The Surprising Role of Leg Exercise in Forming New Brain Cells

Study Methods

The researchers wanted to analyze the impact of prolonged physical inactivity on the nervous system. For ethical reasons that will become very obvious here shortly, the researchers needed to use an animal model. But obviously, you can’t just tell a mouse to lie in bed all the time.

To get around this, each mouse was suspended by a string that was tied to their tail and affixed to the ceiling of the cage, so that only their front legs made contact with the floor of the cage. This is a validated model of motor deprivation that was developed in the 1980s to mimic the impact of prolonged bed rest or space flight on the musculoskeletal system.

Thus, the mice were fully restricted from using their hind legs for a full 14 days. Despite how it sounds, they apparently were pretty cool with this arrangement. The researchers checked on the rodents frequently, and reported that they did not exhibit signs of stress, either in their behavior or in their hormonal profile. At the end of the study period, the mice (as well as a control group, which was allowed free movement) were sacrificed and their brains were dissected. The researchers then performed various analyses on a part of the brain known as the subventricular zone.

You might wonder, why was this particular area a focus of attention?

It was once thought that adults could not grow new brain cells. But we now know that there are two areas in the brain that contain neural stem cells, from which new neurons are generated throughout life (neurogenesis). One of these is the subventricular zone. Importantly, this appears to be the case in both rodents and humans, meaning that this should be a reasonably useful model for understanding the effects of activity (and lack thereof) on neurogenesis.

So what did the researchers uncover when they looked into the brains of these mice?

Findings

Okay, this analysis is a tad complicated. I’ll try to simplify it as much as possible and walk through what the researchers did.

First of all, the researchers counted and compared the number of proliferating cells in the subventricular zone. This refers to stem cells that were dividing to build new neurons. So less proliferation, in this context, would suggest less neurogenesis. And indeed, they found that the mice whose hindlimbs had been suspended had 70% fewer proliferating cells, compared to the freely moving mice. That’s…not great.
To better understand what was going on here, the researchers then extracted neural stem cells from the brains of both the hindlimb-unloaded mice and the control mice and grew them in petri dishes. The researchers observed that it took about 7 days for the neural stem cell count to double in the hindlimb-unloaded mice, but only 2 days for the control animals. So, it seems that the forced inactivity reduced the dividing capacity of the neural stem cells.
Additionally, the neural stem cells in the hindlimb-unloaded mice also showed impaired differentiation capability, meaning that neurons were failing to become fully mature and functional. The percentage of differentiated neurons in the experimental group was only about 0.5%, compared to 6.8% in the control group. Thus, forced inactivity also significantly inhibits the maturation of neurons coming from the neural stem cells.
But what precisely is causing these alterations in neurogenesis? Finally, the team examined gene expression in the neural stem cells of both groups, and observed that two genes seemed to be substantially impacted by the forced inactivity. One, Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1), was downregulated 3.53 fold in the hindlimb-unloaded group compared to controls. The other, cyclin-dependent kinase 6 (Cdk6) was upregulated 2.38 fold. Why does that matter? We know that both of these genes are involved in the regulation of neural cell cycles. Cdk5rap1 in particular is a critical gene for the function of the mitochondria. It seems likely that these epigenetic changes, induced by the reduced movement in the legs, are ultimately responsible for the reduced neurogenesis that we see in the unfortunate hindlimb-unloaded mice.

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Mice whose hind legs are restricted from exercise for 14 days show a 70% reduced neural stem cell count. Don't skip leg day! Click To Tweet

Significance

Our body is, in effect, ruled by our brain, right? Signals from the brain direct the actions of our skeletal muscles, enabling us to pick up a pencil, kick a soccer ball, and do whatever we want to do. But this study suggests that it’s really a two-way street. Signals emanating from the larger muscles in our body are also crucial for the health and regenerative capacity of the brain and nervous system.

You can imagine that this has obvious and immediate relevance for astronauts on space missions. But I can’t help but wonder if it is also applicable, albeit to a much lesser degree, to people who simply are extremely inactive, or even just to the millions of people who have sedentary jobs. Like myself. Now obviously, I have full use of my legs and am still under the influence of gravity, so it’s not a perfectly analogous situation. But people like me do wind up spending considerable amounts of time sitting in front of a laptop. And that prolonged inactivity is probably not fully compensated by sports and physical training. I am reminded of another study, published this spring, that found that sedentary behavior was a predictor of thinning in the medial temporal lobe, a part of the brain that is critical to the formation of new memories. Furthermore, the authors noted that high levels of exercise did not appear to offset this effect.

Studies like this serve as a vital reminder of the impact of physical activity not merely on our bodies, and on how we look, but also on our minds. What could be more important than that?