Top 10 science stories I wish I’d blogged about in 2013

As 2013 grinds to an end, the internet fills with reminiscence of the year’s top stories and moments. I, for one, especially can’t resist ruminating about the past, especially when packaged in a brain-tickling, “top n”  list form. Without further ado, here is my Top 10 list of the year: Science Stories I Wish I’d Blogged About.

Bonus. A List of Reasons Why Our Brains Love Lists. By Maria Konnikova.

To start off, why are we drawn to lists anyway? Is it due to the clean, structured organization that helps us navigate the material efficiently? Or is it more a product of our current “bite-sized” information culture? Maria has the answers.

10. Can we lessen the effects of fearful memories while we sleep?

Sleep therapy can change bad memories. By Helen Shen (original paper here)

Spontaneous activation of memories during sleep is generally thought to strengthen them. However, when researchers in Northwestern University repeatedly brought up a recently learned fear memory in their sleeping participants by presenting a fear-associated odour, the participants showed a smaller fear reaction to the odour after they awoke. According to the researchers, this is the first time emotional memories have been successfully manipulated in humans.

Similar: A gene for forgetting. MIT researchers identified a gene Tet1 that is critical for memory extinction in mice. Original paper in Neuron.

9. Men and women’s brains are wired differently. Is THAT why men can read maps better (or so the cliché goes)?

Here‘s one cover of the study that would let you believe that (gasp) it is indeed so!

Here are a few level-headed analyses that tackle the nitty-gritty of the study and how its conclusions got blown out of proportion. The bottom line? Brain scans don’t tell us anything about behaviour. Here’s the original paper for reference.

Are men better wired to read maps or is it a tired cliché? By Tom Strafford.

Men, Women and Big PNAS Papers. By Neuroskeptic.

Getting in a Tangle Over Men’s and Women’s Brain Wiring. By Christian Jarrett.

8. Mice inherent fears of their fathers. (And update) By Virginia Hughes.

You know how you are what your grandpa ate? Epigenetics offers an answer to how our interactions with the environment can influence the expression of our and our offspring’s DNA. However there is little evidence that stress and fear can directly change the germline, so that offsprings inherit the fear memory (or something akin to it) of their parents. (There was this interesting report earlier in the year on how cocaine-addicted sires lead to cocaine-resistant male pups through a purely epigentic means, though I remain skeptical.)

Virginia Hughes broke this story at the 2013 Society for Neuroscience conference. Since then, it has garnered plenty of attention from media and neuroscientists alike, with opinions from “deep scepticism” to “awe-inspiring”. Here’s the original paper if you’d like all the juicy details.

7. From Club to Clinic: Physicians Push Off-Label Ketamine as Rapid Depression Treatment. By Gary Stix

Ketamine, the clubbing sweatheart and horse tranquillizer, is now being repurposed as a fast-acting antidepressant; this is perhaps THE most breakthrough new treatment for depression in the last 50 years. In this 3-part series, Gary Stix explains the uprising of grassroots ketamine prescriptions, big pharma interest in the drug and how ketamine is directly the development of next-generation antidepressants.

6. Computer Game-Playing Shown to Improve Multitasking Skills. By Allison Abbott.

Rejoice, gamers of 2013! Not only has the year given us PS4 and Xbox One, this study from Nature has also given us an excuse to game (uh, or not): in subjects aged 60-85, playing a 3-D race car-driving video game reduced cognitive decline compared to those who didn’t.

Commercial companies have claimed for years that brain-training games help improve cognition; yet whether their games actually work is hotly debated (I’m looking at you, Luminosity!). In this new study, researchers from UCSF show that a game carefully tailored to a specific cognitive deficit can be useful, even months later. Unfortunately this doesn’t mean any ole’ video game will do. Shame.

5. 23andme versus the FDA.

I’m sure by now you’ve heard about the fight of the year.

David Dobbs has a full page of links over the 23andme and FDA food fight. What’s the big deal? Why did the FDA issue a cease and desist order? Is it simply a clash of cultures between the company and government department? Or are we selling out our own genetic data to the next-generation Google, and should we fear the services the company offers?

4. Sleep: The Ultimate Brainwasher? By Emily Underwood (Here’s another cover by Ian Sample).

Why do we sleep? Reasons range from learning and memory, metabolism and body-weight regulation, physiology, digestion, everything. A study this year proposes that sleep has another function: nightly cleaning, in which the cerebral spinal fluid washes a day’s worth of brain waste down the sewers. That is, if you’re a rat.

3. Death by sugar? by Scicurious.

With fat making a come-back, sugar and/or carbs are the devil this year. This study in Nature Communications says yes: when mice consumed a diet that has an equivalent amount of sugar to that of many people in the US, the animals’ health and reproductive ability declines.

However, as Scicurious astutely asked, can we really directly translate conclusions derived from mice to humans? Is sugar really that evil?

Here is another article on the topic by Ferris Jabr that’s well worth a read.

2. False memories implanted in mouse’s brain by linking portions of two real memories together. Wow. Just, wow.

False memory planted in mouse’s brain. By Alok Jha

Scientists Plant False Memories in Mice–and Mice Buy It. By Joel N. Shurkin

This is one paper I REALLY wish I had the time to cover when it first came out. An MIT group artificially connected the memory of a safe box and the memory of a footshock in another box to generate a new hybrid memory. This is not “implanting” a de novo memory – that is, researchers didn’t use electrical stimulation (or something similar) to generate a memory from scratch. The study also can’t tell us how false memories are generated biologically in our brains (ie linking imagined material to actual memories), but the study is genuinely fascinating all the same.

Here is a link to the paper, and here is the lead author doing an “ask me anything” interview on Reddit.

1. Knockout blow for PKMzeta, the long-term memory molecule. 

Single protein can strengthen old faded memories, Exposing the memory engine: the story of PKMzeta, and Todd Sacktor talks about the memory engine by Ed Yong

In a nutshell, previous studies have identified a single protein called PKMzeta that helps maintain long-term memory. Unlike other kinases (a type of protein involved in many cellular processes, including memory) PKMzeta is always active, and seems to help sustain the strengthening of connections between neurons during memory formation. Inhibit PKMzeta, and the memory’s gone.

These results spurred HUGH interest in the “memory molecule”, often with references to Eternal Sunshine of the Spotless Mind. However, things went for a downward spiral at the 2012 Society for Neuroscience conference, when researchers presented the first evidence that mice without PKMzeta had no impairments in LTP (long-term potentiation, widely considered a cellular mechanism for learning and memory) could still form memories. The two groups published their findings in early January 2013 in Nature (here and here).

These observations don’t necessarily mean that PKMzeta is not a memory molecule – it very well could be one of the MANY memory-associated proteins. Given the redundancy that often comes with evolution, it’s hard to believe that one particular molecule would be the sole guardian of our memories. The question remains whether PKMzeta is a MAJOR player, but overall, the debate is a cautionary tale against putting one molecule on the pedestal. So if (or when) you see another article with the headline “erasing a bad memory”, remember there’re plenty of other players in memory that you haven’t been told about.


The ancient marriage between music, movement and mood

Think back to that moment when you first heard your favorite song. What about it made you stop in your tracks? Was it the incessant buildup, soaring high, filling you with a sense of elation? The flirty high notes, light as wings, bringing a bounce in your step? Or the rumbling base drop, furiously cascading, sending shiver after shiver down your spine?


Feel the music. Source:

Music has always had a special place in my heart. Like many, I use it as an emotional outlet and a painkiller for physical aches. During one of my longer runs a while back I distinctively remember a sense of elation as a drum & bass piece with the perfect BPM came on. I matched my foot strikes to the beat, closed my eyes and ran in a state of pure euphoria. (It helped that I was one of the only people on a flat, spacious wall that hugged the ocean. I must’ve looked high.)

Since that run I’ve been musing over our relationship with music. Across the globe people describe intense pleasure from listening to music, grooving to music, exercising to music. What lies at the core of this abstract euphoria? What is it about our perception that allows us to experience all three in unison?

I hope to answer these questions with my new piece up at Scientific American MIND. It is science writing based on peer-reviewed literature; but it’s also my personal ode to music.

If you have a moment please check it out, and let me know what you think!

EditBeau Sievers, one of the authors of the study, kindly provided feedback on Twitter. She pointed out “The SciAm piece could be misread as saying Kreung music has no tuning, timbre, or scales—they do, they are just not Western.  Kreung mem music does have clear notes in it, articulated to evoke insect sounds—very ‘buzzy’ but still musical. Thanks for the very nice writeup!”

Hope this helped to clarify things!

Kudos to Virginia Hughes at National Geographic blogs (Phenomena: Only Human) for directing me to the cited studies. She has previously written about them individually on her blog. Her writing is FANTASTIC – if you’re not a reader yet, I highly recommend her work.

#SfN13 Running boosts cognition by increasing aerobic capacity

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


Running for health. Source:

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


Rats on treadmills. Source:

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).

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Hippocampal GR negatively regulates the stress response. Source:

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 Tackling depression from both ends

503.Mood Disorders: Preclinical Studies and Animal Models.

503.08. Characterization of CX614, an AMPAkine, as a fast onset antidepressant
Biomed. Sci., Florida State Univ., Tallahassee, FL

503.09. Vortioxetine improves a reversal learning deficit in rats induced by serotonin depletion or chronic stress. DA MORILAK, A WALLACE, A PEHRSON, C SANCHEZ-MORILLO; Pharmacol. and Ctr. for Biomed. Neurosci., Univ. of Texas Hlth. Sci. Ctr., SAN ANTONIO, TX; Lundbeck Res. USA, Paramus, NJ


People generally consider depression as something purely emotional – an inescapable distaste towards oneself, an unshakable apathy towards the world, a persistent slow, sticky feeling of exhaustion, as if walking the path of life with glue on both feet.

Yet depression has a strong cognitive component, one so powerful that some scientists believe it to be the root of emotional imbalance. Many sufferers describe their thought patterns as “stuck in a rut”, where they’re only capable of framing things in a negative light, thus seeing the world as pale and hopeless. This observation has prompted two groups of researchers to ask: can we treat depression by targeting cognitive inflexibility?

AMP-A(p) the synapse

Luckily for researchers from Florida State University, we already have a class of cognitive enhancers on the market. AMPAkines are known to enhance attention span and improve learning and memory in the elderly and those suffering from neurodegenerative diseases. These drugs get their name from strongly enhancing the function of the AMPA receptor as a positive modulator. Interestingly, ketamine, the club-drug-turned-fast-acting-anti-depressant requires AMPAR activation to work, suggesting that AMPAkines may not only alleviate depressive symptoms but also act more rapidly than traditional anti-depressants.

Researchers gave a group of young adult rats a single injection of either ketamine or CX614, one of the best-characterized AMPAkines. 24hrs later, they exposed the rats to water and measured how long they swam before giving up in despair. Compared to saline-injected control animals, both ketamine and CX614 reduced the amount of time they spent immobile, though ketamine was slightly more effective at the doses used.

In another cohort of rats, researchers used a stressor (they didn’t say what, but it could be anything from bullies to cats to robots) to acutely trigger depression-like symptoms. Rats have quite the sweet tooth; normally given the choice between sugar and plain water, they lap up the sweet stuff in earnest. However, once depressed, they seem to loose the ability to enjoy life’s pleasures and no longer prefer the treat. Once again, a single injection of either ketamine or CX614 restored their love for sugar within a day. Remarkably, the antidepressant-like effects of CX614 lasted up to 8 days, even longer than that of ketamine.

On the molecular level, many previous studies show that depression reduces the number of synapses, thus negatively affecting the way neurons communicate. In fact, ketamine is known to rapidly reverse this defect, which may be one of the reasons behind its anti-depressant effect. Does CX614 work in the same way?

Using brain tissue isolated from CX614-injected animals, researchers found that within 30min neurons in the hippocampus were actively making more proteins, as evidenced by increased activity of the protein translation machinery. At the same time, CX614 also triggered a cascade of molecular signalling to reconstruct and stabilize actin, a “skeletal” protein that helps a cell maintain or alter its structure.


Anatomy of a spine. Wikipedia

These two processes – protein translation and actin remodelling – allow neurons to form new spines, the little protrusions along dendrites that host synapses formed with (typically) another neuron. In other words, spines provide an anatomical structure for synaptic transmission. Although researchers did not directly prove their case with imaging techniques, these molecular changes certainly suggest that CX614 increases synapse formation.

Thus, like ketamine, AMPAKines may rapidly reduce depressive symptoms; unlike ketamine, they have very low potential for abuse. Whether their cognitive enhancing effects directly contribute to anti-depression though will have to be answered another day.

Flexible thoughts, sunny mind?

Researchers from the University of Texas and Lundbeck Research took the opposite approach – they picked an anti-depressant and investigated its cognitive enhancing effects. Vortioxetine is a selective serotonin reuptake inhibitor (SSRI) like Zoloft and Celexa. However, it also directly binds to and activates numerous types of serotonin receptors, giving it a unique pharmacological profile.

As mentioned above, patients with depression are often unable to flexibly reframe their thoughts. Neuroscientists can identify and measure a similar deficit in rats with a rather sneaky task. They first trained rats to dig for cheerios (yum!) from several pots, some of which smelled like cloves, others nutmeg; some filled with dry grainy sand, others with moist soft dirt. Unbeknownst to the rat, the digging material was just a distraction. Scent was the only clue they had to follow to find the treat.

After rats finally figured out the rules of the game, researchers suddenly switched the cheerios from the clove-sand pot to the nutmeg-sand pot, sat back, and watched how fast the rats updated their strategy as a measure of cognitive flexibility. In the first set of rats, researchers depleted ~90% of their serotonin levels with a chemical, thus coarsely mimicking the dearth of serotonin transmission seen in depressive patients. Unsurprisingly, they performed horribly, steadily going back to the original pot. However, when researchers gave them an injection of Vortioxetine 30min before testing, they rapidly ditched the old pot for the new.

Researchers then stressed a new group of rats with bouts of intense and unpredictable cold for 14 days straight. This treatment is often used to trigger deficits in reversal learning as well as depression-like behaviours (imagine being randomly thrown into a fridge for two weeks – you’d be constantly on edge and most likely depressed by the end too!). In the meantime, some rats received Vortioxetine in their food while others got placebo. In the end, those on placebo failed miserably on the cheerio-finding task, while those treated with Vortioxetine performed just as well as non-stressed controls.

These results suggest that Vortioxetine, an SSRI-type antidepressant, improves cognitive flexibility in stressed-out (and perhaps depressed) rats. However, the researchers did not show whether it also relived depressive-like symptoms at the doses used, how long the effect lasted, or whether the drug would perform in other (arguably more common) models of depression such as social defeat.

Taken together, these two studies complement each other beautifully, even though the results are still preliminary. Depression is a tough nut to crack, but the search for novel and fast-acting anti-depressants is in full swing. Among those presented at #SfN13 are the anesthetic gas isofluorane and the anti-cough medication dextromethorphan. Unfortunately as of now neither are ready for clinical use for depression.

The discovery of ketamine revolutionized the field of anti-depressant research in the last decade or so. Perhaps tackling depression on both cognitive and emotional ends – with cognitive enhancers or others – will prove to be even more effective at taming the beast.

Sappy little end-note: Back when I was studying pharmacy the best we could offer depressive patients were the atypical SSRIs, which takes weeks to months to start working. Many don’t respond to them at all and those who do built tolerance quickly. I’m so happy to have watched the story of ketamine unfold. If you’d like to know more, Gary Stix has a great 3-part series on Scientific American that’s well worth a read.

Check out my previous post on another potentially fast-acting anti-depressant L- acetyl-carnitine, a common fitness supplement.

#SfN13 Stressed out mice turn to carbs for comfort food

Poster ZZ3 Ghrelin protects against stress by promoting the consumption of carbohydrates.T. Rodrigues. Z. Patterson. A. Abizaid. Carleton University, Ottawa, ON, Canada

In this world nothing can be said to be certain, except death and taxes.– Benjamin Franklin

Personally, I’d add stress to that.

There’s no question that chronic stress is a killer. Handled badly, stress can lead to anxiety, memory impairments, cardiovascular disease and sleep disorders. We all have our own strategies for coping with stress, some healthier than others. Me? I turn to food.


Cavities galore or stress relief? Source: 

Apparently, so do bullied mice. Mice are social creatures; when housed together, larger and meaner ones will quickly assert dominance. The little guys have it rough, usually showing signs of anxiety, depression and increased body weight within weeks.

The reason for their weight gain can be traced back to an increase in ghrelin, a hunger-causing (orexigenic) hormone produced in the stomach. Once released, ghrelin travels to the brain and binds to its receptors to increase calorie consumption. But not all foods are equal; new research from Carleton University suggests that ghrelin promotes the intake of comfort foods – specifically, carbohydrates- because they decrease the level of circulating stress hormones such as corticosterone.

In the study, researchers first measured the amount of chow that mice ate per day for 21 days. They then chronically stressed out one group of mice by putting a dominant bully into every cage; the two mice were separated by a see-through glass wall to reduce violence. Every day, the mice had 24hr access to a standard, high-carb chow and a 4hr-window to a fattier alternative. Compared to non-stressed controls, the bullied mice drastically increased their total calorie intake, paralleled by an increase in ghrelin levels but surprisingly normal corticosterone levels.

When researchers broke down in the increase in calories by the type of food, they uncovered an unexpected result: stressed-out mice did not eat more fat, but instead opted for more high-carb chow. In fact, this high-carb binge almost entirely accounted for the increase in total calorie consumption.

However, mice chow does contain ~50% of protein and fat. To rule out a preference towards these two macronutrients in combination, researchers repeated the experiment, but with sucrose solution as the alternative to high-carb chow. As before, stressed-out mice increased their intake of chow, but this time, they also doubled their intake of sugar water compared to their unstressed peers. At the same time, their corticosterone levels were normal, suggesting that they were coping fairly well in the face of daily terror.

Why is ghrelin triggering a preference for carbs? The answer might be internal stress management. When researchers feed both bullied and control groups the same standard chow (~50% carbs), effectively restricting access to stress eating, the bullied mice suffered numerous negative health effects. Their ghrelin and corticosterone levels shot through the roof. They had abnormally low blood sugar levels, signalling the onset of metabolic problems. They even showed signs of depression, refusing to swim when dropped into a deep container filled with water.

These data suggest that under stress, ghrelin levels rise and tip food preference towards high-carb rather than high-fat foods. To see if this is indeed the case, researchers turned to a strain of mice genetically engineered to lack ghrelin receptors. Normally, compared to wild-types, these mutants show similar patterns of eating and hormone regulation, although they tend to be slightly smaller. Once stressed, however, they didn’t respond by switching to the high-carb comfort chow, instead increasing their nibbling of fatty foods. Behaviourally, these mice could not cope – in the swimming task, they spent most of their time immobile, succumbing to their fates.

Researchers aren’t yet sure why ghrelin-induced carb – but not fat – intake helps to manage stress. One reason could be bioenergetics: stress alerts the brain that more energy is needed (and soon!) through ghrelin, which in turn increases the preference for glucose – a fast and efficient energy source. Or it could just be a matter of comfort. These mice grew up on standard mice chow, which just happens to be high in carbs. Perhaps, just like you and me, mice simply prefer familiar and comforting foods after a long, stressful day.

Shining light on the dark side of oxytocin

Almost everyone’s heard of oxytocin these days. Dubbed “the love/trust hormone” by pop neurosci, oxytocin is to “love” as dopamine is to “reward” – some truth, but WAY too oversimplified! Where to start? In the sack, oxytocin is involved in ejaculation latency, the big O and pair bonding. Out on the streets (or in labs), it helps people recognize facial expressions and recall others’ faces. It may enhance trust among strangers. It may be the key to monogamy, at least in prairie voles. It reduces anxiety and stress, and promotes social interactions. It may even tweak something as abstract as morality.

Screen Shot 2013-07-23 at 3.02.35 PM

Oxytocin’s functions are as complicated as its structure. Source: wiki

“So what if it’s not the love drug?” you might ask. Oxytocin still sounds like the most “amazing molecule in the world.” The problem is, individual people respond to oxytocin very differently. In one study, when socially anxious people were given oxytocin through inhalers, they remembered their moms as less caring and more distant. In another study in people with borderline personality disorder, oxytocin hindered trust and cooperation. Oxytocin also seems to ENHANCE – not mitigate as previously thought – fear and anxiety levels in people who’ve suffered through traumatic events. In these individuals, it even promoted stronger recall of bad memories.

Calling oxytocin the “love drug” is not only inaccurate, but also dangerous. Not recognizing this dark side of oxytocin exploits the vulnerable – those suffering from post-traumatic stress disorder, autism, depression or social anxiety disorder, who think that an internet-bought nasal spray will help them ease their illness. Understanding how oxytocin regulates fear and anxiety is especially important, as the hormone is currently being researched as a potential anti-anxiety drug.

We know a lot about what oxytocin does. We just don’t know how it’s doing it. Oxytocin is released by the hypothalamus, situated at the base of the brain. As a hormone, it circulates and acts throughout the body and the brain. Could it be that oxytocin is acting at different sites in the brain to produce diverse actions? Under what conditions will it promote fear and anxiety? How is it enhancing fear recall?

YF Guzmán et al. (2013) Fear-enhancing effects of septal oxytocin receptors. Nature Neuroscience, doi:10.1038/nn.3465

The authors of this paper tackled these questions head on with two strains of genetically modified* mice: one lacking, and one having more of the oxytocin receptor in an area of the brain called the lateral septal (LS). Just like small molecule neurotransmitters (think dopamine, serotonin etc), oxytocin needs to bind to its receptor to have an effect; manipulating receptor levels in essence eliminates or boosts oxytocin signalling. The researchers chose the LS to study as it contains large amounts of the oxytocin receptor (so under normal circumstances oxytocin is probably doing something there), and because it’s heavily involved in stress and fear. (* For those wanting the nitty-gritty, overexpression and knockdown was achieved through local viral injection of the appropriate vectors, not whole-animal knockdown)

Screen Shot 2013-07-25 at 12.14.10 PM

Contextual fear conditioning. Ouch!

Researchers first tested if oxytocin is directly involved in fear in non-stressed mice. They took the two mutants and normal mice and put them in a distinctive box. They then zapped the mice with a small shock. Mice like electrical shocks as much as you – they’ll quickly associate the box with the shock, and freeze in fear when they’re put back into the box a day later. The idea is, if oxytocin signalling in the LS is involved in enhancing fear, then having more oxytocin receptors should increase freezing.

Screen Shot 2013-07-24 at 12.55.22 PM

Which didn’t happen! As you can see, neither increasing (dark blue bar) nor decreasing (light blue bar) oxytocin receptors had an effect on freezing, compared to the controls (white bar). This suggests that in normal, unstressed individuals, oxytocin in the LS does NOT directly regulate fear and anxiety. Could it be that oxytocin plays a more modulatory role in fear then? As in, it will only promote fear when an individual is already stressed?

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Reminds my of my elementary school years. Sigh.

To test this hypothesis, researchers first needed to stress out the mice. While you can do it with robots, researchers settled on a more socially relevant method: social defeat. They put a large, aggressive bully into the mice’s habitat, and let the him intimidate the mice for 6 hours. Previous results tell us that social defeat increases oxytocin release in the LS, and if extended for long periods, can induce symptoms like depression and social withdrawal in the bullied. After a tortuous 6 hours, researchers removed the mice and once again, shocked them in a box and tested them for freezing a day later.

Screen Shot 2013-07-24 at 12.59.09 PMAs you can see in the left graph, social defeat dramatically increased freezing in normal mice (first two bars, WT/wild-type, orange compared to grey), but this was completely abolished by wiping out oxytocin receptors (last two bars, green bar compared to grey). On the other hand (right graph), in mice subjected to social defeat, mice that have more oxytocin receptors (dark blue bar) froze much more than normal mice (orange bar). These results tell us that oxytocin enhances fear in stressed individuals, but doesn’t affect normal mice.

So what’s going on? Is oxytocin enhancing the EXPERIENCE of social defeat, in which the mice perceive a small aggressor as a more intimidating one? Researchers noticed that all bullied mice, regardless of oxytocin receptor levels, behaved similarly – those having more oxytocin receptors did not cower more than normal. Perhaps oxytocin is not changing the social interaction per se, but enhancing the bad memory of being tormented?

To test this, researchers put the defeated mice back together with the bully. While normal mice tentatively approached the bully several times, mice with more oxytocin receptors kept their distance. Mice without oxytocin receptors seemed to have forgotten the episode and hanged around the bully way more than normal mice. So it does seem that increased oxytocin signalling enhances bad memories, and predisposes a traumatized individual to more fear and anxiety when subjected to further stress later on.

Researchers then tried to figure out how oxytocin strengthens a bad memory, and identified a protein called ERK1/2 as a main signalling messenger. When they inhibited ERK1/2 with a drug called U0126 (black bar on the far right), the effects of social defeat on enhancing bad memories (orange bar) were eliminated. The drug did not affect fear memory in non-stressed (NS) mice (grey and black bars on the left). Interestingly, oxytocin activates alternatively signalling proteins in other brain regions such as the central amygdala, which DECREASES anxiety. So it seems that oxytocin is “two-faced”, and depending on which brain area it’s activating on, can enhance both “love” and fear.

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In mice stressed out from social defeat (SD), inhibiting the messenger ERK1/2 with U0126 erased oxytocin’s enhancing effect on bad memories. NS: no social defeat.

As mentioned before, oxytocin circulates throughout the body and the brain. It would be interesting to see how systemic oxytocin influences fear memory. Could it be that stress differentially alters oxytocin receptor levels in different areas of the brain, changing the balance between promoting and eliminating fear? Does oxytocin have the same effect on different types of stress? Does oxytocin signalling in the LS go awry in people with anxiety disorders? Perhaps giving nasal oxytocin is not the best anti-anxiety med, and targeting its downstream signalling pathways in fear-inducing brain areas (like the LS) might be a better approach?

Finally, what is the role of oxytocin in influencing individual behaviour in social interaction? This study clearly tells us that oxytocin does not unidirectionally decrease anxiety. Maybe, as the authors suggested, it is a signal that focuses our attention to different social contexts and cues, making them more noteworthy and our experiences more long lasting. We don’t yet know. Hopefully, more research will continue to reveal the multiple faces of this complicated and fascinating molecule.
Guzmán YF, Tronson NC, Jovasevic V, Sato K, Guedea AL, Mizukami H, Nishimori K, & Radulovic J (2013). Fear-enhancing effects of septal oxytocin receptors. Nature neuroscience PMID: 23872596

Note: For those interested in learning more about oxytocin, @Scicurious has an awesome blog series going on. Check it out!

Edit: Thanks to Samuel for pointing out in the comments that oxytocin is also considered a neurotransmitter.

Feeling anxious? Run it out!

Woman running by the ocean beach at sunset

Run away from stress! Source:

When life isn’t going well, I go for a run. I’ve always found running soothing. Maybe it’s due to “runner’s high”, the burst of endorphins that dampen physical pain and elevates mood. Maybe it’s because running increases the generation of new neurons in the brain (of mice), which we think is protective against depression.

Or maybe, as this new study shows, it’s because running tweaks the brain’s inhibitory circuits to directly dampen anxiety.

Schoenfeld et al. (2013) Physical Exercise Prevents Stress-Induced Activation of Granule Neurons and Enhances Local Inhibitory Mechanisms in the Dentate Gyrus” J. Neurosci. 33(18):7770-7777

Let’s first zoom in on the ventral hippocampus deep within the brain. This is one of the areas that process emotions, and is implicated in stress and anxiety regulation*. Increased activity in the ventral hippo is correlated (but not causative of) with anxious behaviour. Since running decreases anxiety, researchers wanted to know if runners’ ventral hippo respond differently to stress than sedentary people, in such a way that dampens anxiety.

(* You might remember the hippocampus is important for learning and memory – you’re right! However, increasing evidence is pointing to the dorsal hippo as the processing power behind memory. The hippo is quite a multitasker!)


Elevated plus maze. I even find it scary! Source:

Since directly monitoring brain activity at the single neuron level from people is impossible, scientists turned to mice. If you ever had a pet hamster, you know that rodents love to run – give them a wheel and they’ll go at it for hours. After 6 weeks of voluntary running, scientists placed these mice onto an elevated maze with two dark closed arms and two light open arms (imaging a cross-like mountain with cliffs at the ends, pic left). Runners showed significantly less anxiety as they explored the open “cliffs” than their sedentary peers. They also had more newly born neurons in their brains.

So running decreases anxiety, but is it through lowering hippocampus activation? To tackle this question, scientists exposed the mice to cold water. If you’ve ever tried a New Years polar bear swim, you’ll know that swimming in cold water is very stressful. Indeed, in sedentary mice, cold-water stress caused a spike in neuronal activity in the ventral hippo, as measured by a set of genes that transiently and rapidly get turned on in response to neuron activation. These immediate-early genes act as messengers to tell the neuron to start making proteins to adapt to the stimulus, and are a reliable sign of recent neuron activity.

As you can see below, couch-potato mice showed a spike in neuronal activity (Sed, black bar with a star), as measured by immediate-early genes c-fos and arc. This response was almost completely wiped out in the runners (Run, black bar with no stars). So running decreases ventral hippo’s willingness to react to stress, leading to less anxious behaviors. But how?

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The activity of neuronal circuits is mainly balanced by two antagonistic neurotransmitters: glutamate-mediated excitation and GABA-mediated inhibition. Most anti-anxiety meds right now work by increasing GABA signaling. Researchers found that runners had significantly more GABA neuron activation when exposed to cold-water stress. These mice also released more GABA neurotransmitter, especially during the period of stress (see the peak in the black line below?). So maybe increased GABA in runners is enough to increase inhibition and dampen ventral hippo activity?

One way to test this is to block GABA signaling and see how these runner mice behave. To test for anxiety, researchers brought back the elevated plus maze. As you may remember, this maze has two dark, chill closed arms, and two brightly lit open arms. Usually mice prefer to spend more time in the closed “safe” arms, and this is indeed the case with sedentary mice (white bar). However, runners showed increased exploration of the open “cliff” arms of the elevated maze just like before (black bar). They were way less anxious about the light and openness of those cliff-like arms.

Screen Shot 2013-07-10 at 2.55.09 PMNow, if you block GABA signaling with a chemical called bicuculine in runners, these mice (grey bar above) behaved just like sedentary mice (white bar). Their anxiety returned! Bicuculine only worked when given to the ventral hippo; if you block GABA in the dorsal hippocampus – important in learning and memory but not mood – it didn’t affect the runners’ anxiety levels. These results tell us that increased GABA signaling lowers ventral hippo activation, and this leads to decreased anxiety.

Overall the researchers pretty convincingly show that running reduces anxiety through activating GABA signalizing in the ventral hippocampus. It would’ve been nice to see how runner vs sedentary mice behaved in the maze AFTER cold-water exposure, ie if running can “immunize” mice against stress-induced anxiety as well. It would also be interesting to see how long this anti-anxiety change lasts once the runners stopped running – does GABA signaling go back or does it stay responsive for a long time?

Regardless, this study gives you another reason to go out for a run and keep running. Try it for three weeks (how much the mice ran) and see if it helps with stress and anxiety. Science says it does.
Schoenfeld TJ, Rada P, Pieruzzini PR, Hsueh B, & Gould E (2013). Physical exercise prevents stress-induced activation of granule neurons and enhances local inhibitory mechanisms in the dentate gyrus. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33 (18), 7770-7 PMID: 23637169