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PROFESSOR: So I want to finish up Class 29 on
the action of hormones.
And then I hope we can do quite a bit of the next class
on the hippocampal formation.
I put these chapters online from the book.
I wasn't able to do that until yesterday
because of computer problems.
But this one, it's only overheated once and frozen up.
My older one has done that several times, so I decided it
was a little too dangerous to use it for the class.
And besides, this is a tablet, so I can draw on
it during the class.
So we were talking about the role of hormones and its
importance in seasonal singing of birds.
Nottebohm, at Rockefeller University, and a
post-doctoral student and a technician in his lab first
notice changes in the brain.
Nottebohm, of course, had been studying
birdsong for quite a while.
Knew a lot about the canary, especially.
The was the bird he was using in the lab.
And they were doing histology on the brains.
And they noticed that some brains, certain structures
were very prominent, and the same structures were hard to
find in other brains.
Then they noticed that it was in the males.
And then later, they discovered that it depended on
the season of the year.
And that's what led to the title of one of his papers, "A
Brain for All Seasons." He thought the changes were due
to testosterone.
And I'm sure that's partly right, although Sarah Bottjer,
one of the other students of the brain in singing birds,
has discovered the importance of experience as well in
affecting the brain changes.
This is from the Nottebohm Scientific American paper,
where he shows a picture of the bird brain here.
You can see the cerebellum back here.
Here's the cerebral hemisphere.
That is the optic nerve.
You've got two optic nerves coming in, where
I've just marked it.
And this is the hindbrain.
And it's part of the hypoglossal nucleus that
controls the syrinx in the throat, which is equivalent to
bird's vocal chords.
It's crucial for his ability to sing.
And it's interesting that these brain changes in these
birds also shows a hemispheric dominance.
Usually the left hemisphere is dominant, just as it is for
speech in humans.
Here, in an area that used to be called the hyperstriatum,
is a structure that became known as the
higher vocal center.
Now it's usually not called the hyperstriatum.
And they realized it's not really striatum at all.
It's more equivalent to the neocortex.
So now it's usually called the hyperpallium.
And the best known structure in my hyperpallium is the
Wulst, which is very much like the visual cortex except it
has a more complex layering pattern than the mammalian
visual cortex.
And then the output structure, it doesn't go directly from
the higher vocal center to the hindbrain.
It goes through a structure--
it used to be called the archistriatum, which is what
it's named there.
Now it's called the arcopallium.
But that structure and nucleus robustus has remained the same
in its name.
And it goes directly from that robust nucleus to the
hindbrain structures.
We followed, when we did the auditory system, I showed a
picture of the input up into this Field L, which is like
the auditory cortex of the bird.
And in the arcopallium, it has a number of subdivisions.
It gets its input from an auditory
in the dorsal thalamus.
It's called the ovoid nucleus or nucleus ovoidalis.
And I don't show the pathway there leading up to Field L.
Instead, I show the pathway here.
It's actually [UNINTELLIGIBLE]
show it.
Directly from Field L, the auditory region of the
hemisphere to the higher vocal center.
And then, the most direct pathway to the syrinx from the
higher vocal center is shown here to the nucleus robustus,
and then two pathways, one directly to the hypoglossal
nucleus and one indirectly through the auditory
structures of the midbrain, both reaching hypoglossal
nucleus, which projects to the syrinx.
What is the hypioglossal nucleus in the
mammal best known for?
And what does the word mean?
What does "glossal" refer to?
The tongue.
Controls our tongue movement.
So it's very important in speech in humans too.
This is another pathway from the higher vocal center that,
rather than going directly to the nucleus robustus here, it
goes through this so-called area X--
telencephalic area X--
which has a loop through the thalamus.
Goes to the thalamus and back up to the one structure here,
which then projects to the robust nucleus.
And that's an interesting area, because that's where
lesions, depending on how big the lesion, can delete various
numbers of song syllables from the bird's singing.
It's not that he can't sing at all without that, but to learn
complex song, he needs this area.
So it's been compared to a kind of Broca's
area for the bird.
Well, if you look at the volume of these song control
cell groups in male canaries, you find out that it varies
with the age of the animal.
Here is hatching, and here is one year.
So over the course of this first year, the volume of the
robust nucleus and the higher vocal center are increasing.
But they follow it after that--
and in this particular graph, it doesn't
follow it very far--
it shows a decline.
And it actually cycles with the season.
The same pattern is repeated.
So these nuclei are showing increases and decreases
depending on their seasonal cycle.
And this is how the singing varies.
These are new syllables being added to their song.
So this is called the plastic period when more and more
syllables are added, and then they are added less and less
as testosterone levels rise.
And then this is the period when they're singing the most.
They call that the period of stable song.
They're not learning any more song, and that remains while
testosterone levels are low.
And then when they start up again, the whole
cycle begins to repeat.
Now, they found that here is the period of plastic song,
and that's when the volume is increasing.
So it's during this period more and more that those cell
groups are becoming larger and larger.
And they're becoming larger, it was
discovered, by adding cells.
Cells also get bigger, but they're adding new cells.
And they can discover migrating cells in the
forebrain, not just in that first year but
in later years too.
So this is happening seasonally.
And here, you see cells moving along the process of the
radial glial cell, which is how they migrate.
And these are results from a tritiated thymidine study.
So with tritiated thymidine, you label the DNA of the cells
that are being born.
And if you look at the tissue one day after you do the
injection, you see all the labeled cells in the
ventricular layer here of the hemisphere.
Here after six days, you see some of them
beginning to migrate.
After 15 days, they're migrating over much of the
hemisphere.
The same after 40 days, except after 40 days, they've
[? shown in pink ?]
the cells that are now looking like nerves.
They're no longer neuroblasts.
They're differentiating from neurons.
Now, it was the changes in song production and the
appearance of the brain's [? and Nissl's ?]
that lead to this discovery.
But there's a lot of unanswered questions about it,
because for one thing, these new neurons aren't just going
to those areas that look so different in the males during
certain periods of the year.
They're going over to many different parts.
And same thing is happening in the females, even though the
females don't show that marked dimorphism.
We think sex differences in the brain are many, and
probably many more than I've described here.
A few in the hypothalamus of mammals, including humans.
I think I mentioned structure in the spinal cord too.
There's probably many more to be discovered.
For example, in Toran-Allerand's tissue
culture work, she found the differentiation of the
mesencephalic dopamine cells are affected by sex steroids
and that the sex steroids also affect the production of
neurotrophins.
So growth factors are being affected by the sex steroids.
I can't remember the details of other studies using other
hormones, but it's known that testosterone has a major
impact on brain differentiation.
But it actually acts through--
it doesn't act directly.
It's aromatized and acts as an estrogenic compound.
It was from the 1970s that scientists were believing that
the sex hormones estrogen and testosterone, particularly
testosterone, were mainly responsible--
in fact, they thought it was the factor that led to brain
differences.
That males, though they might be born male, if for some
reason the testosterone could not act on their cells--
and there are genetically-abnormal males who
cannot respond to the testosterone.
And when that happens, their bodies develop as females,
even though they have testes and they're producing
testosterone.
They have to have the receptors.
The cells have to respond to the testosterone.
And we think the same is true for the brain, that brain
develops in the female fashion without these hormones.
Well, then people began to look at expression differences
in genes between male and female.
And the first person I know of that was doing a lot of that
was Eric Vilain at, I believe, UCLA.
And they were looking at whether genetic differences
could explain the variations between the sexes.
And they looked at the expression patterns of over
12,000 genes, so using a screening method and
large-scale screening.
And they looked at differences in male and female brains in
embryonic mice.
They chose embryonic mice because they wanted to look at
the period before there were noticeable hormonal
differences in the blood circulation.
So they looked very early.
Now, these little rodents, they're born at a stage
equivalent to, say, the hamsters, born at a stage
equivalent to humans at about 2 and 1/2 months after
conception.
So they're born in a really immature state.
So it's not until around the time of birth that you begin
to get that first surge in hormonal differences between
male and female.
And they're looking at the embryos.
So they were looking prior to hormonal influence.
They found 18 genes expressed at higher levels in male
brains, 36 in higher levels in female brains.
And that was new, and of course, then the project began
to identify what these genes were.
And that's still going on.
One gene was a particularly interesting one.
It was called SRY because it was found on the Y chromosome.
So females don't have the Y chromosome.
So they found it was expressed in the substantia nigra in
rats and was involved in dopamine secretion.
If they could reduce or block the gene's activity, they got
Parkinson's-like symptoms in the rats.
So they began to speculate that it might explain why men
are more susceptible to Parkinson's disease than
women, making, of course, some pretty big assumptions of
similarity of rats and humans.
And I'm sure there's a little more on that now.
It wouldn't be very hard--
I couldn't last year, when I taught the class, find any
more on it, but there might be something now.
And of course, then we wonder, obviously, female brains are
secreting dopamine as well, without SRY, are there other
similar genes?
There must be other genes involved.
It's also been proposed that gene expression variations can
explain some differences in sexual orientation.
Vilain began to collaborate with Dean Hamer.
This fellow, I underlined it because Hamer has been
involved in genetic differences in heterosexual
and homosexual individuals for some time, and he had found
some other evidence for it.
And then they found this skewing of X chromosome in
activation in mothers of homosexual men, again, lending
more support.
There are several findings of this nature--
genetic involvement.
But that doesn't mean we really understand it.
Just to find the gene isn't enough, just like
this finding in SRY.
It's just the beginning of an area of research that has to
be a lot further explored.
There's also been--
I think I may have mentioned this-- neuroimaging data,
which can do something that you cannot--
yes?
AUDIENCE: What is this skewing on the X chromosome?
PROFESSOR: Skewing of X chromosome in activation.
That's a good question.
I made some big assumptions about what it means.
What do you think?
AUDIENCE: It means maybe only one of the X chromosomes is
active consistently across many groups of [INAUDIBLE]
or something.
PROFESSOR: That's what I was assuming, but I may be wrong.
If you can find anything about it a little more, let us know,
because I'd like to see.
You can check.
I've given the reference there so people can check it out to
see if more is known about it.
And of course, that's not telling you
what the effect is.
This is in the mothers, but obviously, if there's X
chromosome inactivation, that should have some pretty
profound effects on development.
Judith Rapoport gave a talk at the Society for Neuroscience
two years ago.
That's when she first reported her longitudinal studies,
which you can do with magnetic resonance imaging, and you
can't do, of course, in any other [UNINTELLIGIBLE] and use
the living people or animals.
So she can see how the relative size differences are
varying with age when they first appear and so forth.
And initially, she was confirming what we knew
already, that in addition to correlations of size with body
weight were sex differences in hemisphere sizes, she found
that to be true at the various ages she was examining.
And then she found evidence for both genetic and
environmental origins.
So for example, she was looking at the cerebellum, and
she found a lot more variation not necessarily tied to
hemisphere size.
But her suggestion that experiential factors are
explaining the cerebellar differences still had to be
confirmed at the time she gave her talk.
It takes a lot of work to do that, and the best they could
do, of course, with humans is to get correlations.
You don't divide humans up and say, you can join sports teams
and you guys can't.
You just look at the ones that do and the ones that don't and
find out if the more they're learning motor skills, for
example, they develop larger cerebella.
But that's the idea.
And the quantitative methods are precise enough, using
imaging, to begin to get some answers to
questions like that.
She also came up with some surprises, for example, young
people with attention deficit hyperactivity disorder had
different reduction in brain size.
And then not less surprising, she found schizophrenics have
differences.
And there, it depended on exactly where you look.
It wasn't just hemisphere size.
They can look, for example, at the relative size of the
amygdala and hippocampus.
That's where they were finding reduction.
Yes?
AUDIENCE: Is this kind of like PET imaging, or is it a
functional MRI?
PROFESSOR: This is MRI.
And sure, they could get a lot more if, then, they added
functional MRI to it.
But she was doing large-scale screening, so she was running
through all kinds of large numbers, because she wanted to
collect data just on the size of various ages.
So she didn't have time to do--
AUDIENCE: So just sizes of different spots [INAUDIBLE].
PROFESSOR: That's right.
Size of major areas.
But I'm giving you the name there, and by searching under
her name and people also citing her, you will find
quite a few studies like this now.
Began appearing just a few years ago.
AUDIENCE: In young people with ADHD, do you know what sizes
or spots in the brain are different?
PROFESSOR: I can't remember anymore, because that was just
the first report.
And I knew already, what I thought of there is animals
with early damage to the hemispheres show pretty
extreme hyperactivity and hyperreactivity.
I would expect humans to be similar.
In that case, you'd expect to find also correlations with
cerebral palsy and cognitive retardation.
And she did mention that, but what she was talking about,
really, was more subtle differences, saying that maybe
we've missed some of the things that are happening in
people with this problem.
And of course, it raises other issues too.
What is the cause?
Are there hormonal abnormalities?
Are there thyroid abnormalities or something
that could be causing a reduction in brain growth.
So once you begin to get data like this, you're spurred to
do other studies of the causes.
Maybe we can begin to do more about it.
I'm putting these pictures back in just to remind you to
get more familiar with these structures of the limbic
system in the rodent brain.
For example, here, there's neocortex at that level.
And then the temporal lobe there.
You see olfactory cortex down there.
And then, in the position of the striatum
here, it's mostly amygdala.
Maybe I've drawn it a little bit for that
level, caudate nucleus.
You go further forward, of course, the
caudate's very large.
If you follow the neocortex around in either direction,
you get to the limbic areas, both medially
and ventrally here.
The same is true up here.
The limbic area's here, except medially, it becomes the
septum where the two hemispheres are joined across
the midline.
And then down here, you're in the basal forebrain.
Olfactory cortex first, and other structures
of the basal forebrain.
And this is just the caudal end of the hemisphere where
this is all hippocampal formation
on the inner surface.
Entorhinal cortex, and then finally, neocortex up there.
And then, of course, hypothalamus.
And if you follow the hypothalamus back, you're in
the limbic midbrain area there, the ventral tegmental
area, and then dorsal to it, the central gray.
Let's go through the Papez circuit again.
What's this structure at the caudal end of the
hypothalamus?
You remember it?
Somebody must remember.
What do you call it?
AUDIENCE: [INAUDIBLE].
PROFESSOR: Two little protuberances.
AUDIENCE: The mammillary bodies.
PROFESSOR: Mammillary bodies.
OK.
And that projects to the thalamus' anterior nuclei,
which has a projection, goes forward out of the
thalamus up to the--
what's that cortex right above the callosum called?
We do a brain dissection, we'll see it.
Every sheep brain, every human brain, every rodent brain,
what's that cortex right above the callosum.
It's like a belt.
Cingulum.
Belt is "cingulum" is Latin.
The cingulate cortex.
And we follow that around, we get behind the corpus
callosum, and we call it retrosplenial, because the
splenium of the corpus callosum is the
caudal end of it.
And it's those cortical regions on the medial surface
of the hemisphere, including entorhinal down here, that
project into hippocampus--
the hippocampal formation, which then projects out
through this--
there's the arch of the fornix.
Remember, the arches of fornication.
That's why it's called the fornix.
And there, it comes around the thalamus into the septal area.
And we call that the columns of a fornix, because its
formed axons are just bundled together coming through the
caudal into the septum there.
Then we pick them up here, come right down into the
hypothalamus and mammillary bodies again.
So that's Papez circuit.
And there it is here, mammillary bodies, anterior
thalamus, cingulate.
And then I add some complexity to show you what these
connections to the hippocampal formation, which I outlined
there in the dashed line, what those are like.
And then out through the fornix to the mammillary
bodies but also to the parts of the hypothalamus.
And then here, I've asked, what are the inputs to that
circuit and what are the outputs?
Let's look at the inputs.
I'll put them in green Here's an input coming from the
hindbrain, carrying
information about head direction.
We'll go through that again in a minute.
That's one input.
Well, look at the inputs up here, particularly in
large-brain animals with big association areas, association
areas of the neocortex.
That's providing major input.
And it comes in by a couple of routes right into the
hippocampal formation.
And then, if we follow the outputs, how does it get out?
Well, it does have a projection
back into the hindbrain.
The more interesting ones for us are up here, projections
into the association areas.
So the association cortex, the seat of our higher cognitive
function, including speech functions, is being influenced
by the limbic system by these connections seen in the Papez
circuit diagram.
And then, of course, these are all outputs here into the
hypothalamus.
Hypothalamus and septal area.
Hypothalamus, we know, has a major importance in
controlling our motivational states, our
emotions, and so forth.
And this is the summary of the transcortical pathways, all
the way from primary sensory areas through
the association areas--
unimodal and heteromodal--
then through paralimbic areas and limbic regions, including
hippocampus and amygdala, into the hypothalamus.
And that's Mesulam's summary, which we'll come back to again
when we talk about neocortex.
And this is just to remind you that we're dealing with the
substrate for pretty profound mental states.
So now let's go back to the medial pallium, the
hippocampal formation of mammals.
And just a few terms now, just to review.
The term "limbic telencephalon." It means the
endbrain structures that are closely connected to the
hypothalamus.
That's the way we define limbic system.
So in the telencephalon, or endbrain structures like the
amygdala or hippocampus that are closely connected to the
hypothalamus.
And that would include the septum, for example, and
includes olfactory cortex.
Then the term "pallium," which means a "cloak" or a "mantle."
The pallium is all the surface structures of the endbrain in
particular.
And the medial pallium includes what we call
"hippocampus." In fact, "medial pallium" is often
taking as synonymous with hippocampal formation.
So when we're talking about function, and we're dealing
with the medial pallium, we're talking about spatial memory.
We'll define hippocampal place cells, synaptic enhancement
and information in the hippocampus.
And say a little bit about acetylcholine in [INAUDIBLE].
Most of you know the definition of place cells.
I took this from Wilson's website.
Each little box there represents a little area.
I'm not sure exactly how big it is, but as big as part of
this table, with the rats running around.
And the colors represent what a cell in the hippocampus is
doing, how fast it's firing.
So the hotter the color, the faster it's firing.
For example, look at this one here.
Only when the rat's in that one place in the box is the
cell firing.
The opposite sides of the box, it doesn't fire.
Some, he didn't get responses at all.
Some were much broader in their firing patterns.
But many of them fired specifically when the rat was
in a particular place.
And those are the ones we call "place cells." That's why
they're called "place cells."
Another common functional cell type in the hippocampus and
along the circuit coming up from the hindbrain and
mammillary bodies are the head direction cells, the HDCs.
Here, I've defined head direction and the way it's
usually done.
Here, you draw this line along the body axis.
And just draw it forward, and then note how much the head
has deviated from that direction.
So that angle there is the head direction.
So many degrees to the right or from the straight-ahead
position of the body.
So it's different from place cells.
What else do you need besides the place you're at in this
room and the direction of your head in order to predict where
you're going to be in a minute?
Just locomotion information.
Does anybody know how locomotion information gets
into the hippocampus?
I know a lot less about that, because that's not what the
physiologists are talking about.
But I believe Matt and his students are beginning to get
at that as well.
So this is just the review of the Papez circuit.
And I indicated there--
sorry, it didn't [? read the disk ?] very well,
my line around the hippocampal formation structures.
Occasionally, people actually include entorhinal area and
other paralimbic areas that project strongly to the
subiculum and the dentate as hippocampal formation.
So occasionally, all of this will be included as
hippocampal formation.
I point out here that head direction cells are found all
along the pathway and what we think their functional
significance is.
And here, as I mentioned before, the likely role of the
hypothalamus in updating the internal map to add some kind
of activation or motivational component that could affect
priorities and the information the hippocampus is sending to
the hypothalamus.
And it sends it to various parts of the hypothalamus.
I could actually alter the level of various drives,
according to the position of the animal in the environment.
So that brings us back to evolutionary origins of the
medial pallium.
Remember, I had pointed out two major links between the
olfactory system of the endbrain and motor systems in
the midbrain, the through the ventral striatum and then
through the medial pallium, [? what we'll call ?]
the hippocampus.
This is the same outline.
I've just expanded it.
And the one through the medial pallium, I point out that both
of these links through the ventral striatum and through
the medial pallium, were plastic connections so
learning could occur, could alter the nature of those
pathways, depending on what the odors were.
Now, initially, just odors.
But then, of course, other sensory systems came in to
those same structures in both the striatum And the whole
dorsal striatum evolved and the media pallium with many
inputs other than olfactory.
And here, I'm pointing out two major pathways coming out.
Here's the pallium up here, ventral striatum down here.
And by the way, one of the major outputs of the
hippocampus is through the ventral striatum.
And the outputs went to hypothalamus here, one through
subthalamus in the midbrain.
Let's just take a look at that medial pallium in the shark,
the lungfish, the bullfrog, and then
we'll get to a mammal.
And I like the marsupials here because they show hippocampal
formation where there's no corpus
callosum to confuse you.
They do have a connection between the hemispheres, but
it doesn't form a corpus callosum.
They all go through the anterior commissure.
So fibers, in order to get, say, from the visual
association cortex way back here, have to go all the way
forward through the anterior commissure and then all the
way back on the other side.
It's a little bit inefficient, but that's the
way marsupials evolved.
And then with a lot less cortex, the hippocampus is not
pushed into the temporal lobes, because they don't have
a temporal lobe.
So here, in a shark, there's the medial pallium up here.
And you'll notice not enfolded.
It doesn't stand out, except more caudally here, where it's
become much thicker than the rest of the pallium.
There is a rudimentary dorsal pallium up here.
This is all olfactory in nature.
This would differentiate into striatum down here.
The olfactory projections cover most of this.
There may be a small area up here that doesn't get
olfactory projections.
Here's a lungfish.
And again, the medial pallium is starting to differentiate,
and neuroanatomists can separate
different parts of it.
Here especially, you see the thickening of that
area in this part.
But it's a large part of the endbrain.
There's a little bit of a dorsal area up here, but maybe
non-olfactory.
I'm not sure.
I can't remember the studies of lungfish.
I think there are a few.
But most of this is olfactory, including some
of the medial pallium.
And it can be followed through a large part of the
hemisphere.
Here's the bullfrog, where the media pallium has become quite
enlarged, but it's not enfolded.
There's a little bit of cortex up here we call "dorsal
cortex" that gets some other sensory
input other than olfactory.
There's some mixture of olfactory and non-olfactory.
And most of this is just olfactory
cortex and ventral striatum.
Here of course, you're getting into 'tweenbrain.
This is hypothalamus down there.
Now, the opossum.
No corpus callosum.
Some of the pallium has become thicker.
It is now neocortex.
You can find the six layers of mammalian cortex here.
And then here, it become thinner as you go medially.
It becomes thinner.
And this would be the equivalent of
singular cortex here.
It's not a belt of cortex above the corpus callosum.
But then you follow it around, and you can see, now there's
little sulcuses forming there.
And this is now hippocampus that's enfolded.
And then, anteriorally, anyway, it joins with the
septal area, rostrally.
You go around the other way, you go from neocortex through
another sulcus here.
This is the rhinal sulcus.
And then you're in the olfactory cortex.
And olfactory input comes in all of this to the striatal
area down here--
the ventral striatum--
and the piriform cortex there.
So what we're going to do-- we'll do most of this next
time-- we'll answer these kinds of questions, the major
subregions of the hippocampus and the adjacent structures,
the interconnectivity--
we'll use this term, "CA"-- our Cornu Ammonis, the Latin
for Ammon's horn.
It's just a name given by the gross anatomists who were just
looking at the appearance in a dissection.
They weren't looking at stained sections.
So we actually have two words based on that gross
appearance, the hippocampus, meaning "seahorse," because of
its appearance in the human brain, and similarly, based on
human, "Ammon's horn." So they talk about CA for Cornu
Ammonis, CA1, CA2, CA3, CA4, for different regions along
that cortex that look a little different from each other in a
cell stain.
And then we can talk about the major input--
what's become the major input in the human--
namely, the input from the entorhinal cortex that carries
a lot of information other than olfactory.
Only a little bit of entorhinal cortex gets any
olfactory information in mammals.
Most of it is getting other kinds of information,
primarily from association cortex, as
shown in that diagram.
So we'll be looking at various pictures of that in naming
where these structures are.
And we'll do most of that next time.
I will formulate that quiz, which you will all do well on,
as long as you think clearly, coming up with questions about
what we've been talking about.
It'll force you to go back and look at it and try to figure
out what are the important points.