Everyone has moments of forgetfulness from time to time, especially as we get older. But older adults not only have difficulty remembering new information. They also have more difficulty changing those memories when new details emerge. However, little is known about the mechanisms behind memory updating and how those mechanisms go out of whack with age.

A team of researchers at Pennsylvania State University has discovered an enzyme that contributes to age-related impairments in memory updating. After blocking the enzyme, older mice were able to process new information better and showed similar performance to their younger counterparts.

The researchers said the results, which were published in Frontiers of molecular neurosciencecould lead to the development of potential therapeutic targets to improve cognitive flexibility in old age.

“It’s important to understand what happens at the molecular level during a memory update because, in humans, most of our memories are updates. We are constantly building on things we already know and modifying existing memories,” said Janine Kwapis, assistant professor of biology and lead author of the study.

“But no one has really investigated whether the mechanisms behind memory formation and memory updating are identical or whether they are unique to memory updating. This is a step forward in finding that out.”

When a memory forms, the brain rewires itself to hold that memory in place through a process called consolidation. Cells express proteins at the synapse, the gap between neurons that allows communication between nerve cells and connects the cells together, that are activated when the memory is formed. When the memory is recalled, those cells then fire simultaneously.

“When you’re confronted with new information, you have to pull the existing memory out of storage and weaken it so it’s ready to accommodate new information. Once the new information is learned and the new neurons are integrated, the updated memory is consolidated and re-stored,” Kwapis said. Kwapis noted that this process, called reconsolidation, becomes less effective as we age.

In this study, the research team wanted to understand why it is harder to update memories during normal aging. If they could improve gene expression during reconsolidation, could they also improve memory updating?

To test this, they blocked histone deacetylase 3 (HDAC3), an enzyme that regulates gene transcription, the process by which information is copied from a section of DNA into RNA, which ultimately becomes a functional protein. HDAC3 has been shown to negatively affect memory formation and gene expression during consolidation, but the researchers said its role in memory reconsolidation has not been studied until now.

“HDAC3 normally tightens chromatin, a complex of DNA and proteins, and makes transcription more difficult,” said Chad Smies, a doctoral student in biology and first author of the study. “If we block this enzymatic activity, it may help maintain a more open chromatin state and improve gene expression.”

Blocking HDAC3 during the memory reconsolidation phase prevented the typical age-related deficits in memory updating. Older mice performed just as well as their younger counterparts on a memory updating task.

The team used a method called the Objects in Updated Locations Paradigm, which Kwapis developed specifically to test memory updating. It involves three phases: a training session in which the mice learn two locations of identical objects; an updating session in which one of the objects is moved to a new location; and a test session in which the objects are placed in four different locations—the two original training locations, the updated location, and a completely new location.

“Mice like novelty, so if they can remember the training or updating session well, they will explore the new object location more often,” Smies said. “However, if they remember poorly, they tend to explore the previously learned locations as much as the new location.”

By identifying molecular mechanisms such as HDAC3, the research team hopes to find potential therapeutic targets to improve cognitive flexibility in old age.

“If these mechanisms improve memory in normal aging, they could potentially also help in diseases such as Alzheimer’s and dementia,” Kwapis said.

Other authors of the study from Penn State include Lauren Bellfy, a doctoral student in molecular, cellular and integrative biosciences, and Chad Brunswick, a doctoral student in the neuroscience program. Destiny Wright and Sofia Bennetts, who were graduate students at Penn State at the time of the study, Mark Urban, a postdoctoral fellow at Penn State at the time of the study, and Guanhua Shu, who was a doctoral student at Harvard University at the time of the study, also contributed to the study.