Brain mechanism linked to age-related memory loss discovered


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Summary: Researchers have identified a mechanism that occurs in the CA3 region of the hippocampus that appears to be responsible for a common type of age-related memory loss.

Source: Johns Hopkins University

Working with rats, neuroscientists at Johns Hopkins University have identified a mechanism in the brain responsible for a common type of age-related memory loss.

The work published today in Current Biologysheds light on how the aging brain works and may advance our understanding of Alzheimer’s disease and related disorders in humans.

“We’re trying to understand normal memory and why a part of the brain called the hippocampus is so critical to normal memory,” said senior author James Knierim, a professor at the university’s Zanvyl Krieger Mind/Brain Institute. “But even with many memory disorders, something goes wrong in this area.”

Neuroscientists know that neurons in the hippocampus, located deep in the brain’s temporal lobe, are responsible for a complementary pair of memory functions called pattern separation and pattern completion. These functions occur in a gradient across a tiny region of the hippocampus called CA3.

When these functions become unbalanced, memory becomes impaired, leading to symptoms such as forgetfulness or repetition. Johns Hopkins’ team discovered that as the brain ages, this imbalance may be caused by the disappearance of the CA3 gradient; the pattern separation function disappears and the pattern completion function takes over.

Neurons responsible for pattern separation are typically more abundant in the proximal region of the CA3 area, while those responsible for pattern completion are more prevalent in the distal region, said lead author Heekyung Lee, a research fellow 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 dominance in pattern completion.

In normal brains, pattern separation and pattern completion work hand-in-hand to sort and understand perceptions and experiences, from the simplest to the most 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 tell 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 don’t confuse the two experiences—that’s pattern separation.

When pattern separation disappears, pattern completion overwhelms the process. If your brain focuses on the shared experience of the restaurant and shuts out the details of each visit, you may recall a conversation about a trip to Italy during a visit, but you may be wrong about who was speaking.

“We all make these mistakes, but they only get worse as we get older,” Knierim said.

In experiments, the researchers compared young rats with good memory to older rats with good memory and older rats with impaired memory.

While the older rats with undisturbed memory 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.

This shows an older man
This finding is echoed in people who remain surprisingly sharp into old age, the researchers say. The image is in the public domain

Because this physiological finding wasn’t reflected in their behavior, the researchers concluded that something was allowing the rats to make up the deficit.

This finding is echoed in people who remain surprisingly sharp into old age, the researchers say. So, locating the mechanism of memory loss could provide the basis for learning what prevents memory impairment in some people, and therefore how to prevent or delay cognitive decline in older people.

“If we better understand what these compensatory mechanisms are, then maybe we can help prevent cognitive decline with age,” Knierim said. “Or, if we can’t stop it, maybe we can enhance other parts of the brain to make up for the losses that are occurring.”

Other lead authors of the paper were Michela Gallagher, Krieger-Eisenhower Professor of Psychology and Neuroscience at Johns Hopkins University, and Scott Zeger, Professor of Biostatistics at Johns Hopkins University Bloomberg School of Public Health. Gallagher’s lab has previously shown that the anti-epileptic drug levetiracetam improves memory by reducing hyperactivity in the hippocampus. As such, Lee also speculates that this new, more specific information about how memory disorders occur may allow scientists to better target such drugs to the deficits in the future.

“It would give us better control over where we could potentially address the deficiencies that we see,” she said.

About this news from aging and memory research

Author: press office
Source: Johns Hopkins University
Contact: Press Office – Johns Hopkins University
Picture: The image is in the public domain

Original research: Closed access.
“Loss of functional heterogeneity along the CA3 transverse axis with age” by Heekyung Lee et al. Current Biology


See also

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Loss of functional heterogeneity along the CA3 transverse axis with age


  • Young (Y) rats show a transition from pattern separation to pattern completion in CA3
  • Aged memory impaired (AI) rats show pattern completion in proximal and distal CA3
  • AI rats can orthogonalize representations in two spatially different environments
  • Old rats with undisturbed memory show trends intermediate between Y and AI rats


It has been postulated that age-related deficits in pattern separation affect the output of hippocampal memory processing toward pattern completion, which can lead to deficits in accurate memory retrieval.

Although the CA3 region of the hippocampus is often conceptualized as a homogeneous network involved in pattern completion, increasing evidence shows a functional gradient in CA3 along the transverse axis, as pattern-separated outputs (dominant in the more proximal CA3) transition to pattern-completed outputs (dominant in the more distal CA3).

We examined the neuronal representations along the CA3 transverse axis in young (Y), aged memory-impaired (AU), and aged memory-impaired (AI) rats when various changes were made to the environment.

Functional heterogeneity in CA3 was observed in Y and AU rats when environmental similarity was high (changed cues or changed environmental shapes in the same space), with more orthogonalized representations in proximal CA3 than distal CA3.

In contrast, AI rats showed reduced orthogonalization in the proximal CA3 but presented normal (i.e., generalized) displays in the distal CA3 with little evidence of a functional gradient.

Under experimental conditions, when environmental similarity was low (different spaces), representations in proximal and distal CA3 were reassigned in all rats, demonstrating that CA3 of AI rats is able to encode characteristic representations for inputs with greater dissimilarity .

These experiments support the hypotheses that the age-related pattern-completion propensity in the hippocampus is due to the loss of the normal transition from pattern separation to pattern-completion along the CA3 transverse axis in AI rats.

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