Growing older may come with a few benefits, but a fantastic memory is not generally considered one of them. As the old saying goes: with wisdom and wrinkles comes hippocampal shrinkage, leading to increased forgetfulness and a reduced ability to learn and recall new information.
However, a new study published in the journal Nature may hold a glimmer of hope for those of us who lose our keys more than we used to. By transplanting cerebrospinal fluid from the brains of young mice into elderly ones, researchers found that they could trigger the production of myelin in the older rodent brains – and thereby restore the little pensioners’ recall ability.
Cerebrospinal fluid "bathes the brain tissue and contains several protein growth factors necessary for normal brain development,” write Miriam Zawadzki and Maria K. Lehtinen, neuroscientists at the Lehtinen Laboratory at Boston Children’s Hospital, in an accompanying article for Nature.
“The [study] authors therefore examined whether treatment with the young [cerebrospinal fluid] affected the proliferation and maturation of oligodendrocyte precursor cells (OPCs),” they continue – referring to cells that develop into insulation for the brain’s nerve fibers, known as axons. Neither Zawadzki nor Lehtinen were directly involved in the study.
We know what you’re thinking: how do you measure a mouse’s recall ability? Well, the answer, in this case, is “with great difficulty to the mouse,” as the experiment came in the form of a fear conditioning test. This is pretty much what it sounds like: the researchers trained the mice to associate a particular audiovisual cue with pain – specifically, a small electric shock in their feet. A day later, the cue was repeated, and again three weeks after that. If the mice froze in fear, the researchers determined that they still remembered the original lesson.
The study sought to answer two questions: first, whether an infusion of young cerebrospinal fluid could improve recall in old mice – and if so, whether it would be better than an artificial version of the same stuff – and second, what was happening on a biological level to produce their results.
The first answer was a resounding yes – on both counts. The researchers “found that young [cerebrospinal fluid] more than doubled the percentage of OPCs actively proliferating in the hippocampus of old animals,” note Zawadzki and Lehtinen. In terms of freezing mice, this translated to twice the proportion of immobile rodents with young cerebrospinal fluid over those with artificial cerebrospinal fluid – meaning that when it comes to brain juice, real is best.
But the big question is why – and to answer this, the team turned to RNA sequencing. This technique allowed them to figure out which genes in the hippocampus had been most affected by the procedure, giving them a clue as to what was going on.
They soon homed in on one molecule in particular: fibroblast growth factor 17, or Fgf17. This protein is one of many that triggers the brain’s OPCs to produce myelin – the layer of fatty insulation that surrounds and protects the neurons. Fgf17 is “robustly expressed” in young mouse neurons, the team found, and decreases as the mice age. It’s also been shown to promote OPC growth in cultured rat neurons – and if blocked in young mice, seems to impair brain function.
Clearly, this is an important gene when it comes to cognition and memory – and their discovery that Fgf17 lives in cerebrospinal fluid and can aid recall in this way has “broken ground in the field of brain health and ageing,” write Zawadzki and Lehtinen.
“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 [cerebrospinal fluid] could be beneficial in treating dementia,” they conclude. “Any such treatments will be hugely helpful in supporting our ageing population.”