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.

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OTC painkiller may blunt memory loss from puffing pot

Pot’s not the best thing for your memory. Yes, I know there are functional potheads who enjoy their greens and get also their work done. Still, it’s hard to ignore the legions of studies that show Δ9-THC consumption impairs spatial learning and working memory – that is, the ability to hold several pieces of information in mind and manipulate them to reach a mental goal.

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Welcome to downtown BC and BC Bud! Source: cannabisculture.com

Yet paradoxically, THC may benefit those with Alzheimer’s disease. Previous research in rats show that the compound breaks down clumps of disease-causing proteins (called β-amyloid plagues) by upregulating a “scissor” enzyme that chops them up. Sweeping out these junk protein plagues decreased the number of dying neurons in the hippocampus, a brain area crucial for learning and memory. THC also has powerful anti-oxidant effects and may protect the integrity of mitochondria – the “power plants” of our cells.

So here’s the dilemma: THC may potentially battle dementia, yet it also naturally impairs memory. In an unexpected turn of events, scientists from Louisiana State University discovered a key protein that mediates THC-caused memory loss, and show in mice that you can have your edibles and eat it too.

The protein in question is COX-2, a crucial player in inflammatory pain – think headaches, muscle pains and fever. Sound familiar? That’s because COX-2 is one of the targets of OTC painkillers such as Asprin and Tylenol (the other one is COX-1). Scientists have previously linked 2-AG, a THC-like substance produced endogenously in the brain, to inhibiting COX-2 signaling. Blocking COX-2 led to problems with memory retention. So naturally, they wondered whether THC impaired memory in the same way.

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They found the opposite. As you can see on the left (blue bars), a single injection of THC boosted the level of COX-2 in both neurons and astroglias (“structural” non-neurons that play a role in memory and inflammation) in the hippocampus; the more THC, the more COX-2. This effect went away by 48hrs after the injection, but when the mice went on a weeklong THC binge (1 dose/day), their COX-2 levels remained chronically high cough unregulated (right graph, red bar compared to control black bar). When researchers blocked the THC/endocannabinoid receptor CB1R by either genetically deleting it or using a selective pharmaceutical blocker, the effect went away, showing that THC administration is indeed the cause of COX-2 increase.

Why would endogenous cannabinoids (2-AG) and THC have polar effects? Further molecular sleuthing revealed that it’s all in the messenger: although both 2-AG and THC activated the same receptor, 2-AG recruited Gα as courier, while THC opted for Gβγ. It’s like slapping a different address sticker on two boxes shipped to the same sorting facility; they’re now going different places. Indeed, Gβγ triggered a molecular cascade that activated several proteins previously shown to impair memory.

Naturally, researchers went on to block COX-2. After a week of THC, neurons begin to loose their spines – that is, little protrusions along the dendrite that house proteins necessary for forming and maintaining synapses (compare red bar/THC to black bar/control below). The breakdown of spines caused a decrease in the many proteins and receptors needed for normal excitatory signal transmission. Unsurprisingly, eliminating these channels of communication blunted the response of a cohort of neurons in the hippocampus after electrical stimulation. However, giving a COX-2 selective blocker concurrently with THC rescued all these deficits – structural, molecular and electrical (green bar – the spines are back!).

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Spines come in all shapes and sizes. Grey bar: COX-2 inhibitor alone; Green bar: THC+COX-2 inhibitor

As for mutant mice that lack COX-2 at birth? They didn’t suffer any of these problems associated with THC. In the case of spines, as you can see above, THC (burgundy bar) had no effects compared to control (blue).

Do any of these “under-the-hood” changes lead to observable behaviour? In a fear-conditioning experiment, researchers trained mice to associate a box with electrical shocks. They then gave some of the mice 7 days of THC with or without a COX-2 inhibitor. When tested 24hrs later – presumably to weed out THC’s effect on anxiety* – stoner mice showed little fear when put back into the box. Those on the multi-drug regime, however, froze in fear. Like their sober peers, they retained and retrieved the fear memory. (The half-life of THC is ~20.1 hrs in mice, so they might have still been high at the time of testing.)

In a spatial memory task, researchers trained mice to find a hidden platform in a big tub of water. After 5 days of training, they then gave a subgroup a single injection of THC 30min before the test, which resulted in these mice taking roughly twice as long to find the platform as the controls. Once again, concurrent COX-2 administration “saved” the memory of the platform location. 24hrs later, after the mice had sobered up, they were tested again – same results.

Amazingly, inhibiting COX-2 did not destroy THC’s ability to wipeout Alzheimer’s-related protein plagues in a mice model of the disease. Treatment with THC once daily for a month, with or without the OTC COX-2 inhibitor Celebrex, significantly decreased the number of protein clumps (green below) and protected hippocampal neurons (blue).

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Top row: control, middle: THC, bottom: THC+COX-2. Last lane is a magnified look.

Before you reach for the bottle of aspirin, joint in hand, maybe hold back on the self-medication just yet. For one, it’s hard to extrapolate these findings to humans, there are some interspecies differences in THC metabolism. Second, chronic COX-2 inhibition is linked to serious side effects such as ulcers and heart problems (think Tylenol is safe? Think again). Third, mice with inhibited COX-2 showed didn’t seem as couch-locked as they normally would; so if you’re after that body high, an aspirin would be rather counter-productive.

As a molecular neuroscientist, I love the detailed characterization of THC-CB1R signalling pathway, but the behaviour data could use some strengthening. Although researchers claimed that the water maze task assessed working memory, the protocol they used looks at normal spatial memory. To specifically probe working memory, they would’ve needed to move the platform to different locations and see how well the mice updated their memory. The results also directly counter those of a previous study, which showed that once the mice learn the location of the platform, THC did not impair the memory. They also didn’t report whether THC mice were simply too stoned to swim (or motivated enough) – tracking total swimming distance and speed at the time of testing would’ve helped .

This study focuses mostly on neurons*; a previous study published in March 2012 showed that THC impairs memory through a type of glia called astrocytes (the non-neuron brain cells); in fact, marijuana impaired working memory only when it was able to bind to the CB1Rs on astrocytes. That study pointed to deregulation of excitatory neurotransmitters as the cause of memory impairment; could COX-2, which is expressed in glia, also have a role?

*Edit: HT to reddit/u/superkuh. The text suggests that the authors of this paper did not consider the role of astroglia; in fact they explicitly did, when they showed that COX-2 upregulation occurred greater in astrocytes than neurons. The authors also showed that the reduction of glutamate (excitatory) receptors was due to COX-2-induced increase in glutamate release from both neurons and glia.

ResearchBlogging.org
Rongqing Chen et al (2013). Δ9-THC-Caused Synaptic and Memory Impairments Are Mediated through COX-2 Signaling Cell, 155 (5), 1154-1165

#SfN13 Getting rid of an unwanted memory for good

Poster 99.06/JJJ40 – Gradual extinction prevents the return of fear. SJ Gershman, CE Jones, KA Norman, MH Monfils, Y NIV. Brain and Cognitive Sci., MIT, Cambridge, MA; Psychology, The Univ. of Texas at Austin, Austin, TX;Neurosci. Inst. & Dept. of Psychology, Princeton Univ., Princeton, NJ

Poster 99.07/JJJ41 Gradual extinction prevents the return of fear in humans. JW Kanen, SJ Gershman, MH Monfils, EA Phelps, Y NIV. Dept. of Psychology, Ctr. for Neural Sci., New York Univ., New York, NY;Dept. of Brain and Cognitive Sci., MIT, Cambridge, MA; Univ. of Texas, Austin, TX; Nathan S. Kline Inst. for Psychiatric Res., Orangeburg, NY;Princeton Neurosci. Inst. and Psychology Dept., Princeton Univ., Princeton, NJ

Psychiatrists have a problem. Memories, especially fearful memories, are exceedingly hard to erase. Say you’ve learned that every time you touch a doorknob in the winter you get a painful electrostatic shock; fairly soon you might form an irrational fear of the doorknob. What can the good doctor do?

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Ouch! Source: ashafullife.blogspot.com

The go-to therapy is extinction training. Here, you’ll repeatedly touch a doorknob that’s been treated to eliminate static – hence, no shock. After several sessions you loose your phobia. Great. Yet a few weeks later, you once again feel butterflies fluttering in your stomach at the thought of touching a doorknob. Somehow, the fear has returned.

The above scenario may seem ridiculous; yet for those suffering from post-traumatic stress disorder or debilitating phobias, the spontaneous recovery of a fear memory is nothing to laugh at. Scientists aren’t quite sure why this happens. Erasing a memory, or memory extinction, in theory “updates” the original memory trace, such that a fearful stimulus (eg doorknob) is now encoded as safe. Yet in practice, when the object of fear suddenly dissociates from harm (eg no more shocks!), the mPFC generates a large prediction error signal, such that the new information is treated as something entirely new and encoded in a separate memory trace.

Herein lies the problem. The original fear memory, alive and well, competes with the opposing new one for expression. Behaviourally, this often results in the return of fear. But here’s the silver lining: if you keep the prediction error signal small, the brain may opt to modify the old trace rather than encode an entirely new one, thus mitigating or erasing fear in actuality.

Researchers decided to test this theory out. First, they taught a cohort of rats to fear a tone by associating it with a shock. The rats were subsequently divided into three groups: the first received gradual extinction, in which the frequency of shock delivery declined gradually. In other words, as the trials progressed, rats more often than not experienced the tone without the shock. In a sense, researchers “weaned” these rats off the tone-shock association, thus triggering a small prediction error. The second group received the opposite treatment, with the frequency of shock delivery steadily increasing until the last 9 trials, in which all shocks were omitted to facilitate extinction. This is necessary as researchers wanted to observe the return of fear. The third group went through normal extinction; that it, only tones, no shocks. By the end, all rats lost their fear of the tone.

Fast-forward a month. Researchers returned the rats to the testing chamber and played the same tone. Rats that underwent gradual extinction showed significantly less fearful behaviour than the other two groups. In another experiment, researchers re-established the fear memory by giving the rats another shock. Once again, those that had undergone gradual extinction showed less fear. These results strongly suggest that gradual extinction is especially effective at persistently decreasing fear. But how do these results transfer to humans?

Using a similar fear-conditioning paradigm, researchers presented images of snakes to a group of volunteers. This was followed by an uncomfortable electrical shock to the wrist. Fear, as well as other states of arousal, increases sweating and skin conductance, the latter of which was carefully monitored to objectively measure the volunteers’ level of fear. Within a day, volunteers learned to fear the innocuous snake image.

One day later, researchers divided volunteers into groups and eliminated their fear memory through one of the three extinction processes as above. When tested on the third day, those who went through gradual extinction showed a trend towards less spontaneous recovery; that is, they sweated less at the sight of the snake images. However, the results are preliminary and due to the small number size (10-14 per group), the effect was not yet statistically significant.

Clarifying the conditions that facilitate persistent fear extinction may help clinical psychiatrists optimize extinction-based exposure therapies for the treatment of anxiety disorders and phobias. The evidence presented here – from rat to human – strongly suggest that minimizing prediction error through gradual extinction is a more effective way to modify and erase a memory, maybe for good.

Sometimes slow is a better way to go.

#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.

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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.

Rest is work, less is more

Ferris Jabr, one of my favourite science writers, has an intriguing longform article up at Scientific American: “Why your brain needs more downtime“. In it he expertly guides you through a series of research that show why naps, vacations, meditation and other mental breaks unfill your cluttered brain and allow it to run optimally.

I highly suggest heading over and reading the full article; it’s truly longform writing at its best. However, for those exceedingly pressed on time, here’s the TL;DR.

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Chill out: it’s not that you “deserve” it, it’s that your brain needs it. Source: http://www.sziverosito.hu/

While we lounge in the sun allowing our minds to wander, our brains are hard at work. Research over the last two decades have shown that as we rest, disparate regions of the brain activate in coordination in what is called the “default mode network” (DMN) – one of the five “resting-state networks” that scientists have discovered so far. DMN activity may represent a way of introspection as we build a narrative of ourselves and those around us; it seems to be more active in exceptionally creative people and may be the root of epiphanies that seemingly appear out of nowhere. Many studies have found that resting-state networks activate as we rest after learning a complex new task – visual memory, motor skill, or language -which may help us retain the memory better.

As we go through our day, our cognitive resources are gradually depleted; naps and breaks replenish these resources and build their volume. Naps sharpen concentration and improve memory in all types of tasks in all age groups, though length matters: 10min naps immediately boosts performance upon waking, 20-30min ones require half an hour to kick off the “grogginess”. An hour walk in nature has similar memory-boosting benefits, as long as you stay away from city streets and noise. Vacations revitalize your body and mind with new experiences -unfortunately the effects in general fade away between 2-4 weeks.

We also build our attention span during downtime. Mindful meditation – focusing on your thoughts, emotions and the present -seems to improve concentration and memory and nurtures the psyche. Meditation profoundly changes the brain’s physical structure and strengthens connections within brain networks, including the DMN. Frequent meditation sharpens one’s attention regardless of age, such that your middle-aged parents may outperform you on attention tasks. It works -the key is sticking to it daily.

Several studies show that meditating 10 to 20min a day considerably improves working memory – the ability to hold information in mind while manipulating it towards a goal – in college students from multiple countries. Meditation also reversed stress-induced working memory decline in US marines. Considering that working memory is frequently used as a marker for human intelligence, these results are nothing to scoff at.

As I’m typing this, I’m in the 5th day of a break from lab work after a horrendous month-and-a-half stretch of ~14hr workdays that resulted in total burnout. I’m still not really “resting”; my days are filled with neuroscience-related readings, writings and life-related stuff. Like many others, I experience a sense of guilt at the mere thought of some time off. This article comes as a timely reminder: knowing you need a break is not enough – you actually need to do it.

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.

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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)

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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.

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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.

ResearchBlogging.org
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.

Decapitated worms regenerate heads with old memories

Yup, you read that right.

The worm in question is the Planarian flatworm. Compared to C. elegans, the flatworm doesn’t get as much love in neuroscience. But to regenerative medicine, it is a truly incredible gem.

You see, planaria harbors adult stem cells that imbue them with astonishing regenerative abilities. If you decapitate a worm, the tailpiece can regenerate a COMPLETE head with a fully functioning brain within a few days. What makes this even more incredible is that – unlike C. elegans that have a distributed nervous system* – planaria has a centralized brain in the head region, just like you and me. Planarian neurons also talk to each other in ways similar to ours, with the same majority of neurotransmitters. They can also learn simple associations and keep the memory. Oh, and they look like this:

flatworm

Science is only starting the tease out the mechanism behind planarian’s regenerative abilities. But to me, an even more tantalizing question is this: what happens to all the memories stored in the chopped-off old brain after a new one takes its place? Does planaria revert to a state of tabula rasa, or does it carry with it memories of its merry old life?

Shomrat T and Levin M. 2013. An Automated Training Paradigm Reveals Long-term Memory in Planaria and Its Persistence Through Head Regeneration. J Exp Biol. Doi: 10.1242/jeb.087809

This is the question this paper set out to answer. Planarians have this feeding quirk: when fed in a new environment, they tend to be more “cautious”, taking longer to go after the yummy liver morsels that they love. Once they’ve been fed many times in the same environment, they “feel safe” and go right after the food.

Screen Shot 2013-07-11 at 1.46.50 PM

Scientists trained a group of planarians to associate feeding with a rough-floored Petri dish (pictured on the left)– significantly different from the smooth-floored one they’re kept in. 4 days after the final training session, scientists put both trained and untrained worms into the rough-floored dish, with one extra twist: the food was now illuminated by light shining through the dish. Planarians hate light; in order to get the food they’d have to be VERY comfortable with the environment.

As you can see from the red line below, 4 days after the last familiarization session, trained (right side) planarians took much less time to grab the food compared to their untrained (left side) peers. This was also observed 14 days after training (black line), meaning that the memory of the familiar rough-floored dish lasted at least that long.

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Results! Fig 3 from the paper.

Scientists then decapitated the worms (both trained and untrained), and waited patiently while the worms regrew their heads. Roughly a week later, scientists pre-fed the worms to satiety in their home dish, and 4 days later tested them for memory of the rough-floored Petri dish. As you can see from the green line above, the trained-and-beheaded worms seemed to have lost the memory of the feeding environment, taking just as much time to go after the food as the untrained-and-beheaded worms.

Is the memory completely lost? Worms trained to associate food with an environment can re-learn the same association much faster than naïve-untrained worms. (You can brush up on a rusty skill much faster than learn it from scratch.) To see if a hint of the old memory remained, scientists pre-fed both trained and untrained decapitated worms in the rough-floored Petri dish. To the familiarized worm, this is a previously encountered environment; for the unfamiliarized, this is a first introduction to the dish. Previously it took these worms 10 days of training to form a food-environment memory, so this one-time training session shouldn’t result in significant learning.

Scientists tested the worms for memory of the rough-floored dish 4 days later. As you can see from the blue line in the figure above, the trained worms (right) quickly re-familiarized with the feeding environment, taking much less time than the untrained ones (left) to feed. This suggests that maybe the memory is not all gone – it’s just not easily accessible without reactivation.

Screen Shot 2013-07-11 at 4.18.13 PM

Here’s a summary. After decapitation and head regrowth: Pre-feeding in home dish = no difference between trained and untrained. Pre-feeding in rough-floored (training) dish = previously trained worms remember better.

What to make of all this? Can old memories be re-grown along with the head? My first reaction was maybe the decapitated worms had some sort of modification going on in the peripheral nervous system, which resulted in their sensitization to food-environment learning. By comparing the blue and green lines, you can see that both untrained (left) and trained (right) worms learned and remembered the feeding dish after one-time training. However, peripheral modifications doesn’t explain why previously trained worms learned and remembered the feeding environment BETTER.

The authors also designed their experiment very cleverly. In the test dish, the worms had to recognize food and the feeding environment, and make a decision to move towards it against their natural preference (stay away from light). This cautious approach strongly argues that the brain is involved, ie it’s not a simple reflex.

Memory is stored in neuronal communications in the brain. Could it be that a rough correlate is also stored in stem cells of the planaria? This way, when stem cells divide to form a new brain, the memory would return. Although this scenario sounds like sci-fi, it actually could occur through epigenetic mechanisms (changing the pattern of gene expression). There’s just not a lot of evidence for it yet.

While still skeptical, I have to admit the idea that memory can survive decapitation and brain regrowth is tantalizing. Although us humans don’t have planarian’s outstanding regenerative abilities, we do share similar neural transmission mechanisms. What does this study tell us about our own memories?

*Edited for accuracy: many thanks to all the people who pointed out that C elegans do not have “many little ‘brains'” as I first put it. Very bad wording on my part. C elegans have a ring of ganglia (clusters of neurons) but not a centralized brain. For more please refer to the link in the comments.

ResearchBlogging.org
Shomrat T, & Levin M (2013). An automated training paradigm reveals long-term memory in planaria and its persistence through head regeneration. The Journal of experimental biology PMID: 23821717