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.


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.

Screen Shot 2013-11-27 at 1.12.56 PMScreen Shot 2013-11-27 at 1.13.13 PM

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!).

Screen Shot 2013-11-27 at 2.02.09 PM

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).

Screen Shot 2013-11-27 at 2.23.23 PM

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.

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

People with superhuman memories still mistake fantasy for reality

When I was young, the one superpower I craved above all was perfect memory. I’d picture my eyes as camcorder lenses, recording everything that I read, saw and experienced into the Kodak film that was my brain. Anytime I wanted to re-experience something, I’d simply hit a mental “play” button and BAM! The video of my life would play before my eyes, as clear and detailed as the day it was created.


Reality or fantasy? Source: http://www.raanetwork.org/

Little did I know that for those with Highly Superior Autobiographical Memory (HSAM), my fantasy was their reality. Researchers from University of California reported the first case of this phenomenal ability in 2007 when a lady dubbed AJ reached out to them – with a desperate plea for help – with the following email (experts):

Dear Dr. McGaugh,
As I sit here trying to figure out where to begin explaining why I am writing you and your colleague (LC) I just hope somehow you can help me.
I am thirty-four years old and since I was eleven I have had this un-believable ability to recall my past...I can take a date, between 1974 and today, and tell you what day it falls on, what I was doing thatday and if anything of great importance (i.e.: The Challenger Explosion, Tuesday, January 28, 1986) occurred on that day I can describe that to you as well...Whenever I see a date flash on the television (oranywhere else for that matter) I automatically go back to that day and remember where I was, what I was doing, what day it fell on and on and on and on and on.
... Most (people) have called it a gift but I call it a burden. I run my entire life through my head every day and it drives me crazy!!!…

AJ was different than any “memory experts” that the researchers had previously encountered. Her ability seemed completely innate; she did not use little tricks (“mnemonics”), such as mental imagery or story telling to help her remember. Her superior memory only pertained to specific aspects of her own life story and related events; she had trouble learning historical dates and reciting poems. Like your average Joe, she couldn’t remember what each of the 5 keys on her keychain was for. Although specific dates triggered recall in an automatic, “non-stop, uncontrollable and totally exhausting” manner, when asked if she’d talked about a particular date with the researchers in previous interviews, she said she couldn’t remember.

AJ, and the handful of people whom had come forward with HSAM since then, pose a troubling dilemma to memory researchers. Recalling an event is nothing like watching a video recording. Instead, it is an active reconstructive process prone to distortions from misinformation. For example, in labs, researchers have been able to manipulate people into remembering events they’d only previously imagined or trick them into recalling that they’d watched a news video that did not exist. In courts, “corrupt” memory plague eyewitness reports. Elizabeth Loftus, an expert in memory research, had even suggested that planting fake memories in children may be a successful way to modify delinquent behaviour.

Contamination seems like an inevitable part of our memory process, yet common sense suggests that those with HSAM would be spared. Their memories, instead of malleable and fluid, should be etched in stone. But is this really the case?

Screen Shot 2013-11-23 at 11.38.28 AMResearchers from UC Irvine recruited 20 HSAM participants and compared them to 38 age- and sex- matched controls. In the first test, they asked the volunteers to remember a string of related words, such as “light”, “shade” and ”table”. What was missing from the list was the highly similar lure word “lamp”. During the test, when volunteers were asked whether they had seen a particular word in the list, around 70% of the control group (light grey, left graph) falsely remembered seeing the lure. Incredibly, HSAM volunteers (dark grey, left graph) did not fare any better.

Verbal memory is hardly autobiographical. Next, researchers showed the volunteers photos of two separate crimes – a man stealing a wallet and putting it into his jacket pocket, and a man jacking a car with a credit card. Forty minutes after the picture show, volunteers read 50 sentences describing each crime. Unbeknownst to them, 3 sentences included misinformation about minute details, such as “he put the wallet in his pants pocket” or “he used a clothes hanger to break in”. When tested an hour later, the volunteers not only misremembered details but also attributed them to the incorrect source. Astonishingly, those with HSAM were far from immune, generating significantly more false memories than controls.

Again, you may say, the above events did not happen to HSAM individuals themselves. Nor were they particularly disturbing – perhaps volunteers simply didn’t care enough to pay attention to detail? Emotionally charged memories tend to demand attention and stick around for longer than neutral ones; like most people, I have no trouble recalling what I was doing when I first heard of the plane crashes on September 11, 2001 (whether my recall is accurate, however, is another question).

Researchers tapped into this powerful memory. Specifically, they asked what the volunteers remembered about the crash of United Airline Flight 93 with a questionnaire. Hidden in the questions were sprinkles of misinformation and flat-out lies -for example, “a witness had filmed the crash on the ground and the film was subsequently aired”, when no such footage actually existed.

Screen Shot 2013-11-23 at 11.41.13 AM

Fig 3D and 3E from paper. Dark grey=HSAM, light grey=control. High PEQ=better memory on initial screening test.

As you can see in the graph above, later in an interview, roughly ~20% of HSAM participants (D left, dark grey) said they had seen the footage compared to 29% of controls (D left, light grey). The percentages were roughly the same if the fabricated video was mentioned off-hand by researchers during the interview (not shown). Even more mind-boggling is this: in the HSAM participants, those tested at top 50% for autobiographical memory accuracy performed worst; in fact, they were just as bad as the controls (D right, high PEQ=better autobiographical memory on initial test). The participants weren’t reporting vague feelings of “having seen the video” either; when probed further, they gave elaborate details:

Interviewer: OK, Can you tell me what you remember about the footage?
HSAM: Uh, I saw it going down. I didn’t see all of it. I saw a lot of it going down uh, on air.
Interviewer: Ok, do you remember how long the video is?
HSAM: Just a few seconds. It wasn’t long. It just seemed like some-  thing was falling out of the sky. It was probably was really fast,   but I was just, you know, kind of stunned by watching it you know, go down.
Interviewer: Ok, so now is the last question, I would like for you   tell me how well you can remember having seen the video on the scale from 1 to 10, where 1 means no memory at all and 10 means a very     clear memory?
HSAM: I’d say about 7.

So here’s the conundrum: we have a cohort of people with astonishingly accurate and detailed autobiographical memory, whom nevertheless are susceptible to misinformation and false memories. Perhaps, you may have already pointed out, it’s due to the small sample size. While certainly a problem in most studies, here researchers have consistently found false memories in HSAM individuals, thus proving the point that fallible memory is (somewhat) inescapable. In other words, increasing sample size would not reduce misremembering to zero percent and thus would not disprove their conclusion (it may help tease apart differences between low- and high- performing HSAMs though). The results would have been more difficult to interpret if they had not found false memories in those with HSAM.

The second problem is that the crash of United 93 is semiautobiographical in nature. The volunteers witnessed the event vicariously through multimedia rather than experienced them first-hand. Previous experiments with AJ, our first identified HSAM individual, showed that while “she could quickly, reliably and accurately tell what she was doing on a given date, she couldn’t recall specific events from a videotape the month before”. In other words, her –and presumably, other HSAMs- extraordinary memory are selective. Here the researchers show they could “implant” a fake factoid 11 years after the fact, and some HSAM individuals would incorporate the memory into their original set of memories of the crash. What I would love to know is whether researchers could distort the volunteers’ own experience of the event. That is, whether they can alter an existing autobiographical memory rather than introduce a new one.

If HSAM individual have these common flaws, how are they still capable of remembering trivial details from a decade ago down to a tee? Researchers think it’s because very little misinformation is generally introduced in their daily lives. “No one comes up to them and says March 2nd, 2001 was a Monday not a Friday,” said one researcher to National Geographic. I’m not so sure that’s true – I know every time I go down memory lane with my friends we recall things differently; misinformation abounds. Our personal accounts end up influencing each other’s memory of the event.


Regardless, HSAM is in and of itself a fascinating phenomenon. Along with many other studies that investigated memory distortion in people with typical memory, this paper suggest that fallible memory reconstruction (reactivation and reconsolidation) is a basic and widespread part of human memory, a global phenomenon deeply routed in our neurobiology. No one, not even those with superhuman memory, is spared. But who knows, maybe discoveries of future “memory experts” will prove this wrong.

For those interested in HSAM (how could you not?!), here’s a 60 Minute episode on the topic. Pleading to @radiolab to do a show on it.

Patihis L, Frenda SJ, Leport AK, Petersen N, Nichols RM, Stark CE, McGaugh JL, & Loftus EF (2013). False memories in highly superior autobiographical memory individuals. Proceedings of the National Academy of Sciences of the United States of America PMID: 24248358

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: http://ctmusictherapy.com/

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: http://www.stthomas.edu/

There’s no doubt that aerobic exercise benefits the brain. Running, for example, reduces anxiety, improves sleep quality, boosts learning of a new task and maintains spatial memory*. Many of these mental perks stem from an increase in adult neurogenesis; that is, the birth of new neurons in the hippocampus and the olfactory bulb. (*That is, if rats run before new learning. See here for more.)

Yet perhaps the most apparent health benefit of running is increased cardiovascular and lung function. As any runner can attest to, an initially exhausting 10k soon becomes a breeze – you’ve increased your aerobic capacity. This led researchers from Duke University to wonder: is improving exercise capacity –by whatever means – necessary and sufficient to boost neurocognitive function?

Better bodies, better minds

Just like us humans, rats have an innate sensitivity to the effects of exercise. After the same 8-week running regime, high-response rats drastically increased their maximal capable running distance (~75%), while low-response rats barely improved (~22%). Surprisingly, compared to their sedentary peers, only high-response rats showed elevated neurogenesis in the dendate gyrus, a subregion of the hippocampus, as compared to their sedentary peers.

One hypothesized function of the dentate gyrus is pattern separation, or VERY simply put the discrimination between two very similar spatial contexts or things (Jason Snyder of Functional Neurogenesis fame has a great blog post on the matter). Researchers decided to challenge these rats with two Lego pyramids that only differed in the colour of their tops – imagine two Christmas trees with either a yellow or orange star. After the rats familiarized themselves with the yellow-topped Lego, researchers waited a minute before presenting them with both. High-response runners (but not their sedentary controls) instantly realized something was up – they approached and sniffed the new construct in earnest, ignoring the old familiar one.

Low-response runners, on the other hand, behaved just like their sitting peers, spending a similar amount of time with both objects. Low-responders had no problem with their memory; when faced with a mug and a can, they could easily discriminate between the two. They just couldn’t pick out minute differences in the Lego pieces, a skill often attributed to enhanced neurogenesis.

These data, perhaps somewhat dishearteningly, suggest that running doesn’t always boost brainpower – neurocognitive benefits only occur in tandem with improvements in aerobic fitness, as measured by total running distance until exhaustion. These results parallel that of a human study, in which increased lung capacity after training correlated with better performance on a modified pattern separation task (although understandably they did not show enhanced adult neurogenesis, so it’s hard to attribute behavioural output to increased new neurons per se).

Running-improved aerobic capacity seems to be the crux to exercise-induced brain benefits. But is running really needed? To explore this idea further, researchers decided to take treadmills out of the equation and focus on genetic differences in aerobic fitness.

Innate aerobic capacity accounts for cognitive benefits


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

Allow me to introduce to you the low and high capacity runners. Selectively bred for their capability (or not) to “go the distance”, these rats differ up to 3 times in a long-distance standard fitness test, without ever setting foot on a treadmill. At 10 months old, they also had a two-fold difference in the total number of newborn neurons in the dentate gyrus as a result of increased neuron survival, which increased to three-fold at 18 months old.

Researchers took sedentary rats from both groups and challenged them to the Lego task described above. High capacity runners significantly outperformed their low capacity peers, expertly telling apart the Lego constructs. Similarly, in an object placement task in which researchers minutely moved one of two objects, low capacity runners could not identify the moved one after an hour’s delay, though they managed if the wait was only a minute. High capacity runners, on the other hand, excelled in both cases.

These results argue that high aerobic capacity in and of itself promotes pattern separation. But what if, unbeknownst to researchers, high capacity runners were maniacally jumping around everyday in their home cages? A few days of stealthy observation proved this wrong; paradoxically, low – compared to high- capacity runners were much more hyperactive. They also seemed more outgoing in a social interaction test, and exhibited a lower tendency to generalize trained fear from one context to another.

Running-induced neurogenesis is generally considered to ease anxiety. So why do high capacity runners (with higher rates of neurogenesis) seem more neurotic?

Born to laze, born to run


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: http://learn.genetics.utah.edu/content/epigenetics/rats/

Taken together, these data point to increased aerobic fitness– through genetic means or exercise- as the key to enhancing neurocognitive function in rats. Inbred differences in aerobic fitness may alter how one responds to exercise (and perhaps other types of) stress.

These studies beg the question: what if we could artificially mimic the effects of exercise (pharmaceutically or otherwise) and reap its benefits? While “exercise pills” may not necessarily benefit healthy individuals, they could potentially improve both physical and hippocampal health of the elderly or the disabled.

Such research is under way, though as of now the results are not yet convincing.

PS. This is the end of #SfN13 blogging. It’s been hectic, a bit overwhelming and a LOT of fun!! Thank you to all the presenters for your patience & feedback and the PIs who let me write about your work. Thank YOU for reading!

Regular research blogging will resume soon. Stay tuned!

671.01. CL Williams et al. Rats selectively bred for high running capacity have elevated hippocampal neurogenesis that is accompanied by enhanced pattern separation ability. 

671.02. KM Andrejko et al. Rats selectively bred for high running capacity have elevated hippocampal neurogenesis that is accompanied by a greater expression of hippocampal glucocorticoid receptors and altered contextual fear conditioning. 

671.04. JM Saikia et al. Treadmill exercise training only enhances neurocognitive function if it is accompanied by significantly increases in aerobic capacity. Duke Univ., Durham, NC; Univ. of Michigan Med. Ctr., Ann Arbor, MI

Breaking the academic bubble: An interview with NEURO.tv host Diana Xie

I’ve always pictured scientists and philosophers in antiquity as hermits, slaving away in their ivory towers and writing dissertations in obscure languages inaccessible to the most of the population. Even today science is tough to understand, with academic papers locked behind paywalls and filled with jargon.

Fortunately, this sad state of affairs is rapidly changing for the better. The recent launch of Pubmed Commons has finally pushed post-publication peer review into mainstream, which – together with F1000 and PubPeer – will hopefully facilitate constructive criticism and academic discourse between scientists. Figshare is promoting data sharing among researchers, including data that are unpublished and/or negative. Open-access journals have allowed the general public to peek into the ivory tower (though they come with a slew of problems), while research blogs are translating jargon-laded papers into engrossing articles that anyone can understand. Podcasts like the Stanford NeuroTalk and videos like ASAPScience are both fantastic mediums for an earful of science.

Nevertheless, most of these current resources target one discipline or a specific question. This is why NEURO.tv caught me eye. NEURO.tv is the brainchild of Dr. Dr. Jean-François Gariépy, a researcher at Duke University. It is a free-to-download talk show between leading scientists and philosophers whom share their ideas about the brain and mind. It lets you witness the type of debates and discussions that academics engage in over a beer – casual, personal, a little nerdy but packed with ideas.

sebastian and claire

Sebastian Seung, professor of Computational Neuroscience at MIT & Claire O’Connell, MITx Fellow & Education Director of EyeWire. Source: NEURO.tv Kickstarter page

During the Society for Neuroscience Annual Conference I caught up with Diana Xie, the host of NEURO.tv, for her vision of the project.

What differs Neuro.tv from other neuroscience podcasts or videos?

NEURO.tv is different from other science podcasts and videos, because we dive into academic concepts and explain these concepts in parallel, so people from all educational backgrounds can understand the conversations. The discussions that happen on NEURO.tv are the equivalent of what you would have between experts in the field in a university, but the hosts and panelists make sure that the concepts are explained in a way that everyone can understand. We want these conversations to be informal, so the dialogue style in all our videos is what I would describe as laid-back intellectual conversations. Our guests are free to speak about any neuroscience topics that they wish, including their own research, because our videos aren’t intended to adhere to the interview or lecture model. This is a tradition that we will be continuing with our forthcoming episodes, since people seem to really enjoy it.

We also want the show to be interdisciplinary, so we bring in professors from diverse fields – neuroscience, psychology, philosophy – and they talk about science from all the different levels at which the brain and mind can be studied. These conversations between our panel of regular scientists and our guests, all studying different topics within neuroscience, are recorded and subsequently edited to make them accessible to the general public. For example, if a scientific term was to be mentioned that may be foreign to someone who has not yet entered graduate school, a pop-up would appear in the video to define the term in a very clear and understandable way. Rather than glossing over the academic talk, we approach it in a way that reflects our belief that many people on the Internet want to follow such conversations.

I especially like the idea of dialogue between neuroscience and philosophy; why discuss the two in tandem?

Ultimately, philosophers interested in behavior and neuroscientists are after the same question: what are the mechanisms underlying our behaviors? Philosophers tend to develop broad frameworks to better understand the problem itself. Some of them, the best ones, will also care about integrating the vast amounts of scientific data available from neurobiology. That is how neuroscience contributes to the understanding of behaviors by philosophers. On the other hand, neuroscientists often look at very narrow questions, not because they aren’t interested in the bigger question, but simply because they are adopting the scientific approach. They have to care about the experiments that they can do in the present, otherwise things would not advance. The result is that scientists are very much aware of the fine details of experiments, the limitations of the techniques used, etc. By bringing neuroscientists and philosophers into the same conversations, we are certain that both will benefit from each other’s perspective.

Screen Shot 2013-11-15 at 3.02.17 PM

Any teasers on which topics will be covered?

I have discussed extensively with JF about what will be the subjects covered during Season 1 (2014), and all we can say is that what you’re about to see is an eye-opening, broad coverage of all the deep questions that relate to the brain and the mind. We have gathered teams of panelists who are experts in their fields. Some of the people you will see talking with each other on NEURO.tv would never have interacted otherwise. The subjects covered will include molecular biology, cellular physiology, systems neuroscience, cognitive psychology, philosophy of mind, morality and sociology.

Finally, tell me about the inception of NEURO.tv.

Jean-François first conceived of the idea of NEURO.tv, because he wanted to make academic discussions more accessible, not only for the general public, but also for the scientists who would not have otherwise had the opportunity to participate in these conversations with such a broad range of intellectuals interested in studying the brain and behaviors, from the molecular levels up to the level of societies. When I think back to my first meeting with JF in January, I had no idea that fast-forward a year, I would be involved in such a big project. I began as a research assistant working with him to understand the effects of oxytocin on social behavior. He struck me as a very brilliant, forward-thinking person with bold ideas and the boldness to implement them. Not only that, but a person who was incredibly generous with his time and enthusiastic about science education, and by extension, exposing people to the wonders of neuroscience research. For these reasons, needless to say I had much respect for him and consider myself very lucky for having joined the lab that he worked in.

When Jean-François first pitched to me the idea of launching a Kickstarter campaign for NEURO.tv (back in September), I thought it was the craziest idea ever. But he told me about his vision for what he wanted it to be, and I was intrigued and believed in its potential. That’s what led me to take on the challenge of joining as both director of the Kickstarter campaign and host of the 2014 episodes, despite how intimidating these jobs appeared. Even in the early stages of the campaign now, I find the experience to be very rewarding, and I love hearing all the wonderful feedback and encouragement that we have received from both scientists and non-scientists.

NEURO.tv is just taking off. If you’d like to help this fledgling project – by neuroscientists, for the world – check out their Kickstarter page.

#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


            Source: http://www.rochetfamilychiro.com

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 Your coffee habit? Don’t fight it, embrace it.

Poster 236.10 The daily fix: habitual caffeine doses improve performance in attention and executive functions irrespective of food intake. JL Mariano, JCF Galduroz, S Pompeia. Univ. Federal De Sao Paulo, Brazil


Coffee and I: 14+ years of history and counting.  Source: http://caravancoffee.com/

Here’s another reason to love coffee. Researchers from Brazil found that morning coffee consumption not only keeps you awake and alert, but also improves performance on cognitively demanding tasks. That is, if you’re already a habitual drinker.

People often start their day with a cuppa and breakfast. Carbohydrates in food gives the brains a shot of glucose, which is shown to positively affect cognition. Since caffeine also stimulates the brain, researchers wondered if stacking the two may lead to even better performance.

They recruited 58 young healthy coffee drinkers. After an overnight fast, half of the volunteers drank their usual cup (or two) of coffee, intaking 25-300mg of caffeine. The other half drank a placebo decaf. Some ate a cereal bar to chase the coffee, others didn’t. 30min later, researchers bombarded the volunteers with a series of mentally challenging tasks.

In one, volunteers tried to continuously call out numbers between 1 and 9 in a random fashion for 2 minutes straight – randomness and low repetition is the key. Here, volunteers had to actively inhibit our natural preference for number patterns (try it, it’s hard). In another test for  long term memory and recall, they named as many types of musical instruments or animals as possible in one minute. A whack-a-mole like game (hitting a button when a light comes on) tested their reaction speed while a zoo-navigating task tested for efficient goal-directed planning.

Surprisingly, food did not affect the performance on any of these tasks; but coffee certainly did. Coffee drinkers generated random numbers faster and repeated themselves less than controls. Their performance was also more stable within the task, consistent with less feelings of mental fatigue or weakness after the tests. However, these subjects were consistent coffee consumers, so it’s hard to say whether caffeine upped their smarts in a true nootropic-like manner, or if the placebo drinking group simply did worse due to caffeine withdrawal.

But for the average cup-a-day coffee consumer, if you’re in need of a quick boost in mental power (or avoid that nasty brain fog), it might help to go drink a cup. Scientists and lab techs, I’m looking at you.


PS Steve Miller, aka neuroscienceDC and fellow official #SfN13 blogger has a great post on the best time of day to drink coffee, check it out!