Award details

Neuronal circuits that turn off hunger

Reference	BB/V016318/1
Principal Investigator / Supervisor	Dr Giuseppe D'Agostino
Co-Investigators / Co-Supervisors	Professor Simon Luckman
Institution	The University of Manchester
Department	School of Medical Sciences
Funding type	Research
Value (£)	453,914
Status	Current
Type	Research Grant
Start date	07/02/2022
End date	06/02/2025
Duration	36 months

Abstract

Hunger peaks in anticipation of eating and falls during the post-ingestive phase, however the real-time dynamics of hunger during eating behaviour and the exact neurones critical for hunger suppression are mostly unknown. Here we will exploit AgRP neurones in the arcuate nucleus of the hypothalamus - a robust cellular proxy for hunger - as an entry point to study how hunger is modulated during eating behaviour. We will monitor the dynamics of discrete neuronal circuits that converge on AgRP neurones to determine their specific involvement in the anticipatory, consummatory, or post-ingestive phase of eating behaviour. To do this in real-time and with high temporal resolution, we will use in vivo fibre photometry combined with feeding-related behavioural assays. We hypothesise that the multiple circuits cooperate to suppress AgRP neurone activity before, during and following feeding. We will further characterise these circuits genetically, anatomically and functionally, combining gain or loss of function manipulations (including a novel loss of function approach) with in vivo recordings of AgRP neuronal activity.

Summary

The primary reason that we eat is because we feel hungry. Hunger is a natural drive that forces us to eat in order to replenish the energy that we use to move around, do work, look after our bodies and maintain a healthy weight. Normally when we eat, our hunger is switched off and we reach a state of satiety. However, sometimes the natural processes of hunger and satiety are overridden and we lose control of body weight, which can lead to obesity. Obesity itself will cause problems with daily life, including difficulties with walking and stigmatism by others. However, more importantly it can cause very serious disabilities, like diabetes and heart disease. Therefore, it is essential that we understand what controls the way we eat. Eating is similar in humans and mice; like us, mice eat in separate bouts, which we call meals. Each meal is composed of three distinct phases. The first phase involves appetitive behaviour. This is a preparatory phase when animals search for and acquire food. The second phase is when the animal ingests the food, which we call consummatory behaviour. The final phase is "post-ingestive." That is after the animal has eaten and starts to digest the food, eventually reaching satiety. These behaviours seem very simple, but they require very complex organisation by the brain. Our understanding of the brain cells and neural circuits that control eating has remained very vague until some recent breakthroughs. There is a small group of cells (just a few thousand of the 70 million nerves in a mouse brain) that produce a messenger called AgRP and that are critical for controlling eating. It is possible, using the latest neuroscientific tools, to see and manipulate these cells in living, normally behaving mice. We and others have shown previously that AgRP cells increase their activity in response to hunger signals. The hunger signals include a message from the stomach, called ghrelin, and inputs from other nerves. If we artificially stimulate only the AgRP cells, we can make a mouse eat, even if it has just had a meal. Importantly, also we can measure the activity of AgRP cells by shining a fluorescent light into the brain of a specially bred mouse, and measuring the light that bounces back. AgRP cell activity goes up when the mouse is hungry before a meal or if we inject the mouse with ghrelin. Remarkably, the activity of AgRP cells goes down as soon as the mouse finds food (the appetitive phase) and stays down if the animals eats (throughout the consummatory and post-ingestive phases). However, if the mouse does not eat the food, the activity of AgRP cells creeps up again. Thus, together we have shown that AgRP cell activity drives eating behaviour and provides us with a measure of hunger, which can be read with split-second accuracy. In this project, we will investigate the different inputs to AgRP cells to decide which are required to switch off hunger. We believe that different nerves from other parts of the brain control AgRP cells during the three phases of eating. We have preliminary data to suggest that some inhibitory nerves connect directly and inhibit AgRP cells when food is acquired in the appetitive phase. Other nerves, which have an excitatory input onto AgRP cells are switched off during the consummatory phase, and we believe this is required for the low AgRP cell activity when a meal is being eaten. Finally, we have evidence that after the meal is eaten, post-ingestive signals from the gut stimulate additional connections which keep the AgRP silent during satiety. As time passes, these inputs adapt and the activity of AgRP cells increases again, producing hunger before the next meal. By understanding these complex brain circuits, in the future we may be able to manipulate hunger and provide new medicines to control the rise of obesity and eating disorders in our society.

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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