Neurobehavioral Relations in Senescent Hippocampus

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.

Grant Number: 5R01AG003376-40
NIH Institute/Center: NIH
Principal Investigator: CAROL BARNES