Simulation of learning: models and biological validation

模拟学习：模型和生物验证

• 批准号: 7763199
• 负责人: MICHEL BAUDRY
• 金额: $ 57.32万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-02 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7763199
• 关键词: Alzheimer' s Disease; Apical; Back; Basic Science; Bioinformatics; Biological; Biological Models; Biomedical Engineering; Brain; Calcium; California; Collaborations; Communication; Complex; Computer Simulation; Development; Disease; Dose; Drug Combinations; Elements; Environment; Epilepsy; Event; Frequencies; GABA Receptor; Glutamates; Glycine; Goals; Head; Hippocampal Formation; Hippocampus (Brain); Impaired cognition; In Vitro; Individual; Information Storage; Interneurons; Learning; Life; Link; Long-Term Potentiation; Memory; Memory impairment; Metabotropic Glutamate Receptors; Modeling; Modification; Molecular; Molecular Models; N-Methyl-D-Aspartate Receptors; Names; Nervous system structure; Neurologic; Neurons; Occupations; Output; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Physiologic pulse; Potassium Channel; Principal Investigator; Process; Property; Pyramidal Cells; Research; Role; Scientist; Second Messenger Systems; Site; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Therapeutic; Theta Rhythm; Training; Translating; Universities; Validation; Vertebral column; Work; base; cholinergic; cognitive function; desensitization; design; drug efficacy; efficacy testing; hippocampal pyramidal neuron; improved; inhibitory neuron; mathematical model; models and simulation; molecular modeling; network models; neuropsychiatry; new technology; postsynaptic; programs; public health relevance; receptor; reconstruction; research study; response; second messenger; simulation; tool

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.

描述（由申请人提供）：海马结构对于各种形式的信息的长期储存至关重要，并且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。 随着我们对LTP理解的不断深入，我们发现了多个过程以复杂的方式相互作用，这些过程对记忆形成的不同步骤至关重要。 虽然已经开发了几种高水平的海马功能模型，但它们并没有包含了解单个分子事件对海马整体网络功能的贡献所需的详细分子信息。 因此，我们的目标是开发新的技术工具的基础上发生在现实的生物网络中的分子过程的数学建模和计算机模拟，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，而且还有助于设计更好，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长期以来一直在合作，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生活中的应用。 与Rhenovia Pharma合作，我们已经开始开发一个集成平台，该平台包含海马CA 1区的一些元素。 南加州大学和Rhenovia大学的两个研究小组之间拟议的生物工程研究伙伴关系将进一步开发该平台，通过海马切片的体外实验验证模拟的输出，并测试该平台的可能用途，以识别可能导致促进LTP诱导的分子或分子组合。 特别是，我们建议将胆碱能调制CA 1网络功能，以更好地了解θ节律同步神经元放电和LTP形成之间的联系，以及各种类型的代谢型谷氨酸受体，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广泛疾病的大量药物的作用。 鉴于记忆形成机制的复杂性，确定新的认知障碍药物治疗方法既紧迫又困难。 拟议的工作是针对开发生物信息学工具，以促进这一过程，通过提供参与记忆形成的分子和细胞事件的更好的理解，以及用于测试药物或药物组合改善记忆形成的疗效的平台。