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Good morning. All right. So,
it was a lot of fun to tell you

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last time about the work that's
going on here at MIT in genomics.

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It's, it's just fun. I mean it's
fun to share what's going on and

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it's fun that you guys can
understand what's going on already

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with simply one semester of biology,
which I think is really cool.

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What I would like to do today is
talk about another exciting area,

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one I don't work in, but one that I
know many people are interested in.

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And I would like to lay the
foundations for neurobiology.

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Neurobiology is an
incredibly interesting area.

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I confess it's the subject that
got me interested in biology in the

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first place, even though
I don't work on it itself.

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And, I mean, who can't be
interested in the brain.

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But if you want to take on the
brain, you really have to understand

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its working components
in some retail detail.

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And so what we're going to focus
on in this course for the next three

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lectures is the specific molecular
mechanism by which nerve cells are

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able to transmit signals down their
length, how they're able to transmit

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signals from one cell to the next,
and then how they're able to change

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their properties over time,
that is learn and remember.

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So, the fundamental unit of
neurological processing is a nerve

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cell which goes by the name a neuron.
You have approximately ten to the

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twelfth neurons.

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How many bases are
in the human genome?

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About three times
ten to the ninth.

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So, you have a lot more nerve
cells than bases in the genome.

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So, it's unlikely that all of
the wiring diagram is completely

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specified in the sequence of the
genome simply because we have a lot

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of them here. That's just a minor
side point. And what does a typical

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neuron look like? So,
neurons and connections.

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So, a
neuron. Well,

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a typical neuron, your ten to the
twelfth neurons makes contacts with

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other neurons. It
might receive contacts.

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It might get contacts from, oh,
ten to the third other neurons.

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And sends signals to ten
to the third other neurons.

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So, that's a lot of connections if
you figure ten to the third times

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ten to the twelfth. Ten to
the fifteenth connections in

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this circuit diagram. Here's
sort of a, kind of a picture

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of a nerve
cell --

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-- making connections to another
nerve cell. Making connections to

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maybe a muscle.

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Oh, and what activates this nerve
cell? Well, maybe in your eye we

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have a
photoreceptor cell.

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And that photo receptor cell will
synapse upon a first neuron which

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will synapse on a second neuron
which will synapse on your muscle.

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So maybe you'll see something,
send a signal, send a signal,

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activate your muscle to pick it up.
Needless to say, it's pretty much

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more complicated than that because
it will take more than those two

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neurons to figure out this is a
piece of chalk and how to coordinate

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that whole motion and all,
but you get the idea. So, let's

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just take a look at some of
these pieces here. What kinds of

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receptors might we have? We
might have receptor neurons that

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receive
light --

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-- called photoreceptors.

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And these photoreceptors in your
eye are an extraordinary piece of

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engineering. Do you know how
sensitive a photoreceptor can be?

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What's the absolutely minimum
possible detectable unit of light?

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One photon. It turns out
your photoreceptors can,

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under appropriate circumstances,
detect a single photon. Not in the

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bright right but in dark adapted
conditions, you actually have on

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photon sensitivity.
Very impressive.

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Under appropriate conditions,
mind you. Sound receptors. You've

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got sound receptors in your
ear and they are beautiful.

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We're not going to talk
about them at any length,

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but there's little flappy,
these little spiky things going

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along in your ear and they can
translate vibrational energy coming

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from your ear,
hurting your eardrum,

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being translated into a vibration
into the fluid in your ear into a

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physical motion of these little
receptors there into an electrical

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motion, into an electrical
signal that goes into your ear.

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So, all of that, all of
that's pretty impressive

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stuff. We're not going to
talk about the details of it,

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but I invite some of you who
want to learn more about this,

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particularly MIT students I
think find receptors really quite

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remarkable kinds of devices.
We're going to focus, though,

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more on this intermediate
step here of a generic neuron.

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So, here's my generic neuron.
And the first thing that has to be

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said is there are no generic neurons.
Neurons are all very specific,

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but I'm just going to use a
generic neuron for the moment.

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And the important features
of a generic neuron here,

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it has these funny little processes
on its cell body that are called

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dendrites. That's where it's
going to receive signals.

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Processes are the name
for things that stick out.

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So, these processes
are called dendrites.

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Here's our nucleus of our cell.
Here's our cell body. We will

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label this your cell
body with a nucleus in it.

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Then we have this very long
process here called an axon.

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The axon is the wire here. This
region here is called the axon

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hillock and it looks like a little
hill. That's what hillock means,

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it's a little sort of
hill-like region here.

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And it's where all the electrical
signals from the cell body are

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integrated and a, quote,
decision is made about

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whether to fire. And the
neuron will then fire a

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signal down the length of its axon
and then it will get to the end here

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where we have these terminal
processes that'll be synapsing on

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other cells here. These
are called nerve terminals.

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And each will make connections
either with other dendrites or maybe

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with a muscle, although
you wouldn't see both of

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those occurring, so I'm
just drawing this for

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illustration purposes here.
And it will send a signal. And

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these points of contact
are called synapses. So,

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nerve or muscle. OK?
So, that's your general

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picture there. You have
a synapse which transmits.

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This is an electrical signal. This
is typically a chemical signal.

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And, as you might imagine, the
pre-synaptic cell is this guy,

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the post-synaptic cell is that
guy. So, I'll say pre-synaptic and

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post-synaptic. And what
neurobiologists want to do

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is understand how does this all work?
How does the initial signal impinge

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upon the dendrite from a synapse?
How does that signal get collected

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and integrated into a decision about
whether to fire an action potential

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that runs along the nerve?
And then how does that get

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transmitted from an electrical
signal back into a chemical signal

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which then restarts an electrical
signal in the next cell,

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etc., etc., etc? Those are some of
the kinds of questions we want to

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ask. Now, I said generic neuron.
Of course there's really nothing

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generic about it. Some
neurons are very tiny.

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Some neurons are very big. What's
the typical size of an ordinary

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eukaryotic cell in a liver
cell? Ballpark. Ten microns.

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So, a typical eukaryotic
cell might be --

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-- and ten microns.

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But a neuron can be anywhere
from that size, ten microns,

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all the way up to three meters.
Where's the longest neuron known?

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Squid giant axon. That's possible,
actually. I'm not sure how big

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squid, I mean there are these
giant squids and they may qualify.

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The longest one that I know of
is in a similar sort of setting.

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It's in the giraffe. It's a motor
neuron in the neck of the giraffe

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which runs three meters, a
single cell. But these monstrous

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squids that, at least in stories,
glom onto boats might actually get

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up there. Will somebody
check the squid,

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the largest squid on record here?
I might need to revise that. But

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the largest one I know about
definitively is the giraffe that has

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single neurons three meters long.
Ten foot long single cells. So,

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it's really very impressive
what a cell can do there.

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So, I'll put down the giraffe but
we'll check out on the squid there.

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Giraffe neck. OK. So, what
are the kinds of questions that

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we might want to ask? Well,
the kinds of questions we

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might want to ask about this process,
and I'm not going to be able to

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answer all of them but I'll get
them up here. So, how do receptors

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transduce
signals --

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-- from the
outside world?

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Light, sounds,
touch, etc.

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That's a good question.
People know a lot about it.

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How do electrical signals
propagate along the neuron?

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Along
an axon?

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People know a lot about that one,
and that's what we're going to

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discuss today.

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How do signals transmit
across a synapse?

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We'll talk
about that,

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some today and some next time.
And how do they transmit them to

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effector cells? So
how do signals transmit

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specifically to effector
cells like a muscle?

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We'll talk
about that.

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Then how does the
pattern of connections --

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-- give rise to
a computation?

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That's
pretty tricky.

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We'll talk just a teeny little
bit about the simplest kind of

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computation, but the complex
computations of recognizing that

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that's somebody's Volkswagen or that
that's your grandmother or something

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are still beyond us today. But
we know things in between that.

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How does this pattern of
connections arise during development?

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That's a fascinating question.
And a lot is known about it, but

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we're not going to talk
about it in this course.

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How does this pattern of connections
get modified by experience?

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That's something that we'll mention
briefly on Friday that a colleague

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of mine who's very knowledgeable
about this is going to give.

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And that's learning and memory.
And then how does this all give

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rise to consciousness?

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And we haven't got the first clue.
We have no idea. It's fascinating.

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I digress for a second.
A famous biologist, J.B.

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. Haldane in the mid-century,
middle of the 20th century wrote a

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final exam to be given in the year
2000 or so. And on the final exam

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he had about 20 odd questions.
And if you go through the exam

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virtually all of those questions
could indeed be answered by a

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student in the year 2000,
except for the question that says

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consciousness arises on
embryonic day 18, example.

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And we have no progress toward
that particular question.

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That was one that he completely was
way off in terms of being able to

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predict that we'd make any progress
on. Maybe he meant it as a joke.

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Anyway. So, let's now
dive into the specifics.

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So, electrical signals in axons.
Here is an axon. We're going to

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give a very close up view.
Here's the lipid bilayer. I'm just

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going to take a cross-sectional
view of my axon here.

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That's the lipid bilayer.
It turns out if I stick an

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electrode into an axon and I
measure the voltage gradient from the

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outside of the cell to the inside of
the cell, what I'm going to find is

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that the inside of the cell
is negative compared to the

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outside of the cell. There
is an electrical potential

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across the plasma membrane of
this axon. This plasma membrane you

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remember, you know, you
all remember about this.

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This is, what, three nanometers
wide. There's an electrical

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membrane, electrical potential
across this equal to about

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minus 70 millivolts.

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Now, come on, minus 70
millivolts is pretty trivial,

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right? You go to the store,
you buy a battery, what has it,

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what's it got like one and
a half volts or something?

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It's minus 70 millivolts like who
cares, right? Except it's minus 70

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millivolts across three nanometers.
What's the electrical field of minus

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70 millivolts across the incredibly
tiny distance of three nanometers?

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Well, the electrical field strength
minus 70 millivolts over three

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nanometers is about 200,
00 volts per centimeter.

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That's a very impressive number,
200,000 volts per centimeter.

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Suppose I could arrange to change
the electrical potential of a cell

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from minus 70 millivolts inside to,
I don't know, minus 70 millivolts

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outside. That would be a swing
of 400,000 volts per centimeter.

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Do you think that a protein which
had an alpha helix that had a dipole

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moment on it could feel a change
of 400,000 volts per centimeter?

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You bet. Some alpha helix that had
some dipole moment on it would swing

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wildly in the presence of a change
of 400,000 volts per centimeter.

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That's the key to how things work
down there is this tiny little minus

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70 millivolts. It's a
huge potential gradient.

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And if we can change that we
can swing the shapes of proteins

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quite dramatically. OK?
That's the principle.

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Now, it turns out that if you take
this electrode and use it to change

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the electrical gradient, what
you will get is the following

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bizarre and fascinating behavior.
So, take my axon here, I use this,

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and what I do is I start
off, here's zero, at minus 70,

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minus 70, this is the
electrical potential.

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If I use the electrode to change
this to about minus 50 or so then

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all by itself, with no
further input on our part,

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the cell wildly shoots up to plus 50
before rapidly coming back down and

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reestablishing itself at minus 70.
So, this depolarization slightly

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shifting it away from being as polar
as it is, it has a polarity of minus

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70, if we depolarize it, make
it less polar, make it less

223
00:19:21,000 --> 00:19:28,000
negative, all by itself the cell
executes something called an action

224
00:19:28,000 --> 00:19:34,000
potential. This action potential
involves rapidly changing to being

225
00:19:34,000 --> 00:19:41,000
positive inside the cell instead of
negative and then restoring itself.

226
00:19:41,000 --> 00:19:45,000
And, as you would imagine, this
massive change in the field has

227
00:19:45,000 --> 00:19:50,000
a huge effect on proteins in
the membrane. This is called

228
00:19:50,000 --> 00:19:54,000
depolarization phase.
Not shockingly this is the

229
00:19:54,000 --> 00:19:59,000
repolarization that occurs
there afterwards. So,

230
00:19:59,000 --> 00:20:04,000
it goes from minus 70 millivolts up
to about plus 50 millivolts there.

231
00:20:04,000 --> 00:20:09,000
All right. How does this happen?
That's my job to explain right now.

232
00:20:09,000 --> 00:20:14,000
Well, the way this happens,
what kind of a beautiful piece of

233
00:20:14,000 --> 00:20:19,000
engineering explains this?
Well, the first thing you need to

234
00:20:19,000 --> 00:20:24,000
know is that there are some
concentration gradients set up in

235
00:20:24,000 --> 00:20:29,000
the cell. So, the
concentration gradients in the

236
00:20:29,000 --> 00:20:35,000
cell are as follows.
There are certain ions,

237
00:20:35,000 --> 00:20:42,000
sodium. Sodium happens to be low
inside the cell and high outside the

238
00:20:42,000 --> 00:20:49,000
cell. The concentration of
sodium inside the cell is about 12

239
00:20:49,000 --> 00:20:56,000
millimolar. Whereas,
outside the cell is about 145

240
00:20:56,000 --> 00:21:04,000
millimolar. By contrast,
potassium ions are high

241
00:21:04,000 --> 00:21:12,000
inside the cell, 139
millimolar. Whereas,

242
00:21:12,000 --> 00:21:20,000
only four millimolar on the outside
of the cell. Calcium ions also have

243
00:21:20,000 --> 00:21:28,000
a gradient across the cell.
They are virtually rare.

244
00:21:28,000 --> 00:21:33,000
0.1 micro, not milli,
micromolar inside the cell and 2.

245
00:21:33,000 --> 00:21:38,000
millimolar outside the cell. So
there are very big differences in

246
00:21:38,000 --> 00:21:43,000
the concentrations. Let
me try to write these

247
00:21:43,000 --> 00:21:48,000
concentration gradients. If
this is the outside and this is

248
00:21:48,000 --> 00:21:53,000
the inside, sodium has a
concentration gradient higher on the

249
00:21:53,000 --> 00:21:58,000
outside than the inside.
Potassium has a concentration

250
00:21:58,000 --> 00:22:03,000
gradient that's higher on
the inside than the outside.

251
00:22:03,000 --> 00:22:07,000
Calcium has a concentration gradient
higher on the outside than the

252
00:22:07,000 --> 00:22:12,000
inside. This turns out to be
the force that drives this action

253
00:22:12,000 --> 00:22:17,000
potential, is that energy has been
stored up in these concentration

254
00:22:17,000 --> 00:22:22,000
gradients. A concentration
gradient is a form of energy.

255
00:22:22,000 --> 00:22:27,000
Why is that? Well, if
there was no membrane there,

256
00:22:27,000 --> 00:22:32,000
what would be the concentration
on the inside and the outside?

257
00:22:32,000 --> 00:22:35,000
The same. There wouldn't be
an inside and outside but,

258
00:22:35,000 --> 00:22:38,000
you know, so let's imagine.
Suppose I just drilled holes in the

259
00:22:38,000 --> 00:22:41,000
membrane. I get in there vrm,
vrm, vrm, drill a lot of holes,

260
00:22:41,000 --> 00:22:45,000
it will equilibrate and, you know,
because just by diffusion there,

261
00:22:45,000 --> 00:22:48,000
we'll go to the entropy, you
know, entropy will set in and it

262
00:22:48,000 --> 00:22:51,000
will be equal concentrations.
If I want to establish a

263
00:22:51,000 --> 00:22:54,000
concentration gradient then,
I have to work against entropy.

264
00:22:54,000 --> 00:22:58,000
That takes energy here. And
that is a form of energy then.

265
00:22:58,000 --> 00:23:04,000
I had to put work into moving
ions around in order to establish a

266
00:23:04,000 --> 00:23:10,000
concentration gradient. Well,
who's in charge of carrying

267
00:23:10,000 --> 00:23:16,000
out that work? Who is
it that sets up these

268
00:23:16,000 --> 00:23:22,000
concentration gradients in the
cell? Membrane proteins. Certain

269
00:23:22,000 --> 00:23:28,000
membrane proteins. In
particular, membrane

270
00:23:28,000 --> 00:23:34,000
transporters are involved.
So, we're going to talk about

271
00:23:34,000 --> 00:23:40,000
transporters and then we'll
talk about some channels.

272
00:23:40,000 --> 00:23:51,000
All right.
The first one.

273
00:23:51,000 --> 00:24:04,000
There is an ATP-driven
sodium potassium pump.

274
00:24:04,000 --> 00:24:12,000
Any ideas what an
ATP-driven sodium

275
00:24:12,000 --> 00:24:18,000
potassium pump does? It
sets up, how does it set up a

276
00:24:18,000 --> 00:24:24,000
concentration gradient? So,
what does it pump? It pumps a

277
00:24:24,000 --> 00:24:29,000
sodium. Does it pump
a sodium in or out?

278
00:24:29,000 --> 00:24:33,000
It pumps a sodium out. It pumps
potassium in. And it does it as an

279
00:24:33,000 --> 00:24:37,000
even exchange. Why would
it like to do it as an

280
00:24:37,000 --> 00:24:41,000
even exchange, one
sodium for one potassium?

281
00:24:41,000 --> 00:24:46,000
Charge conservation, exactly.
So, there's no electrical work to

282
00:24:46,000 --> 00:24:50,000
be done if it swaps them one
for one. And is there work,

283
00:24:50,000 --> 00:24:54,000
though, to be done? Yes, there
is, because if I'm going to

284
00:24:54,000 --> 00:24:58,000
pump sodium out of the cell,
I'm doing it against the

285
00:24:58,000 --> 00:25:03,000
concentration gradient. Or
at least once I get going I'm

286
00:25:03,000 --> 00:25:07,000
doing it against a
concentration gradient. So,

287
00:25:07,000 --> 00:25:11,000
energy is needed to move a
sodium out of the cell against its

288
00:25:11,000 --> 00:25:15,000
concentration gradient.
Energy is also needed to move a

289
00:25:15,000 --> 00:25:19,000
potassium into the cell against
its concentration gradient.

290
00:25:19,000 --> 00:25:23,000
And where do we get the energy?
ATP. So, an ATP is burned in order

291
00:25:23,000 --> 00:25:29,000
to do that. This guy
gets called an anti-porter

292
00:25:29,000 --> 00:25:36,000
sometimes because it's an
anti-transporter or something like

293
00:25:36,000 --> 00:25:43,000
that. OK. The pump then is ATPA as
it uses the energy from an ATP to

294
00:25:43,000 --> 00:25:50,000
exchange this. Good.
Next. There is an

295
00:25:50,000 --> 00:25:57,000
ATP-driven calcium
pump or transporter.

296
00:25:57,000 --> 00:26:05,000
And, as you might imagine,
what does it do? It transports a

297
00:26:05,000 --> 00:26:13,000
calcium ion out of the cell,
and it happens not to do that in

298
00:26:13,000 --> 00:26:21,000
exchange for any other ion.
And it, too, is driven by ATP.

299
00:26:21,000 --> 00:26:30,000
So, we go pump, pump, pump, pump,
pump, pump, pump, pump, keep going.

300
00:26:30,000 --> 00:26:35,000
Will this thing be able
to keep going forever,

301
00:26:35,000 --> 00:26:40,000
set up arbitrarily large
concentration gradients? Why not?

302
00:26:40,000 --> 00:26:46,000
Well, what is nothing
leaked back in?

303
00:26:46,000 --> 00:26:49,000
Could we, could we keep going?
It gets harder and harder to put

304
00:26:49,000 --> 00:26:53,000
stuff out because you're working
up against a bigger and bigger

305
00:26:53,000 --> 00:26:56,000
concentration gradient. And
the ATP is only going to give

306
00:26:56,000 --> 00:26:59,000
you so much energy.
So, at a certain point,

307
00:26:59,000 --> 00:27:03,000
the burning of that ATP or however
many ATPs it uses for its specific

308
00:27:03,000 --> 00:27:06,000
mechanism won't suffice. So,
there's going to be some natural

309
00:27:06,000 --> 00:27:09,000
upper bound to how far it could
go in setting up a gradient because

310
00:27:09,000 --> 00:27:12,000
there's a nature amount
of energy it can spend. OK.

311
00:27:12,000 --> 00:27:15,000
It's useful to think about
these gradients as, you know,

312
00:27:15,000 --> 00:27:19,000
work that you've got to do and
the hill gets steeper and steeper.

313
00:27:19,000 --> 00:27:22,000
All right. So that could, in
principle, set the electrical

314
00:27:22,000 --> 00:27:25,000
gradient, the concentration
change across the cell.

315
00:27:25,000 --> 00:27:28,000
But there's one other
important component that we have

316
00:27:28,000 --> 00:27:34,000
to think about. And that
is something called a

317
00:27:34,000 --> 00:27:42,000
resting potassium channel.
So, what is a resting potassium

318
00:27:42,000 --> 00:27:51,000
channel? The resting potassium
channel is a protein that sits in

319
00:27:51,000 --> 00:28:00,000
the membrane and it's
got a hole in it, a pore.

320
00:28:00,000 --> 00:28:04,000
And that pore here is designed so
that while a sodium can't escape

321
00:28:04,000 --> 00:28:09,000
through that pore, and you
can imagine there's some

322
00:28:09,000 --> 00:28:13,000
little bit of cleaver molecular
architecture to make the sodium atom

323
00:28:13,000 --> 00:28:18,000
not be able to, sodium
ion not be able to get out

324
00:28:18,000 --> 00:28:23,000
but a potassium ion be able to get
out, a potassium ion can get out.

325
00:28:23,000 --> 00:28:27,000
This is a completely open door that
allows potassium ions to escape.

326
00:28:27,000 --> 00:28:32,000
Now, isn't this stupid? We
just spent all this ATP getting

327
00:28:32,000 --> 00:28:36,000
potassium in and sodium out, and
here I go opening the door for

328
00:28:36,000 --> 00:28:41,000
potassium saying you're free to
leave despite all the work we put

329
00:28:41,000 --> 00:28:45,000
into bringing you into the cell.
That makes no sense. All the

330
00:28:45,000 --> 00:28:50,000
potassium is just
going to rush out.

331
00:28:50,000 --> 00:28:58,000
Can all the
potassium rush out?

332
00:28:58,000 --> 00:29:02,000
The concentration gradient goes
which way? It's more inside,

333
00:29:02,000 --> 00:29:06,000
more potassium inside, less outside,
so the potassium is going to rush

334
00:29:06,000 --> 00:29:10,000
out. Yes. Ooh,
electrical gradient.

335
00:29:10,000 --> 00:29:15,000
If there's an electrical, so
maybe at the beginning there's no

336
00:29:15,000 --> 00:29:19,000
electrical gradient,
so potassium rushes out.

337
00:29:19,000 --> 00:29:23,000
What does it do? It makes it
more positive on the outside.

338
00:29:23,000 --> 00:29:28,000
Now the next potassium
wants to rush out.

339
00:29:28,000 --> 00:29:32,000
It's going to, it's going
down its concentration

340
00:29:32,000 --> 00:29:36,000
gradient but it's going up a teeny
weenie little electrical gradient.

341
00:29:36,000 --> 00:29:40,000
Now that gets out there, and
what does it do to the outside?

342
00:29:40,000 --> 00:29:45,000
Makes it more positive. So, the
third potassium makes it even

343
00:29:45,000 --> 00:29:49,000
more positive. And as
more and more potassiums

344
00:29:49,000 --> 00:29:53,000
rush out, the outside becomes more
positive. And every potassium now

345
00:29:53,000 --> 00:29:58,000
has to do work to get up
that electrical gradient.

346
00:29:58,000 --> 00:30:02,000
But, of course, it's
still got a concentration

347
00:30:02,000 --> 00:30:07,000
gradient pushing it out. So,
will they keep going forever?

348
00:30:07,000 --> 00:30:11,000
No, they're going to balance each
other. There will come a point when

349
00:30:11,000 --> 00:30:16,000
the concentration gradient, the
force driving potassium out due

350
00:30:16,000 --> 00:30:20,000
to the concentration gradient is
offset by the electrical gradient

351
00:30:20,000 --> 00:30:25,000
pushing potassium in,
or keeping potassium in.

352
00:30:25,000 --> 00:30:33,000
So, what happens is potassium
goes out, rushes out,

353
00:30:33,000 --> 00:30:41,000
or goes out, leaks out,
potassium leaks out which now sets

354
00:30:41,000 --> 00:30:51,000
up an electrical gradient.

355
00:30:51,000 --> 00:30:56,000
And what happens is the cell
becomes more positive on the outside,

356
00:30:56,000 --> 00:31:02,000
more negative on the inside, and
an equilibrium potential is reached,

357
00:31:02,000 --> 00:31:09,000
equilibrium
is reached.

358
00:31:09,000 --> 00:31:12,000
So, an equilibrium
electrical potential --

359
00:31:12,000 --> 00:31:22,000
-- is reached when
the concentration

360
00:31:22,000 --> 00:31:30,000
gradient exactly offsets,
when it balances the electrical

361
00:31:30,000 --> 00:31:39,000
gradient.

362
00:31:39,000 --> 00:31:43,000
Any guesses to what that electrical
concentration gradient is?

363
00:31:43,000 --> 00:31:48,000
Minus 70 millivolts. That's where
minus 70 millivolts comes from.

364
00:31:48,000 --> 00:31:53,000
It comes because that's the
concentration gradient at which

365
00:31:53,000 --> 00:31:58,000
potassium going up that
gradient just offsets the, yes?

366
00:31:58,000 --> 00:32:11,000
Well, because,

367
00:32:11,000 --> 00:32:14,000
oh, it doesn't. The
electrical potential wants to

368
00:32:14,000 --> 00:32:17,000
keep it in. The concentration wants
it out. The electrical wants it in.

369
00:32:17,000 --> 00:32:20,000
That's why we have an equilibrium.
Exactly. It's those two balancing

370
00:32:20,000 --> 00:32:23,000
forces. Very good.
So, how much potassium,

371
00:32:23,000 --> 00:32:26,000
by the way, has to rush out
to set this up? It turns out

372
00:32:26,000 --> 00:32:30,000
a trivial amount. It turns
out that about ten to,

373
00:32:30,000 --> 00:32:34,000
one part in ten to the sixth of all
the potassium ions leaving sets up a

374
00:32:34,000 --> 00:32:39,000
gradient of about minus,
of about five millivolts,

375
00:32:39,000 --> 00:32:43,000
minus five millivolts. One part in
a million of the potassium ions will

376
00:32:43,000 --> 00:32:48,000
suffice to set up a concentration
gradient of minus five millivolts.

377
00:32:48,000 --> 00:32:52,000
So, all I've got to do is
set up about, let's see,

378
00:32:52,000 --> 00:32:57,000
I don't know, less than, I
don't know, maybe about one part

379
00:32:57,000 --> 00:33:02,000
in ten to the fifth of all
the potassium ions leaving.

380
00:33:02,000 --> 00:33:05,000
A tiny contribution
of the concentration.

381
00:33:05,000 --> 00:33:08,000
Changing the concentration by one
part in ten to the fifth will get me

382
00:33:08,000 --> 00:33:11,000
minus 50 millivolts already.
So, what's very interesting is

383
00:33:11,000 --> 00:33:15,000
teeny amounts of ions set up a very
big electrical gradient and have no

384
00:33:15,000 --> 00:33:18,000
real effect on the concentration,
but they have a big effect on the

385
00:33:18,000 --> 00:33:21,000
electrical gradient. So, when
I say potassium leaks out,

386
00:33:21,000 --> 00:33:25,000
it only takes a teeny bit of
potassium to leak out in order to

387
00:33:25,000 --> 00:33:29,000
accomplish this. OK, guys.
Now let's get ready to make an

388
00:33:29,000 --> 00:33:35,000
action potential.
Here it goes. So,

389
00:33:35,000 --> 00:33:45,000
the action
potential mechanism.

390
00:33:45,000 --> 00:33:51,000
We've set up our resting
potential by transporters,

391
00:33:51,000 --> 00:33:57,000
by this open channel. Now,
the first thing we have is a

392
00:33:57,000 --> 00:34:03,000
new kind of membrane channel.
We have a voltage gated

393
00:34:03,000 --> 00:34:19,000
sodium channel.

394
00:34:19,000 --> 00:34:26,000
Check this out. This guy
here is a channel that's

395
00:34:26,000 --> 00:34:35,000
closed. It's closed. Except,
so at minus 70 millivolts

396
00:34:35,000 --> 00:34:45,000
it's closed. But if I can
transiently depolarize the cell to

397
00:34:45,000 --> 00:34:56,000
minus 50 millivolts it
opens and it admits sodium.

398
00:34:56,000 --> 00:35:04,000
So, when I get to minus 50 it opens.
Now, what will sodium do when that

399
00:35:04,000 --> 00:35:10,000
door opens? Let's see.
Electrically what would sodium,

400
00:35:10,000 --> 00:35:20,000
what would
sodium do?

401
00:35:20,000 --> 00:35:23,000
So what, well, how
about concentration?

402
00:35:23,000 --> 00:35:26,000
From the point of view of
concentration what would sodium,

403
00:35:26,000 --> 00:35:30,000
oh, what did I just draw
here? Ooh, forget my error.

404
00:35:30,000 --> 00:35:34,000
Electrically what would sodium like
to do? It would like to come in,

405
00:35:34,000 --> 00:35:38,000
wouldn't it? Because it's negative
inside and sodium is positive.

406
00:35:38,000 --> 00:35:42,000
But from a concentration
gradient what would it like to do?

407
00:35:42,000 --> 00:35:46,000
Come in also. So what's stopping
it? Nothing. We've got the ion

408
00:35:46,000 --> 00:35:50,000
that would like to come in
electrically and would like to come

409
00:35:50,000 --> 00:35:54,000
in from the point of
view of concentration.

410
00:35:54,000 --> 00:35:58,000
So what happens? It comes
in. And it comes rushing

411
00:35:58,000 --> 00:36:02,000
in. Now, what
happens as it comes

412
00:36:02,000 --> 00:36:06,000
rushing in? What will it do
to our electrical potential?

413
00:36:06,000 --> 00:36:11,000
We went from minus 70, we got
it transiently up to minus 50,

414
00:36:11,000 --> 00:36:15,000
and as it comes in what does it
do to our electrical gradient?

415
00:36:15,000 --> 00:36:20,000
Brings in positive charge. The
electrical gradient goes towards

416
00:36:20,000 --> 00:36:24,000
zero. Does it stop at zero? No,
because now, even as the cell

417
00:36:24,000 --> 00:36:29,000
becomes positive in the interior,
sodium still wants to keep coming in

418
00:36:29,000 --> 00:36:34,000
because of it's
concentration gradient.

419
00:36:34,000 --> 00:36:39,000
It now has to do some work against
the electrical gradient that's set

420
00:36:39,000 --> 00:36:44,000
up, but it keeps going and going
and going. Does it go on forever?

421
00:36:44,000 --> 00:36:49,000
No, because eventually it reaches a
point where the electrical gradient,

422
00:36:49,000 --> 00:36:54,000
positive now inside the cell,
offsets the concentration gradient

423
00:36:54,000 --> 00:36:59,000
and it'll stop and it'll reach a
new equilibrium potential which turns

424
00:36:59,000 --> 00:37:04,000
out to be at about plus
50. Amazing. Opens the door.

425
00:37:04,000 --> 00:37:08,000
Sodium comes rushing in down its
concentration electrical gradient,

426
00:37:08,000 --> 00:37:13,000
shifts the electrical gradient
from being negative to positive,

427
00:37:13,000 --> 00:37:17,000
and eventually it slows itself down
because it's now going against an

428
00:37:17,000 --> 00:37:22,000
electrical gradient. But
that's not the end of the story

429
00:37:22,000 --> 00:37:27,000
because what there also is,
there are two other interesting

430
00:37:27,000 --> 00:37:31,000
functions. One, after a
certain amount of time,

431
00:37:31,000 --> 00:37:39,000
after a very brief
time interval --

432
00:37:39,000 --> 00:37:42,000
-- this channel also has
the property that it closes.

433
00:37:42,000 --> 00:37:49,000
So now when
it closes,

434
00:37:49,000 --> 00:37:53,000
what's going to happen? The
pumps will start working again

435
00:37:53,000 --> 00:37:57,000
and reestablish our negative 50.
It's going to take too long, though.

436
00:37:57,000 --> 00:38:02,000
I mean it'll happen.
You'd get back to minus 50,

437
00:38:02,000 --> 00:38:06,000
but it's going to take a long time.
So it's good that the channels,

438
00:38:06,000 --> 00:38:11,000
that the voltage gated
sodium channel closed,

439
00:38:11,000 --> 00:38:15,000
but even better nature has
arranged to have a voltage gated

440
00:38:15,000 --> 00:38:25,000
potassium channel.

441
00:38:25,000 --> 00:38:31,000
And what happens to this voltage
gated potassium channel is around

442
00:38:31,000 --> 00:38:37,000
plus 30 millivolts it
opens and admits potassium.

443
00:38:37,000 --> 00:38:45,000
Now, instead of having to wait for
the relatively slow ATP-driven pumps,

444
00:38:45,000 --> 00:38:53,000
what happens when I admit potassium?
Well, if the cell is positive on

445
00:38:53,000 --> 00:39:01,000
the inside, negative on the outside,
what happens to our potassium?

446
00:39:01,000 --> 00:39:08,000
Potassium starts coming out because
there's more potassium on the inside

447
00:39:08,000 --> 00:39:15,000
and there's also a favorable
electrical gradient.

448
00:39:15,000 --> 00:39:22,000
So, potassium explosively
starts rushing out and rapidly

449
00:39:22,000 --> 00:39:30,000
reestablishes the resting potential.
All this happening in a millisecond.

450
00:39:30,000 --> 00:39:34,000
It's very impressive.
So, in something like one

451
00:39:34,000 --> 00:39:38,000
millisecond we open up the
potassium channels. Now,

452
00:39:38,000 --> 00:39:42,000
you have to ask how did it happen
that the channels got open in the

453
00:39:42,000 --> 00:39:46,000
first place? How did we get to
minus 50? That's the work of these

454
00:39:46,000 --> 00:39:51,000
dendrites. The dendrites
integrating a signal from all the

455
00:39:51,000 --> 00:39:55,000
things impacting on it will
get the cell to minus 50,

456
00:39:55,000 --> 00:39:59,000
but once the cell gets to
minus 50 at its axon hillock,

457
00:39:59,000 --> 00:40:03,000
bingo, the action potential fires,
the cell zips up to plus 50 in a big

458
00:40:03,000 --> 00:40:07,000
rush of sodiums and then zips down
to minus 70 again in a big rush of

459
00:40:07,000 --> 00:40:16,000
potassiums. Yes?

460
00:40:16,000 --> 00:40:19,000
Yup. Remember I said it was only
like one part and ten to the fifth

461
00:40:19,000 --> 00:40:22,000
of the ions? It's a trivial actual,
the number of ions necessary to set

462
00:40:22,000 --> 00:40:25,000
up these electrical things is such
a tiny fraction of the concentration

463
00:40:25,000 --> 00:40:29,000
that through this whole thing
those concentrations don't

464
00:40:29,000 --> 00:40:32,000
noticeably change.
That's what's so cool,

465
00:40:32,000 --> 00:40:36,000
is there are different regimes,
right? And they do change. They

466
00:40:36,000 --> 00:40:39,000
change by one part and ten
to the fifth of those numbers.

467
00:40:39,000 --> 00:40:42,000
It's really cool, isn't it?
We haven't screwed up our

468
00:40:42,000 --> 00:40:46,000
concentration gradient? We
moved tiny numbers of ions to

469
00:40:46,000 --> 00:40:49,000
accomplish all this. This
is very cleaver engineering.

470
00:40:49,000 --> 00:40:53,000
It's very cleaver engineering. Now,
how do we manage to transmit this

471
00:40:53,000 --> 00:40:56,000
signal down a cell? Well,
let's talk about how we

472
00:40:56,000 --> 00:41:00,000
propagate. I think
this is really cool.

473
00:41:00,000 --> 00:41:04,000
This is one of the truly great
mechanisms that was invented.

474
00:41:04,000 --> 00:41:19,000
Transmitting an
action potential.

475
00:41:19,000 --> 00:41:27,000
Suppose I transmit my action.
Suppose I have a neuron here and

476
00:41:27,000 --> 00:41:35,000
over here, at the axon hillock, I
transiently depolarize to minus 50.

477
00:41:35,000 --> 00:41:43,000
Then I fire
and fire.

478
00:41:43,000 --> 00:41:49,000
Well, what happens is this part
of the cell was originally minus,

479
00:41:49,000 --> 00:41:55,000
minus, minus, plus, plus, plus,
it becomes positive temporarily,

480
00:41:55,000 --> 00:42:04,000
right? It
now becomes --

481
00:42:04,000 --> 00:42:10,000
-- plus, plus, plus. So,
let's go minus along the

482
00:42:10,000 --> 00:42:16,000
whole cell here.
Plus, plus, plus,

483
00:42:16,000 --> 00:42:23,000
plus, plus. Now, some little patch
of membrane at the beginning of the

484
00:42:23,000 --> 00:42:29,000
axon has become positive inside,
right? Because whatever local

485
00:42:29,000 --> 00:42:35,000
affect here caused this to flip.
If this becomes positive at this

486
00:42:35,000 --> 00:42:40,000
part of the membrane, what
happens to the negative charges

487
00:42:40,000 --> 00:42:46,000
over here a little bit further
down the axon? Some of them will be

488
00:42:46,000 --> 00:42:51,000
pulled over to the positive.
Ho-ho. Some negative charges get

489
00:42:51,000 --> 00:42:56,000
pulled over. Well, what
happens when some of those

490
00:42:56,000 --> 00:43:02,000
negative charges get pulled
over to my minus 70 millivolts?

491
00:43:02,000 --> 00:43:08,000
Is it as negative as it was before?
No. It becomes minus 50 millivolts.

492
00:43:08,000 --> 00:43:14,000
Oh. What happens when this
becomes minus 50 millivolts?

493
00:43:14,000 --> 00:43:21,000
Fires an action potential. So,
what happens is, here's my axon,

494
00:43:21,000 --> 00:43:27,000
I fire an action, I have
an action potential here,

495
00:43:27,000 --> 00:43:34,000
and in the course of that I
pull over some negative charge.

496
00:43:34,000 --> 00:43:38,000
That, of course, transiently
depolarizes here and

497
00:43:38,000 --> 00:43:42,000
causes an action potential to
fire. Then, of course, this becomes

498
00:43:42,000 --> 00:43:46,000
positive which pulls over some
negative charge which causes the

499
00:43:46,000 --> 00:43:50,000
action potential to fire here,
etc., etc., etc. So, if I can

500
00:43:50,000 --> 00:43:55,000
manage to get the thing started
with my dendrites causing a transient

501
00:43:55,000 --> 00:43:59,000
depolarization from minus 70 to
minus 50 then the action potential

502
00:43:59,000 --> 00:44:03,000
itself will draw over some charge
and start the process at the next

503
00:44:03,000 --> 00:44:07,000
patch of membrane, the next
patch of the next membrane,

504
00:44:07,000 --> 00:44:12,000
the next patch of the next membrane
and the next patch of membrane.

505
00:44:12,000 --> 00:44:17,000
And it gets all the way down to
the end. It's a brilliant mechanism.

506
00:44:17,000 --> 00:44:22,000
You can calculate, based on the
diffusion coefficient of ions,

507
00:44:22,000 --> 00:44:28,000
how long it will take to
transmit that signal. And it's OK

508
00:44:28,000 --> 00:44:33,000
but not good enough.
I'd like it to go faster.

509
00:44:33,000 --> 00:44:40,000
How can I make
it go faster?

510
00:44:40,000 --> 00:44:46,000
How about put an insulator around
it? It turns out that with one little

511
00:44:46,000 --> 00:44:52,000
trick, I can speed this
up dramatically. Oh,

512
00:44:52,000 --> 00:44:58,000
sorry. Sorry about that. The
trick is suppose I were to wrap

513
00:44:58,000 --> 00:45:04,000
some insulator around the axon that
would make this such that it could

514
00:45:04,000 --> 00:45:10,000
not, that it was not an
electrical contract outside,

515
00:45:10,000 --> 00:45:16,000
that it was only an electric
contact with the outside solution

516
00:45:16,000 --> 00:45:22,000
here, here, here. Then,
when the action potential

517
00:45:22,000 --> 00:45:27,000
fires here, it's going to pull
charges over, not from the tiny

518
00:45:27,000 --> 00:45:31,000
little patch of membrane here, but
the charges are going to have to

519
00:45:31,000 --> 00:45:36,000
come from here, it turns
out, because that's where

520
00:45:36,000 --> 00:45:41,000
I'm going to next feel my action
potential. And so what'll happen is

521
00:45:41,000 --> 00:45:45,000
that the action potential,
if this stuff is electrically

522
00:45:45,000 --> 00:45:50,000
insulated, will only be happening
at this little gaps between the

523
00:45:50,000 --> 00:45:55,000
insulation. And I can dramatically
speed up the electrical transmission

524
00:45:55,000 --> 00:46:00,000
if I'm willing to
insulate the wire.

525
00:46:00,000 --> 00:46:04,000
Because then there's much
less leakage along the way.

526
00:46:04,000 --> 00:46:09,000
So, it turns out that there are
special cells that wrap themselves

527
00:46:09,000 --> 00:46:14,000
around the axon that
are called Schwann cells.

528
00:46:14,000 --> 00:46:19,000
The Schwann cell wraps itself
around and around and around and

529
00:46:19,000 --> 00:46:24,000
squeezes out all of its cytoplasm
leaving only a lipid bilayer.

530
00:46:24,000 --> 00:46:29,000
Lipid bilayers wrapped around
and around and around make

531
00:46:29,000 --> 00:46:35,000
great insulators. This is
called the myelin sheath of

532
00:46:35,000 --> 00:46:41,000
a nerve. These myelin sheaths allow
the transmission of this action

533
00:46:41,000 --> 00:46:48,000
potential to proceed about a
hundred times faster. Very cleaver.

534
00:46:48,000 --> 00:46:54,000
Now you ask me how do I know this
matters? I mean you can calculate

535
00:46:54,000 --> 00:47:01,000
that it should go
about 100 times faster.

536
00:47:01,000 --> 00:47:07,000
But how would you really know that
it mattered. Try taking them off.

537
00:47:07,000 --> 00:47:13,000
Unfortunately, there is a
disease that takes them off.

538
00:47:13,000 --> 00:47:20,000
Some human patients make autoimmune
reactions against their own myelin.

539
00:47:20,000 --> 00:47:26,000
It attacks their own myelin
and leads to the demyelination

540
00:47:26,000 --> 00:47:32,000
of the nerves. This
disease is called multiple

541
00:47:32,000 --> 00:47:38,000
sclerosis. Multiple sclerosis
involves an autoimmune attack on

542
00:47:38,000 --> 00:47:44,000
your very own myelin sheaths,
and the effects, the very serious

543
00:47:44,000 --> 00:47:50,000
effects that multiple sclerosis can
have on an individual come from the

544
00:47:50,000 --> 00:47:56,000
greatly diminished, hundred-fold
diminished conduction

545
00:47:56,000 --> 00:48:02,000
velocity of electrical signals
down motor neurons along these

546
00:48:02,000 --> 00:48:07,000
large distances.
So, this is, in fact,

547
00:48:07,000 --> 00:48:11,000
the basic electrical setup. We
have taken a situation where we

548
00:48:11,000 --> 00:48:15,000
don't have electrical wires
at all but have concocted,

549
00:48:15,000 --> 00:48:19,000
through chemistry, a powerful
way to create signals.

550
00:48:19,000 --> 00:48:23,000
First, by setting up a resting
potential using pumps and an open

551
00:48:23,000 --> 00:48:27,000
potassium channel. Then by
setting up this explosive

552
00:48:27,000 --> 00:48:31,000
mechanism where a little
change in voltage which,

553
00:48:31,000 --> 00:48:36,000
of course, has a huge change in
field, swings open a sodium channel,

554
00:48:36,000 --> 00:48:40,000
shuts it, swings open a potassium
channel, and then cleverly recruits

555
00:48:40,000 --> 00:48:45,000
charges from down the
neuron and sends the signal.

556
00:48:45,000 --> 00:48:49,000
Next time we shall talk about what
happens when the signal gets all the

557
00:48:49,000 --> 00:48:54,000
way to the other end and it
has to talk to the next neuron.

558
00:48:54,000 --> 00:48:59,000
Till
next time.