All right.
So let me move onto the last lecture in this module.
Not in the module.
In the last lecture in the nervous system
part of the systems module.
And I want to start by talking briefly
about learning and memory, very briefly
about learning and memory.
We talked last time about setting up synapses,
we talked about making connections between the wires,
and we talked about how changes in membrane potential
could either determine whether a synapse fired
or whether it did not.
However, there's more to it than that.
There is significant data that indicates that the more often
you use a synapse the strong that synapse will become.
What do I mean by stronger?
Well, I'm actually not sure what I mean by stronger,
except in a couple of cases that I'll tell you about.
So the term I want to, so synaptic connections, this
is going to be long.
Synaptic connections strengthen with use.
And the phenomenon I want to tell you about
is long-term potentiation or long-term depression.
And this is a phenomenon that was discovered
in neurons that were studied in isolation.
So it's very difficult, it's impossible to study neurons
within the brain of any complex animal, especially mammals.
And so what's done is to use so-called slice cultures.
Where you take a slice out of the brain,
a very thin slice that's just got a few layers of cells,
and you look and see what these neurons do
in some kind of plastic tissue culture dish with media.
And they actually do quite a bit.
The neurons fire and they make synapses.
And a lot has been learned with them,
with these kind of slice cultures.
So here's the deal.
If one has a cell, if you look at this picture
here, if one has a cell and one stimulates the synapse
you see that there is a response to the first stimulus.
And you're actually measuring change
in potential in the cell.
Let's not worry about how the experiment was
done because we're not going to get through the material
I want to cover today.
You can come see me in office hours and I'll explain to you.
What I want to point out is that after a first stimulus
there is a change in the potential of the responding
cell.
If you continue to give that stimulus,
you get a much stronger response later on.
So the strength of the response, the change
in membrane potential in a responding cell
increases with stimulation of that presynaptic cell,
of that synapse.
And that is what long-term potentiation is.
It increases the chances that the postsynaptic cell
will fire.
And it is believed that long-term potentiation has
got a profound role in memory and in learning.
So how does that actually work?
Well, it's not clear in most cases,
but this is an example from your book
that is the shining example of how learning and memory can
work at the molecular level.
And it has to do with glutamate.
You do not have this on today's handout.
It was on your last lecture's in-class handout.
But you can look up here and then
go back to your last lecture's handout
if you don't have it with you.
It has to do with glutamate.
So glutamate is the major excitatory neurotransmitter
in the central nervous system.
And glutamate activates two different ionotropic receptors.
One of them is called the AMPA or the non-NMDA receptor
and the other is called the NMDA receptor.
With low level of stimulation or with single stimulation
of a presynaptic neuron the AMPA receptors are activated.
And these are sodium channels, so these
are ionotropic channels.
And glutamate is released, binds to the AMPA ion channel,
changes its confirmation, and you get an influx of sodium,
and therefore get closer to threshold potential.
However, on the same synapse, like right next door
are these other receptors called the NMDA receptors.
And they are not used if the presynaptic cell is stimulated
at a low level or infrequently.
But if you keep stimulating that presynaptic cell,
eventually these NMDA receptors will open.
And they will open and they will allow
an influx of both calcium and sodium.
And what happens is that you get a much stronger change
in potential because you've got now two sets of receptors open.
And this postsynaptic cell is much more likely to fire
and is actually much more stable in the synapses
that it has made.
So this NMDA channel only open after repeated stimulation.
So that's an example of what repeated stimulation can
do to changing channels.
And there is some molecular data,
although it's really not complete,
as to why you switch this channel usage.
One thing, however, that's very interesting about long-term
potentiation, and indeed about learning and memory anyway,
is that you need --
-- protein synthesis for learning especially.
For classical learning, the kind of learning
that you do before a test, the kind of learning
that a mouse does to find its way through a maze
repeatedly requires protein synthesis.
And this is very interesting because what
I've been telling you about in this module is stuff that
happens in the neuron that is actually independent
of transcription or protein synthesis.
It involves changes in gene activity.
It can involve changes in gene regulation,
as I'll talk about in a moment, but it does not actually
require any transcription or protein synthesis per se.
Learning and memory of the classical kind
that we think about does.
And it's one of the reasons that you
need to get a few hours sleep before you take a test.
It's one of the reasons if you pull an all-nighter,
and there are many, you do not do that well the next day
because you need this round of protein synthesis
that does stuff that probably synthesizes new receptors that
allows the synaptic connections you've
made through your learning to be strengthened.
And that's still a mystery, really,
as to what the protein synthesis is required for.
But if you're interested, this work from [Ed Plezia?] that I
mentioned at the beginning of class has shed some really
fascinating light on it.
So come see me if you want to.
All right.
So I want to move on now to circuitry.
All right.
I'll show you this slide because it's up there.
This is a piece of data that I pulled down
that's kind of interesting.
This looks at the AMPA NMDA ratio,
receptor ratio with cocaine.
So in a control there are about the same number
of AMPA and NMDA receptors on a particular synapse.
It's very interesting in some studies with cocaine use,
you see the amount of the AMPA receptor.
That is the receptor that is the short-term receptor
increases relative to the NMDA ratio, an NMDA receptor level,
indicating that with cocaine you might not
be as good at learning as without cocaine.
It is not clear.
There are a lot of studies like this
and the interpretations of them are complicated,
but this is a solid piece of data
that you do change the ratio of the non-NMDA and the NMDA
receptors.
All right.
So let's move on.
So let's talk about circuitry.
We've talked about the wires, the passage of current
along the wires, we've talked about the connections
between the wires, and now I want
to talk about the circuits.
And I want to start by asking you a question.
In thinking about your brain and how much of your brain
you used in circuitry, how many of you
were taught that you use one-tenth of your brain?
Raise your hands.
I want to see what you've been taught at schools.
It's no reflection on your teachers.
It's OK.
Thank you.
It's a substantial portion.
I feel that it is my duty as your professor
to debunk that myth once and for all forever.
It's not true.
And you might want to actually email your high school teachers
and tell them it's not true.
OK.
And you perhaps even learned about the boy who
used, you know, one-fifth of his brain
and was an unbelievable genius.
There is, none of this, I was taught that as well,
and it is absolutely untrue.
And the data for it is very solid.
For example, any neurosurgeon who goes into your brain
knows that no matter what part of the brain
he or she goes through to remove your brain tumor
or do whatever it is, is going to damage
some aspect of your brain function.
Anyone who has any kind of stroke,
any kind of brain hemorrhage, any kind of leakage of blood
into the brain is going to have some kind of deficit.
It might be a small one or not.
But there is ample evidence that you use all your brain.
And, indeed, why would one go to the trouble of making a brain
that is so large if one was not using it?
So there we go.
Let me talk a little bit about circuitry.
To indicate the complexity of circuitry in your brain
let me point out what parts of your brain
it takes to put together language.
If you're looking at words, it takes this area right
at the back of your brain, the base of your brain.
Listening to words takes a different region.
Speaking words takes a different region.
Generating words take different regions.
And these are very, these are PET scans.
We can talk about what they are.
They measure the energy usage in your brain.
And these are very, very large parts of your brain.
OK?
These are millions, close to billions of neurons involved
in each part of working with language.
OK?
And you can go to your brain and you can actually,
people have mapped these quite finely.
So the circuitry in your brain is enormous,
and the effort to both set up and maintain the circuitry
is enormous.
Here is another interesting piece of information.
About 20% to 25% of all the energy that you use
is used by your brain, which is one of the reasons you probably
need to sleep.
It's not clear why we need to sleep.
But it is a tremendous, there takes a tremendous amount
of effort to get the wiring set up
and to keep the wiring set up and to keep
the circuitry running.
Here's another example of circuitry
that I'm going to come back to.
It's called a retinotopic map.
And I'm going to start talking about it by addressing
the question of how the circuitry
in your nervous system is set up in the first place.
And I'm going to use this as an example
throughout the rest of the class.
So when people realized way back when that there
were circuits set up in the nervous system,
the question was how did these circuits get set up?
How did neurons know which connections to make?
And there were two competing theories.
One I'm going to call the random/survival theory.
They've got lots of names in the literature,
but I call it the random/survival theory.
And the notion here was that neurons
grow all over the place, and if they make connections
that work, if they're productive connections,
those connections will be maintained,
the neurons will survive, and there you go.
You have your circuit.
The other theory is the guidance theory,
that there's actually something telling the neurons where
to go.
And I'll show you a piece of data
that suggested that this guidance
theory was really correct.
But today, in fact, both of these theories
seem to be correct when put together
in a way I'll try to build up for you.
So your eye, your eye and your visual system are very complex.
Your eye starts off sort of like a camera, but very rapidly
that analogy breaks down.
And light falls onto your retina and the photoreceptors
in your retina, and from your retina a series of axons
are bundled together to make the optic nerve, which
goes to your brain.
And, in fact, I should point out,
I'm not going to talk more about this,
but the image that your retina sees we know quite clearly,
a Nobel Prize was given for it, is not the image
that you see when you look at me or you look around the room.
It's a series of shadows and bright points and so on.
It's really not a direct camera image
as the camera does it for us.
But that is no matter now.
What is important is that some set of stimuli
go from your retina through the optic nerve back to your brain.
And they go to two places in your brain.
So here are some diagrams.
Let's look at the very left most one.
This isn't on your handout but look at it up here.
I've got an equivalent one later on.
So in your eye, from your eye the axons from the eye
are sent back, project back to a region in your brain
called the tectum.
It's got a lot of different names, lateral geniculate
nucleus or the thalamus or the tectum.
OK.
We'll call it the, I think I'm calling it
the tectum in this lecture.
Let me see.
Let me make sure I've got it correct.
Yeah, I'm going to call it the tectum.
OK?
So we'll talk about the tectum.
And from the tectum connect synapses are made,
another set of neurons go back to another region
of your brain called the visual cortex.
And it's the summation of all these different connections
that somehow allows you to interpret what you see and see
it.
It's extremely complicated.
What I want to concentrate on are the connections
between the retina and the tectum.
And what's interesting in ourselves
and any animals that see binocularly,
that can see 3-dimensionally, is that the reason you can see
in 3D is that some of the neurons that
come from your right eye go to the right side of the brain
and some of them go to the left side of the brain and vise
versa.
Some of the neurons on the left side of your brain
go to the left side, yeah, and some of them
go to the right side.
And so if you look in some, just look at the diagram
so you're with me.
If you look in some, you'll see that some of the neurons
go to the same side and some cross over
and go to the other side.
OK.
So you can look at this in a different way.
This very beautifully labeling experiment
where you can actually label neurons
in different parts of the retina,
and you can follow where they go.
The label is maintained in their axons.
And as the axons, well, I'll talk about in a moment.
As the axons send out their processes back into,
oh, I've called it the thalamus here, back into the thalamus
then you can see those same axons.
So let's look here.
This is the left eye and the right eye.
What?
The left eye and the right eye.
OK.
And let's look here at the images
that you're going to get here on the left side, the connections
you're going to get on the left side of your brain
that will give you binocular vision
in your right visual field.
Here are a set of neurons.
They're called the nasal neurons because they're
on the side of your retina that's next to your nose.
And these red neurons are going to send their axons back
into the left side of the brain.
Here they are.
And the same time the neurons from the left eye,
from the side of your eye nearest the outside called
the temporal, are going to send their axons back
to the left side or to a different side
of this thalamus or this tectum.
OK?
So what I want you to see is red can go to one side.
Excuse me.
The red here cross over when they
go to that side and the green cross over and go to that side.
So let me diagram this more clearly
so that we can actually discuss this
with the diagram in front of you.
This is number one on your handout.
OK?
So let's look at this and indicate it more clearly.
These N normally in setting up binocular vision,
this circle here is meant to be one eye,
and this back here is meant to be one side of the tectum.
Let me write on the board that in retinal tactile mapping
the tectum can also be called the thalamus.
All right.
So what's important here is that these N neurons go back
to this region of the tectum called the C.
OK?
And I see I have not wrote, I have not
indicated tectum here or retina.
I'll go back and do it.
But you should write here, the circle here is the retina
and this oval here is the tectum.
And then we will be together.
So these N neurons from the retina
send out axons that get to this C or caudal region
of the tectum.
And these T neurons or temporal neurons from the retina
send out axons that get to this R or rostral
region of the tectum.
So this is a long preamble to tell you two things.
Firstly, these connections are what you always
see in every animal with either binocular or monocular vision.
Now, the way this is set up is actually quite confusing.
And I want to, let's not worry about the details too much,
but let's look at, as I see it I realize it's quite confusing.
I took it from a very old paper, which
I thought would be of interest, but as I see it here
there's one point of confusion.
But what I want to point out is an experiment
that was done a long time ago by a guy called Roger Sperry which
addressed this question of whether axons were guided
in a particular way or whether or not
they randomly found their way.
And then by some kind of survival cue
the connections in the nervous system were set up.
So what Sperry did was to take this tectum
and he rotated it 180 degrees.
So the C is now 180 degrees reversed.
And if he did that he had to break the axons that connected
the normal retina and the tectum.
OK?
But what happened was that those axons grew back.
This was done in frogs and they grew back.
And there are two possible outcomes to this experiment.
The first is that these nasal, don't you love it?
Thank you so much.
OK.
The first is that these nasal neurons will grow back
to this R region, which they would not normally do,
but it's far away from them so maybe that's how they work.
The second is that these nasal neurons will grow back
to the C region, N to C in the same way
that they would in the normal case,
even though they're closer together.
And the outcome of the experiment was unequivocal
and it was fantastic and it was one
of the reasons he got a Nobel Prize, which
was that you always get these nasal neurons growing back
to the C region and these temporal neurons
growing back to the R region.
All right?
So this is a very long preamble for a very complex axon writing
system, but the bottom line here that I want you to have
is that these retinal neurons knew which part of the brain
they had to project back to.
And that was very strong evidence
that there was guidance of these neurons
to the correct region of the brain.
All right.
So let's move on to how this guidance takes place.
And I'm going to come back at the end
to talk about survival because that's also
an important part of this.
And the part of the cell that you need to know
is the growth cone.
Now, some lectures ago I gave you
a lecture about 3-dimensional structure.
And we talked in some detail about cell migration
and how cells move in a mechanistic sense.
What we're going to talk about now is very related to that,
but instead of talking about a whole cell moving
we're going to talk about just part of a cell moving.
We're going to talk about this growth cone.
So what is the growth cone?
The growth cone is the axon tip.
It has both sensory function because it's
got various receptors of the type we've talked about,
more in a moment, and it also has motor function
because it has all those actin-based microfilaments that
allow it to move in exactly the same way
that we saw the whole cell moving.
But you remember, of course, that axons are long
and they're far away from the cell body,
so we're just talking about the axon growing now.
This is number two on your handout,
and this is a diagram of the end of an axon in the growth cone.
The axon's structure, the length of the axon
is stabilized by microtubules.
And subsequent to the ending of where the microtubules are,
the cell sends out a series of processes
that are called filopodia or lamellipodia.
I've given you the singular here.
Filopodia are thin.
Lamellipodia are fatter.
It doesn't matter.
And it's in these filopodia and lamellipodia
that there are microfilaments that, you should know,
are comprised of actin polymers.
And I've shown you also receptors
on this growth cone that can bind
two molecules in the extracellular matrix
or can bind two molecules on another cell.
OK.
This is what a growth cone really looks like.
This is a time-lapse of minutes.
And you can see that this is a very dynamic structure.
The cell is sending out processes and retracting them,
sending them out and retracting them.
And the sense that one has when one watches axons sending out
their processes is that they really
are feeling around their environment
and trying to decide where they should go.
I want to remind you this is a diagram from one
of your previous lectures from Formation 4.
The processes by which the axon is moving and sending out
its processes are exactly the same
as the processes that change during mesenchymal cell
migration, but we're just talking about sending out
part of the membrane and not the whole cell moving.
All right.
So what is important in this process?
Well, what seems to be important are several things.
OK.
And one set of things that are important
are called short-range guidance cues.
Short-range refers to how far they can work.
Whether these are diffusible molecules or not.
And I'll talk about long-range ones in a moment.
The distinction between them is a little semantic.
But short-range guidance cues include
things in the extracellular matrix
and include things that are irrevocably stuck onto cells so
that you can really only get interactions directly
between two adjacent cells or between a cell
and something that it is directly just opposed to.
And I want to talk about two classes of cues.
Oh, and them I'm going to indicate later
on long-range guidance cues.
So let me first talk about cell adhesion molecules.
We've talked about the extracellular matrix a bunch.
Laminin, in particular, is a very important molecule
for guiding axons through their paths to where they are going.
This is a movie showing an axon.
This ought to be a movie showing an axon trying
to decide what substrate it wants to migrate on.
Here is an axon.
There it's sending out its growth cone.
And this axon has been put onto a dish that's
got two different kinds of coatings.
On the top half it's got laminin and on the bottom half
it's got polylysine.
And if you look at this you can see
that it's sending out processes that
are touching the polylysine, but as it
goes on it decides it's really not interested in interacting
with the polylysine and it's interested in interacting
with the laminin.
And that's where it lands up.
Other things that you should be aware of that
are important in axon guidance in terms of cell adhesion
are the molecules cadherins that we talked about previously.
Now, some of these are attractive.
In other words, axons will like to grow
on a particular substrate with particular cell adhesive,
with particular cell adhesive or cell interactions.
So attractive cues will promote axon outgrowth.
And one can counter this with repulsive cues
or repulsive signals which will inhibit axon outgrowth.
And this is going to be true both for the cell adhesion
molecules I'll talk to you about and for other molecules
later on.
So let's move onto diffusible molecules or the longer range
molecules.
OK.
And I want to give you, to illustrate
this, an example of a very beautiful axon guidance
phenomenon.
And so we're on number three on your handout.
And this is the example I want to discuss with you.
It has to do with two sets of neurons in the spinal cord
and the brain that are called commissural neurons
and trochlear neurons.
This diagram is a section, it's a cartoon
of a section through a spinal cord.
Spinal cord transverse section.
If you lay on the ground and someone cuts you in half,
that way that is a transverse section.
OK?
So here's the hole in the middle of the spinal cord,
this is the roof plate of the spinal cord nearest the skin,
and something called the floor plate
which is deepest in your body.
The commissural axons grow from this dorsal region
down towards the floor plate.
In contrast, these trochlear axons
that I've shown in blue here grow
from the floor plate away towards the roof plate.
And this data is shown very beautifully
by staining these cells with appropriate markers here.
And I apologize if you're red-green color blind.
I know this is an issue, but this
is how the stains are actually done.
These are the real colors of the stains.
So up here in the top of the spinal cord,
these red dots are the cell bodies of neurons.
And the green are the axons that are sending out
their processes.
And these are the commissural axons
and they are growing down, down, down towards the floor plate.
And actually eventually will cross
to the other side of the embryo.
So how do these axons know where to go?
Well, one model, one model suggests
that these axons are being told where
to go by this little region at the bottom called the floor
plate.
And this was tested in the following way.
One can go into a developing spinal cord,
and one can cut out different pieces of it.
So you can cut out a piece of the dorsal spinal cord
and you can stick it close to a piece of the floor plate
or you can stick it close to a piece of the roof plate.
And then you can look and see what happens.
And what happens with time is that neurons
will develop in these pieces of dorsal spinal cord.
In the case of a set of tissues that's
got the dorsal spinal cord and the floor plate,
you can see very clearly that axons will grow out
towards the floor plate.
However, when you have the roof plate there,
the axons do not grow out from the spinal cord.
There's no outgrowth.
And this type of experiment indicated that the floor plate
was attracting these commissural axons to it,
and they were growing out because of this attraction.
And here's what a real experiment looks like.
Here's a piece of dorsal spinal cord,
here's a piece of floor plate, and here in the control
experiment there was dorsal spinal cord.
And this is just a chunk of tissue culture
cells instead of the roof plate.
And what you see here are these streaks coming out
from the dorsal spinal cord explants towards the floor
plate.
And these streaks are the axons growing out.
So this is actually a very robust assay.
And so using this assay, some years
ago Marc Tessier-Lavigne's lab tried
to find what the floor plate was secreting
to attract these commissural axons.
And it was a long, hard road that involved dissecting 35,
000 chick brains in order to do biochemistry to get
the proteins that were doing this attraction of these
commissural axons.
But they got something in the end.
And what they got is a protein called netrin-1.
Panel B is a section through the spinal cord,
and you cannot see it very well, except for this black glob
at the bottom.
But what this is the floor plate.
And it's been stained for netrin-1 RNA.
And you can see this netrin-1 RNA is only
in the floor plate region.
And if you look at the protein, it's
also in the floor plate region.
Although, it diffuses a little bit out of that region.
Is netrin-1 really important for making
these axons grow in the right place?
Well, yes.
Because if you take a mouse and knock out,
you genetically mutate the netrin-1 gene,
the commissural axons don't grow properly.
So here's a wild type mouse spinal cord, here
are these axons growing down to the floor plate,
and here is a mutant mouse that's lacking netrin-1.
And these commissural axons grow but they never
get to the floor plate.
They don't really know where to go.
Now, if you look back at handout three --
-- there was something else about this floor plate region
in that these trochlear axons were growing away from
the floor plate.
And so one could construct the ultimate hypothesis
that the floor plate was actually
repelling these trochlear axons from growing towards it.
And it turns out that is exactly what's happened,
and netrin-1 can act both as a chemo attractant
and a chemo repellant.
And it does so, and this is number five on your handouts.
It does so by using two different receptors,
one of which makes it attractive to neurons and the other which
makes it repulsive.
So here's netrin indicated as a diffusible molecule.
It binds to a receptor called DCC which was initially
implicated in colon cancer called deleted in colon cancer.
It's not clear if it really is still involved in cancer
or not.
But here's netrin binding to its receptor.
And subsequent there are a bunch of signal transduction
that happens that changes whether or not
these axons move to the floor plate
and whether or not they, in fact, grow out at all.
In the case of repulsion, it turns out
that there's another receptor called unc-5.
And that makes a connection with the DCC receptor.
There's an interaction between the unc-5 and the DCC receptor.
Netrin still binds to the DCC receptor,
but the net result of this is a different signal transduction
pathway activated such that you now
get repulsion of these neurons by activation
of this duet of receptors.
So for this diffusible process, I've
given you the example of netrin that
can act both as an attractant and a repellant.
And many, I have no idea how to spell repellant.
Repellant, I think it's got an E.
OK.
Repellant.
And there are now several receptors known
that are able to be, there are several guidance cues known
that can either be attractants or repellants.
What happens when a growth cone sees a repulsive signal?
This movie will show you.
That is the growth cone collapsing.
Let me show it to you again.
So you start off with a pretty robust growth cone,
and it collapses when you put a little drop of some guidance
cue that it doesn't like up in this corner of the slide.
And what happens is that that actin cytoskeleton that
is there just collapses, depolymerizes, and that axon
tries to get as far away from the repulsive cue as it can.
So we've talked about short-range and long-range
guidance cues.
We've talked about attractive and repulsive guidance cues.
We've talked about how one single guidance
cue can be both an attractant and a repellant.
And now I want to get back to this very old hypothesis
that the way that you actually got
synaptic connections and the way you've got circuitry set up
was by some kind of random way that involved survival
of neurons that made the appropriate connections.
In fact, that is true once you get neurons
to where they're finally going.
So you're setting up neurons, they're
going along their path set up by some guidance cues.
And of course you should be asking the question, well,
how do the guidance cues get there in the first place,
right?
OK?
So that's a question you can go and sit and think about.
But in the end what happens is that you stabilize connections.
And you do it in two ways.
Both of which, or one of which seems to be activity dependent,
or another of which is activity independent.
By activity dependent, I mean that the nerve has to fire.
There has to be synaptic activity.
And that will maintain the connection.
If there is not synaptic activity you will not.
And there are some cases where that is not the case.
This is number six on your handout.
When neurons grow out to the neuromuscular junction
they form a synapse, or when the neurons grow out to the muscle
they form a synapse with the muscle.
The synapse is initially a rather weak one,
and over time there are proteins that are activated.
Acetylcholine receptors, for example,
that are activated that set up the synapse
and stabilize it and maintain it.
So that is one example of stabilizing connections.
Another very famous example is growth factors
that are survival signals.
One of the most famous is NGF which
stands for nerve growth factor.
And this is a protein that is involved
in making certain sets of neurons
survive when they get to their targets.
There seems to be a limiting amount of nerve growth factor
around in specific regions of the animal,
and only those neurons that can capture enough of that nerve
growth factor on their receptors will survive.
So there are neuronal survival signals that may or may not
require a neuronal activity for their effect.
OK.
So two final things.
One is this retinotectal map.
We talked about the outcome of the Sperry experiments
and how you got the neurons going back to where they are.
What's the molecular basis for that?
Well, you can show very beautifully
that the neurons prefer to grow on a particular part
of membrane that you give them.
So, for example, the retinal neurons
will choose to grow on the anterior rostral and not
on the more posterior caudal neurons.
And you can show that the reason for that
is due to a class of molecules called the ephrins.
Ephrins are secreted molecules, but they are short range.
They work just on the cell next door.
And you can show, I'm flashing this up,
I know you can go and look at it later on,
that wherever there is ephrin you
do not see axonal outgrowth.
So ephrins are inhibitory to axonal outgrowth.
And I'm going to refer you to, I'm not going to go through it.
I'm going to refer you to number eight on your handout.
I'm not going to go through this.
You can look at it.
But I will just tell you that there
are different combinations of ephrins and Eph receptors
which guide retinal axons to the correct part of the tectum.
The last thing that I want to spend the last minute on
is a particularly fascinating point.
And that is the question of nerve regeneration,
and nerve regeneration in the central nervous system.
So we believe right now that the same, in fact, we
know that the cues that tell axons
where to go in the first place in an embryo
are maintained in the adult nervous system.
And we also know that if you cut one of the nerves
in your peripheral nervous system in your arm
it will grow back fine.
But we also know if you sever your spinal cord
it will not grow back.
And there has been intense research
to try to figure out what it is that is making
the axons in your spinal cord not grow back to where they
were, although, in fact they should.
Here's a diagram of an intact CNS axon.
If it's severed of course you're going
to get a fragment that's not connected to a cell body,
but the other part of it is still
connected to the cell body.
And what happens is that that dies, that cell dies.
It undergoes apoptosis and dies.
And it's really not clear why it doesn't regenerate.
One hypothesis is that there it is a poor growth environment
in the extracellular matrix around the axon in the CNS.
Another class of proteins of great interest
are the Nogos and related ligands
which are believed to be inhibitory to axon regrowth.
And there's a lot of interest in this kind of thing.
And I'll stop there.
Thanks.