The role of hypothalamic astrocytes in homeostatic regulation of feeding behaviour

食物摄入量的失调导致了肥胖，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，每年给NHS造成的损失估计为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，在这些疾病中，人体调节食物摄入量的机制不能正常工作，这一点至关重要。我们必须彻底和详细地了解食物摄入量是如何正常调节的。基于中枢神经系统(CNS)的机制对控制食物摄入量和体重起着关键作用。虽然大脑的许多区域在控制摄食行为方面发挥了作用，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，这一过程通过神经和荷尔蒙信号传递过程发生。就像这里提出的那样，基础研究已经确定了下丘脑中对调节食物摄入量至关重要的神经细胞的关键回路。其中包括在活跃时增加进食动力的特定神经元，以及会产生相反结果的不同神经元，即抑制食物摄取。虽然神经元是大脑中最广为人知的细胞类型，但它们并不是最丰富的。这一区别属于被称为神经胶质的非神经细胞。神经胶质细胞在调节食物摄取方面的功能仍然知之甚少，尽管这些细胞无疑可以影响其他身体功能。例如，我们知道一类重要的胶质细胞，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在调节身体关键过程中做出了关键贡献。最近，我们发现，通过基因改变小鼠的星形胶质信号，当给予动物可口的高脂肪饮食时，增加了食物的摄入量，首次支持了这些细胞在敏锐调节摄食的过程中发挥的作用。这个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以响应高脂肪饮食的机制，即营养过剩，并确定是否有类似的机制参与对相反极端的营养不足的摄食反应，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。确定星形胶质细胞在调节下丘脑神经元的电活动中的作用。确定下丘脑星形胶质细胞信号的改变如何影响体内营养失衡时的食物摄入量。了解操纵星形胶质信号如何改变整体新陈代谢。对食物摄入调节机制的更好理解将有助于其他致力于开发包括肥胖和厌食症在内的食物摄入障碍的新疗法的科学家和临床医生。

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.