A Systems Biological Approach to Elucidate Local Protein Synthesis Code in Plasticity and Memory

影响神经系统的疾病，如阿尔茨海默氏症、帕金森氏症、抑郁症和精神分裂症，是英国医疗保健系统最大的单一成本，通常与长期残疾和患者及其家人的痛苦有关。这些疾病和其他疾病的一个共同临床特征是认知（通常是学习/记忆）缺陷。然而，学习和记忆是一个非常复杂的生物过程，我们对它只了解了一部分。我们特别感兴趣的是在学习后（即在记忆建立期间）突触中发生的变化——突触是连接两个神经元并在所有大脑中调节信息流动和处理的关键结构。在这项研究中，我们的目标是确定与形成记忆相关的生化变化（在蛋白质水平上）。特别是，我们的目标是测试几个候选分子的参与，这些分子已被牵连，但其重要性尚未得到证实。这项工作还将使我们能够尝试弥合我们在生物化学水平上所看到的分子与它们在大脑（以及随后的动物）实际行为中的丰富程度之间的差距。观察到的生化变化将用于完善和扩展神经元突触的计算模型。这些计算模型将提供一种独特的方法来可视化这些涉及1000多种蛋白质的复杂生化网络。然后将应用数学方法，使我们能够预测哪些分子更有可能参与记忆，并选择最佳候选分子在实验室进行测试。这些新的见解将帮助我们理解记忆是如何在大脑中形成的。首先，解开这些核心生物过程对我们理解动物行为至关重要。从长远来看，我们的研究将与人类认知相关，最终帮助寻找治疗认知疾病的新药。

Diseases which affect the nervous system such as Alzheimer's, Parkinson's, depression and schizophrenia account for the single largest cost to the healthcare system of the UK and are often associated with long-term disability, and distress for patients and their families. A common clinical feature of many of these and other disorders is a cognitive (often learning/memory) deficit. However learning and memory is a very complex biological process that is only partly understood. Of particular interest to us are the changes that occur after learning (i.e. during memory establishment) in the synapses - the critical structures that join two neurons together and mediate information flow and processing in all brains. In this study we aim to identify the biochemical changes (at the protein level) that are associated with forming memories. In particular, we aim to test the involvement of several candidate molecules that have been implicated but whose importance has not yet been proven. This work will also allow us to try and bridge the gap between what we see at the biochemical level in terms of molecules and their abundance with the actual behaviour of the brain (and subsequently of the animal). The observed biochemical changes will be used to refine and extend computational models of neuronal synapses. These computational models will provide a unique method to visualise these complex biochemical networks which involve more than 1000 proteins. Mathematical methods will then be applied that allow us to predict which molecules are more likely to be involved in the memory and a selection of the best candidates will be tested in the laboratory. These new insights will help us understand how memory is formed in the brain. Unravelling these core biological processes is vital to our understanding of animal behaviour in the first instance. In the longer term our research will have relevance to human cognition ultimately aiding the search for new drug therapies for cognitive illness.