ABSTRACTDeclines in spatial cognition and function of brain circuits responsible for these behaviors are amongthe hallmark signs of normative biological aging across species. The objective of this research programis to understand the basis of these age-related memory impairments. Rodent and nonhuman primate modelscan each provide a unique window into understanding how age impacts networks critical for cognition atcellular resolution. These data can then be used to inform experiments conducted in humans to validate ourpredictions. The experiments proposed in the present application are guided by three primary aims. Aim 1 isto understand how brain circuits responsible for spatial cognition are altered in the aged rat. Twoapproaches are taken in this Aim to answer these questions. A novel spatial task is employed (theInstantaneous Cue Rotation task) that enables precise measurement of spatial behavior accuracy andrepresentation updating in the rat. Additionally simultaneous dual-structure recordings from hippocampusand upstream entorhinal cortex will be conducted to identify age-related changes within the hippocampusproper that are driven by entorhinal cortical inputs as well as changes in the entorhinal cortex driven bydegraded hippocampal feedback signals. Aim 2 is to understand how hippocampal representations arealtered in aged freely behaving nonhuman primates. Recent advances in wireless recording technologiesenable new experimental designs for primates that can test directly the widely held assumption that circuitinstability (remapping) in the aging rat will find an analogue in the aging primate brain. Free locomotion is amissing link between the behavioral conditions employed to study place cells in rodents and head restrainedchaired conditions under which most studies are conducted in primates. Our hypotheses are that old monkeyswill show faulty retrieval of hippocampal network patterns (similar to map retrieval failures in old rats) and thatthe global network activity state will be altered in both age groups when the animals are restrained comparedto when completely unrestrained and free to move. Aim 3 is to understand the neural underpinnings ofnavigation deficits in aged humans. High-resolution imaging will be employed to explore age-relatedalterations in both hippocampal subfield-selective ensemble codes as well as entorhinal cortex grid-like activitythat may underlie navigation impairments. Highly immersive spatial environments that include locomotion willalso be used to investigate the impact of age (young versus older adults) on the ability to maintain stablespatial representations during free exploration. Changes in representation stability in older adults would beconsistent with inappropriate map retrieval observed in old rats. Taking advantage of new behavior andrecording approaches in rodents and monkeys and novel high-resolution fMRI and virtual realitymethods in humans we believe significant advances will be made in our understanding of how circuits criticalfor spatial cognition are altered across age and species.