Presynaptic substrates in hypothalamus as pivotal regulators of feeding behaviour

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Animals control calorific intake by instructing feeding behaviour (eat or not eat) based on appetite state (hunger or satiety). Understanding this regulatory mechanism at the level of the underlying brain circuits reveals how the nervous system links internal physiological signals to actions that satisfy the animal - a critical function required for survival. Moreover, detailed knowledge of feeding control mechanisms and their potential dysfunction has major societal importance given the rising incidence of eating-related disorders in modern living. A brain region called the arcuate nucleus in the hypothalamus is thought to play an important role in the correct selection of appetite-related behaviour. In this structure, neurons that signal appetite state connect directly with neurons that instruct feeding behaviour. As such, changes in information flow at these contact points, known as synapses, are likely to be critical for feeding control. However, this circuit is still poorly defined and the nature of the changes that take place in these synapses to encode appetite state and drive the correct behaviour remains unclear.The aim of this project is to investigate these key questions, applying our extensive previous knowledge of adaptive synaptic properties defined in other brain areas to characterize the mechanisms that tune information flow at the contact sites in the arcuate nucleus. Based on our pilot data, we hypothesize that a key regulatory site is the population of small nanoscale spherical structures in synapses, called vesicles, that contain and transmit the chemical signals that underlie transmission. We propose that the number of these vesicles, their physical arrangement in the synapse and the time they take to release chemical signal and become available for re-use, are key variables that determine information transfer, acting as a memory for storing appetite state and determining behavioural selection. To test these important ideas, we will take advantage of state-of-the-art genetic technologies which allow us to fluorescently label the individual vesicles in arcuate circuits taken from the brain, and, with sensitive optical microscopy, follow them through the process of chemical signalling. Likewise, using a powerful electron microscopy method, we will directly visualize the arrangements of these vesicles, testing how changes in their organization relates to alterations in appetite state. Applying our detailed previous knowledge of control pathways in other synapse types, we will also determine the molecular mechanisms that underlie appetite-driven changes in synaptic function. A final proof-of-principle objective will use our findings from these brain circuit experiments to test how imposed adjustments in synaptic vesicle properties actually impact on animal feeding behaviour.Collectively, this work will provide fundamental new understanding of the control mechanisms in the brain that set calorific intake in behaving animals. This topic aligns with the BBSRC's strategic research priority area 'Bioscience for Health' which includes mechanisms of metabolic regulation as a key focus. Uncovering fundamental mechanisms of feeding control will fill in key knowledge gaps for understanding how animals maintain healthy body state, and provide new insights into the mechanisms of dysfunctional control associated with eating disorders.