Studies in rats by neuroscientists at Johns Hopkins University have pinpointed a mechanism in the brain that is responsible for a common type of age-related memory loss. Their results shed light on mechanisms at work in aging brains, and may improve our understanding of Alzheimer’s disease and similar disorders in humans, potentially helping to develop more effective drug treatments.

“We’re trying to understand normal memory and why a part of the brain called the hippocampus is so critical for normal memory,” said senior author James Knierim, PhD, a professor at the university’s Zanvyl Krieger Mind/Brain Institute. “But also with many memory disorders, something is going wrong with this area.” Knierim and colleagues reported their findings in Current Biology, in a paper titled, “Loss of functional heterogeneity along the CA3 transverse axis in aging.”

Aging increases our susceptibility to memory interference, and computational studies suggest that to minimize this interference, neurons in the hippocampus, which is located deep in the brain’s temporal lobe, carry out two complementary processes. The researchers describe these as “ … pattern separation (the ability to orthogonalize similar input patterns to create less overlapping output patterns) and pattern completion (the ability to retrieve stored output patterns when presented with partial or degraded input patterns).”

In normal brains, pattern separation and pattern completion work hand-in-hand to sort and make sense of perceptions and experiences, from the most basic to the highly complex. If you visit a restaurant with your family and a month later you visit the same restaurant with friends, you should be able to recognize that it was the same restaurant, even though some details have changed—this is pattern completion. But you also need to remember which conversation happened when so you do not confuse the two experiences—this is pattern separation.

These functions are believed to occur in a gradient across a tiny region of the hippocampus called CA3. But when they swing out of balance, memory becomes impaired, causing symptoms like forgetfulness, or repeating oneself. “Converging studies from rodents and humans have demonstrated an age-related decline in pattern separation abilities,” the authors noted.

The authors set out to investigate “how age-related dysfunctions may result from an imbalance of the normal gradient of pattern separation and pattern completion along the CA3 transverse axis.” Their studies discovered that as the brain ages, an imbalance between pattern separation and pattern completion may be caused by the CA3 gradient disappearing; the pattern separation function fades away, and the pattern completion function takes over.

Neurons responsible for pattern separation are typically more prevalent in the proximal region of the CA3 area, while those responsible for pattern completion are prevalent in the distal region, said lead author Heekyung Lee, PhD, an assistant research scientist at the Mind/Brain Institute. With aging, neural activity in the proximal region becomes overactive, and the interplay between the two regions becomes abnormal, creating a dominance in pattern completion.

So, when pattern separation disappears, pattern completion overpowers the process. With your brain focusing on the common experience of the restaurant to the exclusion of the details of the separate visits, you might remember a conversation about a trip to Italy during one visit, but mistake who had been talking. “We all make these mistakes, but they just tend to get worse with aging,” Knierim said.

For their experiments, the researchers compared how well young (Y) rats with unimpaired memories, older (aged) rats with unimpaired memories (AU), and older rats with impaired memories (AI), performed a number of tasks. The results, they noted, “support the hypothesis that age-related bias toward hippocampal pattern completion is due to the loss in AI rats of the normal transition from pattern separation to pattern completion along the CA3 transverse axis.”

The results also showed that while the older rats with unimpaired memories performed water maze tasks as well as young rats, the neurons in the CA3 regions of their hippocampi were already beginning to favor pattern completion at the expense of pattern separation. Since that physiological finding had not shown up in their behavior, the researchers concluded that something was allowing the rats to compensate for the deficit.

That finding is echoed in humans who remain surprisingly sharp into their older years, the researchers said. “Although memory function is vulnerable to aging, a subpopulation of aged animals (including aged humans) is able to retain normal memory function,” they wrote. “Although AU rats did not show statistical difference from AI rats in the present study, they also did not show statistical difference from Y rats, suggesting that AU rats are not as impaired as AI rats … It appears that AU rats may be physiologically on their way to behavioral impairment, but have not yet crossed a threshold.” It’s also possible that there are adaptive compensatory mechanisms at work during aging, which allow the animals to perform well even as changes in their brains are leading to dysfunction, the team suggested.

So, pinpointing the memory loss mechanism could lay the groundwork for learning what prevents memory impairment in some humans, and therefore how to prevent or delay cognitive decline in the elderly. “If we can understand better what these compensatory mechanisms are, then maybe we can help prevent cognitive decline with aging,” Knierim said. “Or, if we can’t stop it, maybe we can enhance other parts of the brain to compensate for the losses that are occurring.”

Other senior authors of the paper were Michela Gallagher, PhD, the Krieger-Eisenhower professor of psychology and neuroscience at Johns Hopkins, and Scott Zeger, PhD, professor of biostatistics at Johns Hopkins’ Bloomberg School of Public Health.

Gallagher’s lab previously demonstrated that the anti-epilepsy drug Levetiracetam improves memory performance by reducing hyperactivity in the hippocampus. “ … treatments to reduce hyperactivity with the antiepileptic drug, levetiracetam, improved memory performance in aged rats and in amnestic mild cognitive impairment patients, suggesting that normalizing CA3 hyperactivity restored the balance between pattern separation and pattern completion,” the investigators wrote in their Current Biology paper.

Lee also speculates that the new, more specific information about how memory impairment occurs might allow scientists to better aim such drugs toward the deficits in the future. “It would give us better control of where we could possibly target the deficits that we see,” she said.

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