[MUSIC PLAYING] Stanford University. --out by now, I am
not Dr. Sapolsky. You probably got some cues from
the beard and other things. My name is Nathan. I'm a graduate student. I'm a fourth year PhD student
in the neuroscience program. And I'm going to be giving you
the introductory lecture today on, basically how
the brain works. And just to get a sense of
who is here before I get started, how many
of you are either a biology major or HumBio majors
and decided to come today? That's a lot of people. OK. How many in other hard
sciences or engineering? A few. OK. How many in the social sciences? A few. And humanities? All right, humanities. Anybody else in anything other? OK. We've got a few others as well. OK, great. So for some of you, this
is going to be a review. And hopefully, you'll
still learn something new. For some of you, this is
going to be the first time that you're hearing these terms. And hopefully,
this will give you just a very general
background so that when you hear Dr.
Sapolsky give lectures on neuroscience later, you have
a better understanding of what he's talking about. So we started out this
whole course talking about the everlasting
question of, why did the chicken
cross the road? Yes, that's supposed
to be a chicken. My major is not art. But the chicken is
crossing the road. And we started the
course basically saying that this whole course
is going to teach us why the chicken crossed the road. And specifically, the
first half of this course is talking about the ways
that different sciences have approached this question. So we started out
with evolution, which would ask, how did this
behavior of crossing the road evolve over many, many,
many millions of years? Why was it adaptive? Why did chickens who crossed
the road produce more offspring? All of that. It was studied by
old men going around in boats to the
Galapagos to see how chickens on different
islands crossed the road and then figured out
how that happened over millions of years. The next week, we went
into molecular genetics. And there we talked
about the actual genes that control this evolution
and how it happened. And there we were talking
about people thinking about how genes change
in the genome over time, how they hop around, if we're
thinking about women in corn fields looking at this, and
how those individual genes led to evolution. Then the next week, we went
into behavior genetics. And this, specifically
was asking about what individual
genes are accounting for the variation in the ways
the chicken crossed the road. So some chickens cross
the road really fast. Some of them do it slowly. Some of them don't do it at all. How does the
variation in the way that the genomes are structured
for these different chickens account for that? So that was behavior genetics. And then on Monday, you
heard about ethology, which really talked
about studying this behavior in nature. And we talked about the
fixed action pattern. And we talked about
all the old man in field booths going out into
nature to observe that fixed action pattern and talked about
the stimulus the chicken would receive, why it would
cross the road after that, how it does it, again,
looking at that out in nature. And that was ethology. So today, we're going to talk
about yet another bucket, yet another way to think about
this, which is neuroscience. And neuroscience is going
to focus, specifically on this black box that
we talked about on Monday where you get the input coming
in of some stimulus that makes the chicken cross the road. And neuroscience is about
that black box in the middle and why it is that the
chicken is doing this. What was going on in
the chicken's brain a few milliseconds before
it crossed the road? Why is it that the
specific cells in the brain are doing this? And how are they doing it? So that's the overall
background of why we're thinking about neuroscience. And the goal for today
is really to give you an overview of the brain
and the nervous system, get to know some
different parts of it not so that you memorize a list
of different parts of the brain but so that you get
a general overview that different
parts of the brain are specialized for
different behaviors. And also, we're going
to zoom in a little bit on the actual cells in the
brain, how they communicate. Again, not so that you can
sit there memorizing lists of different things
but that so when it comes up in
future lectures, you will have a better understanding
of what we're talking about. And just as a caveat before we
start, I, as a neuroscientist, think this is the coolest
discipline out there, better than all the others. And you'll see I put in a
quote from Thomas Edison that says, "The chief
function of the body is to carry the
brain around," which is a very brain-centric way
of thinking about the world. And there are a lot of people
who look at neuroscience and think of it that way. Yes, neuroscience
has its limitations. Want to put that out
there from the beginning. It can be very brain-centric. It can be thinking about how
different parts of the brain control different behaviors
without considering the bigger evolutionary aspects or
any of the other aspects. So it does have its limitations. But I think it's really cool. So that's why I'm going to
tell you about it today. So let's start out. You have a brain. Actually, this is my brain. I volunteered for a psych
study back in college and got to look at some
pictures in a scanner. And they gave me this printout
of my brain afterwards. And the brain, I think,
is an absolutely amazing, amazing thing. And one thing that people
love about the brain is that it starts working
and keeps working. But just as a reminder
from this quote, "It never stops working until
you stand up in front of public to speak." So during this
lecture, there may be things that are confusing. If you don't understand them
because I'm not explaining them in a way that makes them
understandable to you, I've put my email
address up there. It's also in the handout. And it was at the beginning
of the presentation. So definitely email me if
you have any questions. Or come to see me after class. And I'll be giving this
first 45 minutes or so introduction to the brain
and the nervous system. Then, Anthony's going to come
up afterwards and tell you a little bit more
about how neurons communicate with each other. So let's think about the
brain and the nervous system. And to give you a
really broad overview, the nervous system is divided
into two really broad classes, the central nervous system and
the peripheral nervous system. And we'll start with the
central nervous system, which is what most people
think about when they think about
neuroscience, which is the brain and spinal cord. So you have this brain
sitting up there in your head. You have the spinal
cord going down communicating to
and from the brain. And this is the
central nervous system. And I'm going to go through
some different parts of the central
nervous system just to give you an idea that
there are different parts and that they do
different things. Again, don't worry
about memorizing them. This is really just to get
you familiar with what's going on up there. So if we look at the
brain more carefully and look at different
parts of the brain, we've got these different parts
that people-- neuroscientists specifically-- have
divided up for us. And if we start at the bottom
down there with the brain stem, the brain stem sits at
the bottom of the brain at the top of the spinal cord. And it's what ends up
relaying the information to and from the spinal cord
and to and from the brain. So you have your
brain up here doing all the processing, spinal
cord down there sending out all the signals to make
you move or to send up sensory information. The brain stem
sits in the middle and helps regulate
what goes through. Then, you have the cerebellum
sitting at the very back of the brain up there. And the cerebellum is a
really cool part of the brain. It's really, really wrinkled. It has lots of different
cells packed into it. And what it does is it helps
control your motor movement and specifically helps when you
have to learn something new. So when you have to learn how
to play piano for the first time or when you have to play
basketball for the first time, you're going to make mistakes. And what the cerebellum
does is it helps correct for those mistakes. So when you are shooting
a hoop for the first time and it goes off to the left,
then you have to learn, OK, I need to move it over
to the right a little bit next time. The cerebellum is
what does that. And when I teach this to middle
schoolers or high schoolers, one fun thing I
do with them is I bring along these
specialized classes, which have prisms on them. So when you wear them,
it skews your view of the world a few
degrees to one side. So if I'm looking,
say, at this marker here, when I put on
the prisms, it's going to look like it's over here. So I do this to the kids. And the kids look
out at the marker, and I tell them to
quickly reach for it. They see it over here. So they start out
reaching this way thinking that the marker is over there. But what happens over
time is that they do this over a few minutes, and
eventually they correct for it. So even though their
vision is out here, they've corrected for it by
moving their arm over here to where the marker is. And that's learning that
happens in the cerebellum. Then, the really cool thing
is they take off the glasses. And because the
cerebellum has taught them that they need to reach
to the left of where the visual field is, they
look out at this marker. They start reaching over
here to try to get it. So the cerebellum
corrects for that. And again, after a
few minutes, they do that a little bit longer. And they eventually
reach for the marker. So that's learning
that's happening in the cerebellum, really
cool part of the brain. Then above the brain
stem and the cerebellum, you have this
wrinkled outer layer of the brain called the cortex. And the cortex we
can broadly think of in four different lobes. And again, broad theme for
this lecture, different lobes, different parts of the
brain are specialized for different functions. So you have the frontal lobe
up, as you would expect, at the front of the brain. And the frontal lobe,
among many other things, plans your actions and
controls your movement. So this is the
part of your brain that's going to be sending
a lot of connections down through the spinal cord
to make you move your arms, move your legs, move the
other parts of your body. And that's all happening
because of the neurons that are up there in the spinal
cord-- in the frontal lobe. And again, broad theme,
different parts of the brain are specialized for
different functions. Different parts of the
frontal lobe, different parts of that part of the cortex
that control movement control different
parts of your body. So you've got a part of
that frontal cortex that controls your foot
and your left foot and your right foot and your
left hand and your right hand. And they're all in specific
places in the cortex. And they line up the way
you would expect them to in the body. So if your foot
cortex is down here, then your leg and
your knee are going to be up here and then
your trunk and then your arms and then the parts
of the cortex that control facial movements up at the top. So it's organized
according to function. So that's one thing that
happens in the frontal lobe. Then, you have behind
it the parietal lobe. And right next to the part
that controls your movement in the frontal lobe is the
part of the parietal lobe that senses the sensory
touch information from the outside world. And again, form
follows function. So different parts
of the parietal lobe are specialized
for different parts of the body, different parts
of your touch information. And not only are there
different parts of it but the sizes of the cortex
that receive that information are also different sizes. So you've got your finger tips
that are really sensitive, have lots of nerve endings,
have lots of sensory information coming from them. Your fingertips have a big
part of cortex represented in the parietal lobe. So again, different parts,
different functions, different sizes. Below the parietal lobe,
you have the temporal lobe, which is sitting here
next to your temples as you might expect. And the temporal lobe,
among other things, receives the
auditory information. Your hearing information comes
into that part of the cortex. And also, as you'll hear
later, deep inside that lobe are the parts of the brain
that help for memory formation. So the temporal lobe
receives auditory information and also has a really important
part for memory formation. Then finally, at the
back of the brain, you have the occipital lobe. And all the way at
the back of the brain here, this occipital
lobe is where you're receiving visual information. So visual information
comes into your eyes, travels all the way to
the back of the brain to the occipital lobe. And that's where
it gets processed. So different parts of the brain
are doing different things. And this is just a really broad
way of thinking about that. So I'm next going to go
over some specific parts of the brain that you're
going to hear a lot about in the coming lectures. For now, it's just
an introduction. But hopefully, when you
hear them again later, you'll be able to say,
ah, I remember that. So the limbic
system, you're going to hear about again
and again and again. It's this series of structures
that are underneath the cortex but sort of above
the brain stem. And in general, the limbic
system controls a lot of things that we associate with
emotion, with learning, memory, really important
things that an animal has to do to behave. And two structures
we're going to hear a lot about time and time
again are the hippocampus and the amygdala. So the hippocampus
up there in blue is-- well, the hippocampus
word itself means seahorse. And supposedly,
when neuroanatomists were looking at
this, they thought it looked like a seahorse. I don't see it, but
let me know if you do. And this part of the brain is
really important for memory and forming new memories. And the way that scientists
first found this out in humans anyway was by a
bit of an accident. The hippocampus, they
found out, is this place where new memories are made. But they didn't do it by any
sort of experimental approach that you would suspect them to. What happened is there
was this patient, one of the most famous patients
in all of neuroscience, named HM. For privacy reasons, his
name up until he died was known just as HM. And this patient had really
terrible seizures, really bad epilepsy that could
not be controlled and was debilitated
by these seizures. So when he was a
young man, they tried all sorts of
different techniques to try to control
these seizures. And in the end,
what they had to do was actually figure out
where these seizures started in the brain and surgically
remove that part. And it turned out that
part in this patient included the hippocampus. So they took out the hippocampus
on both sides of the brain. And after the
surgery, Patient HM didn't have seizures anymore. Great. Wonderful. But what they found out is
that this patient afterwards couldn't form any new memories. When he had nurses
come in to visit him who visited him every
day after the surgery, every time he met them it
was like he was meeting them for the first time. He couldn't store that memory. But the really
interesting thing was when they asked him about
events from his childhood, he could still remember those. He could remember who the
president of the United States was in his childhood. So the memories were stored
somewhere else in the brain. But the ability to
make the new memories was dependent on
the hippocampus. So that's how they
discovered by accident that the hippocampus is the
part of the brain forming new memories. Another part of the
brain you're going to hear about a lot, a lot,
a lot is make the amygdala. And the amygdala are those two
yellow almond-shaped things sitting up in the front
of the hippocampus. And as you've
already heard, these are parts of the
brain that are really involved in fear and anxiety. So if you remember the
example that Dr. Sapolsky gave on Monday when he was
talking about scared sweat versus exercise sweat
and how we can actually tell whether we're smelling
scared sweat or exercise sweat, one way that they
see that difference is when they look at the brains
of people who are smelling sweat from a scared person,
the amygdala lights up. But when you're
smelling sweat that was given off by somebody
who was exercising, it doesn't light up as much. So the amygdala's really
important for sensing fear. And it's important for
forming anxiety as well. So when you look at an angry
face or a fearful face, the amygdala will light up. But when you look at a
happy face, it won't. So that's the amygdala. You'll hear a lot
more about it later, really important part of the
brain for fear and anxiety. Other parts of the brain you're
sure to hear tons and tons and tons about later on are
the hypothalamus and pituitary gland. And these are-- you can think
of them as hormone central. These are the parts
of the brain that control how hormones
are released to the rest of the body, control
a lot of different behaviors. So the hypothalamus sits in
the center of the brain right at the very bottom. And the pituitary
is underneath it and secretes a lot
of those hormones out into the bloodstream. And it's an old joke
but one that gets repeated over and over again. You can think of the
different types of behaviors that the hypothalamus
controls as four Fs. You've got fight. You've got flight. You've got feeding behavior
and reproductive behavior. So you've got those four Fs of
what the hypothalamus controls. [LAUGHTER] Yes. Now, you get it. Yes. So you're going to hear tons
and tons more about this. For now, just know that they
sit at the bottom of the brain and help control a lot
of these behaviors. So what else do we have
in the nervous system? We've got all these
different parts of the brain. But we've also got
the spinal cord coming down from the brain. And just like in
the brain itself, the spinal cord is specialized. You have parts of the spinal
cord that send out information. And you've got parts
of the spinal cord that receive the information. So you've got motor nerves. And you've got sensory
nerves in different parts of the spinal cord. You've got different parts of
the spinal cord, of course, for your arms and your
legs, basically what you need to know for now
about the spinal cord. You're also going to be hearing
a lot more in future lectures about the peripheral
nervous system. And the peripheral
nervous system has all of the motor nerves
and sensory nerves that are outside of the spinal cord. So a lot of the things that
sense touch information or heat or anything else
out in the periphery are part of the
peripheral nervous system. And then, you've
also got a whole part of the peripheral nervous
system that happens pretty much automatically. You don't have to
think about it. So you've got nerves that are
controlling your heartbeat, your digestion, your breathing. And normally, you
don't have to think about keeping those going. So those are another
part that you'll hear a lot more from Dana later on. So that's really
a broad overview of the different parts
of the nervous system and what they do. So now, we're going to think
a little bit more closely about what's actually
inside a brain, what the individual cells
are, what they're doing, how they make you behave. And again, this is not a
list for you to remember. It's just to let you know that
there are different cell types, and they have
different functions. And I'm going to tell you first
about something that came up while I was looking online
and trying to figure out what to say for this lecture. And I realize that it's
illegal in seven states to give an introductory
neuroscience lecture and not mention the name
Santiago Ramon y Cajal. So Santiago Ramon y Cajal,
why is he this god figure in neuroscience? What did he do? So when Santiago
Roman y Cajal was doing most of his scientific
work at the end of the 1800s, mostly in the 1890s,
the general theory about the way the
brain worked was that it wasn't individual
cells that were performing their functions. Instead, the brain was
thought of as this web, this interconnected
web of mush, basically, that did all of its
computational work to make you behave. People knew that the brain
was where behavior started and where it was controlled. But they didn't really
know what it was inside the brain that did that. So the prevailing theory
was that you had this web. And rather than just
take that at face value, Ramon y Cajal decided to
experimentally figure out if that was the case. So he found this really
cool technique invented by a different guy named Golgi. And this technique
allowed him to take small slices of the
brain and turn about 1% of the cells in
that slice black. We still don't
know how it works. But he was able to do it. And then, he drew these really,
really detailed pictures of what that looked
like in the microscope. And these images are
just absolutely gorgeous. There's a whole class
of people that when they see these images, tears
of joy stream down their face. They fall to their
knees weeping, praising the gods of neuroscience. These are the people who become
neuroscience graduate students. So these cells and these
pictures that he drew showed us that
there actually are individual cells in the brain
that are doing this work. It's not a complete mess. It's not a complete web. It's actually individual cells. And so he drew out these
beautiful pictures of neurons and also all of the other
cells that are in the brain. And I have a good
friend who studies all of these other cells in the
brain that are not the neurons, not the ones that are actually
doing the computational work. And I promised her I'd never
give an introductory lecture without mentioning these. So first, I'll start
out with those cells. So 90% of the cells in
your brain and spinal cord are not actually neurons. They're called glia. And glia basically,
by definition is anything in the
brain or spinal cord that is not a neuron. And glia, the word,
means glue because people saw these cells in there and
thought they were just glue sticking the neurons together. But it turns out they actually
do a lot more than that. You've got cells called
astrocytes, which are these star-shaped cells. And they, in a
very general sense, supply nutrients to
the neurons and help regulate how they fire. Then, you've also got these
cells called oligodendrocytes, or Schwann cells. Again, long names you
don't need to memorize. But they wrap around
the wires of neurons and make their firing go faster. Then, you've got
microglia, which are yet another glial cell
that are in the brain. And they're basically the
brain's immune system. They move around the brain. They send out little processes
out into parts of the brain to figure out if the brain is
getting infected by viruses or bacteria or if there
are any dead cells that need to be cleared up. And they do all of that work. So 90% of your brain is actually
all of these other cells doing this work. But what they're
doing this work for is so that you can have
your neurons working. And the neurons are
what we're going to focus on for the next
10, 15 minutes or so. And these are the
complicated but wonderful computational
units of the brain. And in an average
human brain, you've got about 100 billion neurons. And each of those has
about 10,000 connections to other neurons. And those connections
are called synapses. So if you think
about that, you've got roughly a
quadrillion synapses in your brain, a quadrillion
connections between neurons. And just to give you some
perspective, the number of stars in the
Milky Way, the number of stars that you can see
out there in our own galaxy is about 300 billion. So you've got a
quadrillion synapses just sitting there in your
brain, which is already more than 1,000 times more
than the number of stars that are out there in
the Milky Way galaxy. So you've got all of
these connections packed in there in their brain doing
all of this computational work. So how does it actually work? So here I'm actually going
to switch over if I can. Great. So here we're going to talk
about the neuron itself and what the different
parts of it are, what the different
parts of it do, and how it works,
how it communicates. So this is a very badly
drawn picture of a neuron. But it will give you an
idea of what a neuron is and how it functions. So you've got
different parts of it. You've got out here, dendrites. And these are what receive
the information on a neuron. They get the information
from the cell before it and pass it on
down into the cell. Down here you've got the soma
or the cell body of the neuron. And importantly, you
have the nucleus, just like you do in
any other cell that has all the DNA in it. And then, there's an
important part down here. So you're getting all of
this input from the dendrites from the cells before giving
you information at the dendrites that goes into the cell. And somehow the
cell has to decide whether to pass that information
on to the next cell or not. And that happens at this
specialized part of the cell called the axon hillock. I guess it's like a hill
but not quite as big. So you have the
axon hillock there. And then down here,
you have the axon, which you can think
of as the wire that's sending the information
on to the next cell. And then down here,
you have the terminal. And this is where the cell
will send on information on to the next neuron. So these are the general
parts of a neuron that you'll need to
think about in terms of how neurons communicate. And information
is generally going to flow from dendrites
down to the cell body, get summed up at
the axon hillock. The cell will decide
whether to fire or not and send that on
down to the terminal. So that's a basic
overview of a neuron and how those
different parts work. So how does it actually work? How does it actually
send that signal? And this is just going to give
you a really broad overview of how a neuron does this. So if you think about
a neuron sitting there in the middle of
the brain, there's lots of electrical activity,
lots of things going on. Somehow a neuron if
it sends a signal has to get heard
above all that noise. So the way a neuron
solves this problem is it is either on or completely
off, completely quiet. It's not a system where
you have a continuum, where you have-- where
the cell is kind of on, a little bit more
on, a little bit more on, and then totally on. It's not that way. Because that wouldn't really get
heard above all of the noise. So what you have is a cell
that's either on or off. And a neuron really
wants to make sure that it stays off until
it's ready to send a signal. So that's how the
neuron stays quiet. And when we talk
about that in biology, we talk about the neuron
keeping a resting potential, a resting quiet
level of activity. So how does a neuron do that? So the way that
neurons communicate and the way that they
send on electrical signals is going to be
through the movement of these chemicals called ions. For those of you who
are not science people, just think of them
as charged chemicals. We're just going to
talk about general ions for today, which
are charged atoms. So they can have a positive
charge or a negative charge. And we're going to talk about
mostly positive charges today. So the neuron has to keep quiet. And the way it does
that is by keeping positive charges, positive
ions outside of the neurons. So you have all of these
positive ions sitting there outside of the neuron. And this is how it stays quiet. Because the flow of these
ions is going to be what communicates the signal. So how does it do that? It keeps these ions out of
the cell by using these pumps. So it has pumps
that will pump out positive charges from
the inside of the cell to the outside of the cell. So by using those
pumps, the neuron is keeping all of the
positive charges, all of the positive ions mostly
on the outside of the cell, rather than on the inside. So that means that
the net charge on the inside of the cell
is going to be negative. So you've got this imbalance. And this is how the
neuron stays quiet, how it make sure that
it is not firing. So you've got this cell sitting
there trying to figure out if it's going to fire or not. Right now it's quiet. How does the whole process
get started to make it fire? So if you have another
neuron up here-- and you'll hear a lot more
about this from Anthony-- sending out a chemical
signal, that chemical signal is going to get received
at the dendrites. And when that chemical-- called
a neurotransmitter-- hits a particular receptor
out on the dendrite, that receptor is going
to open up a channel. And that channel is going to
let some of these positive ions in, just like receiving email. It's receiving a signal. So you get these positive
ions going into the dendrite. And you get a change in charge. The neuron is now getting
more positive on the inside. Before it was really negative. Now, it's getting a
little less negative. Another way to say that is it
was really polarized before. It had a big negative
charge on the inside. And now, it's getting a
little bit depolarized. It's getting some positive
charge going into it. Great. So you've got a little
bit of charge coming in. You've got a little
bit of signal. But somehow the neuron has to
decide, am I going to fire? Or am I not? It's all or nothing,
one or the other. So you get the signal coming
in from this dendrite. And you're going to get some
positive charge going in, flowing into the neuron. And you'll get a little
bit out in the cell body. But from one signal sent,
you might not get a lot. Well, let's say you're
getting really, really frequent chemical
messages from here, getting lots of positive
charge into the cell. Or you're getting several
different messages at the same time, getting
lots of positive charge into the cell. Then, you can end up with
enough positive charge down here at the axon hillock to make
the neuron decide to fire. So what is it that
makes it decide? There are more
channels down here that can open up to let
more positive ions in. And the way they make that
decision is whether there's enough positive charge. If there's enough positive
charge, they open up. And they allow lots more of
this positive ion to go in. And once that happens,
it's going to feed forward. Right? You're going to get more
positive ion going in. You're going to get more
of these channels opening because the positive
ions are going in. And it's going to keep
going and feed forward. And you're going to get the
neuron sending a signal. And the way it does
that is it keeps having positive ions go in
all the way down the axon, all the way down
to the terminal. And then, when you get positive
ions going into the terminal, it's going to tell that
to go ahead and send a chemical message
on to the next cell and start the whole
process over again. But the big message
from all of this is that this decision that's
made here is all or nothing. You've got positive ions
that are traveling in. If they don't get to
the threshold here, if they don't get
enough of them here to make the axon hillock
decide to let more of them in, the cell's going to stay quiet. If they do get enough
in to reach threshold, then you're going to get
lots more pouring in. And the cell's going to fire. There's no turning back. It's going to send the signal
down its axon to the terminal. And you're going to get
the message sent on. And that's called
an action potential. And what happens here is you get
all this positive charge going in. You get the cell getting
to a really positive level of charge. And then, somehow
it has to stop. So how does it stop? You have a number of other
positive ions on the inside. And right after
this opens and you get all of these
ones pouring in, you can get the cell opening
up these other channels to let the positive ions,
a different kind of them, flow out. And then, you get restoration
of the balance and charge. And remember, you
have these pumps that continue to send the
positive ions out of the cell. So you get the cell being
restored to the quiet state afterwards where it's negative
on the inside compared to the outside. So there you have it. You have an all-or-nothing
action potential. You have the cell deciding
at the axon hillock whether it's going
to fire it or not and then sending the
message on to the next cell. So that's a really
basic understanding of how a neuron fires. Hopefully, that was basic
enough that everybody could understand it. You're going to hear more about
it later in other lectures. But for now, that should give
you a really basic overview of what's going on. So take-home messages
from this first part of the lecture, different
parts of the brain do different things. As we talked about
when we were looking at the brain and
spinal cord, you've got the different
parts that function for different behaviors. You'll hear a lot more
about that in the future as we talk about
specific behaviors and what parts of the
brain have to do with them. You've also got
different cells that are doing different
functions within the brain. You've got neurons. You've got glia. You've got different
types of neurons as well. You'll hear a lot more
about how some neurons send one type of chemical
signal, some send another, and how that's
going to be really important to different
behaviors later on. You also learned that neurons
are individual cells making this decision. They're the functional
unit of the nervous system, as we learned from
Ramon y Cajal. And finally, when they do
decide to send that signal, it's an all-or-nothing process. It's an all-or-nothing
action potential that makes the sell send on
the message to the next one. So hopefully, if you
understood all of that, you have a really basic
understanding of neuroscience. We're going to take
a five minute break. And then, we'll move on to
Anthony's lecture, which will talk more about what
actually happens at the synapse as we think about
applying this to behavior. Thanks. [SIDE CONVERSATION] All right. My name is Anthony. I am a first year biology
student, a graduate student in the PhD program. Right now, I'm just
wandering from lab to lab trying to figure out
what I want to do research in. Again, like Nathan,
there's going to be some topics in here
that might confuse you. And if it is
confusing, let me know. Stop me. Ask questions. My email is on the
handout that you can download from CourseWorks. And after the
lecture, I'll actually write it down on the
bulletin board right there. But feel free to send me
or Nathan an email anytime if you have any questions
over the lectures today. I'm going to start by recapping
a little bit about what Nathan talked about,
the neuron doctrine. So up until the
late 1800s, neurons were all thought to be
connected by cytoplasm. And really the
concept of a neuron as an individual cell, it was
difficult to conceptualize. Because all people were
really able to observe was this mesh-like
network of interconnecting fibers and processes. And it wasn't until the
advance of microscopy and staining that people were
able to suspect that something else was going on here,
that maybe this story was a little bit different. In 1891, a German anatomist
named Heinrich Wihelm Gottfried von Waldeyer-Hartz-- [LAUGHTER] I practiced that--
proposed what is now referred to as the neuron
doctrine, which is basically that this network was made
up of individual cells. He wasn't unable to
propose this without work done by many others,
including Santiago Ramon y Cajal, god of neuroscience. So if you have these separate
neurons that are separate cells, if one is to
communicate to another, it cannot happen by
electrical means only. If you think about it, if this
communication is to happen, it must happen by
chemical means. And so before the events at the
synapse can really take place, I have to introduce
you-- sort of back up and go back to the
action potential, which if you remember, starts
here at the axon hillock. So this is where the decision
to fire or not fire an action potential will be made. And once the action
potential is fired, it will travel along
the length of the axon and reach a dead end
that is conveniently called the axon terminal. Now, the axon terminal
is a structure at the end of the axon
that stores large amounts of neurotransmitters. And these neurotransmitters
aren't just freely floating or diffusing
around inside the cell. They're actually packaged
in these discrete quantities in these membranous spherical
structures called vesicles. And so you'll see those balls
housing these black dots. The balls are the vesicles. And the black dots are
the neurotransmitters. OK. So when the axon potential
reaches this axon terminal, it will trigger an influx
of positive charge, which will then trigger the
release of neurotransmitter from these vesicles. So the vesicles will move to
the edge of the axon terminal. And they'll dump their
neurotransmitter out. So I have to sort of dive into a
little bit of terminology here. We try to avoid that
with this class. But the signaling neuron is
called the presynaptic neuron. The neuron that
receives the signal is called the
postsynaptic neuron. And the junction at
which these two neurons connect and communicate
is called the synapse. So once this neuron is
bound to the receptor, it can trigger one of
two temporal effects. One can be an
immediate effect, which is the opening of
a channel, which will allow ions to jump in,
which Nathan illustrated earlier right here. These ions could either
be positively charged or negatively charged. If they're positively
charged, they will persuade an
action potential to happen if there are
enough of these charges. If it's a negative
charge, it might act to dissuade an
action potential to be initiated at the axon hillock. So that's the immediate effect. But an effect that might
last a little bit longer is when a genomic
effect is induced. So a neurotransmitter
might be released. And it might bind to a receptor. And this event might
influence the activation of a transcription factor. And this transcription factor
might induce the production of more receptor
channels that might find its way onto the dendrite here. So if you think about it, if you
produce more channels or more receptors, you can
make this synapse more responsive to the same
amount of neurotransmitter. So that's strengthening
the synapse. And you'll hear,
definitely, more about that later in future lectures. So not only can a single neuron
respond to many different types of neurotransmitters,
could be inhibitory, could be excitatory,
it is also possible for a single
neurotransmitter to have an effect on multiple
neuron types located in different areas of the
brain with different functions. And so you might ask yourself,
how is this possible? So we have like 100 billion
neurons in our brain. Why is it that we
don't have 100 billion unique neurotransmitters
for each brain-- or sorry, for each neuron? And the concept can
be sort of related to the concept of the alphabet. So we only have 26
letters in our alphabet. Yet, we can create an
infinite number of messages. The idea of the brain
having different functions in different areas,
each of these functions are going to be-- they're going
to have different functions because different neural
networks, different networks of neurons are going
to be responsible for these functions. And they are actually going
to, for the most part, have a physical separation
between different areas, different neural networks of the
brain with different functions. And so it is possible to use a
single type of neurotransmitter in many areas of the brain with
different functions because of this physical separation. Sorry. I was opposed to
put this slide up. So we call this
compartmentalization of the brain, many
different functions in many different
physical areas. And so because of this redundant
use of neurotransmitter, you really don't need
more than a few hundred. That's where the
current estimate lies. Not all of them have
been discovered. Quite a few have been. But there are still
a lot out there that have yet to be discovered. And so this brings me
to sort of a exercise that we could do to help hammer
in certain-- these properties of a neurotransmitter. Say you are a scientist. And say you are in the
business of identifying novel neurotransmitters. And you have this
putative molecule. And you want to prove to
the scientific community that this molecule is
a neurotransmitter. What pieces of
evidence might you need to provide to prove
that your molecule's a neurotransmitter? First thing that
you sort of have to do is you have to sort
of ask yourself, well, where are
neurotransmitters located? They are just located
anywhere in the brain. They're located
in specific areas. They're located in
the axon terminal. So you have to prove that it
localizes in the axon terminal. Another thing that
you might want to ask is, what triggers the action
of a neurotransmitter? So you're going to also have
to demonstrate its release following an action potential. So if you remember,
an action potential will hit the axon terminal
and through a series of events trigger the release
of neurotransmitter. And lastly-- but this
is not good enough. So you have two pieces
of evidence so far. But you need one more to make
a pretty strong case for why you have a neurotransmitter. And this is you have to
ask the question, what is the effect of a
neurotransmitter? And so you also have to prove
that after a neurotransmitter is released and it
binds to the receptor that it induces some
sort of influx of charge in the postsynaptic dendrite. And I just missed another slide. No I didn't. So fortunately for
us, a lot of this work identifying neurotransmitters
has already been done. And there are a few
notable transmitters, neurotransmitters that
I kind of want to get you guys familiarized with. And so right now, you
don't have to memorize any of the functions that
I'm going to talk about. So the whole purpose
is to sort of to introduce you to
some neurotransmitters so if you hear about
them in later lectures, it won't be the first
time you hear about them. So one type of neurotransmitter
is called dopamine. And it's most commonly
associated with the reward system, with pleasure. But dopamine, like many
other neurotransmitters, has a very diverse
array of functions. It's not just involved
in reward or pleasure. And so just a quick recap. How could it have many
different functions? Well, if the brain
is compartmentalized, if these networks are
physically-- for the most part physically
separated, you can have one type of
neurotransmitter with an effect in these
different areas of the brain. Therefore, one type of
neurotransmitter in an organism may have many
different functions. And dopamine is no
exception to that. You have another type
of neurotransmitter called epinephrine. And I know everyone in this
room has heard about it in one form or another. Another way to-- another word
for epinephrine is adrenaline. And so adrenaline is involved
in the fight or flight response. So if you're-- Nathan also
talked about this earlier-- if you come across a risky
situation or you're feeling threatened you can either fight
off and vanquish your foe. Or you can flee, neither
of which are bad ideas. And norepinephrine, which
you may hear about later on in the course, is
pretty much interchangeable with epinephrine. They share a very
similar structure. And you don't really
need to do much to change epinephrine to norepinephrine
and vice versa. So another neurotransmitter that
you might hear about later on is serotonin. And serotonin again, is one
of those neurotransmitters that has a lot of functions. And few of them are
involved in the regulation of sleep, appetite, and mood. But certainly it's
not limited to those. Acetylcholine, I know you'll
hear about it on Friday. And so I'll leave that for
Friday for you to discover. GABA is-- and you really can't
talk about neurotransmitters without talking about
GABA and glutamate. So these are the two most common
neurotransmitters in the brain. GABA is the most common
inhibitory neurotransmitter. And glutamate is the most common
excitatory neurotransmitter. And again, these two have
very diverse functions and are involved in
many different areas. So I'm going to, for a brief
moment, dive into a tangent and tell you about the
neuromuscular junction. You cannot have animal
behavior-- in fact, you can't even behave
unless you are able to move. And the basis behind
movement lies in the muscle, in the contraction of muscles. So what you're going to see
here is a similar motif. You're going to see a synapse. You're going to see
a neurotransmitter. The synapse is going to
occur on the nerve that signals to the muscle. It's going to release the
neurotransmitter, which is actually going to be
oftentimes acetylcholine. And it's going to
bind to receptors in the muscle, which is going
to trigger a contraction. And so unlike many neurons
in the brain, which respond to multiple different
neurotransmitters in general, neuromuscular junctions
only use one type. So with that out of
the way, I'm sort of going to dive into
neuropharmacology. So what is neuropharmacology? It is the external manipulation
of synaptic events. Why would people want to
manipulate a synaptic event? Well, you can do it
for research purposes. You could manipulate
the neurotransmitter or the receptor
to figure out more about what their functions are. Or you could do it to
correct for disease states. We as humans are very interested
in trying to help people who have certain illnesses. So the general purpose is
to increase or decrease the strength of communication
across a synapse. So sometimes you can
do this by faking out the postsynaptic neuron. You can give it a compound,
an artificial compound that's not seen naturally
in the body that closely resembles something that
is seen naturally in the body. And you'll see a lot
of hallucinogenics that utilize this principle. So hallucinogenics, such as
mescaline, LSD, and psilocybin, these interact
with the serotonin receptors because they have very
similar structure to serotonin. And so there are a variety of
ways that you can strengthen the synaptic response. One of which is to increase
the release of neurotransmitter from the presynaptic neuron. How might you go
about doing this? You could increase the
synthesis of neurotransmitter. You could force
the release-- you could force the released
neurotransmitter to linger in the synapse. And there are a variety
of ways to do this. You could block-- wow, I
just skipped something. Oh, don't worry about it. OK. So you can block
reuptake or degradation. I can talk about it now. So when a neurotransmitter
has done its job, has bound to the
receptor, is used up, you can't just leave
it in the synapse. You've got to get
rid of it somehow. Otherwise, it's going to keep
signaling to the receptors. One way to do this is a
process called reuptake. This is essentially,
the reinsertion of a used up
neurotransmitter back into the presynaptic neuron. OK. And so there are a
variety of proteins that mediate this process. You can have protein pumps that
pump the neurotransmitter back into the presynapse. You can have-- you're
going to have proteins that are required to repackage
the neurotransmitters in the vesicles. And you're going to
be able to-- you're going to have to
reform these vesicles. And so this is called reuptake. You can also degrade used
up neurotransmitters. And when you do so, these
degradation products can be detected in certain
fluids in your body, such as cerebral spinal
fluid or blood or urine. And so this is
important for when you want to detect levels
of neurotransmitter when you're trying
to diagnose diseases. So right, so you can force
the released neurotransmitter to linger in the synapse
by blocking either reuptake or degradation. You can increase
neurotransmitter receptor activity. So if the receptor
on the postsynapse has a certain amount of affinity
to the neurotransmitter, if you are able to find some
way to make it bind more efficiently to
the neurotransmitter, you're able to amplify the
neurotransmitter signal and essentially, strengthen
that synaptic response. So conversely, if you would like
to weaken synaptic response, you could just block any
of the processes that are required to release
neurotransmitter, that are required for
the neurotransmitter to bind to the receptor and
trigger this influx of charge in the dendrite. So you can do that by blocking
neurotransmitter receptors, blocking
neurotransmitter release. You can block, or you can
decrease the receptor affinity. So again, we don't
really want you to focus on memorizing really
the many mechanisms of doing this. If you do need to know
it, it will come up later on in the course. But what this really is--
the whole point of this is to get you thinking about
the many ways in which you can manipulate events that
take place at the synapse. OK. So there are a lot of ways
people can manipulate it. So how would you find out more
about some neuropathology? If somebody has
something wrong with them and it's going on
in their brain, it's really difficult to
make direct measurements of neurotransmitters,
or neurotransmitter levels in their brain,
especially in a live patient. These measurements are often
done in breakdown products, breakdown products of
neurotransmitters in the urine, in the blood, or
cerebral spinal fluid. And these are often
serving as clues. These can often serve as clues. So if you had a patient with
Parkinson's and you would like to treat that patient
and alleviate that person's symptoms, you might
find it pretty difficult. So Parkinson's- people
with Parkinson's have an insufficient or decreased
level of dopamine in a certain area of their brain that
controls motor movement. And if you were to
increase, globally increase, dopamine levels in the
brain, you might fix, you might alleviate the
symptoms of Parkinson's. But you're going to be
increasing it everywhere else that dopamine has an
action in, has a function in. And so you might change levels
in the mesolimbic pathway from normal to too high
and induce symptoms that resemble schizophrenia. And so this really
harks back on the theme that we've been trying to
tell you that the brain is compartmentalized. It's got different functions
in different areas. It can have the same
neurotransmitter in these different
areas functioning. And if you were to treat
some sort of effect that you want to fix, you might
see adverse or deleterious side effects in other areas. Yeah, so that's pretty
much all I have. So there are a few take home
messages and important points. You have to know that
this process of axon-- the process of action
potential moving along the axon and how it influences the
influx of positive ions at the axon terminal, which
will release neurotransmitter. So you have to be familiar
with that concept. You have to understand that
neurotransmitters after they're used up can be
degraded or recycled in a process called reuptake
and that degraded products can be detected in blood, urine,
and cerebral spinal fluid. You also have to understand
this idea, again, of compartmentalization. It's very important. And that pharmacological
manipulations, you have to be
careful because things could happen that you
are not expecting, especially when something
is wrong in only one area of the brain. And with that, you guys are free
to leave and/or ask questions. We do have one more
thing we wanted to show. Oh yes. One of the other
TAs in our class last year made an
absolutely wonderful video about the synapse and about the
synaptic cleft, in particular. And we wanted to
share this with you. [VIDEO PLAYBACK] [MUSIC PLAYING] --[SINGING] HumBio kids,
put your books down. Put your books down. And report to the cleft,
the synaptic cleft. I'm B Bobby Voltage
introducing the Glut-tang Clan. -Check out the synaptic cleft. Thanks to vesicular trafficking,
interneuronal signal can be transmitted from
electrical to chemical and back again. -Hot and turns to
the land of the nerve where firing and wiring
will occur and will occur. will occur. Follow me. Neurons gotta be ready to
fire at any opportunity. Dendritic input make it hot. Make it hot. Sum it up in the axon hillock. The potential will rise
to a constant size. Shape of action potentials
ain't no surprise. Snap back to the focus of the
rap, tiny little space aka synapse. -Boom. -Voltage sweeps through
the end like a broom. Calcium rushes in. Vesicles go boom. -Boom. -Exocytosis so exciting. ACH bonds light it
up like lightning. Synapse fanatics gather around. Questions about the story? What? -3, 2. Hmm. Do the transmitters
always excite? -No. They can be
inhibitory, depending on whether they're the ions
of [INAUDIBLE] positive charge gone. -Only one synapse? What if there's more? -The hillock will sum it
up, like I said before. The synapse is the location for
neuron to neuron communication. Remember what Russ Fernald said. -The mind arises from the brain. -Now listen. -Open. Open. Close. Close. -Check out the synaptic cleft. But thanks to
vesicular trafficking-- -Ion channels. - --interneuronal signals can
be transmitted from electrical to chemical and back again. -Ion channels. -S to the "ynapse"
is where things act like [INAUDIBLE]
to chemicals that make you relax or collapse. The synapse cleft has receptors
that rock to the sympathetic. Ligands [INAUDIBLE]
by clinics that mimic your chemical condition. That's a small
problem for medicine, a hundred trillion synapses. Drugs screaming-- -Let us in! -The disease is only
one part of the brain. A pill's not a sniper. It's a hand grenade. It'll act wherever there
reside effects plus everywhere else come side effects. Don't want to
sound like a cynic. We've all got a protein
they call nicotinic. It's a receptor that can't
tell the diff between ACH and nicotine. -Get a grip. -But nicotine leads
to too much binding. ACH receptors get to hiding. Neuromuscular junction,
it can't quite function because your
receptors went out to lunch. Now, dopamine's on for
a [? war ?] prediction. But it's down-regulating,
then you're getting addicted. Fixing to kick the habit. We're busting synapses. How tragic. -Synaptic receptors
getting abducted. -A healthy synapse ain't
nothing to mug with. -I hope this rap has
been instructive. -Because a healthy synapse
ain't nothing to mug with. -Open. Open. Close. Close. -You don't have to
leave your [INAUDIBLE]. [INTERPOSING VOICES] -Close. Close. Open. Open. Close. Close. -Ion channels. -Cajal, give me some
more neurons to study. Those don't ensure our find. -Ion channels. -Open. Open. Close. Close. Open. Open. Open. Close. Close. Open. Open. Close. Close. -A game of chess is
like a sword fight. [DRAWING A SWORD] You must think first
before you move. [MUSIC PLAYING] [END PLAYBACK] For more, please visit
us at stanford.edu.
