8.10.2011

Neuro-Not-So-Basics: Diving Into a Bit More Detail on Neuroplasticity

The previous installment on neuronal plasticity involved a lot of wand waving in order to keep it very basic. There is far less of that here. This is a more detailed review of neuroplasticity and one of its components, Long Term Potentiation (early phase) (e-LTP). The second installment with cover Long Term Potentiation (late phase). Certainly not all of the known processes involved in learning and memory will be presented in this review but hopefully it gets us closer to what’s really going on behind our eyeballs. These next two installments will review some of the current knowledge about learning and memory at the synaptic level, and following that, the focus will shift to a review of cellular changes that can create new connections or prune unneeded old ones.

Below is a rendition of an excitatory synapse in the CNS with some of its critical components displayed in their ‘resting state’ Resting state is a misnomer since a great deal of energy is required to maintain the baseline charge gradient against diffusion. Separated by the synaptic cleft, the axon is the input to the synapse, the dendrite is the receiver and output, and the astrocyte is there to support the metabolic needs of the neurons but it also serves some other vital functions as well. The astrocyte provides some of the interlacing structure that holds the synapse together (not shown for simplicity) and it polices the synaptic cleft absorbing neurotransmitters and their byproducts between firings. I’m not going into too much detail on that part but it should be noted that failure of that function by the astrocytes is associated with known diseases including ALS.


The axon terminus contains vacuoles filled with gluamate (glutamic acid or Glu). Glutamate is an amino acid, a preservative in Chinese food and the most common neurotransmitter in the CNS.

The synaptic cleft is maintained with a resting excess of sodium (Na+) and Calcium (Ca++) ions relative to the interior of the cells.

Embedded into the cell membrane of the dendrite are a number of protein complexes that span its lipid bilayer. Among these are AMPA (Alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) ionotropic receptors for glutamate (Glu). An inotropic receptor is one that selectively admits ions to the cytoplasm of the cell when activated (in this case by Glu). There are also metabotropic receptors that bind with transmitter. Metabotropic receptors are those that activate intracellular second messenger cascades within the cell. What does that mean? When the transmitter binds to the external portion of the metabotropic complex, it causes a conformational change in the portion of the complex that extends into the cytoplasm. Once this happens this usually results in a configuration of the protein that allows it to catalyse some important reaction to create an intercellular messenger that communicates with structures within the cytoplasm. The most famous metabotropic complex is the one associated with adenyl cyclase (the Western Union of eukaryotic cells) which creates the ubiquitous intracellular messenger, cyclic AMP (which will play a roll in the discussion of the late phase of LTP).

So ionotropic receptors allow ions to pass into the cell, while metabotropic receptors switch on some intracellular machinery. You should also note that not all of these receptors are located within the synapse. This will be of some importance after a bit.

This is pretty much the state of things until an action potential makes its way to the synapse as a wave of membrane depolarization moves toward the terminus of the axon.


Once the terminus deploraizes, the vacuoles containing Glutamate (Glu) bind with the cell membrane and discharge Glu into the synaptic cleft.


Glutamate binds to AMPA which opens these ion channels to the cytoplasm allowing Sodium ions (Na+) to rush into the cell.


This changes the electrical potential of the dendritic cell membrane,


Which may or may not be enough to generate a responding action potential in the target neuron. Absent any additional stimulus within a short period of time, the Glu is reabsorbed and the membrane potentials return to baseline. This can occur over and over again without any noticeable plastic change to the synapse.

However, the situation changes considerably if the synapse is subjected to high frequency bombardment. Imagine situation like below, where the axon is being stimulated over and over again with such frequency that the dendrite cannot return to baseline polarity before the next signal hits.  Since the dendrite is unable to return to baseline between firings, the potentials begin to stack one onto the next until a critical electrical threshold is exceeded.


Once this threshold is exceeded several things happen as part of what is called Long Term Potentiation (early phase) (e-LTP).
  1. The electrical charge changes are sufficient to dislodge magnesium ions (Mg++) that normally block the ion channels of NMDA.
  2. Glutamate binds to NMDA and Calcium ions (Ca++) enter the cell.
  1. There is plenty of surplus Glu about to bind to the metabotropic receptors in the synapse to activate second messengers in the cytoplasm. (not shown)
  2. Calcium ions in conjunction with the second messengers activate a number of intracellular cascades including Protein Kinase (PKC) and Calmodulin kinase II (CaMKII).
This activated complex does a couple of things. First, it phosphorylates AMDA which dramatically improves each molecule's ability to transmit Sodium ions to the cytoplasm. This change can persist for some time even if no other changes occur. The enhanced ion channels are far more sensitive to future stimulation and may even promote neuron depolarization at signal frequencies that previously would have been below the threshold for response. So this is a plastic change to the synapse.


The second effect is that AMPA receptors outside of the synapse are drawn into it. The result is more available receptors without the need for additional protein synthesis further strengthening the synapse's responsiveness to future stimulation.


Protein synthesis is vital to the next stage of the process, which is the late phase of Long Term Potentiation (LTP) which fixes and extends these changes. But that is a story for another day. Hope this is interesting.

34 comments:

Jared said...

Awesome post, very concise. A few quibbles, though:
Is the Early Phase of Long Term Potentiation to be denoted as E-LTP, eLTP or simply LTP (early phase)?
I always thought tetany refers to muscle movement and its associated neuronal firings, not just the neuronal firing pattern--I thought repeated rapid neuronal was referred to as a burst (although, granted, this is a very general term).

Pliny-the-in-Between said...

Thanks Jarod. I've seen it written all 4 ways, unfortunately. I suppose it makes sense to stick to a single convention, so I'll use LTP (early phase) from this point on.

Tetany I suppose betrays my medical background since it gets used in this way in some medical literature. Both muscle and neuronal effects are largely due to stacking Ca++ infux. I usually have seen burst associated with epilepsy in some of the clinical work I'm doing in AI support, so I tend to avoid it. but that's not necessarily a good thing.

GearHedEd said...

That's all well and good as far as it goes. Most of us here already accept the physiology involved in synaptic connections. But does understanding what goes on at the molecular level contribute anything to an understanding of consciousness? (I'm asking because neurophysiology isn't my field--but it seems that something like where this series of posts started i.e., "the illusion of cansciousness" depends more on a systems approach. I guess what I'm asking is, "are we getting bogged down in too much detail here?")

Jared said...

Ed, in (sort of) short, understanding the way in which long term potentiation happens is very key in understanding memory, self, and perception. It forms the groundwork for all of these. It is how the "plastic hardware," upon which the software of streaming consciousness takes place, is altered (as well as many processes which we are not aware of). The firing of the neurons (sometimes) directly alters the hardware upon which perception processes happen. These alterations form the pathways which are known as "memories" and influence our perceptions by altering how we receive signals. This changes our behavior as a result. These details are the "glue" that holds the philosophical construct known as "mind" together and makes it all make sense in a scientific framework.

Hope that wasn't too complex, I'm on benadryl after having cut grass and I'm a bit loopy. The wine I had with dinner didn't help.

Pliny-the-in-Between said...

Ed it's a fair question but my view is that the details will help in the end to show the incredible distance between the vague philosophy of mind and the hard science of it. Deists and philosophers will dive for any ambiguities we leave off. The point is to show that regards to the mind, the god of the gaps is shrinking.

Besides - you always clamor for more science - well here it is ;)

Pliny-the-in-Between said...

Plus I think you need these basics before the higher structures of the brain involved in memory and perception can be appropriately understood.

Pliny-the-in-Between said...

Finally, (well maybe, I may go off some more on this) philosophy has taken a top down approach to mind. This is a bottom up approach. We have to see if the basic components of the system can account for the range of behaviors we observe, not some arbitrary construct which is the currently accepted notion of mind that most people take for granted.

Saint Brian the Godless said...

I had mistakenly posted this on your 'basic science' post, so I'll re-post it here.
----------------

After a cursory read I agree, the clearest explanation of quantum tunneling that I've ever heard. You are already an accomplished writer, and you're apparently also a very good science educator. Y'Ever think of becoming the next Carl Sagan?

Okay, unrealistic, but how about a gripping novel where basic understanding of science saves the day?

I shall endeavor to read this article in it's fullness either tonight or more likely, tomorrow. And your previous ones that I've missed as well. When I feel that I'm actually LEARNING SOMETHING, I get interested, and so I am.

You are pretty fucking cool, pliny. Don't let it go to your head, though. Your lack of egotism is one of your best qualities.

Nicely done, sir.

Saint Brian the Godless said...

If I were to put on my mystic hat, I might point out how when someone points out how natural and explicable things like quantum tunneling are, as if to say that 'see, there's no need for supernatural explanations' how if mysticism is right, science will come upon these points and show how very explicable and natural they are. As they should be. I mean, think about it. I'll commit your fallacy and for a moment act as if they're 'billiard balls' to make a point.
Something that has mass, can pass through a barrier, just by statistical anomaly in it's probability wave. It can cross barriers, just by chance. I see how it's logical and explicable. Sure it is. It must be. It all makes perfect sense. Because we've developed the science to explain it now. And if 'all is mind' as we go along, at each incremental step, we'll develop the science to explain it as if it weren't. That is precisely what would be expected given the parameters of the scenario of holistic idealism.

Saint Brian the Godless said...

Until eventually science will describe the mind that is reality, or the dream if you prefer, in it's own scientific terms that all make sense and fit in with the rest of science, and yet it will describe the same thing as a mind or a dream, but with a neat new technical name that nobody would connect with such an insane, unscientific type of thing.

Saint Brian the Godless said...

Maybe at first it might be something like 'the two-dimensional event-horizon that projects our multidimensional universe holographically.'

Something cool like that.

And later, with more modifiers, who knows?

A field of data. One of my favorite terms, because it is most neutral.

How different are 'a field of data' and a two-dimensional field that projects reality in multiple dimensions that we can perceive

I mean, it could happen.

But I'm more of a skeptic than you are sir. And more than pboy. To me, as Jerry once said, all I can really be sure of in this deceptive reality, is that I, Rene Descartes, exist! Or whoever I am...

So given that that's all I can actually be totally sure of, I can see how this reality might be just one level more deceptive than science is giving it credit for.

Of I'm totally all wet, and science will prove me to be just that.

I can handle that.

I'm content to wait, rather than jump to conclusions. I am, after all, a very limited organism in a complex world....

Saint Brian the Godless said...

And you like to think of a quantum size particle as a cloud, I believe you said. The cloud illustrations.

That implies that it's present at all points in the cloud, to a greater or lesser (probabilistic) extent, no? You're envisioning the entire probability wave.
But sir, it's a mathematically based statistical wave with no actual existence, no? A convenience of discussion.
Did it ever occur to you that it's so hard to envision, because it isn't 'real' like we think of real? It's very duality, which makes sense to us now because we've discovered the rules that can describe it, defies common sense before we had those rules. So we say 'the realm of the very very small defies common sense' and are left to envision that which cannot be envisioned as best we can, using the tatters of our common sense that it just violated, because that's all we have at that level.

Maybe it defies understanding because we're trying to understand it using common sense, our real-world-conditioned (and perhaps biased) common sense which is based in observable reality, when perhaps here we're looking at the fringes of unreality showing it's skirt, and our scurrying to explain it.

I guess what I'm saying is, the more our scientific descriptions become seemingly outlandish, the more we just might be trying to describe the truly outlandish. The idea that our precious matter and energy, are more accurately described as kinds of thought. Or if you prefer, data. I think data might be best, yes. It's not like human thought, so data comes closest for me. Perhaps it's like a mind or a computer program with no computer necessary; perhaps it's the event horizon of some immense singularity. But data nonetheless.

I may be misunderstanding you. I definitely need to reread all of this, likely more than once. It's late. I'll try harder tomorrow.

Saint Brian the Godless said...

Oh, and how does the interference of the mass of a photon (say) used to locate the particle, cause the collapse of the probability wave in the delayed choice quantum eraser experiment? That one I'd like to understand better. Perhaps you sir pliny might elucidate it to me? (Serious here; it's hard to grasp!)

Saint Brian the Godless said...

I think that's the one where they used a sensor to tell which slit the electrons went through, but then had it *dump the data' after the measurement. Obviously this was designed entirely to prove or disprove that the culprit in the collapse was the measuring particle itself and not the fact that someone tried to observe it.

And after it took the measurement, after it 'knew' which slit the electron went through, it erased that data so no human could ever know the result, *and the probability wave didn't collapse.*

Am I getting that right? Because that's how it reads to me. To me, if that's the case, then I can't see anything else other than *human consciousness* that collapsed the waveform.

Am I seeing this at kindergarten level or something here?

Saint Brian the Godless said...

Human consciousness, last I checked, has no mass, not even that of a photon.

If it can collapse a waveform, then sir, all bets are most definitely off.

So it's a telling point for me.

Do tell!

:-)

pboyfloyd said...

Now Brian, take your mystic hat off for a second and imagine doing that test. We know the conditions which make the wave-form collapse, right?

No-one actually 'needs' to look at it to know, no-one actually 'needs' to know what's going on to report where there is interference or not, so it's not someone's brain waves making it do what it does.

Christ Brian, you could train a monkey to push 'lever A' if it's a diffraction he's seeing and 'lever B' if it's not. Would that mean it's the monkey's observation doing it?

I don't think so.

Okay, mystic hats at the ready? Wait for it, wait for it, mystic hats ON!

pboyfloyd said...

Oh, sorry for the double post, but if it had to do with the mind of the observer, we might have a situation where the wave collapses or not depending on whether the observer is told that the data has been dumped or not.

We could be looking at a diffraction pattern after being told that the data was dumped, then watch it change to a single point after the 'tester'(now testing the power of our 'mind') told us that he had in fact lied to us and didn't dump the data!

Even worse, one of us might be told one thing and see a diffraction pattern and the other see a 'point', no?

Saint Brian the Godless said...

We know the conditions which make the wave-form collapse, right?
--------------
I don't think you understood the experiment.

The test was done both times. The sensor tested, and determined which slit the electron went through. Both times.

When no-one looked at the results, when the results were erased before anyone could see them, the waveform didn't collapse.

When someone looked, it did.

This determines conclusively, if I am describing it right of course, that the only single difference, the only one, which made all the difference, was that the results were known. By people. The test both times was done identically, and the only difference was that people could see the data in one instance, and not ever see it in the other. And that mattered.

Hello!? Are you receiving me?

Saint Brian the Godless said...

When I say the waveform didn't collapse, I mean of course that the interference pattern showing a 'wave form' rather than a particle, showed up on the screen. The particle goes through both slits.

When no sensor is present, the particle, in wave form, goes through both slits. At the same time.

When a sensor is present, and we are reading the results, the wave form collapses and we see particle form, going through only one of the two slits.

Now, with that same sensor present, we run that last test, but we program the sensor to still take it's measurement, to still test and see which slit the electron will go through. Identical to that last test where the WF collapsed, but this time nobody gets to ever see the data. The sensor takes that measurement, but dumps the results so nobody can ever see them.
And then, the waveform doesn't collapse.

Only single difference, the only difference, is that a human got to see the results, after the test was taken.

If this isn't counterintuitive to you, you're not reading it right.

Saint Brian the Godless said...

Christ Brian, you could train a monkey to push 'lever A' if it's a diffraction he's seeing and 'lever B' if it's not. Would that mean it's the monkey's observation doing it?
-------------
Sure, it might well mean that. That any conscious observation matters, even a nonhuman one. Or it might take a human to see the monkey's choice. That would be an interesting variation on the test.

You're acting like it's too silly. This is good; maybe you ARE getting it now. It IS silly. But it is the result.

Saint Brian the Godless said...

We could be looking at a diffraction pattern after being told that the data was dumped, then watch it change to a single point after the 'tester'(now testing the power of our 'mind') told us that he had in fact lied to us and didn't dump the data!
-------------
It's not illusory. The pattern does change. For real. And if the 'tester' already knows the result, the pattern has already collapsed. If the test is done and the data is taken, but the reading of the result is delayed, the pattern still collapses. However, if instead of delaying the reading, if that data is instead erased so that nobody will ever know, the pattern remains; the waveform doesn't collapse.

That's how I read the results anyhow, and because it is indeed so incredible in the literal sense of the word, I am here asking pliny for clarification and correction if I am mistaken.

Saint Brian the Godless said...

You must see how this result eliminates the idea that it is the mass of the testing photon that causes the waveform of the passing electron to collapse. In both cases, the sensor took the test, used it's photon, collided it with the electron, read the result.

Only difference is, in one instance of the test, the result is erased before anybody can see it.

Time itself is also violated here, unless I'm reading it wrong.

The result can be read after the fact, and it still collapses the waveform in the past when the test was taken. And of course conversely, when one says that in another test the sensor took it's test but THEN dumped the data, that is a sequence in time. It didn't dump the data at the same time it took the reading, it dumped it after it took it's reading. But still changed the result of it's own reading. After the fact.

WTF?

pboyfloyd said...

Let's say the dumping/not dumping of the data is done by computer.

We 'observers' can look at the diffraction pattern/point to decide if the computer has dumped the data or not, making the 'observation' by a consciousness 'after the fact', right?

Saint Brian the Godless said...

Another line of experimentation:

Quantum entanglement.

You twin two particles, give them correlated spin, then move one of them off at a distance, ANY distance, and no matter how far apart, when you change the spin of one of them, the other 'twin' changes to still correlate with it, INSTANTLY. Seems to violate lightspeed.

Now when I ask for the explanation, I tend to get 'oh Brian you're seeing it wrong! When they're twinned, they're not really technically two particles anymore, they're really one particle in two places. So nothing is violated...'

Oh Thank You! That Clears Up Everything! Not so incredible after all then... Sure, that makes common sense. Sure.

pboyfloyd said...

We set up the equipment as normal but gave control of dumping to a computer, first observing when the computer didn't dump the data, we saw a point as expected. We then observed when the computer did dump the data and as expected, saw a wave-form.

Finally we let the computer randomly either dump or not dump the data and observed, in tiny writing, "Hey, no fair, that's cheating!"

Saint Brian the Godless said...

We 'observers' can look at the diffraction pattern/point to decide if the computer has dumped the data or not, making the 'observation' by a consciousness 'after the fact', right?
----------
Now you're getting it, I think. But even if we just look at the non-dumped data, it's still after the fact.

Yes, it appears that the fact of 'knowing' the result travels back in time to change that result. That is how the tests are coming out. Consistently and repeatably. You've got it.

Counterintuitive in the extreme.

Saint Brian the Godless said...

We set up the equipment as normal but gave control of dumping to a computer, first observing when the computer didn't dump the data, we saw a point as expected. We then observed when the computer did dump the data and as expected, saw a wave-form.
-----------
Why is it that you sound like you're making a point that refutes mine, but all that you're saying seems to agree with me instead? I'm confuzzled here.

Saint Brian the Godless said...

I'm gonna go way out on a limb here:

IF, and I say IF, it is possible in any situation or scenario, for just the observation of a human being to collapse a particle's waveform, if that is what is happening in those tests as it certainly seems, then I can't see any other option other than for this universe to be grounded in consciousness rather than matter and energy and space and time.

Yes, I think that is a sound conclusion, given that it is consciousness doing the collapsing.

If it is.

Saint Brian the Godless said...

Especially if it even violates time. As it seems to.

Saint Brian the Godless said...

I mean, pboy, you seem to be saying 'see brian, that violates time, so you must be mistaken' when I'm saying 'pboy, this violates time, so it 'must be' wrong, and yet the tests are repeatable and convincing; so it can't be happening, but it is.'

Am I on the right page with that?

Pliny-the-in-Between said...

I go away for a day and see what happens? ;)

For now I am going to defer getting into detail on quantum effects since I plan to do a series on this in the future similar to the tunneling one and the questions presented are too big for me to answer effectively in a short response.

For now, let me just say that the effectors and modulators of the processes described here (this post on e-LTD) are several orders removed from the quantum world. Many of these things are true macromolecules with very well defined morphologies that behave very classically.

Saint Brian the Godless said...

One question then, Pliny.

Is there any instance where consciousness collapses the waveform?

I've seen many interpretations of the experiments that seem to not only suggest that, but prove it. Even if I just read the experiments myself it seems to prove it, to me.

Just wondering. It's a big question for me.

Pliny-the-in-Between said...

I'm not totally sure of your meaning, but I'm not aware of consciousness having that effect, except from an observational perspective.

I will be hitting some basic science of observational bias, medication and recreational drug effects, and conditioning soon but I have to cover the general processes first or else I don't think it makes much sense.

pboyfloyd said...

http://www.youtube.com/watch?v=mF-dtD9qY64

Take a break.