The brainstem signals dual motivational valence following ingestion

Currently, many people in the UK struggle with their weight, and this can lead to related problems like diabetes and cardiovascular disease. As well as the burden on individuals, treating the rise in obesity puts immense strain on the NHS. The main reason that people put on excess weight is that they simply over eat; therefore, it is important to understand what controls our eating behaviour. If we have not eaten for a while, we feel hungry and agitated. This is not a very pleasant feeling and, so, we are motivated to consume food. When we do this, the feelings of hunger disappear and we can feel pleasantly full. We call the period in between meals, when we do not feel hungry, satiety. Thus, we can imagine our appetite is controlled by competing feelings: hunger (a negative feeling) and satiety (a positive feeling). Alternatively, we can lose our appetite when we experience different negative feelings, caused by sickness, because we have eaten something that has upset our stomach or if we have caught a bug. Finally, we may feel nauseous or unwell after taking a prescription drug, perhaps to help us cope with diabetes or cancer. In all of these situations, the decision about whether to eat or not is controlled by two parts of our brain. The hypothalamus, near the base of the brain, collects lots of information from the rest of the body about our energy status (have we just eaten or not), the time of day, are we active, etc. Information about what and how much we have eaten comes from the gut to the second part, at the back of the brain, the so-called brainstem. The brainstem collects all the information from the gut and then relays it to the hypothalamus. Thus, complex circuits in the brainstem and hypothalamus, together with other parts of the brain, control our eating behaviour.

We have identified cells (neurones) in the brainstem of mice which respond to the different signals coming from the gut. For example, one type of neurone responds when the mouse has eaten a meal, while another responds when the mouse has eaten something which makes it feel unwell. Our laboratories have new genetic "tools" which allow us to investigate how these different neurones function. For example, we have generated different types of mice which allow us to artificially activate these neurones selectively and stop the mice from eating, even if they are very hungry. However, activating some of the connections made by these neurones, cause the mice to feel contented, while others make the mice feel unwell. We believe that these two types of neurone signal satiety and aversion, respectively, to the rest of the brain. We will use our tools to map connections in the brain, demonstrate their importance and show how eating behaviour is managed in both health and disease. This knowledge will help in the development of new drugs to control body weight, but also drugs to treat diabetes, cancer and other diseases, which have fewer side effects.

Hunger is an unpleasant need state which increases arousal and appetitive behaviours. Thus, it is hypothesised that part of the reason we are motivated to eat is to remove the negative emotional valence. In addition, we normally eat until we are sated, which provides a feeling of pleasant "fullness" (positive motivational valence). Thus, in behavioural terms, the termination of a meal is dependent on both negative (the reduction of negative valence) and positive (the increase in positive valence) reinforcement. Alternatively, we can lose our appetite and stop eating in other circumstances, such as when we feel ill or nauseous, which also produce a negative motivational valence. We have shown that artificial stimulation of brainstem neurones can induce positive or negative valence depending on which projections are activated. We will demonstrate the importance of parallel pathway using both gain of function and loss of function studies. Since we have already identified brainstem neurones which respond to different modes of gut signalling, we believe that we will be able to map the different pathways to states of satiation, nausea and gastric illness. We also predict that these pathways will converge on the tegmental-striatal system, and so we will measure dopamine transients in the striatum using the latest "dLight1" technology. Furthermore, using fibre photometry to record neuronal activity in freely behaving mice, we can see that gut-derived satiation signals switch off "hunger-inducing" AgRP neurones in the hypothalamic arcuate nucleus, whereas signals which cause aversion do not. We will investigate these pathways by chemogenetically controlling brainstem neurones while recording the activity of AgRP neurones in vivo.

In 2010, 26% of adults and 16% of children in the UK were classed as obese. A further 42% of men and 32% of women were overweight. Co-morbidities related to obesity, such as diabetes, heart disease and kidney disorders, create a massive public health problem, and are projected to cost the NHS £9.7 billion per annum by 2050. 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 become resistant to anorectic signals. In order to understand new interventions to treat obesity safely, we will separate different aspects of appetitive behaviour, the pathways involved and the factors that regulate them. The applicants' laboratories are well placed to make a major impact on understanding the brain networks that control appetite, as we have available the necessary models, tools and expertise. Their findings will be disseminated to academic and clinical colleagues at international conferences and by publication in high-impact journals during the grant's duration.

The potential global market for obesity drugs is over $100 billion. This project will guide future development of new classes of drugs for the regulation of appetite. The PI has been involved previously in successful collaborative projects with a number of industrial partners, providing evidence for several novel targets for drug development that has underpinned programmes by AstraZeneca, Eli Lilly, Servier and Novo Nordisk. We will use the project to further develop industrial collaborations, which the PI has done successfully previously with the award of four Industrial Partnership Awards. Any intellectual property derived from this project will belong to the applicants and The University of Manchester. Any future contract negotiations will be carried out through the University's Intellectual Property company, UMI3 Ltd.
The PI will continue to provide consultations to different bodies regarding obesity research (in the past with commercial companies, funding agencies, The Royal Society and with The Department for Business, Innovation and Skills), which will affect future funding policy. During the lifetime of the grant, the basic research will be discussed at meetings organised by patient and professional health worker groups. These annual meetings are forums for basic researchers, psychologists, clinicians, community nurses and other health professionals, patient group representatives and policy makers.

The 2014 workshop on "Gut-brain communication", organised by the MRC, highlighted the "...need to ensure the UK was at the forefront in understanding how brain circuits process information to create neural representations that guide behaviour. It was recognised that this would require multidisciplinary approaches linking cutting-edge genetic tools and other new technologies..." This project will provide strong training in both in vivo skills and specialist techniques in fibre photometry, chemogenetics and optogenetics, electrophysiology, metabolic and behavioural research. In the last twelve years, the applicant has supervised 14 PhD students, 23 Masters students and 10 PDRAs, the majority of whom have remained in science (some have their own independent research groups and others have moved into the commercial sector). The PI is external examiner on another University's integrative Masters course and regularly examines PhD theses. He directs a cross-University Integrative Mammalian Biology 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.