Research Project
10297282
ABSTRACT Declines in spatial cognition and function of brain circuits responsible for these behaviors are among the hallmark signs of normative biological aging across species. The objective of this research program is to understand the basis of these age-related memory impairments. Rodent and nonhuman primate models can each provide a unique window into understanding how age impacts networks critical for cognition, at cellular resolution. These data can then be used to inform experiments conducted in humans to validate our predictions. The experiments proposed in the present application are guided by three primary aims. Aim 1 is to understand how brain circuits responsible for spatial cognition are altered in the aged rat. Two approaches are taken in this Aim to answer these questions. A novel spatial task is employed (the Instantaneous Cue Rotation task) that enables precise measurement of spatial behavior accuracy and representation updating in the rat. Additionally, simultaneous, dual-structure recordings from hippocampus and upstream entorhinal cortex will be conducted to identify age-related changes within the hippocampus proper that are driven by entorhinal cortical inputs, as well as changes in the entorhinal cortex driven by degraded hippocampal feedback signals. Aim 2 is to understand how hippocampal representations are altered in aged freely behaving nonhuman primates. Recent advances in wireless recording technologies enable new experimental designs for primates that can test directly the widely held assumption that circuit instability (?remapping?) in the aging rat will find an analogue in the aging primate brain. Free locomotion is a missing link between the behavioral conditions employed to study place cells in rodents, and head restrained, chaired conditions under which most studies are conducted in primates. Our hypotheses are that old monkeys will show faulty retrieval of hippocampal network patterns (similar to map retrieval failures in old rats) and that the global network activity state will be altered in both age groups when the animals are restrained, compared to when completely unrestrained and free to move. Aim 3 is to understand the neural underpinnings of navigation deficits in aged humans. High-resolution imaging will be employed to explore age-related alterations in both hippocampal subfield-selective ensemble codes as well as entorhinal cortex grid-like activity that may underlie navigation impairments. Highly immersive spatial environments that include locomotion will also be used to investigate the impact of age (young versus older adults) on the ability to maintain stable spatial representations during free exploration. Changes in representation stability in older adults would be consistent with inappropriate map retrieval observed in old rats. Taking advantage of new behavior and recording approaches in rodents and monkeys and novel high-resolution fMRI and virtual reality methods in humans, we believe significant advances will be made in our understanding of how circuits critical for spatial cognition are altered across age and species.
