Presynaptic substrates in hypothalamus as pivotal regulators of feeding behaviour

动物通过根据食欲状态（饥饿或饱腹）指示进食行为（吃或不吃）来控制热量摄入。从潜在脑回路的层面上理解这种调节机制，揭示了神经系统如何将内部生理信号与满足动物的行为联系起来——这是生存所需的关键功能。此外，详细了解进食控制机制及其潜在功能障碍具有重要的社会意义，因为现代生活中饮食相关疾病的发病率不断上升。人们认为，下丘脑中一个被称为弓状核的大脑区域在正确选择与食欲有关的行为方面发挥着重要作用。在这个结构中，指示食欲状态的神经元与指示摄食行为的神经元直接相连。因此，在这些被称为突触的接触点，信息流的变化可能对摄食控制至关重要。然而，这个回路的定义仍然很模糊，这些突触中发生的变化的本质是什么，以编码食欲状态并驱动正确的行为，仍然不清楚。这个项目的目的是研究这些关键问题，运用我们广泛的知识，适应突触特性定义在其他大脑区域表征的机制，调整信息流动的接触点在弓状核。根据我们的实验数据，我们假设一个关键的调控位点是突触中被称为囊泡的小纳米级球形结构，它包含并传递传递基础的化学信号。我们提出，这些囊泡的数量、它们在突触中的物理排列以及它们释放化学信号并可供再利用的时间是决定信息传递的关键变量，它们作为存储食欲状态和决定行为选择的记忆。为了验证这些重要的想法，我们将利用最先进的基因技术，使我们能够荧光标记取自大脑的弓形电路中的单个囊泡，并用敏感的光学显微镜跟踪它们的化学信号传递过程。同样，使用强大的电子显微镜方法，我们将直接可视化这些囊泡的排列，测试它们的组织变化与食欲状态的变化之间的关系。运用我们之前对其他突触类型控制通路的详细知识，我们还将确定食欲驱动突触功能变化的分子机制。最后的原理验证目标将使用我们从这些脑回路实验中得到的发现来测试突触囊泡特性的强制调整如何实际影响动物的摄食行为。总的来说，这项工作将为行为动物设定卡路里摄入量的大脑控制机制提供新的基础理解。该主题与BBSRC的战略研究优先领域“健康生物科学”一致，其中包括代谢调节机制作为重点。揭示进食控制的基本机制将填补了解动物如何保持健康身体状态的关键知识空白，并为与饮食失调相关的功能失调控制机制提供新的见解。

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.