The role of dentate gyrus mossy cells in coordinating episodic memory formation and retrieval

项目总结

PROJECT SUMMARY In order to accurately store and retrieve memories, information about novel or salient experiences must be flexibly integrated into existing memory networks while maintaining the stability of previously stored memories. To accomplish these goals within the same circuit, the hippocampus must encode novel experiences and retrieve neural representations of familiar ones in parallel. Disruption of this balance between encoding and retrieval may underlie memory deficits observed in numerous neurological disorders that affect the hippocampus. The dentate gyrus (DG) and CA3 subfields of the hippocampus are often considered to be essential for memory encoding and retrieval, respectively. Encoding and retrieval in these regions rely on two complementary computational processes, pattern separation and pattern completion. Pattern completion in CA3 allows for a full memory to be retrieved despite incomplete inputs, while pattern separation in the DG prevents interference between similar memories during encoding. Mossy cells, a relatively understudied DG cell type, occupy a key node in the DG/CA3 circuit and mediate communication between these areas. Mossy cells, which receive extensive neuromodulatory inputs, may regulate DG/CA3 activity to enhance encoding of novel experiences and retrieval of familiar experiences. The central hypothesis of this proposal is that mossy cells promote encoding of novel environments by regulating the activity and neural computations of the DG/CA3 circuit. Technical limitations have prevented extensive study of mossy cells in vivo, and it is unknown how exploration of novel environments affects DG/CA3 circuit dynamics. I will perform two-photon calcium imaging in the dorsal hippocampus of mice as they explore novel and familiar virtual tracks to evaluate the role of mossy cells in encoding novel environments and regulating DG and CA3 activity. In aim 1, I will directly record activity from mossy cells to determine how their spatial activity differs in novel and familiar virtual environments. In aim 2, I will examine how mossy cells regulate communication between the DG and CA3 by recording granule cell and CA3 pyramidal cell population dynamics while optogenetically inhibiting mossy cell activity. Finally, in aim 3, I will generate a computational model of a combined DG/CA3 circuit to directly examine how pattern separation and pattern completion within this circuit are regulated by mossy cells. Understanding the neural basis of memory encoding and retrieval is an instrumental step toward lessening the burden of memory impairments observed in numerous cognitive disorders. The results of this proposal will provide fundamental insights into the role of mossy cells in regulating these essential memory processes.