Simulation of learning: models and biological validation

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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.