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PROFESSOR: We had gone through these two systems, somatic and
limbic, and how they have separate pathways coming out
of the endbrain.
And I pointed out that the neocortex is involved in both
systems because of these major connections
that I'm showing here.
I've left out a lot of connections, and this region
here would be the thalamus.
I'm just showing it as a link between these structures.
One of the major problems with what I've said before is that
this striatum here, I just talk about dorsal striatum.
And I've just lumped the ventral striatum in with what
I call limbic structures here.
If we put the ventral striatum here, I would put it together
with the limbic structures, and then I show some of its
connections.
It makes it a lot more complicated,
which is why I don't.
I actually left this one out of the book chapter.
What you should know, though, are these connections.
What's the other connection of neocortex that
I've left out here?
We talk about its outputs.
There's actually a two-way connection here between
neocortex and thalamus.
But we won't get to neocortex in a very specific way until
we start talking about specific systems, and then
we'll have a special unit on it at the end.
But here's thalamus.
I'm only focused on the neocortical outputs, there.
OK.
Let's just review some of the things we've been
trying to go through.
You should know now the subdivisions of the CNS,
definitions of a few of the major cell types.
I've shown you the shapes of the neural tube, at least in
the embryonic brain at various levels.
And we talked about sensory channels of conduction, and we
defined the term "dermatome."
We talked about diaschisis.
That referred to effects of damage.
Leson-induced removal of inputs to cells can cause a
functional depression.
And unfortunately, it's been taught in neurology as sort of
this mysterious distance effect of the lesion.
Well, it's not mysterious at all.
Its due to connections.
And if you don't want to know the connections, then yes,
it's all going to seem mysterious.
But diaschesis is certainly not a mysterious phenomenon.
If you remove a major connection between the motor
cortex and spinal cord, of course you're going to affect
the spinal chord.
Change its function.
You can even lose spinal reflexes, at least
temporarily.
We talked a bit about evolution of the neocortex
with its major ascending and descending connections.
We just talked about that today, briefly.
We talked about spinal cord structure, showed differences
between the different levels.
What's the major difference as we go from cervical spinal
cord to the sacral spinal cord?
What's the difference in the white matter?
As you come down, it gets smaller and smaller, because
more and more axons are leaving, if
they're descending axons.
And then, as you go up the cord, more and more axons are
joining the cord, because different parts of the body
are contributing axons that go up to the brain.
What's another difference in levels in the spinal cord?
Two things.
Spinal enlargements due to the limbs.
You need a lot more neurons to enervate the limbs.
And then, the lateral horn's only present in thoracic and
upper lumber levels.
Those are the pre-ganglionic motor neurons of the
sympathetic.
And we reviewed the autonomic nervous system, its major
components.
Then we went hindbrain.
How it's closely related to the spinal cord.
I talked about how the basic plan becomes a bit distorted,
especially two factors.
Huge growth of certain components with functional
specializations, like for taste, because taste input
comes in with the hindbrain.
And then the enormous growth of the
cerebellum in some species.
OK.
Then we set a little more about cranial nerves,
especially the fifth, the trigeminal nerve enervating
it's just like dorsal root.
The inputs to the cord, we have the trigeminal input to
the hindbrain.
We got up to the midbrain and talked about the tectum, and
then the underlying reticular formation.
We just usually call it the tegmentum.
I mentioned the species differences,
mainly due to two things.
In humans, remember, the huge peduncles.
All the axons there coming from the cortex, and going to
the pons and the brainstem and spinal cord.
And what was the other difference?
Well, difference in size of the tectum.
Some species, the auditory tectum, the inferior
colliculus.
Dolphins and bats.
And then the very visual animals.
The very visual animals would include the fruit bats,
because they're fruit eating and they use vision a lot.
They have a large superior colliculus.
Then we got to the 'tween-- we just introduce the
diencephalon and the telencephalon,
'tweenbrain and endbrain.
And talked about the two major divisions, which have a
functional definition and a structural definition.
And then the endbrain.
Cerebral hemispheres, primarily, but then the basal
forebrain in the middle.
Just the forward extension of the hypothalamus
is the basal forebrain.
If we kept going, what would we come to?
You go from hypothalamus, the basal forebrain, then what's
in front of that, if we're not in the hemispheres?
There's only one more thing up there.
Olfactory bulbs.
Don't worry, I don't expect you to
automatically know all this.
But as you get used to it, it'll become obvious.
Then I talked about some major axonal pathways in the
mammals, these somatosensory pathways, spinal reticular and
trigeminal reticular.
Mostly ellipsoidal pathways.
Then the spinalthalamic.
The longest axons get to the ventral basal nucleus.
Dorsal columns to the medial meniscus,
which goes to the thalamus.
Same place, ventral basal nucleus.
And then the descending pathways that appear in
mammals, cortical spinal and corticopontine.
A little bit more about the forebrain
here relevant to evolution.
The term "neuromere" means a segment of the nervous system,
of the CNS.
We talked about the neuromeres of the hindbrain already.
They're called rhombomeres because they're in the
rhomencephalon.
There are seven or eight of them.
Separate segments.
And they have different gene expression patterns.
Well, there is some segmentation rostral to those
rhombomeres, too.
Usually in the midbrain, there's only, well, there's
one or three depending on how you define it.
Because there's the midbrain, the mesomere.
Then there's a segment right behind it that is often
defined as the isthmus, and then a segment in front of it,
the pretectal area, that's sometimes separately defined.
And then there's forebrain.
The prosomere, it's sometimes called.
They're the neuromeres of the forebrain.
And then I'm going to show you some pictures here, and then
we'll talk about origins of neocortex.
Here's a picture from the side of the embryonic neural tube
as the enlargements are occurring.
The hindbrain, the midbrain, and then all the rest of this
is the forebrain.
It's getting complicated because the budding out of the
hemispheres is beginning there.
And here, you see the segmentation.
They're just showing the segmentation of the
rhomencephalon.
This particular diagram shows seven, but then it shows the
isthmus there.
And then here's the midbrain.
And then here's the forebrain mesomeres.
The forebrain neuromeres, they're called prosomeres,
which is why they're called p.
Remember, prosencephalon, meaning forebrain, OK?
So prosomere comes from that.
And notice that when that was first done, they thought that
the whole endbrain here and hemispheres where extensions
of these more rostral segments of the
forebrain, p4, p5, and p6.
Later studies, it was actually pretty complicated trying to
figure that out, and I don't think there's complete
agreement even now.
But now, the feeling is that it's only this one segment
here, p5, that gives rise to most of the hypothalamus
that's in some way genetically, anyway, related
to the segments of the endbrain.
So there's segmentation there.
But the more interesting thing here is how we relate
different species.
Let's say a little bit about the forebrain of amphibians,
reptiles, and birds, and see how it relates to the
forebrain of the mammals.
We know that mammals have this neocortex, which seems to be
unique to mammals.
But we also know that some birds are pretty highly
evolved, so some reptiles are, too.
They even have considerable intelligence, some of them,
particularly the parrots, the crows and ravens.
These groups of animals.
But yet, when you look at the brain, they don't have a
cortex, a neocortex, the way mammals do.
So in mammals, we know that each sensory system connects
to thalamic cell groups.
And you can find the separate senses projecting to different
cell groups in the thalamus.
And we'll learn all that, if you don't know it
already, later on.
Now you just have to know the concept.
That's how sensory systems connect to cortex.
They don't go there directly.
The only sensory system that goes more directly without
going through some cortical regions is the olfactory, and
that goes to olfactory cortex, not neocortex.
The olfactory cortex, there's no argument that it's been
present long, long before there were mammals.
That's from very early chordates.
There are a few pathways to neocortex that do bypass the
thalamus, but they're not major, and some of them come
directly from the brain stem.
Most of it goes through thalamus.
But in birds, and also in reptiles and amphibians, there
is a thalamus, and it also contains these
unimodel cell groups.
There's one that gets visual input from the optic tectum.
There's another one that gets input from the auditory part
of the midbrain, and it represents an auditory
structure in the thalamus of these animals.
Well, the connections of these structures in birds begin to
be studied by this fellow, Carton.
I was actually in the lab when he was doing that, because I
was also with Walle Nauta, and Carton had come
to work with Nauta.
He found that it projected to parts that looked like
striatum, a part called the ectostriatum in the bird.
He was using mainly the pigeon.
It was later found in other birds, too.
And in the course of his studies, he wondered about
this structure, because he wasn't convinced that it was
really like the striatum of mammals.
And later, the genetic studies verified that, that it's not
really like the corpus striatum at all.
OK?
Now we know it grew out of the what we call the dorsal
ventricular ridge, and I'll show you
that again in a minute.
But he came up with a very novel proposal at that time.
He thought that maybe the cells in the dorsal
ventricular ridge stay in that position in the birds, but in
mammals they migrate.
They migrate away.
They migrate up into the cortex.
So maybe the cells of the visual cortex that are getting
visual input in the neocortex are actually embryologically
the same cells as in birds, but just end up
in a different place.
It's a very novel idea, and it's been tested now.
It's proved to be partially correct, but not quite in the
way Carton envisioned.
But I give him a lot of credit for the stimulus it provided.
It was a new way to think about developmental
mechanisms.
Now, here's a picture I showed you once before that has
allowed people to put together what must have been the
ancestral neural tube at the level the hemispheres,
dividing it into these three major components according to
gene expression data.
With the striatum, ventrally, shown in the green, there.
The structure that gives rise to the neocortex in mammals
and hyperstriatum in birds, and we just call the dorsal
cortex in reptiles and amphibians.
And then, this structure that's called the dorsal
ventricular ridge that's been found now in mammals to
correspond--
the main structure would be amygdala in the mammalian
brain, but there's also a part that you really should show it
going out in the deep layers of the cortex there, a
structure called the claustrum.
Now, here you see it, here.
Here's a mammal, and if you just follow the long processes
of radial glial cells that cells migrate along in the
mammal and the bird, you see that dorsal ventricular ridge
area, here.
Much larger in the bird.
In the mammal, you see it extending down there into what
became the temporal lobe later in development
in the larger mammals.
And then here's the gene expression data that verifies
this pattern of the glial cells.
All right.
So here was the Carton idea on the left.
Here's the dorsal ventricular ridge of a mammal.
And he knew that cells could move from there into the
striatum and into the olfactory
cortex, as he shows here.
And then he thought cells moved up and at least to layer
four of the cortex, the layer that gets major
input from the thalamus.
When the studies were done, they found that that's not
quite the way it happens, because it's not the dorsal
ventricular ridge, but these more ventral and medial parts
of this matrix layer, here, the ventricular layer, that
gives rise.
Especially this one, the medial ganglionic eminence.
And there, they find cells that not only become striatum,
but they migrate into all these cortical regions.
So it's a complication that in the development of the
mammalian brain that to this day is not fully understood,
because many of the cells of the cortical layers there
don't come from there.
They come from the ventricular layer of the cortex.
So the cortex seems to get these different contributions
from different parts of embryonic
layer of dividing cells.
All right.
I want to go back to the process of growth a little
more, and talk about the growth of axons.
And then their plasticity, including whether they can
regenerate or not.
We'll say a little bit about that on Friday.
Today, we'll talk about the axonal growth.
We've already talked about some of the major stages of
nervous system development.
We talked about proliferation, remember?
We talked about the different kinds of mitosis, the
symmetric and asymmetric mitosis.
That symmetric mitosis is when cells remain proliferative.
So one's cell becomes two stem cells, those two become four,
four become eight, and so forth.
And then the asymmetric division, when one of the
post-mitotic cells stops proliferating, stops dividing,
and migrates.
And then of course, most of those eventually stop.
They all become post-mitotic.
It's only in recent years that we know that there's some
cells, even in the adult brain, that
are still being generated.
In certain places, at least.
But then we talk about differentiation.
All of those migrating cells, when dividing cells and
migrating cells, they all look pretty much alike.
You can't really distinguish them.
But at some point, they start to differentiate.
They become different from other cells.
And it actually happens in its gene expression a little
earlier, but we start seeing it when we see the growth of
these various extensions, the axons, the dendrites.
Axons, dendrites, and of course, the dentritic spines.
And then later, we see some loss, even death of cells, and
we see other maturational changes and some plasticity in
many systems.
More of that's being worked on all the time, particularly
here at MIT.
All right.
What did Cajal see?
Cajal developed a pretty accurate picture of axon
growth without ever seeing it.
That is, he never saw live axons growing.
How was that first done?
How did people first see a growing axon?
AUDIENCE: Stains?
PROFESSOR: Sorry?
AUDIENCE: Stains?
[UNINTELLIGIBLE]
PROFESSOR: Can't see them.
I mean, Cajal had the stain.
He had the Golgi stain.
So if we ask how did he observe these dynamics that
he's showing here in the pictures, just by seeing a lot
of pictures, they were all still pictures, right?
He never saw a movement.
But he did see the little filopodia, there.
He doesn't show them as being as long as they really are.
You know, if we wanted to say it really looks more like
this, these processes can be much longer.
But they're transient.
They extend, and they pull back, and they extend, and
they pull back.
So whenever in his fixation process he lost many of them,
and he only saw a few of them, OK?
But he did come to a pretty accurate picture
of what it was like.
His imagination was very vivid, and he imagined fairly
accurately what was happening.
I asked you to read a little bit.
I put a reading from Purves and Licthman.
It's an older book, but still a very good book, because it
covers the classical studies before the present emphasis on
molecular mechanisms.
So a lot of the earlier descriptive studies in neural
development are in that book.
And it's useful for that, because if you don't know
what's happening, you don't know what you're trying to
explain when you study the molecules and cellular
mechanisms.
And he reviews the early experiments that show how a
new membrane is added.
If an axon's growing and growing and growing, it's not
getting thinner and thinner and thinner.
It's adding membrane.
So how was that happening?
Where is it happening?
How does a tree grow?
The tree's extending branches.
How is it adding new wood?
Where does it add?
Does it grow in the ground and get pushed up?
AUDIENCE: It grows out lengthwise?
PROFESSOR: It does that, too.
It gets thicker.
But how does it get higher?
It grows way out at the tip.
It keeps adding at the tip.
And that's what axons do.
They add membrane at the tip.
How does the membrane get there?
Axonal transport.
In what form?
Is it just the molecules go down to the tip, and then it
assembles the membrane?
Actually, not.
It assembles the membrane mostly in
the cell body region.
And they become these little vesicles, like little cells,
little membrane enclosed packets of
molecules and fluid.
And that gets transported.
It gets moved down the axon by an energy
using, active process.
And then, when the membrane gets to the tip, those
vesicles can fuse with the axon in the
growth-prone region.
I don't think it only happens there.
There's some evidence that it does happen along the way, and
I'll show you pictures of that.
We can make more sense of it when we see the pictures.
OK.
I asked a minute ago how people first
really saw living axons.
This was the guy that first saw the living axons.
What was the technique that he invented?
Tissue culture.
You can grow cells in tissue culture.
You can grow neurons and get them to extend axons in
culture, and see it happening.
We'll look at some in just a minute.
Speidel also had a method for looking at growing axons, but
he didn't use tissue culture.
He used animals that were transparent enough that with
the right kind of microscopy, he could see through their
body and see the growing axons, like
in the tadpole tail.
He could see the peripheral axons growing out in the
tadpole tale.
And that was important work, because he was looking at
real, whole animals, but he saw the same kinds of things
that Harrison was seeing in culture.
We always wonder when we use tissue culture whether we're
seeing phenomena that are valid for the whole animal.
That's why these different, multiple
methods are so important.
So we want to talk a little bit about that growth cone,
first named by Cajal "cone of growth" for its shape.
And those little extensions that are called the little
feet, filopodia.
The filamentous feet, filopodia.
The singular word is filopodium.
We know that those little processes are transient, and
you'll see them in a video clip.
They're extending and retracting.
They contain contractile proteins.
Now, if they contain contractile proteins, they
can't really pull the axon along unless they're adhering
to something.
Well, there can be selective adhesion at the tips of those
filopodia if the membrane there contains
cell adhesion molecules.
The first cell adhesion molecule to be widely studied
was [UNINTELLIGIBLE]
N-CAM.
This means neural cell adhesion molecule.
There's a number of different kinds of CAMs, and
this is one of them.
And then when the filopodium, if it adheres to something, if
the filopodium contracts, it can pull the growth cone in
that direction.
This is a picture done with a scanning EM, where the tissue
is fixed by freezing, usually.
Though there are other methods you can use.
And then it's fractured, and it will tend to fracture along
lines where there are membranes.
And you can see there some preservation of filopodia in
the body of the growth cone, where there's a thinner
membrane, there.
There's the trunk of the axon.
This is just an example of tissue culture where a
peripheral ganglion was put in the culture.
And depending on the culture medium, axons will extend out
of that clump of cells.
And there's one major difference between these two
cultures that made the axons grow so prolifically in the
bottom one, and that was the addition of
nerve growth factor.
[? Levi-Montalparita ?]
Levi-Montalcini, working with Victor Hamburger in Saint
Louis, was the discoverer of nerve growth factor, and it
led to a whole enterprise identifying growth factors and
working out some of their properties.
So I'm gong to go to the--
This'll be a large growth cone, and I would like to--
the light is--
I hope it's dark enough to see this.
Can you see the growth cone there?
Here's the trunk.
And here's the growth cone.
You see the filopodia extending out.
We'll play it again.
Can you make that out?
Do we have to make it darker?
We can pull down that shade if you want, and turn that light
off in the back.
Can you see it or not?
Yeah, OK.
Now here, there's an axon from the retina and one from a
dorsal root ganglion.
Not two axons that would normally encounter each other
in reality.
When they do encounter each other in tissue culture, it's
very interesting.
Here, they began to interact.
This one holds back and leaves some filopodia still attached.
The interesting thing is that the growth cone collapses, and
the whole axon pulls back.
It's a retraction reaction.
And how the probability that when it touches another axon
that it will retract or keep extending simply depends on
the membrane's properties.
And cells differ.
And it turns out that when retina and dorsal root
ganglion cells are put together, the retinal axons
will usually retract like that.
Now, here there's three of them.
There's one down here that's going to branch.
There's one here, and there's one up here.
There's the growth cone, there's the growth cone,
there's the growth cone.
There's a little bit of junk in the culture.
These two are going to meet right up here, and other
filopodia are starting to encounter each other.
And this one seems to have been stuck there, but it
starts forming collateral.
A little bit of it is going to the right, most of it's going
to the left.
And it looks like a third branch is starting.
It's like the axon is starting to arborize.
But look what's happened up here.
As soon as they encountered, this axon is showing a
retraction reaction.
What was the body of the growth cone has pulled way
back to here, now, when it was way up here when it
encountered the cell.
But just get an idea of the dynamics.
You'll see an incredible amount of movement.
Of course, you see the clock up there.
It's greatly speeded up.
Here's where they're touching.
Here's the collapse of the growth cone and the
retraction.
It's retracting in a couple of globs of--
there, they come together, and it keeps moving back.
And the dynamics of that retraction reaction have been
worked out.
And it differs a lot depending on the axon and what it's
encountered.
It's just how far it will pull back, and then it will
generally stop after a pause, and often change direction,
and then keep growing.
It's only one more here.
I just show an axon encountering--
this is a fibroblast, here.
So it gets stopped by the fibroblast.
And just look at it.
It looks like it's looking for a place to go.
It starts then moving down the side of the fibroblast.
You can imagine a cell looking for a compatible
place to form a contact.
It's been found that these axons here that look so evenly
spaced, staying separate from each other as they grow, what
the reason they grow in that pattern, rather than in some
other pattern, simply has to do with
that retraction reaction.
Because other cultures will extend out and
form bundles, vesicles.
Others look like this.
And it turns out that just by varying the parameters of that
retraction reaction, you can get these different patterns,
including this one.
And I've done that in computer simulations, so I was able to
verify that completely.
OK.
So this is a model of the growth cone.
It shows the trunk of the axon, and then what they call
the peripheral domain, here.
The growth cone.
Here where there's a thinner membrane, you can cal it often
the lamellipodia.
Lamellipodia, written there for you.
And then the filapodia, these little filaments that extend
out filled with the actin filaments,
or contractile proteins.
OK.
Now, that's all the time we have.
We'll come to the grasshopper leg, next time.