The brainstem signals dual motivational valence following ingestion

摄入后脑干发出双重动机效价信号

• 批准号: MR/T032669/1
• 负责人: Simon Luckman
• 金额: $ 66.63万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT032669%2F1
• 关键词: brainstem; signals; dual; motivational; valence

Currently, many people in the UK struggle with their weight, and this can lead to related problems like diabetes and cardiovascular disease. As well as the burden on individuals, treating the rise in obesity puts immense strain on the NHS. The main reason that people put on excess weight is that they simply over eat; therefore, it is important to understand what controls our eating behaviour. If we have not eaten for a while, we feel hungry and agitated. This is not a very pleasant feeling and, so, we are motivated to consume food. When we do this, the feelings of hunger disappear and we can feel pleasantly full. We call the period in between meals, when we do not feel hungry, satiety. Thus, we can imagine our appetite is controlled by competing feelings: hunger (a negative feeling) and satiety (a positive feeling). Alternatively, we can lose our appetite when we experience different negative feelings, caused by sickness, because we have eaten something that has upset our stomach or if we have caught a bug. Finally, we may feel nauseous or unwell after taking a prescription drug, perhaps to help us cope with diabetes or cancer. In all of these situations, the decision about whether to eat or not is controlled by two parts of our brain. The hypothalamus, near the base of the brain, collects lots of information from the rest of the body about our energy status (have we just eaten or not), the time of day, are we active, etc. Information about what and how much we have eaten comes from the gut to the second part, at the back of the brain, the so-called brainstem. The brainstem collects all the information from the gut and then relays it to the hypothalamus. Thus, complex circuits in the brainstem and hypothalamus, together with other parts of the brain, control our eating behaviour.We have identified cells (neurones) in the brainstem of mice which respond to the different signals coming from the gut. For example, one type of neurone responds when the mouse has eaten a meal, while another responds when the mouse has eaten something which makes it feel unwell. Our laboratories have new genetic "tools" which allow us to investigate how these different neurones function. For example, we have generated different types of mice which allow us to artificially activate these neurones selectively and stop the mice from eating, even if they are very hungry. However, activating some of the connections made by these neurones, cause the mice to feel contented, while others make the mice feel unwell. We believe that these two types of neurone signal satiety and aversion, respectively, to the rest of the brain. We will use our tools to map connections in the brain, demonstrate their importance and show how eating behaviour is managed in both health and disease. This knowledge will help in the development of new drugs to control body weight, but also drugs to treat diabetes, cancer and other diseases, which have fewer side effects.

目前，英国许多人都在与体重作斗争，这可能导致糖尿病和心血管疾病等相关问题。除了给个人带来负担外，治疗肥胖症的增加给国民保健服务带来了巨大的压力。人们体重超重的主要原因是吃得过多;因此，了解是什么控制着我们的饮食行为非常重要。如果我们有一段时间没有吃东西，我们会感到饥饿和焦虑。这不是一个很愉快的感觉，所以，我们有动力去消费食物。当我们这样做时，饥饿感消失了，我们可以感到愉快的饱足感。我们把两餐之间的这段时间，当我们不感到饥饿时，称为饱腹感。因此，我们可以想象我们的食欲是由相互竞争的感觉控制的：饥饿（一种消极的感觉）和饱腹感（一种积极的感觉）。或者，当我们经历由疾病引起的不同的负面情绪时，我们可能会失去食欲，因为我们吃了一些让我们胃不舒服的东西，或者如果我们抓住了一个错误。最后，我们可能会在服用处方药后感到恶心或不适，这可能有助于我们科普糖尿病或癌症。在所有这些情况下，是否吃东西的决定都是由我们大脑的两个部分控制的。下丘脑，靠近大脑底部，从身体的其他部分收集大量关于我们的能量状态的信息（我们刚刚吃了或没有），一天中的时间，我们活动，等等，关于我们吃了什么和吃了多少的信息来自肠道，位于大脑后部的第二部分，所谓的脑干。脑干收集来自肠道的所有信息，然后将其传递到下丘脑。因此，脑干和下丘脑中的复杂回路，连同大脑的其他部分，控制着我们的进食行为。我们已经在老鼠的脑干中识别出了对来自肠道的不同信号做出反应的细胞（神经元）。例如，一种神经元会在老鼠吃了一顿饭时做出反应，而另一种神经元会在老鼠吃了让它感觉不舒服的东西时做出反应。我们的实验室有新的遗传“工具”，使我们能够研究这些不同的神经元如何发挥作用。例如，我们已经产生了不同类型的小鼠，使我们能够人工选择性地激活这些神经元，并阻止小鼠进食，即使它们非常饥饿。然而，激活这些神经元建立的一些连接会使小鼠感到满足，而另一些则会使小鼠感到不适。我们相信，这两种神经元分别向大脑的其他部分发出饱腹感和厌恶感的信号。我们将使用我们的工具来绘制大脑中的连接，展示它们的重要性，并展示如何在健康和疾病中管理饮食行为。这些知识将有助于开发控制体重的新药，也有助于开发治疗糖尿病、癌症和其他疾病的药物，这些药物的副作用较少。

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

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation.

• DOI: 10.1016/j.molmet.2021.101407
• 发表时间: 2022-01
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Costa A;Ai M;Nunn N;Culotta I;Hunter J;Boudjadja MB;Valencia-Torres L;Aviello G;Hodson DJ;Snider BM;Coskun T;Emmerson PJ;Luckman SM;D'Agostino G
• 通讯作者: D'Agostino G

Hypothalamic AgRP neurons exert top-down control on systemic TNF-a release during endotoxemia.

下丘脑 AgRP 神经元在内毒素血症期间对全身 TNF-a 释放进行自上而下的控制。

• DOI: 10.1016/j.cub.2022.09.017
• 发表时间: 2022
• 期刊: CB
• 作者: Boutagouga Boudjadja M