Episode 118      29 min 40 sec
Controlling our impulses: Communication pathways and signal transmission in the nervous system

Neuroscientists Prof Bruce Carter and Dr Simon Murray explain how nerve cells conduct information efficiently and the processes that underlie the orderly creation and destruction of nerve and supporting cells. With Science host Dr Shane Huntington.

"We tend to think of myelin as a very static coating on these neurons but I think what is now beginning to evolve is this idea that actually it is very plastic – it can change a lot." -- Professor Bruce Carter




           



Professor Bruce Carter
Professor Bruce Carter

Bruce Carter is Professor of Biochemistry at the Vanderbilt University Medical Center.  Professor Carter’s research focuses on the signaling mechanisms regulating neuronal survival during the development of the mammalian nervous system. Programmed cell death in the nervous system is a naturally occurring process in mammalian development; however, abnormal apoptosis is the basis for many neuropathologies. The delicate balance between neuronal survival and death is regulated, in part, by a family of growth factors referred to as the neurotrophins. The neurotrophins promote neuronal survival and differentiation through binding to the Trks, a family of tyrosine kinase receptors. In addition, these factors bind to a member of the TNF receptor family, p75. This receptor has a wide variety of functions, it can promote cellular survival or induce apoptosis, regulate neurite outgrowth, and promote Schwann cell myelination, depending on the cellular context. The molecular mechanisms by which p75 mediates this variety of signals is largely unknown. Through the use of in vitro systems, as well as transgenic mice, Dr. Carter's lab investigates the molecular components of these pathways and the physiological contexts in which they are activated.

Dr Simon Murray
Dr Simon Murray

Simon Murray is a Lecturer and Laboratory Head in the Department of Anatomy and Cell Biology.  He graduated as a Physiotherapist in 1992, worked for several years before returning to study and graduating with his PhD in 2000.  He spent 3 years as a post-doctoral fellow at the Skirball Institute at the New York School of Medicine, before returning to Australia to work at the Florey Neuroscience Institutes in the Multiple Sclerosis Research Division.  He moved his laboratory to the Centre for Neuroscience in 2005, and joined the Department of Anatomy and Cell Biology in 2010.  His scientific training is in the molecular and cellular biology of neurotrophin signalling, and is applying this to the analysis of myelination, and how neurotrophin-based strategies could be developed to promote remyelination in the context of demyelinating disease such as Multiple Sclerosis.

Credits

Host: Dr Shane Huntington
Producers: Kelvin Param, Eric van Bemmel
Associate Producer: Dr Chrstine Bailey
Series Creators: Eric van Bemmel and Kelvin Param
Audio Engineers: Gavin Nebauer (Melbourne), Brian Smokler (Nashville)
Voiceover: Nerissa Hannink
Transcription: Andy Fuller

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Controlling our impulses: Communication pathways and signal transmission in the nervous system

VOICEOVER
Welcome to Up Close, the research, opinion and analysis podcast from The University of Melbourne, Australia.

SHANE HUNTINGTON
I’m Shane Huntington, thanks for joining us. The body’s central and peripheral nervous systems, on which we and other mammals so crucially rely are complex and depend upon the interplay between numerous chemicals to get their work done. Cells are created and later die, signals are transmitted, and a myriad of bodily functions are regulated, all based on these chemical reactions. But one of the most important processes going on in our nervous systems is myelination. To tell us more about myelination, we are joined from Nashville, Tennessee, by Prof  Bruce Carter of Vanderbilt University Medical Center and here in the studio by Dr  Simon Murray from the Department of Anatomy and Cell Biology and head of the Neurotrophin Signalling Laboratory, Centre for Neuroscience at The University of Melbourne, Australia. Welcome to Up Close, Bruce and Simon.

SIMON MURRAY
Thank you Shane.

BRUCE CARTER
Thanks.

SHANE HUNTINGTON
The body essentially – Bruce if I can start with you – has two nervous systems, it has the central nervous system and the peripheral nervous system. Can you give us an idea of the difference between the two and the roles that they play in the body?

BRUCE CARTER
Sure. The central nervous system is basically the brain and spinal cord and obviously the brain is involved in higher order thinking or reasoning, while the peripheral nervous system is an older – evolutionary speaking – an older nervous system and it will regulate things like heart rate, gives us sensory perception, so, we know where are limbs are and space, we can feel pain, things like that.

SHANE HUNTINGTON
Can you give us an idea Bruce of just how this compares to the nervous systems in other animals that we find, mammals and others?

BRUCE CARTER
Well, in all vertebrates there is both a peripheral and central nervous system. Lower organisms have more rudimentary nervous systems. For example the nematode C. elegans has a very crude nervous system – well, I say ‘crude’, I’m sure my colleagues may disagree. It is a much more simplified, for example, obviously no brain. Hydra don’t even have an organised nervous system like we do. Theirs is more of a neural net. But most higher organisms have both a peripheral and central nervous system.

SHANE HUNTINGTON
Simon, let me turn to you for a second, um, can you describe for us, what is involved in a nervous system, what makes it up and how it works within the body?

SIMON MURRAY
Sure. The nervous system consists of a heterogenous population of cells that have very organised and very discreet connections. Bruce alluded to the relatively disorganised nervous system in hydra and as we go through evolution so the demands of interacting with our environment required a more precise, a more interconnected nervous system, and so, as a consequence of this, different heterogenous populations cells arose with different particular functions and in fact we now see both in the central nervous system and the peripheral nervous system segregation of function to the particular parts of the nervous system. These have evolved to become interconnected. And to give, really, a whole body, or a more unified sense of purpose to what we do.

SHANE HUNTINGTON
Let me ask you about, myelin, this is obviously the material that has been referred to before on Up Close in a previous episode, what is it? What sort of material is it? And, what is it there for?

SIMON MURRAY
So, we have been talking about a nervous system and the interconnections of neurons and this heterogenous population of cells, it is important to realise that myelin is actually non-neuronal. It arises from distinct, specialised cells within the central nervous system known as oligodendrocytes and also in the peripheral nervous system known as schwann cells. And I suppose, at the most basic level, what myelin is, is a specialised membrane outgrowth of the oligodendrocyte and of the schwann cell and what this membrane outgrowth does is that it wraps around or ensheathes neurons themselves, multi-lamellar wrapping which then actually compacts down on itself and actually fundamentally alters the way nerve signals are propagated down the nerve cell.

SHANE HUNTINGTON
Simon, can you just clarify what schwann cells actually are?

SIMON MURRAY
So, schwann cells are very highly specialised cells within the peripheral nervous system and their main function, in fact, arguably, their own function is to produce this myelin sheath to wrap around the neuron and to compact down so that it can exert this very specific insulating influence.

SHANE HUNTINGTON
And oligodendrocytes are the same?

SIMON MURRAY
Very much in the same vein. Oligodendrocytes are really unique to the central nervous system and they in essence do the same thing as schwann cells, but they do it in a slightly different biochemical manner. Fundamentally, the function of myelin is identical in both the peripheral nervous system and central nervous system. If we go back, to the early vertebrates, when myelin first appeared, the constituent proteins of myelin have in fact changed over time. So that, in early evolution myelin protein and the lipids that make up myelin were relatively uniform in both the peripheral and central nervous system. Now, in humans the proteins that constitute myelin are actually quite different in the peripheral nervous system and the central nervous system. So, over time, over evolution, oligodendrocytes and schwann cells have in fact diversified and generated their own specialisation.

SHANE HUNTINGTON
And presumably are more then optimised to the particular role they are playing in the two different nervous systems.

SIMON MURRAY
That is exactly right. And in fact, it is quite clear not that peripheral myelin cannot substitute for central myelin. In fact, there are quite eloquent studies that have shown this to be absolutely true. And I think, when discussing myelin, it is important to really identify the impact that it has upon the nerve cell itself. Um, I have alluded to the fact that myelin wraps around or ensheathes a neuron – now this is intuitively it makes you want to think something like an electric cable which is ensheathed by plastic to give it a protective feature, this to a degree is true for myelin but there are important differences, important specialities that myelin confers upon a neuron which gives it this real advantage, this real specialisation. I think there are two contexts, where it is most informative. The first context is in evolution. And in essence, nervous system function is all about speed. So, predatory behaviours and escape behaviours and how a nimble and efficient and quick nervous system will help you adapt to the environment and survive the environment. Now, evolution has thrown up, in fact, two ways, to increase the speed of which an electrical impulse runs down a neuron. The first mechanism, is by, what we call axon gigantism to grow bigger axons. The speed of which an impulse propagates down an axon is proportional to its diameter. And in some invertebrates, the cephalopods for example, so we are talking squid, we are talking octopus, they have evolved very large axons to allow them to propagate signals a lot faster and as a result they can grow a lot bigger because they can get signals to and from more distant regions in relatively quick time. The second way evolution has thrown up the solution to faster conduction is to generate myelin. And it is this myelin sheath that in essence increases the speed at which a nerve cell can propagate its electrical information. Its impulse. And it does this bio-chemically. We have to imagine how an un-myelinated neuron propagates its signal and it does this by a biophysical mechanism called de-polarisation. So, what happens is that, the neuron receives a signal that gets activated and then it propagates this signal down the length of an axon in a very smooth, in a very co-ordinated and it is often referred to in a wave-like fashion. So, in this un-myelinated axon you get this very smooth propagation down the length of its neuron. In a myelinated axon, this is completely different. What myelin does, because it ensheathes or wraps around the neuron it forces a concentration of these - what we call - channels. So, perhaps my analogy to an electric cable is quite misleading to a degree, because myelin is not a smooth ensheathment along an axon. It is in fact interspersed with these periodic - what we call nodes or, nodes of Ranvier. And these nodes of Ranvier are critically important to how a myelinated axon functions because instead of this smooth, even propagation you get this jumping of the electrical impulse down the axon. This makes the conduction dramatically quicker. Such that in an un-myelinated axon, might conduct at one meter per second, if you myelinate that axon it might conduct at 50 meters a second or 100 meters a second. So there is a substantial increase in speed for really no increase in size. So, we have solved the gigantism problem by evolving myelin to increase the speed. This has other benefits as well. You might imagine it is metabolically more efficient because you are only depolarising at these nodes, instead of down the whole length of the axon. As a result of being metabolically more efficient, it is also energetically more efficient. So, myelin really conferred a significant selectable advantage upon the nervous system to allow us to evolve more complex nervous systems that propagate signals more efficiently and more quickly than would otherwise be the case.

BRUCE CARTER
If I could just add to that a little bit, myelin is also important for axonal integrity. So, if you lose myelin due to a damage or a disease or something, the axons start to degenerate. So, there seems to be a protective and trophic aspect where the myelin seems to help the axons survive and be robust. The other thing that I think is fascinating is the differences in the way the central and peripheral myelin promotes regeneration, or inhibits it. So, in the central nervous system, myelin actually inhibits the regeneration of axons. That is one the reasons why, after a spinal cord injury, you can’t regenerate your axons. Among the other inhibitors, myelin actually blocks that. While on the periphery it actually helps it. So, after a peripheral nerve injury, your neurons will regenerate, the fibres will grow right back along the schwann cells. They each express unique proteins that regulate that.

SHANE HUNTINGTON
I’m Shane Huntington. And my guest today on Up Close are Prof Bruce Carter and Dr  Simon Murray. We’re talking about myelination and we are coming to you from The University of Melbourne, Australia. Bruce, specifically, what are the some of the things that can go wrong with the production and operation of myelin itself?

BRUCE CARTER
There is a wide range of things that can go wrong. If we start off by talking about the peripheral nervous system, there are a number of diseases that occur as a result of problems with peripheral myelination. Actually, the most common hereditary neuropathy is a disease called Charcot-Marie-Tooth disease. And this is a genetic disease. It is really more of a syndrome than a disease because there are multiple forms of it. So, it can range from somebody who develops the disease in their 40s and has a problem walking. They just walk a little funny. To, other people who have it from birth and are severely disabled and can’t walk at all. And, there are about 30 different genes that have been identified where there are mutations leading to Charcot-Marie-Tooth, but there are many patients still where we don’t know what the mutation is. There is another peripheral de-myelining condition called Guillain-Barré syndrome. And this is a strange autoimmune condition where different things like, let’s say you have a viral infection. For some reason it triggers the immune system to attack the peripheral myelin and this actually happened to a friend of mine from college and he had a flu and then within a couple of weeks he collapsed in the shower and was totally paralysed because he had lost pretty much all of his peripheral myelin. Both of these conditions the Guillain-Barré and the Charcot-Marie-Tooth are exclusively peripheral. So, it doesn’t affect your cognitive ability at all. Your brain works fine. Strange thing about the Guillain-Barré syndrome is it almost always completely recovers. So, this guy is almost totally fine now. The myelin reforms and there is no problems after that. On the central nervous system, there are again a variety of different conditions that the best example would by multiple sclerosis which you heard about in a previous podcast. And there are other leukodystrophies where you have de-myelination caused by a variety of things that could be virally induced or induced by a different series of problems that cause this de-myelination in the central nervous system.

SHANE HUNTINGTON
Bruce, what is happening in these cases? Is the myelin just not forming? Is it breaking down? What is going wrong?

BRUCE CARTER
Well, that depends on the specific situations. So, in Charcot-Marie-Tooth disease, sometimes the myelin will fail to form properly and it will kind of keep trying so you get these weird myelin structures where you get a little bit of myelin and then it tries to form more, and then it is messed up so the cell degenerates all the myelin. And, basically you get this ongoing condition where you have periods where the myelin will start to form and then it will degenerate and then the myelin will go away, of course that leaves to axonal problems or the neuron itself has problems as a result. In the situation, like Guillain-Barré or similarly with multiple sclerosis, there is an attack of existing myelin and the myelin is stripped away and then that causes problems. So, it just depends on the particular disease you are talking about.

SHANE HUNTINGTON
Bruce, I’d like to talk now about programmed cell-death, I assume as with other parts of the body this occurs in the nervous system.

BRUCE CARTER
Right, in fact during development you lose about half of the neurons that are generated and that is just a normal pruning process.

SHANE HUNTINGTON
What is actually prompting these neural cells to die?

BRUCE CARTER
Well, that is something we are actively studying now. There seems to be two different mechanisms going on. One is that all neurons and glial cells – almost every cell in the body really needs some kind of trophic support, so, the proteins that bind to the cell, the neuron and keep it alive. And, if you don’t get that trophic support then the neurons or other cell types will die. However, there is actually also an active form of cell-death where there are proteins on the surface of the cell, like, the neuron that when they are activated they will kill that neuron. And this also seems to be going on in development where, for example, one of the proteins we are studying is called p75 neurotrophin receptor. So, it binds to neurotrophins which include nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4. And while these factors can promote survival through a different group of receptors, they can bind a p75 and actually cause the neuron to die. And, so, really there is this balance between a survival support and an active cell-death mechanism.

SHANE HUNTINGTON
Simon, let me turn to you for a moment, what differences do we find in terms of the neurotrophins or other nerve growth factors between the central and the peripheral systems and what do those differences tell us, if they exist?

SIMON MURRAY
Perhaps surprisingly, there aren’t a lot of differences between these growth factors that are important in central nervous system and peripheral nervous system development and function. And in fact, in case of the neurotrophins which Bruce has been talking about, virtually all receptors for the neurotrophins can be found in both the central nervous system as well as the peripheral nervous system. And we are well aware of studies of mice in which particular neurotrophin genes or receptors for the neurotrophins have been deleted we can see problems with the development of both the peripheral nervous system and the central nervous system. And that is not to say it is all equal, in fact, I alluded to this heterogeneity of neurons within the central nervous system and the peripheral nervous system and what we find is that particular neurotrophins, nerve growth factor, for example, is really important for the development of one particular class of neurons brain-derived neurotrophic factor is important for the development of a distinct population of neurons within the central and peripheral nervous systems.

SHANE HUNTINGTON
Bruce, how do we go about determining what role a particular neurotrophin plays? Is this all Petri dish type work? Or, is it done, sort of, indirectly? How do you know which one is doing what?

BRUCE CARTER
One of the ways people have studied this is by doing a gene deletion. So, for example, if you want to know what BDNF does, you knock it out in a mouse and see what is wrong. The limitation there is, when you knock out something that is so fundamentally important, the animal dies. So, then, there are nifty tricks where you can do a conditional knockout where you knock it out in specific places or at specific times. And that requires a little bit more fancy genetic tricks. But that certainly is a major way of seeing in an animal what it is important for. But, you know, the experiments done in a dish are also very revealing. We can also kind of go in between an isolated neuron in a dish and a whole animal. There are many studies that take slices of the brain and they keep the neurons alive in a slice, at least for a short time, and they can electrically stimulate it or manipulate levels of genes in that slice and then look at responses.

SHANE HUNTINGTON
We are talking about an incredibly dynamic system here. Bruce, when we refer to neurotrophins, are they something that are static in the system? Or, are they themselves evolving like many of the other components?

BRUCE CARTER
Well, we talked earlier about worms, C. elegans, it is pretty clear that there is no neurotrophins in worms. And that is probably because of the simplicity of their nervous system and how small they are. Just because you don’t need to fine tune things quite as much as you do in higher organisms. The neurotrophins are actually very highly conserved though between a wide range of vertebrate species. In fact, we talked about hydra earlier, hydra actually, not a vertebrate, does have something that looks very similar to neurotrophin-3. So, neurotrophins have been a part of the nervous system from pretty early on mostly regulating survival and differentiation in the periphery and then as vertebrates evolved a higher order, nervous system – the central nervous system, the roles there have become more complex, not only regulating survival and differentiation but even regulating electrical signalling that is thought to be linked to learning and memory.  

SHANE HUNTINGTON
Bruce, are we at the point technologically now where we can control the production and use of neurotrophin in the human body?

BRUCE CARTER
Well, there is ongoing clinical trials right now where people have designed viral vectors that produce neurotrophins. So, in sort of an artificial way we can control neurotrophins. For example this would be in relation to Alzheimer’s disease. One of the ideas is that if we can increase the amount of nerve growth factor this might help specific neurons in the brain survive. But in terms of being able to regulate the endogenous neurotrophins, no, unfortunately we are not quite there yet in figuring out how to do that.

SHANE HUNTINGTON
Bruce, can you clarify what a viral vector is?

BRUCE CARTER
A viral vector is taking advantage of the fact that viruses can infect cells and stick in foreign genes. So, when I was talking about introducing nerve growth factor into the brain, one of the ideas is to use a virus which is modified of course to be safe and inject that into the brain cells so that it will infect neurons or other cell types and then put a gene into that cell, like for nerve growth factor, so that the cell will actually start producing nerve growth factor.

SIMON MURRAY
I just might add there, Shane, Bruce and I are actually engaged with the lab at the Department of Pharmacology here, the Drug Design Laboratory and what Tony Hughes does who is the head of the lab there, Tony undertakes computer molecular modelling of growth factors to identify important regions upon these growth factors which bind selectively to these receptors and he can model these and make small peptide mimetics of these particular regions. And this is something Bruce and I have recently been engaged with Tony in identifying. We’ve already alluded to a neurotrophin called brain-derived neurotrophic factor. And Tony has produced a number of mimetics for brain-derived neurotrophic factor and Bruce and I are using these in our work to see if we can more acutely define the nature of the interactions between BDNF and its receptors and exactly what role it is playing when BDNF activates p75 for example as opposed to its other cognate receptors that we have alluded to.

SHANE HUNTINGTON
Simon, what do you mean by mimetic?

SIMON MURRAY
A mimetic is a much smaller protein that is designed to replicate the function of a much larger protein. In essence what we go about doing is looking at the particular shape of a particular region of a large protein and in designing a much smaller protein we can actually replicate a particular shape, so it can activate a particular receptor and thereby mimic the function of this much larger protein. And what I mean by peptide, is actually a much smaller protein, ultimately if you break a protein down, you get into smaller peptides and ultimately if you break peptides down you get into amino acids which are the building blocks of all proteins.

SHANE HUNTINGTON
I’m Shane Huntington and my guests today are Prof Bruce Carter and Dr Simon Murray. We’re talking about myelination here on Up Close, coming to you from The University of Melbourne, Australia. Simon, let me ask you, technologically, over the last sort of decade what advances have occurred that have perhaps changed the way we go about this sort of work?

SIMON MURRAY
Well, the genetics has exerted a profound influence. The ability, as Bruce alluded to, to generate mice in which genes are deleted in specific neuronal cell types or in fact any cell type in the body has really proved to be critical and provided great insight to our understanding of how the nervous system functions, how myelination proceeds. These are the genetic tools that have allowed us to become more definitive and get much greater understanding of how these processes are ongoing.

SHANE HUNTINGTON
Some of these chemicals we are talking about, just how complex are they? Are they the sort of thing we hope one day to be able to replicate in the pharmacy lab or are they just, you know, too complex for us to reproduce?

SIMON MURRAY
They’re not too complex. And in fact through this computer-aided design, identification of residues within the molecules that are important for receptor activation, we are gaining a substantially greater understanding of the interactions between these molecules and their receptors. So, there is in a sense a great evolution in our understanding of how these are occurring. And this is perhaps best illustrated by some of the early clinical trials that have been undertaken. For example, in a disease called motor neuron disease and in some peripheral neuropathies, the neurotrophins have been injected into humans in order to promote neuronal survival or in an attempt to promote maintenance of myelination of neurons. Now, these clinical trials have been largely unsuccessful and this is I think in part due to the relative size of the molecule. If they’re  relatively large molecules they are quickly cleared through the kidneys and there is a complex interaction between different receptor types. And I think we are getting a much more refined view now of how we might go about selectively activating one class of receptors and not another class to really provide greater specificity in the action of what these potential drugs are doing.

SHANE HUNTINGTON
Bruce, let me just finish up with yourself, what do you see on the horizon for this sort of area of study within the next sort of ten years? What can we expect to see coming out?

BRUCE CARTER
Well, one of the fascinating things to me is, there is more evidence for the fact that in the brain, myelin is not static that even in fully mature adults, myelin can be formed and removed in ways that are controlled. So, for example, if you analyse myelin tracks in musicians, the more they have practiced, the thicker the myelin that you see. And there has been a number of studies now indicating that the pathways that are used a lot, you see more myelin formed. And that is fascinating because we talked about these electrical signals coming from the neuron, well of course they produce those signals in response to other neurons. So, if like five neurons are all signalling to one neuron, the speed of the signal coming in is really important because you want them all coming in together if you want to get a big result. But if you have them come in at different times you get a different kind of level of activity. So, if you myelinate something and change the speed at which it is coming it can have an effect on the output. And I think this is a fascinating area because we tend to think of myelin as a very static coating on these neurons but I think what is now beginning to evolve is this idea that actually it is a very plastic – it can change a lot. And I think we are going to see more and more of that as the research evolves and reveals some of this plasticity that is there not only in terms of the neurons forming new connections but in terms of the myelin wrapping around these neurons.

SIMON MURRAY
And of course, for every upside, which is what Bruce has been talking about, there is also a downside. And in mental health, if you look at the autopsy of major depression, bi-polar, one of the commonly observed features is changes in myelin so whether this – this is a bit of a chicken and egg sort of argument – but it is clear that myelin is significantly influencing how neurons function to a degree where it can be extremely beneficial in learning and it can have adverse effects and be at least formally integrated with sort of adverse mental health behaviours.

SHANE HUNTINGTON
Prof Bruce Carter from Vanderbilt University and Dr Simon Murray from The University of Melbourne, thank you very much for being our guests today on Up Close.

SIMON MURRAY
Thank you Shane.

BRUCE CARTER
My pleasure.

SHANE HUNTINGTON
For listeners who are interested in myelin and the role it plays in multiple sclerosis we refer you to episode 105 in which we covered this topic in detail. Relevant links, a full transcript and more info on this episode can be found at our website at upclose.unimelb.edu.au. Up Close is brought to you by Marketing and Communications of The University of Melbourne, Australia. This episode was recorded on the 26th October, 2010 and our producers were Kelvin Param and Eric van Bemmel. Audio engineering in Melbourne was by Gavin Nebauer and in Nashville by Brian Smokler. Background research by Christine Bailey. Up Close is created by Eric van Bemmel and Kelvin Param. I’m Shane Huntington. Until next time, goodbye.

VOICEOVER
You've been listening to Up Close.  For more information visit http://upclose.unimelb.edu.au.  Copyright 2010, the University of Melbourne.


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