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

人类酒精（乙醇）消费在许多社会中有着长期的地位，尽管其严重的负面影响有时可能超过其积极影响。虽然酒精的化学结构非常简单，但它是一种对人类行为有深刻直接影响的药物，从放松和失去社会抑制，通过口齿不清和步态不稳，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存在差异，这突出表明一个人的遗传背景和他们以前的酒精经验在酒精体验中起着重要作用。最后，人们经常注意到，一个人第一次喝酒的味道并不好，但继续喝酒有时会导致对酒精的喜爱，这在极端情况下可能涉及依赖性的发展。一旦建立了依赖性，一个人的生活就可能被维持供应的需要所支配，并避免在戒酒时所经历的不愉快的症状。酒精是如何工作的？像所有药物一样，酒精会影响行为，因为它可以与神经系统（包括大脑的部分）细胞相互作用，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。当酒精以这些方式起作用时，它是通过特殊类型的化学结构（称为蛋白质）来起作用的，这些化学结构存在于细胞中，并且可以根据个人的过去经验和遗传结构而有所不同。这意味着乙醇在不同的人和同一个人在不同的时间会产生不同的影响。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个神经细胞的总和。这种复杂性意味着找到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，我们希望使用一个仅由20条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，以改变神经功能。这是通过使用一个简单的蠕虫C的大脑的一小部分来完成的。优雅这个简化的大脑模型可以用来梳理神经细胞是如何由于遗传因素和酒精暴露而发生微妙变化的。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，除了试图了解酒精在一个非常简单的神经系统中的作用方式外，我们还可以尝试了解人类酒精依赖的重要行为。例如，正如持续饮酒会导致人类行为的变化，当酒精被戒断时，我们也观察到了C的行为变化。优雅的人，当酒精被撤回。该项目的一部分旨在试图确定哪些基因参与酒精戒断反应。重要的是，在各种酒精研究中发现的许多基因也存在于秀丽隐杆线虫中。出于这个原因，我们可以利用这项研究来了解酒精在人类行为中控制和导致功能障碍的方式。

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can become dominated by a need to maintain a supply and avoid unpleasant symptoms that are experienced when alcohol is withdrawn.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.