Frontiers in Neuroscience Journal

The journal, Frontiers in Neuroscience, edited by Idan Segev, has made it Volume 3, issue 1.  Launching last year at the Society for Neuroscience conference, its probably the newest Neuroscience-related journal.

I’m a fan of it because it is an open-access journal featuring a “tiered system” and more.  From their website:

The Frontiers Journal Series is not just another journal. It is a new approach to scientific publishing. As service to scientists, it is driven by researchers for researchers but it also serves the interests of the general public. Frontiers disseminates research in a tiered system that begins with original articles submitted to Specialty Journals. It evaluates research truly democratically and objectively based on the reading activity of the scientific communities and the public. And it drives the most outstanding and relevant research up to the next tier journals, the Field Journals.

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IARPA and trust detection

Neurodudes reader Jason M. sent me some information about a funding agency, IARPA, or Intelligence Advanced Research Projects Activity, that is funding neuroscience-related research. I had never heard of IARPA before but it has existed since 2006 as something of an intelligence-focused DARPA. There upcoming funding deadline (Aug 21) is for projects on detecting trust signals between humans.

Just last night, I watched the tense but amazing film The Hurt Locker (don’t let the name disuade you, see the phenomenal Metacritic rating), which is about a bomb disposal squad during the recent Iraq War. There is one particularly stirring scene with a suicide bomber who claims that he was forced to wear a vest with explosives and doesn’t want to go through with it. The difficulty in the limited time before the bomb explosion revolves around whether to actually trust the man and the challenge of trusting someone when neither party speaks the other’s language. You can certainly at least understand (putting aside the ethics of war itself) why governments are interested in detecting nonverbal trust cues.

Details about the IARPA call for proposals are after the jump. Continue reading

Zeo sleep analyzer

Last night was not a restful one for me. Can neurotechnology help make us more aware of our sleep problems? Over at the NYT, David Pogue thinks so. He recently reviewed an alarm clock with an EEG headband transmitter that analyzes sleep (“To Sleep, Perchance to Analyze Data“).

As he says in the article, the initial reaction to this kind of product might be, I don’t need something to tell me when I didn’t sleep well. I know when I haven’t slept well! As he says in his nice video review, there are some advantages to all this technology (automation is good!… I certainly don’t keep a daily journal of sleep quality…):

But as my wife said, “If I wake up and feel lousy, I don’t need a $400 gadget to tell me it’s because I didn’t sleep well.”

Ah, but that’s where the coaching comes in.

The Zeo stores your sleep records on a memory card. As often as you can, you’re supposed to pop it out and insert it into a U.S.B. card reader (also included) on your computer. At this point, you can go to MyZeo.com and upload your data to the Web.

Now the real fun begins. This Web site lets you slice, dice and cross-compare your sleep data in a million ways.

Broad PsychHTS brings chemical biology to neuroscience

There’s a nice editorial in Nature Neuroscience about the Broad Institute’s PsychHTS initiative. The initiative invites scientists from outside the Broad to suggest new high-throughput screens that the Broad will perform. The Broad has invested heavily in capital equipment and expertise for chemical biology screens (ie. small molecule drug libraries with robotic delivery and automated screening). These libraries are huge: 50,000-500,000 molecules can be screened. Although much science is hypothesis driven, this kind of large-scale hypothesis-free exploration just hasn’t been possible before. And this certainly isn’t the kind of thing that can be done in a single lab; only dedicated facilities like those at the Broad could carry out this type of “big science.” For collaborators hoping to use the Broad platform, the key appears to be in developing a good automated assay:

Readouts may be anything from classical enzymatic reactions, through FRET for changes in protein interaction, up to subcellular changes captured by automated high-content imaging. An investigator may send a group member to the Broad to take advantage of its resources or may entirely ‘outsource’ assay development to the chaperone. Assay development typically takes two to three months, sometimes up to a year. The assay is then used to screen one or more compound libraries, encompassing at present up to 400,000 substances and growing. (PsychHTS pays for screening a 50,000-compound subset.) ‘Hits’—compounds that affect the assay results in a way that indicates potential usefulness in a psychiatric research context—are automatically retested at several concentrations. The resulting collection of typically between 50 and 500 confirmed hits is then evaluated and prioritized according to criteria of scientific interest and potential drug promise, and thereby winnowed down to the top 10 or 20. The Broad Institute’s organic chemists then synthesize and retest these compounds plus a series of their chemical derivatives, with goals such as improved solubility and more specific binding to putative targets. The goal of the entire procedure is to deliver small-molecule probes that modulate a specific cellular function—essentially tools for subsequent research into the initial hypothesis regarding a psychiatric disease mechanism.

At this point, the new small-molecule probes will need to be tested in animal models of mental illness.

The most appealing aspect is that the Broad is opening up the process to anyone with good ideas for potential screens. The next application deadline is in September. Considering both PsychHTS and the Allen Brain Atlas, is neuroscience moving away from an individual lab model and more toward a “big science” model of projects with lots of collaboration?

Putative (unpleasant) psychedelic effects of anti-smoking drug Varenicline

http://en.wikipedia.org/wiki/Varenicline

“Varenicline is a partial agonist of the ?4?2 subtype of the nicotinic acetylcholine receptor.” — this is apparently the subtype that nicotine acts on in the CNS. Varenicline is also a partial or full agonist of some other nicotinic receptor subtypes.

The following article describes various disturbing psychedelic effects of long-term varenicline use. Excerpts after the break:

http://nymag.com/news/features/43892/

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Longitudinal study on happiness and success

The Atlantic‘s Joshua Shenk has a fascinating story about a long-running study, started in the 1930s (!), that attempts to discern what makes people happy in life. The study has collected extensive data on subjects over a 70 year period. I couldn’t stop reading the article… what an amazing dataset. But, before I say more about that, here is Shenk’s synopsis of a single case file (ie. actual data) from the study:

Case No. 158

An attractive, amiable boy from a working-class background, you struck the study staff as happy, stable, and sociable. “My general impression is that this boy will be normal and well-adjusted—rather dynamic and positive,” the psychiatrist reported.

After college, you got an advanced degree and began to climb the rungs in your profession. You married a terrific girl, and you two played piano together for fun. You eventually had five kids. Asked about your work in education, you said, “What I am doing is not work; it is fun. I know what real work is like.” Asked at age 25 whether you had “any personal problems or emotional conflicts (including sexual),” you answered, “No … As Plato or some of your psychiatrists might say, I am at present just ‘riding the wave.’” You come across in your files as smart, sensible, and hard-working. “This man has always kept a pleasant face turned toward the world,” Dr. Heath noted after a visit from you in 1949. From your questionnaire that year, he got “a hint … that everything has not been satisfactory” at your job. But you had no complaints. After interviewing you at your 25th reunion, Dr. Vaillant described you as a “solid guy.”

Two years later, at 49, you were running a major institution. The strain showed immediately. Asked for a brief job description, you wrote: “RESPONSIBLE (BLAMED) FOR EVERYTHING.” You added, “No matter what I do … I am wrong … We are just ducks in a shooting gallery. Any duck will do.” On top of your job troubles, your mother had a stroke, and your wife developed cancer. Three years after you started the job, you resigned before you could be fired. You were 52, and you never worked again. (You kept afloat with income from stock in a company you’d done work for, and a pension.)

Seven years later, Dr. Vaillant spoke with you: “He continued to obsess … about his resignation,” he wrote. Four years later, you returned to the subject “in an obsessional way.” Four years later still: “It seemed as if all time had stopped” for you when you resigned. “At times I wondered if there was anybody home,” Dr. Vaillant wrote. Your first wife had died, and you treated your second wife “like a familiar old shoe,” he said.

But you called yourself happy. When you were 74, the questionnaire asked: “Have you ever felt so down in the dumps that nothing could cheer you up?” and gave the options “All of the time, some of the time, none of the time.” You circled “None of the time.” “Have you felt calm and peaceful?” You circled “All of the time.” Two years later, the study asked: “Many people hope to become wiser as they grow older. Would you give an example of a bit of wisdom you acquired and how you came by it?” You wrote that, after having polio and diphtheria in childhood, “I never gave up hope that I could compete again. Never expect you will fail. Don’t cry, if you do.”

What fascinates me is the absolute novelty of this kind of data. Normally, when someone relates their “life story,” we willingly participate in something of a shared lie. Both listener and story-teller know that the “life story” is being told in hindsight: Memory is not perfect and humans sometimes (often, perhaps) add meaning and create unifying themes in stories where they may be none. We emphasize the good parts and try to forget the not-so-good parts. In a sense, history recounted is never truly veridical but instead tainted with everything that happened after. Which is precisely why the availability of an objective history than spans an entire lifetime (or, as objective as possible) of both a qualitative (interview) and quantitative (medical) nature is so novel.

As you might expect, the data is confusing and hard conclusions are not easy to come by. There are however some tangible factors that seemed to correlate/predict success in life, which I’ve included after the jump. Continue reading

Sunday afternoon reading: Genetic tools "primer"

I came across this fantastic review of tools for the Genetic Dissection of Neural Circuits in Neuron a few days ago. It’s by Liqun Luo, Ed Callaway, and Karel Svoboda. I highly recommend it, as it spans the gamut from genetic targeting (recombination, binary logic, viral delivery) to circuit reconstruction (super resolution LM, EM, brainbow) to activity modulation and functional mapping (uncaging, artificial GPCRs, light-gated channels, MIST). I don’t think I’ve ever seen quite a review of so many cutting edge neurotechnologies in one place. I can’t recommend this piece enough really. For me, with my lack of molecular expertise, the first sections on combinatorial gene targeting/expression techniques were great, pulling together Gal4, Cre/Flp, and Tet systems into a unified framework, along with more general concepts like site-directed integration, enhancer-trap, and repressor trap (eg. Thy1 mice).

Neuroengineering memory: Something old, something new

Over the last week, it seems like everyone has sent me this NYT piece on PKM-zeta (about work in Todd Sacktor’s lab). I’m not sure why this work is being featured in the Times right now, since it’s a few years old. But it was news to me and I think it is of interest to anyone trying to understand structure-function relationships in the brain. In the original Science paper (from 2007), a pseudosubstrate inhibitor of PKM-zeta caused irreversible loss of a conditioned taste aversion memory (news and views here). I was unfamiliar with PKM-zeta, which appears to be a constitutively active form of PKC-zeta (a kinase that some might be more familiar with) and that lacks the autoinhibitory regulatory domain of PKC. The amazing phenomena is that, after treatment with ZIP (the pseudosubstrate that ties up PKM-zeta), the memory is permanently erased and doesn’t seem to return.

What’s going on? One tantalizing possibility is that the enzyme itself is directly related to the memory trace. This contradicts the (unproven) assumption of modern neuroscience that memories are stored solely in the synaptic strengths (ie. membrane-bound receptors) of a neuron. The other suggestion is that PKM-zeta is actively maintaining synapses and that enzymatic inhibition disrupts the precise maintenance of receptors or synaptic machinery. The effects happen quite fast (within 2 hours after drug injection), which seems short for receptor recycling but perhaps long enough for structural change to occur. I’m no expert on receptor movement: Is 2 hours long enough to add/remove a significant number of receptors?

Fascinating work but the method is blunt, wiping all experimentally-induced memories (and probably others too). Last month, another group reported (also in Science) selective erasure of a fear-conditioned memory using an interesting new genetic tool. Here, neurons in the amgydala that overexpressed CREB were found to be preferentially recruited into a fear memory trace (as shown in a previous Science paper). Incorporation into the memory trace was assayed by expression of the immediate-early gene (ie. activity-dependent) Arc. In the present study, they combine overexpression of CREB in a subset of neurons with cell death (via Diphtheria toxin in a transgenic mouse vulnerable to diphtheria). Apparently, normal mice lack the receptor (here a simian version is used) that confers pathogenicity for diphtheria. Thus, the viral construct both overexpresses CREB in a subset of neurons and selectively makes the same subset vulnerable to diphtheria. Ablation of just these neurons causes a permanent loss of the memory. Subsequent similar learning proceeds just fine (using the remaining neurons).

Can we say that the race is officially on to ablate just the synapses involved in the memory? I think so. Extra points if the ablation is reversible too!

VS Ramachandran's TED Talk

Although I’ve been a longtime fan of Ramachandran’s excellent book Phantoms in the Brain, this TED talk is like a compressed summary of the highlight’s of his research. He’s a great speaker and he covers in 20 minutes my two favorite examples in the book (Capgras delusion and mirror treatment for phantom limb syndrome). Perhaps the best part of the talk is that, after listening to it, I was convinced more than ever before of the statistical nature of sensory perception (ie. the brain attempts to find the most likely explanation for sensory observations) and the integrative nature of central processing of multiple modalities. 

http://video.ted.com/assets/player/swf/EmbedPlayer.swf

Atul Gawande also recently wrote a New Yorker article about treating phantom itch with Ramachandran’s mirror box. I found this part of Gawande’s article on statistical inference in perception most interesting:

You can get a sense of this from brain-anatomy studies. If visual sensations were primarily received rather than constructed by the brain, you’d expect that most of the fibres going to the brain’s primary visual cortex would come from the retina. Instead, scientists have found that only twenty per cent do; eighty per cent come downward from regions of the brain governing functions like memory. Richard Gregory, a prominent British neuropsychologist, estimates that visual perception is more than ninety per cent memory and less than ten per cent sensory nerve signals. When Oaklander theorized that M.’s itch was endogenous, rather than generated by peripheral nerve signals, she was onto something important.

I’m not familiar with this field but I wonder if anyone has tried to quantify what percent of our conscious experience that we normally believe to be 100% due to sensory input is actually recall from memory/inference based on past observation. Also, can this percentage adaptively change? Perhaps there are situations where the brain chooses to rely more heavily on memory and other cases where it relies more on primary sensory input.