The role of hypothalamic astrocytes in homeostatic regulation of feeding behaviour

对食物摄入的调节紊乱会导致肥胖，这是英国一个主要的、日益严重的公共健康问题。肥胖症已经影响了超过25%的成年人口，并且每年花费NHS估计42亿英镑。为了使科学家和制药公司能够针对肥胖等疾病开发最有效的治疗干预措施，其中身体调节食物摄入的机制不能正常工作，我们必须全面详细地了解食物摄入是如何正常调节的。中枢神经系统（CNS）内的机制对控制食物摄入和体重至关重要。虽然许多大脑区域在控制进食行为中发挥作用，但被称为下丘脑的区域对于协调食物摄入的调节至关重要，这是通过神经和激素信号过程发生的。基础研究，就像这里提出的那样，已经确定了下丘脑内神经细胞的关键回路，这些神经细胞对调节食物摄入至关重要。这些包括特定的神经元，它们在活跃时增加进食的动机，以及不同的神经元，它们可以产生相反的结果，即抑制食物摄入。虽然神经元是大脑中最知名的细胞类型，但它们并不是最丰富的。这种区别福尔斯落在了被称为神经胶质的非神经元细胞上。神经胶质细胞参与调节食物摄入的功能仍然知之甚少，尽管这些细胞无疑会影响其他身体功能。例如，我们知道一类重要的神经胶质细胞，即星形胶质细胞，可以直接调节控制生殖和血压的下丘脑神经回路的活动，这表明星形胶质细胞对调节关键身体过程的重要贡献具有优先性。最近，我们发现，通过基因改变小鼠的星形胶质细胞信号，当动物被给予可口的高脂肪饮食时，食物摄入量增加，这是第一次支持这些细胞在急性调节进食过程中的作用。本项目的总体目的是跟进这一重要发现，并确定星形胶质细胞调节食物摄入的机制，以响应高脂肪饮食，即营养过剩，也要建立类似的机制是否涉及到喂养反应的相反极端，营养不足，例如禁食。我们的具体目标是：1.确定导致下丘脑星形胶质细胞激活的营养失衡状态。研究星形胶质细胞在调节下丘脑摄食神经元电活动中的作用.确定下丘脑星形胶质细胞中信号的改变如何影响食物摄入以响应体内营养不平衡。4.了解如何操纵星形胶质细胞信号改变整体代谢。提高对食物摄入调节机制的理解将有利于其他科学家和临床医生致力于开发新的治疗食物摄入紊乱，包括肥胖和厌食症的新疗法。

Disturbed regulation of food intake contributes to obesity, which is a major, and growing, public health issue in the U.K. Obesity already affects greater than 25% of the adult population and is costing the NHS an estimated £4.2billion annually. To enable scientists and pharmaceutical companies to develop the most effective therapeutic interventions for diseases like obesity, where the body's mechanisms regulating food intake are not working correctly, it is critical that we develop a thorough and detailed understanding of how food intake is regulated normally.Mechanisms based within the central nervous system (CNS) contribute pivotally to control of food intake and body weight. Although many brain areas play a role in control of feeding behaviours, a region known as the hypothalamus is vital for orchestrating the regulation of food intake, something that occurs through both nervous and hormonal signalling processes. Basic research, like that proposed here, has already identified critical circuits of nerve cells within the hypothalamus that are vital for the regulation of food intake. These include specific neurons which increase the motivation to eat when they are active and different neurons which can produce the opposite outcome, namely suppressing food intake. Although neurons are the best known cell type within the brain, they are not the most abundant. This distinction falls to non-neuronal cells known as glia. The functional involvement of glia in the regulation of food intake remains poorly understood, although these cells can unquestionably influence other bodily functions. For example, we know an important class of glial cells known as astroglia can directly regulate the activity of hypothalamic nerve circuits that control reproduction and blood pressure, demonstrating precedence for a critical contribution of astroglia to the regulation of key body processes. Recently, we discovered that genetically altering astroglial signalling in mice, increased food intake when the animals were given a palatable high-fat diet, supporting for the first time, a role these cells in a process that acutely regulates feeding. The overall purpose of this project is to follow up on this important finding, and to identify the mechanisms by which astroglia regulate food intake in response to a high-fat diet i.e. nutrient excess, and also to establish if similar mechanisms are involved in the feeding response to the opposite extreme, nutritional insufficiency e.g. fasting.Our specific aims are:1. To identify states of nutritional imbalance that cause astroglial activation in the hypothalamus.2. To establish the role of astroglia in modulating the electrical activity of hypothalamic neurons that regulate feeding.3. To determine how altering signalling in hypothalamic astroglia impacts food intake in response to in vivo nutritional imbalance.4. To understand how manipulating astroglial signalling alters overall metabolism.An improved understanding of the mechanisms by which food intake is regulated will benefit other scientists and clinicians working towards developing new therapies for disorders of food intake including obesity and anorexia.