The dilemma of gene-expression models of memory

invert_nexus said:
Alas. No.
I only have Science, I'm afraid.
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Okay.

This is the approach and model:

A well-defined system for the study of memory is the olfactory/electric shock paradigm of Drosophila (Tully and Quinn, 1985). A memory of odor associated with electric shock can be induced in phases that include short-term (STM) and long-term (LTM), phases that are distinguished by their dependence on training protocol, genetic pathway, and protein synthesis. A requirement for protein synthesis in olfactory LTM was demonstrated long ago (Tully et al., 1994) and reinforced by the identification of longterm memory mutants as genes with functions in mRNA transport and translation (Dubnau et al., 2003). This system presents an opportunity to determine how and where protein synthesis is deployed and what mechanisms regulate it during the formation of a memory.

To approach these questions, we devised fluorescent reporters of synaptic protein synthesis using sequences of the Drosophila Calcium/Calmodulin-dependent Kinase II (CaMKII), the homolog of the mammalian αCaMKII, which is synthesized at synapses and required for memory (reviewed in Kelleher et al., 2004). We show that the induction of a long-term memory in Drosophila is accompanied by transport of mRNA to synapses and patterns of synaptic protein synthesis that have features of memory specificity. These events are regulated by components of the RNA interference (RISC) pathway. At least one RISC factor, Armitage (Cook et al., 2004), is localized to synapses and degraded by the proteasome in response to neural activity or the induction of an LTM. Therefore, degradative control of RISC underlies the pattern of synaptic protein synthesis associated with the establishment of a stable memory.
 
...the RNA interference (RISC) pathway
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Derr.
That's where I know RISC from.

...patterns of synaptic protein synthesis that have features of memory specificity.
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I wonder exactly what and how these proteins are utilized. Are they the framework of the dendritic spines? Are they part of the cytoskeleton of the dendrites?

This does take place in the dendrites, yes? Not the axon?

Interesting stuff, but I'd like to see a more explanatory model. I suppose it's rather early in the game yet...
It's a start though.


By manipulating the RISC pathway, Kunes and colleagues were able to alter flies' memory, changing their response to stimuli in subsequent behavioral tests. Using a classical learning test that simultaneously exposes the insects to an odor and an electric shock, the researchers found that long-term memory could be greatly increased by adjusting the activity of the RISC pathway in the fruit flies.

"In essence, these flies had twice the memory of their normal counterparts," Kunes says. "When RISC was knocked out, so was long-term memory, and flies would remember to alter their behavior in the presence of the shock-linked odor for perhaps an hour; that is, they only had short-term memory. When the pathway was normally active, the flies remained averse to the odor for a day or more."
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Alright.
So.
What we have here is that the mRNA that is translated into proteins that get somehow utilized in memory incorporation are sent down the dendrites willy-nilly. Little to no direct addressing.

At the sites where memory incorporation is occurring, the RISC factor Armitage (among others) is removed and thus the mRNA is able to be translated at these sites into the necessary proteins.

That's pretty simple.

And when RISC is knocked out completely, I'm thinking, then LTM is eradicated as the mRNA being sent down the dendrites is being translated everywhere (although it might well be getting used up in the dendritic spines closes to the soma and never reaching the outlying reaches.

This effect, I would think, would have a large number of side effects other than a disappearance of LTM. Unless I'm conceiving this wrong.


I'd really like to know how the proteins are utilized in incorporating a memory. The only thing I can think of is by making temporary synapses permanent.... Hebbian learning at its finest....

Interesting stuff, really.

Thanks, Sam.
 
http://www.sciencedaily.com/releases/2004/02/040206085619.htm said:
Long-lasting memories are stored in the brain through strengthening of the connections, or synapses, between neurons. Researchers have known for many years that neurons must turn on the synthesis of new proteins for long-term memory storage and synaptic strengthening to occur, but the mechanisms by which neurons accomplish these tasks have remained elusive.
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So. Pretty much what I conjectured above.

However, this is still crude and lacks a truly effective model.
For instance, how is it that synaptic structure of the neural network translates to memory? This is a key discovery waiting to be made.

Getting closer though.

So. I suppose.. Back to proteins.
The proteins are probably many.
Some proteins go into the cytoskeleton.
Some proteins go into the ion channels.. although. No. that wouldn't work unless there was an endoplasmic reticulum at the synapse as well. And I seriously doubt this. So, ion channels and other membrane proteins would have to be transported all the way from the cell body.

This brings up addressing again, because the specific membrane proteins must be delievered to the specific synapses in order to be effective.

Anyway.
There's a whole host of proteins and uses of proteins that can be made in situ.
But, still, transmembrane proteins put a crimp in this particular model...

Hmm.


Edit:

ahh.

An immediate question that Tonegawa and colleagues are pursuing is how neurons target the newly synthesized proteins to the specific synapses participating in memory formation while not modifying other synapses.
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Heh heh heh.
Yup. That's the thing, eh?

Looks like these guys aren't talking about the same protein pathways as the others. This pathway (MAPK) seems to be targeted towards the ordinary somatic protein synthesis.

I imagine that it probably takes part in the RISC option as well.

It would be interesting to see the differences in proteins utilized by these two separate pathways.
I suppose one 'obvious' would be that membrane proteins would, by necessity, be part of the MAPK pathway rather than being created in situ via RISC.

But what other categories of proteins are involved in LTM?

And, in this model, is STM merely the temporary formation of the neural network which will vanish within hours if not strengthened and made permanent via protein synthesis?

And what about working memory?

How do these physical models combine with the psychological models?

Ah.
What an era looms on the horizon.
FINALLY.
 
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Ample evidence indicates that the expression of genes in the mature organism is influenced by the environment.It is ,therefore,tempting to consider a role in memory for alteration in gene expression.Before proceeding to discuss experimental evidence for the macromolecular synthesis hypothesis,I should clarify what role the newly synthesized proteins could have.I assume that these proteins modify properties of neuronal systems,by stabilizing and extending mechanisms used in short-term memory,or by initiating new types of cellular change.Note that the neuronal loci subserving short - and long - term memory are expected to overlap,at least at first,but need not be identical.An example from Aplysia illustrates this:
short term habituation of the GSW reflex was portrayed as homosynaptic depression,but long-term habituation involves additional central neurons and heterosynaptic depression(Montarolo 1988).However,regardless of wich cellular loci are modified in short and long term memory,one point is clear: macromolecules subserve changes in the representational properties of neuronal circuits,but do not directly encode a specific representation.The latter is encoded in the connectivity and molar activity of the circuit.In other words,similar molecular changes may subserve different modifications in different internal representations,depending on the cellular context in wich these molecular changes take place.

Fausto Intilla
www.oloscience.com
 
Fausto Intilla said:
Ample evidence indicates that the expression of genes in the mature organism is influenced by the environment.
Click to expand...

Only in specific cases and hence the whole discussion that follows is pointless. You will have to address the specific cases.
 
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