Originally published on the PLOS Neuroscience Community
This Thanksgiving, many of us will be manipulating our energy balance — in one way or another. Most will be building our energy stores with a hefty dose of Turkey and pumpkin pie, while others may tap into those reserves at their local turkey trot. Either way, we’ll need to look no further than the mirror to be reminded how diet and exercise mold the body.
Less obvious, however, is how energy availability regulates brain health. Emerging research is showing that tweaking our energy use through diet and exercise elicits positive metabolic changes that promote better neuronal and mental health. In their symposium “Exercise, Energy Intake, and the Brain” at this year’s recent Society for Neuroscience conference, scientists Henriette van Praag, Monika Fleshner, Michael Schwartz and Mark Mattson discussed the mechanisms underlying the brain-energy relationship.
In her talk, Fleshner demonstrated the powerful effects of exercise on our response to stress. Not only does physical activity make many organisms — of all shapes and sizes — simply feel good (rats, frogs and even slugs will voluntarily run on wheels in the wild!), but it also does wonders to protect us against the hazards of stress. After only six weeks of regular running, an individual will begin to show signs of stress-robustness, including being more resilient and resistant to stress. But just how does that morning jog help us combat a stressful day at work?
According to Fleshner, exercise attenuates the typical stress-induced activation of the dorsal raphe nucleus — a major source of serotonergic projections. Although a logical player in this process might be the medial prefrontal cortex (mPFC) since this area regulates serotonin transmission in the dorsal raphe nucleus, the mPFC isn’t necessary for exercise-related stress resistance. Rather, six weeks of wheel-running increases levels of 5HT1A inhibitory autoreceptors and reduces stress-induced serotonin release. Thus, it appears that exercise effectively puts the breaks on the dorsal raphe nucleus-mediated serotonergic response to stress. What’s more, this stress-robustness likely involves a widespread coordinated response including exercise-induced epigenetic changes. In fact, Fleshner showed that a host of stress-related genes are differentially expressed in physically active and inactive individuals.
Mattson opened his discussion with some inspiring anecdotes on the subjective benefits of exercise and fasting. For instance, celebrated writer Joyce Carol Oates is known to do some of her best writing while running, an experience with which I — a runner and writer myself — am dearly familiar.
Sure, it may feel like physical activity makes our thoughts flow more fluidly, but just how and why might exercise spark greater neural efficiency? Exercise promotes mitochondrial growth and development systemically, and it’s well accepted that what’s good for the body is good for brain; the benefits of exercise aren’t limited to muscle cell mitochondria, but extend to neuronal mitochondrial as well. Mattson outlined a molecular pathway by which physical activity influences mitochondrial integrity, neurogenesis and plasticity in the hippocampus. While the nitty-gritty details of the circuit are beyond the scope of this post, two key players are worth mentioning: the protein PGC1-alpha which is activated by exercise, and SIRT3, levels of which are increased in runners compared to non-runners. Notably, PGC1-alpha is necessary for mitochondrial biogenesis, including in hippocampal neurons, and activates SIRT3, which is important for normal long-term potentiation and synaptic calcium release. In short, exercise triggers a cascade of cellular processes that promote efficient mitochonondrial and neuronal function.
Mattson next highlighted some parallels between the neuroprotective effects of exercise and intermittent energy restriction (such as fasting or calorie restriction). Notably, running has been shown to up-regulate BDNF, CREB-activation and DNA-repair mechanisms which may combat the deleterious effects of aging. Energy restriction similarly elicits a host of positive neurobiological effects — for instance, increased synaptic density and neurogenesis — and even promotes longevity (30% greater lifespan in rats isn’t bad!). There’s some evidence that intermittent fasting may actually be more beneficial than calorie restriction, as it more effectively lowers heart rate, a process likely mediated by increased BDNF. Finally, Mattson pointed out that both exercise and fasting enhance production of ketones, a highly robust source of neuronal energy that have also been shown to enhance cognitive function and neural plasticity.
Unfortunately, I was only unable to attend the additional talks by van Pragg and Schwartz. But fortunately, the symposium speakers compiled a Journal of Neuroscience review highlighting their key points.
Running! If there’s any activity happier, more exhilarating, more nourishing to the imagination, I can’t think what it might be. In running the mind flies with the body; the mysterious efflorescence of language seems to pulse in the brain, in rhythm with our feet and the swinging of our arms. — Joyce Carol Oates