Researchers have identified an enzyme that plays a key role in updating existing memories with new information, a process that naturally declines with age. Blocking the enzyme improved memory impairment and opened the door to developing treatments for age-related memory problems.
While scientists know that our ability to change or update existing memories declines with age and can contribute to age-related cognitive impairment, there has been a lot of research on how memories are formed, but less on how existing memories are updated with new information. But now, new research has identified the underlying molecular mechanism behind memory updating.
Researchers from Pennsylvania State University (Penn State) wanted to understand why normal aging makes it more difficult to update memories. In search of an answer, they found an enzyme that, when blocked in older mice, prevented the typical age-related memory deficits.
“Understanding what happens at the molecular level during a memory update is important because as humans, most of our memories are updates,” said Janine Kwapis, assistant professor of biology at Penn State and senior author of the study. “But no one has really looked at whether the mechanisms behind memory formation and memory updating are the same or unique to memory updating. This is a step forward in understanding that.”
Consolidation is the process of converting a newly formed short-term memory into a more stable, long-term memory. This stabilization relies on protein synthesis, controlled by genes, at synapses, the gaps between neurons that allow them to transmit signals to each other. As new experiences and memories are acquired, the brain essentially reorganizes itself to create more of these synaptic connections. Eventually, two neurons that are connected to each other become sensitive to each other, so that recalling a memory makes them fire at the same time.
“When you encounter new information, you have to pull the existing memory out of storage and weaken it so that it is ready to take on new information,” Kwapis said. “When new information is learned and those new neurons are incorporated, the updated memory is consolidated and stored again.”
This process is called reconsolidation, and it becomes less effective with age. So the researchers looked at whether increasing gene expression during reconsolidation would also increase memory updating ability. They knew that histone deacetylase 3 (HDAC3), an enzyme that regulates the copying of information from a section of DNA to RNA and eventually into a protein, negatively affects memory formation and gene expression during consolidation, so they focused on that.
“HDAC3 typically tightens chromatin, a complex of DNA and proteins, and makes it harder for transcription to occur,” says Chad Smies, a Penn State biology doctoral student and lead author of the paper. “If we prevent this enzymatic activity from occurring, it could help maintain a more open chromatin state and improve gene expression.”
Older male mice (18 to 20 months) were subjected to the Objects in Updated Location task. After habituation to an environment, the animals were exposed to two identical objects placed in specific locations. Twenty-four hours later, the environment was updated: one of the identical objects was moved to a new location. Immediately after the updating session, the mice were given a placebo or a drug that would block HDAC3. The mice were then tested for memory of the objects. Four identical objects were placed in specific locations in the environment: two in the original locations, one in the updated location, and the fourth in a completely new location.
“Mice love novelty, so if [a] “If they have a good memory for the training session or the update 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.”
The researchers found that blocking HDAC3 immediately after the updating session reduced age-related memory impairments without affecting the original memory. The older mice performed as well as the younger mice during the memory test.
The research team hopes that identifying molecular mechanisms that affect memory, such as HDAC3, will pave the way for the development of therapeutic targets to improve age-related decline in cognitive flexibility.
“If these mechanisms improve memory in normal aging, they may also help disorders like Alzheimer's disease and dementia,” Kwapis said.
The study was published in the journal Frontiers in Molecular Neuroscience.
Source: Penn State