Neuronal circuits that turn off hunger

消除饥饿感的神经回路

• 批准号: BB/V016318/1
• 负责人: Giuseppe D'Agostino
• 金额: $ 57.84万
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV016318%2F1
• 关键词: Neuronal; circuits; turn; off; hunger

The primary reason that we eat is because we feel hungry. Hunger is a natural drive that forces us to eat in order to replenish the energy that we use to move around, do work, look after our bodies and maintain a healthy weight. Normally when we eat, our hunger is switched off and we reach a state of satiety. However, sometimes the natural processes of hunger and satiety are overridden and we lose control of body weight, which can lead to obesity. Obesity itself will cause problems with daily life, including difficulties with walking and stigmatism by others. However, more importantly it can cause very serious disabilities, like diabetes and heart disease. Therefore, it is essential that we understand what controls the way we eat.Eating is similar in humans and mice; like us, mice eat in separate bouts, which we call meals. Each meal is composed of three distinct phases. The first phase involves appetitive behaviour. This is a preparatory phase when animals search for and acquire food. The second phase is when the animal ingests the food, which we call consummatory behaviour. The final phase is "post-ingestive." That is after the animal has eaten and starts to digest the food, eventually reaching satiety. These behaviours seem very simple, but they require very complex organisation by the brain. Our understanding of the brain cells and neural circuits that control eating has remained very vague until some recent breakthroughs.There is a small group of cells (just a few thousand of the 70 million nerves in a mouse brain) that produce a messenger called AgRP and that are critical for controlling eating. It is possible, using the latest neuroscientific tools, to see and manipulate these cells in living, normally behaving mice. We and others have shown previously that AgRP cells increase their activity in response to hunger signals. The hunger signals include a message from the stomach, called ghrelin, and inputs from other nerves. If we artificially stimulate only the AgRP cells, we can make a mouse eat, even if it has just had a meal. Importantly, also we can measure the activity of AgRP cells by shining a fluorescent light into the brain of a specially bred mouse, and measuring the light that bounces back. AgRP cell activity goes up when the mouse is hungry before a meal or if we inject the mouse with ghrelin. Remarkably, the activity of AgRP cells goes down as soon as the mouse finds food (the appetitive phase) and stays down if the animals eats (throughout the consummatory and post-ingestive phases). However, if the mouse does not eat the food, the activity of AgRP cells creeps up again. Thus, together we have shown that AgRP cell activity drives eating behaviour and provides us with a measure of hunger, which can be read with split-second accuracy.In this project, we will investigate the different inputs to AgRP cells to decide which are required to switch off hunger. We believe that different nerves from other parts of the brain control AgRP cells during the three phases of eating. We have preliminary data to suggest that some inhibitory nerves connect directly and inhibit AgRP cells when food is acquired in the appetitive phase. Other nerves, which have an excitatory input onto AgRP cells are switched off during the consummatory phase, and we believe this is required for the low AgRP cell activity when a meal is being eaten. Finally, we have evidence that after the meal is eaten, post-ingestive signals from the gut stimulate additional connections which keep the AgRP silent during satiety. As time passes, these inputs adapt and the activity of AgRP cells increases again, producing hunger before the next meal.By understanding these complex brain circuits, in the future we may be able to manipulate hunger and provide new medicines to control the rise of obesity and eating disorders in our society.

我们吃东西的主要原因是因为我们饿了。饥饿是一种自然的驱动力，迫使我们吃东西，以补充我们用来走动，工作，照顾我们的身体和保持健康体重的能量。通常，当我们吃东西时，我们的饥饿感被切断，我们达到饱足的状态。然而，有时饥饿和饱腹感的自然过程被推翻，我们失去了对体重的控制，这可能导致肥胖。肥胖本身会导致日常生活的问题，包括行走困难和他人的耻辱。然而，更重要的是，它会导致非常严重的残疾，如糖尿病和心脏病。因此，我们必须了解是什么控制了我们的进食方式，人类和老鼠的进食方式是相似的;像我们一样，老鼠也是分开进食的，我们称之为进餐。每一餐都由三个不同的阶段组成。第一阶段是食欲行为。这是动物寻找和获取食物的准备阶段。第二个阶段是当动物摄取食物时，我们称之为完成行为。最后一个阶段是“消化后。“这是在动物吃完并开始消化食物，最终达到饱腹感之后。这些行为看起来非常简单，但它们需要大脑进行非常复杂的组织。我们对控制进食的脑细胞和神经回路的理解一直非常模糊，直到最近的一些突破，有一小群细胞（老鼠大脑中7千万条神经中的几千条）产生一种称为AgRP的信使，对控制进食至关重要。使用最新的神经科学工具，可以在正常行为的活体小鼠中观察和操纵这些细胞。我们和其他人以前已经表明，AgRP细胞在响应饥饿信号时会增加它们的活性。饥饿信号包括来自胃的信息，称为ghrelin，以及来自其他神经的输入。如果我们人工刺激AgRP细胞，我们可以让老鼠吃东西，即使它刚刚吃过一顿饭。重要的是，我们还可以通过将荧光照射到特殊饲养的小鼠的大脑中并测量反射回来的光来测量AgRP细胞的活性。AgRP细胞的活性会在老鼠饭前饥饿时上升，或者如果我们给老鼠注射生长激素释放肽。值得注意的是，一旦老鼠找到食物（食欲阶段），AgRP细胞的活性就会下降，如果动物吃东西（在整个完成和摄食后阶段），AgRP细胞的活性就会保持下降。然而，如果老鼠不吃食物，AgRP细胞的活性又会上升。因此，我们共同证明了AgRP细胞活动驱动进食行为，并为我们提供了一种饥饿的测量方法，可以以瞬间的准确度读取。在这个项目中，我们将研究AgRP细胞的不同输入，以决定哪些是关闭饥饿所需的。我们相信，在进食的三个阶段，来自大脑其他部分的不同神经控制着AgRP细胞。我们有初步的数据表明，一些抑制性神经直接连接，并抑制AgRP细胞时，获得的食物在食欲阶段。其他对AgRP细胞有兴奋性输入的神经在完成阶段被关闭，我们相信这是吃饭时AgRP细胞活性低所必需的。最后，我们有证据表明，在进食后，来自肠道的摄食后信号刺激了额外的连接，使AgRP在饱腹感期间保持沉默。随着时间的推移，这些输入适应和AgRP细胞的活动再次增加，在下一顿饭之前产生饥饿感。通过了解这些复杂的大脑回路，未来我们可能能够操纵饥饿感，并提供新的药物来控制我们社会中肥胖和饮食失调的上升。

项目成果

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

Negative energy balance hinders prosocial helping behavior.

• DOI: 10.1073/pnas.2218142120
• 发表时间: 2023-04-11
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Pozo, Macarena;Mila-Guasch, Maria;Haddad-Tovolli, Roberta;Boudjadja, Mehdi Boutagouga;Chivite, Inigo;Toledo, Miriam;Gomez-Valades, Alicia G.;Eyre, Elena;Ramirez, Sara;Obri, Arnaud;Bartal, Inbal Ben-Ami;DAgostino, Giuseppe;Costa-Font, Joan;Claret, Marc
• 通讯作者: Claret, Marc