Understanding how the brain changes with experience is a fundamental question in neuroscience. Memory systems are supported by multiple circuits that connect the neuronal ensembles that contain bits of information from particular learned experiences. We propose to investigate how synapses within the hippocampus circuit are changed by the persistent storage of a spatial memory. Our goal is to define the organization of memory traces at the level of synaptic circuits as part of a comprehensive research program to understand the processes and mechanisms of cognition, the malfunction of which may underlie cognitive disorders. We characterized the functional changes of hippocampal (CA3) and entorhinal cortical (EC layer III) synaptic inputs to CA1 neurons in mice that learned an active place avoidance task, a spatial learning task that depends on synaptic plasticity and its persistence in the dorsal hippocampus. Importantly, changes in hippocampal synaptic function persisted for at least 1 month after training and were observed only in animals in which the place avoidance memory also persisted. Changes in synaptic function did not occur in animals that were exposed to the behavioral arena (untrained control) or received delivery of unavoidable shocks (yoked control). Thus the changes in synaptic function were a consequence of the learning experience and were associated with the spatial memory itself. Interestingly, our observations indicated that these changes are rather large, probably reflecting an impact of learning experience on synaptic circuits beyond the few synapses that are inferred to store the specific bits of explicit information. This is a novel perspective; it seems that storing memory in a neural circuit involves broad changes in synaptic circuit function that may act as a supporting framework for the expression of the explicit information. We propose to use this robust experimental paradigm to further study how the storing of memories changes synaptic function within the hippocampal circuit. We seek to determine whether the persistent synaptic changes are localized to the subset of neurons that were active during the learning experience (Specific Aim 1) and to determine whether these changes parallel changes in the expression of mRNAs and proteins of known synaptic plasticity products (Specific Aim 2). Using this approach, we will direct our efforts to provide an analysis of how particular learned experiences persistently modify CA1 neurons at the level of CA3- CA1 and EC-CA1 synaptic inputs to gain insight toward the identification and organization of memory traces within synaptic circuits of the hippocampus. We hope to expand our understanding of how neural ensembles support memory at the systems level by investigating how learned information modulates the synaptic circuits that underlie the ensemble activity. As such, this scientific effort is expected to bridge the scales of the synaptome and the connectome.
The human hippocampus is a key brain area for the processing of spatial, episodic (autobiographical) and semantic (factual) memory - failures of hippocampal function are implicated in various cognitive disorders. Our proposed research is aimed at understanding a fundamental function of the hippocampus of laboratory mice, namely, how a spatial memory is encoded within hippocampal circuits. The goal is enhancing the knowledge of the processes and mechanisms whose malfunction underlie increasingly common cognitive disorders.
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