This project will study of memory formation at three levels - behavioral, network, and cellular, with a specific focus on the evaluation of the transformation of event-specific (episodic) memory to context-independent (semantic) memory. A basic working hypothesis in the study of memory consolidation is that the process of establishing longer-term memory in the neocortex involves a transformation of event-specific information that is maintained within the hippocampus, into more generalized, context-independent forms. We will be specifically studying cross-contextual generalization in entorhinal cortical representations, evaluating both the structure of these representations and their dynamics as a function of time, pattern of behavioral exposure (training), behavioral performance, and neural activity and memory reactivation during offline states such as sleep. The study of memory representations at the network level using behavioral electrophysiological techniques will be complemented by the study of cellular and network mechanisms for regulating plasticity and function using molecular genetic manipulations. In particular, collaborative efforts with the Tonegawa laboratory using EC and DG specific knockouts will be carried out to study the contributions of activity and plasticity within these regions to the formation of specific and generalized memory representations. A hypothesis [regarding the essential involvement of specific properties of synaptic plasticity, such as the timing and/or coincidence detection abilities of NMDAR-dependent synaptic modification, in the formation of hippocampal memory traces will be examined through collaboration with the Heinemann, Sheng laboratories and the study of GluR2 mutants. Together these approaches will provide insight into the mechanisms of memory consolidation and the functional role of brain systems that are affected by neurological disorders of memory such as schizophrenia and Alzheimer' s disease.
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