Biology 1A - Lecture 38: Summation


Uploaded by UCBerkeley on 30.11.2012

Transcript:
>>INSTRUCTOR: Let's begin. This last lecture will continue with the nervous
system. As you recall, in the last lecture we had
sort of just gone over some of the functional constraints. What would we like, what does
the nervous system actually accomplish? And establish that it's evolutionarily ancient
and so now we want to talk about the functional basis of everything that goes on in the nervous
system. And the functional unit, not surprising to
you, is the cell. Neuron.
But even this was something that had to be discovered. If you read the history of science
sort of stuff, originally, people were thinking once they had seen that there were nerves
and actually there was a tremendous influence of a good idea, you know, like, William Harvey,
in the 1600s described circulation, right? That there's a fluid flowing around the body
in the veins and arteries. And you know, any time you get a good idea,
a good paradigm you want to stick with it and use it to explain as much as you can.
This is why weハ today we're analogizing everything in front of computers.
A hundred years ago was everything was thinking in terms of machines.
Right. So, there's a dominant school of thought and
the idea that there was people thought things were going on with nerves they can see them
anatomically and so they had this idea was that there were fluids or neumas(?) that were
goingハ that nerves were actually continuous hallow tubes, they connected from one part
of the body toハanother and it was sort of like a pneumatic system that you would squeeze
out some little bit of fluid and that would make your muscle contract.
Then, this persisted for quite a while, this time it'sハ you need to slouch a little bit,
thank you. And then in the 19th century, there were these
two scientists who shareハ it looks like 3, it'sハハ its not Ramoneハ Ramon y Cajal,
I use to think it was this close it in scientific partnership because they always published
together. Turns out its one guy. A famous Spanish anatomies
there's another guy named Golgi, who developed a wonderful staining method that could take
this tremendously complex material of the brain and reveal it one cell at a time, with
a special silver stain, magical silver stain, but even with that, Golgi persisted in the
ideaハ he wasn't thinking of neumas(?) anymore, but Golgi was a proponent of a reticular model
in which call of the nerves were a continuous network, cytoplasmic continuity that was essential.
And Cajal, Ramon y Cajal, profused golgi staining method to document the factハ to argue for
the fact that it was individual neurons just like in pretty much every other tissue.
So, they were bitter rival, and they shared the Nobel Prize in 1960, so that must have
been an interesting social diplomatic challenge for the King of Sweden, but I'm sure he was
up to it. So, you can see that the neurons come in remarkably
diverse morphologies they're usually characterized by a polarized structure.
In which you have 1 set of specializedハ what we know now as receptive ends, and transmitting
ends the dendrites and the synaptic terminals. And then all of the machinery that we think
about nucleus, most of the biosynthetic machinery is in the cell body, which could have various
places relative to all of this. For the purposes of our discussion, I'm going
to omit the fact that actually, our brains our nervous system have approximately 10 times
as many glial as many neurons the glial are essential for maintaining, repairing the nervous
system they play roles in guiding neuron growth, especially during reinnervation of muscles
there's beautiful stories that they permit to miniaturize our nervous systems by allowing
us to get away with smaller diameter axons and still have rapid conduction ofハinformation.
But we're going to ignore all of that. Along with a lot of other things.
It's curious to think that maybe this polarized structure, where do these things come from?
Evolutionarily, cell types also must evolve, right? And it's been speculating, I would
say, that maybe the neuron specializations arose from a polarized epithelium, originally
as a specialization, back in the Cnidarians or ancestor of the Cnidarians.
So, key thing to know that I'm sure you already know is that electrical signaling is the key
to neural functions. Not neumas(?), not anything else.
And so, there's two features that we're going to talk about, first is the resting potential.
Action potential. When we say potential here, we mean electrical potentials just like in
your radio. Okay. So the resting potential is generated
by the combination of our good friend the sodium potassium ATPize, ion pump in combination
with ion selective leak channels that are just passive transports always there.
So you can think about this in this way, if you have a random salt solution equally distributed,
now this is a thought explanation, this isn't what happens in your body, but in terms of
thinking about how these things working. If you have a plasma membrane with no channels,
no electrical conductive across this because ions cannot cross you can insert in this sodium
potassium ATPases, and they're going to put sodium out, potassium in, and a ratio of 3
to 2 and this generates concentration gradients so that you have higher potassium on the inside
higher sodium on the outside. And now the fact that you're moving three
ions out and only two in, that alone would seem to generate a potential, but that doesn't
get you much more than a few millivolts and in fact it's sortハ usually equilibratedハ
you can't have a net, so much gross charge difference, so there's chloride channels where
chlorideハ you can think of chloride going out, and so actually there's a higher chloride
concentration outside and inside, and a lot of the anions on the inside of the cell are
going to be what? Macromolecules, DNA, RNA, all of those phosphates the ATP, those are
all going to contribute to negative charge where as most of theハ on the inside of the
cell, so these are large anions that can't diffuse out, and most of the external charge
will be born by the chloride in negative. So, you've got these ion gradients, okay.
And now, you introduce yet kind of channel. And don't think you're going to memorize all
ofハthe different kinds of channels there are way too many.
We're just introducing the sort of functionalities of channels.
And so you need to think of them in terms of sort of what they do operationally. What
we have is a potassium leak charge, sorry I just screwed up what you just said, you
do need to memorize the fact that there are potassium leak channels and things like that,
there are many different molecular versions of different kinds of channels and different
kinds of cells, so. So if you have now a channel that only lets
potassium out, sorry that's lets potassium flow through it, passively, either way, driven
by electrical charge or concentration differences, okay.
The selectivity is generated how? By the particular con fir ration and distribution of amino acids
that form sort of a hydrophilic pore across the membrane, okay.
So you have lots of these potassium channels. If you have a higher concentration of potassium
inside of the cell it will tend to go out, this will be more potassium going out than
in. Driven by the concentration difference.
But now every time you take out a net potassium charge you leave a net negative charge on
the inside, theseハ they repel each other, so any net charge will sort of spread apart
and be right against the plasma membrane. Okay.
And the net positive charge on the outside will be attracted to that.
So that will be right against the membrane, so this is acting sort of like a capacitor
with charged distributed across a non-conducting interval.
Okay. So, as this charge builds up, what happens?
It gets harder and harder to move a potassium ion out, easier to move one in, so eventually
this random diffusion occurs till the point where you have equal flows of potassium in
and out across the potassium channels, okay. And when that happens you've generated the
membrane potential inside negative and based on the concentration differences, there's
a chemical formula that you can use is called the [Indiscernible] equation that would tell
you that basically you're at aboutハ ハ90ハmillivolts. Okay.
So, atハ ハ90ハmillivolts with a concentration ratios that we see in cells, the flow of potassium
ions in and out of these cells is equal. Now, when you actually measure the resting
potential, of a cell, so this is the way the cell is just sitting there normally. And a
neuron resting potential is actually more likeハ ハ70ハmillivolts.
Okay. Instead ofハ ハ90.
And that's because the potassium channels are not purely selective for potassium, and
in addition there are also a few sodium leakage channels, okay.
And if you think about what sodium is trying to do, trying to do inハ if it is allowed
to diffuse in, it would carry in positive charge and sort of counter act the effects
of the potassium, right? And when you aハ ハ70,ハ ハ90 millivolt potential, sodium
is being driven in both along a concentration gradient and its electrical gradient, right?
So, there's a big driving force for any sodium that can go in.
But theハ it doesn't make much of a contribution because there are very few sodium channels
active in the normal resting neuron. So, the resting potential is predominantly
determined by the effects of these potassium channels, which are making use of a gradient
that is established by the sodium potassium pump, okay.
Another way to think of this is sort of electrically, if you think of the membrane as that capacitor,
and now we haveハ we're measuringハ so this is the membrane, and across that membrane
we also have a battery that's driven by the potassium concentration and a battery in the
opposite direction that's driven by the concentration differences in sodium ions.
Beautiful drawing, David. Man, and the eraser all escaped me.
So, these little squiggles are the channel resistance, how hard is it to pass ions through
the potassium channels or the sodium channels? Right.
And in the first approximation if we don't have any sodium channels at all, the potential
we're going to measure across here is just the potassium battery, right?
That's theハ ハ90ハmillivolts. And what we're doing in affect is turning
on this battery but with a high resistance, so just a little bit of sodium can go through.
So this battery is contributing only a little bit to the net potential across the membrane.
Okay. And you can imagine changing the membrane
transmembrane potential by changing the [Indiscernible] values of these resistances which would be
changing the conductivity or the density of the different kinds of channels, okay.
So that's the resting potentials, are there questions about that?
Okay. The iClicker question.
The resting potential of a neuron arises primarily in the combined affects of a difference in
potassium concentration with the predominance of ion selective channels in the membrane
or it's just driven by the difference in ion concentrations, just the difference in ion
channel density, no, thatハ the resting potential arises from the excess positive charge by
the sodium potassium pumpハ actually I forgot to tell you, there's a electrogenic chloride
pump that I didn't even mention so this is a total trick question.
Okay. Go. 30 seconds.
10 more seconds. Okay.
Right. Oh.
Okay. Come see me if youハ A is the answer.
What have I got? Yep. Review session, we're just waiting to
have the room assigned. So, electrical signalingハ there is a resting
potential, okay. We've stipulated that.
And those channels are all there they're always working it's sort of the study state situation.
The sodium pump generates a sodium potassium pump generates a gradient, and the dominance
of potassium channels means that gets converted then into a inside negative electrical potential
across the membrane. But that doesn't transmit any information,
right? Where does the information come?
Information comes from the action potentials flowing along neurons.
And an action potential is a transient, just usually just a couple of milliseconds in duration,
self propagating, means you can start it in one place and it will move along those long
axons. And it's a reversal of the resting potential.
So, theハ in an action potential, if weハ the here's the resting potential, an action
potential has aハ soハ ハ70 + 30ハmillivolts, so now, very briefly, the inside of the cell
is positive, with respect to the outハside. Then there's usually a recovery phase followed
by an after hyperpolarization. Gee, that's a long word.
And then, return to the normal. Okay. And so these action potentials can be fired
in bursts, singly and these are the basic units of information that gets transmitted
along axons through the system, this is sort of all or none feature. And these action potentials
are brought to you, courtesy of a different set of ion channels in addition to the resting
potential channels, there are channels that are now sensitive to voltage and time. Okay.
Some are selective for sodium others are selective for potassium ions.
So let's see what's going on here. These are all or none so it is sort of digital
and then there's a threshold for firing that determines whether you get one or a burst
of action potentials, so we will see that a small depolarization can trigger an action
potential. And if you have a small depolarization you
might get one F you get a bigger depolarization you can get multiple action potentials.
And we'll also see that there's a refractory period, so that these things cannot be arbitrarily
close, there'sハ during this period here, it's impossible to start another action potential.
So, they can't be any closer than a few milliseconds apart.
Okay. So, let's see if we can explain theseハ and
that alsoハ there's also a one way propagation, we'll talk about later.
I hate this. So, let's just assume for a minute that we're
happily sitting at the resting potential, and something that we'll talk about later,
something gives a slight depolarization of the membrane.
Okay. So, that it moves fromハ ハ70 or so up towardsハ
ハ60,ハ ハ50, something around there. Okay.
Now, what happens is that these sodium channels voltage sensitive sodium channels are activated
they're normally shut off, but when you start to depolarize, these channelsハ because of
their amino acids structure, they have a voltage sensitive property that allows the channel
to open when it depolarizes. And what happens when this sodium conductance
opens? Obviously sodium ions rush in along the concentration gradient and the electrical
gradient so there's a strong driving force for sodium ions.
What happens when selectively you emit sodium ions to the cell?
That will depolarize the cell a little bit. Right.
And what happens when you depolarize the cell? Sodium channels tend to open.
And when they open, more sodium ions rush in and so forth, this is an example of home
stasis? No. This is the example of a feed forward, a positive feed forward loop, okay.
So, it gives you this explosive depolarization, okay, until you reach a point essentially
where all of the sodium channels are open, and even though theハ even though the potassium
channels are still doing the thing they normally do, now we've got this sodiumハ the voltage
sensitive sodium channel, it has essentially minimized its resistance, so now this becomes
the predominating battery, the sodium battery overwhelms the potassium battery in determining
the transmembrane potential. Okay.
And so you've gotten up to here... And then what happens is that this time dependence
kicks in. These sodium channels have the remarkable
property of self inactivation. So, when the sodium channel opens, ions are rushing in,
but there's also a loop, one of these transハ cytoplasmic loops in the peptide, multipass
transmembrane protein has a loop that can then lodge in the pore and shut off the pore
to ion flow and as that happens, more and more of these sodium channels get shut off
two things happen, first our good old potassium channels are chugging away rye trying to repolarize
the membrane, but also there's a voltage sensitive potassium channel that kicks in.
Okay. So, that's shown here...
So this is a different potassium channel it's voltage sensitive but just not as quick off
of the mark as the sodium channels. So the sodium channels activate and self activate
other channels, you know, really quickly. Giving rise to this explosive depolarization.
Butハ and then as this depolarization is sensed by the potassium channel, voltage sensitive
potassium channels, gradually turn on help repolarize the membrane.
Okay. So, in a point right here, now, the sodium
channels are inactivating the potassium channels are activating, and down here at .5, this
after hyperpolarization, what you have is these channels have turned off, high resistance
now, this channel is still on, as usual. But these channels are still on. So you have a
greater contribution from potassium relative to those little sodium leak channels, okay.
So that's why you actually go lower and then gradually these voltage sensitive potassium
channels gradually turn off because now you're at this hyperpolarized situation so they turn
off. And you go back to the resting potential.
Okay. Questions about that?
What's amazing about thisハ one of the most beautiful experiments that indicates the molecular
nature of biological phenomena, you can biophysicists can actually take patches of membrane with
pipettes and measure the current flow across individual channels, okay.
The channels areハ if you look at the surface of the membrane, the channels are not continuously
distributed, there's space in between, so you can get a patch of membrane with a small
number, a finite number of channels in it. Okay.
And you can then say, what's going onハ let's say you're looking, of course it's done [Indiscernible]
you might get potassium channelsハ and you can control the conditions so that you're
only looking at the flow of sodium or potassium by changing what ions are in this experimental
device, right? And you can change the voltage across this
and ask what happens toハthe conductance of these different channels. Okay.
So, if you're just looking at potassiumハ at sodium channels, what you see is little
noise and then a little bloop. Bloop.
So these are unitary conductance with a very fast on and off rate and they're sort of a
random distribution of whether it's active or not, okay, over time.
But when you look at trace after trace
you can look at trace after trace and when you've done this under conditions where you've
got a depolarization here, across this membrane, across these channels, you can add up all
of these individual conductance events over time. And you see that you get something that
reproduces this macroscopic flow of sodium, okay. And you can do the same thing for potassium
ions and you see that you get potassium ions are going to be flowing the other direction
so that goes something like that... Right and you had these together, and you get the
observed effect. So these macroscopic voltage changes, macroscopic current flows across
the membrane, are composed sort of the random decisions, the probabilitistic decisions sodium
and potassium channels to open or close, this is really beautiful Nobel Prize winning biophysical
experiments. So, this is how you can transmit information
from your spinal cord to your leg or something, right?
Self propagating, they don'tハ they're self renewing, so they're all or none.
The height and frequency of the action potentials at the initiation point in your brain or spinal
cord is the same as at the terminals. Okay. But, now we come to a question, how do we
know how much sensory information we've got? What is theハ how do we encode the strength
of a sound? Or the concentration of a chemical in our nose? Or the brightness of light?
Okay. And that we come to this question of sensory
transduction, and here we have yet a different sort of electrical potential with different
sorts of channels. Right?
And these are specialized domains of cells, and specialized cells that are required for
sensory transduction. And they generate graded potentials that are
proportional in amplitude and duration to the whatever stimulus it is.
And the potential could be either depolarize or hyperpolarizing depending on the cells
you're looking at. These are often called generator potentials.
And these generator potentialsハ we're not going to make it.
If you have a stimulus that's onハ okay. These generator potentials are going to be
set up like that... they'll beハ and if you have a smaller, longer stimulus, you'll get
a smaller and longer response, okay. And these are not self propagating.
Okay. So, if you're looking at the generator potential,
if this is the cell, and you can record theハ the activity at the site ofハ let's say it's
a mechanical transduction, okay, you push down and you generate a generator potential
here and now if you're recording out here, that potential is gene sort of as a shadow
of itself, it's delayed in time and degraded in amplitude as well.
So here's the point of initiation... Here are two points of recording...
Okay. Now, you have lots and lots of different kinds
of transducers. Sometimes the transducer is itself a neuron.
Sometimes it's a specialized cell that's associated with a neuron and it talks directly to a neuron.
There are all the different senses we perceive are associated with different mechanisms of
transduction. Phototransduction in the eyes is pretty much
the best understood, most of our chemoreceptors in our nose and tongue, most but not all of
that is mediated by these famous G protein coupled receptors of which there's so many.
Okay. And so, what happens in effect is that these
generator potentials give you different degrees of stimulus, which thenハ when they're transmitted
to aハ to the actively propagating part, the action potential generating part of a
cell, if you get this sort of thing then you'd have a burst of slow action potentials. And
if you have a stronger stimulus, you'd get a burst of more closely spaced, shorter interval
action potentials. So, you can encode the nature of the stimulus,
the duration and intensity of the stimulus, by the timing and spacing of the action potentials
that get propagated, okay. So this is sort of analog device, and here
we've got digital encoding in a manner of speaking.
So, didn't I already say this? Oh, yeah.
So, if it's allハ if everything is just action potentials, how do we know it's light verses
taste verses sound? Okay.
And maybe you've heardハ there are people who actually perceive numbers with particular
colors. Or see sounds in particular colors, they mix
different sensory modalities, okay. But in any case how do we do it? It's question
all of the neural anatomy, where the nerves go, what part of the brain gets activated
by touch, okay. So, it's all a questionハ what this perception
of reality is just different areas of the brain being activated electrically.
And you can do experiments, you shouldn't do this at home, but you can go into the brain
with electrodes, very specifically activate one area verses another, and you can elicit
sounds, you can elicit smells, or lights, stars, right?
I think even different memories, okay. So it's not that oneハ it's not that there's
a special action potential for smell verses sound verses light, it's the conductivity
of the nervous system that does this. And so, all of your reality is really just
the amount of differentハ the distribution of electrical activity in your brain.
It's wonder why we agree on anything at all. So, here's an example: Taste buds in the tongue.
There are different cells with different kinds of receptors, different GPCRs, that connect
to different nerves so here's a cell with receptors for bitter compounds and that connects
to one set of nerves that go into the brain that takes the information say, bitter.
Similarly there would be salty or sweet receptive cells and they transmit that information to
the brain and you say, sweet, salty, etc. And this has been demonstrated by beautiful
experiments done in mouse, there's a chemical that humans can taste, it's called: PBDG synthetic
compound, tastes very bitter to us, but mice have no receptors for this compound at all.
Okay. It's just not there; it doesn't exist for
their taste system. So, you canハ with the miracles of molecular
biology you can engineer a mouse, in which this receptor is put into cells that are normally
tasting sweet or into cells that are normally tasting bitter and then you can have a control
and now put some of this material in the drinking water.
Okay. Not toxic it's okay its sort of a nasty trick,
okay. Here's the normal water consumption, if you
put that bitter receptor gene into a sweet tasting cell in the mouth they start drinking
more water because they think its sweet. If you put it in the bitter receptive cells,
they think it is bitter and they drink less, okay.
Questions about that? You'll wish you had asked.
So, based on these results, if we did the opposite experiment, if we took a sweet receptor
and expressed in cells that are normally expressing theハ encoding bitter taste sensation, do
you expect to the results in reduced consumption in sweets? Increased consumption of bitter
foods? Or no change?
30 seconds. 15 more seconds.
Okay. Expressing a sweet receptor in cells for bitter
taste will cause them to eat less sweets because the sweets are going to taste bitter, right?
And so, these are hard concepts that I'm really rushing through it we shouldn't have spent
so much time on the immune system, but we'll go over itハ ah.
So, now, we want to think of how you communicate from cell to cell within the nervous system.
This is achieved by synaptic transmission. You can have some direct connections if you
have gap junctions linking the cytoplasma of two cells and then ions can flow directly
from one cell to another spreading depolarization through that cytoplasmic continuity that gives
you very fast electrical transmission but not much opportunity to modulate the information.
In contrast, chemical synapsis, juxtapose specialized domains of pre and postsynaptic
neurons or non neural cells. And in essence what's going on is that in the presynaptic
cell at the ending, you have calcium channels that get activated by that depolarization.
And calcium is higher on the outside of the cell than the inside, so it will rush in in
response to channel opening, just like sodium would, through sodium channel. So calcium
we know is a second message, and that canハ in neuron endings it triggers the fusion of
presynaptic vesicles filled with specialized chemical signaling called neurotransmitters,
peptides, usually small molecules, acetylcholine, tryptophan, even glutamate can be used as
neurotransmitters and there's a probabilistic release, and in the postsynaptic cell, you
have ligand gated channels that respond to theseハ to the neurotransmitters, and they
generate local depolarizations or hyperpolarizations or even changes in the metabolism of a cell,
so that there are no action potential channels in that postsynaptic zone. And that means
thatハ you have a separate area of the cell so you might get your synaptic endings out
here, but the ionハ the action potential generating cell channels are only in this
region, so it's the question of how these local synaptic potentials are perceived here
that leads to the firing or non firing decisions. So, here's a diagram, there's the synapse
and at the synapse you have release ofハchemical neural transmitters and whether or not the
cell downstream fires depends on the activity of theハ these local potentials.
So, this means that you can have different neurons impinging on this postsynaptic cell
and it will be looking at what happens presynaptically, so you have summation of two excitatory inputs,
neither of which brings you to threshold, but if you have them very close together,
they will add, summate to drive the action potential initiation event.
Similarly, you can have two different cells firing at the same time, and they're spatially
desperate transmitハ synaptic potentials will generate an action potential. And similar
you can have inhibitory and excitatory combinations as well.
Soハ (making crying sound). All of these lecturesハ in conclusion, everything
we've been talking about are examples of how in the universe biological processes occur,
they're partially deterministic. I think it's time to go.
All life processes are subject to the laws of chemistry and physic, including that probabilistic
nature. Each step, when you're talking about physiology,
development of evolution is constrained by the prior state but it also leads to multiple,
possible next states and at each level of organization, increases in complexity, or
accompanied by the emergence of new properties that were not predicted from the knowledge
of the previous level. You take that basic element of the neuron and you take 10 to the
12th of them and now you've got something that we call: Consciousness, something that
we call free will, something that actually tries to understand how it, itself, functions
and where it came from in the universe. Good bye.