Poster: 671.Learning and Memory: Genes, Signalling and Neurogenesis II.
There’s no doubt that aerobic exercise benefits the brain. Running, for example, reduces anxiety, improves sleep quality, boosts learning of a new task and maintains spatial memory*. Many of these mental perks stem from an increase in adult neurogenesis; that is, the birth of new neurons in the hippocampus and the olfactory bulb. (*That is, if rats run before new learning. See here for more.)
Yet perhaps the most apparent health benefit of running is increased cardiovascular and lung function. As any runner can attest to, an initially exhausting 10k soon becomes a breeze – you’ve increased your aerobic capacity. This led researchers from Duke University to wonder: is improving exercise capacity –by whatever means – necessary and sufficient to boost neurocognitive function?
Better bodies, better minds
Just like us humans, rats have an innate sensitivity to the effects of exercise. After the same 8-week running regime, high-response rats drastically increased their maximal capable running distance (~75%), while low-response rats barely improved (~22%). Surprisingly, compared to their sedentary peers, only high-response rats showed elevated neurogenesis in the dendate gyrus, a subregion of the hippocampus, as compared to their sedentary peers.
One hypothesized function of the dentate gyrus is pattern separation, or VERY simply put the discrimination between two very similar spatial contexts or things (Jason Snyder of Functional Neurogenesis fame has a great blog post on the matter). Researchers decided to challenge these rats with two Lego pyramids that only differed in the colour of their tops – imagine two Christmas trees with either a yellow or orange star. After the rats familiarized themselves with the yellow-topped Lego, researchers waited a minute before presenting them with both. High-response runners (but not their sedentary controls) instantly realized something was up – they approached and sniffed the new construct in earnest, ignoring the old familiar one.
Low-response runners, on the other hand, behaved just like their sitting peers, spending a similar amount of time with both objects. Low-responders had no problem with their memory; when faced with a mug and a can, they could easily discriminate between the two. They just couldn’t pick out minute differences in the Lego pieces, a skill often attributed to enhanced neurogenesis.
These data, perhaps somewhat dishearteningly, suggest that running doesn’t always boost brainpower – neurocognitive benefits only occur in tandem with improvements in aerobic fitness, as measured by total running distance until exhaustion. These results parallel that of a human study, in which increased lung capacity after training correlated with better performance on a modified pattern separation task (although understandably they did not show enhanced adult neurogenesis, so it’s hard to attribute behavioural output to increased new neurons per se).
Running-improved aerobic capacity seems to be the crux to exercise-induced brain benefits. But is running really needed? To explore this idea further, researchers decided to take treadmills out of the equation and focus on genetic differences in aerobic fitness.
Innate aerobic capacity accounts for cognitive benefits
Allow me to introduce to you the low and high capacity runners. Selectively bred for their capability (or not) to “go the distance”, these rats differ up to 3 times in a long-distance standard fitness test, without ever setting foot on a treadmill. At 10 months old, they also had a two-fold difference in the total number of newborn neurons in the dentate gyrus as a result of increased neuron survival, which increased to three-fold at 18 months old.
Researchers took sedentary rats from both groups and challenged them to the Lego task described above. High capacity runners significantly outperformed their low capacity peers, expertly telling apart the Lego constructs. Similarly, in an object placement task in which researchers minutely moved one of two objects, low capacity runners could not identify the moved one after an hour’s delay, though they managed if the wait was only a minute. High capacity runners, on the other hand, excelled in both cases.
These results argue that high aerobic capacity in and of itself promotes pattern separation. But what if, unbeknownst to researchers, high capacity runners were maniacally jumping around everyday in their home cages? A few days of stealthy observation proved this wrong; paradoxically, low – compared to high- capacity runners were much more hyperactive. They also seemed more outgoing in a social interaction test, and exhibited a lower tendency to generalize trained fear from one context to another.
Running-induced neurogenesis is generally considered to ease anxiety. So why do high capacity runners (with higher rates of neurogenesis) seem more neurotic?
Born to laze, born to run
Sitting on a couch is really not that stressful. Don’t make me run!
Running is physiologically stressful in that it increases the level of corticosterone (CORT), a stress-response hormone. Unlike chronic stress that continuously elevates CORT, running only induces a transient, benign increase that quickly returns to baseline after recovery.
Researchers trained low- and high- capacity rats on treadmill running 5 days a week for a month. By the end, both groups showed increased running capacity, though trained low-capacity rats were only as good as untrained high-capacity ones (life’s unfair!). However, their acute stress responses drastically differed in a running-stress test.
Untrained low-capacity rats remained calm throughout the test, as measured by unchanging CORT levels. “They waddled on the treadmill for a bit, got tired and gave up.” said the researcher, “so they really weren’t that stressed out.” Trained low-capacity rats however hated the treadmill – their CORT shot through the roof. “You’re chronically forcing them to do something they’re terrible at, of course they’re going to be stressed out” explained the researcher, “and once they’re done, their CORT goes back to normal.” (I’m paraphrasing.) While this scenario is certainly possible, an alternative explanation is that only trained low-capacity rats were able to exercise to the point to induce a normal elevation in CORT levels; untrained rats simply don’t workout hard enough.
Intriguingly, untrained high-capacity rats had elevated levels of CORT during the running test, while previous training eliminated this response. Why? Researchers believe that chronic running habituated them to the stressor: “You know when you have this itch to run? You get stressed out when you can’t, and feel relieved when you finally do exercise.” In other words, these rats were “born to run”.
On the cellular level, running did not significantly increase neurogenesis in the ventral hippocampus in either low- or high-capacity rats, which I find rather surprising. Finally, high-capacity rats (compared to low) had less Mmneralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the amygdala and hypothalamus, but not in the hippocampus. This is also surprising, as MRs and GRs in the hippocampus are crucial for negative feedback to the stress response axis (below).
Taken together, these data point to increased aerobic fitness– through genetic means or exercise- as the key to enhancing neurocognitive function in rats. Inbred differences in aerobic fitness may alter how one responds to exercise (and perhaps other types of) stress.
These studies beg the question: what if we could artificially mimic the effects of exercise (pharmaceutically or otherwise) and reap its benefits? While “exercise pills” may not necessarily benefit healthy individuals, they could potentially improve both physical and hippocampal health of the elderly or the disabled.
Such research is under way, though as of now the results are not yet convincing.
PS. This is the end of #SfN13 blogging. It’s been hectic, a bit overwhelming and a LOT of fun!! Thank you to all the presenters for your patience & feedback and the PIs who let me write about your work. Thank YOU for reading!
Regular research blogging will resume soon. Stay tuned!
671.01. CL Williams et al. Rats selectively bred for high running capacity have elevated hippocampal neurogenesis that is accompanied by enhanced pattern separation ability.
671.02. KM Andrejko et al. Rats selectively bred for high running capacity have elevated hippocampal neurogenesis that is accompanied by a greater expression of hippocampal glucocorticoid receptors and altered contextual fear conditioning.
671.04. JM Saikia et al. Treadmill exercise training only enhances neurocognitive function if it is accompanied by significantly increases in aerobic capacity. Duke Univ., Durham, NC; Univ. of Michigan Med. Ctr., Ann Arbor, MI