This proposal is intended to further our understanding of the internal dynamics of hippocampal information processing that may assist in the efficient storage and retrieval of sequence information. Among other things, the hippocampal formation is necessary for certain kinds of memory that have a temporal dimension, such as memory for episodes, serial order of places visited, routes to goals, and associative conditioning that bridges temporal gaps. Several theories suggest that the anatomical and physiological organization of the hippocampus may be particularly well suited to the encoding and storage of sequential relationships among events, and we have obtained evidence for the storage and retrieval of sequences of hippocampal neuronal ensemble activity. A sequence A-B-C can be learned by selectively strengthening synapses from A to B, and so forth; however there are two principal constraints. One is that the neural patterns to be sequentially associated must change rapidly relative to the time-constant of the associative mechanism (e.g., the NMDA receptor). Otherwise the network gets trapped in one state. For example, the sequence A-A-B-B0-C-C might get stuck but A-B0C would not. The other constraint is that, if items of the input sequence are repeated, then sequential (temporal) context information must be encoded or the prediction of the next item becomes ambiguous. Thus, in a sequence A-B-C-B-D, the two Bs must be encoded differently if C and D are to be retrieved correctly. The dynamics of hippocampal neural ensemble representations exhibit two properties that may serve to overcome these constraints. First, when an animal passes through the """"""""place field"""""""" of a given pyramidal ('place') cell, the cell begins firing late in the theta rhythm cycle and the firing phase shifts progressively earlier as the rat runs through the field (a phenomenon known as """"""""phase precession""""""""). This means that a sliding window of the global sequence of place fields is replicated in a compressed form within each cycle, thus making the ensemble codes at the beginning and end of the theta cycle essentially uncorrelated. This could solve the first constraint i.e., rapid change of the code. A better understanding of the origin of the phase precession effect and the dynamics of information flow in relation to it must be reached, however, in order to verify this hypothesis. Second, the hippocampus has the property of being able to create completely different codes for the same spatial location, depending on behavioral and other contextual variables. It may thus also be able to orthogonalize place representations that occur as ambiguous elements of sequences, thereby solving the ambiguous sequence problem; but this needs to be determined. In addition, to understand the role of the hippocampus in both spatial and general episodic memory, it is necessary to achieve a better understanding of the factors that govern the spatial and temporal scales of hippocampal neuronal activity. The experiments described in this proposal address these issues.
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