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

人类饮酒(乙醇)在许多社会中的地位由来已久，尽管其严重的负面影响有时可能超过其积极影响。尽管酒精的化学结构非常简单，但它是一种药物，它对人类的行为具有深远的直接影响，从放松和失去社交抑制，到说话含糊和步态不稳，再到意识丧失和死亡。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不同，这突显了一个事实，即一个人的遗传背景和他们以前的酒精经验都对酒精的体验起到了重要作用。最后，人们经常注意到，一个人的第一杯酒味道不好，但持续饮酒有时会导致对酒精的喜爱，这在极端情况下可能会导致依赖的形成。一旦建立了依赖，一个人的生活可能会被维持供应和避免戒酒时出现的令人不快的症状所支配。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细胞(包括大脑的一部分)相互作用，导致细胞变得更兴奋或更受抑制。实际上，酒精具有像万能钥匙一样打开(兴奋)或关闭(抑制)神经细胞的能力。当酒精以这些方式发挥作用时，它是通过特殊类型的化学结构来实现的，这种结构称为蛋白质，存在于细胞中，根据个人过去的经验和遗传结构而有所不同。这意味着乙醇对不同的人和同一人在不同的时间会有非常不同的影响。然而，要弄清楚酒精对高等动物的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着数百万神经细胞的总和。这种复杂性意味着，在一个简单得多的大脑中，找到简单的方法来研究乙醇对神经的影响是很重要的。在我们的方案中，我们想要使用一个只由20个神经组成的模型大脑，在这个模型中，我们可以顺序地移除乙醇作用于改变神经功能的各种蛋白质。这是通过使用简单线虫的一小部分大脑来完成的。这个简化的大脑模型可以用来梳理神经细胞如何因遗传因素和酒精暴露而发生微妙的变化。重要的是，这种蠕虫还表现出了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在人类酒精依赖中至关重要的行为。例如，就像持续饮酒会导致戒酒时人类行为的变化一样，我们也观察到了戒酒时线虫行为的变化。该项目的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线虫中。因此，我们可以利用这项研究来了解酒精对人类行为的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can become dominated by a need to maintain a supply and avoid unpleasant symptoms that are experienced when alcohol is withdrawn.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.