NERVOUS SYSTEM BASICS

[Diane]

I've recently completed a study of nervous system basics, into compilations that I think make good sense, using as a take-off point Jay Angevine's wonderful chapter in Encyclopedia of the Human Brain.

I'm going to link them here, in this thread, and sticky it so it will be easy to find.

Each paper uses a separate "focal length" but they all need each other to be a complete overview, to give a complete sense of the nervous system. In them are traces of historicity; the study of the nervous system over the last couple centuries has been as dogged by dogma as any other field has ever been, and often debates languished for decades until some bright spark would come along with a new way to see deeper or image better.

It's impossible to read at any length or depth about the nervous system without ending up feeling oneself carried along by the historical traces, twists and turns. One's own synapses become reshaped a little by soaking up this material, but I doubt anyone's will be any the worse for wear.
Enjoy.

NERVOUS SYSTEM BASICS:

1. Organizing Principles (http://docs.google.com/Doc?id=dg8sf6hf_4865tmp8dm)

2. Main Divisions (http://docs.google.com/Doc?docid=dg8sf6hf_110frc6d3z3&hl=en)

3. Main Regions (http://docs.google.com/Doc?docid=dg8sf6hf_124d495msgx&hl=en)

4. Six Crucial Properties (http://docs.google.com/Doc?id=dg8sf6hf_151f73kxqfb)

5. Neuron Parts and Classifications (http://docs.google.com/Doc?id=dg8sf6hf_153ft66g7rm)

6. Anatomy of a Neuron (http://docs.google.com/Doc?id=dg8sf6hf_154f46kfcct)

7. Anatomy of a Synapse (http://docs.google.com/Doc?id=dg8sf6hf_173dczp3qcm)

8. Where Nervous Systems Come From (http://docs.google.com/Doc?docid=dg8sf6hf_87hbh4s2qc&hl=en)

9. Nervous System Basics: Glia (http://docs.google.com/Doc?docid=dg8sf6hf_106g3mp73df&hl=en)

[Stuart]

Excellent work and organization! Excellent. Thank you for sharing.

[Mary C]

Hi Diane

I found and printed them yesterday. (I'm one who needs hard copy to digest the material.:rolleyes:)
I found them so good, I was going to suggest you link them here.

Anatomy of a Neuron had to be copied into Word to print. The others did just fine with a little fine tuning of page set-up.

I'll get them into a spiral binding at work. My library is growing. :D

[Diane]

You're welcome Stuart. I'm honored Mary.

I've added one more to the list in the first post, at the end. It seemed to fit in after Anatomy of a Synapse, since synapses preceeded nervous systems in evolution.

Please do check the attached links too.

The whole thing can seem so big and hard to study as to be completely daunting, and I've never quite trusted the basic NS information as funnelled through manual therapists, because they tend to slant things heavily toward the PNS and never explain the brain, which always left me confused. But when I found that Angevine chapter, I felt like I'd finally found an overall perspective I could relax into.

That Emes/Grant synapse paper that just came out in June is an earth-shaker paper, IMO. I think it will turn the compost of neuroscience over once again. Maybe evolutionary considerations and embryologic ones as well.

[NateM]

Each human nervous system is unprecedented. The work of each (expressed or hidden) is unpredictable, ever-different, surprising, startling, at times horrifying, but not infrequently magnificent." - Jay B. Angevine

What a fantastic line.

Thanks for the links, Diane.

[Diane]

I love that line too Nate.
You're welcome.

[Julie]

Wow. Diane. Do you ever sleep? Fantastic.

[Diane]

Yes, I do sleep. A lot. Whenever the urge comes over me. Unless I'm at work. :)

[Diane]

I've added a new set of notes to the list in post 1, on glia, from several different sources.
It took quite awhile to post it, because I kept finding more and more stuff and got much too fascinated to stop looking. Not only are glia amazing for all the non-neuronal jobs they do in the CNS and PNS, but in particular microglia have got a big finger pointed at them as being highly implicated in producing central sensitization in the dorsal horn. (I can remember Butler being excited about this 4 or more years ago, but didn't get what the buzz was, because I didn't have much of a clue about microglia.)

To understand microglia, it really helps to have more than a passing acquaintance with embryology, because things like cell origins get a bit murky here - neuroscience is quite divided about the origin of microglia. It accepts that all the other "glias" come from neural tube, but a bunch of scientists assume that because microglia act like macrophages in that they can become detached, and individually motile, crawl through the brain and cord looking for dead neurons to gobble like opportunistic little vultures (my own take on them), they must be part of the immune system and therefore hemopoietic, i.e., derived from blood-immune system- mesoderm.

Well, it doesn't necessarily mean that just because a cell in the brain acts like a cell in the body that it necessarily is the same cell. Others think that the microglia arise from ependymal cells, which are a type of glia in the brain whose precursors make some kinds of blood cells early on in embryologic development, even before there is a functional heart to pump blood around. The study notes take a look at the debate. There is evidence for both sides, and the debate is ongoing for now. But if I were going to lay odds, I'd bet on ectoderm being creative enough to build any kind of cell it wants, even scavenger cells in the brain which are also pain-enhancing cells in the cord. It makes everything else, why not microglia? It can make anything.

Microglia have a purpose, even though they mostly lie around in stasis, only [music from "Jaws"]activating if they "smell blood"... then they migrate[/music from "Jaws"] to wherever the stroke or the head injury is, and clean up debris. The CNS microglia take a lot longer to do this than the immune system does in the outer body, for the PNS. But in the dorsal horn, it seems they get excited every time a barrage of raw nociception comes through. They start to secrete cytokines, and the cytokines etc. inhibit the secondary ascending fibers. So what? you might ask. Is inhibition not good? Not necessarily. The secondary ascending fibers are there as a buffer zone in the first place, only willing to do so much in the course of a day's work. But if they are inhibited, in other words, if their normal function is to be a bottleneck, and then the bottle-neck function gets inhibited, they become capable of conveying way more (too much) information to the brain. That can't be good...

I think this might be the "horrifying" part of the nervous system from that line Nate quoted in post 5.

Another thing I found out as if I'd never heard of it before was the whole myelination story, how it is handled peripherally versus centrally, the various demyelinating diseases (they are not all MS). What continues to rivet my attention is that these are all living cells, cooperating with each other, chemically sensing each other, living together in an ecosystem, communicating through channels in membranes, molecules moving through gap junctions. Very cool. It's a jungle in there.

[BB]

Diane,

Thanks for all of this.

In reading the glial notes a case is made for microglia's role in mechanical allodynia. It lists cases of activation including pathology and inflammation. Have you come across any evidence of microglial activation in absence of pathology or inflammation? I'm curious as this would implicate a different mechanism in mechanical allodynia of non-pathologic or inflammatory origin.

[Diane]

Not yet, but I'm still swimming in the sea of basic microglial info that exists, and of course that will be something that catches my eye if I see it.
Meanwhile, this already did catch my eye, from the study notes:
- Activation of microglial in the dorsal horn is concomitant with the development of neuropathic pain in a wide variety of nerve injury models:

* spinal nerve ligation
* chronic constriction injury
* dorsal rhizotomy (Tsuda et al 2004)


Chronic constriction injury , AKA mechanical deformation over a long enough period of time.

[Diane]

Cory, I found 209 papers from several different journals by searching microglia AND pain, in ovid medline... I pdfed the abstracts and can send them to you maybe, if you want. Then, if there are any you especially hanker after, I can retrieve them. Sound OK?
In Nature, there are about 1300 hits for microglia. Looks like I'll be busy.

Meanwhile, apologies for hogging the entire "latest threads" box with all the microglia stuff I pulled out of PAIN...
I'll put a link to them here in this post, and they can go buried again, no problem.
Bernard wants each paper on its own thread... so... it's a bit of a barrage but makes individual threads easier to find I guess.

Links:
1. The Brain's Garbage men (http://www.somasimple.com/forums/showthread.php?t=5871)
2. Snake venom phospholipase (http://www.somasimple.com/forums/showthread.php?t=5870)
3. HIV-1 gp120 Stimulates proinflammatory cytokine-mediated pain (http://www.somasimple.com/forums/showthread.php?t=5869)
4. More Snake Venom (http://www.somasimple.com/forums/showthread.php?t=5868)
5. ERK (http://www.somasimple.com/forums/showthread.php?t=5867)
6. Minocycline (http://www.somasimple.com/forums/showthread.php?t=5866)
7. Activation of glia and microglial p38 MAPK in medullary dorsal horn (http://www.somasimple.com/forums/showthread.php?t=5865)
8. methotrexate reduces peripheral nerve injury-evoked spinal microglial activation (http://www.somasimple.com/forums/showthread.php?t=5863)
9. Characterization of cell proliferation (http://www.somasimple.com/forums/showthread.php?t=5862)
10. Chapter on Microglia (http://www.somasimple.com/forums/showthread.php?p=55501#post55501)

Here is a quite long and thorough open access article on microglia (http://cmr.asm.org/cgi/content/full/17/4/942).

[BB]

Thanks Diane. I've got some work to do, it appears.

[Diane]

We all have work to do, it appears.

[Diane]

I think taking an ecosystem approach works fairly well in thinking about dorsal horn sensitization and microglial numbers activating and increasing. Like any living creature in any ecosystem, an increase in the population of one leads to response and necessary adaptation by the others.

I keep thinking about the time I stupidly put some hamburger meat that had gone off, into my worm compost bin, thinking the worms would take care of it, as easily as they took care of coffee grounds and vegetable peelings. What happened instead was about ten days later my apartment suddenly filled with a cloud of buzzing flies. Obviously the worms had become quickly outnumbered by fly larvae, who went to work hatching and eating the hamburger and had developed themselves into a new and highly populous next-gen cloud of scavengers, all set to go find another "carcass" to eat/multiply within. I opened the window and helped them out with a broom.

So let's say the microglia get activated in the dorsal horn at the synapses where they lurk, just waiting for a change to happen. In comes information reporting damage to a nerve. The microglia swing into action, depressing the function of the secondary ascending fibers, swelling their own numbers, looking for something to eat, and excreting all over the place (flyspecks)! Their excretion includes cytokines, chemokines, things referred to as "growth factors" but which I will refer to as "fertilizer." Some of which, neurons evidently use to help themselves repair, but other stuff will just irritate them, make them more cranky. This might even help the microglia gain and retain some sort of upper hand, neurochemically (or some sort of upper pseudopod in the case of microglia)... the balance has tipped in their favor. Maybe as in real ecosystems, they take advantage of favorable situations as hard as they can. But the spinal cord is enclosed. That can't be good. That's like a bunch of flies hatching in an apartment without windows or any other escape hatch.

I wonder then, how the system rights itself, gets microglia back under control. Maybe more or different descending, downregulating pathways get activated by one means or another. Maybe as the microglia die off, they are gradually consumed (cannibalized) by their own kind ("Microglia eat their dead") until their population is back under control and the remainder goes dormant again. As I read, I'll try to find out.

In any case, the dorsal horn seems to be where rubber hits road in terms of central sensitization of peripheral input. If you were to add head injury to this, it's kind of easy to see that ah, yes, the little varmints could gain the upper hand and keep it. So, good drugs that control microglial receptors, keep them from activating or that can put them back to sleep, will likely be the way of the future. The future of pain control will likely belong to whoever learns to control microglial behavior. The future of pain control is not likely to belong to any orthodigm in PT or any other HPSG group.

[Diane]

I am about to drive everyone (look out, proud...) mad here on this forum this summer, bringing forward information about glia. I just got Glial Neurobiology (http://ca.wiley.com/WileyCDA/WileyTitle/productCd-0470015640,descCd-tableOfContents.html) (Verkhratsky and Butt) and Neuroglia 2ndEd (http://www.amazon.com/Neuroglia-Helmut-Kettenmann/dp/0195078470) (Kettenmann and Ransom) in the mail. Whoohoo. Look out.

[Diane]

Bonanza!
I found an online version (http://www3.interscience.wiley.com/cgi-bin/bookhome/114294747) of a new book I bought, Glial Neurobiology. It just came out last year.

You have to download it in chunks, and it's not free, but it's great.
Preface

Contemporary understanding of brain organization and function follows the neuronal doctrine, which places the nerve cell and neuronal synaptic contacts at the very centre of the nervous system. This doctrine considers glia as passive supportive cells, which are not involved in the informational exchange, and therefore secondary elements of the nervous system.

In the last few decades, however, our perception of the functional organization of the brain has been revolutionized. New data forces us to reconsider the main postulate of the neuronal doctrine – that neurones and synapses are the only substrate of integration in the central nervous system. We now learn that astroglial cells, which are the most numerous cells in the brain, literally control the naissance, development, functional activity and death of neuronal circuits. Astroglial cells are in fact the stem elements from which neurones are born.

They also create the compartmentalization of the CNS and integrate neurones, synapses, and brain capillaries into inter-dependent functional units. Furthermore, astroglial cells form a functional syncytium, connected through gap junction bridges, which provides an elaborate intercellular communication route. This allows direct translocation of ions, metabolic factors and second messengers throughout the CNS, thereby providing a sophisticated means for information exchange. In a way the binary coded electrical communication within neuronal networks may be considered as highly specialized for rapid conveyance of information, whereas astroglial cells may represent the true substance for information processing, integration and storage.

Will this truly heretical theory which subordinates neurones to glia be victorious at the end? Forthcoming years hold the answer. When writing this book we have attempted to create a concise yet comprehensive account of glial cells and their role in physiology and pathology of the nervous system. We hope very much that this account may help the reader to discover a
fascinating world of brain ‘secondary’ cells, which in fact are essential elements of the nervous system, whose functions and importance are yet to be fully appreciated.

Alexei Verkhratsky (http://www.iem.cas.cz/article.asp?nArticleID=587&nLanguageID=2) (now at U. Manchester)
Arthur Butt (http://www.port.ac.uk/departments/academic/pharmacy/staff/title,44170,en.html)

[Diane]

I haven't found out yet whether or not microglia eat their own dead, but they certainly eat all the other dead. Here is a paper (http://www.somasimple.com/forums/showthread.php?p=55901#post55901) about it.
What is so cool about this, in my mind anyway, is the reference to the ancient-ness of receptors of various kinds. It really does look like it's the receptors where all action is, that are the "immortal" parts, i.e., not changing much through time. I guess once a good one gets built, one that works to reduce a chemo-gradient, there is no point in changing it. "Nature abhors a gradient" (Into the Cool, Sagan/Schneider). Back to Seth Grant and System Proteomics (http://www.somasimple.com/forums/showthread.php?t=5682), which is what finally got me going on glia in the first place.

[Diane]

I'm still checking out glia, in particular microglia, and their relationship to the nervous system, dorsal horn, pain facilitation. In looking up information about Linda Watkins I found this paper, Gateways to Pathological Pain (http://www.the-scientist.com/2005/03/28/S24/1/)at TheScientist.com.

Points to take home:
1. With regard to what turns p38 on in the spinal cord, "the search is on," says Linda Watkins, professor of psychology at the University of Colorado, Boulder (http://www.somasimple.com/forums/showthread.php?t=5910). Imagine the peripheral neuron firing with intensity, sending signals into the dorsal horn of the spinal cord. "Some are very unique neuron-to-glia signals, such as fractalkine," says Watkins. Fractalkine is a protein in the chemokine family that is expressed only on the outside surface of neurons. Shed from neurons sending distress signals, fractalkines bind to and activate nearby glial cells. "The only cells that express receptors for [fractalkine] are microglia," says Watkins.

OK, so the neurons send out distress calls, and like a nervous sweat, fractaline emerges on their surfaces, and microglia are drawn like sharks to blood.

2. In addition to hypertrophy, there is hyperplasia. "Perhaps the most dramatic thing that [microglia] do is they divide," says Wolfgang "Jake" Streit, professor of neuroscience at University of Florida's Evelyn F. and William L. McKnight Brain Institute in Gainesville. "They divide like you wouldn't believe."

They are capable of nearly tripling their numbers in a short time.

[Diane]

I found a recent paper (see Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain) (http://www.somasimple.com/forums/showthread.php?p=60527#post60527)

It talks about those P2X receptors. Every time I see P2X I immediately associate it with microglia - for better or worse, microglia have definitely made themselves apparent to me as being unavoidable players in pain.

[Diane]

Here is another one, open access this time.
Monocyte chemoattractant protein-1 functions as a neuromodulator in the dorsal root ganglia neurons (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2186066). Abstract:
It has previously been observed that expression of chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor CCR2 is upregulated by dorsal root ganglion (DRG) neurons in association with rodent models of neuropathic pain. MCP-1 increases the excitability of nociceptive neurons after a peripheral nerve injury, while disruption of MCP-1/CCR2 signaling blocks the development of neuropathic pain, suggesting MCP-1 signaling is responsible for heightened pain sensitivity. In order to define the mechanisms of MCP-1 signaling in DRG, we studied intracellular processing, release, and receptor-mediated signaling of MCP-1 in DRG neurons. We found that in a focal demyelination model of neuropathic pain both MCP-1 and CCR2 were upregulated by the same neurons including TRPV1 expressing nociceptors. MCP-1 expressed by DRG neurons was packaged into large dense-core vesicles (LDCVs) whose release could be induced from the soma by depolarization in a Ca2+-dependent manner. Activation of CCR2 by MCP-1 could sensitize nociceptors via transactivation of transient receptor potential (TRP) channels. Our results suggest that MCP-1 and CCR2, upregulated by sensory neurons following peripheral nerve injury, might participate in neural signal processing which contributes to sustained excitability of primary afferent neurons.
Karen has probably already seen this. In fact Karen has probably already linked it here somewhere.. :D

One other thing I've learned, for better or worse, monocyte = immune system = microglia = little pests.