Simulation of learning: models and biological validation

描述(申请人提供)：海马体结构对各种形式的信息的长期存储至关重要，人们普遍认为突触传递的长时程增强(LTP)现象是参与记忆形成的分子/细胞机制。我们对LTP的理解的进步导致了多个过程的发现，这些过程以复杂的方式相互作用，这对记忆形成的不同步骤至关重要。尽管已经开发了几个高水平的海马体功能模型，但它们没有包含了解单个分子事件对海马体整体网络功能的贡献所需的详细分子信息。因此，我们的目标是开发基于对现实生物网络中发生的分子过程的数学建模和计算机模拟的新技术工具，以达到这样的理解。我们相信，这种方法不仅可以深入了解特定分子事件对整体网络功能和突触可塑性的贡献，而且有助于设计更好、更安全的学习和记忆障碍治疗方法。南加州大学的科学家们进行了长期的合作，以了解LTP的分子和细胞机制，并开发模型将基础研究转化为现实应用。在与Rhenovia Pharma的合作中，我们已经启动了一个集成平台的开发，该平台结合了海马区CA1的一些元素。南加州大学和Rhenovia的两个研究团队提议的生物工程研究伙伴关系将进一步开发这一平台，通过在海马片上进行体外实验来验证模拟的结果，并测试使用该平台识别可能导致LTP诱导的分子或分子组合的可能性。特别是，我们建议结合胆碱能对CA1网络功能的调节，以便更好地了解神经元放电的theta节律同步与LTP形成之间的联系，以及各种代谢型谷氨酸受体，以探索这些受体在突触传递和突触可塑性过程中的作用。最后，整合各种GABA受体将提供一个独特的工具，以更好地了解目前用于治疗从癫痫到阿尔茨海默病的各种疾病的大量药物的效果。公共卫生相关性：学习和记忆障碍是许多神经和神经精神疾病的重要方面。鉴于记忆形成机制的复杂性，寻找新的认知障碍药物治疗既紧迫又困难。拟议的工作旨在开发生物信息学工具，通过更好地了解参与记忆形成的分子和细胞事件，以及测试改善记忆形成的药物或药物组合的有效性，来促进这一过程。

DESCRIPTION (provided by applicant): The hippocampal formation is critically involved for the long-term storage of various forms of information, and it is widely believed that the phenomenon of long-term potentiation (LTP) of synaptic transmission is a molecular/cellular mechanism participating in memory formation. Progress in our understanding of LTP has led to the discovery of multiple processes interacting in complex ways that are critically important for different steps of memory formation. Although several high level models of hippocampal function have been developed, they do not incorporate detailed molecular information of the type necessary to understand the contribution of individual molecular events to the overall network function of the hippocampus. It is therefore our goals to develop new technological tools based on mathematical modeling and computer simulation of the molecular processes taking place in realistic biological networks to reach such an understanding. We believe that this approach will not only provide an intimate understanding of the contribution of specific molecular events to overall network function and synaptic plasticity, but also facilitate the design of better and safer therapeutic approaches for learning and memory impairments. Scientists at the University of Southern California have had a long- standing collaboration to understand the molecular and cellular mechanisms of LTP and to develop models to translate basic research into real-life applications. In collaboration with Rhenovia Pharma, we have initiated the development of an integrated platform that incorporates some of the elements of field CA1 of hippocampus. The proposed bioengineering research partnership between 2 research teams at the University of Southern California and Rhenovia will further develop this platform, validate the outputs of the simulation by in vitro experimentation in hippocampal slices and test the possible use of the platform to identify molecules or combination of molecules that could result in facilitation of LTP induction. In particular, we propose to incorporate cholinergic modulation of CA1 network function in order to better understand the links between theta rhythm synchronization of neuronal firing and LTP formation, as well as various types of metabotropic glutamate receptors in order to explore the roles of these receptors in synaptic transmission and synaptic plasticity processes. Finally, integrating various GABA receptors will provide a unique tool to better understand the effects of a large number of drugs currently used to treat a wide range of diseases from epilepsy to Alzheimer's disease PUBLIC HEALTH RELEVANCE: Learning and memory impairments are important aspects of numerous neurological and neuropsychiatric diseases. Identifying new pharmacological treatments for cognitive impairment is both urgent and difficult in view of the complexity of the mechanisms involved in memory formation. The proposed work is directed at developing bioinformatics tools to facilitate this process by providing a better understanding of the molecular and cellular events participating in memory formation as well as a platform for testing the efficacy of drugs or combination of drugs for improving memory formation.