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PROFESSOR: So I want to talk a little bit about--
finish up talking about neocortex.
It's hardly a finish.
I mean, there's so much to talk about when
you deal with neocortex.
But I want to try to make just some--
what I think are the most important issues for the class
about development and plasticity, and some of the
special adaptations of the cortex.
I want to focus here on the period of proliferation and
migration of cells.
Earlier, we talked about the earlier period of
neurulation--
formation of the neural tube.
And we've also talked about growth of axons and a little
bit about differentiation of cells.
So these are some pictures of the neocortex of the rat.
The only difference in a large primate like our own species
would be that the cortex gets a lot thicker.
And we'll deal with that in a minute.
So here at the beginning, you'll see the embryonic day
for the rat there-- embryonic to eight and a half.
That's eight and a half days after conception.
AUDIENCE: Do you know when a rat's born?
PROFESSOR: It's either 21 or 23 days.
I'm not sure, since I work with hamsters.
AUDIENCE: [? Is it ?]
23?
PROFESSOR: 23 days.
I think the mouse 21.
And the hamster's born on the 16th day after conception.
And the opossum?
Does anybody know that?
13 days.
But, of course, the opossum's sort of a born embryo and
can't live without attaching to the nipple in the pouch and
living there--
similarly, of course, for other marsupials.
So here we are.
Here's the ventricular zone and an area of mitosis
occurring at the [? two ?]
[? in ?]
[? prop ?]
[? forward ?] migration of the nuclei.
And then cells, when they become postmitotic, then
migrate up into this region.
At that stage, this is called the preplate.
Because by embryonic day 12, you have a layer of cells that
have migrated up to this layer below a zonal
layer of very few cells.
We call that the cortical plate.
The subplate region still has a few cells in it.
Because the subplate region and an intermediate zone,
which gets thicker and thicker, that's where you find
the fibers of--
where many of the growing axons are growing.
And you still have here a ventricular zone.
And there's also forming in the cortex-- and this doesn't
happen everywhere.
There's a layer like it in the cerebellum, a layer called the
subventricular layer.
And what that is is it's a layer of dividing cells, where
the cells don't round up and undergo mitosis right against
the ventricle.
There's so much neurogenesis going on in the cortex and
cerebellum of large animals.
That extra layer of mitosis--
mitotic cells-- is necessary.
And here's a picture of the adult with the six cortical
layers, below which is the [UNINTELLIGIBLE PHRASE].
OK, so here, the ventricular zone and subventricular zones
are layered.
But in addition, they're showing these cells in blue,
that aren't neurons.
They're glial cells.
They're called radial glia.
And they form a scaffold for migrating neurons.
In the earlier period, the neuron extended its processes
all the way between the ventricular layer and the
[? PO ?] layer.
And that's the way it is in many-- in most of the brain
stem and spinal cord.
But in the cortex, this becomes--
that would require a lot of growth of membrane that
wouldn't be very efficient.
So what the cells do, is when they become postmitotic, they
attach themselves to one of these radial cells and migrate
up into the cortex.
[UNINTELLIGIBLE]
in the cartoon here shows that.
And we talked about two kinds of mitoses earlier.
It's particularly important to understand that--
understand about cortical evolution.
Here's the cell in its mitotic cycle synthesizing DNA here--
moving to the ventricle, rounding
up, and then dividing.
And the division can happen in a symmetric
way, as you see here.
And this is called asymmetric division,
where the cell splits.
The part of it that's furthest from the ventricle becomes
postmitotic.
The cell that originates in the part-- the half-- the cell
furthest from the ventricle.
Now why is that?
Here it just summarizes what they are-- symmetric and
asymmetric.
So I'm asking what causes the differences in
fates of the cells.
And what are the consequences of that for neocortex?
It's apparently due to the distribution of these two
proteins, particularly, the protein Numb.
[? Notch1 ?]
is also asymmetrically distributed.
And that's shown in the cartoons down here, where you
see the Numb protein nearest the ventricle.
So as long as the cell divides symmetrically, you get equal
amounts of those two proteins in both cells--
both daughter cells.
But when the cell splits asymmetrically, as you see
here and here--
and you get different amounts of those proteins.
And without much Numb protein, the cell becomes postmitotic
and begins to migrate.
OK.
Now remember, when the cell is undergoing--
in the period of symmetric cell division, every time the
cells divides, you're getting twice as many cells at the
ventricle and near the ventricle.
So what's happening?
Is it, more and more cells are proliferating the area of
cortex is increasing?
So the longer that period it was just
symmetric cell division--
no asymmetric division--
the larger the cortex will be.
So Pasko Rakic summarized the consequences here back in a
Trends in Neurosciences article in 1995, where he
compared the rhesus monkey and the human in the period of
symmetric cell division.
And here you'll see them beginning
almost at the same time.
Blow that up so you can read it.
[? E-40 ?]
in the monkey.
[? E-43 ?]
in the human about six weeks after conception.
But look at when it ends.
It's done by [? E-100 ?]
in the rhesus.
The equivalent age for human is about [? E-120. ?]
AUDIENCE: 17 weeks.
PROFESSOR: And it's that additional period of cell
proliferation that results in the human cortex
being so much larger.
So the longer it undergoes--
here's cells that form a migrating column along the
radial glial cell.
And they pile up up here.
OK?
Well, Rakic and others worked out other
properties of that migration.
But first, let's look at something we
looked briefly at before.
How much actual increase is going on?
And this was an interesting study by Finlay and
Darlington in '95.
They took data from the German stuff [UNINTELLIGIBLE PHRASE]
who had simply calculated the volume of different brain
structures, which are listed here.
You can see what they are here.
So here's neocortex.
They've plotted it against--
this is a logarithmic plot-- against the total brain size
in cubic millimeters.
And then they plotted the structure--
the size of an individual structure.
So you can see is as the brain gets bigger, the neocortex is
getting bigger, as you would expect.
But you notice that that's--
the slope here is greater than say for the medulla oblongata,
which is down here, or the older parts of cortex--
paleocortex.
Here's the midbrain, the septum, the hippocampus,
Schizocortex is just a name used for the entorhinal cortex
and cortex in that region between entorhinal and
hippocampal formation.
There's the cerebellum, [UNINTELLIGIBLE]
brain, corpus striatum, and neocortex.
This is basically--
and then they show it for these different animal groups.
All the simians are in the orange color, the prosimians
in green, insectivores, and bats.
And you'll notice that they all fit pretty
neatly along one line.
There are just slight differences.
And if you look at the actual values, rather than--
Here they still plotted the total brain
size on a log scale.
And here they have a linear scale--
the actual size.
And you'll see how much greater the neocortex is
increasing size.
Cerebellum next.
And basal [UNINTELLIGIBLE]
medulla, the least on that particular plot.
And they did a mathematical analysis of how much variation
across all these species there was for these different
structures.
And you'll notice here they've got the amount of variance
explained for one group of structures here and another
group of structures here.
This is what these mean.
Their blue bars was one factor.
The orange bars were another factor.
The first factor counted for over 96% of the total variants
for these 11 structures.
And it was most correlated with neocortex and the least
with olfactory bulb.
Whereas the orange bars was least
correlated with the neocortex.
It was correlated most with the olfactory bulb and limbic
system structures.
Here's the olfactory bulb up here.
Here's the neocortex down here.
So that's the way the factor analysis can be used to find
out the amount of--
what did [? Streeter ?] call that?
He called it concerted evolution.
How much concerted evolution there is in neocortex,
cerebellum, and these other structures, compared to the
olfactory system and limbic system structures.
You can see that there's a lot more specialization in the
olfactory system than there is in the cortex.
OK.
Let's go back to migration.
Now, before we talked about three
different kinds of migration.
Nuclear translocation, where we just get the nucleus moving
along in the elongated cell.
The cells attach to the ventricular layer and to the
[UNINTELLIGIBLE] surface.
And then with greater distances, the cells are
moving along radial glial cells.
But you also get tangential migration, where the whole
cell will move along a particularly adhesive pathway.
Now, in the neocortex, a major type of migration as I've just
noted, is along radial glial cells.
But you also have tangential migration that we know much
less about.
Some of you may remember, when we were talking about
development a long time ago, I mentioned that there were
neurons coming from the area they became
striata in the adult.
But they move from that area up into the neocortex.
It was a kind of movement initially predicted by a
comparative anatomist, who, when he first proposed it, was
working at MIT--
Harvey [? Karten. ?]
And it turns out that many of the
interneurons of the cortex--
the small interneurons--
originate that way.
We know that, but we don't know a whole lot more about
how that happens.
Rakic has certainly emphasized [UNINTELLIGIBLE] migration
from ventricular layer, as he summarizes here.
And you see he's emphasized the--
You see the relative thickness?
So the great length of these radial cells--
There's the cortical plate up there.
This is all the area that will become white matter.
In fact, there are a lot of axons already forming there
during the developmental period.
And to prove his point, he'd actually used the electron
microscope to reconstruct these cells and follow over
many, many sections with the electron microscope--
[? all ?] the ultrathin sections--
to verify that in fact the neuron was adhering to a
radial cell.
And I didn't bring the pictures, but it took many
years before people were able to actually just see that in
slice cultures.
But they have been able to do that now, just to verify that
that's really happening.
OK.
But before they knew that--
this is actually an earlier finding using tritiated
thymidine, out of radiography.
Remember what that is?
So you inject--
this was done for monkeys here at Harvard when Rakic was
still working at Harvard.
He moved to Yale after that and is still at Yale.
So it shows the age at which the thymidine--
a thymidine pulse was injected into the fetus.
And here's the embryonic day.
Here they injected [? E-60, ?]
for example.
In the adult, they found the labeled cells in
layers five and six.
Whereas, if they waited here until [? E-90 ?], 30 days
later, see where the cells end up?
Now they're all up in layers two and three.
So the deepest layer-- and this was known earlier for the
mouse and rat.
The earliest cells to be born are in the deepest layers.
The latest cells to be born are in the
more superficial layers.
The only thing this doesn't show is-- and I'm not even
sure of the answer--
exactly when those cells that become interneurons are born.
And they don't come from the ventricular layer at all.
So we call that an inside-out pattern of migration.
Because this is on the inside closest to the ventricle.
That's where the cells go first.
But then the later migrating cells migrate past the earlier
ones and end up on top of the pile in the cortical plate
before they begin
differentiating into adult neurons.
So the next question is how does a cortex get specified?
Why does one cortex become visual cortex and get the
projections of the geniculate body?
Why does another area of cortex get the lateral nucleus
projections, another get the auditory projections from the
medial connective body, and so forth.
It might just be that the cortex is uniform--
just becomes bigger and bigger--
and that the pattern is determined by the axon--
the organization of axons.
And in fact, if you look for that order, it's been worked
out pretty well and they are organized.
They follow a pattern when they're growing
from thalamus to cortex.
They [? maintain ?]
some order based on their thalamic origins.
I showed a picture of how that's done for the midbrain.
The midbrain projects into the thalamus.
There's an order of the axons before they ever come in.
And that order sort of recreates the pattern in the
midbrain, in the termination of the axons in the thalamus.
So that could be happening.
Or it could be that in fact, that doesn't make the largest
difference.
That these different cortical areas
are genetically different.
Or it could be some combination.
And these two hypotheses got dubbed protomap and
protocortex hypothesis.
And nobody can ever remember which is which.
But think of them as--
Rakic was the one championing the protomap hypothesis.
He said there was a protomap at the ventricular surface.
And the different areas of the ventricle
were genetically different.
And so the map was laid down very early in
the ventricular zone.
So at some early age, they became differentiated, before
you could actually see differences in the
differentiation of the different cortical areas
before the axons ever terminated there.
Other people emphasize what we call the epigenetic factors.
They didn't truly become one type of cortex or another type
of cortex until their connection's formed.
AUDIENCE: [INAUDIBLE]
PROFESSOR: What?
AUDIENCE: [INAUDIBLE]
PROFESSOR: There's actual data supporting both.
And for example, the Rakic type of genetic influence was
first supported by the discovery of a LAMP, the
limbic associated membrane protein, specific for limbic
cortical areas.
And if you take a piece of limbic cortex and transplant
it in the embryo into somatosensory area, it will
become limbic cortex.
It won't become somatosensory cortex.
But it depends on when you do it.
See, if you do it before embryonic day twelve, it'll
just become somatosensory cortex.
It hasn't been determined yet.
But once it's determined, it becomes genetically different.
It produces LAMP, that protein.
And now you can't change it.
And I've given you a website here of a later article
published just in 2006.
And there might be--
I'm sure there's more since that time.
I hear about them every year here and talk to people who
are mentioning others where they're finding other genetic
differences.
But there is support from the epigenetic factors as well.
So for example, they've used two areas of cortex that look
really different, even in [UNINTELLIGIBLE].
The striate cortex--
the visual cortex--
of a rodent and the face area where the barrel fields form,
where there's different clusters of
cells for each whisker--
in the rat or the mouse--
and if you take visual cortex and--
or let's say you switch a piece of visual cortex and a
piece of the face area of the somatosensory cortex--
you switch them around in the embryo.
And if you're a good surgeon, you do that right.
You can get the cortex to live in the new place.
And they found that in fact, what used to be visual cortex
will become somatosensory and vice versa.
But in fact, the formation of the barrels does depend on the
[UNINTELLIGIBLE]
coming in.
Now, those experiments were done by O'Leary and others.
And in fact, there is also some dependence on age.
But in fact, the differentiation happens only
after the connections are formed.
As long as you do that before the connections are formed,
you get them to change.
So we have to conclude that both factors influence
cortical development.
Some cortical areas perhaps are genetically a lot more
similar to each other and do depend more on the
connections.
Now what about--
not connections, not genes, but activity--
physiological activity--
the later effects on the development of cortical
connections?
This has been of particular interest in people in this
department studying synaptic activity in the construction
cortical circuits and a number of activity-dependent
molecular mechanisms that influence cortical wiring.
And also, rewiring has been studied that is, altering
connections in development and in the adult.
And I just want to just mention a few key things.
The visual system's a good model for this because the eye
sits out there.
You can control the input to the eye.
You can deprive the animal of visual input.
And also, the structures getting the input, like visual
cortex, optic tectum, are fairly accessible to the
experimenter.
Now we know that the projections of visual system
in a lot of species become highly organized before birth.
So in other words, sensory experience, after the animal
is born, can't be playing a major role in exactly how
those connections are forming and their initial
organization, anyway.
So then the question is, does it still play some role,
perhaps in later development?
What happens to experience?
Is there activity in sensory pathways before there is
sensory input?
That's a question that wasn't even asked
in the initial work.
But Carla Shatz, when she was at Berkeley--
she's now at Harvard--
did some interesting studies on the embryonic retina.
And she was able to show that there are waves of activity
going across the retina.
She shows here, activated cells moving across.
This is time in seconds.
So in just three and a half seconds, you have this wave of
activity moving from one edge of the retina to the other.
Well, that organized activity could play an important role
in how connections form.
How could you test that?
Well, you could get rid of the activity by using a blocker of
action potentials.
And things like that have been done.
And they found that in fact, projections--
how precise they are, at least-- is
affected by that activity.
But you still get organized projections without it.
And we know from other studies-- and I
mentioned some of them.
We talked about visual system.
That there are genetically determined protein--
gradients of proteins--
in both retina and tectum--
also in other structures--
the visual system-- that affect that topography.
But in fact, normal activity does play a role.
A lot of the studies have focused on binocular
responsiveness of neocortical neurons.
I'll say a little bit about that.
We talk about ocular dominance of a cell-- how much it
responds to the right eye or the left eye.
And we talk about columns representing the right
eye and left eye.
We saw a picture of that earlier.
These are the way it's pictured in some of the
physiological studies.
Here's a normal adult.
You see, cells in the cortex are--
most of them here.
A larger number of them are responding to both eyes.
But in fact, there's some cells that respond only to one
eye or the other eye.
And there's some distribution of cells.
It's similar in the neonate.
But if you deprive the animal--
put a patch over one eye so [UNINTELLIGIBLE PHRASE]
deprivation--
then most of the cells are, in fact,
responding to the open eye.
A few cells are responding to the deprived eye.
And almost none are getting input from both eyes.
Here's what happens if you block action potentials
[UNINTELLIGIBLE PHRASE]
Most all of them are now responding to both eyes.
Of course, they have to remove the [UNINTELLIGIBLE] toxin.
Now to do that study.
Here's what happens if you--
this proves that it's organized activity that causes
that result.
Because if you produce strabismus, which means you
make the eyes move not in a coordinated way.
In strabismus, the two eyes look at different things.
Look what happens.
Most of the cells now are responding either to one eye
or the other, but not both.
OK, this is just what happens when you intershare with
inhibitory connections in the cortex.
AUDIENCE: How can you induce the strabismus?
PROFESSOR: They cut eye muscles.
Just like a person-- if he's born with strabismus, they can
straighten the eye by actually cutting and
reattaching eye muscles.
If they do it real early, they can actually
affect binocular vision.
But it's difficult to do that surgery very early, so it's
usually a cosmetic thing, just to get the eyes
straightened out.
All right.
Well, this--
the change in connections have been found.
We know--
look at that now.
But it depends on the experience
in a critical period.
Once you get beyond a certain age, the changes happen very,
very slowly or not at all.
There's been some debate about that-- just how much can occur
after the critical period.
But it happens very readily here in the critical period.
There's evidence that, in fact, the two eyes--
the activity of neurons that represent one eye or the other
because they're coming from different layers in the
geniculate body--
compete with each other in the cortex.
So let's look at that evidence briefly.
This is just a summary of it here.
So at the top, I'm just going to look at the mammal here.
The other one is the frog.
You could look at that and study the tectum.
Here, you see, they just show a two-layer geniculate body.
Of course, there's more, but they just want to show that
the two eyes terminate in different layers in the
geniculate body and then the axons go up to the cortex.
Well, early in development when they go up to the cortex,
cells representing one eye, cells
representing the other eye--
getting their input from different eyes--
just overlap with each other as you see there.
If you block activity, they continue to overlap, OK?
As long as you're blocking the activity.
In the normal adult, though, they separate.
And you end up with these ocular dominance columns.
The cells here are getting termination from one layer of
the geniculate--
one eye.
Cells in the adjacent layer, column are getting input from
the other eye.
If you block one eye, the eye going to this layer, the
column becomes much smaller.
And we can see some of the experiments that were done by
a former student here at MIT-- one of Peter Shor's students,
Michael Stryker, who's been at-- many years now--
UCSF.
He's reconstructed--
and actually, three-dimensional
reconstructions--
axons from the geniculate body coming up into--
terminating in layer four of the cortex.
And at the top, you see a 17 [UNINTELLIGIBLE] axon and a 17
[UNINTELLIGIBLE] kitten--
very broad--
huge arbors.
And if you look later, those axons are terminating only in
a particular column.
And sometimes one axon will determine
more than one column.
But if it's coming from--
it represents just one eye.
It's coming from one particular layer of the
geniculate, it will not go very much into the
[UNINTELLIGIBLE] column.
And here's a monocularly deprived cat.
And you see some of the axons are quite big-- others are
quite small.
And he found out that those effects--
I'm sorry I don't have better pictures here--
because these were given to me by Mike before he
published it all.
And I never updated them.
But look here.
These are axons that are activated by the open eye.
Here, from the deprived eye.
And this is just short-term deprivation.
It didn't even last very long.
And you can see the vast differences that
happen quite quickly--
little, stunted axons from the deprived eye and pretty
robustly arborizing axons from the open eye.
That's long-term monocular deprivation.
These effects are maintained--
become a little bit greater.
Well, the changes are found at the level of the
arbors, as we just saw.
There are changes in synaptic details as well.
And we [UNINTELLIGIBLE]
in learning the idea that cells that fire
together wire together.
And the molecular mechanisms that I'm sure you heard about
or studied here, are found to be happening in development.
So it's like learning in that respect.
And particular molecular mechanisms have been
discovered involving [UNINTELLIGIBLE]
receptors, for example.
And people continue to discover more mechanisms of
that kind of learning.
We also know that activity promotes the
vigor of axonal growth.
In fact, it can cause release of neurotropins in the cells
of [UNINTELLIGIBLE].
And that then influences axonal growth.
That has also been discovered.
OK, I, just briefly, talk about three additional
paradigms now, not directly studying development--
one involving rewiring sensory pathways--
getting them to terminate it in the wrong places.
And because of activity, it can play such an important
role that you can get organized visual system
projections, for example, and auditory system structures.
Then--
and this is equally important--
we're going to talk about changes that can
happen in the adult--
the adult somatosensory cortex--
I mean, this I'm sure happens in humans as well.
And then we'll mention what happens in
blinded or blind animals.
OK, this is one experiment we talked about.
This shows retinal projections to geniculate and superior
colliculus.
And if when the animal's a baby, you oblate the
colliculus and you oblate the auditory pathways from
inferior colliculus--
that's the main pathway coming into the
medial geniculate body--
you get growth of the retinal axons right into the medial
geniculate, which then results in a pathway carrying visual
information to the auditory cortex.
And that was done by [UNINTELLIGIBLE]
and his students.
So what he did then with the students was to record in the
auditory cortex and find out how organized is that
projection.
And because of--
and we're assuming it's because of-- the activity, you
get tuning of the cells for different line orientations,
even in the auditory cortex.
Even though it's not as precise, these are just
representations of how precise that tuning is.
It's not as good in the auditory cortex.
But it does still form, in spite of that being a very
different area of cortex that normally would not get any
input directly coming from the thalamus carrying visual
information.
OK, let's talk about the adult somatosensory cortex.
A remodeling of hand representation is determined
by the timing impact of stimulation.
We won't read all this.
I want to show you the pictures just to get the sense
of how this was done.
It was done by Michael Merzenich and collaborators,
especially Wang.
Merzenich is on our visiting committee.
He often comes here from California to help us analyze
the progress in this department.
So here they show a monkey hand.
And let me go to a different picture here.
Here is the hand representation and the
somatosensory cortex.
This is the central sulcus.
There's the hand representation.
And they're showing representation here-- in the
blown-up view here-- of different digits.
And here, they're showing the hand of the monkey and how
they applied stimulation with bars.
OK?
Like this.
So they activated--
always at the same time-- all four fingers, here or here.
OK?
And so they were training the monkey to grab
the bar and do this.
And so he did it, again and again.
He had to do it thousands of times, repetitively.
OK, now the question was--
we know that normally, a receptive field of a neuron of
somatosensory cortex will respond to one digit or
another digit.
It won't respond to both.
OK?
There will be a few that respond.
For example, to the area between the fingers.
Very few will respond to stimulation here and here.
But when you apply repetitive stimulation like that for a
long enough period, you get more and more cells that are
responding to this digit and this digit--
sometimes to several digits-- sometimes [? all ?]
[? four. ?]
And they're plotting in the--
I colored them in, in the red here--
the areas where you get multiple
digits receptive fields.
A lot more after training than before training.
And it doesn't happen in the thalamus.
This is just a study of the thalamus.
It doesn't happen there.
It's all happening in the cortex.
So that's a form of adult plasticity.
It doesn't mean the anatomy is necessarily changing.
But it is being rewired in the sense that the synaptic
connections are changing.
Let's just take a look at the blind mole rat, a blinded
opossum and a normal opossum.
Look at the blind mole rat.
Now, this is the dorsal.
I don't know why in this figure they put--
I had to figure that out.
This is a dorsal view.
These are side views.
But look here.
Auditory and somatosensory areas are expanded.
This would be--
the visual area should be in here.
But it's shrunken, and some cells in it are responding
directly now to auditory input.
And somatosensory input has expanded so it overlaps what
used to be or should be visual cortex.
If you blind an opossum which was born at such
a very early stage--
here's the normal opossum down here.
Note that the somatosensory cortex extends back into what
should be visual cortex.
The auditory cortex doesn't actually expand, but you do
get auditory input, as well as somatosensory input, right in
the so-called visual cortex.
So the visual cortex is taking on different functions.
It's now getting input.
And again, I don't think that means that the ventral
posterior nucleus or the medial geniculate body is
necessarily expanding its projections.
I think what's happening is that the multimodal cells, and
the lateral nucleus, and the posterior nuclear group,
because they've lost visual input-- are now dominated by
their somatosensory and auditory input.
And that input's becoming more important and
causing this expansion.
Or both things may be happening.
So if we ask about what's plastic in normal neocortex, a
number of anatomists, including [? Kahal ?] and
[? Aldman ?]
and others have suggested that the short axon interneurons
are the ones that can most readily change their
connections.
We know this kind of thing is happening in
hippocampus, for example.
These little neurons are the granule cells and the
[UNINTELLIGIBLE]
do change their connection.
Well, the short axon interneurons are the hardest
to study anatomically.
You can stain them with the Golgi
method, but getting them--
you can't just stick in a label very readily.
It's only now in the very recent years we can begin to
get genetic tags selectively mark one cell type.
So there's not very much work of this nature yet.
Looking at altered connections of those cells, there is
evidence that many of these short axon
neurons express GAP-43.
But the evidence hasn't been at the single cell level.
And that's been the problem.
I did one experiment, for example--
then I was at Harvard-- where we looked at the internuerons
in the thalamus.
And we found out that in fact, deprivation can make a big
difference in how--
in the distribution of GAP-43 within the thalamus.
And it was completely explained by sprouting of the
GAP-43 neurons.
And then I noted here the other day--
I think last time-- that GAP-43 is at the highest
levels in the association layers of the multimodal
association cortex.
It's just a summary of the regions where we know there's
plasticity.
Physiologists have studied [UNINTELLIGIBLE]
corpus striatum, motor learning in the cerebellum,
changes in the hippocampal formation, and then in other
areas, including the midbrain--
short-term habituation and sensitization.
And that's probably the most common type of plasticity.
We used to think that these changes we're just at the
synaptic level.
But [? Kandel ?]
and others now are finding that in fact, you get actual
anatomical changes in the [UNINTELLIGIBLE]
arbors, as well.
So people have stressed learning and memory capacity
in the neocortex, and the closely associated structures.
And it's certainly a marvel.
But I wouldn't want you to conclude that everything's
plastic hemispheres.
Because the major patterns and organization of CNS pathways
and connections are inherited.
They've resulted from a long period of evolution--
from genetically directed development.
I've also emphasized here that everything's not connected to
everything else, which-- some people give up studying
neuroanatomy because they think that that's true.
It's far from true.
Specific connections do matter.
They determine function.
And that's what a lot of this class has been emphasizing.
And I've--
you can read these.
I've outlined my conclusions about neocortex.
The things that added acuity--
motor acuity-- and sensory acuity.
But I think its greatest innovations were the ability
to anticipate and plan.
And I've outlined--
and you can look at those last few slides-- the ones that are
correct are this.
I'm gonna post them.
--about the kind of problems they raise for future
neuroscience.
And these are major problems.
And I think we have a lot to do.
As I point out here, neuroscientists scarcely begun
to explore some of these abilities.
And I hope some of you will go on in that and will be doing
some of that.
I'm just asking you to remember this.
I was looking to see.
I'm pretty sure it's [UNINTELLIGIBLE]
[? Goodman ?] that said this.
But I couldn't verify it.
It's probably in my notes from [UNINTELLIGIBLE] lectures.
But anyway, it was in German.
I've just translated it there.
First anatomy, then physiology.
But if you gotta do physiology first, then don't do it
without anatomy.
So I will post this-- review slides for you.
And I will certainly be available to answer questions
as you guys get ready for your exam.