Emotional disturbance is found in a number of psychiatric disorders including depression, autism, schizophrenia, obsessive compulsive disorder and frontal lobe dementia. However, the specific psychological nature of these deficits is poorly understood as is the nature of the brain damage causing such disturbances. To address these issues it is important that we have an understanding of the basic psychological processes that contribute to an emotional response and the neural structures and chemicals in the brain that control these processes. This application considers these questions with respect to positive emotional responses in a new world primate. To do this we have devised tests that will enable us to study different aspects of positive emotion. Thus, positive emotional responses may be elicited by the pleasure of eating a particularly tasty meal but also in wandering around Tesco?s selecting what foods you?re going to buy for a dinner party. The former is thought of as a primary reward while the latter are stimuli that evoke the thought of reward (called conditioned stimuli) and that can be rewarding in their own right. Indeed, learning about stimuli in the environment that predict reward and that take on reinforcing value in their own right is highly advantageous as it allows us to be able to anticipate and prepare for that reward and also to be motivated enough to go out and find the reward. This is equally true for negative situations in which hearing the bark of a neighbours vicious dog is enough to keep you out of harms way. We therefore propose to present marmosets with intrinsically neutral stimuli such as a light or tone that predict highly tasty food reward and under certain circumstances require the animal to learn a response to gain access to the primary reward or the conditioned stimulus in order to study what parts of the brain and chemicals in the brain allow an animal to learn about these stimuli and to show positive emotional reactions to these stimuli including changes in bodily responses that accompany such reactions. We will investigate the contribution made by two specific brain structures, the prefrontal cortex and amygdala in positive emotion as well as how they are modulated by particular chemicals. The benefits provided by this Programme lie in understanding the neuropsychological and neurochemical basis of emotion, information that can contribute to the development of pharmacological treatment strategies for various neuropsychiatric disorders.

In early life, children can develop serious life threatening problems with their internal organs. These include the inappropriate passage of urine from the bladder back up to the kidneys, which can damange the kidneys, and abnormal twisting of the gut which may need urgent surgery. These problems are usually diagnosed using X-rays, but these carry a radiation risk, particularly to children. Non-X-ray alternatives would be preferable in children, particularly as many investigated are normal. Magnetic resonance imaging (MRI) is a safer technique, and may now be accurate enough to diagnose these diseases in small children without the need for X-rays or sedation. However, small children in are a special population that present additional challenges in an MRI environment, such as communication, cooperation, physical size, access and parent/carer contact. This project aims to refine a new MRI method for children which has been pioneered in Cambridge, and test how well it works. When children come for an X-ray test, we propose to also perform this new MRI test, to see whether (a) the MRI test is acceptable, and (b) whether the MRI test is just as accurate.

Heart disease is the most common cause of death in patients with diabetes mellitus, and the combination of type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) is a major cause of premature cardiovascular morbidity and mortality. Therapy to improve glucose metabolism by the heart have not been widely adopted as they are cumbersome, offer limited benefit and have therefore not been widely adopted in clinical practice. This proposed research builds on existing funding from the British Heart Foundation and the MRC to assess the effect of metabolic factors to improve the ability of the heart to tolerate the effects of a reduced blood supply due to coronary artery disease (ischaemia, clinically recognised as angina). A peptide, glucagon-like peptide 1 (GLP-1), that is secreted mainly by upper intestine in response to food has recently been found to improve the action of insulin in patients with T2DM and improve glucose metabolism. A number of drugs that limit the breakdown of this peptide have now been licensed to treat T2DM, and the proposed research will investigate whether increasing the level of GLP-1 in the blood improves the ability of the heart to tolerate ischaemia. Our preliminary results suggest that GLP-1 does indeed protect the heart against contractile dysfunction that occurs both during and after ischaemia. I addition, pilot studies in a small number of patients undergoing coronary angioplasty and stenting suggest that an infusion of GLP-1 protects the heart during the therapeutic procedure, which is particularly important in those with T2DM. The research will be informative by allowing the efficacy of a safer metabolic therapy to be tested and confirmation of efficacy in patients with T2DM will provide novel information about the mediation of a therapeutic effect and provide the basis for subsequent interventional studies in patients with CAD and T2DM.

Many adult tissues are maintained by stem cells. Failure to control the generation of stem cells or the differentiation into their progeny contribute to cancer. Thus, the goal of this project is to identity key regulators and mechanisms that control the maintenance of healthy skin by regulating stem cell growth and differentiation. Once we have identified important factors regulating stem cell fate, we further investigate whether their mis-regulation contribute to cancer. These approaches are being developed and exploited to uncover novel mechanisms and pathways that are involved in cancer development and could well lead to the discovery of novel anti-cancer drug targets.