[LINK] Hypothesis about the mechanism for storing long-term memory

by Andy_McKenzie1 min read10th Jul 20138 comments


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As proposed by Roger Tsien, open access here. The first paragraph offers a potentially biased but still useful overview of the state of the field: 

A major problem in understanding memory is how it can be very long-lasting and stable from early childhood until death, despite massive interruptions in brain state as extreme as prolonged comas. Current prominent candidates for molecular substrates for long-term memory storage have focused on macromolecules such as calmodulin-dependent protein kinase II (CaMKII) coupled with the NMDA receptor and protein phosphatase 2A (2), protein kinase M zeta (PKMζ) (3), and cytoplasmic polyadenylation element binding protein (CPEB) (4), all of which are inside postsynaptic spines. To retain information despite metabolic turnover, all such candidates need to have some sort of bistable switch (e.g., state of phosphorylation or prion conformation) and a mechanism by which older copies of the molecule pass on their status to newer copies to preserve the information. A major problem is that individual intracellular molecules typically last at most a few days before being turned over. Therefore, the information would have to survive being copied tens of thousands of times in a long-lived human, despite metabolic interruptions. Such robust fidelity would be extremely difficult to engineer. Even dynamic computer memory with sophisticated refresh and error correction circuits cannot cope with even a momentary hiccup in its power supply. Instead, long-term information storage in both computers and human civilizations requires writing the information onto physically stable storage media (e.g., magnetic disks, clay tablets, or acid-free paper), which do not require frequent energy-dependent recopying. Aside from some nuclear pore constituents, all of the known really long-lived proteins are insoluble [extracellular matrix] components such as crystallin, elastin, collagen, and proteoglycans (5), which gain stability by extensive cross-linkage and remoteness from intracellular degradative machinery, such as proteasomes, lysosomes, and autophagy.

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Can you preface the title of this post with [LINK]?

Can anyone explain what is wrong with the hypothesis of a largely structural long-term memory store? (i.e., in the synaptome, relying not on individual macromolecules but on the ability of a graph of neurons and synapses to store information)

There's nothing wrong with it, it's just that the strength of connections (local synaptic concentration of various neurotransmitters and receptors) has been demonstrated to be just as important as their graph-theoretical structure for long-term memory. Synapses can regulate their strength and maintain the strength over long time periods. The problem that the quoted paragraph is trying to illustrate is that a simple chemical concentration explanation doesn't cut it since chemicals are being diffused and turned over inside synapses all the time. Thus there must be some mechanism for long-term persistence of memory.

Not only that, but there is evidence that in a lot of brain regions neurons simply connect to whatever cells they touch with the average topology of any region defined by the growth properties of the cell types that exist there. From there, the individual connection strengths are reinforced or worn away or otherwise altered by actual neural activity via changes in membrane, cytoskeleton, kinase, etc activity/composition at the individual synapse (on both sides).

That was also roughly my mental model, and Wikipedia points in that direction too.

Interestingly, Wikipedia suggests that the mechanism is relatively easy (read: already successfully done in rats) to manipulate in some cases to restore (partially and temporarily at least) the superior learning ability that children have and adults lose (probably at the cost of degrading some of the already learned memories and skills).

It would be nice to have a pill you could take when trying to learn a new language, for example. If that works, it might be even more useful, e.g. to help learn skills that a child could not even try to practice. I mean, we can’t tell if the young brain is better at "getting" quantum mechanics intuitively, because other changes in the brain are needed (which only adults have access to) before you can really begin to think about it, and it’s hard to test if someone who flies (e.g. a plane) regularly since birth would have better vertical awareness orientation, because planes are too dangerous to let children try to fly them before they learn to walk.

(I suspect that much of the difference in intuitiveness between 3D and 4D universes is actually "learned" by the brain, rather than a consequence of the brain existing in a 3D universe. Weak evidence is that blind-from-birth people who get their vision restored can’t really make much sense of what they see, though that could be specific to vision; incidentally, such people would be excellent test subjects. It would be unethical to raise a child in VR, but there’s no reason why an adult couldn’t try living in it for a while. The Oculus Rift is already good enough I expect, though I’m not sure we can do good-enough real-time stereo renderings of 4D simulations with usual hardware.)

I only just learned about this today, so I don’t put a lot of weight in my conclusion, but this sounds like the most promising first step to superhuman (relative to today) intellectual skills.

Interestingly, Wikipedia suggests that the mechanism is relatively easy (read: already successfully done in rats) to manipulate in some cases to restore (partially and temporarily at least) the superior learning ability that children have and adults lose (probably at the cost of degrading some of the already learned memories and skills).

I don't really think that children have a superior ability at learning languages. There are plenty of adults who can learn a new language in under a year if they undergo complete immersion and use mnemonics to help them.

I think children are usually only better than adults is bad at learning or if the adult has to unlearn a bunch of things that he learned to practice the new skill.

At least some things are easier for (most) children than for (most) adults. For example, most adults will have to work very hard to speak a foreign language without an accent. Children who were exposed to a second language, even if they don’t speak it for years, will be able to pronounce it correctly later. See this.

I suspect some grammatical structures are also harder to acquire later, given how hard it is for adults to learn syntax elements that don’t exist in their native language (see the stereotype about foreigners always forgetting “the” in English).