Everyone has moments of forgetfulness, especially as we get older. But older adults don’t just have trouble remembering new information. They also find it harder to change those memories when new details emerge. Yet little is known about the mechanisms behind memory updating and how these mechanisms go wrong with age.
A team of researchers from Penn State has identified an enzyme that contributes to age-related impairments in memory updating. When blocked, older mice were better able to absorb new information and performed similarly to their younger counterparts. The researchers said the findings, published in Frontiers in molecular neurosciencemay lead to the development of potential therapeutic targets for improving cognitive flexibility in old age.
It’s important to understand what happens at the molecular level during a memory update because most of our memories, as humans, are updates. We continually build on things we already know and modify existing memories. But no one has really looked at 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 figuring that out.”
Janine Kwapis, assistant professor of biology and senior author of the article
When a memory forms, the brain rewires itself to keep that memory in place through a process called consolidation. Cells express proteins in the synapse, the gap between neurons that allows communication between nerve cells, connecting the cells that were activated when memory was formed. When the memory is recalled, these cells fire together at the same time.
“When you are presented with new information, you have to take that existing memory out of storage and weaken it so that it is ready to absorb new information. Once the new information has been learned and those new neurons have been absorbed, the updated memory is solidified and stored again,” Kwapis said. Kwapis noted that this process, called reconsolidation, becomes less effective with age.
In this study, the research team wanted to understand why it is more difficult 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 DNA segment into RNA that will eventually form a functional protein. HDAC3 has been shown to negatively impact memory formation and gene expression during consolidation, but the researchers said its role in memory reconsolidation had not been previously investigated.
“HDAC3 typically tightens chromatin, a complex of DNA and proteins, and makes it difficult for transcription,” said Chad Smies, a doctoral student in biology and first author of the paper. “If we prevent this enzymatic activity from happening, it could help maintain a more open chromatin state and improve gene expression.”
When HDAC3 was blocked during the memory reconsolidation phase, it prevented the typical age-related deficits in memory updating. Older mice performed as well as their younger counterparts during a memory updating task.
The team used a methodology called the objects in updated locations paradigm, which Kwapis developed specifically to test memory updating. It involves three phases: a training session where mice learn two locations of identical objects; an update session where one of the objects is moved to a new location; and a test session where the objects are placed in four separate locations -; the original two training locations, the renovated location and a completely new location.
“Mice love novelty, so if they have a good memory for the training session or the updating session, they will explore the new object location more,” Smies said. “But if they have a poor memory, 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 provide potential therapeutic targets for improving cognitive flexibility in old age.
“If these mechanisms improve memory in normal aging, they may also help in conditions such as Alzheimer’s disease and dementia,” Kwapis said.
Other Penn State authors on the paper include Lauren Bellfy, doctoral student in molecular, cellular and integrative biosciences, and Chad Brunswick, doctoral student in the neuroscience program. Destiny Wright and Sofia Bennetts, who were students at Penn State during the study; Mark Urban, a postdoctoral researcher at Penn State during the time of the study; and Guanhua Shu, who was a graduate student at Harvard University at the time of the research, also contributed to the article.
This research was funded by the National Institute on Aging, Hevolution/American Federation for Aging Research, and the Penn State Paul Berg Early Career Professorship.
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Magazine reference:
Smies, CW, et al. (2024). Pharmacological HDAC3 inhibition alters memory updating in young and old male mice. Frontiers in molecular neuroscience. doi.org/10.3389/fnmol.2024.1429880.