Functional Role of Hippocampal Neuronal Representations

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The hippocampus is believed to be necessary for learning sequences and for disambiguation, and computational models predict that different subregions of the hippocampal formation play distinct roles in memory. However, these predictions have not been tested experimentally, and no one has demonstrated a causal relationship between patterns of activity in hippocampus and animal behavior. This project will address both issues in animals performing a delayed non-match to place (DNMP) task in a "T" maze. In Aim 1, we will study the emergence of context-sensitive sequences neural activity in region CA1 of dorsal hippocampus as animals learn the task, and compare activity from the Sample, Delay, and Choice phases of the task in both correct and incorrect trials. Positive results will allow us to develop a stronger tie between electrophysiological and behavioral data. In Aims 2-3, we will extend this approach to region CAS and dorsolateral entorhinal cortex (EC). Computational models predict that CAS neurons should generate queued representations of temporal context, and that separate populations in EC should code for temporal context and and sequences of paths from the current location. In Aim 4, we will test the hypothesis that the period of the theta rhythm can be divided into encoding and retrieval phases. In Aim 5, we will study spatial trends in receptive fields of context-sensitive neurons. In Aim 6, we will test the hypothesis that cells encoding a given temporal context (left-turn vs. right-turn trial) are spatially clustered. In Aim 7, we will stimulate selected hippocampal neurons in an attempt induce "false memories" in the DNMP task. Aim 7 is technically challenging, but if successful, provides direct evidence that manipulation of hippocampal acitivity leads to alterations in episodic-like memory. The long-term goals of the proposed work are to establish a causal relationship between hippocampal activity and behavioral performance in episodic-like tasks, and to understand more completely how memories of relevant episodic experiences are encoded in entorhinal cortex and in regions CA1 and CAS of hippocampus. Such levels of understanding will be of great value in working toward treatments for memory disorders. The value of the planned experiments is not contingent on positive results from the high-risk Aim 7.