Tag Archives: exercise

Astrocytes may Hold the Key to Exercise-Induced Cognitive Enhancement

Originally published on the PLOS Neuroscience Community


Forget expensive pills or exotic miracle supplements. Exercise may be the most effective – not to mention free and accessible – cognitive enhancer on the market. Research in humans has shown that physical activity can improve cognitive function and may help stave off dementia, yet the biological mechanisms underlying these benefits aren’t fully understood. Animal studies have made substantial progress on this front, demonstrating such positive responses to running as enhanced neurogenesis and elevated levels of neural growth factors. However, much of this research has been relatively narrowly focused, with particular attention devoted to neuronal changes and one notable brain region – the hippocampus. The hippocampus is selectively important for certain functions like learning and episodic memory, but exercise improves a range of cognitive processes, many of which depend on other, non-hippocampal brain regions. Therefore, researchers from Princeton University looked beyond the hippocampus and neurons to more thoroughly characterize the neural events that impart cognitive protection from physical activity. In their study recently published in PLOS ONE, Adam Brockett and colleagues report that running enhances performance on various cognitive tasks, improvements which may be mediated by changes in astrocytes, the lesser appreciated brain cells.

Running selectively boosts some cognitive functions

To manipulate levels of physical activity, rats were divided into a group of runners who were allowed free access to running wheels for 12 days, and another group of sedentary controls. Prior studies have shown that running improves performance on tasks requiring the hippocampus, like learning and memory. Here, the runners and non-runners were subjected to three tests to determine how exercise affects cognitive functions that are not dependent on the hippocampus. An object-in-place task, which tests how well rats remember the location of previously encountered objects, relies on the medial prefrontal cortex, hippocampus and perirhinal cortex. A novel object task, in which rats distinguish novel from familiar objects, selectively depends on the perirhinal cortex. Lastly, a set-shifting task, supported by the orbitofrontal and medial prefrontal cortices, measures attention and cognitive flexibility.

Compared to their non-runner companions, the runners performed better on the object-in-place test and on several measures of the set-shifting task. However, there were no differences between runners and non-runners in performance on the novel object recognition test. Of course, the cognitive benefits of running don’t end here, since many cognitive domains were not assessed in this test battery. But these findings highlight a striking selectivity of the brain-boosting powers of exercise. In particular, they suggest that running may enhance functions that specifically depend on the medial prefrontal and orbitofrontal cortices, along with the hippocampus, but it does not appear to modulate perirhinal-dependent functions.

Cognitive enhancement is linked to astrocytes

Although behavioral changes provide a window into the underlying neural events, they do not tell the complete mechanistic story. To directly examine how running affects the brain, the researchers assessed changes to both neuronal and non-neuronal brain cells. Running induced widespread neuronal changes, including higher levels of pre- and postsynaptic markers throughout the brain (including in the hippocampus and orbitofrontal, medial prefrontal and perirhinal cortices), and increased density and length of dendritic spines in the medial prefrontal cortex. While these effects suggest that exercise elicits generalized synaptic changes, they do not explain why particular cognitive functions are selectively boosted over others.

The researchers therefore looked for this crucial link to behavior in astrocytes. As Brockett explains, “We hypothesized that all cells likely change as a function of experience. We chose to focus on astrocytes because there is lots of evidence suggesting that astrocytes could be implicated in cognitive behavior. Loss of astrocytes correlate with impairment on a cognitive task and astrocytes connect the majority of neurons to blood vessels. They extend numerous processes that envelop nearby synapses, and gliotransmitters have been implicated directly in LTP-induction.”

Confirming their suspicions, in runners, astrocytes increased in size (Figure, A-B) and showed more contacts with blood vessels (Figure, C-D). But these changes only occurred in the hippocampus, medial prefrontal cortex and orbitofrontal cortex – critically, all regions that support the tasks showing running-related improvement. In contrast, running did not alter astrocytes in the perirhinal cortex, a region necessary for novel object recognition, which did not benefit from running. Thus, while running modified both neurons and astrocytes, the pattern of selective cognitive enhancements corresponded only with changes to astrocytes.

In the hippocampus, medial prefrontal cortex and orbitofrontal cortex, astrocytes were larger and made more contacts with blood vessels for rats who ran than those who did not. Brockett et al., 2015

In the hippocampus, medial prefrontal cortex and orbitofrontal cortex, astrocytes were larger and made more contacts with blood vessels for rats who ran than those who did not. Brockett et al., 2015

Implications for the active human

Although the varied and widespread cognitive benefits of exercise have long been appreciated, this study provides some of the first insight into the remarkable selectivity of these enhancements. Follow-up studies will help elucidate why, from both biological and evolutionary perspectives, running would demonstrate such selectivity. Might, for example, attention or task-switching abilities have been more important than object recognition for the efficiency of both animals and our persistence-hunting, distance-runner ancestors? Does running more heavily recruit certain brain regions over others, making them more susceptible to remodeling?

Given the cognitive and neurobiological differences between rats and humans, future research will be important to help extrapolate beyond rodents. Currently it’s unclear how different forms of exercise enjoyed by humans – for instance, swimming, yoga or strength training – uniquely influence distinct cognitive functions. According to Brockett,

“There is a lot of evidence that running has numerous beneficial effects on rodent and human cognitive functioning, but it is likely that aerobic exercise in general is responsible for these effects rather than running per se.”

Perhaps most notably, these findings add to the growing pool of studies underscoring the importance of astrocytes in neural processes that support cognition, and reveal a novel role for these cells in experience-dependent plasticity. As Brockett explains:

“Astrocytes are a unique cell type that haven’t been explored as much as neurons by the field of Neuroscience at large. Few studies have directly examined the role of astrocytes in complex behavior, and this was our first attempt at investigating this question.”

References

Alaei H, et al (2007). Daily running promotes spatial learning and memory in rats. Pathophysiology. 14:105–8. doi:10.1016/j.pathophys.2007.07.001

Brockett AT, LaMarca EA, Gould E (2015) Physical Exercise Enhances Cognitive Flexibility as Well as Astrocytic and Synaptic Markers in the Medial Prefrontal Cortex. PLoS ONE 10(5): e0124859. doi:10.1371/journal.pone.0124859

Gibbs ME, O’Dowd BS, Hertz E, Hertz L (2006) Astrocytic energy metabolism consolidates memory in young chicks. Neuroscience 141(1): 9-13. doi:10.1016/j.neuroscience.2006.04.038

Henneberger C, Papouin T, Oliet SH, Rusakov DA (2010). Long-term potentiation depends on release of D-serine from astrocytes. Nature. 463:232-6. doi:10.1038/nature08673

Kramer AF, Erickson KI (2007). Capitalizing on cortical plasticity: influence of physical activity on cognition and brain function. Trends Cogn Sci. 11: 342–8. doi:10.1016/j.tics.2007.06.009

Marlatt MW, Potter MC, Lucassen PJ, van Praag H (2012). Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Dev Neurobiol. 72:943–52. doi:10.1002/dneu.22009

van Praag H, Kempermann G, Gage FH (1999). Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 2:266–70. doi:10.1038/6368

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#PLOS #SfN14 Highlights: Exercise, Energy Intake and the Brain

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 PraagMonika FleshnerMichael Schwartz and Mark Mattson discussed the mechanisms underlying the brain-energy relationship.

FLESHNER

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?

Animals of all types love to run!

Animals of all types love to run!

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

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.

Running seems to allow me, ideally, an expanded consciousness in which I can envision what I’m writing as a film or a dream. — Joyce Carol Oates

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

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