Summary: Spatial memory — the brain’s ability to remember “where” — is among the earliest cognitive skills to decline with age and a characteristic sign of dementia. New research shows that in older mice, grid cells in the medial entorhinal cortex — the brain’s internal GPS — become less stable and less precise, reducing the animals’ ability to distinguish between similar environments.
While many aged mice showed impaired spatial mapping and confusion when contexts changed, a subset of older animals maintained sharp spatial maps and accurate navigation, suggesting biological factors that promote resilience against age-related decline.
Key Facts:
- Grid cell instability: Aging diminishes the reliability of navigation cells in the medial entorhinal cortex, undermining spatial memory.
- Super-agers observed: Some older mice preserve youthful memory performance and precise neural activity.
- Genetic signals: Researchers identified 61 genes whose expression correlates with stable or unstable spatial coding during aging.
Source: Stanford
Remembering locations—where you left an item, where you ate, or where you first met someone—is central to daily life. Spatial memory, which encodes those locations, is among the first cognitive domains to weaken with age and can be an early indicator of dementia. Scientists at Stanford Medicine and collaborators set out to determine what changes in the aging brain cause spatial memory to fail and whether some brains are protected from that decline.
The study compared young, middle-aged and old mice and found that activity in the medial entorhinal cortex (MEC) — often described as the brain’s GPS — becomes less stable and less tuned to environmental cues in older animals. Those mice with the most disrupted MEC activity performed worst on spatial memory tests.
“You can think of the medial entorhinal cortex as containing all the components you need to build a map of space,” said Lisa Giocomo, PhD, professor of neurobiology and senior author of the study, published in Nature Communications. Prior work offered little detail on how this spatial mapping system changes during healthy aging; this study fills an important gap.
Although the average performance of older mice lagged behind younger groups, individual variability among aged animals was striking. That variation suggests that decline in spatial memory is not inevitable and that some animals resist aging-related changes.
Mental maps
The MEC is critical for navigation and contains several cell types that encode speed, head direction, boundaries, and the geometry of space. Grid cells, a focal point of this study, form repeating firing patterns that serve as a coordinate system for laying out an internal map of the environment—roughly analogous to latitude and longitude.
Researchers tested three age groups of mice: young (around 3 months), middle-aged (around 13 months), and old (around 22 months), approximating human ages of roughly 20, 50, and 75–90 years, respectively. While the mice searched for small water rewards, their brain activity was recorded as they ran along virtual reality tracks on a stationary ball surrounded by screens that displayed the environment.
All mice ran the tracks many times over six days. Given repetition, animals across ages learned the reward locations on a single track and developed distinct grid-cell firing patterns that matched each track, effectively building unique mental maps for those contexts.
Switching tracks
When the task became more demanding—mice were randomly switched between two previously learned tracks, each with its own reward location—older mice struggled. They often could not identify which track they were on and therefore failed to search at the correct reward sites.
“This task is similar to remembering where you parked in two different lots or where a favorite café is in two different cities,” Giocomo explained. Instead of pausing to search for rewards, many aged mice would run straight through, while others licked indiscriminately along the track.
Grid-cell recordings mirrored that behavior: although aged animals had formed distinct firing patterns for each track during training, those patterns degraded or became erratic when the tracks were alternated, reflecting impaired rapid discrimination between contexts.
By contrast, young and middle-aged mice reliably matched their grid-cell activity to the current track by day six and quickly recalled the appropriate reward location. Middle-aged animals showed slightly weaker patterns than the youngest group but performed similarly in the task, suggesting that this aspect of spatial cognition remains largely intact through midlife.
Super-ager
Notably, the oldest group displayed the greatest variability in task performance. Male mice tended to outperform females in this cohort, though the cause of this difference remains unclear. One aged male, however, stood out as a “super-ager”: it performed as well as the younger animals, accurately recalling reward locations on alternating tracks.
Its grid cells fired with unusually clear, context-specific patterns, supporting the link between robust MEC activity and superior spatial memory. This single animal helped demonstrate how individual variability in aged populations can reveal correlations between neural function and behavior.
Prompted by the variability among aged mice, the team sequenced RNA from MEC tissue and identified 61 genes whose expression correlated with unstable grid-cell activity. These genes may either contribute to decline or reflect compensatory responses. One example, Hapln4, is involved in the perineuronal net—a set of extracellular matrix proteins that surround neurons and may stabilize circuit function and protect spatial coding with age.
“Understanding why some individuals remain resilient while others are vulnerable to aging is a key goal of this work,” said Charlotte Herber, PhD, lead author and MD-PhD student.
Researchers at the University of California, San Francisco, collaborated on the study.
Funding: The study received support from the Stanford University Medical Scientist Training Program, the National Institute on Aging, the NIH BRAIN Initiative (grant U19NS118284), the National Institute of Mental Health (grants MH126904 and MH130452), the National Institute on Drug Abuse (grant DA042012), the Vallee Foundation and the James S. McDonnell Foundation.
Key Questions Answered:
A: The medial entorhinal cortex (MEC), often called the brain’s GPS, builds internal maps that support navigation and spatial memory.
A: In older mice, grid cells in the MEC fire less reliably and form unstable spatial maps, which leads to confusion when alternating or learning new environments.
A: Not necessarily. Some aged mice, described as “super-agers,” retained strong grid-cell activity and navigational performance similar to younger animals.
About this aging and cognition research news
Author: Lisa Kim
Source: Stanford
Contact: Lisa Kim – Stanford
Image: The image is credited to Neuroscience News
Original Research: Open access. “Spatial coding dysfunction and network instability in the aging medial entorhinal cortex” by Lisa Giocomo et al., Nature Communications
Abstract
Spatial coding dysfunction and network instability in the aging medial entorhinal cortex
Spatial memory commonly declines with age across species, potentially reflecting altered function in the hippocampus and medial entorhinal cortex (MEC). Yet the state of cellular and network-level spatial coding in aged MEC was not well defined.
Using in vivo electrophysiology, the authors evaluated MEC function in young, middle-aged, and aged mice navigating virtual environments. Aged grid cells showed impaired stabilization of context-specific spatial firing, and this impairment correlated with spatial memory deficits.
Aged grid-cell networks also shifted firing patterns frequently but did not reliably align those shifts with context changes. Spatial firing in aged animals was unstable even in a constant environment. Transcriptomic analysis revealed 458 genes differentially expressed with age in MEC, 61 of which correlated with spatial coding quality; these genes were enriched in interneuron-related and synaptic plasticity pathways, including components of the perineuronal net.
Together, these coordinated transcriptomic, cellular, and network-level changes in MEC are implicated in impaired spatial memory during aging.