Optical activation of a C. elegans neural circuit underpinning feeding behaviour

支撑摄食行为的线虫神经回路的光学激活

• 批准号: BB/F009208/1
• 负责人: Lindy Holden-Dye
• 金额: $ 54.62万
• 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%2FF009208%2F1
• 关键词: Optical; activation; C.; elegans; neural

Communication between neurones is a fundamental aspect of brain function. This is mediated by chemical neurotransmitters that signal from one nerve cell to the next at specific sites on the nerve cell called synapses. There are trillions of these synapses in the human brain and their correct function is essential for good mental health. Dysfunction in this synaptic communication is the basis for the majority of psychiatric and neurodegenerative disorders including depression, anxiety, schizophrenia, Parkinson's disease, Alzheimer's disease and many other prevalent and distressing conditions. Indeed, many of the drugs used to treat these disorders act to improve synaptic communication to ameliorate the symptoms of the disease. However in many cases these drugs are fairly 'blunt instruments'. A major problem is that chemical neurotransmission is complex and also very plastic. There is still a relatively superficial understanding of its subtleties. Specifically, any given synapse will store a multitude of neurotransmitters which can be released in different proportions depending on the activity of the nerve cell giving rise to a synaptic 'cocktail'. Different 'cocktails' have different consequences for signalling at the synapse. It is clear that the ability of the synapse to 'mix a cocktail' and alter its signalling properties is related to the ability of the neuronal circuits, and ultimately the brain, to alter its output and change behaviour. Therefore a fundamental goal of neuroscience is to understand the role of distinct classes of neurotransmitters within neuronal circuits and how altered signalling leads to a change in behaviour. This is a complex problem and many neuroscientists, including ourselves, have chosen to work on simple invertebrate nervous systems to address it. The advantage of the model that we have chosen, the nematode worm C. elegans, is that although it has a very simple nervous system with only 5000 synapses rather than trillions, it has the same complex mechanism for signalling between nerve cells as humans. Furthermore, the animal exhibits simple behaviours and will adapt in an appropriate way according to its environment. This indicates that it has the capacity to re-configure its neural circuits in much the same way as higher animals. The attraction of this as a model system is that it is easy to study a specific problem from the level of the gene through to the molecule, neurone, circuit and the intact behaving animal. The behaviour we are investigating is the response of the animal to food deprivation. Here we are taking advantage of a new technical advance that will enable us to activate specific elements of the neuronal circuit that regulates this adaptive response and record synaptic signalling. By performing this analysis in different genetic mutants we will be able to define the properties of the signal in a circuit and describe changes in the signal that parallel the change in the behaviour of the animal. This will provide a unique insight in to the fundamental problem of how altered synaptic signalling leads to a change in behaviour and pave the way for further genetic analysis of this problem.

神经元之间的通信是大脑功能的一个基本方面。这是由化学神经递质介导的，化学神经递质在神经细胞上称为突触的特定位置从一个神经细胞向下一个神经细胞发出信号。人脑中有数万亿个突触，它们的正确功能对于良好的心理健康至关重要。这种突触通讯功能障碍是大多数精神疾病和神经退行性疾病的基础，包括抑郁症、焦虑症、精神分裂症、帕金森病、阿尔茨海默病和许多其他流行且令人痛苦的疾病。事实上，许多用于治疗这些疾病的药物可以改善突触通讯，从而改善疾病的症状。然而，在许多情况下，这些药物是相当“钝的工具”。一个主要问题是化学神经传递非常复杂，而且可塑性很强。对其精妙之处还存在比较粗浅的认识。具体来说，任何给定的突触都会储存大量的神经递质，这些神经递质可以根据神经细胞的活动以不同的比例释放，从而产生突触“鸡尾酒”。不同的“鸡尾酒”对突触信号传导有不同的影响。很明显，突触“混合鸡尾酒”并改变其信号传导特性的能力与神经元回路以及最终大脑改变其输出和改变行为的能力有关。因此，神经科学的一个基本目标是了解不同类别的神经递质在神经元回路中的作用，以及信号传导的改变如何导致行为的改变。这是一个复杂的问题，许多神经科学家，包括我们自己，都选择研究简单的无脊椎动物神经系统来解决这个问题。我们选择的模型（线虫秀丽隐杆线虫）的优势在于，虽然它的神经系统非常简单，只有 5000 个突触而不是数万亿个，但它与人类一样具有神经细胞之间信号传递的复杂机制。此外，动物表现出简单的行为，并会根据环境以适当的方式适应。这表明它有能力以与高等动物大致相同的方式重新配置其神经回路。作为模型系统的吸引力在于，可以很容易地研究从基因水平到分子、神经元、电路和完整行为动物的特定问题。我们正在研究的行为是动物对食物匮乏的反应。在这里，我们利用一项新技术进步，使我们能够激活调节这种适应性反应并记录突触信号的神经元回路的特定元件。通过在不同的基因突变体中进行这种分析，我们将能够定义电路中信号的特性，并描述与动物行为变化平行的信号变化。这将为了解突触信号传导改变如何导致行为改变这一基本问题提供独特的见解，并为该问题的进一步遗传分析铺平道路。