Scientists identify key component of how exercise triggers neurogenesis

A recent study suggests that some of exercise’s brain-enhancing benefits can be transferred through tiny particles found in the blood. Researchers discovered that injecting these particles, called extracellular vesicles, from exercising mice into sedentary mice promoted the growth of new neurons in the hippocampus, a brain region important for learning and memory. The findings were published in the journal Brain Research.

Aerobic exercise can enhance cognitive functions, in part by stimulating the birth of new neurons in the hippocampus. This process, known as adult neurogenesis, is linked to improved learning, memory, and mood regulation. Understanding the specific mechanisms connecting physical activity to brain health could lead to new therapies for age-related cognitive decline and other neurological conditions.

However, the exact biological conversation between active muscles and the distant brain has remained largely a mystery. A leading hypothesis suggests that exercise releases specific factors into the bloodstream that travel to the brain and initiate these changes. Previous work has shown that blood plasma from exercising animals can be transferred to sedentary ones, resulting in cognitive benefits. This observation has narrowed the search for the responsible agents.

Among these potential messengers are extracellular vesicles, which are minuscule sacs released by cells that carry a diverse cargo of proteins, lipids, and genetic material. During exercise, tissues like muscle and liver release these vesicles into circulation at an increased rate. Because these particles are capable of crossing the protective blood-brain barrier, researchers proposed they might be a key vehicle for delivering exercise’s benefits directly to the brain.

“The hippocampus is critical for learning and memory and atrophy of the hippocampus is associated with common mental health problems like depression, anxiety,, PTST, epilepsy, Alzheimer’s disease and normal aging. So figuring out ways of increasing the integrity of the hippocampus is an avenue to pursue for addressing these problems,” explained study author Justin Rhodes, a professor at the University of Illinois, Urbana-Champaign.

“It is known that exercise increases the formation of new neurons in the hippocampus, and is a natural way to combat all the aforementioned mental health problems. It is further known that there are factors released into the blood that contribute to adult hippocampal neurogenesis. But most likely a mixture of factors rather than one magic chemical. The idea that extracellular vesicles containing lots of different kinds of molecules could communicate with complex chemical signatures from the blood to the brain and contribute to neurogenesis was not known until our study.”

To examine this, the researchers used two groups of mice. One group had unlimited access to running wheels for four weeks, while the other group was housed in cages with locked wheels, serving as a sedentary control. As expected, the running mice showed a significant increase in new brain cells in their own hippocampi, confirming the effectiveness of the exercise regimen.

After four weeks, the team collected blood from both the exercising and sedentary donor mice. From this blood, they isolated the extracellular vesicles using a filtration method that separates particles by size. This process yielded two distinct batches of vesicles: one from the exercising mice and one from the sedentary mice.

The team then administered these vesicles to a new set of sedentary recipient mice over a four-week period. These recipients were divided into three groups. One group received injections of vesicles from the exercising donors, a second group received vesicles from the sedentary donors, and a third group received a simple phosphate-buffered saline solution as a placebo.

To track the creation of new cells in the recipients’ brains, the mice were given injections of a labeling compound known as BrdU. This substance is incorporated into the DNA of dividing cells, effectively tagging them so they can be identified and counted later under a microscope. To ensure the reliability of their results, the entire experiment was conducted twice with two independent groups of mice.

The researchers found that mice that received vesicles from the exercising donors exhibited an approximately 50 percent increase in the number of new, BrdU-labeled cells in the hippocampus compared to mice that received vesicles from sedentary donors or the placebo solution. The findings were consistent across both independent cohorts, strengthening the conclusion that something within the exercise-derived vesicles was promoting cell proliferation.

“I was surprised that the vesicles were sufficient to increase neurogenesis,” Rhodes told PsyPost. “That is because when you exercise, there is not only the contribution of blood factors, but things going on in the brain like large amounts of neuronal activity in the hippocampus that I thought would be necessary for neurogenesis to occur. The results suggest apparently not, the vesicles alone without the other physiological components of actual exercise, are sufficient to increase neurogenesis to a degree, not the full degree, but to a degree.”

The researchers also examined the identity of these new cells to determine what they were becoming. Using fluorescent markers, they identified that, across all groups, about 89 percent of the new cells developed into neurons. A smaller fraction, about 6 percent, became a type of support cell called an astrocyte. This indicates that the vesicles from exercising mice increased the quantity of new neurons being formed, rather than changing what type of cells they became.

Finally, the team assessed whether the treatment affected the density of blood vessels in the hippocampus, as exercise is also known to promote changes in brain vasculature. By staining for a protein found in blood vessel walls, they measured the total vascular area. They found no significant differences in vascular coverage among the three groups, suggesting that the neurogenesis-promoting effect of the vesicles may be independent of vascular remodeling.

“One of the reasons exercise improves mental health is that it stimulates new neurons to form in an area of your brain that is important for learning and memory and for inhibiting stress, and now we know a big piece of the puzzle as to how exercise does this,” Rhodes said. “Exercise causes tissues like muscle and liver to secrete vesicles (sacs that contain lots of different kinds of chemicals) that reach the brain and stimulate neurogenesis.”

“Those vesicles can be taken from an animal that exercises and placed into an animal that is not exercising, and it can increase neurogenesis, not to the full level of that exercise does, but significantly increase it. That strongly suggests the vesicles themselves are carrying critical information. One can imagine a therapy in the future where either vesicles are harvested from exercising humans from their blood and introduced into individuals or synthetic vesicles are made that carry the unique mixture of chemicals that are identified in the exercise vesicles.”

While the findings point to extracellular vesicles as key players in exercise-induced brain plasticity, the study also highlights several areas for future inquiry. A primary question is whether the vesicles directly act on the brain or if their effects are mediated by peripheral organs. It is not yet known what fraction of the injected vesicles crossed the blood-brain barrier. The vesicles could potentially trigger signals in other parts of the body that then influence the brain.

The specific molecular cargo within the vesicles responsible for the neurogenic effect also needs to be identified. A companion study by the same research group found that vesicles from exercising mice were enriched with proteins related to brain plasticity, antioxidant defense, and cellular signaling. Future work will be needed to pinpoint which of these molecules, or combination of molecules, is responsible for the observed increase in new neurons.

“I think there are a lot of ways this could go,” Rhodes told PsyPost. “First, it is a pretty big black box between injecting the animals with vesicles and neurogenesis happening in the hippocampus. How many of the extracellular vesicles make it to the brain? Are they acting in the brain or in the periphery, i.e., maybe via peripheral nerves, mesenteric nervous system, immune activation or other ways we didn’t think of yet.”

“If they are reaching the brain, how do they merge with brain cells, do they reach astrocytes first? How do the vesicles get taken up by the brain cells is it through phagocytosis? What do the chemical signals do to the brain cells that causes increased neurogenesis? Do they act directly on neural progenitor cells, or astrocytes or mature neurons? What are the signaling mechanisms involved in the communication from the extracellular vesicles to the neurons/astrocytes/progenitor cells that causes neurogenesis to occur?”

The study, “Exercise-induced plasma-derived extracellular vesicles increase adult hippocampal neurogenesis,” was authored by Meghan G. Connolly, Alexander M. Fliflet, Prithika Ravi, Dan I. Rosu, Marni D. Boppart, and Justin S. Rhodes.