Reward networks and appetitive behaviour

Animals and humans must eat to fulfil the energy requirements of their bodies, and they have evolved powerful mechanisms to increase appetite when required. An excellent example of one such mechanism is the production of a hormone, called ghrelin, by the gut in between meals. Ghrelin acts on the brain to increase food seeking, but also to make food seem more rewarding. It is easy to see why hunger has evolved to make an animal go and search for and procure food. But why make eating food so rewarding? It is believed that this evolved so that animals will maximise eating if food is normally scarce. Food sources that are rich in energy, for example which contain a lot of sugar or fat, are preferred, especially if an animal has limited opportunities to eat or is under threat of predation while it is out in the open. The downside of food being rewarding is that, in a modern environment, where high-energy food is abundant and easily available, we are still motivated to over consume. It is a widely held view that the current epidemic in human obesity is due to the fact that over-weight people, even though they have adequate energy stored in their bodies, are still driven to over eat because they do not disengage reward circuits. Simply put, even after eating a full meal, we will still find space for some pudding!
In order to understand why obese humans over eat, it will help to understand how the brain responds to hunger, and what may change as we put weight on. Importantly, we wish to understand the different brain pathways which control different aspects of the hunger response. For example, how eating food turns off the negative, unpleasant feelings of hunger, versus how eating food turns on the positive, pleasant feelings of eating a nice meal. These behaviours are controlled by an extremely complex network of brain cells (neurones), which we are only just beginning to understand. In this project, we want to determine how different types of these neurones connect with each other. We are able to do this because, for the first time, we can see the different neurones in mice because they have been made to shine with fluorescent light. We can record the activity of these neurones while stimulating the other cells that connect with them - all in a petri dish! However, what is also very new is that we can stimulate specific types of neurone in mice while they are behaving perfectly normally. This can be done by either giving the mice an injection of a new drug or by shining light into the mouse's brain using an optic fibre. We can also inhibit the activity of the same neurones and see if the mice still respond to hunger or to the hormone, ghrelin. By doing this, we can see whether the mice eat normal food, or if they prefer to put in a bit more effort to receive a more rewarding sugar pellet. By stimulating different pathways in the brain, we will be able to build up a complete picture of the complex network of neurones that control eating behaviour. Only when we have done this, will we then be able to ask what changes when a mouse or a human becomes obese.

We will use the latest techniques of chemo- and optogenetics (both in vitro and in vivo) to dissect the pathways that make up the forebrain network that respond to and integrate different aspect of hunger and the resulting behaviour. Hunger is an unpleasant state that increases arousal and anxiety, to drive appetitive and foraging behaviours. Secondly, hunger increases the reward salience of food, allowing the animal to maximise intake if food is normally scarce. Eating food will remove the unpleasant state of hunger (negative reinforcement of eating behaviour) and, if the food is high in sugar and/or fat, eating will also act as a reward (positive reinforcement of eating behaviour). A recent publication, using real-time measurement of intracellular calcium in vivo, has shown that, though NPY/Agrp neurones in the hypothalamic arcuate nucleus are very active in a hungry mouse, they immediately become inactive when the mouse comes into contact with food. This could be interpreted that the activity of NPY/Agrp neurones themselves transmits the negative state of hunger, which could be manifested through orexin neurones, since the latter stimulate both the arousal and stress axes. This is important, since orexin neurones are thought to also mediate the effect of hunger to increase reward salience. Different orexinergic pathways may be involved in both the positive and negative reinforcing aspects of eating. This will be tested directly by activating orexin neurones in the presence or absence of food and measuring appetitive, consummatory and displacement behaviours. The latter are believed to relieve stress by substituting for consummation in the absence of food. We will also investigate the origin of tonic inhibition of orexin neurones by leptin-responsive GABAergic inputs which need to be tuned down in the hungry mouse.

Nearly 25% of the UK population is obese and it is estimated that the UK spends £47 billion a year on the healthcare and social consequences. The NHS itself is spending approximately £6 billion of its budget on treatment of obesity, and a further £10 billion on diabetes (most of which is caused by obesity). It is a widely held view that the current epidemic in human obesity is due to the fact that over-weight people, even though they have adequate energy stored in their bodies, are still driven to over consume because they do not disengage the hedonistic drive to eat. Ultimately, in order to understand why obese individuals over consume, it will be necessary to separate different aspects of appetitive behaviour: the pathways involved and the factors that regulate them. Our laboratories are well placed to make a major impact on understanding the forebrain network that controls hedonistic eating, as we have available a number of new models and tools. Our findings will be disseminated at international conferences and by publication in high-impact journals during the grant's duration. Following publication, each of the mouse models we develop will be made freely available.
A conservative commercial estimate of the annual market opportunity for anti-obesity drugs is over $100 bn. This project will guide future development of drugs and provide a sound knowledge environment to understand the mechanisms that affect behaviour. Both applicants have excellent track records of collaborating with a number of industrial partners, providing evidence for several novel targets for drug development. The Co-I runs a University-based contract research organisation, "b-neuro", testing novel targets for cognition. Before the end of the project, we may be in a position to approach the company which may be interested in making peptide mimetics, which could provide composition of matter filings on novel therapeutics comprising long-lasting peptide derivatives.
During the lifetime of the grant, the basic research will be discussed at meetings organised by the Child Health Research Network, the Diabetes and Obesity Research Network and the Association for the Study of Obesity. These annual meetings are forums for basic researchers, psychologists, clinicians, community nurses and other health professionals, patient group representatives and policy makers. Outreach work will be encouraged at all levels within the laboratory. Over the three years, the applicants will lecture at two local schools and at a local Café Scientifique-type meeting. The PDRA will be strongly encouraged to follow the example set by previous lab members, to tutor for the Manchester Access and STEM programmes (aimed at helping under-privileged children into further education), and to complete both a Wellcome Trust Researchers in Residence Scheme and a UK GRADschool.
This project will provide strong training in both in vivo skills and specialist techniques in electrophysiology, chemogenetics and optogenetics, metabolic and behavioural research. In the last twelve years, the applicants have supervised thirteen PhD students, nineteen masters students and eleven PDRAs, all of whom have remained in science (some have their own independent research groups and others have moved into the commercial sector). The PI directs a cross-University IMB initiative to promote and expand research and training in in vivo biology. This problematic area is crucial to the UK economy and to the ambitions of Manchester to be a world-leading university. The applicants are external examiners on a number of integrative masters courses.