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PROFESSOR: All right.
This is session two of 9.14, and we have a few slides from
session one.
I'm not going to rearrange the slides all the time.
If I didn't finish, I'll just continue with the previous
class in the next session and then we'll just
try to catch up.
The book chapters that you're reading, that were written by
me, I would greatly appreciate any comments.
I've already gotten a good comment
from my teaching assistant.
Did you introduce yourself?
AUDIENCE: I'm a teaching assistant.
PROFESSOR: And also when I list in the assignment sheets,
what I call readings and study questions, those readings, if
it's just written out with no brackets, it means I expect
you to read them for sure.
I put brackets around the things that are recommended,
and if you don't have time to read them all that's fine.
But it will help you, and a good thing to do with those,
if I posted them, is to at least look at the figures.
This is a class where you learn a lot from pictures,
which is one reason I use the tablet PC, so I can show the
pictures and draw on them and so forth.
And sometimes I add notes to them, and then when I post the
slides online, you can see those notes.
OK, we were talking about primitive cellular mechanisms
and how these are expressed in neurons.
We mentioned that movement is found in neurons too, but
mainly when they're developing.
Muscles, of course, with these proteins that some version of
these proteins have been around.
These contractile proteins have been around since
protozoa, but first they'd become specialized, and
especially in striated muscles.
Now we want to say more about secretion.
Much more important to neurons.
I mentioned it was used in protozoa, for attacking prey.
It's used that way in sponges too, in pretty much the same
way as in protozoa, except now these secretory cells are
located near these little openings.
They also use for ingestion.
And that property has evolved in many cells, of course.
But it's specialized in neurons.
And I want to talk a little bit about the discovery of
chemical transformation at the synapse.
How many of you know the story of Otto Loewi and his dream?
A few of you?
And you didn't hear it from me, right?
Good.
Glad a few of you know it.
This was in the early years of the 20th century when there
was a lot of debate going on, whether synaptic transmission
was chemical or electrical.
Well, how did they know about synaptic transmission?
Well, from electrophysiological studies.
Charles Scott Sherrington in England especially, was a very
dominant figure in electrophysiology.
His favorite preparation was the spinalized cap, so he was
looking at spinal reflexes.
And he worked out a lot of the properties of synapses without
ever seeing them.
Or, without knowing exactly how they worked.
So there was quite a bit known.
They knew they were excitatory and inhibitory synapses.
They knew, there was even some evidence about how much time
was involved in crossing the synapse.
But they still didn't know what to do to figure out
exactly how it worked.
And then Otto Loewi, who had one of the labs working on
this, he had a dream.
And in his dream he realized how you could demonstrate
chemical transmission, and if it took place at least he had
a good idea.
And he scribbled notes.
Went back to sleep.
And when he got up the next morning, he neither remembered
the dream nor could he read the notes.
They were scribbles.
Fortunately, he had the dream again.
And this time he didn't take a chance.
He got up and went to the lab.
And the experiment he did was this.
He took two frog hearts.
Dissected from the frogs with their main
nerves still attached.
The accelerator nerve, which it was known, if you
stimulated the accelerator nerve, you got faster beating
of the heart.
The decelerator nerve, when that was stimulated, slowed
the heart down.
And he one each in two Petri dishes.
And so what did he do?
Well, he took the one in one Petri dish and stimulated the
accelerator nerve.
And he stimulated for a while.
So the heart really speeded up, and then he transferred
with a pipette some fluid from that dish to
the other Petri dish.
And that heart speeded up too.
The only way that could have happened would be by some kind
of chemical means.
So then he did the same thing for the decelerator nerve and
he got it slowing down just with a transfer of fluid.
He didn't know what the substances were.
That was discovered later.
It was later found out that the--
what were they?
What's the accelerator, acceleransstoff, in German,
that's what he called it.
It was norepinephrine, released by the sympathetic
nervous system axons.
What was the decelerator?
The vagusstoff?
The vagus stuff.
Because it was a branch of the vagus nerve that caused the
slowing of the heart.
So that's why he called it.
He named it after the vagus.
That was found to be acetylcholine, used in the
parasympathetic nervous system in many parts of the body.
Now, electrical synapses are found.
That was discovered much later.
They have somewhat different properties than
the chemical synapses.
They've also discovered, of course, there are many
different kinds of chemical synapses with different
properties.
He had just discovered two of the types.
The chemical synapses they can see with electron microscopy.
No-one saw synapses, at this time.
They didn't see them until the electron microscope was
applied to nervous system tissue after careful fixation
with osmium tetroxide in the 1950s.
So roughly 50 years ago, finally we
started seeing synapses.
And the first book summarizing a lot of that early work was
done right here in Boston.
Harvard Medical School, by Sandy Palay and people to work
with him Peters, Palay, and Webster are the authors of
that first book, and it's still a very good book on the
morphology of synapses seen with the electron microscope.
And this is a commonly used type of cartoon
of a synaptic junction.
One misleading thing about this is it shows a single
enlargement at the end of one axon, with one synapse.
That's actually not very common.
Most enlargements would contain more than one synapse.
There are other small pieces of the membrane are involved.
But this allows the artist to summarize major properties.
The depolarization of this membrane when it enters this
terminal region, and that membrane's depolarized by the
action potential, which will cause an influx of calcium.
Now, that calcium is not very important to the conduction of
the action potential, but it's very important for the release
of neurotransmitters.
And the amount of depolarization will determine
how much calcium comes in, and what the calcium influx is,
and how many of these little vesicles will bind to the
presynaptic membrane and release neurotransmitter into
the synaptic gap here between the membrane of this cell,
membrane of the blue tongue, the enlargement, and the
membrane of the post-synaptic cell.
And then the post-synaptic cell has
molecules in its membrane.
We call them receptor molecules.
They bind to those neurotransmitters.
And that binding causes changes in the membrane.
It can be depolarization or it can be hyperpolarization.
So if you record, in this cartoon you see electrodes
inside a cell.
And you see two cells, the pink one and the blue in here,
contacting that cell.
With synaptic junctions.
If you stimulate this one, it causes
depolarization of the membrane.
So here's the resting potential here, and you see
this is the presynaptic, response the action potential.
Here's the post-synaptic response.
A little depolarization.
The EPSP, excitatory post-synaptic potential.
And then for the inhibitory cell here, an inhibition is
almost always through a short axon
interneuron, as you see here.
Where excitatory effects often, it's a long axon cell.
Doesn't have to be a short axon interneuron like you see
in the picture here.
So here's the effect of the same thing on the presynaptic
side, the action potential invading the terminal.
But now, with a release of inhibitory neurotransmitter,
the result is an IPSP, inhibitory
post-synpatic potential.
A slight hyperpolarization of the cell.
It's moving the cell further from the threshold for
triggering an action potential.
Most of you know all these things from 901 or other
things you've read in neuroscience.
But maybe you don't know all of this.
Synapses have varied structural arrangements.
This one is really only one of many types, and not very
accurate for morphological details.
You can find axosomatic terminals from an axon to a
cell body, axodendritic.
These are the common ones.
But you could also have axon to axon.
An axon terminal ending on another axon terminal.
And that can cause what's called presynaptic inhibition
and facilitation.
I'll say more about that in just a second.
You also actually find dendodendritic, dendroaxonal,
just about every combination that you can think of.
You have reciprocal synapses, I'll show a picture of that.
You have serial synapses.
It's a kind of gating mechanism.
I'll show you a picture of that.
And you even have synapses that aren't really synapses at
all, because synapse means, like, clasping together.
But you have endings with the morphology of a synapse, but
there's no post-synaptic membrane
that they're up against.
So they're releasing their neurotransmitter into the
intercellular space.
They are modulators in the nervous system.
For example, dopamine and norepinephrine in the cortex
often end like that.
They just release neurotransmitters and affect
cells in the region.
Not just a single cell.
So I've sketched these from EM pictures,
electromicroscope pictures.
Here's an axosomatic terminal and I'm just showing the
direction of the effect.
Here you see a synaptic bouton.
Here's a synapse.
It might actually have several.
And on the presynpatic side you have the
accumulation of vesicles.
And then there's a thickening of the membrane, usually a
thickening on both sides.
I show it here on the presynaptic side.
And here are axodendritic synapses.
And of course, we know that dendrites can be just studded
with synapses.
Most of the synapses that we are concerned in studies of
neuronal function are axodendritic.
Here is an axoaxonal synapse, up here.
So here's axon A, here's axon B. So, how does it work?
If axon A fires an action potential, what's going to
happen here?
Well, let's say it depolarizes is the
membrane of axon B's terminal.
It de-causes depolarization.
When that depolarization happens, it's not triggering
any action potentials.
It just depolarizes the membrane momentarily.
Now, what if an action potential arrives through axon
B here, just afterwards?
What will be the difference in the effect
of axon B on C here?
Let's say that's a cell.
What will be the difference, whether a fires or not?
Well, if A has depolarized B's membrane, then the membrane
depolarization, when the B action potential arrives,
wouldn't be as great.
And it won't release as much neurotransmitter.
So we call that presynaptic inhibition, even though it's
due to a depolarization of the membrane.
Do you understand?
We call it presynaptic inhibition.
It's common in dorsal root axons
entering the spinal cord.
Now, if in fact this causes a hyperpolarization, you'll get
the opposite thing.
If you get presynaptic facilitation, you'll get an
even larger action potential.
Because the membrane was hyperpolarized.
So if the depolarization is greater at that terminal, more
neurotransmitter will be released.
You'll enhance its effect.
So you can modulate the effect of the terminal on axon B here
by the kind of contact made on A.
Now, reciprocal synapses down here.
Notice I show a terminal here.
A somewhat larger terminal.
And there's a synapse going from left to right here.
And then, this process, it could be a dendrite, it could
be a cell, there's a synapse there too.
But it's going in the opposite direction.
So when the membrane of the second cell here, on the right
side, is depolarized, it activates this, and gives
feedback to that prior cell.
So it might in fact reduce the likelihood of another
potential, or reduce the size of subsequent excitatory
post-synaptic potentials.
So that's a reciprocal synapse.
You can also have serial synapses.
All these arrangements have been seen, for example, in the
superior colliculus of the visual part of the midbrain.
Where there have been a lot of detailed studies of
synaptology.
Here's a kind of gating mechanism.
Here's the first axon.
I've labeled it here, one.
Terminates on this process.
Probably a dendrite.
And that process then has a synapse on the third process.
So the status of the cell here represented by the number two,
that effect on three will depend on its state of
polarization when the first action potential
arrives over axon one.
And I've already mentioned the cells without
a presynaptic side.
I didn't try to illustrate that.
You can just draw a terminal with no
post-synaptic membrane.
OK.
So we've talked about these things on the left.
I didn't say much about neural hormones, that just means a
neuron that is secreting into the bloodstream.
Not just at a synapse.
It's like a synapse, but it's secreting into
the blood, on a capillary.
And we'll mention some of those later on.
Now, let me just make sure you can define these terms.
Exocytosis, endocytosis.
What are they?
Well, when we talk about secretion of a chemical by a
cell, we're talking about exocytosis.
So at a synapse, you have exocytosis of the
neurotransmitter.
It's coming out of the cell.
What is, then, endocytosis?
Well, that means the substance is taken up by a cell.
And that happens commonly in cells all over the body, and
we know that happens commonly in neurons because we can
inject proteins of various sorts, for example, in a
region of terminals.
The cell will take up those proteins.
And then, those proteins often get transported by an active
mechanism we call intracellular transport.
We don't just mean diffusion of a protein, or some other
substance through the cell.
That happens too.
We mean an active mechanism that uses energy, and we get
intracellular transport of organelles as well as various
kinds of molecules,
particularly protein molecules.
And that transport can be retrograde or anterograde.
What does that mean?
If it's retrograde, it means it's moving down an axon
opposite to the direction of the normal action potentials
of the cell.
So it's going from the endings back towards the cell body.
That's retrograde.
And it involves a protein called dynein.
If it's anterograde transported, it's going from
the cell body to the endings.
That's the way a cell that's manufacturing a
neurotransmitter, or components of the
neurotransmitter, will transport these substances.
Or it might be translating vesicles and moving membrane
down the axon to the terminals.
That involves a different protein, kinesin.
Then we get to this more complex cellular mechanism,
parallel channels of information flow which require
some kind of integrative activity.
That is needed in all multicellular organisms in
particular.
How does one the end of the animal
influence the other end?
How does one side coordinate with the other side?
When you're dealing with multiple inputs and outputs,
which you have in all organisms, how
do you avoid conflicts?
So that leads to study of the evolution of interconnections
among multiple subsystems of the nervous system.
And that's the main topic of the class.
How do we study such connections by the methods of
neuroanatomy, or neural morphology is a synonymous
term there, for neuroanatomy?
But it can also be studied by neurophysiology and studies of
neurochemistry and studies of behavior contribute a lot to
the way these connections work as well.
So that's what we're going to be doing now, with this class.
So this is where we just ended up.
I didn't say anything about endogenous activity yet, but
we will get to that.
Of course, this need for integrative action increased
with greater size and complexity of the organism.
These are the questions we asked before.
So to make sense of that lump of porridge that's the brain,
we study the connections.
And we subdivide the brain into different modules which
can be defined anatomically and functionally, and often
those two definitions pretty much jive with
each other, not always.
And often we have to use multiple methods to study the
very same brain.
We often use not only the neuroanatomical methods, but
these other methods that I mentioned.
And in recent years, various imaging methods have been
invented and applied to not only fixed brains but living
brains of people and animals.
So now we can get evidence, for example, in localization
of damage to brain.
We can get it in some details of major regions of the brain,
even without using the anatomical methods, by just
using the imaging methods.
I've been involved in studies recently of some cetaceans,
the Atlantic white-sided dolphin, for example.
And also the California sea lions, with Eric Montie, who
is the lead investigator in these studies.
I just help to figure out what's what.
It's a lot of fun, and we are learning a lot just by
applying these magnetic resonance imaging methods.
Most of them are done on porpoises and sea
lions that are dead.
They've been washed up on the shore, but not always.
Sometimes we get a chance to do it on live ones.
So, to look at neuroanatomical methods.
The initial steps, they always start with
fixation of the tissue.
In order to do anatomical studies, you can't really use
unfixed tissue.
What is that unfixed tissue like?
Like a lump of porridge.
Or like vanilla pudding.
It's really a mess.
And it falls apart.
I once was offered to get some brain tissue
from autopsy in India.
I wanted to get a fetal brain for study here at MIT.
And the doctors insisted they would get the
brain out for me.
I didn't have to come to the hospital.
And I warned them, it's not as easy as it sounds.
And sure enough, they were trying to give me a young one.
They messed up every one.
It's just really hard without doing some kind of fixation.
And then, we often embed those brains.
Sometimes after fixation they're frozen solid before
their sectioned.
Into thin sections.
But usually they're surrounded with something to hold the
brain together when you cut it.
And we don't have to freeze it.
There's other methods.
You can infiltrate the tissue with paraffin, for example.
Or with celloidin.
Just in order to be able to cut these sections.
So here's a brain of a little rodent, like a
hamster or a mouse.
And it's illustrating their frontal section.
However did this was interested in the hippocampus,
so he's showing where the dorsal hippocampus is there.
And he's showing a slice made, and then that slice, you make
a lot of these slices.
And sometimes you're not mounting them as you're
cutting them.
Sometimes you're just collecting them in the fluid,
and then you're mounting them one by one on the slides.
Or if they're a small brain, sometimes you can mount up to
six or eight of them on a single glass slide.
And then after you get that fixed tissue cut in thin
slices on the glass slide, now you can do things with it.
For example you can apply a basic dye like crystal violet,
which is what was done here.
And that dye will bind to particular components of the
cell in the cell body region.
Now, whenever you're in an axon bundle, you'll just get a
little bit of staining in the oligodendrocytes that make up
the myelin sheath in the central nervous system.
But you can see a little bit.
What do you see here?
I've pointed out one that's really obvious.
This cell group in the hypothalamus, there, this is
the hypothalamic region, you can see a cell group there.
It stands out because the cells are staining a little
darker and it's a little lighter, there's fewer cells
in this halo around it.
And that really defines the ventromedial nucleus in many
different animals very well.
But you can see some structure in the thalamus up above here.
In the epithalamus here you can see one little group
there, which is highly packed, dark staining cells.
But look up here.
Look at the nice layers of cells, and the folding of the
tissue that you see up there.
This is the hippocampal formation here.
And up here you have neocortex, and if you look
carefully you can see very clearly layers, not only the
obvious one at the top there, but you'll see some evidence
of layers here.
And so we can say there's layer one,
there's two and three.
There's four.
There's five, the big cells.
And then, six-A, six-B, six-C. We like to say there's six, so
even if there's more we keep just
subdividing the other layers.
Now, I drew that too low, sorry.
Because right below that line, there's a light staining area
that doesn't have neurons.
Only the oligodendrocytes, and that's the so-called white
matter of the brain.
Now here's a close-up.
This was taken from a human.
This is from the [? Nauder ?]
book.
And if I haven't posted some of these readings, like where
figure 112 is there, you can often find it.
A lot of those documents are in the things I
imported from last year.
And I move them into the appropriate topic when we get
close to it.
But here's the very surface of the brain.
You can see the very surface doesn't seem to have cells.
What is tissue without cells?
Well, there are cells there.
There's parts of cells.
But they're mostly dendrites and axons.
And they're not staining with this stain.
This is the Nissl stain again, and it's staining the cell
body region.
So you can see the big cells in the upper part
of layer six here.
And here are some large cells in layer five.
Layer four, in this region, in area 17 the striate cortex or
visual cortex of the human, has multiple sub layers.
The same is true in monkeys and apes.
And so forth.
You can define differences.
And you'll also see that one cortical area, you can see
that there's some kind of border right there.
And to the left there, we're in a different kind of area
than to the right.
So we can subdivide the brain according to cytoarchitecture.
The architecture of cell arrangements.
And here's another kind of architecture.
Here this is a kind of fiber architecture, we can even call
it myeloarchitecture because we're using a myelin stain.
This is a myelin stain applied to a slice of human midbrain.
And you can see these enormous bundles of axons coming along
the base of the brain.
Very large in humans.
Cerebral peduncles.
They carry fibers from the biggest part of
our brain, the neocortex.
And that's how fibers go from the cortex to two major
structures.
Cerebellum and spinal cord.
Of course there's many.
The neocortex communicates with all levels.
And then you can make other pathways.
And I'm not naming them all here, it would drive
you crazy if I did.
But we will gradually get to the point where you'll be able
to give me a pretty good estimate of what a lot of
these things are in this midbrain.
Now what is this one?
Suddenly a lot less myelin.
This is a horizontal section through a seven
week old human brain.
And a lot of myelin hasn't formed yet.
And yet a lot of the brain is there.
And there's a lot of axons, but they're just beginning to
be myelinated.
The myelin doesn't form until after the axons have grown.
And the axonal pathways are already formed.
And you can see that in the cerebellum here, the white
matter-- we call it white matter because in unfixed
issue it looks whiter than matter where
there's more cells--
but here we've stained it with myelin
stain, stained it black.
And we also see three pathways coming up into the cerebral
hemispheres, the cortex.
The visual radiations, the auditory radiations, and the
somatosensory radiations.
So they myelinate relatively early
compared with other pathways.
In fact, that was an early method of figuring out things
about pathways and connections.
Here's an example of chemoarchitecture.
We used a stain specifically for a particular chemical.
In this case it's acetylcholinesterase, the
enzyme that destroys acetylcholine when it's
released in the brain.
And we see the midbrain has concentrations in layers and
patches, in the deeper part of the colliculus.
In that layer we see little patches.
And also in the deeper layers.
And we also see in the central part, near the aqueduct, where
the ventricular fluid can be found.
There's one little region on either side there.
So that's acetylcholinesterase.
Here's another example of acetylcholinesterase.
Histochemistry, we call it.
Histo-, meaning we're doing it on sections.
Like in histology, the study of sections.
Here we're looking at the endbrain of a pigeon and a
squirrel monkey.
And you'll notice that this subcortical structure in both
animals is very heavily stained, whereas the overlying
structure, surrounding structures,
are not well stained.
So we can help define something about the
similarities in these brains by looking at
chemoarchitecture.
This happens to be the corpus striatum, by the way, in the
two animals.
And it was such pictures that helped us learn that lot of
the brain of the pigeon up here, and other birds, was not
really striatum at all, even though the cell stain looked
like it probably was.
But the acetylcholinesterase indicated something different.
And studies of connections have confirmed that.
Another kind of chemoarchitecture uses
immunohistochemistry.
Histochemistry meaning we're still going
to leave you sections.
In this case, though, we're using an antibody that's
specific to a certain molecule, in
this case opiate receptors.
And we see the opiate receptors are concentrated in
certain regions.
This is a horizontal section.
This is anterior and posterior.
So there's the olfactory bulbs.
Neocortex on the outside.
Here's midbrain back here, thalamus up here.
There's a corpus striatum.
And you can see some regions have high concentration, shown
by the yellow and orange.
And other regions have much lower concentrations of the
opiate receptors.
And then, newer tech--
that's all of course fairly recent, the use of antibodies
for histochemical studies--
but even more recent is the study of
gene expression patterns.
And I'm just pointing out here that you can go online and
learn something about expression patterns of about
200,000 different genes.
And I brought a picture from this study published in 2007
where we're looking here at little slices of cortex with
six different methods.
Looking at different genes that are specific not-- sorry,
this is the Nissl stain--
but here's one that's staining the few cells up
there in layer one.
Here's one specific to layer two.
Here's two and three, and a deep part of layer three.
Layer four.
Large layer five cells down here.
Can you see that little spot?
Am I wasting my time here?
How many can see that little spot?
You can see it?
OK, maybe you can see it better than I can.
Because I could bring, I probably have a laser pointer
here someplace, so I could bring it and point to the
screen if that's easier for you.
So, different groups of cells have different gene
expressions.
Now we want to talk about, how do we get to study
connections.
The histochemistry is not going to tell us that.
A lot of these methods allow us to draw lines around
different regions of the brain that are
different from other regions.
But they're still not telling us about what's
connected to what.
And we want to move towards that now.
Because that's extremely important
to understand function.
In this case, I'm showing you a picture using the stain of
Camillo Golgi, a stain that was used most prolifically by
Ramon y Cajal, who we consider sort of the father of
neuroanatomy.
I think we showed his picture in the first lecture.
I probably have it here, too.
There he is.
And in this case, this is a slice of neocortex, a frontal
section, and the black cells are Golgi stained.
The blue cells in the background are done with a
counterstain that's staining cell bodies.
They're not very well stained, but you can see them there in
the background.
And it's just to illustrate that the Golgi stain only
stains a few of them.
Somewhat haphazardly.
But usually fairly randomly.
And notice that many of these cells have a characteristic
shape, they have sort of a triangular shape here.
They have a series of dendrites radiating out from
the base, and then they have this long dendrite going up
towards the surface.
Those are pyramidal cells, the most common cell type in the
neocortex, the one that really defines the neocortex.
This particular cell is not a pyramidal cell.
There's a pyramidal cell body.
And there's its apical dendrite.
And the Golgi method was used a lot by Ramon y Cajal, long
before we had any experimental anatomical methods for
defining connections in the brain.
We could use an axon stain like a myelin stain or there
were silver stains developed in Russia.
Bielschowsky, for example.
It's a good axon stain for using silver methods, which
could stain smaller fibers.
Even unmyelinated fibers.
But just staining normal fibers doesn't prove anything
about connections.
The advantage of the Golgi stain is because even though
it stained only a few, when it did stain the axons, you could
often follow them all the way to the endings.
And you could see the end arborizations, you could see
the little enlargements.
And even though Ramon y Cajal never saw a synapse, because
the electron microscope wasn't invented yet, he was able to
come to the right conclusions.
He guessed right about a lot of things.
He was a great man and a great
neuroanatomist and very prolific.
And in this case he's applying it to a spinal cord and you
can see axons coming in from dorsal roots, distributing to
different layers in the cord with
different kinds of arbors.
In this case, he's showing just the ventral part of the
spinal cord.
And here he's focusing, he had a stain that was staining very
well these large neurons in the ventral part
of the spinal cord.
These happen to be motor neurons.
And you could see that because there's a neuron and he's
pictured the axons in a color, because they looked a little
different to him.
And he was usually able to tell the axon
from the other processes.
So here, you see all the dendrites.
And you see they're covered with little protrusions.
They're spines, dendritic spines.
And then he was able to follow the axons.
Sometimes the axon originated from a large dendrite.
So here's one, and it goes out.
So that's going out to a muscle cell.
And then the same axon often has branches that are
connecting within the cord, giving some kind of feedback
to the cells within the cord.
They connect with interneurons.
So Cajal was the first person to see a connection all the
way from the input side to the output side.
And that's what he's picturing in this little cartoon, where
he's sketching this from his many different studies of
brains and spinal cords that he had done.
And he's showing a primary sensory neuron with the
dendritic arbors out here in the periphery, in the skin.
And he's saying that the information has to be flowing
in the direction of his arrow, towards the spinal cord.
There's the cell body off to the side, pseudounipolar cell
of a dorsal root ganglion, that we mentioned yesterday.
And then the axon comes into the cord and as it branches it
goes up and down the cord with many little
arbors inside the cord.
And some of those arbors he saw connecting directly with
motor neurons.
And the motor neurons, he could trace
right out to muscles.
So that would be a pathway for monosynaptic reflex.
The monosynaptic reflex arc.
He was the first anatomist to be able to define it
anatomically.
So suddenly, the people who studied the function and
talked about the SR model of behavior, they
now had a real champion.
They had somebody who had actually seen it.
And this wasn't just a black box anymore.
We could begin to understand actual connections that
underlie function.
In this case it would be the stretch reflex.
We know that these wouldn't actually be coming from skin,
they'd be coming from muscle.
And the muscle to muscle reflex, the terminals there
would be in the same muscle.
It's a response to stretch of the muscle.
So to say a little more about brain connections and
behavior, I like to tell the story of Karl Lashley, who we
often consider Lashley the father of experimental
neuropsychology, because of the way he applied
experimental methods to study brain behavior relationships
in the laboratory.
Rats were used for many of his studies, but as a student he
encountered slides of a frog brain done by anatomists.
And he realized this.
At least he thought he did.
He says, if I could use this kind of material to see all
the connections, it would be possible to
explain the frog's behavior.
In other words, he could take a mechanistic approach to
explaining behavior in terms of connections.
And of course he was assuming the SR model, that behavior
depended on connections between the stimulus side and
the response side.
That started with Rene Descartes.
He was in the 1600s and we often attribute to Descartes
the origin of the concept of the reflex arc.
He described it for the first time, even though he didn't
have the methods to actually see the details of the
connections.
And that influenced the field of philosophy in
the following century.
Le Maitre wrote a lot about that.
And in the 1800s, Ivan Sechenov, who was really
important to a philosophical movement in Russia called
reflexology.
Explaining everything in terms of reflexes.
And the Russians carry that very far.
And the one who made that a more complete explanation of
behavior was this guy, Pavlov.
Because he added a very important thing.
He said, well, reflexes aren't all just fixed.
They can change by learning.
Conditional reflexes, or conditioned reflexes.
And that was Pavlov's great contribution.
Well, Lashley himself did not stick with
the reflexology idea.
He argued against the adequacy of this kind of model, because
he, for example, looked at the speed of finger movements of
the pianist during performance of a piece.
And he knew enough about how long, how fast axonal
conduction was.
And he realized you couldn't get all these rapid movement
and changes just with reflexes.
It was impossible.
And so he invented the idea of a central program that could
be learned.
And now we know, of course, that endogenous activity,
activity generated from within a neuron and generating
changes in behavior of the neuron, it
doesn't fit the SR model.
We know that motivational systems can trigger behavior.
That there are state changes.
For example, with deprivation and so forth.
But I just want to point out that among neuroscientists,
the SR model is still very commonly used.
Many neuroanatomists will talk about function in those terms.
But even whether you accept that model or not, a knowledge
of brain organization and connections is pretty basic
for understanding how behavior is produced and controlled.
So how do we know about them?
And we'll do most of this next time.
We know from dissection.
We know from staining techniques, which
we've talked about.
We have to ask how can we be sure that a
connection really exists.
The Golgi method has a big problem.
We can't follow axons over very long distances.
We lose them.
It's extremely difficult to follow them very far, with the
Golgi method.
And we usually lose them in a maze of other axons and cells.
In the 19th century, I was reading German
papers doing my Ph.d.
thesis, and I saw that--
I never read this in any of the books I
was reading in English.
But I found out that the anatomists
at that time thought--
they knew about occipital cortex being
important in vision.
And then, they of course knew that it of course originates
in the eyes.
So they asked the natural question, how do you get from
the eye to the visual cortex?
And I found that they didn't even know about the lateral
geniculate body in the thalamus.
They thought the pathway went to the midbrain tectum, the
superior colliculus.
And from there it went into the thalamus.
And then to the cortex.
And that became the textbook picture.
People forgot about that later because experimental work was
done that found that the geniculate bodies in the
thalamus were the cells that project to that visual cortex.
And then studies were done with experimental techniques,
tracing pathways from eye to the geniculate bodies.
So they forgot all about the midbrain.
That theory went out the window, and now they just
focus on the visual system.
Retina to geniculate body to striate cortex.
And it was only much later we began to realize we need a
more balanced view.
There's actually a lot of other connections to the
retina, too.
And we'll be talking about some of that.
And then we have electrophysiological methods.
We could stimulate the endings, for example.
And it leads to a particular waveform in the cell bodies.
The action potential travels in a retrograde direction up
the axon to the cell, and you can tell, if you're recording
near that cell, you could tell if it's antidromic activation
of the cell.
Because it's different from synaptic activation.
So they could find out about connections that way,
and that was done.
But I'm going to focus next time mostly about this,
experimental methods of tracing axon pathways.