#SfN13 Running boosts cognition by increasing aerobic capacity

Poster: 671.Learning and Memory: Genes, Signalling and Neurogenesis II.

120228mde186_012-620x340

Running for health. Source: http://www.stthomas.edu/

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

cardio-rats-on-treadmill

Rats on treadmills. Source: http://healthyurbankitchen.com/

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

rat-cartoon-0050-couch-potato

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).

Screen Shot 2013-11-16 at 7.50.14 PM

Hippocampal GR negatively regulates the stress response. Source: http://learn.genetics.utah.edu/content/epigenetics/rats/

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

#SfN13 Adult neurogenesis and the fluidity of memory flow

Poster III32. Adult neurogenesis protects against proactive interference.

JR Epp, R Silva Mera, LCP Botly, AC Gianlorenco, S Kohler, SA Josselyn, PW Frankland. Hospital For Sick Children, Toronto, ON, Canada; Federal Univ. of Sao Carlos, Sao Carlos; Univ. of Western Ontario, London, ON, Canada

Think about the last time you started up iTunes in search of a song. Every flick of your finger brought a new, dazzling piece of cover art into view. With one goal in mind, you fixed your gaze steadily on the centre of the screen, barely noticing as previous covers gradually drifted from your sight and disappeared from your mind.

Coverflowitunes7mac

Need a reminder? Cover Flow, iTunes. Source: wikipedia.com

This is how I picture memory. As we go through our daily lives, new memories silently replace older ones that are similar in context and scheme. The neurobiology behind this “refreshing” of memory is mind boggling in complexity and not well understood. Now, researchers from the Hospital for Sick Children in Toronto, Canada have uncovered a potential, if somewhat surprising, mechanism – adult neurogenesis.

Throughout our adult lives, the olfactory bulb and the dentate gyrus constantly produce new neurons; rapidly in infancy then gradually slowing as we age. Increasing adult neurogenesis in the dentate gyrus, either through drugs or exercise, helps the brain encode and differentiate between two or more similar memories. As such, high rates of neurogenesis have always been considered a “good” thing: more computational power, better memory.

Yet as new neurons reach out and connect into an existing neural network, it inevitably disrupts old information stored within. Following this line of thought, could adult neurogenesis paradoxically deteriorate existing memories?

Researchers first trained adult mice on a spatial recognition task. Picture a large pool filled with murky water with a platform hidden just beneath the surface. Mice are efficient swimmers, but they prefer to relax on the platform (who doesn’t?) if given the chance. A few training sessions later, all the mice managed to find and remember the location of their resting spot. Researchers then separated them into two groups: the “couch potato” group was housed in a standard cage; the “runner” group was given a running wheel. Mice are like your average pet gerbils – give them a wheel and they’ll happily go at it for hours.

4 weeks later, compared to the couch potatoes, the runners had significantly more new neurons in their dentate gyrus. When challenged with the same water maze, a clear difference in performance emerged. Compared to sedentary controls, the runners had a hard time homing in on the right spot. They spent much less of their time circling waters close to the platform, suggesting that their memory of the location had deteriorated by a greater extent. On the contrary, when researchers used a chemical-genetic method to eliminate new neurons in another cohort of water maze-trained mice, they remembered the platform location even better than sedentary controls.

Before you go and throw your running shoes out the window, pause and consider this: far from disadvantaged, the runners’ memories were more “flexible”. When researchers covertly moved the platform to a new location, runners learned much faster than their sedentary peers. Conversely, mice with disrupted neurogenesis stubbornly clung onto their old outdated memory, taking longer than controls to find the new platform location in every single training session. These changes in memory flexibility weren’t a generic effect of running but a specific result of neurogenesis: when runners had their numerous new neurons ablated, they behaved just like sedentary controls – better retention, slower relearning.

Incredibly, neurogenesis only seems to help with learning new information that is highly similar to that previously remembered. Researchers trained mice to discriminate between two boxes: one was shaded on one side and smelled of coffee; the other was striped with a hint of cinnamon. A month later, researchers swapped the odours between the two boxes. Once again, mice that ran during the interim learned the reversed odour-box pairings faster than their sitting peers. However, when researchers trained these mice in a similar task with two completely new odour (ginger, thyme)-box pairings, both groups learned at the same rate.

Taken together, it seems that adult neurogenesis after learning weakens old memories, which in turn facilitates learning of new but similar information. This is not to say that adult neurogenesis induces a state of tabula rasa; the data clearly shows that existing memories are weakened, not completely wiped clean. In a sense, adult neurogenesis tips the static-fluid memory scale just enough so that new information about the environment can be incorporated, either through altering the original memory trace or the formation of a new one. Hence, we live and thrive in the present.

There are cases where we resist: when learning a new language, you often automatically refer to a more familiar language for guidance – a headache dubbed “proactive interference” by psychologists. This study suggests that maybe you should close your books and go for a run. Come back later and who knows? You just might learn that second language faster.

My previous posts on adult neurogenesis can be found here.

#CAN13 Why you don’t remember your days as a baby

Poster: Inhibiting hippocampal neurogenesis protes memory persistence in infant mice. Axel Guskjolen, Sheena Josselyn, Paul Frankland. University of Toronto  the hospital for sick children.

baby_mice_by_servaline-d2yg1i2

Why don’t we remember 😦 Source: http://fc00.deviantart.net/

I don’t know if you were ever forced to watch your baby videos with an SO. It’s MORTIFYING. I remember staring in horror as baby-me yanked off her dress, ran around butt naked, chasing ducks and doing other unspeakable things (long story).

Thankfully, I don’t actually remember any of my baby days. Nor, probably, do you. This is due to something called “infantile amnesia”. We don’t really know why this happens. Some think it’s because babies need to develop language before they can describe and encode events. Others think babies don’t have a representation of themselves, so to babies, “there is no me”. Unfortunately, none of these theories tell us anything about what’s going on in the brain to mediate baby forgetfulness.

Researchers now think that neurogenesis may the key. After birth, our brains continually produce new neurons, rapidly at first, then gradually slowing down as we age. Adult neurogenesis adds more functional units to the brain, increasing its computational power. In adults, it’s tightly linked to the formation of new memories.

But neurogenesis may have a “dark side”. By elbowing their way into existing networks, new neurons may disrupt the old memories stored within. Baby brains – in mice and men – generate A LOT of new neurons. Is this why they forget?

Researchers used a genetic-chemical method to selectively kill off newborn neurons in a group of baby mice (17 days old, not yet weaned and super cute!). They then trained these mice, along with normal baby and adult controls, to associate a box with a nasty foot shock. Mice hate electrical shocks as much as you; they quickly learned to fear the box.

28 days later, the adult mice still recalled the trauma: when placed back into the box, they froze in fear. Normal baby mice, however, went about their merry ways – they’ve forgotten that the box is a dangerous place. Further testing showed that the memory was even shorter-lived than 28 days; in normal baby mice, it lasted more than a day, but less than a week.

New neurons generally need a week to mature and “infiltrate” into the brain’s network. Researchers think that is why the “creepy-box” memory still lasted a day in normal mice: the newborn neurons simply didn’t have enough time to “do its thing”. But give it a week, and the memory’s gone (or repressed so that the mouse can’t retrieve it. We don’t really know.).

After inhibiting neurogenesis, however, a completely different picture emerged. These mice froze 18% more than their normal peers, which is quite significant. This tells us that they, on average, remember that the box is a terrifying place. The only thing that sets them apart from normal baby mice is their inhibited neurogenesis. These results, then, strongly suggests that neurogenesis is one of the factors that drive babies to forget.

This is the first study to show that neurogenesis may be involved in infantile amnesia. It also offers a biological reason to why we forget. Next up, the researchers want to know if it’s possible for a baby memory can persist into adulthood by inhibiting neurogenesis. It also opens questions on the opposite end of the age spectrum. Elderly people have massively reduced rates of neurogenesis. If, and how does this influence their lifetime of memories?

Blood magic: old blood ages the young

“Our ancient countess was refused her desires will
To bathe in pure fresh blood
She’d peasant virgins killed

Elizabeth, in the chasm where was my soul
Forever young, Elizabeth Bathorii in the castle of your death
You’re still alive, Elizabeth”

                                                                        -“Elizabeth”, Ghost 

As folklore has it, Elizabeth Bathorii, Countess of Hungary, often bathed in young virgins’ blood to keep her beauty and youth. Macabre, no? As repulsive as it sounds, she might actually be on to something.

When we age, our brain gradually looses the ability to give birth to new neurons (neurogenesis). This sad decline is linked to impairments in cognitive functions such as learning and memory. The brain, like any other organ, feeds off of nutrients and chemicals in the BLOOD to keep it going. This made researchers wonder: is something in the blood affecting neurogenesis as we age?

Villeda SA et al (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 447: 90-94

To explore this, researchers hooked up the circulation of young and old mice (with young-young & old-old pairing as control) so that their blood intermixed. This incredibly cool technique, called “heterochronic parabiosis”, has been around for over 150 years. It’s often used to look at circulatory factors in immunology, metabolism and aging.

Screen Shot 2013-05-19 at 8.23.29 PM

Yellow is young, grey is old. Looks like an intense surgery!

Several weeks after the surgery, researchers examined the animals’ brains to look for changes in neurogenesis. Young mice, when linked with older mice, had significantly fewer newly born neurons and neural progenitor cells than young-young controls. This impacted their brains’ functionality: fewer neurons fired together after an electrical stimulus, and those that did refused to maintain their enhanced signal transmission for long. In stark contrast, old mice seemed rejuvenated from sharing blood with the young, with dramatically increased neurogenesis and neural stem cells than their old-old counterparts.

Screen Shot 2013-05-19 at 8.23.44 PM

Vat is dis magic? Blood!

Further experiments (as pictured above) confirmed blood as the bearer of youth (and aging). Researchers isolated the liquid component (plasma) of young and old mice, and injected it multiple times into young mice. In 10 days, old plasma-receiving mice rapidly aged, showing lower neurogenesis and deteriorated memory. This is amazing, since it suggests that factors in old blood can overcome youth-promoting factors in young blood, ending in an aged phenotype.

The authors then worked some proteomics magic, and isolated a cytokine called CLL11 that seemed to be mediating the “aging” effect. CLL11, an obscure protein in neuroscience, is secreted from the intestine and smooth muscle and mostly involved in the allergic response. CLL11 increased with aging in mice and men, as well as in young mice that have been hooked up to old mice.

Is CLL11 the harbinger of aging? Researchers injected the protein into young mice, and indeed found decreased neurogenesis after 10days. This was blocked if an antibody against CLL11 (which neutralizes it) was also given. So the observations seemed specific to CLL11. This cellular-level decline in brain function paralleled a functional deterioration in memory. As seen below, when dropped into a big mater maze, young mice usually rapidly learn to find a hidden platform that they can rest on (training phase). However, young mice receiving multiple doses of CLL11 gradually forgot the location of their sanctuary, swimming around in circles, trying to find the platform in vain (testing phase – see how CCL11-injected mice make more mistakes?).

Screen Shot 2013-05-19 at 8.32.45 PM

CLL11 is clearly promoting brain aging. But maybe the protein isn’t directly inhibiting neurogenesis, instead indirectly affecting the brain through primary effects on the body? In one last experiment, researchers amped up CLL11 in young mice through several abdominal injections. They then specifically neutralized CLL11 in the hippocampus, a part of the brain important for learning and memory. This was sufficient to rescue the decline in neurogenesis, suggesting CLL11 is directly linked to brain aging.

1-s2.0-S1568997212002728-gr1

But…but!! No one wants to accelerate aging! What about eternal youth?
Source: SA Villedaa & T Wyss-Coraya (2013). The circulatory systemic environment as a modulator of neurogenesis and brain aging. Autoimmunity Reviews 12 (6): 674–677

 So science is saying old blood can age the young, but what about the other way around? Can young blood slow or stop aging? While premature and unpublished as of now, further studies from these researchers show that blood from the young can rejuvenate old mice, both in terms of neurogenesis and memory. However, they don’t yet know which proteins are driving the effect. In a recent published study, another group used the same “blood-to-blood” technique to identify a blood-borne factor that reversed aging of the heart. Finally, in a study in Nature, researchers identified gonadotropin-releasing hormone (GnRH), a circulating peptide decreased in old age, as an important factor in aging. Giving GnRH supplements to aged mice not only increased neurogenesis, but also slowed WHOLE BODY aging (covered astutely –as always- by Scicurious and Ed Young).

This (obviously) doesn’t give you free reins to hunt down and drink the blood of the young. Not that you would. Or want to. We’re not sure if the same anti-aging effect happens in humans. (However, there are cases of humans drinking human blood, such as “witches” in certain cultures who drink blood as part of rituals and ceremonies. I’d love to know if & how their brains are changed.) But scientists seem optimistic. To quote the study’s lead author: “Do I think young blood could have an effect on a human? I’m thinking more and more that it might.”

ResearchBlogging.org
Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, & Wyss-Coray T (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 477 (7362), 90-4 PMID: 21886162

ResearchBlogging.org
Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, Sinha M, Dall’osso C, Khong D, Shadrach JL, Miller CM, Singer BS, Stewart A, Psychogios N, Gerszten RE, Hartigan AJ, Kim MJ, Serwold T, Wagers AJ, & Lee RT (2013). Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy. Cell, 153 (4), 828-39 PMID: 23663781

ResearchBlogging.org
Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, & Cai D (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature, 497 (7448), 211-6 PMID: 23636330

What makes me, me? The cellular correlates of individuality

Somewhere in Germany, a group of 40 genetically identical females are being constantly watched. Implanted with radio-frequency identification transponders (RFID) since 4 weeks old, they are allowed to roam free in a rich, 5-storey mansion, with 20 antennas monitoring and recording their whereabouts. 3 months later their brains will be examined for traces of emerging personalities.

While sounding sinister, that was the set up of an experiment investigating the neurobiological reflections of individuality. Why is it that maternal twins, growing up in the same environment, nevertheless develop different personalities? What processes in the brain are responsible for this effect? And the age-old question: what makes me, me?

twin mice

Why do genetically identical mice have different “mouse personalities”? Source: http://vetmed.duhs.duke.edu/

Freund J et al (2013) Emergence of Individuality in Genetically Identical Mice. Science, 340 (756).

Scientists set out with the idea that the way individuals interact with the environment will cause the brain to physically change. Personalities, then, emerge as a result of these changes. This simple hypothesis is –unfortunately- very hard to prove experimentally, since brain rewiring happens at both synaptic and network levels. This makes changes very hard to track.

Another way to approach this is to look at adult neurogenesis, or the birth of new neurons. We know that interesting and new environments trigger the brain to generate new neurons, which integrate into existing networks and causing the brain to change. Could it be then, that twins develop different personalities because of differences in neurogenesis?

Screen Shot 2013-05-10 at 3.58.02 PM

Creepy, but still a paradise.

Researchers tagged 40 inbred young female mice with RFIDs and followed them for 3 months as they explored their 5-storied mouse paradise. During this time, the “blank slates” increasingly shed their “sameness”: some roamed every corner of the mansion, spending most of their time feeding their wanderlust; others stayed near their home area, only occasionally venturing out of their comfort zones. Many didn’t seem to care where they stayed.

3 months later, all of the mice grew bigger brains with many new neurons and astrocytes (“supporting” cells). This isn’t surprising, since physical activity by itself stimulate neurogenesis. However, mice that regularly explored large areas had significantly more new neurons than those that stayed put. In other words, in each animal, the degree of exploration positively correlated with the amount and speed of new neurons born. Looking at all the rats as a group, the increasing difference in exploratory behavior could also be partially explained by different levels of adult neurogenesis.

What to make of all this? We know for sure that adult neurogenesis has something to do with the divergence of mouse personalities. This could mean many things. Different exploratory behaviors may be due to differences in the mice’s ability to generate new neurons to begin with. Although genetically identical, minute changes may still happen in the genome during gestation, which could account for differences in neurogenesis. Conversely, mice may have equal ability to generate new neurons, but those that explore more are cognitively challenged more, hence give birth to more new neurons as an adaptive response. Or perhaps, the mice differed in their capability for neurogenesis (amount, speed) at the beginning, which was further amplified by their different interactions with the environment. Or maybe neurogenesis isn’t even an important factor – perhaps small changes in the genome or how genes are expressed change the animal’s perchance for exploration at birth, and it’s subsequent interaction with the environment is reflected in it’s level of neurogenesis.

correlation

How to interpret the data? Just keep in mind: correlation does not imply causation. Source: xkcd.com He’s awesome.

As of now, we don’t know the cause-and-effect of neurogenesis and personality. What we do know is that the brain is extremely malleable, constantly re-sculpted by our interactions with the environment, which could underlie something as essential as our personalities. Perhaps the animal model in this study can –in future studies- help us provide a scientific and neurobiological answer to the big question: what makes me, me?

ResearchBlogging.org
Freund, J., Brandmaier, A., Lewejohann, L., Kirste, I., Kritzler, M., Kruger, A., Sachser, N., Lindenberger, U., & Kempermann, G. (2013). Emergence of Individuality in Genetically Identical Mice Science, 340 (6133), 756-759 DOI: 10.1126/science.1235294

#SfN12 Tipping the memory scale

Post-learning increase in adult hippocampal neurogenesis leads to forgetting

*K. G. AKERS, A. MARTINEZ-CANABAL, A. L. WHEELER, L. A. RESTIVO, A. J. GUSKJOLEN, H. SHOJI, T. MIYAKAWA, S. A. JOSSELYN, P. W. FRANKLAND

New neurons are constantly produced in the brain, where they slowly mature and integrate with existing neurons into neural networks. While the precise function of these new neurons are not very well understood, researchers believe that they may be part of the reason why anti-depressants work. Theses adult-generated neurons also seem to be involved in boosting memory performance – after all,  the more computational units, the more computing power, right? Along this line of thought, may labs have shown that if you artificially enhance neurogenesis through exercise or anti-depressant administration in rats, they are able to separate two very similar memories better.

However, newly generated neurons can also disrupt existing neuronal networks when they integrate into an existing network. Since established memories are stored in these networks, it is conceivable that old memories may be disrupted during enhanced neurogenesis.

To show this, researchers exposed adult rats to a certain room, waited for 28 days before putting the rats back into the room and shocking them with an electrical zap. During the wait, one group of rats were allowed to chill out as usual, while the other was subjected to an intense running regime, which has previously been show to increase the production and survival of new neurons. After the shock, the rats were put back into the room to see whether they remembered it as a “bad” place, which can be measured by how much they froze. This is called one-trial learning. Since the rats were shocked only once immediately after being placed in the room, for them to actually associate the room with the shock, they would need to remember that they had previously seen the room 28 days ago. Hence, if they freeze, it would mean that they still retained the memory of the room 28 days later.

What was surprising was that the running rats showed less freezing, meaning that they had harder trouble remembering the room than rats that didn’t run. This seems to suggest that running-induced increase in new neurons disrupted the memory of the room.

If this were true, other methods that increase neurogenesis would show the same trend. And indeed, when adult rats where given certain drugs that help the brain produce more neurons (such as fluoxetine, the antidepressant), the adult rats showed less freezing, hence less memory of the room in which they were shocked.

Young animals have a much higher rate of neurogenesis than adult rats. Since the neural networks are constantly being built and destroyed in young animals, the researchers reasoned that decreasing neurogenesis in young rats could help stabilize an existing memory. The researchers trained a group of infant rats in the same task, and showed that indeed, a drug that slowed the production of new neurons led to an increase in the retention of the memory of the room.

So if new neurons disrupt old memories, how is this beneficial to a young animal?  Infants are bombarded constantly with new information, and it makes sense to update an existing association when the old memory is no longer true. To test this, the researchers trained rats on a Morris Water Maze task, where the rats had to swim in a big tub of milk until they found a hidden platform to rest on.  As before, the rats that had more new neurons had a tougher time finding the platform, meaning they remembered its location less clearly. However, when the researchers sneakily moved the platform to a new location, the rats with increased neurogenesis learned faster, suggesting they were better able to update their memory.

This is a super cool study showing that increased production of new neurons may not benefit memory per se, but is more important in allowing memory flexibility.