How the brain makes myelination activity-dependent

January 10, 2014 by John Hewitt, Medical Xpress report
Oligodendrocytes myelinating glutamatergic but not interneurons. Credit: Plos Biology

(Medical Xpress)—A major question regarding how axons acquire a coat of myelin, is the role of spiking activity. It is known that in culture systems oligodendroctyes will at least try to wrap anything that feels like an axon—even dead axons and artificial tubes. As axons acquire additional layers of myelin they conduct signals faster, and presumably become more efficient. It would therefore seem logical that the nervous system should apportion the most myelin to those neurons that are seeing the greatest activity. In that way the brain gets the most bang for its buck, energetically speaking. A new study in PLOS Biology suggests that while myelination is in many cases activity-independent at first, neurons can significantly ramp things up by flipping various molecular switches, one which appears to be Neuregulin (NRG).

Recreating the process of myelination in culture can be difficult to get right. One recipe that works well is to use embryonic dorsal root ganglion neurons from rats, grow them for two weeks, and then plate post-natal oligodendrocyte precurser cells (OCPs) on top of them. With this kind of setup, cells can be patch-clamped to record and control their electrical activity. Using this protocol, and various pharmacological manipulations, the researchers were able to show that the activity-dependent mode of myelination was acting through NMDA receptors on the oligodendrocytes.

When the cultured neurons were spiking, their axons puffed glutamate through whatever release machinery was available to them at that stage of development. The researches measured a sixfold increase of NMDA receptor currents in the oligodendrocytes under these conditions. This was correlated with a significant increase in the expression of myelin basic proteins, which reflected increased myelination. These results were all neat and tidy, but a larger problem lurked behind the scenes. Numerous other studies had shown conflicting results with regards to spiking activity and NMDA receptor activation on myelination. In several studies, there was no effect at all.

Of course we know there is no real conflict here—rats don't seem to be seizing up mid-stride—we just don't have the whole picture yet. The resolution to this paradox that the researchers provide, is that there are two modes of myleination with neuregulin controlling the transition. Previous studies have shown that this NRG increases the expression of NMDA receptor subunits, at least in neurons. When the researchers looked into it, they found that the sensitization by NRG was the reason for the sixfold NMDA current increase in oligodendrocytes. If NRG is causing myelination to become NMDA receptor dependent, many of the experimental conflicts in the literature evaporate.

Much remains to be discovered as far as how myelination happens at all. Chemical switches are nice to know about, but without an understanding of how they translate to actual physical mechanisms, we are really no further along. One recent idea put forward is that certain kinds of phase transitions are exploited to drive myelination. If such phase transitions are happening, one question might be, in what direction does myelination tend to occur both within an axon segment, and down the entire extent of the axon?

Spikes in axons would clearly provide some directionality to , and may even provide some of the forcing. The brain, especially in development, is a touchy-feely place with direct sensing often acting as a prelude to more intimate chemical exchanges. Receptor-mediated events surely happen all the time, but when introduced via cytonemes, cilia, or plain old pseudopods, they can be made more likely, and more likely to last.

Explore further: Brain electrical activity spurs insulation of brain's wiring

More information: Neuregulin and BDNF Induce a Switch to NMDA Receptor-Dependent Myelination by Oligodendrocytes, PLOS Biology, www.plosbiology.org/article/in … journal.pbio.1001743

Abstract
Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. In vivo, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.

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Egleton
not rated yet Jan 10, 2014
I think that Sheldrakes idea of Morphic resonance might have some bearing on the matter. I have read many skeptical comments on the issue but they all fail to address the evidence offered by Sheldrake.
It is a very similar problem faced by Darwin's Evolution of the Species. Have you read it? I mean you personally, have you read The Origin of the Species?
I would suggest that you actually get a copy of Sheldrake and read it.
And then tackle the evidence and not Sheldrake.
Vaccuous assertions that there is no evidence don't cut the mustard, for I could assert that the moon was made of green cheese.
russell_russell
not rated yet Jan 11, 2014
Myelination is a neat way archived changes. The archived changes aren't as durable for the storage of memory as for the storage of hereditary information. The storage for both is the same.
russell_russell
not rated yet Jan 11, 2014
Myelination is a neat way [to] archived changes.
Typo addition/correction in brackets
thingumbobesquire
not rated yet Jan 11, 2014
Thanks for the update. In reference to your previous reply to me on the issue of torque and soliton nature of action potentials I forwarded the paper you cited to Ludmila Yakushevich, a theoretician of DNA solitons, that I belatedly read with the comment: "I think you will find this paper http://arxiv.org/...0117.pdf interesting from the perspective of your model for DNA. I found the discussion of melting especially enlightening. I think there is a principle of self similarity for potential in wave dynamics that evinces itself in a manner that is dependent upon whether the medium of transmission is in the realm of inorganic or biophysical. The paper by Riemann in 1859 that developed the principle of shockwave propagation provides a hint that an analogous limiting transmissibility for biophysical solitons would be the melting temperature for DNA, etc".
johnhew
not rated yet Jan 11, 2014
Interesting thingumbob, although I really have no clue what would be going on down at those scales. For something like nonlinear conformational excitations of canonical base pair bonds I wouldn;t even know what carried a soliton: a physical displacement, electrical effect, twist, bend, accessory molecule bonding?

thingumbobesquire
not rated yet Jan 11, 2014
Here is Yakushevich's explanation of the model; http://www.marcor...0DNA.pdf What I find particularly remarkable is the self similarity across scales, regimes, classes and media of transmission for solitonic wave functions. Almost a sort of unified field theory of a totally different type.

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