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Exploiting C. elegans to provide insight into neural substrates of human alcohol dependence

利用秀丽隐杆线虫来深入了解人类酒精依赖的神经基质

基本信息

批准号：
BB/E022251/1
负责人：
Lindy Holden-Dye
金额：
$ 68.24万
依托单位：
University of Southampton
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FE022251%2F1
关键词：
Exploiting C.elegans provide insight

项目摘要

Human alcohol (ethanol) consumption has a longstanding position within many societies despite the fact that its serious negative effects can sometimes outweigh its positive effects. Although alcohol has a very simple chemical structure it is a drug that has profound immediate effects on human behavior from relaxation and loss of social inhibition, through slurred speech and unsteady gait, to loss of consciousness and death. These changes in the pattern of behavior with increasing alcohol intake reflect its complex effects on the brain. There is also variation in the impact of alcohol on different people highlighting the fact that an individual's genetic background and their previous experience with alcohol both play an important role in how alcohol is experienced. Finally, it is often noted that ones' first drink does not taste good but continued drinking sometimes leads to a liking for alcohol which in the extreme can involve the development of dependence. Once dependence is established an individual's life can become dominated by a need to maintain a supply and avoid unpleasant symptoms that are experienced when alcohol is withdrawn. How does alcohol work? Like all drugs alcohol affects behaviour because it can interact with cells of the nervous system (including parts of the brain) causing cells to become more excited or inhibited. In effect alcohol has the ability to act like a skeleton key and open (excite) or close (inhibit) nerve cells. When alcohol acts in these ways it does so through special types of chemical structures, called proteins, that are found in cells and which can differ depending on the past experience and genetic structure of an individual. This means that ethanol can have quite different effects in different people and within the same person at different times. However, it seems to be an impossible task to be clear about the exact details of alcohol effects in higher animals because any observed effect represents the sum action of millions of nerve cells. This complexity means it is important to find simple ways of studying the effect of ethanol on nerves in a much simpler brain. In our proposal we want to use a model brain which is made of only 20 nerves in which we can sequentially remove the various proteins which ethanol works on to modify nerve function. This is done by using a small part of the brain from a simple worm C. elegans. This simplified model brain can then be used to tease apart how nerve cells might subtly change as a result of genetic factors and as a result of alcohol exposure. Importantly, this worm also shows some remarkably 'sophisticated' behaviours / it can move, explore its environment, find sources of food etc. Thus, as well as trying to understand the way alcohol works in an extremely simple nervous system we can also try to understand behaviours that are important in human alcohol dependence. For example, just as continued consumption of alcohol leads to changes in human behaviour when alcohol is withdrawn, we have also observed changes in the behaviour of C. elegans, when alcohol is withdrawn. Part of this project is aimed at trying to determine which genes are involved in alcohol withdrawal responses. Importantly, many of the genes that have been identified in different kinds of research into alcohol also exist in C.elegans. For this reason we can use this research to understand the way alcohol acts to control, and cause dysfunction, in human behavior.

人类酒精（乙醇）消费在许多社会中具有长期地位，尽管其严重的负面影响有时会超过其积极影响。虽然酒精的化学结构非常简单，但它是一种对人类行为产生深远直接影响的药物，从放松和丧失社交抑制力，到言语不清和步态不稳，再到失去意识和死亡。随着酒精摄入量的增加，行为模式的这些变化反映了酒精对大脑的复杂影响。酒精对不同人的影响也有所不同，这突出了一个事实，即一个人的遗传背景和他们以前的饮酒经历都在如何体验酒精方面发挥着重要作用。最后，人们经常注意到，人们第一次喝酒并不好喝，但持续饮酒有时会导致对酒精的喜爱，在极端情况下可能会导致对酒精的依赖。一旦建立了依赖，一个人的生活就会被需要维持供应和避免戒酒时经历的不愉快症状所支配。酒精是如何起作用的？像所有药物一样，酒精会影响行为，因为它可以与神经系统的细胞（包括大脑的一部分）相互作用，导致细胞变得更加兴奋或抑制。实际上，酒精就像一把万能钥匙，可以打开（兴奋）或关闭（抑制）神经细胞。当酒精以这种方式起作用时，它是通过一种叫做蛋白质的特殊化学结构来实现的，这种化学结构存在于细胞中，它可以根据个人过去的经历和基因结构而有所不同。这意味着乙醇在不同的人身上，在同一个人身上，在不同的时间会产生完全不同的效果。然而，要弄清楚酒精对高等动物影响的确切细节似乎是一项不可能完成的任务，因为任何观察到的影响都代表了数百万神经细胞的作用总和。这种复杂性意味着找到一种简单的方法来研究乙醇对更简单的大脑神经的影响是很重要的。在我们的提议中，我们想使用一个只有20个神经组成的模型大脑，我们可以依次去除乙醇作用的各种蛋白质来改变神经功能。这是通过使用简单蠕虫秀丽隐杆线虫大脑的一小部分来完成的。这个简化的大脑模型可以用来梳理神经细胞如何在遗传因素和酒精暴露的影响下发生微妙的变化。重要的是，这种蠕虫还表现出一些非常“复杂”的行为/它可以移动，探索环境，寻找食物来源等。因此，除了试图理解酒精在极其简单的神经系统中的作用方式外，我们还可以尝试理解人类酒精依赖的重要行为。例如，正如持续饮酒导致人类在戒酒后行为发生变化一样，我们也观察到秀丽隐杆线虫在戒酒后行为发生变化。该项目的一部分目的是试图确定哪些基因与酒精戒断反应有关。重要的是，在不同类型的酒精研究中发现的许多基因也存在于秀丽隐杆线虫中。因此，我们可以利用这项研究来了解酒精控制和导致人类行为功能障碍的方式。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A differential role for neuropeptides in acute and chronic adaptive responses to alcohol: behavioural and genetic analysis in Caenorhabditis elegans.

DOI：
10.1371/journal.pone.0010422
发表时间：
2010-05-03
期刊：
PloS one
影响因子：
3.7
作者：
Mitchell P;Mould R;Dillon J;Glautier S;Andrianakis I;James C;Pugh A;Holden-Dye L;O'Connor V
通讯作者：
O'Connor V

AutoEPG: software for the analysis of electrical activity in the microcircuit underpinning feeding behaviour of Caenorhabditis elegans.