Infusing Youthful Brain Juice Restores Older Mice’s Memories

Infusing the brains of aged mice with cerebrospinal fluid (CSF) taken from young mice can improve memory function, suggests a new study. The research, conducted by a team from the Stanford University School of Medicine, suggests that the cognitive benefits of the CSF transfer may be due to increases in the population of oligodendrocyte precursor cells (OPCs) in the older mice’s hippocampus.

Juicing up older mice

The concept of transferring fluids from a young individual to rejuvenate an older one may sound faintly vampiric, but it’s an approach that has been borne out in repeated studies. Murine heterochronic parabiosis, which is a fancy way of saying “stitching a young mouse to an old mouse so that their circulatory systems become connected” has previously been shown to restore youthful function to the aged brain. Similarly, the transfer of a younger mouse’s plasma into an older mouse also appeared to improve memory function.

CSF is a bodily fluid that is especially relevant to the issue of brain aging.  This “brain juice” is distributed between hollow areas in the brain, such as the ventricles and the subarachnoid spaces. It is a form of plasma, like that coursing through our bloodstream. CSF, however, is an ultrafiltered plasma that is secreted by the choroid plexus, a nexus of capillaries and cells that acts as a barrier between the brain and blood supply. In the human brain, the CSF’s total volume of 150 ml is replenished 4–5 times a day.

In the new study, researchers, including first author and postdoctoral researcher Dr. Tal Iram, investigated how young CSF altered the brain and cognition of older animals. To do so, they slowly infused CSF directly into the right lateral ventricle of aged mice using subcutaneous pumps, Iram tells Technology Networks. The team then tested the effect of the infused CSF on the mice’s performance in hippocampal-dependent learning and memory tests. Mice transfused with young CSF performed significantly better than those given artificial CSF.

Iram and colleagues then burrowed into the mice’s genetic data to identify potential molecular changes that could be stimulating this improvement to memory. “When we took a deeper look into gene changes that occurred in the hippocampus (a region associated with memory and aging-related cognitive decline), we found, to our surprise, a strong signature of genes that belong to oligodendrocytes,” says Iram.

Unexpected role for sheath cells

Oligodendrocytes are cells that perform a specialized function in the brain; they produce myelin, a sheath that wraps itself around neurons, providing both a protective and conductive coating that makes fast nerve cell signaling possible. Previous studies of young-to-old infusion and parabiosis had looked at how these systemic changes affected neurogenesis, the creation of new neurons from stem cell populations. Neural stem cells are present in the aged brain, but in very limited numbers, however. Some scientists suspect that in humans, adult neurogenesis might not happen at all in the mature brain, although this topic continues to be debated.

Iram explained that their data instead led them to focus on the formation of oligodendrocytes from a precursor population known as OPCs. “Oligodendrocytes are unique,” explains Iram, “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.” The team noted that OPCs in both the aged mice’s hippocampi and in vitro showed increased proliferation and differentiation in mature oligodendrocytes.   

The team dug down further into the cellular processes that occurred after CSF infusion, identifying serum response factor (SRF) as a key mediator of the resulting spread of OPCs. SRF is a type of protein called a transcription factor. These control the rate of gene transcription. In OPCs, SRF appears to help remodel the cell’s structure. Closing the loop, the team showed that a molecule found in CSF called fibroblast growth factor 17 (Fgf17) was a strong inducer of SRF-mediated changes to OPCs.

Pinning down a mechanism

Could it be that FGf17 was all that was required for a boost to old age memory? The team showed that mice injected with this molecule alone also had OPCs with higher rates of proligeration and improvements in memory that partially mimicked the effect of whole CSF. In turn, blocking Fgf17 in younger mice impaired their memory.  

The team admit there is plenty more research to be done to work out how this potential memory-boosting pathway works, and whether it has relevance to humans. Fgf17 plays important roles in the developing brain but is poorly studied in the adult nervous system. The study’s small size is another consideration – only nine mice were infused with young CSF.  But the basic technique used to target the fluid most intimately associated with the brain is one that could be used in humans, says Iram: “This type of drug administration in humans can be accomplished with an intrathecal pump or catheter and is used in the clinic for some drugs.”

Given that additional barriers protect the brain beyond the choroid plexus, entrance of a drug to the CSF doesn’t necessarily mean it will access the brain, Iram concludes, “We believe that more research is needed to identify what regulates protein transfer from the CSF to the brain and how it can be manipulated to increase drug transport into the brain.”

Reference: Iram T, Kern F, Kaur A et al. Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17. Nature. 2022. doi: 10.1038/s41586-022-04722-0