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The Other Brain
I read The Other Brain by R. Douglas Field recently and if you're interested in the brain, this is a fascinating book. He is a cheerleader for glia and research on glia. Glia are all the non-neuron brain and nervous system cells. Glia means glue and glia have been second-class citizens behind neurons in terms of scientific research. They were thought of as bubble wrap for the brain and seen exclusively as supporters of neurons. That there is a recent special section of Science on glia (http://www.scientificamerican.com/blog/post.cfm?id=glia-the-new-frontier-in-brain-scie-2010-11-04) suggests that there is now greater appreciation for the role of glia and their complexity.
Most of the cells in the human brain (around 85%) are glia. Vertebrates have glia whereas invertebrates don't. Interestingly, the ratio of glia to neurons increases as you go from lower vertebrates to more intelligent vertebrates. Biopsy of Einstein's brain found that it was not unusual in terms of his gray matter or neurons, but rather in his abundance of glial cells, especially in certain areas of the brain, such as an area where abstract concepts, visual imagery and complex thinking take place.
There are four kinds of glia.
1. SCHWANN CELLS. These are found only in the peripheral nervous system (outside the brain and spinal cord). There are really three main types, but when scientists were naming things, they didn't bother to distinguish between the three. These are myelinating, non-myelinating, and terminal. The myelinating ones look like flattened pearls on a necklace or like a string of like railroad cars on a track clinging to axons. They are only found around large fiber nerves.
2. OLIGODENDROCYTES. These are really important to us because they form the myelin insulation on axons in the central nervous system, which is one of the obvious things that gets messed up in MS. Axons (long nerve fibers that come off neurons and send signal to other neurons) in the CNS are coated with a substance that looks like a wrapping of shiny ice on a tree branch. At first scientists didn't understand how it got there, although they did figure out that it was a fatty substance. Oligodendrocytes had appeared to be free-floating cells. Myelin was only connected with oligodendrocytes when a better staining technique found that the oligodendrocytes were actually like octopi. They have dozen of long, thin tentacles which they wrap many many times around different axons. This is somewhat different from how I had envisioned it. I knew oligodendrocytes made myelin, but I somehow had the impression that they just glopped it on the axons and left.
3. MICROGLIA. Microglia protect the brain from injury and disease. They are the immune system of the brain. The regular immune cells in the blood normally can't get past the blood-brain barrier to get into the CNS. Of course, this is another thing that goes wrong in MS when the blood-brain barrier is breached, allowing errant T cells and B cells into the CNS. Microglia are neurotoxic and can kill oligodendrocytes in MS, but may also have a neuroprotective role (http://www.ncbi.nlm.nih.gov/pubmed/19409897)
4. ASTROCYTES. The role of astrocytes is a little less clear to me, but they support neurons by providing a physical matrix for structural support, by delivering energy to neurons and removing their waste products, and by reacting to brain injury by forming scars. Astrocytes have a mixed role in MS and contribute to both "degeneration and demyelination, by promoting inflammation, damage of oligodendrocytes and axons, and glial scarring, but also in creating a permissive environment for remyelination by their action on oligodendrocyte precursor migration, oligodendrocyte proliferation, and differentiation." (http://www.ncbi.nlm.nih.gov/pubmed/17626262)
There is an interesting discussion about why nerves in the peripheral nervous system heal after an injury, but nerves in the central nervous system don't in the context of what happens when someone has a spinal cord injury.
Fields talks about how CNS glia play a role both in healing and in the prevention of healing. For example, glia that are trying to clean up the damaged tissue also release toxic substances in that process, which kill neurons.
Various processes beyond the initial insult cause the injury to spread. When oligodendrocytes die, they leave neurons with bare axons, which causes those neurons to die. Damaged neurons release neurotransmitters, such as glutamate, that kill oligodendrocytes. Neurons begin to die when their axon is cut even if there's nothing wrong with their cell body. This is because they're not receiving an "all's well" signal from their target. In normal development, many axons don't grow to reach the correct target and it's adaptive for the neurons that don't end up where they're supposed to be to die off. There's more, but I'm in over my head explaining it and I think you get the idea.
After a time, astrocytes form a barrier along the perimeter of the injured area to prevent the injury from spreading any more. Microglia inside the barrier consume all the debris until there's nothing left but a fluid-filled cyst.
At this point, theoretically the CNS could try to repair itself. Axons in the PNS can regrow after an injury and some neuron in the CNS do try to grow new axons. At first scientists thought maybe CNS axons were too weak to regrow for some reason or that there weren't enough neurotrophic factors (things that feed and support neural growth) in the CNS. However, they eventually figured out that the problem is inhibitory factors in the CNS.
There appear to be several obstacles that prevent axon regrowth in the CNS.
1. Lack of path to follow. In the PNS, the remaining chain of Schwann cells make a path of stepping stones for axons to follow when they regrow. In the CNS, when oligodendrocytes die or axons whither, myelin is withdrawn from the path and nothing is left.
2. Scar as barrier. The scar formed by astrocytes around the injury is not just a physical barrier for new axons. The scar is coated with proteins that repel cells, including new axonal growth. So when new axons touch the scar, they retract.
3. Oligodendrocytes as killers. Myelin also stops and kills new axonal growth. It does this through a number of redundant pathways. This seems to be connected with the need to prevent uncontrolled growth of new neurons and axons in the mature brain. The brain myelinates gradually over time and is not done until around age twenty. As various areas of the brain are myelinated, they lose plasticity and pass out of critical periods where major structural changes can happen. Since the development of myelin corresponds with end of new wiring, the use of myelin as a tool to stop new axonal growth is adaptive most of the time. Unfortunately, this isn't so after an injury.
Fields is keen on all the progress that is being made in understanding what's going on with glia and CNS injuries, but I despair at how complicated it all is. This is an important area to follow, though, since glia seem to have a lot of implications for understanding and treating MS.
There's a lot about how glia have a more active role in learning, memory, and many other brain functions than previously thought. This is long enough already, though. If you want to know more, read the book.
sho
Most of the cells in the human brain (around 85%) are glia. Vertebrates have glia whereas invertebrates don't. Interestingly, the ratio of glia to neurons increases as you go from lower vertebrates to more intelligent vertebrates. Biopsy of Einstein's brain found that it was not unusual in terms of his gray matter or neurons, but rather in his abundance of glial cells, especially in certain areas of the brain, such as an area where abstract concepts, visual imagery and complex thinking take place.
There are four kinds of glia.
1. SCHWANN CELLS. These are found only in the peripheral nervous system (outside the brain and spinal cord). There are really three main types, but when scientists were naming things, they didn't bother to distinguish between the three. These are myelinating, non-myelinating, and terminal. The myelinating ones look like flattened pearls on a necklace or like a string of like railroad cars on a track clinging to axons. They are only found around large fiber nerves.
2. OLIGODENDROCYTES. These are really important to us because they form the myelin insulation on axons in the central nervous system, which is one of the obvious things that gets messed up in MS. Axons (long nerve fibers that come off neurons and send signal to other neurons) in the CNS are coated with a substance that looks like a wrapping of shiny ice on a tree branch. At first scientists didn't understand how it got there, although they did figure out that it was a fatty substance. Oligodendrocytes had appeared to be free-floating cells. Myelin was only connected with oligodendrocytes when a better staining technique found that the oligodendrocytes were actually like octopi. They have dozen of long, thin tentacles which they wrap many many times around different axons. This is somewhat different from how I had envisioned it. I knew oligodendrocytes made myelin, but I somehow had the impression that they just glopped it on the axons and left.
3. MICROGLIA. Microglia protect the brain from injury and disease. They are the immune system of the brain. The regular immune cells in the blood normally can't get past the blood-brain barrier to get into the CNS. Of course, this is another thing that goes wrong in MS when the blood-brain barrier is breached, allowing errant T cells and B cells into the CNS. Microglia are neurotoxic and can kill oligodendrocytes in MS, but may also have a neuroprotective role (http://www.ncbi.nlm.nih.gov/pubmed/19409897)
4. ASTROCYTES. The role of astrocytes is a little less clear to me, but they support neurons by providing a physical matrix for structural support, by delivering energy to neurons and removing their waste products, and by reacting to brain injury by forming scars. Astrocytes have a mixed role in MS and contribute to both "degeneration and demyelination, by promoting inflammation, damage of oligodendrocytes and axons, and glial scarring, but also in creating a permissive environment for remyelination by their action on oligodendrocyte precursor migration, oligodendrocyte proliferation, and differentiation." (http://www.ncbi.nlm.nih.gov/pubmed/17626262)
There is an interesting discussion about why nerves in the peripheral nervous system heal after an injury, but nerves in the central nervous system don't in the context of what happens when someone has a spinal cord injury.
Fields talks about how CNS glia play a role both in healing and in the prevention of healing. For example, glia that are trying to clean up the damaged tissue also release toxic substances in that process, which kill neurons.
Various processes beyond the initial insult cause the injury to spread. When oligodendrocytes die, they leave neurons with bare axons, which causes those neurons to die. Damaged neurons release neurotransmitters, such as glutamate, that kill oligodendrocytes. Neurons begin to die when their axon is cut even if there's nothing wrong with their cell body. This is because they're not receiving an "all's well" signal from their target. In normal development, many axons don't grow to reach the correct target and it's adaptive for the neurons that don't end up where they're supposed to be to die off. There's more, but I'm in over my head explaining it and I think you get the idea.
After a time, astrocytes form a barrier along the perimeter of the injured area to prevent the injury from spreading any more. Microglia inside the barrier consume all the debris until there's nothing left but a fluid-filled cyst.
At this point, theoretically the CNS could try to repair itself. Axons in the PNS can regrow after an injury and some neuron in the CNS do try to grow new axons. At first scientists thought maybe CNS axons were too weak to regrow for some reason or that there weren't enough neurotrophic factors (things that feed and support neural growth) in the CNS. However, they eventually figured out that the problem is inhibitory factors in the CNS.
There appear to be several obstacles that prevent axon regrowth in the CNS.
1. Lack of path to follow. In the PNS, the remaining chain of Schwann cells make a path of stepping stones for axons to follow when they regrow. In the CNS, when oligodendrocytes die or axons whither, myelin is withdrawn from the path and nothing is left.
2. Scar as barrier. The scar formed by astrocytes around the injury is not just a physical barrier for new axons. The scar is coated with proteins that repel cells, including new axonal growth. So when new axons touch the scar, they retract.
3. Oligodendrocytes as killers. Myelin also stops and kills new axonal growth. It does this through a number of redundant pathways. This seems to be connected with the need to prevent uncontrolled growth of new neurons and axons in the mature brain. The brain myelinates gradually over time and is not done until around age twenty. As various areas of the brain are myelinated, they lose plasticity and pass out of critical periods where major structural changes can happen. Since the development of myelin corresponds with end of new wiring, the use of myelin as a tool to stop new axonal growth is adaptive most of the time. Unfortunately, this isn't so after an injury.
Fields is keen on all the progress that is being made in understanding what's going on with glia and CNS injuries, but I despair at how complicated it all is. This is an important area to follow, though, since glia seem to have a lot of implications for understanding and treating MS.
There's a lot about how glia have a more active role in learning, memory, and many other brain functions than previously thought. This is long enough already, though. If you want to know more, read the book.
sho
This is all really good information. I have always been interested in the brain but only took a few classes in college that covered it. I am going to look for the book.
Red
Red
Thanks Sho for the synopsis and new information (at least to me) about the glia.
Ren
Ren
None really. I was involved in the first clinical trials (as a researcher) on Verapamil at NIH in 1981. It is very is a broader CA+2 channel antagonist. There are new CA+2 antagonists that are specific to certain channels (like cardiac slow channel antagonists.) I'm really out of the loop on that stuff. For that last 20 years, I have worked on applying IT to solving business problems.
Bob
Bob
In relation to this part of your post:
Many of the anti-seizure drugs today work on altering ion conduction in the brain. The emphasis has been on the sodium channel, but Gabapentin and Verapamil with are both used by MS patients have known specific effects on action potentials and the voltage gated Calcium channels.
My neuro has prescribed Verapamil as a migraine preventer for me. Do you have the info to explain exactly WHAT "specific effects" this drug has on MSers? Is it positive or negative?
Many of the anti-seizure drugs today work on altering ion conduction in the brain. The emphasis has been on the sodium channel, but Gabapentin and Verapamil with are both used by MS patients have known specific effects on action potentials and the voltage gated Calcium channels.
My neuro has prescribed Verapamil as a migraine preventer for me. Do you have the info to explain exactly WHAT "specific effects" this drug has on MSers? Is it positive or negative?
Bob: Thanks for bringing up the ion channel angle. You've got me intrigued
Also, if anyone is interested in axon regeneration, you might want to check out this study http://www.medicalnewstoday.com/articles/207788.php. As I said above axons don't regrow in the CNS, much as we would like them to, due to inhibitory factors that stop them. One of these is myelin itself. These researcher have found a way to stop some of proteins in myelin from killing growing axons that they come in contact with. They haven't solve the whole problem, but it's promising.
"Axons [in the CNS] have a limited capacity for regrowth; this restriction is caused by myelin-associated inhibitors (MAIs).
"A release from myelin inhibition thus improves neuronal regeneration, and the three researchers from IBEC's Molecular and Cellular Neurobiotechnology group have discovered that blocking two of some of these proteins' shared receptors NgR1, together with its coreceptors p75(NTR), TROY and Lingo-1, and paired immunoglobulin-like receptor B (PirB) prevents the inhibitors from restricting axonal sprouting and limiting the regeneration of damaged fibre tracts.
"Other elements of the myelin inhibitory pathway are still unknown,"
Also, if anyone is interested in axon regeneration, you might want to check out this study http://www.medicalnewstoday.com/articles/207788.php. As I said above axons don't regrow in the CNS, much as we would like them to, due to inhibitory factors that stop them. One of these is myelin itself. These researcher have found a way to stop some of proteins in myelin from killing growing axons that they come in contact with. They haven't solve the whole problem, but it's promising.
"Axons [in the CNS] have a limited capacity for regrowth; this restriction is caused by myelin-associated inhibitors (MAIs).
"A release from myelin inhibition thus improves neuronal regeneration, and the three researchers from IBEC's Molecular and Cellular Neurobiotechnology group have discovered that blocking two of some of these proteins' shared receptors NgR1, together with its coreceptors p75(NTR), TROY and Lingo-1, and paired immunoglobulin-like receptor B (PirB) prevents the inhibitors from restricting axonal sprouting and limiting the regeneration of damaged fibre tracts.
"Other elements of the myelin inhibitory pathway are still unknown,"
WARNING: Geek information follows about THEORETICALLY why MS may be more than just Demyelination and how MS might be more than just a CNS disease.
There is some research over the last 10 years or so that suggests that some of the "signaling failures" in the MS brain (and possibly the peripheral nervous system of PwMS) may be related to action potential imbalances between the Sodium channels and the Calcium channels within the axons. It seems that it is not just a failure of insulation, but a failure in the chemistry that maintains the action potentials (voltages) within the axons. A lot of this started at Yale with their work on Sodium Channels in about 2002
http://www.nature.com/nrn/journal/v7/n12/full/nrn2023.html
The recognition of ion channels playing a role is he MS disease process theoretically explains how many MS patients have neurologic symptoms that extends beyond the CNS. Ion channel disfunction can extend all the way to the small fibers and may contribute to the axonal dysfunction that many researchers have identified.
Many of the anti-seizure drugs today work on altering ion conduction in the brain. The emphasis has been on the sodium channel, but Gabapentin and Verapamil with are both used by MS patients have known specific effects on action potentials and the voltage gated Calcium channels.
Some Neurologist keep up with this research. Others will call it "fringe science" since it is not a mainstream view (yet.) There are a few drug companies that are looking at the research closely.
I know Quix has a big interest in some of this and I started looking into more after she brought it to my attention.
Bob
There is some research over the last 10 years or so that suggests that some of the "signaling failures" in the MS brain (and possibly the peripheral nervous system of PwMS) may be related to action potential imbalances between the Sodium channels and the Calcium channels within the axons. It seems that it is not just a failure of insulation, but a failure in the chemistry that maintains the action potentials (voltages) within the axons. A lot of this started at Yale with their work on Sodium Channels in about 2002
http://www.nature.com/nrn/journal/v7/n12/full/nrn2023.html
The recognition of ion channels playing a role is he MS disease process theoretically explains how many MS patients have neurologic symptoms that extends beyond the CNS. Ion channel disfunction can extend all the way to the small fibers and may contribute to the axonal dysfunction that many researchers have identified.
Many of the anti-seizure drugs today work on altering ion conduction in the brain. The emphasis has been on the sodium channel, but Gabapentin and Verapamil with are both used by MS patients have known specific effects on action potentials and the voltage gated Calcium channels.
Some Neurologist keep up with this research. Others will call it "fringe science" since it is not a mainstream view (yet.) There are a few drug companies that are looking at the research closely.
I know Quix has a big interest in some of this and I started looking into more after she brought it to my attention.
Bob
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