Memory circuits in the hippocampus are critical for storing and retrieving information about our life experiences, allowing us to construct accurate representations of the world around us-a basic requirement for normal cognition and behavior. Dysfunction of hippocampal memory circuits can lead to devastating memory impairments, errors of cognition, dementia, and psychosis which are common psychiatric symptoms of schizophrenia, Alzheimer's disease, and other mental disorders. To develop better treatments for these conditions, it is essential to understand the cellular computations that support learning and memory in the hippocampus. Invasive neurophysiological experiments cannot be performed in humans, so much of what is known about cellular memory mechanisms has been learned from animal models, especially rodents. Rodents are very good at learning to navigate through familiar territories, and these abilities depend upon spatial memory circuits within the hippocampal and parahippocampal regions of the brain (as in humans). The rodent hippocampus contains neurons called """"""""place cells"""""""" that fire selectively when the animal visits specific locations, providing a neural substrate for encoding memory representations of familiar spatial environments. However, it is not well understood how incoming signals from outside the hippocampus are processed by place cells to encode spatial memories. Very recently, it has been discovered that the rat entorhinal cortex contains a previously unknown population of neurons called """"""""grid cells."""""""" As a rat navigates through a spatial environment, grid cells fire selectively at multiple locations which form a hexagonal grid pattern that tiles the surface of the environment with remarkable geometric precision. Entorhinal grid cells send dense projections to hippocampal place cells, suggesting that grid cells may provide the elementary building blocks from which the hippocampus constructs spatial memory representations. The research proposed here will combine theoretical modeling studies with neurophysiological recording and lesion experiments in awake rats to investigate how grid cells generate their remarkable hexagonal firing fields, and how these firing fields can serve as a computational basis set for constructing hippocampal memory representations. This interdisciplinary research plan holds immense potential to revolutionize our understanding of cortico-hippocampal interactions, by revealing how the cortex packages incoming sensory information about the world into a form that can be utilized by the hippocampus for constructing coherent memory representations of familiar locations, objects, and events. Knowledge gained from these studies could usher a new era of discovery leading to novel therapies for reducing the burden of cognitive and memory deficits in patients suffering from psychiatric disorders. ? ? ?
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