Reward networks and appetitive behaviour

奖励网络和食欲行为

• 批准号: BB/N007549/1
• 负责人: Simon Luckman
• 金额: $ 57.61万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN007549%2F1
• 关键词: Reward; networks; appetitive; behaviour

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.

动物和人类必须进食以满足身体的能量需求，并且它们已经进化出强大的机制来在需要时增加食欲。这种机制的一个很好的例子是在两餐之间由肠道产生一种称为ghrelin的激素。Ghrelin作用于大脑，增加对食物的寻求，但也使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。但为什么要让吃食物这么有意义呢？据信，这种进化使动物在食物通常稀缺的情况下会最大限度地进食。富含能量的食物来源，例如含有大量糖或脂肪的食物，是优选的，特别是如果动物在户外进食的机会有限或受到捕食的威胁。食物奖励的缺点是，在现代环境中，高能量食物丰富且容易获得，我们仍然有动力过度消费。人们普遍认为，目前人类肥胖症的流行是由于超重的人，即使他们体内储存了足够的能量，仍然会因为没有脱离奖励回路而过度进食。简单地说，即使吃了一顿饱饭，我们仍然会找到一些布丁的空间!为了理解为什么肥胖的人吃得过多，这将有助于了解大脑如何对饥饿做出反应，以及当我们增加体重时会发生什么变化。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，吃食物如何关闭饥饿的消极，不愉快的感觉，而吃食物如何打开吃一顿美餐的积极，愉快的感觉。这些行为是由一个极其复杂的脑细胞（神经元）网络控制的，我们才刚刚开始了解。在这个项目中，我们想确定不同类型的神经元是如何相互连接的。我们能够做到这一点，是因为我们第一次可以看到老鼠身上不同的神经元，因为它们被制造成发出荧光。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，同样非常新颖的是，我们可以刺激小鼠中特定类型的神经元，而它们的行为完全正常。这可以通过给老鼠注射一种新药或用光导纤维将光线照射到老鼠的大脑中来实现。我们还可以抑制相同神经元的活动，看看老鼠是否仍然对饥饿或生长激素释放肽有反应。通过这样做，我们可以看到老鼠是否吃正常的食物，或者他们是否更愿意付出更多的努力来获得更有价值的糖丸。通过刺激大脑中的不同通路，我们将能够建立一个控制饮食行为的复杂神经元网络的完整图像。只有当我们这样做了，我们才能问当老鼠或人类变得肥胖时会发生什么变化。

项目成果

Brainstem peptides and peptidergic neurons in the regulation of appetite

• DOI: 10.1016/j.coemr.2022.100339
• 发表时间: 2022-03
• 期刊: Current Opinion in Endocrine and Metabolic Research
• 作者: Giuseppe D’Agostino;S. Luckman

The hypothalamic RFamide, QRFP, increases feeding and locomotor activity: The role of Gpr103 and orexin receptors.

• DOI: 10.1371/journal.pone.0275604
• 发表时间: 2022
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Cook, Chris;Nunn, Nicolas;Worth, Amy A.;Bechtold, David A.;Suter, Todd;Gackeheimer, Susan;Foltz, Lisa;Emmerson, Paul J.;Statnick, Michael A.;Luckman, Simon M.
• 通讯作者: Luckman, Simon M.

Central administration of ghrelin induces conditioned avoidance in rodents.

• DOI: 10.1016/j.euroneuro.2017.05.001
• 发表时间: 2017-08
• 期刊: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
• 作者: Schéle E;Cook C;Le May M;Bake T;Luckman SM;Dickson SL
• 通讯作者: Dickson SL