Grant: Operating Grant

Obesity now poses a epidemic health crisis in the developed world. The abundant availability of palatable and highly caloric foods in the western diet is a major contributor to this disease. Traditionally, most research focuses on energy balance regulation in the hypothalamus. However, much less is known about how peptides that signal the cessation of eating, such as insulin, modulate motivation and reward. Dopamine neurons of the Ventral Tegmental Area (VTA) are a critical component of the neural circuit that mediates reward seeking behaviours, either for drugs of abuse or natural rewards. Indeed, dopamine has been shown to reinforce ingestive behaviours like food intake. Furthermore, evaluation of reward or motivation can be substantially modified by the metabolic status of the animal or by the administration of insulin into the brain. Dopamine neurons may serve as a direct target for insulin in these paradigms. Receptors for peptides that increase food intake and modulate dopamine neural activity, such as ghrelin and orexin, in addition to others that decrease food intake such as insulin and leptin are abundantly expressed in dopaminergic neurons. Recently we have identified that orexin increases the neural activity of dopamine neurons to motivate animals to forage for food. Therefore, we are interested in how these reward signals are turned off. Insulin is released after meals and recent evidence suggests that the post-ingestive consequences of food can alter reward pathways. The proposed experiments will examine how insulin can modulate neuronal activity and output of VTA dopamine neurons. Further, we will determine if this insulin modulation the reward system is dysregulated in either genetically-prone or diet-induced models of obesity. These experiments will expand our knowledge of the mechanisms of insulin action on the dopamine reward circuit and ingestive behaviour and may lead to the development of therapeutic agents for the treatment of obesity.