Why the brain’s GPS fails with age, and how some minds are challenging it

Now, researchers at Stanford Medicine and their colleagues are discovering what goes awry in the brains of older people when spatial memory falters and whether these changes can be prevented.

In a new study comparing young, middle-aged and elderly mice, researchers found that activity in the entorhinal cortex — which sometimes resembles the brain’s global positioning system — becomes less stable and less attuned to the environment in older animals. Those with poor activity in this brain area were the most confused on a spatial memory test.

“You can think of the medial entorhinal cortex as having all the components you need to build a map of space,” said Lisa Giocomo, PhD, professor of neurobiology and senior author of the study to be published on October 3. Nature Communications.

“Before this study, there was very limited work on what actually happens to this spatial mapping system during healthy aging.”

Although the elderly mice were, on average, significantly worse than their younger counterparts at navigating their environments, there was wide variation among them — a sign that spatial memory decline may not be an inevitable part of aging.

Mind maps

The medial entorhinal cortex is an essential part of the brain’s navigation system. It contains a variety of cells that track various information, including the animal’s speed and head direction, as well as the dimensions and boundaries of space. In the new study, the researchers focused on so-called grid cells, which create a map of the environment, almost like a system of latitude and longitude.

They studied mice in three age groups: young mice about 3 months old, middle-aged mice about 13 months old, and large mice about 22 months old. These ages roughly relate to people between 20 and 50 years old and 75 to 90 years old.

Researchers recorded the brain activity of slightly thirsty mice as they ran virtual reality tracks in search of hidden rewards – a lick of water. They ran on a fixed ball surrounded by screens displaying the virtual environment, like a mouse-sized treadmill in a mouse-sized IMAX theater.

Each mouse played the tracks hundreds of times over six days. (The researchers note that mice are naturally avid runners.)

With enough repetition, rats of all age groups can learn the location of a hidden reward on a given path. By day six, they only stopped to lick the reward sites. Accordingly, grid cells in the medial entorhinal cortex developed distinct firing patterns for each pathway, as if building custom mental maps.

Switch tracks

But in a more challenging task, where the mice were randomly switched between two different paths they had already learned, each with a different reward location, the elderly mice were stymied—seemingly unable to decide which path it was on.

“In this case, the task was like remembering where you parked your car in two different parking lots or where your favorite coffee shop was in two different cities,” Giocomo said.

Unsure of where they were, the elderly mice tended to sprint down the rest of the track without bothering to stop and look for treats. Some took a different tactic and tried licking everywhere.

Their grid cells reflected their confusion. Although developing distinct firing patterns for each pathway, their retinal cells fired intermittently when the pathways were switched.

“Their spatial recall and rapid discrimination of these two environments was really poor,” said Charlotte Herber, MD, PhD student and lead author of the study.

The results appear to be consistent with human behavior. “Older adults can often navigate familiar places, like their home or the neighborhood they’ve always lived in, but it’s really hard for them to learn to navigate a new place, even with experience,” Giocomo said.

In contrast, the young and middle-aged mice understood the task by day 6, and their retinal cell activity quickly matched whichever path they were on.

“Over the course of days one to six, they had progressively more stable spatial firing patterns that were context A-specific and context B-specific,” Herber said. “Aged mice fail to develop these separate spatial maps.”

The middle-aged mice had somewhat weaker patterns of brain activity, but their performance was very similar to the young mice. “We think this is an intact cognitive ability at least until about 13 months of age in the mouse, or perhaps 50 to 60 years of age in the human counterpart,” Herber said.

Super brick

Although the performance of young and middle-aged mice was uniform across their age groups, the older group showed greater variation in spatial memory.

Male mice generally performed better than female mice, although researchers don’t yet know why.

One elderly male rat stood out, succeeding in the test, remembering the locations of hidden rewards on alternating paths just as well as young and middle-aged rats, if not better.

“This was the last mouse I recorded, and honestly, when I was watching him run the experiment, I thought: ‘Oh no, this mouse is going to mess up the statistics,'” Herber said.

Instead, the ultramodern mouse was shown to confirm the relationship between grid cell activity and spatial memory. His retinal cells were as unusually active as his behavior, firing clearly and accurately in every environment.

“The variation in age allowed us to establish these correlations between neural function and behavior,” Herber said.

The aging mouse also encouraged researchers to look for genetic differences that might underlie variation in aging. They sequenced the RNA of young and old mice and found 61 genes that were more expressed in mice with unstable reticulocyte activity. The researchers said that these genes could be involved in driving or compensating for decreased spatial memory.

For example, the Haplin4 gene contributes to the network of proteins that surround nerve cells, known as the perineuronal network, which can help support grid cell stability and protect spatial memory in aging mice.

“Just like mice, people also show varying extents of aging,” Herber said. “Understanding some of this variation — why some people are more resilient to aging and others are more vulnerable — is part of the goal of this work.”

Researchers from the University of California, San Francisco, contributed to this study.

The study received funding from the Stanford University Clinical 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 Valley Foundation and the James S. McDonnell.