Few tasks executed by the brain hold greater survival and adaptive value than keeping us fed and in adequate nutritional state. The regulation of energy metabolism represents a prototypical homeostatic system, with the brain acting as the central coordinator. Any alteration of these mechanisms can lead to pathological states threatening the survival of the individual.The main brain region regulating food intake behaviour is the hypothalamus. The endocannabinoid system (ECS), formed by cannabinoid receptors, their endogenous ligands (endocannabinoids) and the enzymatic machinery for the synthesis and degradation of endocannabinoids is centrally involved in the regulation of food intake.This project aims at defining the mechanisms of the ECS-mediated control of food intake. We will reach the following goals:1.We will generate advanced genetic tools allowing conditional deletion, rescue and overexpression of ECS elements. The integrated use of these tools will lead to the detailed mapping of the brain neurocircuitries where the ECS controls food intake.2.We will provide strong evidence pointing to differential functions of the ECS in food intake, depending on the specific circuits activated.3.We will determine which endocannabinoid(s) are involved in specific aspects of food intake.4.We will detail the electrophysiological impact of the ECS on the hypothalamic neuronal network regulating food intake.5.We will identify novel biochemical mechanisms, linking the ECS to hypothalamic neuronal activity, mitochondrial functions and regulation of food intake.This project has the ambitious aim to explore new scientific avenues and to provide “in depth” knowledge on the neuronal mechanisms regulating ingestive behaviour in mammals. The results of this project will pave the way to novel lines of research for the physiology and pharmacology of the ECS in the control of energy balance.