Can mice hold the secret to improved memory?

An international team of scientists have succeeded in improving memory function in older mice by injecting them with cerebrospinal fluid from young mice.

They removed small amounts of cerebrospinal fluid (CSF) from young mice, and injected them into the brain of older mice without harming the test subjects. Their findings were published in the journal Nature.

In the same Nature journal issue, there is a News & Views piece by Miriam Zawadzki and Maria Lehtine with Boston Children’s Hospital that outlines the work carried out by the team in this new research.

There has been some research in recent years discussing the benefits of blood transfusions from young people to older people in order to slow the ageing process. In this new research, the scientists have taken it a step further by removing CSF from a young mouse and injecting it into the brain of an older mouse to observe whether it would have any effect on memory.

How did researchers improve memory?

Cerebrospinal fluid is a “clear fluid, which surrounds and bathes the brain and spinal cord, [and] is rich with proteins that activate oligodendrocytes, a group of cells that help speed up message delivery within the brain’s vast network of neurons,” the Daily Beast reports.

Researchers spent many months trying to find a method to extract a small amount of cerebrospinal fluid from a young mouse so that the specimens would not be tainted.

Once they did, they had to come up with a way to inject the specimen into an older mouse while being cautious not to cause damage or infection.

When they perfected these techniques, the researchers trained a group of older mice to associate a flashing light with an electric shock to the foot.

The researchers collected multiple samples of CSF from several young mice before injecting it into the brains of several of the older, trained mice. They also had a control group.

Letting two weeks pass, they tested both groups afterwards and discovered the older mice that had received the CSF injection better remembered what was going to happen (froze in place) when the light flashed.

After the experiment was concluded, researchers dissected the brains of some of the older mice that had received the CSF injections. This was done to discover why administering CSF improved their memory.

The research team found higher-than-normal levels of serum response factor in the older mice: “we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of [oligodendrocyte progenitor cell (OPC)] proliferation following exposure to young CSF.

“With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF.

“We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice.”

The injections, which boosted fibroblast growth factor 17 (Fgf17) led the researchers to conclude: “These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.”

How about gene changes?

The researchers conducted further experiments on the older mice, and according to Science Alert, “certain genes (that are different in young-versus-old CSF) could be used to get the same response. In other words, without needing to extract someone's brain fluid.”

"When we took a deeper look into gene changes that occurred in the hippocampus (a region associated with memory and ageing-related cognitive decline), we found, to our surprise, a strong signature of genes that belong to oligodendrocytes," Tal Iram, a postdoctoral fellow at Stanford University and the study’s lead author, told ScienceAlert.

"Oligodendrocytes are unique because their progenitors are still present in vast numbers in the aged brain, but they are very slow in responding to cues that promote their differentiation. We found that when they are re-exposed to young CSF, they proliferate and produce more myelin in the hippocampus."

What are the reactions to the findings?

“Obviously, we’re not going to be harvesting cerebrospinal fluid and injecting it into people,” Dwight Bergles, a neuroscientist at Johns Hopkins University who was not involved in the study, told the Daily Beast.

“But if we could identify which components in there were able to have the largest influence on ageing, disease progression, and, in this case, the generation of new oligodendrocytes, then we could think about providing and developing new drugs that stimulate those pathways.”

“Some of the initial motivation for this study was to take a step across those [blood-brain] barriers and perform transfers of cerebrospinal fluid, which has a very different protein composition to blood and more unique to the needs of the brain,” Iram told the Daily Beast.

“We thought that cerebrospinal fluid holds the potential to rejuvenate the [mice] brains.”

"Iram and colleagues have broken ground in the field of brain health and ageing by discovering that young CSF contains a factor that aids memory recall in older mice," write Zawadzki & Lehtinen in an accompanying News and Views piece.

"Not only does the study imply that FGF17 has potential as a therapeutic target, but it also suggests that routes of drug administration that allow therapeutics to directly access the CSF could be beneficial in treating dementia. Any such treatments will be hugely helpful in supporting our ageing population."