fact, GDF15 is commonly released by most tissues if they are diseased or damaged. This project will examine how the brain coordinates each of the important sickness responses: nausea and vomiting, aversion and avoidance, digestive function and the partitioning of energy.

In our work leading up to this project, we have characterised the only cells in the body that can respond directly to GDF15. They are brain cells (neurons) located in a very small and distinct region at the back of the brain. These neurons are the only cells that have the receptor for GDF15 - a kind "lock" that is the gateway to the rest of the brain. The GDF15 receptor is known as GFRAL. Thus, the gateway is formed by GFRAL neurons. We have now discovered...