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[NOISE] [CROSSTALK]
Okay. [NOISE] Let's get started.
My name's Robert Sapolsky in the biology department.
What I will be doing over the course
of six lectures is hopefully not only convincing all
of you to become neuroscientists, but to recognize
that the brain is the best organ, that, ever.
That is much more interesting and more
sophisticated then any other part of the body.
Okay let me begin to prove this to you. Think back, if you will, think back to
the day that you hit puberty think back to that your parents had
like thrilled you with all these
embarrassing books to read about cows ovulating.
And you were all set for this happening, and
that morning you woke up and you felt different.
And you realized your jammies were all soiled, and you
ran into your parents room and said, it has happened.
And they got all tearful, and they made your favorite breakfast, and they
carried around the neighborhood on a sedan chair.
[LAUGH] And all the neighbors came and then they sacrificed a cow in your honor.
[LAUGH] And this was a big deal. This was a big deal.
But be completely honest with yourself. Would things have been all that
different in your life if those endocrine changes instead had occur 24 hours later.
Second scenario,
you finish the lecture today you go outside
and unexpectedly there is a rhino that chases you.
You run for your life in sheer
panic and hopefully increasing the energy delivered to
your muscles, your heart rate increases because
your brain is enabling it to do so.
Think about if instead that heart rate had increased 24 hours later.
And there we see why you need a nervous system.
You can decide to grow.
You can decide to do something or other while making new antibodies.
Your spleen could say something to your big toe.
And if it does it now, if it does it 5 minutes
from now, it's not a big deal with your nervous system, though.
When you want to have neurons talking to each other and talking
to the rest of your body, they have to do it that instant.
Everything is about speed,
everything is about not only if you are a nervous system screaming your head off
when you've got something to say, but
being unbelievably quiet the rest of the time.
It's all about contrast.
Because what you could do with your nervous
system, you can not do with any other part
of your body, in terms of just the sheer
speed of signals being turned on and turned off.
Okay. Let me give you an example.
And this is the only demonstration for all these lectures so watch carefully.
[LAUGH]
Planelia would kill to be able to do something that
cool but, they can't because they don't have nervous systems.
[LAUGH]
You have a spectacular ability to turn on signals to turn
off signals.
What we're going to see over and over as we go through
these lectures, everything about this part of your body is the fanciest, is
the most expensive, parenthesis, the most vulnerable to injury, all built around the
fact that neurons are doing stuff that no other cells have to do.
With those cells, you want to grow your fingernails longer,
you can do it this afternoon, you can do it tonight.
Everything about
your nervous system consists of screaming your head off when you've got
something to say, and being wildly silent the rest of the time.
Okay.
What we're going to do in these lectures
is go through this process starting writ small,
and eventually writ large, starting off today with
how does one brain cell, one neuron, get excited.
And what we'll see is how you go from one end of it to the other
end and prepare it for the next lecture.
What we will then look at is how one neuron talks to the next neuron in line.
Then, with that under our belts, now that we'll have been up to
two neurons, the next lecture we will make a massive leap into the world
of three neurons at a time, beginning to see how neural circuitry works, how
all sorts of computational stuff comes out of circuits built around the fact that
neurons don't talk to just one other
neuron at a time, there's fantastic networks.
Okay, so at that point, we're up to large clusters of neurons.
What we'll then do, the lecture after that, is look at the first two
ways that your brain has the ability to control everything going on in your body.
The first way in that lecture by
way of hormones going through the endocrine system.
At that point, you'll hear two lectures from Professor Heller
looking at the endocrinology, the specific domain in the reproductive system.
Then, I will come back with the second way in which your
brain controls everything in your body, which is the autonomic nervous system.
Projections coming down your spinal cord, going out
everywhere, responsible for goose flesh, responsible for blushing,
responsible for all the stuff that you can't consciously
control, all the automatic stuff, all the autonomic stuff.
What we'll have done by then is gone from today, one single neuron, up
to how your brain is collectively controlling
every single little outpost in your body.
What we will then do in the final lecture is
we'll get the most important fact about the nervous system,
which is every single thing you will have heard from now to the fifth lecture can
change, can change over time. It can change in response to experience.
It can change in response to trauma, to stimulation, to nutrition, plasticity.
Everything about the nervous system shows enormous plasticity.
What we'll do in the final lecture is look at how the nervous system
changes, specifically in the context of how learning occurs.
And what we'll see is, some of the time learning is a great thing
for your nervous system, in terms of
learning stuff, say in time for the finals.
Some of the time, it's a disaster, for example, when your
nervous system learns to be afraid in circumstances where there's no need.
Okay, so that is our general strategy starting today.
One neuron eventually
building up how whole networks of neurons control every single outpost of your body
and then finally, looking at how all
of that could change in response to experience.
Okay, so we start off here.
We start off with our basic neuron.
And I want to thank the Smithsonian for making it
possible with funding for me to still have access to overheads.
But what we've got here is your basic
neuron, your basic. There's two types of cells in the brain.
One type one is neurons. The other are glial cells.
Just between me and all of you, what we're going to decide over the course
of these lectures is that glial cells are
unbelievably boring and we're going to ignore them.
Half a dozen colleagues of mine would stab me for having
said that, but for the moment we're going to ignore glial cells.
They've got to actually be interesting because
there's ten of the for every neuron.
Nonetheless, for our purposes, they were boring.
And we've just eliminated them from your brains.
The basic cellular nervous system is the neuron.
And here it is.
The neuron.
As required by law, all neurons go from left to right.
And what we have first off is the most
distinctive thing, is this is an incredibly polarized cell.
It's got all sorts of stuff that makes it look different from some rounded
up little red blood cell, wherever neurons have all sorts of specialized processes.
Neurons are outlandishly large.
There are neurons in your average cell, there's supposed to be a gazillion
of them that'll fit into a period at the end of this sentence.
You have neurons in your body that are three feet long If you're a
blue whale you have neurons that are 60 feet long going down your spine.
This is a absurd from the standard of cell biology.
They are big cells, they are fancy cells, as
we will see, they are stupendously expensive cells, parenthesis again.
And thus wildly vulnerable to all sorts of
types of injuries, this is our basic neuron.
Okay, building blocks. We start on the far left dendrites.
Dendrites, little fiberules coming out
the left side of every neuron, and what these are, are our metaphorical ears.
This is where information flows in to a neuron from
all the neurons that are left of the board here.
Information comes in by way of the dendrites.
As we'll eventually see in more detail,
on the dendrites are a gazillion little things
sticking out, called the dendritic spines, and
these are where the actual inputs of information
come in.
You will learn plenty about that in the days to come.
Okay, so we've got the dendrites scattered all around
the left side of the neuron, our metaphorical ears.
Then, boring, basic, off the rack cell biology.
You got your cell body.
You got your nucleus. You got all the usual organelle stuff.
That's routine.
Then, coming out the other end, is the other specialized
part of the neuron, a projection cable reaching out to
talk to the next neurons in line. Thus, our dendrites are our
metaphorical ears the axon's long projection cable reaching
out is our, our mouth, our megaphone, whatever in the metaphor there.
The axon shockingly enough, terminates in axon terminals.
This long projection thing that eventually turns into all these little fibrils
that reach out to the dendrites of the next neuron in line.
And what we will see on Monday is they don't
quite touch and the opens up a whole world of complexity.
So we've got the axon reaching out there.
You will see the very beginning of the axon is the axon hillock
and by about a half hour from now you will realize it is
hugely important. So we've got the axon there.
Axon reaching out to the axon terminals.
Information comes in the dendrites, flows over
the cell body in the form of excitation.
And you will know what excitation means in more detailed level soon.
Excitation comes in by way of dendrites,
flows over the cell body, reaches the axon,
heading to the axon, axon terminals and you talk to the next neuron in line.
Okay.
This is actually not at all how stuff
works with the neurons for a very simple reason.
The left side of the neuron.
Everything from the dendrite up to the axon hillock have this property,
which is when excitation comes in in one of those little dendritic
fibril thingy sticking out there when excitation comes in, it doesn't
spread all the way down to the rest of the neuron.
It only goes a certain distance.
Metaphor, you take a pebble, and throw it into a pond and you will get
a ripple that ripples outward and as it
ripples outward as it heads outward it dissipates.
It eventually disappears any given bit of excitation coming into
any given little dendrite there will spread outward and get weaker
to further it goes until eventually it dissipates.
And you throw in a larger pebble and you get a bigger ripple but the same thing,
spreading outward, it is going to, passively disappear after a while.
In other words, any given dendritic input is not enough
to get excitation all the way down to the axon terminal.
Instead, you gotta get a whole bunch of dendrites at once.
You've gotta get a whole bunch of inputs.
You have to have summation, jargon, summation in
the form of a lot of dendritic inputs.
Getting a lot of pebbles thrown into a lot of little ponds, and the ripple
is eventually big enough for something to happen at the axon hillock.
You either have to have enough dendritic inputs getting excited all at
once, or you have to have a handful of them getting excited over and over
and over, summation, spatial summation, temporal summation.
Any given little pebble isn't enough to do it because at
the axon hillock you have something critical, we've got a threshold.
You've got
your pond and there's some dam at the end there
or whatever and the rule is that nothing happens in the
axon, unless you get some of that ripple coming over the
top of the dam, unless you pass a threshold of excitation.
One pebble four counties over from the pond isn't going to do it.
The ripple will have dissipated. Forty rip-, forty pebbles out there,
eleventy of them finally, when you get enough
cumulative summated excitation sweeping from the dendrites over the
cell body, eventually when you get big enough of
a wave you pass a threshold at the dam.
You pass a threshold at the axon hillock and something
very different happens there, which is all hell breaks loose.
You get a massive wave of excitation
that starts at that point, called the action potential.
A massive wave and it works real different from how
stuff is going on at the dendritic end of things.
Dendrites, you get a little bit of excitation and we've
got our pebble thing going there, and the group will disappears.
The stuff on the left side is graded, graded excitation that dissipates.
You pass threshold at the axon hillock, and you get your first action
potential, and is going to be a gigantic burst of excitation, and you're going to
get just as big of a one on the next bit of the
axon, and the next bit and the next bit and the next bit.
The jargon is that it has an all-or-none property.
If you pass threshold, you get the action potential, and [COUGH] it would
be just as large, shooting all the way down
the axon, all the way down to the axon terminals.
It is a regenerating signal of excitation.
In other words, what we have is the left
side of the neuron is more like an analog system.
The right side of the neuron is more like a digital one.
The left side is decrementing, and all these
graded inputs, and all these little mumbles of
pebbles being tossed in the pond, past the
threshold of the axon hillock, and now you've
got this explosive all or none property, this
action potential thing that goes shooting down to
the axon terminal and goes to all the
little fibrils at the end there and does
what Monday's lecture is going to be about.
Talk to the next neuron in line.
So computationally,
a neuron is a very different thing from the left up to
the axon hillock and from the axon hillock down to axon turnpike.
And everything that is going on on the left
side is all about summation, all about integrating different
inputs coming in that you get one little dendrite
excited, no way are you getting an action potential.
You get ten, you get whatever, you get sufficient
threshold there, and you're in business.
One final detail, which is the cinnamon roll
sort of things wrapped around the axon there.
Back two neurons are gigantic.
This is a gigantic part.
It is an axon that's going three feet down your spine, breaking
all the rules as to what cells are supposed to be like.
And if the electrical events that we will
see, that constitutes the action potential, were left on
their own, it would work its way down the axon and about four hours
from now you would pull your foot back from the flame that you're standing on.
You gotta have a way for this signal, the action potential, to shoot down the
axon after a very clever thing that evolved
is thing shown there called the myelin sheath.
The myelin sheath is okay, I told you that word for you to think about
glial cells, the myelin sheath is made out of glial cells.
They wrap around the axon, and they're
these fatty, membranous cells, and they're insulators.
They insulate the wire that is the axon and
that allows the action potential to shoot down faster.
Because of this critical property shown there, actually, not shown there.
Pardon me, not showing, but we'll get it,
which is between each of the little glial
cells that wraps around each of the cinnamon buns.
There's a little bit of space where you've got just a naked
axon sitting there, and what happens is the action potential jumps from one
of these gaps to the next one, to the next one, shooting down
a lot faster through these nodes, so we'll see, called nodes of Ranvier.
Ranvier, I guess, was the person who had
the best nodes ever seen.
And, you know, the action potential shooting
down, you have what is termed saltatory conduction.
Those of you who grew up with kangaroos will know kangaroos saltate.
They hop.
The signal jumps down. It saltates.
The action potential leaps down the axon from one of these nodes to the
next and is a way of making it all much, much faster and very useful.
Very useful because all you got to do is
look at one disease where, for example, the myelin
is destroyed, Multiple sclerosis, an autoimmune disease, and you
got a nervous system that does not work very well.
Or alternatively, you look during child development, and as different parts of the
brain myelinates at different points, different things suddenly start working.
The part
of the brain in babies that processes language
myelinates fully by about nine months of age.
It's not until about two months later that the part of
the brain that generates language is getting to the same point.
So this myelination stuff is critical.
Okay, so we have what potentially is an
extremely boring scenario here, as shown on top.
Okay, there are the nodes of Ranvier.
We've got
the myelin sheath.
What is shown on top, what we have is one neuron talking to the next neuron.
We've got two neurons in line, in other
words, all of the axon terminals of the first
neuron are being devoted to talking to all
of the dendrites of the next neuron in line.
A straight line of communication. What does that mean?
It means if the
first neuron has an action potential, it is going to
be throwing a gazillion pebbles and boulders into the
pond; the second neuron's going to have an action
potential, if the first one does, the second one does.
And all that sumral gradation stuff is totally
irrelevant here in a boring straightforward, linear pathway,
of one neuron talking to the next one,
the complexity of the wiring isn't very interesting.
That's your spinal cord.
And that's why your spinal cord doesn't write poetry for you.
When you get into the brain itself, it's different because
you have one neuron that can talk to multiple neurons.
One neuron that can hear from multiple neurons.
Okay, here is the, sort of, factoid that is supposed to make you gasp in wonder.
Your average neuron has about ten thousand
of these dendritic spines, and makes about ten thousand axon terminals, and thus what
you suddenly have is hugely complicated networks with a very simple rule.
So the neuron on top is only talking to the second neuron.
That's not very impressive.
But what is impressive is how much control it has over the second neuron.
If the first
one has an action potential, the second one's going to.
In contrast, you can have a neuron that talks to ten
thousand other neurons, that can influence events in ten thousand other neurons,
but what the down side is, as you can guess is,
it can influence but ti doesn't have a whole lot of influence.
The more input from one neuron to the
other the more tightly coupled they are functionally,
and by the time you get to neural networks, which
we will look at a few lectures down, what you
see is a vast capacity for the neurons to influence
each other, but each one can't do a whole lot.
Okay, so just giving you a sense of the complexity.
Okay, so this is the overall view of how the system works.
Time for more details and back to the
difference between puberty and running around from rhinos.
That whole business about how your nervous
system has to be fantastically built around contrasts.
On top here we have everything in your body that's not your
nervous system and along comes a signal saying, ooh kick into gear there.
And it starts, or maybe it starts a two milliseconds later, or
maybe it starts two hours later, and it kind of gets going.
And eventually, you get the signal saying it's over,
where there somebody eventually remembers to put their foot on the brake.
This is the rest of the body.
The nervous system is the second layer.
The nervous system is maximizing signal to noise ratio.
The nervous system is all about contrasts.
So we start off looking at this critical thing about neurons, which is
not only do they have to yell really loudly when they've got something
to say, they've gotta be as opposite of that as possible when they're silent.
They have to be actively, energetically, robustly
silent when they've got nothing to say.
Okay.
What's the version of the not very energetically silent.
Okay.
On the left, we've got some hypothetical
circumstance where we have a very polarized state.
Those two compartments are very different.
All of something-or-other is in the left compartment,
none of it is in the right one.
This is a tremendous contrast.
This is a cell when it's got something to say.
So what's a passive, lazy version of having
nothing to say, the thing in the middle.
You just have equilibrium.
You don't do anything that resembles that. You just
have equilibrium. That's fine for one of your bladder cells.
If you're a neuron, you've got to maximize the
contrast between when you've got something to say, on the
far left, when you have nothing to say, it
can't be a default into just a neutral equilibrium state.
You've gotta work very hard to have whatever the
something-or-other is during the yelling loudly do exactly the opposite.
Being silent, for a neuron, is as expensive as being, as yelling loudly.
It's a very active state. It's got to work to separate the charges.
Okay, so what is the charge separation about.
So, we now make our two schematic compartments here,
slightly less schematic, we've got inside a neuron versus outside.
The inside world,
the outside world.
Outside world, giving them, all of us for one single-celled organisms.
Outside world is like the ocean. It is a salt-water environment.
Outside is lots of sodium and chloride.
The extra cellular environment in the brain is full of sodium and chloride.
Inside neurons, in contrast, you've got lots
of potassium, and no surprise, lots of proteins
whose net charge is negative. So we've got everything wonderfully
in balance, perfectly in balanced, in an equilibrium state.
That's the last thing we want if we're talking about neurons.
What we've got to do is start off with how a neuron is silent, equilibrium
isn't going to be sufficient. We've gotta have neurons doing something
very expensive [COUGH] to make for a dramatic charge separation.
So the way it begins to do that is, the way the membrane functions.
The membrane is, as membranes are wont to do, good
at keeping stuff out and keeps sodium and the chloride outside.
As we'll see in a while, that requires
very expensive pump, but it keeps those guys outside.
Meanwhile inside, when negatively charged proteins are not going anywhere, they're
not just going to be magically, sort of, diffusing through the membrane.
So, the proteins are inside.
Sodium-chloride is outside and the proteins are inside and suddenly we
realize the world very much dependant on what's going on with potassium.
Because potassium flows across the membrane very well.
So what does potassium do at that point?
And what you know is going to happen is it's going to wind it in a way that is
going to produce some sort of inequality, some sort of
polarized state, which is going to be our resting silent condition.
What does potassium do?
So, at this point, potassium, poor potassium
is immensely confused because it has two desires
at that point.
Suppose potassium can flow across the membrane perfectly freely.
Sodium and chloride are stuck outside.
Proteins are inside. What does potassium want to do?
Potassium from it's world of chemical forces and influences.
What does it want to do?
Obviously it wants to flow this concentration grade.
It wants to flow outside the neuron. The chemical forces on the system
push potassium to flow out.
Meanwhile, potassium, conflicted has electrical forces on the system.
And what's that suggesting that it stay inside
to counteract the negative charge on the protein.
So the chemical forces on the system push for potassium to flow out.
Chemical forces do that, electrical forces push for exactly the opposite.
How does potassium resolve this terrible, painful conflict in its life, as
to how much of it is going to flow out of the neuron.
Because how much of it flows out is going
to determine what that silent resting state is about.
And the way to begin to make sense of it,
how potassium resolves this conflict, is with the following equation.
This is the most important
equation in neuroscience.
This is the most important equation you will encounter in your entire lives.
You need to memorize this, you need to understand it and love it.
You need to cherish it.
It will make you happier and more content for your entire lives.
On your death bed, as your lips turn blue you will think
of this equation and realize your life was lived well in this equation.
This equation tells what potassium does.
This is the iconic equation telling how potassium deals with these
conflicting desires on it's part and thus, just how screamingly
silent a neuron is when it's got nothing to say, the Nernst equation.
Nernst, I have no idea who Nernst was but his is what he came up with.
The Nernst equation, this is a way of factoring in the chemical
forces on the system and the electrical forces.
This is the chemical forces suggesting
that potassium flow outward, the electrical
forces suggesting just the opposite, and what we have here is a constant.
And we have a measure of a chemical
forces, the gas pressure and temperature as the numerator.
As the denominator, Faraday's constant and measured the electrical forces there, and
essentially that winds up being a measure of how it balances the two.
You've got potassium concentration outside versus
inside, and once you factor those in,
what you get on the left side of the equation is the resting potential.
A measure of just how negative the neuron is
going to be when it's got nothing to say.
Total arbitrary business in the field. What we
wind up seeing here is, because the
proteins inside are negatively charged and they're
not going anywhere, the sodium chloride on the outside are not going anywhere either.
Potassium, some of the potassium is going to flow out because of the chemical
forces, as a result the inside is going to be more negative than the outside.
Totally arbitrary convention, you talk about how the inside of the neuron
is negative relative to the outside or you can talk
about how the outside is more positive relative to the inside.
Just arbitrary in the field people stated in
terms of what the charges like on the inside.
So, the resting potential when a neuron
has nothing to say, there's a negative charge.
The inside is more negative than the outside world.
And what we've just
figured out with the Nernst equation is, it's
determined just how negative the resting potential is, is
determined by what potassium has done to resolve it's
conflicting forces there between flowing out versus staying inside.
The way that balances how determines just how negative the resting potential is.
And what the Nernst Equation winds up telling you is the resting potential
is like negative 60 millivolts or so.
That's what a neuron is like when it's silent.
And the main point of that is, back to those schematic
boxes there, equilibrium where being silent is this lazy default state.
Equilibrium would be the resting potential was zero.
That's not good enough for a brain cell. That's fine for any other cell.
You want to do the maximal contrast
stuff, and what you're doing here is, you
are working to separate the charges under resting condition.
You are making the neuron polarize, polarize that there
is a negative resting potential, rather than just zero.
And what we'll see shortly is the neuron, okay, let's see it now,
the neuron working like crazy to do this because how's that sodium and
chloride being kept out.
There's pumps that are working like mad to push them out and pumps that
are also working on the potassium component
in there to eventually get it back in.
All of this is not coming for free. The neuron is working like crazy
to maintain this charge separation with a sodium potassium pump
and that pump consumes, just to maintain a resting potential,
the sodium potassium pump consumes 43 and a half percent of the ATP in the neuron.
I just made up that number.
[LAUGH] What we have here is, it uses a lot, it uses like half the ATP.
Back to that stuff I went on about, you're going to be so sick of me saying this.
When you have something to say and you're a neuron, you scream your head off.
When you have nothing to say, you energetically sweaty, clammy,
armpits hard work energetically, bring about that silent state.
You're using half your energy just to say nothing.
This is how your nervous system does all
that amazing stuff, because it's all built around contrast.
And what the Nernst equation formalizes is how potassium controls just
how negative that state is while the neuron is working like crazy to keep
the charge separation, is using half of its budget to do so.
Okay, so at this point we've
got everything explained about neurons, except there
was a problem, so people start figuring out how to stick electrodes into
neurons and they've measured how much potassium there is inside and outside and
they calculate everything and there was a problem, which is the resting potential
didn't match what was predicted by the Nernst equation.
It was off a little bit.
Instead of negative 60 millivolts it was like negative 70
millivolts or so in your average mammalian neuron, something was off.
And at this point everybody had this massive
crisis in the field until it was figured
out that the Nernst equation in fact, is
not the most important equation on Earth because,
oh God, not that.
This one is no where near as important, except conceptually.
It turns out that, okay, the scenario we set up
before we had our membrane and as a result all
the sodium chloride is kept outside and that's the basis
of the chart of separation Turns out the membrane isn't perfect.
A certain amount of sodium and chloride leak into the neuron, leak in because the
pumps extruding them back out are not 100% efficient, there's a
little bit of leakage of sodium coming in, and chloride coming in.
Chloride coming in, what's it going to do?
It's going to make the rest of the tension more
negative, sodium coming in is going to make it less negative.
Oh no, we've got the the same conflict as weak potassium all over again.
We've gotta figure out how much they're flowing in.
What we have here is the Goldman Equation.
All it is, before you freak out, is an expansion of the Nernst equation.
All it is is saying alright, okay, because there's a little bit
of flow of sodium and chlorine, we've gotta factor them in also.
And what you're doing with the Goldman Equation
is the exact same thing as you're doing
with the Nernst it's the same sort of
things on the left, factoring in chemical and
electrical forces, and are you're doing now is you gotta
keep track of not just potassium, but sodium and chloride.
Sodium ratio outside, inside, chloride ratio inside, outside because of the
negative charge, and you got to factor in all of that.
But as you know, even though sodium and
chloride turn out to play some sort of role
here, it's no where near as much of a
role because they're nowhere near as much flow and
potassium is.
You gotta have some sort of modifier, and you gotta have have
some sort of measure there of how permeable the membrane n each.
And that's what the key is.
You've got to weight the voice of each one of those in there.
So you have to go over the equation, which
is heavily carried by potassium, but not entirely so.
And when you put all the pieces together, then you've got this expanded
version of Nernst, Nernst that is now open to
the diversity of not just potassium, but sodium and chloride.
Put it in and instead of predicting a resting
potential of negative 60 millivolts, it's predicting negative 70.
Perfect, that explains everything.
Okay, so we've got the Goldman Equation.
We've got the Goldman Equation and we've
got the sodium potassium pump working like crazy.
And this picture of enormous effort on the part of neuron
to be completely silent. So, time to begin to have the neurons
stop being completely silent. What happens when you begin to stimulate.
So, we start here way out at the dendritic end.
We've got one of those little dendritic spines coming out of
one of those dendritic fibrils and through the mysterious process you'll know
about on Monday, the axon terminal to the
left from the neuron over there has just talked
to you, has just released a chemical messenger, dramatic
foreshadowing for Monday, has just stimulated this dendritic spine.
What does this stimulation consist of?
The chemical messenger is going to go from
the axon terminal of that neuron over there and
reach the dendrite here and bind to a receptor.
Lots of details on Monday about them and as a result, a sodium channel opens.
The sodium channel that is coupled to that receptor.
That receptor, which responds to this messenger that goes from one neuron
to the next, the term for it, in response to the neurotransmitter,
that that neuron is using to talk to this neuron.
A neurotransmitter that goes from that neuron
to this one, stay tuned, binds to it's
receptor and as a result in the receptor
gated sodium channel, the sodium channel opens up.
Suddenly, things start looking different.
What is sodium going to do at that point? You know exactly from your
Goldman Equation and the logic of it, the chemical forces
is going to make sodium flow in down a concentration gradient.
The electrical forces, the inside being more negative than
the outside is going to attract sodium as well.
Sodium comes pouring in there and suddenly, at
right around number one, when the sodium channels
open, suddenly, as a result, the inside of
the neuron right around there gets a little
bit less negatively charged.
Because the positively charged sodium is coming in there.
It is less polarized.
It is less extreme, you are beginning to depolarize the neuron.
It is getting less negatively charged. And you know exactly what that means.
We're heading in the direction of that threshold for the axon hillock.
Oh dream on
at this point that is not going to happen just from this one little dendrite.
Look at what happens instead.
So you begin to depolarize the resting potential and it
starts to go from negative 70 to a less negative point.
So here's the rule, as soon as the area right around inside the
membrane where the sodium is rushing in, as soon as it get to like
negative 50 millivolts the sodium channel closes.
And that's it.
It's not getting anymore depolarized than that.
That's all the sodium that's coming in.
That's all the depolarization that's going to happen.
And what happens at this point?
This is the pebble hitting the pond.
At this point the sodium that had
just entered the neuron at that dendrite where's
the sodium going to go it's now at a negative
50 millivolt environment and all around it is negative 70.
It's going to get pulled outward and this is the ripple beginning to move outward.
It gets pulled outward and because now this amount of sodium is spread into a
ring, it's depolarizing each of those spots not as much, maybe negative 60.
And at that point,
it's negative 50 behind you, but it's getting through
next to you, and it's negative 70 out there,
so further this is the ripple heading further outward,
and with each moment it's getting smaller and smaller.
And this is why the pebble is going to
have its rippling dissipate into nothing after a while.
Because the pumps start pumping the sodium out again.
And what happens?
You go back to where you started. And this is the ripple in the pond.
This is why no single dendrite, no single
excitation at the dendritic end is going to
get all the way the cell body, because
the ripple disappears and sodium gets pumped out again.
Okay, so this is the analogue graded end of the
neuron, the whole world of the dendritic end, any given
input isn't enough to do it.
So now, we're going to have to get to the axon hillock, and
see how things suddenly change to this digital system of all or none.
Okay.
We have the axon hillock starting.
Axon hillocks always start with dotted lines, so you've got it there.
And just to the left of the axon hillock
is the very last smidgeon of the world of dendrites
in cell bodies, and you know how that
works there now, which is, you got a receptor
for the neurotransmitter and coupled to it you
have the sodium channel there, it's the receptor-gated channel.
And you know the rule, the neurotransmitter comes over
from the next neuron over and binds to the receptor.
You open up the Sodium channel, ripples in the pond dissipate over time, all of that.
Now at the very first smidgeon of axon
hillock, you've got something different. You've got a sodium
channel that works very differently. Here's what you've got.
It has a very simple rule which is if, and only if,
the area just underneath the channel gets sufficiently depolarized,
it opens up. That's critical.
Channel over there in the dendritic world has a very simple if-then clause.
If, and only if, neurotransmitter bonds to the receptor, the channel opens up.
On the right, there's a different if event.
If, and only if, the area immediately under the the channel gets sufficiently
depolarized, it opens up. What does this translate into?
This is all that summation stuff I was going on about before.
This is that whole business that no given little pebble is going to be enough.
So you've got some dendrites, somewhere down to the left there, and
it's gotten excited, and sodium has rushed in, and now it's dissipating outward.
And if this axon
hillock here, if this first channel has a rule that it's got to
get to negative 40 millivolts in order to open up, that one little
hiccup of that dendrite is not going to do it, because there's going to
be enough sodium reaching here to make negative 70 to negative 69.8 or something.
That's why you need a whole bunch of the dendrites over at that end getting excited
all at once to finally get enough sodium coming in to summate
all those little smidgens of sodium influx to summate them enough
to finally pass threshold here, to finally depolarize there enough
to open up the very first sodium channel which in this case is voltage-gated.
In this case is if then clause
is if, and only if, enough sodium has come in through enough
little dendritic inputs there to finally pass threshold here I will open up.
What's an implication in this?
Really interesting one, okay so on scale if this is the first channel on the
axon hillock, and that's the last one on the dendritic cell body end of it.
By stale the rest of the dendrites on that neuron
are somewhere in like Hawyard or the East Bay or Idaho or something.
In terms of size, it means where the dendritic
input is matters with the likelihood of an action potential.
This dendritic input right there has a hell of a lot more influence
over what happens here than the dendrite that's somewhere over in the east bay.
There's a spatial factor
that comes into it.
Dendritic inputs that are closer to the
axon hillock have more control over what occurs.
And what you wind up seeing during neural development is literally wiring
competitions, where neurons not only compete
to form connections with other neurons there.
But they especially compete to try to get as close
to the axon hillock as possible and a remarkable feature of neural development,
your fetal brains back when, made twice as many neurons as you needed.
And what you did with that neuronal overproduction was then
run a wiring competition where all the neurons try to
wire up and half of them were going to wind
up with insufficient wiring and what you did in your
fetal brains was, in a very controlled manner, killed all the excess neurons.
Wonderful term for this neural Darwinism, selection for only of
the neurons that make optimal connections and you get rid
of the rest, and get rid of the rest in
a very controlled process of suicide genes programmed cell death occurring.
This is this brilliant thing in the mammalian nervous systems evolve,
neuronal over production, and then you run a wiring
competition and get rid of the 50% of the losers.
And the competition is not just to make connections but is to preferentially
make connections in all the great places where you've got the most influence.
Okay.
So we've just opened up our very first voltage-gated sodium channel.
And now,
we've got something very different indeed from that graded, wimpy
little pebble in the pond scenario out of the dendrites.
What do we have?
We have step number one.
We've got the area there beginning to depolarize because it's sodium coming
over from whatever dendritic nonsense is occurring to the left, we've got
sodium leeching in there, we've got sodium depolarizing inside of the neuron,
and you're slowly moving from negative 70 milavolts to something less negative.
And finally, at point number two, you hit the threshold.
You hit the threshold of that neuron for
when it opens up its first voltage-gated channel, around
negative 40 milivolts or so, you open it
up and everything goes explosively different at that point.
Massive amounts of sodium rush in.
The channels open up far more than
those dendritic receptor gated channels to the left.
They open up and sodium
comes pouring in and down it's concentration gradient
attracted by the negative charge comes pouring in, goes
pouring in so much that you go for negative
40, negative 30, negative 20, to zero, to positive.
You overshoot, you go into the positive range the peak of the action
potential given that positive 30 millivolts
this is the screaming your head off.
This is the diagram before of you've
got the two compartments and it's completely blackened on this side
under resting conditions and is completely black on that side under excitation.
You go from a negative charge to a positive one.
So much sodium rushes in that there is no neuron in
the universe that is going to mistake this for a resting potential.
This is the contract. This is the screaming your head off.
This is the
maximizing signal to noise ratio. Signal is positive.
Resting is negative.
There's no missing.
The action potential shoots up to positive 30 or so.
At that point the rule is the sodium channels close.
No more sodium coming in.
That's as positive as you are going to get.
You've just achieved a peak.
So what happens at this point?
What happens at this point if you're an uninspired dendrite is the sodium
is going to, in the axon, dissipate outward and the pumps are going to
start working and somewhere about four hours from now, you're going to get from
positive 30 millivolts, get down to the
resting potential, that is not good enough.
That's okay if you're bone cell.
You've stopped having something to say, you
want to get back to your silent statements
as fast as possible.
You don't just passively decrement the charge difference by
keeping the dendritic end, you gotta do something very dramatic.
You've got to rectify this situation of this positive charge, because you
want to get back to where you started as fast as possible.
As soon as you no longer have something to scream your head off
about, you want to get back to being muscularly silent as fast as possible.
What do you do? You open the potassium channels.
You open the potassium channels, way wide at that point.
So what does potassium do at that point?
You're positively charged.
Potassium, inside, is going to flow out, because of the electrical forces.
It's going to flow out, because of the chemical forces.
It's going to flow out and that positive charge goes crashing
back down negative as fast as possible. It's over with.
Nobody in the world can mistake the fact
that this axon, this action potential is finished.
You are very dramatically rectifying that situation, term for it
delayed rectification. The way you go from the positive 30
state back to negative is you have these delayed rectifier potassium channels
that open up at that point.
And out comes potassium and you crash back to where you were, and it's all over with.
Except if you look closely, you'll see it's not
all over with because something weird happens at this point.
OK.
Okay, so you go from positive 30 to positive 10 to 0, you're negative range
and you're hurdling, kind of riding on the back
of your potassium, hurdling back to the negative
70 you started from.
And you get back to negative 70 and you don't stop you keep going.
Afterward you dip even deeper.
You go to around negative 90 millivolts or so.
After an action potential, not only do you repolarize, you hyperpolarize.
You become even more negative.
What's this about?
This is that same theme that's concept with neuronal
contrast all over again.
You are so intent on telling the world that whatever
that excitement was about that there have been positive 30
neuronal state, whatever that was about is so over, it
is so past, that you're not even back to negative 70.
You're back to negative 90, and making the contrast even more extreme.
You hyper-polarize, and at that point, the potassium channels close, and
all your pumps work like crazy, and you get back
negative 70 millivolts and you're back to where you started.
You have this extreme deep dip there just to enhance the contrast.
Okay.
So suppose you are in a hyper polarized state at four, you are now at negative
90 millivolts and you, that neuron, are receiving dendritic inputs,
excitation coming from other neurons.
Are you likely to have an action potential at that point?
Absolutely not.
You are less likely than usual because you are hyper polarized.
You're more likely to be silent, you're more likely
to be out of the business at that point.
Jargon, you have entered the neurons refractory period.
The refractory period and famous in other contexts as well, you got the neuronal
refractory period, and what's that about is you've made the neuron really unlikely
to have an action potential at that point it's a way of enhancing the contrasts.
Okay, so, what's important about this here, the
explosion that occurs at this point, because at
the point the sodium comes pouring in there
enough to shoot you into the positive rage,
what's that sodium going to do once it's outside the neuron?
It's going to look down the axon and say, whoa, negative 70
territory there and come pouring down and open up the next voltage channel.
And sodium pours in and heads down.
It's going to head this direction, because this direction is depolarized.
Is going to go in one direction it is unidirectional its going to go blasting
down there and open up the next channel, and blasting down and
opening up the next, and this is the all or none property.
This is why a pebble thrown in that's big enough
to cause an action potential doesn't enough at that point.
The action potential regenerates each time the next channel opens up and
comes pouring in, as you regenerate the action potential goes shooting down.
Back to that myelin stuff, wrapped around those nodes or Ranvier,
the gaps, why does the action potential shoot down faster that way?
Because the sodium goes blasting down.
One of the pages of the handout with use this, you decrease the capacidents on
the system it shoots down to the next open spot where the channels open up.
Action potential shoots all the way down to the next one who opens
up, what you find during development is all
along the axon, there is these voltage-gated sodium channels.
And once you get the myelin, the neuron retracts the sodium channels from
most of the places and packs them all into that nodes or Ranvier.
So you've got this one little outpost, sodium comes blasting
down, opens it, comes pouring and blasting and that's the saltation.
That's the action potential jumping from one node to the next.
Okay, so, what we've got here is, this picture of how you're going from the
pebbles in the pond decrementing in over the
dendritic end to the action potential being regenerated.
Obviously, a really critical player in all of
this is that very first voltage-gated channel in
the axon hillock.
And people have done a ton of work
understanding the molecular biology about how that channel
works, its ion specificity, all of that, huge
amounts of work, understanding the notion of what
the threshold is, how it is set up so that it suddenly opens up around negative 40
and it suddenly closes about positive 30 or so, how that works in that regard.
Okay, so what this begins to bring in now is sort of a
prelude to the lecture that will come about five from now, which is plasticity.
So how does this change over time?
How does this change?
Because, as noted earlier, every single
factoid that I mentioned, something can change
over the course of time in response
to experience, in response to changing stimuli.
Once a critical piece of the story, the axon
hillock, that voltage gated channel, its threshold can change.
Its threshold, as to just how depolarized that neighborhood
has to get in order to open it up.
Its threshold can change molecular level, what you have is the channel is
a complex, it's got multiple proteins
making it with alternative splicing strategies and
you change the splice variants and you change the threshold for how it fires.
When might that occur?
So here's some examples of a threshold changing.
First one.
First hormone we are going to look at it, foreshadowing for
what will come a few lectures from now, the most famous, infamous,
hormone on Earth there, testosterone.
Testosterone, everybody knows what testosterone does which
makes males really unpleasant, testosterone causes aggression.
And there's part of the brain called the amygdala that's all about aggression.
You get certain types of tumors in there and you get uncontrollable aggression and
various cases of that, and aggression and testosterone, has tons of receptors there.
So obviously what testosterone tends out to do is go into the amygdala and cause
neurons there to have action potentials. That isn't what it does.
That would be the equivalent of turning on a radio.
What does testosterone do? It makes the neurons more excitable.
It causes in splice alternatives of the voltage gated
channel to change to a type that's more excitable, that has a lower
threshold for opening up and thus, the neuron fires more readily.
What's that? That's not turning on the radio.
That's increasing the volume.
Testosterone is not causing aggression there.
It's causing neurons to be more sensitive to whatever out there
triggers aggression, because if there's no stimulation happening to that
neuron it doesn't matter if the threshold is negative 69 millivolts.
It is making the neuron more sensitive to
what in the outside world is triggering it.
Testosterone doesn't cause aggression, what it does is, it makes
organisms more sensitive to the social stimuli that cause aggression.
And the way it does it
is, it's not causing action potentials, it's making
easier for neurons, other inputs, to cause action potentials.
Second example of this, okay, and this one has to do with the form of Estrogen.
Hamsters, female hamsters, female hamsters ovulate once every four days or so.
And that's their amazing rodential life that
they go about, with their ovulatory cycles
there, so every four days.
And what you see is the female
hamsters, there's a certain spinal reflex, as follows.
If you go and you press on the flanks of a female
hamster the backs of the back legs there and you press there and
if enough of a stretch receptor responsive neurons are sitting on the
surface, if enough of them get activated, what you have is a reflex.
The female arches her back. She has what is called a lordosis reflex.
The back is arched and what you have, with the lordosis reflex, is very helpful from
the standpoint of Darwin because what the female
is doing is, by arching her back, she
is exposing her hamster genitals and hence making it easier for a male to mate with
her and passing copies from their genes and,
in most cases, who's pressing on her flanks.
It's a male who's doing that. And this is a great adaptive reflex.
However, it only works if the female is ovulating.
It only works when she's fertile.
And what you've got there is, at other times, you could be like
the entire Encyclopedia Britannica pushing on the back of this female's flanks there.
[LAUGH] And believe me, there are generations of grad students that
have had to do this 24 seven, and what you see there
is you can elicit the lordosis reflex if the female isn't ovulating.
What's estrogen doing?
You guessed it.
Estrogen is changing the conformation of that first voltage-gated channel
in the neurons in the spine that do this reflex.
You only get this reflex under certain endocrine conditions.
And in certain species when you've got this, where you have reduced
ovulation, some male shows up in your territory and leaves his smelly pee
all over the place and that causes the increase in estrogen and
it does that thing, and suddenly you ovulate and have this lordisis reflex.
You've got the smell of somebody's urine in your territory changing
the confirmation of your voltage gated channels in your spinal cord.
This is
where you begin to see that plasticity. One other domain of platicity.
Okay.
Now let's consider what's going on at
number 4 there, back to that hyper-polarization.
You've got the potassium channels and they open up and you crash back down.
And the rule is, don't close even if you're negative 70.
Yes, we know that's where we're aiming for, but
stay a little bit longer, go to negative 90,
get that refractory silent period afterward, you are
energetically telling the world it's all over with.
What if you got a mutation, though, in that potassium channel?
You've got a mutation so that it closes at negative 80 instead of negative
90 Suppose that hyper polarized state is a little more shallow.
What's the consequence of that going to be?
What does that wind up being in terms
of what that neuron does with firing profiles?
Guesses, yeah.
>> It's going to fire more quickly. >> Yeah, fires more quickly.
So, suppose you have that mutation, what disease
are you going to have now? Oh, I just heard somebody whisper it.
Autism? Autism,
no. Okay, that's a no.
Okay, what disease, you got neurons that are firing more often than they're suppose
to because the hyper polarized period is
not as hyper polarized, is not as refractory.
You got a disease of neurons firing too much.
Epilepsy, seizures, you get a seizure, the most common
form of genetically, inheritable epilepsy, the mutation
is a mutation in the potassium channels.
Because you don't get as deep of a hyper polarization.
So we begin to get a sense there of all the types of plasticity.
Okay.
So what have we got at this point? We've got inputs coming in the dendrites.
We've got action potentials.
We've got this critical deal, which is no neuron there has a whole lot of influence
over any other because the summation, the complex network.
We've got the action potential, we've got the critical role of the axon hillock,
we got the critical fact that you can change the threshold of the axon hillock.
You've got a sense of this now.
What do we need to do next?
What do you need to do on Monday at eleven o'clock right here?
What we need to do now is, we've gotten to the axon terminal.
We're shooting all the way down.
We know how to regenerate. We get
all the way to the end.
How now are we going to release neurotransmitters
and talk to the next neuron in line.
Okay, so we will continue with that on Monday.