neurodudes

When we learn new information we use only a tiny fraction of the neurons in our brain for that particular memory trace. In order to allow the molecular study of those specific neurons we combined elements of the tet system with a promoter that is activated by high level neural activity (the cfos promoter) to generate mice in which a genetic tag can be introduced into neurons that are active at a given point in time. The tag can be maintained for a prolonged period, creating a precise record of the neural activity pattern at a specific point in time. Using fear conditioning we found that the same neurons activated during learning were reactivated when the animal recalled the fearful event. We also found that these neurons were no longer activated following memory extinction, consistent with the idea that extinction modifies a component of the original memory trace.

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Supplementary Figure 1: A schematic illustrating the main finding. Slow gamma is maximal on the descending portion of the theta wave, and fast gamma peaks near the trough. Slow gamma serves to synchronize CA1 with inputs arriving from CA3, and fast gamma synchronizes CA1 with MEC input.

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Replay of behavioral sequences in the hippocampus during sharp wave ripple complexes (SWRs) provides a potential mechanism for memory consolidation and the learning of knowledge structures. Current hypotheses imply that replay should straightforwardly reflect recent experience. However, we find these hypotheses to be incompatible with the content of replay on a task with two distinct behavioral sequences (A and B). We observed forward and backward replay of B even when rats had been performing A for >10 min. Furthermore, replay of nonlocal sequence B occurred more often when B was infrequently experienced. Neither forward nor backward sequences preferentially represented highly experienced trajectories within a session. Additionally, we observed the construction of never-experienced novel-path sequences. These observations challenge the idea that sequence activation during SWRs is a simple replay of recent experience. Instead, replay reflected all physically available trajectories within the environment, suggesting a potential role in active learning and maintenance of the cognitive map.

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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!

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. 

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.

Although it’s a few months old, Larry Abbott has an excellent article in Neuron on the recent (last 20 years) contributions of theoretical neuroscience. (He came by MIT last week to give a talk and that’s when I found out about the article.) It’s a review that is not too long and provides a good overview with both sufficient (though not overwhelming) detail and original perspective. It’s rare to find a short piece that is so informative. (And for a more experimentally-oriented review with an eye toward the future, see Rafael Yuste’s take on the grand challenges.)

Click on for some of my favorite passages from the Abbott piece. (more…)

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Fascinating. The first case of a person with virtually perfect autobiographic memory. In the interview, she says that she runs her entire life through her head every day. Perhaps the difference isn’t in memory capacity but rather the automatic (unconscious) practicing of all past sensory experience.

NPR interview with patient, John Gabrieli and Larry Cahill.

Link to paper. Abstract:

This report describes AJ, a woman whose remembering dominates her life. Her memory is “nonstop, uncontrollable, and automatic.” AJ spends an excessive amount of time recalling her personal past with considerable accuracy and reliability. If given a date, she can tell you what she was doing and what day of the week it fell on. She differs from other cases of superior memory who use practiced mnemonics to remember vast amounts of personally irrelevant information. We propose the name hyperthymestic syndrome, from the Greek word thymesis meaning remembering, and that AJ is the first reported case.

Jonathon Keats (no, not that one) has written a scorching review of neuro grad student Jonah Lehrer’s new book, Proust was a Neuroscientist.

I saw this somewhat more favorable review a few weeks in the NYT and was intrigued by the book. As an undergrad, I majored in cognitive science and English and, naturally, was fascinated by the cultural differences of academics in these disparate fields.

As in the Salon article, I also think attempts to unify the “two cultures” (ie. arts and sciences) are misguided. A work like Lehrer’s book (which I have not read) will need to work hard to “prove” its thesis and likely sound very forced. What can we really say about arts vs. sciences? For that matter, is it important to make value judgments on this topic? I’d say, no. We seem to have a natural urge to categorize our activities and then try to order them. Science is more worthwhile. Art is a more creative endeavor. Are these blanket generalizations productive?

But there is overlap between the two cultures and those regions seem more and more important to me. And I think neuroscience in particular has a lot to say here, too. If we know what makes good art good (in a scientific way), will we stop appreciating it or enjoying it? (This is similar to the idea that if someone told you free will was simply an illusion would the illusion be any less powerful than it is right now?) Often, the surprise of creative thought underlies the best science and the best art. Okay, there’s my attempt at a unification!

On a separate note, there certainly seems to be a hunger amongst the reading public for neuroscience books, despite our incomplete picture of how the brain works. For those frustrated with slow progress in research, maybe we should just go write a book.

Finally, they’ve figured out something that neural systems have capitalized on for a while: Using all 3 dimensions. Check it out:

NYT article on Stuart Parkin and racetrack memory
IBM Almaden page on racetrack memory

And a nice semi-technical discussion from EE Times on current 2D RAM and how racetrack memory takes advantage of 3 dimensions. A key concept here (and an old one, see bubble memory below) is “massless motion”: Applying a current to a tape moves the magnetic domains along in a similar manner to mechanically moving the tape.

On the macro scale, a similar type of memory called bubble memory was available up to the early 1980s when it was replaced with hard disks. Seems like high speed (pushing the correct magnetic portion of the nanowire to the read head) and doing so without excessive current are what really make this a viable technology now.