Reward networks and appetitive behaviour

动物和人类必须进食才能满足身体的能量需求，它们已经进化出强大的机制，在需要时增加食欲。这种机制的一个很好的例子是在两餐之间的肠道产生一种名为Ghrelin的荷尔蒙。Ghrelin作用于大脑，增加对食物的寻求量，但也让食物看起来更有价值。很容易理解为什么饥饿会进化成动物去寻找和获取食物。但为什么要让吃东西变得如此值得呢？人们认为，这是进化而来的，这样动物就会在食物通常稀缺的情况下最大化进食。富含能量的食物来源，例如含有大量糖或脂肪的食物，是首选的食物来源，特别是当动物在野外进食的机会有限或面临捕食威胁时。食物带来回报的不利方面是，在一个高能食物丰富且容易获得的现代环境中，我们仍然有动力过度消费。人们普遍认为，目前人类肥胖的流行是由于这样一个事实，即超重的人即使体内储存了足够的能量，也仍然会被驱使暴饮暴食，因为他们不会脱离奖赏回路。简而言之，即使在吃了一顿饱饭之后，我们仍然会有空间吃一些布丁！为了理解为什么肥胖的人吃得太多，这将有助于理解大脑对饥饿的反应，以及随着我们体重的增加可能会发生什么变化。重要的是，我们希望了解控制饥饿反应不同方面的不同大脑通路。例如，吃东西如何消除负面的、令人不快的饥饿感，而吃东西如何让人产生一顿美餐的积极、愉悦的感觉。这些行为是由一个极其复杂的脑细胞(神经元)网络控制的，我们对此才刚刚开始了解。在这个项目中，我们想要确定不同类型的神经元是如何相互连接的。我们之所以能够做到这一点，是因为我们第一次可以在老鼠身上看到不同的神经元，因为它们被制造成用荧光灯发光。我们可以记录这些神经元的活动，同时刺激与它们相连的其他细胞--所有这些都在培养皿中！然而，同样非常新的是，我们可以刺激老鼠体内特定类型的神经元，而它们的行为完全正常。这可以通过给小鼠注射一种新药或通过光纤照射小鼠的大脑来实现。我们还可以抑制相同神经元的活动，并观察老鼠是否仍然对饥饿或生长激素Ghrelin有反应。通过这样做，我们可以看到老鼠是否吃正常的食物，或者它们是否更愿意付出一点努力来获得更有回报的糖丸。通过刺激大脑中的不同路径，我们将能够建立起控制饮食行为的复杂神经元网络的完整图景。只有当我们做到了这一点，我们才能问，当一只老鼠或一个人变得肥胖时，会发生什么变化。

Animals and humans must eat to fulfil the energy requirements of their bodies, and they have evolved powerful mechanisms to increase appetite when required. An excellent example of one such mechanism is the production of a hormone, called ghrelin, by the gut in between meals. Ghrelin acts on the brain to increase food seeking, but also to make food seem more rewarding. It is easy to see why hunger has evolved to make an animal go and search for and procure food. But why make eating food so rewarding? It is believed that this evolved so that animals will maximise eating if food is normally scarce. Food sources that are rich in energy, for example which contain a lot of sugar or fat, are preferred, especially if an animal has limited opportunities to eat or is under threat of predation while it is out in the open. The downside of food being rewarding is that, in a modern environment, where high-energy food is abundant and easily available, we are still motivated to over consume. It is a widely held view that the current epidemic in human obesity is due to the fact that over-weight people, even though they have adequate energy stored in their bodies, are still driven to over eat because they do not disengage reward circuits. Simply put, even after eating a full meal, we will still find space for some pudding!In order to understand why obese humans over eat, it will help to understand how the brain responds to hunger, and what may change as we put weight on. Importantly, we wish to understand the different brain pathways which control different aspects of the hunger response. For example, how eating food turns off the negative, unpleasant feelings of hunger, versus how eating food turns on the positive, pleasant feelings of eating a nice meal. These behaviours are controlled by an extremely complex network of brain cells (neurones), which we are only just beginning to understand. In this project, we want to determine how different types of these neurones connect with each other. We are able to do this because, for the first time, we can see the different neurones in mice because they have been made to shine with fluorescent light. We can record the activity of these neurones while stimulating the other cells that connect with them - all in a petri dish! However, what is also very new is that we can stimulate specific types of neurone in mice while they are behaving perfectly normally. This can be done by either giving the mice an injection of a new drug or by shining light into the mouse's brain using an optic fibre. We can also inhibit the activity of the same neurones and see if the mice still respond to hunger or to the hormone, ghrelin. By doing this, we can see whether the mice eat normal food, or if they prefer to put in a bit more effort to receive a more rewarding sugar pellet. By stimulating different pathways in the brain, we will be able to build up a complete picture of the complex network of neurones that control eating behaviour. Only when we have done this, will we then be able to ask what changes when a mouse or a human becomes obese.