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PROFESSOR: All right, we're talking about the hippocampus,
which was the medial palial area in the non-mammals, like
here, in the bullfrog, or it's clearest in an animal like the
lung fish, where you have a neural tube that's closer to
the embryonic mammal.
And the medial side here is equivalent to what has become
the hippocampal formation in the mammal.
And here it is in a marsupial, where you see it, again--
there's the ventricle.
That's all ventricle.
And you see the ventral and lateral part is very thick
because of the presence of the striatum there.
The cortex on the outside, but then the medial side is
already beginning to in-fold.
And in an animal it's going to be a smooth-brained animal--
that is, the cortex isn't large enough because a lot of
[UNINTELLIGIBLE]
form.
Majority have a hippocampal fissure.
So let's look at that some more now in the major
sub-regions of the hippocampus in mammals.
Definition of Ammon's horn, which is a one-celled thick
layer of pyramidal cells in the hippocampus.
So whenever you see that term, CA, it means according to a
moan Cornu Ammonis, or horn of the Ammon.
When we talk about these different
subdivisions of the CA field--
CA 1, 2, 3, and 4.
And then we'll define the major inputs.
So here we are in a rat.
You have neocortex here, which has,
remember, multiple layers.
Usually, we define six.
These are the five and six, which are the
thicker layers here.
Here's 2 and 3, which are often lumped
together, and layer 4.
When you get into right entorhinal and other
paralimbic areas, it's always reduced to just a few layers.
Usually only four layers.
And by the time you keep going here, if we're
following the surface--
let's take my pointer here.
Here's the surface.
We follow it in to hippocampal fissure.
This is still the original surface.
And it ends there.
Now, you follow the cell layers.
They come around like this, and when you get to subiculum,
you're down to one cell thick.
Subiculum is really part of it the hippocampal formation.
Then that layer becomes thinner when
you're in the CA fields.
And it ends right there, in the CA4, it becomes somewhat
more scattered in the cells.
And then at the end of it here, you
have a layer of cells.
It's like a little extra piece of cortex there that's
stitched on the end, like the hem on a skirt.
It's interesting, this is supposed to be rat, but
Isaacson, in this figure, has drawn a configuration of the
dentate cells that's more like human.
I'm going to draw it there just like the rat.
Here's where you find that structure in the rat if you're
looking at the dorsal view here, in the upper right.
You would have to cut through the cortex to expose the
hippocampus underneath, but actually the hippocampus is
the in-folded edge, as we saw here.
This neocortex just in-folded, becomes hippocampus.
This is a horizontal slice in a rat.
The cortical edge that's in-folded in
the rat is this edge--
just about that much.
And there it is with the cortex cut away.
So you can see that in-folded region.
So here's the cortex as it's in-folding, ending in the
dentate gyrus.
And fibers that are going out in the hippocampus are
collected here.
And I just want to point out one thing with this figure--
namely that any place you cut across the long axis of the
campus here, whether you're down here, or here, or here,
you always will get a similar kind of section that looks
something like this.
You'll always find dentate at the end.
And you'll always find the CA fields
there and the subiculum.
And as soon as you're outside the subiculum, you're in the
parahippocampal regions.
Now here it is in human.
And I want to point out something about this view.
Are we looking at the hemisphere here?
What they do to get this picture?
They had to cut the hemisphere away from the brain stem, from
the upper part of the brain stem.
So what was in here?
They had to cut this.
Well, the thalamus was sitting there, and all of the fibers
coming out of the thalamus, forming the internal capsule.
They've cut through that.
So when you do a dissection--
and Andrew, we've got to schedule those.
Just schedule the dissection.
We'll try to do it a couple of evenings, I guess.
We could do it during the class, but we have so little
time during the class, I'm going to try to find at least
one evening.
The class isn't so big.
We could even do it in one if we could get
everybody to come.
But when you do the sheep brain, in order to get the
hemisphere off, you're going to have to to cut through all
the fibers.
And that's what was done here.
And what is this?
Corpus collasum.
So you had to cut that.
Of course that is holding the two hemispheres together.
So you have to cut through it.
And as soon as you cut that, the hemispheres will tend to
push apart very easily.
And you'll see that.
Here's the in-folded edge of the hemisphere here, in the
temporal lobe.
This is all temporal lobe down here.
It shows the position of the amygdala.
there in front of the hippocampus.
And the hippocampus doesn't go up dorsal to the collasum as
it does in the rat because of this incredible growth of the
hemisphere into the temple lobe, except above the corpus
collasum, there is a tiny bit of hippocampus.
And we can follow that--
it's called the hippocampal rudiment.
We can follow it all the way around like this
to the septal area.
It's not a very large structure, and most people
will ignore it, but when you're interested in brain
evolution, these things can be important.
So we can follow that, even in the human, and rat or hamster.
You'll always find that rudiment.
It's prominent enough in the hamster that I
can see it very easily.
It becomes larger up in front here and it's right this
region in the hamster, and I'm sure in a number of other
small mammals that get some direct input from the
olfactory bulb.
Probably the original hippocampus was mostly an
olfactory structure.
Let go back to the--
this just points out one additional thing here, namely,
one of the major inputs.
We just talk about olfactory--
that's no longer the major input to the hippocampus.
We don't orient to places primarily
by olfactory anymore.
That might have been true of the earliest mammals that were
on the floor of a forest trying to avoid being eaten by
the visual animals-- the lizards, the dinosaur group.
The inputs from other sensory modalities coming from the
cortex are coming in through parahippocampal areas, and
this is the main one in the large mammals.
This is the entorhinal cortex out here.
And it shows some axons from the medial--
they're not really at the surface as it shows here.
Sorry about that.
They're propanol cells in [? the deep gray ?]
layer here.
But they come from the lateral and medial.
Entorhinal--
they show them separately because they terminate in
different layers in the dentate.
Rather than following the white matter all the way
around, like this to give to the dentate, they actually
perforate right through the hippocampal fissure through
what used to be the surface of the brain.
So this is clearly something that evolved much later after
that in-folding much, much later.
Remember, this was just the in-folded cortex and it didn't
get input from coming through the surface like this.
So here you'd see it penetrating through the
surface, which is why it's called the perforant path, in
terminating the entry to dendrites
of the dentate gyrus.
And those dentate gyrus cells then project
into Ammon's horn.
And the circuit that they're pointing out here, you can
easily just stretch out.
Here, they show it again, up here.
But it's easiest to stretch it out and look at it this way.
Here is entorhinal cortex out here.
And here are the axons from those different parts of
entorhinal cortex.
So here, they show two of them coming from the lateral and
medial entorhinal cortex, through the perforant path.
And they're terminating on the dendrites of these dentate
gyrus cells.
That's how the inputs come in.
Then the axon of the dentate gyrus neuron--
is called mossy fiber--
goes into the Ammon's horn.
And it's major termination is in CA3.
And when we talk about hippocampus, we're usually
only talking about the circuit, which is ignoring a
lot in the hippocampus.
The hippocampus is much more complex in its
interconnections than we're talking about here.
But the focus of study has always been on this circuit.
It's a very simple circuit.
Termination of the mossy fibers from the dentate on the
dendrites of the hippocampal CA3 cells.
Those CA3 cells have some output through the white
matter of the hippocampus.
Some of them go down to the septal area, but what the main
circuit of interest here is this collateral, called a
shaffer collateral, which is why it's called this SCH
there, by the person who first described it.
And then here, the axon goes to another adjacent part of
the hippocampus the CA1 area.
And those terminate--
depending on where they're coming from-- terminate in
different layers of those dendrites, as you see there.
And those cells have an axon that goes through the white
matter of the hippocampus, with this labeled alv there
for alveus of the hippocampus.
The alveus is at the surface there,
the ventricular surface.
And there it goes to the next cell in
line, the cell subiculum.
And the subiculum is really--
somehow it didn't get included in this part of Ammon's horn,
but it could've been.
It's right next to CA1, in your subiculum.
And those subiculum cells have axons that project into the
fornix bundle.
So they're projecting then to hypothalamus,
to the septal area.
They also have axons that cross to the opposite side,
which is why they show the branch there.
So we'll come back to that anatomy in a minute.
When I've talked about evolution of hippocampus, I've
pointed out the probable early role in forming a different
kind of memory than the habits of the ventral striatum, which
were specific objects that gave off particular odors.
Animals learned to respond in specific ways.
Here, they're responding to odors of places, so it didn't
have to be attached to any object--
simply the way the place smelled.
And the hippocampus, when you study its functions, in
animals, its major functions is memory for places--
that's the way animal learns where it is.
But when we talk about humans, what's so amazing about this
structure is that we find that all kinds of episodic memory
depend on the formation of the episodic memory and their
retention depends on hippocampus.
It doesn't mean that changes in the synapses of the
hippocampus are where we retain all these memories.
That would be pretty shocking if it were true because of its
relative size.
But remember there are strong connections to the neocortex
through the parahippocampal areas.
We think the long-term memories are actually forming
the cortex.
And there's good evidence for that.
But in order to form those memories you need the
[? activity of the ?]
hippocampus.
So out of these place memories, we've developed our
ability to remember specific event in our lives.
And in this circuit here, physiologists have discovered
a simple kind of plasticity that may be very important in
forming spatial memories.
And there is evidence for that.
That was a fairly recent big effort here at MIT in the
Tonegawa Lab, was just to establish that correlation.
That the long-term potentiation increased
sensitivity of synapses activated in hippocampus
actually have something to do with the
formation of these memories.
And they've been able to get evidence for that.
But each of these synapses that we're talking about here
in this circuit will show long-term potentiation.
Meaning that if you stimulate it artificially, if you
electrically stimulate repeatedly,
that train of pulses.
And then give a test stimulus and record the response.
The response will get bigger.
So we say it's potentiated.
The LTP is just a model for plastic changes in the
hippocampus.
We think that's what's happening all the time in the
normal functioning of the hippocampus.
Changing sensitivity of the synapses that's altering the
flow of information of the hippocampus.
So what kinds of memories aren't dependent on
hippocampus?
What have we talked about?
You could lose your hippocampus and you can't
remember who you just talked to once you turn your
attention away.
People with these--
just the fornix bundle cut show this
incredible lack of ability.
We say they have a short-term memory deficit.
That's not very accurate.
They actually have good short-term memory, but they
lose it as soon as they turn their attention to something
else because they don't form a long-term memory.
You can't move the memory out of the hippocampus to the
cortex, so they never form long-term memories.
And yet, they still do remember events from before
the damage.
So they'll remember their childhood, they'll remember
things that happened to them earlier.
And they live.
And their awareness is of that world and of what's going on
around them right at the present time.
And if you tell them a joke, they will laugh.
They'll say it's funny and everything.
You can tell them the joke again as soon as they've
forgotten it, at which they do quite readily, and tell them
the joke again and they'll laugh just as hard.
And some of the MIT students that have had these patients
here have actually done that and verified
that that's what happens.
It's funny, but it's very sad when someone has robbed that
ability to remember anything.
But yet, that same person can learn things.
But he won't remember that you taught it.
He can learn a skill.
He can form habits when he is rewarded by your words or by
other means of reward.
He could learn to ride a bicycle.
He could learn these kinds of habits, but if you asked him,
you remember when I was teaching you how to do that
yesterday, he will not remember.
And yet he will acquire the skills because that depends on
a different parts of the brain.
That depends, of course, in humans, it still depends on
input from the cortex, but it's the input that goes to
the corpus striatum.
I'm not saying that's the only places in the brain that
changes are happening that underlie our memories.
But they seem to be the dominant ones.
Yes?
AUDIENCE: Do Alzheimer's patients [INAUDIBLE]?
PROFESSOR: Do--
AUDIENCE: People with Alzheimer's.
PROFESSOR: No, they don't have, but
they have other problems.
And we'll come a little more of that.
AUDIENCE: It just reminded of-- my grandmother has
Alzheimer's, and we'd tell her a joke.
She'd laugh really hard, and then she'd forget it.
And seconds later, you tell the same joke, same joke.
And she just keeps laughing.
So it just reminded me of that.
PROFESSOR: The Alzheimer's has--
there's a number of problems.
And memory is a complex-- again, it depends on,
remember, the formation of the and retention of the long-term
memory depends on cortex.
And we think it's input to the cortex that's mainly affected,
the modulatory input.
The question here is this one-- what's the pathway for
subcortical projections to and from the hippocampus?
Well, there are-- the fornix that we talked about is an
output of hippocampus into the septum and hypothalamus.
The long axons reaching the mammilary bodies.
Some of them may have been going into the
midbrain limbic areas.
There are also axons going in the opposite direction.
And many of these come from the septal area--
cells that use acetylcholine as a transmitter.
And it's a kind of major neuromodulatory system,
regulating hippocampal activity.
Now, there are also dopamine axons coming in there.
The limbic areas of the forebrain tend to
get dopamine input.
So this is human now.
So here's the hippocampus down in the temple lobe, and here
are these axons of the arch of fornix.
Here's this narrow little area in between the hemispheres,
medial to the lateral ventricles.
It's called the septal area.
And the cells there, they're just illustrating a little
cartoon of one of them there showing a septal neuron using
acetylcholine as its transmitter projecting to the
hippocampal formation.
And then they just show other major inputs here.
Here's a projection from hippocampus by way of the
fornix to the septum and, of course, would go onto the
mammilary bodies and other parts of the hypothalamus, but
it also projects to the subiculum and back to the
entorhinal cortex, which is a very major input to the
hippocampus in human.
But the new projection here we're talking about is this
one from the septum to the hippocampus.
So one kind of plasticity we've mentioned and we think
what we see in LTP is changes like that are
happening during learning.
But there's also plasticity after brain lesions that's
more remarkable in the hippocampus than in neocortex.
If you make lesions like this in neocortex, you don't get
these kinds of plasticity.
You get very little.
But in the hippocampus, you get changes that are like I've
been able to observe in baby animals, in my studies of
early brain lesions.
So what is this now?
Each of these boxes is a column
through the dentate gyrus.
Just imagine that the cells of the dentate are down here.
And here are the dendrites.
And those cells are all along there.
And we're just showing different projections
terminating on those dendrites.
So what we have here--
this is the input from the entorhinal cortex, from the
ipsilateral entorhinal cortex, dense input to the outer 2/3
of the dendritic tree of the dentate gyrus.
That was the projection I talked about earlier--
the major input into the hippocampal
formation of mammals.
And there's some that go across the hippocampal
commissure to the opposite, but it's much sparser.
And then you have inputs from the opposite side that are
much denser here, but they also come from different parts
of the same side.
But different parts of the hippocampus.
So we call them associational connections.
They go down here near the cell body.
And then here's where the inputs from the septum-- those
acetylcholene axons terminate.
And the outer part of the dendrite and
right next to the cells.
So the question here is what happens if you eliminate those
by making an entorhinal cortex lesion?
Just eliminate it.
What happens to all those other projections?
What happens is quite amazing.
These projections from the opposite side, which were very
sparse normally, become very dense.
So that projection across the mid-line now becomes major.
The association connections expand--
they expand out this way.
Now they're occupying all of this, and even the projections
from the septum are increasing their density.
Here, I've just shown what these cells look like, which
I've already drawn.
And these are the axons of--
the association axons that I'm just showing, how they would
have to be sprouting to account for that change.
This change, whether they go from this to this in the
experiments that have been done this.
So they must be sprouting like this.
Before we leave, talk about other
parts, the limbic system.
I want say a little bit more about things going on in this
part of the brain.
It involves these neuralmodulatory inputs to
neocortex as well as hippocampus, coming from
acetylcholine axons, epinephrine axons, and
serotonin axons, like hydroxytryptamine.
If you look at the activity in these kinds of axons coming
into neocortex during waking, slow wave sleep, or REM sleep,
you find the norepinephrine and serotonin as the deeper
sleep becomes the less their activity.
Greatest in waking, least in REM sleep.
REM sleep, we're taking here as the deepest form of sleep
because it's harder to wake you up during that period.
But look what happens to acetylcholene.
It goes way down in slow wave sleep, but in REM sleep, it
goes way up.
So what's going on?
That might have to do with some special
function of REM sleep.
And the theory is that the function has to do with memory
consolidation because it would change the flow of information
between neocortex and hippocampus.
And that's illustrated here, if you look at these pictures.
So here they diagram neocortex, and these are
transcortical pathways and feedback pathways.
And they know it here that more acetylcholine--
some of these glutamatergic axons, excitatory axons, will
be less effective.
And the similarly, the input--
here, you have neocortex projecting to dentate gyrus.
Now, it does so through the entorhinal cortex.
They're not showing where all the synapses are here.
And then here's Ammon's horn.
And they're showing feedback within Ammon's horn, and
connections within the hippocampus, that are being
affected by acetylcholene.
They show it being blocked, it's actually just partially
suppressed.
These are still all active connections in the waking
state, but they become less effective with acetylcholine.
In slow wave sleep, if acetylcholine goes way down,
this is what's going to happen.
The traffic between neocortex and
hippocampus is going to change.
Hippocampus now will drive neocortex much more than it
did in waking.
And that's exactly the kind of thing that you would expect if
information in the hippocampus is moving into neocortex.
That's the theory.
And that's been proposed for that kind of connection.
It might seem far-fetched, but physiologists have collected
evidence for this kind of change in these connections
and the effects of acetylcholine, and proposed
this theory.
And of course, tests of theories like this are
important if we're ever going to understand these events.
You can read this.
This is another theory.
I want to show you a few pictures of human brain here,
so you'll see where these things are.
What they've shown here is a photograph of a side view of
the human brain--
cerebellum down here and brain stem.
Here's the left hemisphere.
And then they've shown where the hippocampus is if the
brain were transparent.
And the hippocampus in the purple there, and the amygdala
in the reddish color.
And then the darker color here, the axons coming from
hippocampus.
So there's the hippocampal formation mainly in the
temporal lobe.
There are the axons coming out, arching over the
thalamus, and into the septal area and then to
the mammilary bodies.
This is a front of view, and a rear view of the brain.
And here we are, the top view.
So here, we're out in the medial part of the temporal
lobe, which is why it's so far medial.
And it's underneath--
if you saw the brain from underneath, it would become a
little more evident where these structures are.
And there's the temporalization of the
hippocampus, and there's the [INAUDIBLE]
arch of the fornix.
Now, if we look at a Nissl section, this is much harder
for you to make out.
Let me just try to point it out here, make it large enough
so you can actually see something there.
This is the surface here of the brain, and
some of it's cut off.
And here is again.
Here, we're following the surface.
And then the hippocampal fissure--
now we're inside the hippocampus.
That's dentate.
Dentate always looks like this.
The granule cells form a very dense layer.
And that's the surface of the dentate out there, where those
dendrites are that are getting all that input.
So that means the perforant path is going
through this way.
So what are these cortical areas?
I've followed the surface through this roundabout route,
and we ended in the dentate.
This is entorhinal cortex here.
I can tell it's entorhinal because the cells in layer two
there-- the first layer is always mostly, not cells, but
mostly dendrites.
So it's mainly neuron free.
And these cells are in little pumps here, which is
characteristic of the entorhinal cortex.
And you can see there's different layers there.
You can make out that this is a distinct
layer, this looks different.
There's a slightly denser layer there.
And finally, you get to white matter here at the bottom.
There's a lot of axons in there.
And then something changes right here.
You're no longer in entorhinal area.
These clump cells change.
Now you're in transitional areas.
There's still more than one layer.
Until you get somewhere in here, about right here,
suddenly multiple layers change to a single layer.
It's a rather thick layer.
Runs all the way to the end of the hippocampus there.
Where it becomes a one layer, somewhere in
here, it's a subiculum.
And subiculum then changes where it becomes a narrower
layer here into CA1, CA2, CA3.
And then these scattered cells in the hilus of
the dentate are CA4.
These are axons that are going out.
And these are axons of the hippocampus all along here.
So I'm marking it there.
They're not stained very well because it's not a cell stain.
It's not an axon stain.
If we add an axon stain, we would see a lot of axons all
along the surface here and then they would collect in the
large bundle here.
These are diagrams of the hippocampus in the human.
You see the temporal lobe, the arch of the fornix, and then
they follow it through the septum here to
the mammilary body.
Here's a top view.
And in the top view, I've drawn it over here for you so
you can see which part of this hippocampus
where the axons are.
And I've shown the axons in blue.
So that coming out, all along the
hippocampus, there's output.
And they're joining together, medial side, in a bundle.
And we can follow them forward, all over the
thalamus, into the septum, and then to the hippothalamus.
And there, axons are forming this crossing pathway, the
commissure of the hippocampus.
If I could do the mirror image here, I would show that same
thing over here in the right hemisphere.
So that's just gives you an idea what it looks like.
These are just more pictures.
This is a fiber staying here, where you see this is the
midbrain down below, caudal thalamus up above here.
This is the cerebral peduncle and it's showing there, in the
temporal lobe this region, this region, this hippocampus,
in the front section.
And they're showing a few details of the circuitry here.
And if you blow that up on your computer, you'll get a
look at that.
And here, they just show that you can section that in-folded
structure there that forms hippocampus, and get about the
same cross section.
It looks like this anywhere you are along it.
And then they're showing the axons coming in.
These must be entorhinal, terminating the dentate there.
And there's the circuit within hippocampus and the axon going
out into the fornix.
And then you don't get that kind of detailed picture when
you look at MRI, magnetic resonance imaging, but you can
still find at the hippocampus.
We have so much better resolution in our studies of
sea mammals.
And we can look at a higher resolution, blow it up a bit,
and make out sub-parts of the hippocampal formation there.
And here, in a parasagittal view, you see these eye here,
so you know you're off the mid-line and you're cutting
through like this.
And you're out on the temporal lobe, and
you can see the position--
the amygdala there, the [? left arrow ?] and
hippocampal formation [INAUDIBLE].
Not much time here but I'll have two
classes to talk about--
somebody tell me what rhinencephalon means.
What's the term mean?
It means nose brain.
What were the structures that were the nose brain?
Well, all the olfactory structures--
and they thought that most of what we now call limbic system
was rhinencephalon.
And that was the old term.
And then we thought it was totally dominated by
olfaction, which turned out not to be true in humans.
So the rhinencephalon became the limbic system in modern
language, and limbic lobe was the term
from Paul Broca, remember.
The human brain seen from the medial side.
These structures that can be seen at the edge of the
hemisphere.
And I've just summarized here, again, what we learned about
Papez circuit.
I won't go over it again now.
I want you to review the Papez circuit, know the major
structures in it.
I've underlined them in red, and they're usually named in
this order.
We just lumped together these structures here, in the
hippocampus.
In fact, we usually lump these two.
There's the perforant path.
Here's other pathways coming into the subiculum.
And then the major inputs coming from the hindbrain and
from the association areas of the neocortex.
If you've got a question like this-- how can neocortex
influence the autonomic nervous system?
And you're thinking of large mammals, it's this
[? mesalum ?]
picture you want to use that shows transcortical
projections, which are mainly going between
adjacent areas, like this.
There actually are two ways.
I'm showing them, just emphasizing this direction of
primary sensory areas through association areas, to the
paralimbic areas and then the limbic areas, like hippocampus
and amygdala.
But I've added here to the original picture.
I've shown that from neocortex, the heteromodal
association cortex, there are some direct connections in the
limbic system.
For example, in [? front temple ?] cortex,
directly to the amygdala--
finding of Nauda in the monkey.
And there's good evidence from magnetic resonance--
functional magnetic resonance imaging in humans as well.
And I'm also pointing out here that the caudal orbitalfrontal
neocortex functions like a paralimbic area.
It's the only area of neocortex projecting directly
to the hypothalamus.
Most about the hypothalamic input is coming from these
limbic system structures.
So we're going to, next time, define the amygdala.
It's really very much like the striatum, except it's
concerned with different kinds of things.
It's not concerned so much with habits of action, but
with habits of feeling and motivation.
So that's what we'll be talking about next time.
We'll start with the grab-it picture that we saw when we
talked about olfactory system.