Stanford researchers have discovered why our mental maps fade with age, identifying genetic markers that may explain why some people age more gracefully. Their findings could pave the way for new treatments for dementia and cognitive decline.
One of the first cognitive abilities to decline with age is our spatial memory, the mental map that helps us remember where we left our keys or parked our car. Scientists at Stanford Medicine, in collaboration with the University of California, San Francisco, have discovered new insights into why this happens, comparing brain activity across young, middle-aged and elderly mice in their latest study.
Published on Oct. 3 in Nature Communications, the study finds that the medial entorhinal cortex — often dubbed the brain’s GPS — becomes less stable and less attuned in older mice.
These changes correlate with impaired spatial memory, a discovery that could have significant implications for understanding aging and dementia.
“You can think of the medial entorhinal cortex as containing all the components you need to build a map of space,” senior author Lisa Giocomo, a professor of neurobiology at Stanford, said in a news release. “Before this study, there was extremely limited work on what actually happens to this spatial mapping system during healthy aging.”
A Challenging Task
To conduct their research, the scientists employed a fascinating experimental setup.
Mice of varying ages — young (3 months old), middle-aged (13 months old) and old (22 months old), which roughly correspond to 20, 50 and 90 human years — ran on stationary balls within a virtual reality environment, searching for hidden rewards.
Over multiple days of repetition, all age groups learned to locate these rewards.
However, when the task was modified to randomly alternate between two different tracks, each with distinct reward locations, older mice struggled significantly more than their younger counterparts.
“In this case, the task was more similar to remembering where you parked your car in two different parking lots or where your favorite coffeeshop is in two different cities,” Giocomo added.
Young and middle-aged mice adjusted quickly to the alternation, but the older mice showed confusion, reflected in erratic brain activity captured through grid cell firing patterns in their medial entorhinal cortices.
Hope From an Unexpected Source
Interestingly, there were variations even among the older mice.
One elderly male mouse, in particular, excelled at the spatial tasks, performing as well as, if not better than, younger mice.
This “super-ager” mouse revealed important insights into the genetic and neural mechanisms that might protect against cognitive decline.
“It was the very last mouse I recorded and, honestly, when I was watching it run the experiment, I thought, ‘Oh no, this mouse is going to screw up the statistics,’” added lead author Charlotte Herber, a medical-doctoral student at Stanford.
The researchers discovered 61 genes with higher expression levels in mice with unstable grid cell activity.
One, Haplin4, contributes to the network of proteins surrounding neurons and might help maintain grid cell stability.
Bridging to Human Health
The findings have crucial implications for human health, especially for understanding diseases like Alzheimer’s and other forms of dementia.
“Just like mice, people also exhibit a variable extent of aging,” Herber added. “Understanding some of that variability — why some people are more resilient to aging and others are more vulnerable — is part of the goal of this work.”
Source: Stanford Medicine