Significance of microtubules

[bobmfrptx]

Could someone read this and let me know if it is significant?
http://www.uvm.edu/~annb/faculty/PDFs/C747.pdf
Thanks
Bob

[Diane]

Why don't you go ahead and explain the paper to the readers bob, a summary of the key points, and what you think its relevance is.

[EricM]

Significant for what Bob?

[bobmfrptx]

The dynamic fibroblast responses to changes in
tissue length demonstrated in this study have important implications
for our understanding of connective tissue responses to
changes in posture, normal movement, and exercise. These
cellular events may also be key to the therapeutic mechanism
of a wide variety of treatments using mechanical stimulation of
connective tissue including physical therapy, massage, and
acupuncture. (adaptation to injury shortening tissues, changing the function of cells)

Brown et al. (7) proposed that, by such a cytoskeletal
“tensegrity” mechanism, fibroblasts balance “stored” internal cellular
tension (tissue memory) with matrix tension, thus maintaining tissue tensional
homeostasis levels against opposing influences of external loading.
The morphological and cytoskeletal changes found in this
study are in agreement with this model, illustrated in Fig. 9.
Another potentially important consequence of fibroblast responses
to connective tissue tension may be homeostatic adjustment of
interstitial fluid pressure and transcapillary fluid flow. Transmission
of forces from fibroblasts to the extracellular matrix via focal
adhesions has been shown to cause changes in interstitial hydrostatic
pressure (40). Alterations in these functions may play an
important role in the influence of mechanical forces on the
response to injury and inflammation.

(Mechanical forces, manual therapy, influencing the "stored" tissue length settings to return to a more normalized and homeostatic state given the right input)

Communicated via microtubules which appear to stay even with fibroblastic changes. But,
"However, at the level of tissue stretch used in this study, our results suggest
that, during fibroblast contraction, cytoplasmic retraction may
have involved detachment of some cell-matrix connections but
existing cell-to-cell connections were maintained. The significance
of these connections, and how they are affected by mechanical
forces, is at present unknown."

Still more research needs conducted.
Significant for the use of manual therapy to change cellular function.

[Diane]

Well bob, I presume you brought this paper here because to you it represents a pinnacle of proof for your particular belief system/treatment construct, JFBMFR, or MFR in general. Correct?

It might be a very good exercise to deconstruct the paper in excruciating detail, and see what exactly it says. I like to start at the end of a paper first.


Part I of deconstruction of bob's paper

It was funded by NCCAM. Please see this blog post from Science-Based Medicine (http://www.sciencebasedmedicine.org/) for a report on this agency: The National Center for Complementary and Alternative Medicine (NCCAM): Your tax dollars hard at work. (http://www.sciencebasedmedicine.org/?p=36)
Excerpt: In tight budgetary times my view is that it is a grossly irresponsible use of taxpayer money not to prioritize funding for projects that have hypotheses behind them that have a reasonable chance of being true. Scarce NIH funds should not be for projects that have as their basis hypotheses that are outlandishly implausible from a scientific standpoint. Second, I’ve seen over the last few years how NCCAM is not only funding research (most of which is of the sort that wouldn’t stand a chance in a study section from other Institutes or Centers)) but it’s funding training programs. Indeed, that was the core complaint against NCCAM: that it facilitates and promotes the infiltration of nonscience- and nonevidence-based treatments (http://www.sciencebasedmedicine.org/?p=28) falling under the rubric of so-called “complementary and alternative” or “integrative” medicine into academic medicine. However, NCCAM cannot do otherwise, given its mission (http://nccam.nih.gov/about/ataglance/):


Explore complementary and alternative healing practices in the context of rigorous science.
Train complementary and alternative medicine researchers.
Disseminate authoritative information to the public and professionals.


The Science-Based Medicine blog is a relatively new port in a pseudoscientific storm. Here are its authors (http://www.sciencebasedmedicine.org/?page_id=2).

So, back to the article, let's start looking for the parts that promote CAM - we don't have to look far. Going back to page 1, the author says in the abstract; The dynamic, cytoskeleton-dependent responses of fibroblasts to changes in tissue length demonstrated in this study have important implications for our understanding of normal movement and posture, as well as therapies using mechanical stimulation of connective tissue including physical therapy, massage, and acupuncture.

(keywords)mechanotransduction; connective tissue; tensegrity; musculoskeletal manipulations; acupuncture Really. My understanding of normal movement and posture will be enhanced by her research on fibroblasts? I'm not saying it's not interesting, but I doubt that the human organism systems we treat are going to turn around pain and dysfunction by knowing about fibroblasts and cytoskeletons.

The "implications" seem to fully be in the realm of promoting the "therapies" (as we are warned by Science-Based Medicine) rather than understanding how those "therapies" work at a macro-interactional level.

Also on page 1 we see this:
The primary objective of this study was to characterize the
response of fibroblasts to stretching of loose connective tissue.
Loose connective tissue forms a continuous network through-
out the body, including subcutaneous and interstitial connec-
tive tissues surrounding and permeating muscles and organs.
Therapeutic mechanical deformation of loose connective tissue
is used routinely in physiotherapy (e.g., in stress-relaxation
techniques), as well as in many “alternative” therapies such as
massage, myofascial release, and osteopathic and chiropractic
manipulations. In addition, acupuncture was recently shown to
cause winding, pulling, and deformation of subcutaneous con-
nective tissue (30). Mechanotransduction through connective
tissue with resultant effects on fibroblast cell shape and func-
tion was recently proposed as a mechanism for the therapeutic
effect of acupuncture (29). Understanding the downstream
cellular and molecular effects of mechanotransduction in loose
connective tissue may therefore give key insights into the
therapeutic mechanisms of a variety of treatments for muscu-
loskeletal pain.

This is pretty fuzzy, don't you think, given all the other research around that suggests pain arises in the nervous system? I guess the authors haven't spent much time researching pain itself. It would appear that the authors not only did not rule that body of painstakingly accumulated data out first, they apparently failed to consider it at all, so eager they are to interpose a science base under the mesodigm.

This is a telling little red flag, at the very bottom of the page: The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

However, let's bend over backwards and look at the actual stuff that was written, not how it was written or who paid for it. That will be Part II.

[Bas]

I think that little red flag is not so little!! (good eye Diane!)
In addition to what Diane has written:

The conceptual leaps in this article are just too great to ignore - they go right over top of the nervous system and the brain in their conclusions.....

And in one part :
"Alterations in these functions may play an
important role in the influence of mechanical forces on the
response to injury and inflammation."

My bolds. "May" - an idea.
"Important" - a value without support here.
"influence" - not demonstrated or shown.
in an attempt with a convoluted mix, to link injury, inflammation, mechnical forces to these findings... Wow.

Interesting findings about the stretchability of tissue with small amounts of force - that alone is supporting the need to touch gently. It does not support much else at this time.

[Diane]

Part II: Looking at what was actually studied, histological conclusions etc.

The authors compared effects of stretch on ex vivo and in vivo mouse tissue, building on previous work:
Our group recently showed (31) that, in mouse subcutaneous tissue excised and fixed immediately after death, fibroblasts have long branching processes and form an extensively inter-connected cellular network.
So, that's nice. They showed something of how the body, made of a community of physically connected cells, holds itself together.

In the present study, we used ex
vivo and in vivo mouse subcutaneous tissue models to investigate whether the morphology of this cellular network is responsive to changes in tissue length. We hypothesized that tissue stretch has an effect on fibroblasts’ cell shape and that this effect is dependent on an intact cytoskeleton. We used quantitative morphometric analyses of histochemically stained tissue imaged with confocal microscopy, allowing differentiation of dendritic vs. expanded cell body morphologies. Unlike cell culture experiments, this in situ approach allowed examination of fibroblast cytoskeletal changes in a “native” environment where cell-matrix and cell-cell connections are maintained.

My bold. That's nice. They are showing how a live community of cells holds itself together as opposed to a dead community of cells.
There are a few pages of scrupulously described materials and methods. Some really nice pictures, some good graphics.

They did three experiments:
1) ex vivo experiments to evaluate the influence of tensile stretch on fibroblast morphology (as controls for these experiments, we evaluated tissue fixed before and after excision),
2) in vivo experiments to evaluate whether stretch has similar effects on fibroblast morphology in vivo as ex vivo, and 3) pharmacological experiments to evaluate which cytoskeletal elements contribute to altered fibroblast morphology under stretch. Our primary outcome measures were cell body cross-sectional area, cell body perimeter, cell field perimeter, cell body-to-field ratio, and cell body thickness (see Confocal scanning laser microscopy and morphometric analysis for detailed definitions). An additional secondary outcome measure was the number of cell-to-cell connections.
Looks like they really wanted to get at what goes on in tissue at the cellular level when tissue is exposed to a mechanical stretch. Very impressive, all this deep analysis.

So, in the first experiment, they stretched 'dead' tissue to see what happens. They took 23 mice, decapitated them, took a chunk of tissue measuring 8x3 cm from each mouse back, dunked the chunks in body-temp saline, stretched some for 10 minutes to two hours and left others alone. Their controls were mice that were decapitated then dunked immediately in ethanol; tissue flaps were taken from the immersed mice.

In the second, they anesthetized six mice and stretched them out unilaterally. There's a nice graphic of this in the paper. They were fixed in this position for a half hour then decapitated, put immediately in ethanol, and their flaps removed, and tissue examined as in 1.

In the third experiment they put either colchicine (http://www.google.ca/search?hl=en&q=define%3A+colchicine&btnG=Google+Search&meta=) (a poisonous alkaloid) or cytochalasin D (http://www.google.ca/search?hl=en&q=define%3A+cytochalasin+D&btnG=Search&meta=) (a mycotoxin) on the flaps before stretching them. Some control samples (without "inhibitors" applied) were spared for purposes of comparison.

I'm not a lab scientist so I can't comment on how they arrived at their data, all the measuring techniques used etc. I'm sure it was all very scientific and done properly.

The results: Effect of pre- vs. postexcision tissue fixation.
1. Mean cell body cross-sectional area, cell body perimeter, and cell field perimeter were 51%, 40%, and 37% lower, respectively, when tissue was fixed after excision compared with before excision.
Makes sense - the tissue (cell community) stretched after excision was likely less capable of withstanding the stretch likely because it wasn't as hooked into the whole body, so its subunits (cells) ended up 'smaller'. Standard physics.
2. However, the cell body-to-field ratio (ratio of cell body perimeter to cell field perimeter) was not significantly different between the two conditions.
3. There was also no evidence of a difference in mean cell body
thickness in tissue fixed before vs. after excision (Table 1).

I guess they found out that cells of ex vivo (dead) connective tissue still "connect" when dead, fixed or unfixed, whether control group or not.

To be continued.

[Diane]

So far, my take on this reasearch paper is uh-huh... uh-huh.... when are we going to get to the good part?

In the second experiment, Langevin (http://www.med.uvm.edu/neurology/WebBio.asp?SiteAreaID=717), acupuncture researcher, and her colleagues, decided to take apart freshly killed mice that had been stretched while still alive and anesthetized. Results of in vivo experiments examining the effects of tissue stretch on cell morphology paralleled the findings of the experiments conducted ex vivo. Shoot. Too bad for the mice - I hope this experiment doesn't have to be duplicated too many times. So many mice have already died in the interest of pain science, which seems to have been bypassed in this work, even though apparently, according to the link, this researcher is ostensibly interested in pain...

[Diane]

Something very weird happened. I completely finished the paper, with a long post, most of which vaporized.
Whatever. I'll plug on.
I'm going to start copying my posts before hitting the preview button.

[bobmfrptx]

I hope this experiment doesn't have to be duplicated too many times. So many mice have already died in the interest of pain science, which seems to have been bypassed in this work, even though apparently, according to the link, this researcher is ostensibly interested in pain...



I thought the research was to this as stated......

"The primary objective of this study was to characterize the
response of fibroblasts to stretching of loose connective tissue.
Loose connective tissue forms a continuous network throughout
the body, including subcutaneous and interstitial connective
tissues surrounding and permeating muscles and organs.
Therapeutic mechanical deformation of loose connective tissue
is used routinely in physiotherapy (e.g., in stress-relaxation
techniques), as well as in many “alternative” therapies such as
massage, myofascial release, and osteopathic and chiropractic
manipulations. In addition, acupuncture was recently shown to
cause winding, pulling, and deformation of subcutaneous connective
tissue (30). Mechanotransduction through connective
tissue with resultant effects on fibroblast cell shape and function
was recently proposed as a mechanism for the therapeutic
effect of acupuncture (29). Understanding the downstream
cellular and molecular effects of mechanotransduction in loose
connective tissue may therefore give key insights into the
therapeutic mechanisms of a variety of treatments for musculoskeletal
pain."

Bob

[bernard]

I'm sorry to say the paper do not tell us a single word about a communication (other than mechanical) within microtubules.
It doesn't tell us, either, a single word about a microtubule network that sends/receives messages.

[Diane]

How carefully did you read the paper bob?
1. The actual experiments were done on tissue removed from carcasses of mice.
2. The tissue was stretched either before the mouse died, or after it died, and the results were the same.
4. Tissue that had "pharmacological" substances added behaved sightly differently, didn't flatten out as far.

I think she threw a sentence into the abstract, and another in at the end, that had to do with CAM, just so she could collect a paycheck from NCCAM. The paper itself did nothing to convince me that microtubules are anything great and wonderful or that they are "a second nervous system".

What can we learn from the actual experiments, all three of them?
We learned that tissue cells are glued together, they stay glued even after being severed from the nervous system. They have "physicality", cling-together-ability, which was what was tested through stretching for periods that were 10 minutes to 2 hours. Their "materiality" was tested. Simple physics. If you take a material and stretch it, it will change shape.

Back to the significance of the paper, i.e., to practitioners, I think it showed that there is physical cellular integrity in terms of "stretchy corpse" capacity - of course tissue keeps from coming apart - that's its job in the body. (Maybe this is meant to be reassuring to chiropractors. ;))

As far as cellular communication goes, that's another property that cells have - they are alive after all, of course they'll chat to each other, signal chemically and mechanically.. I don't know much about microtubules, maybe cells communicate to each other through them, but I would have to say, so what? Maybe fibroblasts do this too. Again, so? All cells in the body are "alive" ... they all have their jobs, they live, metabolize, excrete, reproduce, die, and do "jobs"..

What the paper leaves out (not a surprise in that she is focused on fibroblasts) is that there are only three "cells", really really l-o-n-g skinny ones, i.e., nerve cells, between any patch of skin surface anywhere on any mammal body, and a little something something called a "brain", which has a whole bunch of cells in it that really chatter to reach other, and which can hugely affect anything going on out in the periphery, any place where the organism they are part of comes in contact with the "environment", e.g., a practitioner. This is called exteroception. Studies that would highlight this, of course, wouldn't be CAM-y enough to get funding from NCCAM.

The interesting thing about neurons is in addition to whatever microtubule communication they might have going on, assuming microtubule communication is indeed some kind of important phenomenon, is that they have high electrical signalling capacity as well. They can get messages around the whole body, fast, is the point I'm making here. They can, because signalling (rather than hanging together physically) is their job. Just based on their shape, if nothing else.

I thought the paper was quite interesting on several levels. I'm nerdy enough to be interested in cells themselves to a certain extent. The actual measuring and so on seems quite on the up and up. One step closer perhaps to someone eventually knocking out the hypothesis that local tissue has anything much to do with any treatment effect other than remain intact.

[bobmfrptx]

Thanks for your honest opinion Diane. I agree that the paper did nothing for the advancement of tubules but ask for more research.
Bob

[Diane]

Thanks for your honest opinion Diane. I agree that the paper did nothing for the advancement of tubules but ask for more research.
You need more research? Research like this? Funded by a CAM mesodigm only interested in preserving itself? That pays some sort of lip service to CAM so the researcher can afford to do what she really wants to do - study fibroblasts?
If the researchers are honest, you may have to face some sort of "truth" some day that destroys dopamemes, that concludes that microtubules in/of/between fibroblasts are no big deal whatsoever when it comes to patient-therapist interaction.

[bobmfrptx]

How do you really feel?
Actually more research on the tubules...It is interesting to me that they migrate towards tissue which calls for them...must have some function?

"Further experiments are needed to elucidate the biochemical mechanisms (including the respective roles of microtubules and microfilaments) that control
cellular expansion and contraction responses to tissue
tension."

[bernard]

It is interesting to me that they migrate towards tissue which calls for them
Yes and then? Does that mean tubules speak or communicate or are associated in network or send message at light speed?

A shortcut was made somewhere in the myofascial network for sure. :angel:

[bobmfrptx]

NO, It means more research needs done. You would be further ahead to stop reading into posts and just read them.
Bob

[bernard]

You would be further ahead to stop reading into posts and just read them.
Does that mean I must stop correlations and conclusions? :angel:

[bobmfrptx]

No, not unless you want too. I didn't suggest or state any reason why I read the article and most of the replies had me linking it to MFR. Preconceived notions lead to faulty findings. If you hav e a question ask.
Bob

[Diane]

Here is a pioneer, Vernon Mountcastle (https://sciencegrants.dest.gov.au/SciencePrize/Pages/Doc.aspx?name=previous_winners/Aust1993Mountcastle.htm), whose work on sensation would have not been funded by NCCAM in a million years, mostly because it's dopameme (http://thewonderofwords.blogspot.com/2008/03/dopameme.html) free, i.e., doesn't give mesodigms any leverage in the science world.

[bobmfrptx]

AND THIS RELATES TO MICROTUBULES AND COMMUNICATION HOW?

[Diane]

Mountcastle? His work relates completely to "communication" bob, .. of the kinesthetic or otherwise sensory sort, how it's processed in the brain. Didn't you get that?
Personally, I don't consider microtubules of any importance clinically.

[bernard]

If you have a question ask.
Bob
Bob,
You brought the subject on the table and bold lined some words that seem important to you. (tissue memory...)
Have you a single reference that shows the nature of the message stored in microtubules?
Have you a paper that describes the process of the memory recording?

Nobody there doubt that protein/peptide are able to take predetermined shapes under chemical/mechanical stresses. This memory has nothing to see with emotion that are processed by brain and within brain.

[bobmfrptx]

communication AND microtubules....not OR....I know the brain receives, interprets, responds..(i.e. communicates) Diane.....
Bernard, I didn't link memory of tubules with emotion...I thought it was interesting that the tubules migrate to where they are needed...must be a reason for it?
Regarding the questions No and No ...hence the statement... needs more study to determine the significance of this process.....
This has been a wonderful play on the reactionary state of the ectoderms ...keep the cause alive...
I choose to remain a ectomesodermalist gently treating the whole equally and allowing it to unfold as only it can regardless of belief system.

[Bas]

"allowing it to unfold as only it can regardless of belief system."

And are we not lucky that it does......It allows people to do whatever they can come up with, strictly based on belief - regardless of science - and still get good outcomes......

[Diane]

bob, maybe microtubules are used for communication between cells, but what importance would that have for treatment, when the brain is there, five times bigger than it needs to be to operate a mammal our size, when the nervous system is there ready to cooperate or to veto anything we do to anyone? With only three highly excitable neurons cells spanning the distance between any patch of skin and brain, compared to several hundred billion cells of mesoderm, possibly able to communicate through your lovely dopa-meme microtubule system, but laid in discretely connected walls in a manner designed to protect the nervous system physically rather than communicate with it directly?

What I really don't get about the JFBMFR crowd is the complete refusal to observe the human organism and function as it is - instead it would rather make up and believe and act on implausibilities as if they were true. Hang on "research" about mesoderm, funded by mesodigms with money, that keeps dopamemes on life support.

[bobmfrptx]

"allowing it to unfold as only it can regardless of belief system."

And are we not lucky that it does......It allows people to do whatever they can come up with, strictly based on belief - regardless of science - and still get good outcomes......


The clients are the lucky ones if they get "handled" appropriately.
And Bas I agree with your statement.

Diane,
We JFB MFR' ers do not neglect the function of the humn being as it is...we allow it to perform at its maximum potential.
Bob

[Diane]

Diane,
We JFB MFR' ers do not neglect the function of the humn being as it is...we allow it to perform at its maximum potential.
BobAnd you keep the entire field of human primate social grooming the laughing stock of the world of actual science, by keeping your conceptual underpinnings based on nothing but dopameme sustaining, dopameme paid for, so-called research. Advertisement science. Makes my chunks rise, actually. You imply that it's necessary to maintain fiction in order to treat optimally. Wrong. And you don't recognize that Bas is being sarcastic.

[Bas]

"We JFB MFR' ers do not neglect the function of the humn being as it is...we allow it to perform at its maximum potential."

We allow. Ouch

So, why is it necessary to introduce the garbage of Oschman, Hameroff and such, by people like Carol Davis? If the body has such innate potential, why is it necessary to introduce weird and unnecessary explanations? I will tell you: because without those far-fetched constructs, JB could not charge as much..... He HAS to come up with this woo-woo to justify the ongoing milking of gullible sheep.

[bobmfrptx]

You guys are way too easy.....
Enjoy your world.
Bob

[Bas]

Aaaaah, Bob: "The reed that bends in the storm"......

You are such a gentle soul.
And yes, we are easy....on you. And you know, "our" world is the same as yours, but the way your brain interprets the input makes it looks much different.

Happy grazing.

[Diane]

Bottom line, microtubules are held up to be some sort of anatomy that "energy" might flow through (I think this is the gist, anyway...) And that by convincing the world that they a) exist, and b) that they do stuff, the world might get convinced that they are "significant", mesodigmic dopamemic belief systems will be finally "proven", and maybe next, someone will actually be able to measure (and validate existence of) the elusive "energy" itself, that rumored to be able to be passed from person to person.

All the scientists will then go, "ah... now I see, whereas before I was blind... Ahhh... so sorry for all the bad press we've given you kind and gentle love and light folks... you were right and the entire science edifice must now crumble because it was wrong all along. The nervous system does nothing and microtubules do everything through quantum energy... how dumb of us to have thought otherwise. Gee, if it weren't for you body workers holding the fort for so long, keeping these ideas going, we would have wandered in the dark forever. Thank goodness for NNCAM, because now we see that chiro, energy fields, acupuncture meridians are all real and medical science is nothing but wrong wrong wrong... there is no such thing as disease, and without all these microtubule studies we might never have "got" it."

I think this must be the secret hope of the JFBMFR people. I.e., that microtubules will turn out to be "significant", in the way I've outlined.

Is that what JFBMFRers think, bob? That microtubules carry "energy"?

[bernard]

I'm amazed that Helen Langevin, a neurologist, wrote in the paper (http://www.somasimple.com/forums/showpost.php?p=50388&postcount=1) presented by Bob only one "neural" term. Just only one.

By the way, I do not clearly understand why the CAM camp choose her, really. Her articles are quite well written and it easy to see the supervision of James Oschman behind the scene (the link is presented here (http://www.somasimple.com/forums/showpost.php?p=49812&postcount=84))

I do not understand, either, why the MFR theory supports them. Maybe because a first and superficial reading of the papers could perhaps give a little material to the thin science there is in the fascia-therapy.

I must thank the doctors Oschman and Langevin. They dug so "deeply" the energy" model that it looks, now, like a grave.

[EricM]

Bernard, I don't think the purpose of the paper had anything to do with neural structure or function, which may explain your observation. It is distressing to read that the authors had to somehow tie-in a link to manual therapy as this introduced a whole host of fatal assumptions that were really irrelevant to the actual study.

[Diane]

I'm thinking if "microtubules" are so ubiquitous they'd likely be in neurons too. The author doesn't say that explicitly, because of course the source that paid her is leaning wayover toward perpetuating the Mesodigm, which bases its thinking (and makes up new hypotheses) on mesodermal derivatives having more signalling importance, not merely structural importance.

If "microtubules" are ubiquitous, truly ubiquitous, and truly "significant", the worst thing for Planet Mesodigm would be if it were to find neurons had them as well; it would mean that mesodermal derivatives would have no perceived advantage in "communication", which is the story (dopameme) being sold/perpetuated by people like bob, Carol Davis and John F. Barnes.

[bernard]

the worst thing for Planet Mesodigm would be if it were to find neurons had them as well;

Diane,

Neurons have such microtubules. It is known fact.

[bernard]

Two examples over 2139



J Cell Biol. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27J%20Cell%20Biol.%27%29;) 2008 Feb 11;180(3):619-32.
Related Articles (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed&LinkReadableName=Related%20Articles&IdsFromResult=18268107&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract), Links (http://javascript%3Cb%3E%3C/b%3E:PopUpMenu2_Set%28Menu18268107%29;)
http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-standard-jcb_final.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=Abstract-def&uid=18268107&db=pubmed&url=http://www.jcb.org/cgi/pmidlookup?view=long&pmid=18268107)
Microtubule stabilization specifies initial neuronal polarization.

Witte H (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Witte%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract), Neukirchen D (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Neukirchen%20D%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract), Bradke F (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bradke%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract).

Axonal Growth and Regeneration, Max Planck Institute of Neurobiology, 82152 Martinsried, Germany.

Axon formation is the initial step in establishing neuronal polarity. We examine here the role of microtubule dynamics in neuronal polarization using hippocampal neurons in culture. We see increased microtubule stability along the shaft in a single neurite before axon formation and in the axon of morphologically polarized cells. Loss of polarity or formation of multiple axons after manipulation of neuronal polarity regulators, synapses of amphids defective (SAD) kinases, and glycogen synthase kinase-3beta correlates with characteristic changes in microtubule turnover. Consistently, changing the microtubule dynamics is sufficient to alter neuronal polarization. Application of low doses of the microtubule-destabilizing drug nocodazole selectively reduces the formation of future dendrites. Conversely, low doses of the microtubule-stabilizing drug taxol shift polymerizing microtubules from neurite shafts to process tips and lead to the formation of multiple axons. Finally, local stabilization of microtubules using a photoactivatable analogue of taxol induces axon formation from the activated area. Thus, local microtubule stabilization in one neurite is a physiological signal specifying neuronal polarization.

Publication Types:
Research Support, Non-U.S. Gov't (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27ptyp%27,%20%27Research%20Support,%20Non-U.S.%20Gov%5C%27t%27%29;)PMID: 18268107 [PubMed - indexed for MEDLINE]

J Struct Biol. (javascript:AL_get(this, 'jour', 'J Struct Biol.');) 2008 Mar;161(3):469-80. Epub 2007 Oct 22.
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Electron tomographic analysis of cytoskeletal cross-bridges in the paranodal region of the node of Ranvier in peripheral nerves.

Perkins GA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Perkins%20GA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract), Sosinsky GE (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sosinsky%20GE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract), Ghassemzadeh S (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ghassemzadeh%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract), Perez A (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Perez%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract), Jones Y (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jones%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract), Ellisman MH (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ellisman%20MH%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract).

National Center for Microscopy and Imaging Research, Center for Research in Biological Systems, University of California, San Diego, 9500 Gilman Drive, La jolla, CA 92093-0608, USA. perkins@ncmir.ucsd.edu

The node of Ranvier is a site for ionic conductances along myelinated nerves and governs the saltatory transmission of action potentials. Defects in the cross-bridging and spacing of the cytoskeleton are a prominent pathological feature in diseases of the peripheral nerve. Electron tomography was used to examine cytoskeletal-cytoskeletal, membrane-cytoskeletal, and heterologous cell connections in the paranodal region of the node of Ranvier in peripheral nerves. Focal attachment of cytoskeletal filaments to each other and to the axolemma and paranodal membranes of the Schwann cell via narrow cross-bridges was visualized in both neuronal and glial cytoplasm. A subset of intermediate filaments associates with the cytoplasmic surfaces of supramolecular complexes of transmembrane structures that are presumed to include known and unknown junctional proteins. Mitochondria were linked to both microtubules and neurofilaments in the axoplasm and to neighboring smooth endoplasmic reticulum by narrow cross-bridges. Tubular cisternae in the glial cytoplasm were also linked to the paranodal glial cytoplasmic loop juxtanodal membrane by short cross-bridges. In the extracellular matrix between axon and Schwann cell, junctional bridges formed long cylinders linking the two membranes. Interactions between cytoskeleton, membranes, and extracellular matrix associations in the paranodal region are likely critical not only for scaffolding, but also for intracellular and extracellular communication.

Publication Types:
Research Support, N.I.H., Extramural (javascript:AL_get(this, 'ptyp', 'Research Support, N.I.H., Extramural');)
Research Support, U.S. Gov't, Non-P.H.S. (javascript:AL_get(this, 'ptyp', 'Research Support, U.S. Gov\'t, Non-P.H.S.');)
PMID: 18096402 [PubMed - in process]

[bernard]

Microtubules are labelled Mikrotubuli (http://www.uni-mainz.de/FB/Medizin/Anatomie/workshop/EM/EMMikrotub.html)
http://www.uni-mainz.de/FB/Medizin/Anatomie/workshop/EM/externes/Wartenberg/mhNerv5E.html

In English =>
http://www.uni-mainz.de/FB/Medizin/Anatomie/workshop/EM/EMMikrotubE.html

[Diane]

Allrighty then. :D
So, the Mesodigm will have to show that fibroblast microtubules are faster/better than neuron mirotubules, at keeping a body organized and processes regulated.

[bernard]

So, the Mesodigm will have to show that fibroblast microtubules are faster/better than neuron mirotubules, at keeping a body organized and processes regulated.

I think that replying to such a question is a trap. I think (evidences) that microbubules play a key role in cell's architecture and maintenance but do not speak at all. BTW, there is a lot of microtubules in all cells.

If microtubules are engaged in a communication process then what is the nature of the message and how the message is proceeded?

[Diane]

If microtubules are engaged in a communication process then what is the nature of the message and how the message is proceeded?Bernard, exactly. Maybe bob could tell us what he thinks the message, mechanism of message is. Then perhaps we'd know a bit more about their significance or insignificance.

[bobmfrptx]

Communicating Tubes

http://www.youtube.com/watch?v=9dF2WcrdxdQ&feature=related

[Diane]

bob perhaps you could post a cleaner link - this one seems to go nowhere.

[bernard]

Bob,

I'll second Diane. It is not because Microtubule contains "tub" as YouTube that the latter will give an once of communication to the connective fascia.

[bernard]

Bob,
I found it?

Micro-tubular Bells

xPEt5OTR6Vc

[Diane]

Log ago in this thread I should have posted a link to this thread about fascial contractility (http://www.somasimple.com/forums/showthread.php?t=4902#post50933), by Kim LeMoon. I would especially like to point out post #46 (http://www.somasimple.com/forums/showpost.php?p=45256&postcount=46).

In it she dismantles a paragraph written by a JFBMFRer about an event that took place last year, a conference on fascia. The paragraph contains one assumption after another and (as she does in the whole thread) Kim applies Occam's razor deftly to every single one.

[gilbert thomson]

I'll try to handle the toxic material cautiously...

I fully agree with the need to protest the pseudoscience and CAM rubbish that so easily sucks people in, BUT I have a problem with the tendency toward a one-system view of the body. Agreed, the nervous system is a very specialised, unique system that is powerfully influenced by manual interventions. However, it still interests me that fibroblasts respond to an imposed stretch as described here. We put our hands on people and move the tissue, and there is a physiological response in the connective tissue, as well as neural tissue effects. Why would you not be interested in that?

cheers - Gilbert

[Barrett Dorko]

We know there's a physiologic response in the connective tissue - how could there not be?

The issue is this - does the known physiologic response have anything to do with the sensory and functional changes we see consequent to gentle care? If the answer is "no" - and it is - why must we be told over and over to keep looking there. Are we just trying to be polite? What for?

I for one don't mind telling someone with an opposing idea that they are wrong, not when it comes to observable phenomena that we can carefully study, and I couldn't care less about the feelings of all the therapists who have been wrong and continue to ignore the nervous system. They make the profession look foolish.

[Nick]

Why the assumption that those who emphasize the nervous system with regard to pain are only considering one system? Especially when the nature of that system easily alows one to see the interactions of other systems, even though they are quite clearly less relevant to pain.

Neuroscience provides a bird's eye sort of view of everything that goes on in someone's body and in their environment. Everything other just helps the brain go where it wants to go.

[nari]

Gilbert,

Many PTs concentrate on muscle and CT management, and ignore to a large extent the very driver of these other systems. They don't deliberately ignore the nervous system; they simply see it as secondary to the real problem of pain and dysfunction.

There is a PT who comes on ABC Radio 666 each month for an hour to discuss (dys)function. She is well known in Sydney and has written quite a lot of stuff. I listened last night and was ready to throw something at her. A bloke rang up with a sore neck on one side, and she told him that was due to muscle weakness which was why he had pain.

Another bloke mentioned he experienced hamstring pain after walking for 4 hours. He was told it was probably due to pelvic asymmetry and he needed the SIJ assessed plus core stability work.
I've no doubt this stuff might work, but the rationale behind the pain was inaccurate. And it gets perpetuated....

As Nick has implied, the nervous system runs the show. But the cast gets full attention, while the director gets a nod, (OK, maybe a glance, too). ;)

Nari

[gilbert thomson]

Point taken.

I quite agree about the primacy of the nervous system, and about the importance of our practice being firmly grounded in reality. Just some of the tone of the posts occasionally gets me concerned. I don't think that replacing an extreme "mesodigm" with an extreme "neurodigm" is necessarily the best way forward for our profession. After all, without the mesodermally derived musculature the NS would not be able to do much ;)

That said I know how DIFFICULT it is to change the way people think and work. (First you need to get people to think, which in itself seems nearly impossible at times.)

-Gilbert

[bernard]

After all, without the mesodermally derived musculature the NS would not be able to do much ;)
After all, without the ectodermally derived nervous system the muscle would not be able to do... Nothing. ;)

[nari]

I agree that the body's systems are interdependent to a certain degree.
You can take out various bits and pieces and the body will function normally (whatever the definition of narmality is).

The point quite a few members on this board are making is that the nervous system is often forgotten when dealing with pain/dysfunction that appears to be mesodermal in origin.
For instance, a painful neck that is pathologically OK, might be helped by mesodermal interventions. Or might not. Calming down a hypersensitive nerve or two can result in rapid resolution of pain and return of function. No guarantees either way, but no method or technique has those attached. Attention to neural sensitivity can be more effective and longer-lasting; and a few on this site are doing studies to indicate its usefulness.

First, you need people to think, which in itself seems nearly impossible at times

Absolutely!

Nari

[Diane]

Ditto what Nari said, and Bernard.

I'd like to add that by turning out batch after batch of human primate social groomers focused only on mesodermally derived tissue, and what mobilipulating it ostensibly does to it biomechanically, and not providing us with the most coherent model or even the simplest model of how or why the organism responds and at what levels for better or worse, insults our (collective) intelligence, plus leaves us (collectively) vulnerable to wild goose chases like this whole microtubule fascination, and trying to latch on to them, link them into mesodermal derivatives without any real idea of what is actually talked about in the field.

Not that I'd know anything about that either...just that the topic of "microtubules"

seems like one of those "unnecessary hypotheses" that Occam "admonished" people to "eliminate"
seems to be considered quite a conceptual stretch at any level of examination, including at the neuroscientific level.

[Diane]

Here is what Jeffrey Gray (http://en.wikipedia.org/wiki/Jeffrey_Alan_Gray), author of Consciousness: creeping up on the hard problem (http://www.amazon.com/Consciousness-Creeping-up-Hard-Problem/dp/0198520905), has to say, after writing from page 241 to p. 259 a careful description of the Penrose Hammeroff theory in quite a favorable light, actually:

Conclusions
Despite its magisterial complexity, then, we see that, in the end, the Hameroff-Penrose theory of how different quantum superpositions inmicrotubules in different brain areas give rise to different qualia must rely for the origin of these differences on arguments taken from neuroanatomy and neurophysiology. And, despite its intricate Gothic architecture, the theory is incomplete. It offers no account of how differences at the Plank scale might relate to differences between qualia; nor of how differences in space/time in one brain might relate to differences in another brain observing the same scene at the same time. Nonetheless, the theory does offer an account in principle of the origin of differences in qualia. Whether even this is testable in practice is another matter...

(Apparently he died (http://users.ecs.soton.ac.uk/harnad/jeffrey.html) shortly after or before this book was published.)

Nowhere in the entire chapter is fascia mentioned. Why? because after embryonic differentiation occurs, fascia ceases to have any ability to signal anything but mechanoreceptors, physically, I should think.

Plus, there is the opinion (http://www.colorado.edu/philosophy/vstenger/Briefs/QBrain.htm) of particle physicist Victor Stenger (http://en.wikipedia.org/wiki/Victor_Stenger) to consider. He says, In a 1999 paper, physicist max Tegmark looked at the problem of quantum coherence in the brain and determined that the decoherence timescales would be ten or more orders of magnitude shorter than the timescales for events in the brain. The brain is simply too large and too hot to be a quantum device, coherent or not.

[gilbert thomson]

Diane
You'd be encouraged by the amount of attention here in Australia directed towards the nervous system, neural mechanosensitivity, and pain science among normal Ortho PTs. At the Aussie Physio Association Musculoskeletal Conference in Cairns last October some of the topics were:
"training the brain" and "the brain in chronic pain" by Lorimer Moseley,
David Butler's "explain pain" workshop, some great research on central sensitivity following Whiplash by Michelle Sterling and others at the University of Queensland, low back pain and motor control changes in the lumbar spine (Paul Hodges)
There seems to be a widespread awareness of, and attention to, neural involvement in painful conditions which I think you would appreciate.
- Gilbert

[nari]

Gilbert, I'm gald to hear that.

I've been out of the workforce for 2.5 years and when I left the general orthopaedic focus was still very musculoskeletal, with passing reference to the nervous system.
However the 4th year students took a keen interest in neural matters in considering topics such as gait anomalies, the dreaded SIJ and pelvic issues.

I suspect South Australia would be something of a leader in managing pain - the home of Butler et al...

Nari

[marcelk]

Regarding the "fuzz" of this thread; microtubuli do things to people
http://images.google.nl/imgres?imgurl=http://www.ge.cnr.it/m%26M/p_tessuti/braccio/images/microtubuli%2520di%2520cellule%2520epiteliali.jpg&imgrefurl=http://www.ge.cnr.it/m%26M/p_tessuti/braccio/braccio2.htm&h=283&w=425&sz=67&hl=en&start=2&tbnid=LbEHrNb6eBWF8M:&tbnh=84&tbnw=126&prev=/images%3Fq%3Dmicrotubuli%26gbv%3D2%26hl%3Den%26sa%3DG

(Also) Looking at cellular level as a PT can be (is) a good thing for understanding and perhaps coming up with new ideas.
Of course one has to be cautious with publications; as shown all to clear in this thread.
Microtubili play a role in axonal transport (as far as I know; and have other functions) so why not look at that cellular part (D.Butler
paid attention in his book : the sens.nerv.sys.) but the info will only be important as it has it place in the bigger picture.

As a fresh PT (years ago) I was excited about hearing about nerve growth factors and thought about the possibillities for SCI-patients.
Still has to happen, unfortunately.

Just a question regarding this thread in general : is your contact with patients any similar how you replied in this thread?

Thanks,
Marcel

[marcelk]

Regarding the "fuzz" of this thread; microtubuli do things to people

Looking at cellular level as a PT can be a good thing for understanding and perhaps coming up with new ideas.
Of course one has to be cautious with publications; as shown all to clear in this thread.
Microtubili play a role in axonal transport (as far as I know; and have other functions) so why not look at that cellular part
(D.Butler paid attention in his book : the sens.nerv.sys.) but the info will only be important as it has it place in the bigger picture.

As a fresh PT (years ago) I was excited about hearing about nerve growth factors and thought about the possibillities for SCI-patients.
Still has to happen, unfortunately.

Just a question regarding this thread in general : is your contact with patients any similar to how you replied in this thread?

Thanks,
Marcel

adjusted....

[EricM]

is your contact with patients any similar to how you replied in this thread?

Marcel, who is this question directed to?

[Diane]

Mo at Neurophilosophy blog turned up with a post today to do with this topic (http://scienceblogs.com/neurophilosophy/2008/04/memory_enhancing_drugs.php#more). By reading this post it's more clear to me what "microtubules" actually are, in the first place. From reading this, it seems to me that their "significance" if there is some, has more to do with brain/neuronal function/attempts to create stronger synaptic connection (neuroplasticity) and nothing to do with fascia. Nada.

The function of fascia appears to still be to physically hold things together, keep things from coming apart, no more; no matter how hard the fascialists try to bestow special microtubular powers of communication on fascia, if it had any, the neuroscientists would have probably noticed it by now.

This isn't to say that the mechanoreceptors strewn through the body, including through fascia, aren't important signalers. But they are ectoderm, not mesoderm.

[bernard]

Here is the result of an experience on a two dimensional network:

If fascia is an elastic network then what happens when it is stretched?

=> Quite nothing since the property of an elastic network is dampening!
Of course, with a tri dimensional network the effect will be much more reduced.

[gilbert thomson]

Very nice demonstration Bernard! :thumbs_up

The physical effects of deforming the tissues are dampened, so any distant effects would need another explanation, (like a nervous system response).

[bernard]

Yes. A huge (100% in my picture) mechanical deformation ends, at a cellular level, in few micrometers.
This is why a mechanical aspect of energy is easily discarded.

[bobmfrptx]

http://www.springerlink.com:80/content/n503270672354763/

More food for thought.
And again mechanotransduction is affected by tensions of stretch.
http://www.nae.edu/NAE/bridgecom.nsf/weblinks/MKEZ-65RHQL

Bob

[marcelk]

Hi,

I agree with Barett and Nari.

Funny that this afternoon I've read some of Barett's essay's, somewhere comes the point of " a patient believe's his/her pain is in the muscle, and it must be there because thats what he/she is being thought/told;.....(PT) education still focusses much on pain origin from muscle tendon etc.,... why? because the teachers where being told it came from there(connect.tiss.); in fact a belief that is quite strong even if being presented with modern ideas in contrary to it.
But what about the microtubules?
A year ago I saw something on tv about (near death,) out of body experiences. An idea was postulated that in microtubules the organisation of atoms & molecules was the perfect enviroment for quantum effects to have place.
I looked up the refferences and it turned out a dutch dentist had made up a quassi review of very common ideas on quantum theory, neurology etc.
I'd like to say : just leave the microtubules, the fibroblasts and the other cytes,blasts, clasts for doing what they do best.

[bernard]

And again mechanotransduction is affected by tensions of stretch.
And again mechanotransduction deserves directly the nervous system. :angel:

[Diane]

I finally got around to reading up on microtubules. I took a few notes from Gray's. Here they are. I've highlighted the word "microtubules" as it appears. It looks like they are involved mostly in axonal transport. Let's be clear - we're talking about microtubules in neurons here.

It seems their main significance is most cell types is in helping with cell division, and in neurons they get retained for transport duties inside the cells. It doesn't say anywhere I could find that they are involved in signalling between cells, even nerve cells, per se.

NEURONAL SOMA (CNS)

Membrane:

* plasma membrane of the soma is unmyelinated, and contacted by inhibitory and excitatory axosomatic synapses
* very occasionally, somasomatic and dendrosomatic contacts may be made
* the non-synaptic surface is covered by either astrocytic or satellite oligodendrocyte processes


Cytoplasm:

* cytoplasm of a typical soma is rich in rough and smooth endoplasmic reticulum and free polyribosomes
* this reveals a high level of protein synthetic activity
* free polyribosomes often congregate in large groups associated with the rough endoplasmic reticulum
* these aggregates of RNA-rich structures are visible by light microscopy as basophilic Nissl (chromatin) bodies or granules and are more obvious in large, highly active cells, such as spinal motor neurones, which contain large stacks of rough endoplasmic reticulum and polyribosome aggregates
* maintenance and turnover of cytoplasmic and membranous components are necessary in all cells
* the huge total volume of cytoplasm within the soma and processes of many neurones requires a considerable commitment of protein synthetic machinery
* neurones synthesize other proteins (enzyme systems, etc.) which are involved in the production of neurotransmitters and in the reception and transduction of incoming stimuli.
* various transmembrane channel proteins and enzymes are located at the surfaces of neurones where they are associated with ion transport
* the apparatus for protein synthesis (including RNA and ribosomes) occupies the soma and dendrites, but is usually absent from axons
* cytoplasm contains many mitochondria and moderate numbers of lysosomes. Golgi complexes are typically seen close to the nucleus, near the bases of the main dendrites and opposite the axon hillock.
* nucleus is characteristically large, round and euchromatic, with one or more prominent nucleoli, as is typical of all cells engaged in substantial levels of protein synthesis


Cytoskeleton:

* neuronal cytoskeleton is a prominent feature of its cytoplasm - gives shape, strength and rigidity to the dendrites and axons
* neurofilaments (the intermediate filaments of neurones) and microtubules are abundant
* they occur in the soma and extend along dendrites and axons - proportions vary with the type of neurone and cell process
* bundles of neurofilaments constitute neurofibrils which can be seen by light microscopy in silver stained sections
* neurofilaments are heteropolymers of proteins assembled from three polypeptide subunits, NF-L (68 kDa), NF-M (160 kDa) and NF-H (200 kDa)
* NF-M and NF-H have long C-terminal domains which project as side arms from the assembled neurofilament and bind to neighbouring filaments
* they can be heavily phosphorylated, particularly in the highly stable neurofilaments of mature axons, and are thought to give axons their tensile strength
* some axons are almost filled by neurofilaments


Microtubules:
* microtubules are important in axonal transport
* centrioles persist in mature postmitotic neurones, where they are concerned with the generation of microtubules rather than cell division
* centrioles are associated with cilia on the surfaces of developing neuroblasts
* their significance, other than at some sensory endings (e.g. the olfactory mucosa), is not known
* dendrites usually have more microtubules than axons


Pigmentation:

* pigment granules appear in certain regions, e.g. neurones of the substantia nigra contain neuromelanin, probably a waste product of catecholamine synthesis
* in the locus coeruleus a similar pigment, rich in copper, gives a bluish colour to the neurones
* some neurones are unusually rich in certain metals, which may form a component of enzyme systems, e.g. zinc in the hippocampus and iron in the oculomotor nucleus
* ageing neurones especially in spinal ganglia accumulate granules of lipofuscin (senility pigment)
* they represent residual bodies, which are lysosomes packed with partially degraded lipoprotein material (corpora amylaceae)


Dendrites:

* dendrites are highly branched, usually short processes which project from the soma
* branching patterns of many dendritic arrays are probably established by random adhesive interactions between dendritic growth cones and afferent axons which occur during development
* dendrites are overproduced in early development, then pruned in response to functional demand as the individual matures and information is processed through the dendritic tree
* there is evidence that dendritic trees may be plastic structures throughout adult life, expanding and contracting as the traffic of synaptic activity varies through afferent axodendritic contacts
* groups of neurones with similar functions have a similar stereotypic tree structure suggesting that the branching patterns of dendrites are important determinants of the integration of afferent inputs which converge on the tree
* dendrites differ from axons in many respects:

they represent the afferent rather than the efferent system of the neurone
receive both excitatory and inhibitory axodendritic contacts
may also make dendrodendritic and dendrosomatic connections, some of which are reciprocal

* synapses occur either on small projections called dendritic spines or on the smooth dendritic surface
* dendrites contain ribosomes, smooth endoplasmic reticulum, microtubules, neurofilaments, actin filaments and Golgi complexes
* the neurofilament proteins of dendrites are poorly phosphorylated
* dendrite microtubules express the microtubule-associated protein (MAP-2) almost exclusively in comparison with axons

* dendritic spine shapes range from simple protrusions to structures with a slender stalk and expanded distal end
* most spines are not more than 2 μm long, and have one or more terminal expansions, but they can also be short and stubby, branched or bulbous
* free ribosomes and polyribosomes are concentrated at the base of the spine
* ribosomal accumulations near synaptic sites provide a mechanism for activity-dependent synaptic plasticity through the local regulation of protein synthesis


AXONS

* axon originates either from the soma or from the proximal segment of a dendrite, at a specialized region, the axon hillock, which is free of Nissl granules
* action potentials are initiated here
* the axonal plasma membrane (axolemma) is undercoated at the hillock by a concentration of cytoskeletal molecules, including spectrin and actin fibrils, which are thought to be important in anchoring numerous voltage sensitive channels to the membrane
* the axon hillock is unmyelinated and often participates in inhibitory axo-axonal synapses
* this region of the axon is unique because it contains ribosomal aggregates immediately below the postsynaptic membrane


Myelin:

* when present, myelin begins at the distal end of the axon hillock
* myelin thickness and internodal segment lengths are positively correlated with axon diameter
* in the PNS unmyelinated axons are embedded in Schwann cell cytoplasm, in the CNS they lie free in the neuropil
* nodes of Ranvier are specialized constricted regions of myelin-free axolemma where action potentials are generated and where an axon may branch
* the density of sodium channels in the axolemma is highest at nodes of Ranvier, and very low along internodal membranes
* in contrast, sodium channels are spread more evenly within the axolemma of unmyelinated axons
* fast potassium channels are also present in the paranodal regions of myelinated axons.
* fine processes of glial cytoplasm (astrocyte in the CNS, Schwann cell in the PNS) surround the nodal axolemma
* the terminals of an axon are unmyelinated
* they expand into presynaptic boutons which may form connections with axons, dendrites, neuronal somata or, in the periphery, muscle fibres, glands and lymphoid tissue
* they may themselves be contacted by other axons, forming axoaxonal presynaptic inhibitory circuits. Further details of neuronal microcircuitry are given in Kandel & Schwartz (2000)


Axons:

* contain microtubules, neurofilaments, mitochondria, membrane vesicles, cisternae, and lysosomes: they do not usually contain ribosomes or Golgi complexes, except at the axon hillock
* however, ribosomes are found in the neurosecretory fibres of hypothalamo-hypophyseal neurones which contain the mRNA of neuropeptides
* organelles are differentially distributed along axons, e.g. there is a greater density of mitochondria and membrane vesicles in the axon hillock, at nodes, and in presynaptic endings
* axonal microtubules are interconnected by cross-linking microtubule-associated proteins (MAPs) of which tau is the most abundant
* microtubules have an intrinsic polarity: in axons all microtubules are uniformly orientated with their rapidly growing ends directed away from the soma towards the axon terminal
* neurofilament proteins ranging from high to low molecular weights are highly phosphorylated in mature axons, whereas growing and regenerating axons express a calmodulin-binding membrane-associated phosphoprotein, growth-associated protein-43 (GAP-43), as well as poorly phosphorylated neurofilament
* axons respond differently to injury, depending on whether the damage occurs in the CNS or PNS:
* the glial microenvironment of a damaged central axon does not facilitate regrowth, and reconnection with original synaptic targets does not normally occur
* in the PNS, the glial microenvironment is capable of facilitating axonal regrowth, however the functional outcome of clinical repair of a large mixed peripheral nerve, especially if the injury occurs some distance from the target organ, or produces a long defect in the damaged nerve, is frequently unsatisfactory


Axonal transport:

* neuronal organelles and cytoplasm are in continual motion
* bidirectional streaming of vesicles along axons results in a net transport of materials from the soma to the terminals, with more limited movement in the opposite direction
* two major types of transport occur, one slow, and one relatively fast:
* slow axonal transport is a bulk flow of axoplasm only in the anterograde direction, carrying cytoskeletal proteins and soluble, non-membrane bound proteins at a rate of c.0.1-3 mm a day
* in contrast, fast axonal transport carries vesicular material at c.200 mm a day in the retrograde direction and c.40 mm per day anterogradely
* rapid flow depends on microtubules
* vesicles with side projections line up along microtubules and are transported along them by their side-arms
* two microtubule-based motor proteins with ATPase activity are involved in fast transport: kinesin family proteins are responsible for the fast component of anterograde transport, and cytoplasmic dynein is responsible for retrograde transport
* fast anterograde transport carries vesicles, including synaptic vesicles containing neurotransmitters, from the soma to the axon terminals retrograde axonal transport accounts for the flow of mitochondria, endosomes and lysosomal autophagic vacuoles from the axonal terminals into the soma
* retrograde transport mediates the movement of neurotrophic viruses, e.g. herpes zoster, rabies and polio, from peripheral terminals, and their subsequent concentration in the neuronal soma


Synaptic transmission:

* transmission of impulses across specialized junctions (synapses) between two neurones is largely chemical
* depends on the release of neurotransmitters from the presynaptic side: this causes a change in the electrical state of the postsynaptic neuronal membrane, resulting in either its depolarization or hyperpolarization


Patterns of axonal termination vary considerably:

* a single axon may synapse with one neurone, e.g. climbing fibres ending on cerebellar Purkinje neurones, or more often with many, e.g. cerebellar parallel fibres, which provide an extreme example of this phenomenon
* in synaptic glomeruli, e.g. in the olfactory bulb, and synaptic cartridges, groups of synapses between two or many neurones form interactive units encapsulated by neuroglia


Electrical synapses (direct communication via gap junctions) are rare in the human CNS and are confined largely to groups of neurones with tightly coupled activity, e.g. the inspiratory centre in the medulla