[MUSIC PLAYING]
Stanford University.
Where have we got to now?
You guys have all
the basics in hand
now for our next two buckets--
neurobiology and endocrinology.
What you have now, I hope, is
a sense of especially the neuro
as the final common
funnel out of which
comes all that behavior
stuff we've been thinking
about-- genes-- whether they
are changing in a static
and then punctuated way
or a gradualist way.
What they code for we
now know are proteins.
And in the realm of behavior,
what that's all about,
you now know, are enzymes that
make neurotransmitters, enzymes
that break them apart, receptors
for neurotransmitters, the ion
channels that allow all
the excitability stuff--
all of that should be a
way of conceptualizing
what all that gene stuff that
we've had so far funnels into.
Likewise with the
endocrinology-- all those ways
in which reproductive
status is going
to change how the
brain works, all
of those great evolutionary
models, blah, blah.
That's now endocrinology.
That's now the
ability of hormones
to affect the nervous system.
And what came
through, hopefully,
over and over for all of you in
the lectures over the last week
are two themes-- lots
of different ways
by which the nervous system
and the endocrine system
can change its
function over time.
And number two, lots
of different realms
where there will be
individual differences--
all the ways in
which you will have
a brain and a bunch
of glands that
are different than the
person sitting next to you.
And what you should be able
to piece apart readily by now
is where some of those
individual differences
are coming from in the
form of genetic influences,
where some of them are coming
from environmental ones,
to begin to take some
of those if/then clauses
back in the genetics lectures--
if it smells like a relative,
then cooperate with them--
to begin to imagine now
how the nervous system,
how hormones would actually
translate that stuff
into this next bucket.
So this will be our last bucket.
Today we'll be looking
at all the ways
in which everything you
heard in the last week
is vastly more complicated.
And on Friday what
we will do is focus
in on the part of the
nervous system that
is most pertinent to
rest of the course.
Should you ever
happen by some chance
to stumble into medical school
somewhere down the line, when
they get around to the
nervous system there,
you are going to hear about
the spinal cord endlessly.
You're going to hear
about the cerebellum.
You're going to hear
about parts of the cortex.
You are going to
hear next to nothing
about the part we'll be
talking to on Friday.
And what it's about is
emotion, and behavior,
and affect-- a part of the
brain called the limbic system.
In medical school, they
will pound into your head
over and over and over
how the spinal cord moves
different motor systems.
Because that's 99%
of what neurology
can concern itself with.
Because it at least has a
fighting chance of doing
something therapeutic there.
This is the part
of the brain that
is most defining to who we
are-- personality, temperament,
all of that.
And it will be central
to making sense
of all of this stuff coming in
the second half of the course.
So it's going to be a
very different domain
of the nervous system.
So what today is about
is taking everything
you've learned
over the last week,
and discovering that the ways
in which it is tragically
distortive and not quite right,
and comes with all of these
but wait-a-seconds and
qualifiers, and all
the ways in which this first
pass you had in the last week
sets you up now for
appreciating an enormously more
complicated system than
you've already seen,
one which generates, thus,
vastly more possibilities
of communication, of
information contained
within these neural
pathways, one which generates
vastly more possibilities
of individual differences
and of experience
leaving its imprint,
one that generates vastly
more possibilities for things
to go really wrong in the
realms of abnormal behavior.
OK so a lot of
what we'll be doing
is taking what you
got in the last week
and seeing where, in fact,
current research shows that it
is much, much more complicated.
OK, first version--
one of the rules that
runs through all
of neurobiology--
you start learning the
field and at some point,
they pull out the
name of this guy Dale.
Dale who was the law giver.
Dale was some
neurobiologist early
in the 20th century
who generated two laws
that every single
child was forced
to learn throughout
the 1920s and 1930s
about how the nervous
system worked.
Some time later than
that, Dale's two laws--
and we will start
off with one of them.
And it makes perfect sense
until you see that, in fact, it
has no basis in reality.
Here is Dale's first law,
which was you got your neuron--
and you should know
by now we are dealing
with our schematic neuron.
And once we get into
circuits in more detail,
we will give up the diamond
shape on the neuron cell bodies
and switch over to
circles, showing
just how fast evolution can be.
But we've got the neuron here.
And what we've got are the
axon and the axon terminals.
And what Dale's law number
two-- and of course, it's
irritating that we're doing
number two before number one,
but tough-- what you've got
here with Dale's law number
two is, each neuron has
one characteristic type
of neurotransmitter--
one and only one.
And that's what it's releasing
from all of its axon terminals.
And thus, you could
categorize any given neuron
as this is one that
releases serotonin.
This one is one that releases
dopamine, et cetera, et cetera.
Notice that's a
world of difference
as to what types of
neurotransmitters
it has receptors for.
That's something else entirely.
That's what neurons over
there it's listening to.
But any given neuron is
releasing only one kind
of neurotransmitter.
So that one went down
the tube during the '80s
with the discovery,
in fact, that there
are multiple neurotransmitters
released by neurons.
And this was boggling to
people, and forced people
to give up on Dale number two.
And initially, this just seems
like pointless complication.
What you wind up
seeing is it puts
a lot more potential
for information
into the whole business here.
OK, so here we have our
archetypal synapse here,
going from left to
right as always.
And we've got the one on the
left here with its vesicles--
those little water balloons
filled with neurotransmitter.
Along comes the
action potential.
As a result, the vesicle
moves to the cell membrane,
merges with it, dumps the
neurotransmitter into there.
As you might guess, that
actual process of exocytosis,
dumping the neurotransmitter,
is vastly more complicated.
But this is our general model.
And what people began to realize
was that all sorts of neurons,
all sorts of neurotransmitter
types, in fact,
came with two different
colors of neurotransmitters
in the vesicles-- came
with two different kinds.
Notice this is different
from in this axon terminal
you release this type
of neurotransmitter.
And in this one, you
release that type.
No, every single
axon terminal would
contain both of these
types of neurotransmitters.
And notice also, it
would not be one vesicle
was a blue neurotransmitter
vesicle and one was a red.
Each one of them had a
mixture of the two types.
What has been found
is that occurs in lots
of different types of neurons.
I believe the record
is that there are now
some vesicles that contain
three different types
of neurotransmitters.
So what we've got here
are two different classes
of messengers coming out.
And what you should be
able to immediately imagine
is, that's going to
produce a lot more
potential for information.
Two different types
of messengers-- one
of the characteristics that
tends to be the pattern
is that when you get
two neurotransmitters
in the same neuron,
the same axon
terminal and the
same vesicle, they
tend to be structurally very
different sorts of classes
of neurotransmitters.
One might be a type made from
a simple single amino acid.
Another one is somewhat
of a complicated protein.
They tend to have fairly
different structures.
And what that
often tells you is,
they're going to have
different mechanisms of action.
They're going to have
different speeds of action.
What you wind up seeing
is very often, when
two different types
of neurotransmitters
are contained in the
neuron, one of them
works much more
rapidly than the other.
One has a rapid, short-term
effect-- quickly decrementing.
The other will have
a longer effect.
And by now, you can
begin to imagine
what counts as a longer effect.
You change gene
transcription in that neuron.
You change structural
stuff happening,
as opposed to the short
one, where just suddenly
some little ionic
excitability change occurs
in a couple of milliseconds.
You begin to see this pattern of
two different ways of coding--
coding for different
types of information.
What we'll see shortly is one
of the truly bizarre things that
pops up a lot with these cases
of multiple neurotransmitters.
One of them will have receptors
for it on the neuron itself.
And we will focus
on that shortly.
That actually winds up making
a fair amount of sense.
OK, so Dale trashed
in terms of the notion
of any given neuron having
only one neurotransmitter.
In some types of neurons
you have, instead, pairs,
but following the
same sort of rules.
And thanks to the typical
structural difference
between the pairs of
neurotransmitters,
you tend to get different
sorts of functions.
You see a similar principle
over at the endocrine end
of things-- a world of more than
one single messenger carrying
the same message, or the
same source of information
carrying multiple messengers.
Where we see here is what by
now should be familiar as well,
here where you got
your pituitary,
and you got your
anterior pituitary,
which is always facing left.
And the anterior here, we have
the glandular cells releasing,
as you saw the other day, ACTH.
Lots of this lecture
is going to be
about the regulation of the
adrenal cortical system--
the glucocorticoid
system-- because it's
the best hormone on Earth.
And I'm willing to prove it.
But what we have here
is ACTH coming out.
And you remember what you
had the other day, which
is incorrectly named.
You've got CRH.
That's that business about the
brain as an endocrine gland,
the brain releasing hormones
into this little portal
circulatory system.
And out comes its characteristic
pituitary hormone.
So what you saw the
other day is CRH
is the hormone, the
hypothalamic hormone
at the base of the
brain here that's
released into this local
circulatory system, which
stimulates these
cells to dump ACTH
into the general circulation.
And that's the pattern
you've gotten already
of neuroendocrine axis.
The brain releases a hormone
into the local circulation,
which stimulates the
pituitary to release
a typical hormone in response
to it, which then goes and does
something rather
to a distant gland.
You've got that one already.
You have Follicle Stimulating
Hormone, releasing hormone
up here, which triggers Follicle
Stimulating Hormone, which then
goes does something or other to
your follicles or to your sperm
if you don't have
follicles, and these sort
of three-step cascades.
What we see with
the CRH system here
is one example of
how you can also
have a version of
multiple messengers.
Turns out CRH is not the
only hormone coming out
of the base of the hypothalamus
that could release ACTH
during stress.
And instead, you've got
a whole array of these.
There are neurons in the
hypothalamus that instead
release vasopressin into
the circulation here,
others that release
oxytocin, others that release
norepinephrine, others
that release epinephrine.
And collectively,
what they're doing
is stimulating the
release of ACTH.
You have an entire
array of these.
And a huge amount
of work in the '80s
went into sorting this out.
And what's going on here-- what
you have are stress signatures.
Different types
of stressors will
trigger different orchestrations
of these ACTH-releasing neurons
up there-- different
orchestrations as to which
hormones bring it about.
And it will be things like low
blood pressure or hypotension
will tend to trigger
CRH and vasopressin.
Low blood sugar,
I think, was CRH
and epinephrine
and norepinephrine.
The whole point is that
you get a signature up
at the hypothalamic
level regulating
this release of ACTH.
Why have all these
different ways of doing it?
Two advantages--
one is depending
on which orchestration of these
you use, the shape of the ACTH
secretory curve
will be different.
It's the same deal here.
You use two of these to
get a short, rapid effect,
a more prolonged one.
Here, depending on
which mixture you have,
you will have a different
profile of ACTH secretion.
That's so you get
control on that level.
The other thing is that
each one of these not only
helps to release ACTH
from the pituitary.
It does other stuff
down here as well,
so that you get a way of coding
under this sort of stressor
you want to release ACTH and do
something or other in addition.
The way you bring it about
is getting these two.
With some other
stressor, you want
to secrete ACTH, and bring about
some additional step there.
And you do it with these
three-- that sort of thing.
So you get control over the
shape of the stress response,
and to fine tune it there.
So here we've got this
completely more complicated
picture of all these
different releasers of ACTH.
In addition, just to make
things even more complicated,
there are clearly
hormones coming in there
which, instead of releasing
ACTH from the pituitary,
they inhibit its release.
And they release their hormone
into the circulation also.
And people have had evidence for
these corticotropin-inhibiting
factors for decades and
decades and decades.
And people have had an amazingly
tough time trying to figure out
what these things actually are.
The best implicated
molecule so far
is a peptide called Delta
Sleep Inducing Factor.
Think about that--
you go to sleep.
And that's a very good
time for turning off
your stress response.
So that making
wonderful sense there.
The main point for
our purposes is
you've got
bi-directional control.
You've got a bunch
of hormones that
stimulate the release of ACTH.
You've got at least one
fairly well-implicated
that inhibits the release.
There is no way that
there's not a whole bunch
of other ones doing the
same sort of signature
coding at the inhibitory end.
And you've got different ways of
translating different stressors
into different
endocrine profiles.
And of course, what
that winds up meaning
is you get stressed-- like
your big toe is telling you
you just burned it-- and you
are going to have projections
to a different array
of these than if you
were getting stressed, you
were thinking about mortality.
That's going to be having
a different projection
profile onto these neurons.
What that suggests
is a huge amount
of coding information
going on in the brain
and the spinal cord producing
these different arrangements
of how you dump out ACTH
and the other hormones.
OK, so that as a
first complication
in these various neural
and endocrine systems.
You can actually have multiple
neurotransmitters coming out
of the same neuron.
You can have an array
of different hormones
that bring about the
same general response,
but they differ in terms
of fine-tuning the system.
Next elaboration--
one now having
to do with some spatial
characteristics of how
these systems work.
And here we have the
same exact neuron again.
And now we deal with
Dale's law number one,
which is you know by now you
get the depolarization here,
sufficient to get
to the axon hillock.
You get your action potential.
All hell breaks loose-- very
exciting ionic of events
of excitation-- all
or none regenerating
go shooting down the axon
to the axon terminals.
Dale's lawyer number one was you
get an action potential started
here, and it is going
to result in the release
of neurotransmitter from
every single axon terminal.
So Dale's two laws-- an
action potential causes
neurotransmitter to be
released from every single axon
terminal of a neuron.
Dale's law number
two just trashed.
And it's going to be the same
neurotransmitter released
from every single axon terminal.
And Dale's law number one
has held reasonably well,
except for some work by a guy.
And this is one of these sort
of mad geniuses of neuroscience,
a guy at MIT named
Jerry Lettvin.
What he did was, as
far as I can tell,
he just sat around in a dark,
sort of abandoned warehouse
for decades on end.
And about once every
decade, he would
write a paper that would
transform neuroscience.
And he actually was like this.
I met the guy once.
And it was one of the more
terrifying experiences I had.
I was working in
a lab where I had
to go get an oscilloscope from
someplace, and pick up one
because ours was broken.
And everybody agreed
the place to find
it was in Jerry
Lettvin's warehouse
that he lived in, because
he lived with oscilloscopes.
And going in there, and it
was basically pitch dark.
And there was this
sweaty, Sydney Greenstreet
kind of guy sitting there.
And he was in a ripped t-shirt.
And he had been in
there for decades.
And he was chain smoking
and sweating in there,
because it was 150 degrees.
So he spent a large part of the
last part of the 20th century
inside that warehouse
writing one paper per decade
that was transforming.
So this was his
particular paper.
And I think this one
was from the '70s.
And what he showed was that
under some circumstances,
with him lined up with his
hundreds of oscilloscopes
proving this, you in fact had a
violation of Dale's law number
one, which was you
can get blockades here
or there that would
stop the action
potential from
propagating down some
of the branches of this
whole axonal treee--
in other words, a whole
different domain of controlling
the flow of information.
More subtlety
there-- neurons could
regulate which of
their branches actually
were sending on the message.
And remarkably little has been
learned in the years since then
as to how this works, let alone
how common a phenomenon it is.
Most people wound
up ignoring it.
What has since been shown
also is the wave of excitation
that could come in through
different dendritic spines
back at the end-- that there are
ways in which branch points can
be sort of blocked on one side
so that the flow is shunted
in one direction on the
branches and not the other.
This is this whole
unexplored world
suggesting there's all
sorts of regulation going on
at these branch points.
It's not simply the
case, action potential
and you are going to
dump neurotransmitter
from every single axon terminal.
So down goes Dale
on that one as well.
Equivalent over at
the endocrine end--
and here we have our
pituitary, which now no longer
has a brain connected to it.
But you've got the
theme by now, which
is you've got the
hypothalamic hormone
and out comes the
pituitary hormone.
And there's a whole bunch of
different pituitary hormones
producing the acronym flat
bread, peg leg, flat, flat peg.
FLAT PEG-- go to your death
bed remembering that acronym,
because it will make
you happy and fulfilled.
OK, so here's a bunch
of pituitary hormones,
and whatever verkakte acronym
these guys came up with.
But what we have here,
just to make life simpler,
is we'll focus in
on four of them.
FLAT PEG-- so we're
missing some of them there.
But we've got growth
hormone that comes out,
prolactin ACTH, Follicle
Stimulating Hormone.
I'm picking these
completely randomly.
OK, in the simplest
possible of worlds,
you would have all sorts of
secretory cells, glandular
cells, sitting in here.
And each one of them
is capable of secreting
all of those flat bread
hormones coming out of there.
It could be doing that.
And it would simply be choosing
which as a result of which
hypothalamic hormone is
coming down the pike there.
That's not what you see.
Instead, you have specialized
cells within the pituitary.
There's one type that only
secretes growth hormone, which
causes somatic growth, somatic
body, somatic something
or other.
And those are
called somatotrophs,
and don't memorize that.
Ones that only
secrete prolactin,
which cause lactation-- these
are lactotrophs, corticotrophs,
gonadotrophs,
something or other.
So all of these, in fact,
have specialized cells.
Within the pituitary,
there are cells
that specialize in
releasing only one
of these types of hormones.
So you got into that.
So what would be the next
simplest thing going on?
So here's the growth hormone
releasing into the pituitary,
and there is going to be
the ACTH releasing end.
No, that's not what you see.
Instead, there is a mosaic all
across the pituitary of all
the different flat bread
cell-secreting types there,
all throughout it.
OK, so that's just this mosaic.
Good, somebody was sloppy at
the sort of fetal end gluing it
all together, and just
scattered them all over.
And what winds up
happening is you
get local, little
neighborhood effects.
For example, here
we have somatotrophs
that secrete growth hormone.
And one is in a FSH
neighborhood and the other
is in a prolactin neighborhood.
And what you see is you throw in
the hypothalamic hormone, which
causes growth hormone
to get secreted.
And this particular
cell is going
to be secreting totally
different amounts of growth
hormone than this one will.
Because it's in a different
sort of neighborhood.
And what's the
implication of that?
There's all sorts
of communication
going on between the individual
cells in the pituitary.
And it depends on what
sort of neighborhood
each particular
cell is living in,
how it is responding to the
hypothalamic signal coming
down, wildly complicating.
What that lets you do
instead is different areas
of the hypothalamus will turf
its hormones to different parts
of the pituitary where
its particular cell
targets will be living
in different sorts
of neighborhoods.
Simply more regulation, more
complexity going on there.
Next theme that comes through
in terms of elaboration--
we all have the negative
feedback concept by now
that came through throughout
the lectures last week.
The whole notion
you get excited.
You release a neurotransmitter
into your synapse
if you're a neuron.
You've got to do some
regulation there.
You have to clean
up after yourself.
You remove the neurotransmitter
from the synapse.
You break down the
neurotransmitter.
You have to finish
the whole thing.
You are the endocrine system.
You are the brain.
And you have gotten
it into your head
that you want your adrenals
to secrete glucocorticoids.
And you start that whole
cascade in which everywhere--
and you need to know
when to stop secreting
those hormones up on top.
You need negative
feedback information.
All of these biological
systems are characterized
by that-- you have enzymes
where this enzyme turns this
into this.
And how does it know when
they should stop doing it?
When there is so
much of this stuff
building up that this
inhibits its activity.
You get negative feedback,
feedback regulation.
You're making a lot of x.
And whatever is making it
has to be able to measure
the levels of x.
That is the simple rule of all
this negative feedback stuff.
So a first example on the
neurobiological level-- so
what we have are what are
called auto receptors.
What I inferred before,
which is this weirdo world
in which you not only
will have receptors
for a neurotransmitter
exactly where they should
be on the post-synaptic
neuron on the other side
of the synapse, but you will
have them on the neuron that's
releasing the neurotransmitter.
It is an auto receptor.
It is a receptor
right there on it.
What's it doing?
It's for bookkeeping.
What you have is
some sort of rule.
If the neurotransmitters
come pouring out of there,
and most of them go floating
across-- let's assume
these are only red
neurotransmitters here,
and bind to their
red receptors there,
and do their thing
to the next neuron.
And just thanks to
the floating around,
random life in the Brownian
synaptic sludge there,
a certain number of them
are going to, instead, bind
to this one.
And all there has
to be is some sort
of rule in this
pre-synaptic neuron
that for every time
one of these hits here,
it means I've
released 1,000 copies
of this neurotransmitter,
or 1,000 molecules of that.
And that's how I keep
track of the numbers.
And I will have
a rule that if it
gets below a certain
level of my picking
up this bookkeeping
signal, that will
be a signal to start
making more of the stuff.
If I'm getting too
much of a signal,
decrease the release-- feedback
regulation along those realms.
This is where you see
one of the elaborations
on this two-neurotransmitter
business.
What you very often see is
one of the neurotransmitters
will exclusively work on a
pre-synaptic auto-receptor.
That one is stuck
in there merely
in order to do the bookkeeping.
You would think neurons
might have figured out
a more direct way
of keeping track,
like how many
vesicles they dump.
But instead, this
theme is there is
some pre-synaptic
auto-receptor, which tells you
on some statistical basis, every
time we get buzzed at this end,
it means we buzz these
guys 100 zillion times.
And that's how we keep track
of how much we want to make--
negative feedback loops there.
You then see the
exact same equivalent
in endocrine systems, which
is all this negative feedback
stuff.
Something that was
under-emphasized
in the endocrine
lectures last week
has been this element
of neuroendocrinology.
What you mostly
heard about is what's
going to be most
dominating in the classes
to come, which is hormones
get into the brain
and change how you think,
and feel, and behave,
and all of that stuff.
But also, some of the time what
hormones are doing in the brain
is letting the brain know
how much hormones there
were in the
circulation, in order
to do the bookkeeping, the
negative feedback regulation.
Your brain decides it wants
to have this much growth
hormone in the bloodstream.
And thus, it releases
its hypothalamic hormone,
which goes.
And all over, the pituitary
gets those somatotrophs
to release growth hormone
and does its thing elsewhere
in the body.
And the brain has
to be measuring
some consequence of that
growth hormone doing its thing,
measuring up there, in
order to figure out,
have we gotten where
we want to yet?
Same thing with prolactin.
Same thing with
every one of those.
You have to have negative
feedback regulation.
So what do you need to
do to pull that off?
You need to have a
part of the brain that
is sensitive to that hormone
signal-- sensitive in some sort
of quantitative way, where
it can, in effect, count
how much of the stuff there
is in the bloodstream using
the exact same sort of rule.
If I've had one of those
hormones in the circulation
come and bind to
one of my receptors,
it means I have released
100 billion copies of it,
thanks to my starting
this whole cascade.
Did we want 100 billion?
Did we want 107 billion?
Do we want 93 billion?
What do we do now?
Does that tell us we've
completed what we want?
You get this negative
feedback signal there.
So the first thing
you have to have
is cells-- parts of the
brain-- that will measure,
that will be responsive
to a hormone signal.
Those cells have to be able
to have some kind of set point
rule in there.
This is the point of
life that I am at,
the point of my menstrual cycle.
This is the point of
reaching adolescence.
This is the point of
am I stressed or not?
This is the set point.
This is the amount
of hormone I would
like to have in
the bloodstream--
this particular type of hormone.
And what you need to
then be able to do
is, if levels have not
reached that set point yet,
you send a stimulatory
signal to the hypothalamus.
Keep doing what you were doing.
We need to push the
levels up higher.
And if the levels reach
here or get even higher,
you need to be able to turn this
into an inhibitory signal going
to the hypothalamus.
So what you see are
all sorts of regions
of the brain that are sensitive
to these various hormones, not
just in terms of
hormones affecting
all the behaviors we're
going to hear about,
but also negative feedback
regulation-- so a way now
of showing just how much
more complicated it can be.
So what would you assume
is the general rule?
Here's an example of--
OK, let's make it simpler.
OK, so what would
you expect to see?
You're able to
measure CRH coming out
of the base of the hypothalamus.
And the deal is something
stressful occurs,
and so it's pumping out CRH.
And at some point, you've
got as much glucocorticoids
in the blood stream
as the brain would
like for that sort of stressor.
And that leads to
the negative feedback
signal, which stops
the hypothalamus
from releasing CRH.
What measuring is
the brain doing?
Most obvious version
would be what
the brain does is measure
how much glucocorticoids
are in the bloodstream.
And a simple rule, the
more glucocorticoids
there are in the bloodstream,
the more likely levels
are to have reached
the threshold, the set
point, that you want.
So the higher the levels, the
more of a negative feedback
signal.
And thus, the less
CRH being secreted.
Totally straightforward,
logical,
measuring the level of
hormone in the bloodstream.
And this is how most endocrine
negative feedback works.
Measuring how much
of the stuff--
the more stuff there is,
the greater the likelihood
that you shut down the system.
You put in the negative
feedback signal.
But in addition, there's
a whole other domain
of glucocorticoid negative
feedback regulation,
where in this domain,
what the brain
is doing is not measuring
how much glucocorticoids
there are in the
bloodstream, but measuring
the rate of change-- the rate
at which levels are increasing.
And that's a totally different
domain of information there.
Now what you're
doing is measuring
how many units of increase
per second are you getting.
And what you've got is
this bizarre world there,
where you go from 10
units of glucocorticoids
in the bloodstream to
12 units in one minute.
And that means the
same exact thing
as going from a million
and 10 units to a million
and 12 units in the
same length of time.
It's not measuring
absolute levels.
It's measuring rate of change.
And the faster the rate of
change, the less likely CRH
is to get secreted.
And it turns out there are some
domains of stress responses
where what the brain
is paying attention to
is rate of change of
hormone in the bloodstream.
There are other circumstances
where it's paying attention
to absolute level.
This tends to be what
the brain listens
to very early on in
a stress response.
This tends to be the
more delayed response.
But totally different dynamics
there-- cells that measure
the amount of
hormone-- that's not
that hard to imagine-- number
of receptors, stuff like that.
Cells that measure
the rate of change,
where going from 10 to 12
is the exact same thing
as going from a million
10 to a million 12.
What is that wiring
going to be like?
To this day, nobody has a clue.
This was first sort of
figured out in the 1960s.
An amazing scientist
up in UCSF named
Mary Dallman who just sat and
out of sheer just modeling
work in terms of
endocrine systems
predicted with
glucocorticoids, there
are going to be two different
domains of feedback.
There is going to be a rapid
rate-of-change sensitive
system.
There is going to be a
delayed level of hormone
in the bloodstream system.
And here's exactly why
I'm predicting this.
And she turned out to
be absolutely right.
And decades later,
people still don't fully
understand how a cell
measures the rate of change
of something independent
of the absolute levels.
One thing that makes
life a little bit easier
is it's different parts
of the nervous system
that do each type here.
The very rapid rate-of-change
stuff, in fact,
is not even occurring
at the brain.
It's occurring at the
level of the pituitary.
And thus, it's not so much
regulating CRH release,
but ACTH release.
OK, complicated-- the
main point of that
is, even something
as logical as how
do you keep your toilet
bowl sort of thing
from overflowing the
tank in the back there?
You need a negative
feedback signal.
You need a way for
the toilet bowl tank
to measure how much water there
is there, and the flotation
device, and for that to have
a set point and a way of then
transducing, reaching that
point into putting the lid
on the top of the pipe
that's generating the water.
Totally all these logical
negative feedback loop stuff,
and then suddenly, in these
neuroendocrine systems,
you get much, much more subtle,
complicated things going on.
In some cases, you
have positive feedback.
The more of a hormone
in the bloodstream,
the more you stimulate
the system to do more.
You get that at certain
points in reproduction--
reproductive life
histories where
you have massive changes
of estrogen, progesterone.
And what you have will be
transient periods where
you have positive feedback.
All of these somehow have to
get translated into how cells
are working-- very unclear.
OK, so negative feedback-- the
next elaboration-- something
going on at the receptor level.
It's something known
as auto-regulation.
And you could probably
begin to figure out what
that one's about.
And it will make perfect
sense as follows--
if somebody screams
at you all the time,
you stop listening to them.
And what you have done is just
down-regulated your sensitivity
to this pain-in-the-neck person.
If they give a
very large signal,
you down-regulate your
sensitivity to the signal.
If a signal, instead,
becomes very weak,
very often you will increase
the attention you pay to it.
You are showing auto-regulation.
Within the realm of
neuroendocrine stuff,
you will be changing
the amount of receptor
for a neurotransmitter
or hormone
as a function of the
levels in the bloodstream.
And thus, you have
this logic-- if you
get a huge increase in
the levels of some hormone
in the blood stream,
there will be a likelihood
that various target
tissues will begin
to down-regulate the number
of receptors for that hormone
or neurotransmitter.
Conversely, levels go way
down, they go right up.
And this is a
general feature all
these neural and
endocrine systems.
Why is that interesting?
When this regulatory,
auto-regulatory stuff
screws up.
In principle, it
should work perfectly.
OK, for some reason,
there's a doubling
of the hormone
message coming through
in the bloodstream
under some circumstance
where it's going
on for a long time.
And that's not right.
And somebody down at
some gland down there
is messing up and drooling
out way too much hormone.
So what are we going to do?
We have no idea
what's up with them.
But you've doubled
the level of hormone.
Most folks down
there, OK, let's have
an auto-regulatory response.
Let's cut the number
of our receptors
in half to compensate.
You can see in a rough way
that's going to compensate.
So massively increase the
signal thanks to some disease
state, something weird going on,
and do a compensatory decrease.
Have some disease
or abnormal state
where levels of some
hormone or neurotransmitter
go way down-- what do you do?
Let's up the amount of receptor
enough to compensate for it.
That's great.
Where problems occur is if you
don't compensate quite enough,
or if you overshoot, if you
begin to get a mismatch.
And that's where
you've got problems.
We will see, as you read
in the [INAUDIBLE] book--
with hopefully great detail--
the chapter on depression,
that's probably a critical
thing that's happening.
Because we'll see with
depression what's probably
wrong are levels of a few
different neurotransmitters--
serotonin, dopamine,
norepinephrine.
All of this is
going to come soon.
And all of the standard
anti-depressant drugs
change the levels of
these neurotransmitters
in the bloodstream.
And that's great.
And we know just how it
works, except there's always
a problem making sense of that.
Which is you throw in some of
these standard drugs-- SSRIs,
things of that sort-- don't
worry about the details.
All of this will come later.
The main point being that
these anti-depressant drugs,
when you throw them
in, they're changing
levels of neurotransmitters
within minutes to hours.
You get somebody who
is deeply depressed.
And you start them off
on an SSRI like Prozac.
And they don't start feeling
better for days to weeks.
There is some sort of
lag time going on there.
And as people have
sorted it out,
what the common sort
of conclusion is,
these drugs are
not working so much
by changing the levels of
these neurotransmitters.
What they're really doing
is by changing the levels,
they are eventually going to
cause an auto-regulatory change
in the number of receptors.
And these change within
minutes to hours.
These change within
days to weeks.
And that's what these
drugs are probably doing.
We will go through that.
Just to give you a sense of
how awful it is going to get,
there are some reasons
to think that some
of these anti-depressant
drugs work
not by changing the level so
much of this neurotransmitter,
or not so much
secondarily causing
an auto-regulatory
change here, but instead,
causing an auto-regulatory
change in these auto-receptors.
Unbelievably complicated.
We will come to that.
For our purposes
right now, what that
begins to tell you
is that certainly,
the amount of hormone and the
amount of neurotransmitter
makes a difference.
The amount of receptor, as well.
And have big
pathological changes
in the levels of the messengers.
The body attempts to regulate
with auto-regulatory changes.
And a lot of what
disease is about
is overshooting
or undershooting.
So that's one realm within
the nervous system--
neurotransmitters--
pertinent to depression.
OK within endocrine
systems, an equivalent one
is as follows--
something that you
see that goes wrong in
diabetes-- adult-onset
diabetes.
One of the things you have
is a number of ways things
can go wrong.
But what your body
does is, when there's
glucose in the bloodstream,
when you've just
had a meal, when you
have all these nutrients
in the bloodstream,
your pancreas
can detect the levels of
glucose in your bloodstream
and secretes insulin.
Sugar shows up in the
bloodstream-- glucose.
You secrete insulin.
And what insulin does
is tell your fat cells
to absorb the sugar
and store it away.
Great, but you've
got a problem, which
is that your fat cells
are already full.
Because you are a typical
Westernized human,
and you've been
eating to excess.
And what you have is fat
cells that are full up.
And they stop listening
to insulin, because they
can't take it anymore.
Because they can't take up any
more stuff and store it away.
The cells begin to
be insulin resistant.
And we'll see in a
minute how that works.
So suddenly, you
have fat cells that
aren't responding to insulin.
And what happens is your
pancreas says, this is crazy.
We're trying to get rid of the
sugar from the bloodstream.
And it's not disappearing.
The person just ate
eight Hershey bars,
and their fat cells
are already full.
But we're not clearing the
sugar out of the bloodstream.
So let's secrete
even more insulin.
And let's secrete
even more insulin.
And what happens at the
fat cells, they say,
this is ridiculous.
We're full up.
Forget it.
We're not taking up any more
of these nutrient things.
And in fact, what
we're going to do is,
we're going to decrease
the number of our insulin
receptors.
We're going to down-regulate
our number of insulin receptors.
And the pancreas freaks out,
and secretes even more insulin
as a result.
And you down-regulate even more.
And what you have is
this downward spiral.
Because at some
point, your pancreas
is working so hard to dump
these boatloads of insulin
into the bloodstream that your
body's paying no attention to,
that you burn out the
cells in your pancreas that
make insulin.
And now you've got yourself
a real serious problem.
What's the key of
what's gone wrong here?
Too much nutrients, and
thus too much insulin.
And the fat cells
begin to say, we're
not going to listen to it.
And they down-regulate
receptors.
More insulin, down-regulate,
down-regulate-- and this
is at the core of what
goes wrong in diabetes.
So we see these
auto-regulatory changes.
And they can emerge slowly.
They can help explain why
some of these drugs work.
Almost certainly,
they help explain
what's wrong in some of
these psychiatric diseases,
metabolic diseases.
What's the punchline there?
Number one, the amount of
a messenger is important,
but the sensitivity
to the messenger
is at least as important.
You have as much
capacity to regulate this
as this in these
biological systems,
and thus you have
as much potential
for screwing up at
this end as screwing up
with the amount of messenger.
Yeah, did I see a
hand up someplace?
Yes.
[INAUDIBLE] but wouldn't
the SSRI example, then,
be the opposite of what
you're saying [INAUDIBLE]?
Because you'd expect
increasing neurotransmitters
to eventually cause a
decrease in receptors.
So you should see
that [INAUDIBLE].
Great, OK.
Don't listen to
anything she just said,
because she's just gotten to an
incredibly subtle, complicated
point about how
this stuff works.
Go and read, and memorize,
and recite to your roommates
the section on the zebra
chapter about-- the section
in zebras-- on
depression, looking
at the paradoxical things
where, at the end of the day,
people are not sure say, an
SSRI, a selective serotonin
re-uptake inhibitor.
What it does is it blocks
the re-uptake of serotonin.
And thus, you wind up with more
serotonin in the bloodstream.
Somebody feels less depressed.
I bet their problem was they
didn't have enough serotonin.
Work through the logic of all
this auto-regulatory stuff
going on.
And people still
are not positive
if the problem with depression
is too little serotonin or too
much.
Because depending on whether
the auto-regulation partially
compensates, completely,
whether it overshoots,
and whether it's these
receptors or these,
will completely determine
whether the problem
is too much or too little of a
neurotransmitter-- incredibly
complicated, exactly some
of the complexities there.
And that is so
complicated, in fact,
that it is essential
that everybody
stand up now and go to the
bathroom for five minutes.
OK, again, back from the
other [INAUDIBLE] day.
Your pituitary is
releasing all sorts
of different types of
hormones under the control
of all sorts of different
types of hormones
signaling from the brain.
What you get is, the
pituitary is not just
made up of one type of
cell that can secrete
every single type of
hormone and response
to each type there of
messenger from the brain.
Instead, you've got
specialized cells.
You've got types
of pituitary cells
that only secrete
prolactin in response
to what's happening there,
types that only secrete ACTH,
or secrete luteinizing hormone,
follicle stimulating hormone,
so on.
OK, so they're
specialized cells.
Rather than having one part
of the pituitary, which
is the we're in charge of
secreting growth hormone
neighborhood, and one part
that's the we do prolactin,
and rather than it being
broken up like that,
instead, it's just a mosaic of
all the different types that
are scattered throughout there.
So that would initially just
seem like sheer sloppiness.
Embryology-- they didn't
quite get it together
to have discrete neighborhoods,
that sort of thing.
But it's just scattered there.
What's interesting
about that is,
you will see any given
cell in the pituitary
will go about its
business, which
is responding to its
specific hypothalamic signal
by secreting whichever
hormone it specializes in.
Every single cell in
the pituitary going
about its business will be
a little bit more or less
sensitive to its
hypothalamic signal,
depending on what sort of
neighborhood it's living in,
depending on which other
types of these cells
it's surrounded by.
So that you will
get, for example,
FSH secreting cells,
when they tend
to be in a GH
neighborhood, are far more
responsive to their
signal than when
they're in an ACTH
neighborhood or one that's
a hodgepodge of any of these.
I don't know what the rules are.
But what you've got
there are increased
ways for regulation of
the amount of secretion
by determining which way
you, the hypothalamus,
turf the signals.
Are you aiming for these types?
Or are you aiming
for these types?
More regulation that
way-- how does that work?
What it has to be is all sorts
of communication going on
amongst the various
pituitary cells.
So the pituitary is not
just sitting there passively
responding to whatever the
hypothalamus is saying.
Instead, there's all this local
regulatory stuff happening.
One additional thing
that was asked-- so
in this case, what
we go back to is
that business of the
more glucocorticoids
in the bloodstream in this
boring, level-sensitive domain
of you're just measuring
how much of the stuff
there is in the
bloodstream, you're
measuring there--
some part of the brain
is measuring the levels
of glucocorticoids.
And the part is actually known.
It's measuring there,
and it has its rule.
Once glucocorticoid
levels get this high,
I will send an an inhibitory
signal to those CRH neurons.
And as a result, they'll
secrete less CRH.
And that turns off
the stress response.
The more glucocorticoids
in the bloodstream,
the more of a negative
feedback signal.
What the person brought up was
the very astute observation
that wait, what about
all those other types
up there-- oxytocin,
vasopressin, epinephrine?
What that means is
there are sensors
that are talking to each
one of those types there.
And the brain at
any given point,
depending on the
stressor, is saying,
well, we want this
much CRH, and we
want this much of vasopressin
and this much oxytocin.
And we're going to
determine it all
by measuring the level and the
shape of glucocorticoid levels
in the bloodstream, so that
there's feedback going on--
not just onto the CRH neurons,
but to all those other types
of neurons as well-- incredibly
messy and complicated,
nonetheless very elegant.
Pushing on-- next
version of complications.
Now what we've got
is another feature
of how receptors go
about their business.
This general principle
doesn't apply all the time.
But in general, more of
a ligand for a receptor.
A ligand, for folks
not familiar with this,
a neurotransmitter is a
ligand for a neurotransmitter
receptor.
A hormone is a ligand
for a hormone receptor.
The ligand is whatever the
receptor normally binds.
So this general-- not
universal, but general-- rule
of the higher the ligand
levels, the more likely
you are to trigger this
compensatory down-regulation
to lower the
levels, all of that.
Here's another level of
regulation that can go on.
So you've got these receptors.
They are complicated,
because their job
is to bind their ligand and
to then do something or other.
And the cell, as
a result, opens up
some channel that allows
a change in excitability
in the neuron,
that sort of thing.
These receptors tend
to be very complicated.
And what you wind up seeing is,
in lots of realms of receptors
for different types of hormones,
neurotransmitters, et cetera,
you actually have
the receptor made up
of a number of
different proteins,
of a complex of proteins.
So that for example, here
we have a receptor that's
binding a ligand that looks like
that, just like your premolars.
And what you have
there is, it's got
to come up with a complementary
shape and lock and key,
blah, blah, all of that.
And in this particular
case, this receptor complex
is made up of three
different proteins that
are needed to pull this off--
three different proteins, three
different genes--
a receptor being
coded for by multiple genes.
When you get the more
fancy, complicated receptors
they tend to be complexes of
more than one protein forming
this pattern.
So you've got multiple genes.
That's interesting.
And of course, we're off
and running with that.
What that means,
then, is you've got
the potential for
variation, different flavors
of the different genes,
more different ways
that this could appear.
There's two different
variants on this gene.
There's 17 on this one.
And you just do the
combinatorial stuff.
And thus, you've
got a huge number
of ways of generating different
versions of that same receptor,
which, of course, will work a
little bit better, or a little
slower, or a little whatever--
variation like that.
Next complexity that
you get with receptors--
you can have a
receptor that's made up
of three different proteins.
And there's four
different genes that
make proteins that
can help construct
one of these receptors.
So you can make a receptor out
of proteins 1, 2, 3, or 1, 2,
4, or 1, 3, 4, or
off you go with that.
Or you can make a receptor out
of three copies of number one,
or two copies of number two
and one copy of number four.
There's these possibilities of
all these different subunits
being different--
variability that way.
So another realm
of regulation is
when cells change the
subunits on their receptors,
when cells will cause,
say, degradation of-- OK,
so here we've got this
three-protein receptor complex.
And there's four
different proteins
that potentially plug into it.
And this version has one
copy of A, one copy of B,
and one copy of C.
Something may happen
which will cause the neuron
to degrade the copies of B
and replace it with
D, or replace it
with another copy of A, replace
all this combinatorial stuff,
and thus change a little
bit how well the receptor is
doing its job.
And you see these subunit
changes all over the place.
One domain, in terms of the
neurobiology neurotransmitter
stuff-- aspects of
glutamate receptors--
you guys heard something about
that the other day-- glutamate
receptor's essential
for learning,
very complicated receptors,
insanely complicated.
Part of what learning
appears to be about
is not only
increasing the number
of copies of a certain
type of glutamate receptor,
but changing the
subunit composition,
and making for a more
responsive, more excitable
version of that receptor.
There's other realms with a
different type of receptor
where, in fact, you've got
an abnormal subunit that's
not supposed to be there.
And as a result,
this now produces
a cell that is prone
towards insanely high levels
of excitation.
This is a congenital reason
for causing epilepsy.
This is one of the genetic
forms of epilepsy, where you've
got the wrong subunit winding
up in another neurotransmitter
and its receptor.
All we're seeing here is lots
of room for more regulation
here, mixing and matching,
changing the subunit stuff.
That's how you begin to do
that critical principle.
Remember, all the stuff
from the basic functioning,
the flow of information
from the dendrites
to the axon hillock--
what's that all about?
No single dendritic input is
enough to trigger an action
potential.
Instead, you have to have enough
of them, enough summation,
to reach the threshold that the
axon hillock has to initiate
the action potential.
And the threshold
could change over time.
Translate that into this.
What does it mean when an axon
hillock's threshold is changed?
Those critical first channels
that open up-- you've
changed the subunit composition.
So that is a theme all
throughout this world
of receptorology and channels
that open and close and stuff,
where cells can change which
are the pieces that make it up,
and change the
properties subtly.
Similar theme that could
come through with hormone
receptors-- same exact deal.
A whole bunch of them are
multi-protein complexes--
exact same story.
You can see something a
little different when you
have steroid hormone receptors.
And as we saw the
other week, remember,
it's got two domains-- one
which binds the hormone--
glucocorticoid, just to pick
a random steroid or estrogen,
progesterone, or whatever-- and
one that binds to the promoter
element in the DNA.
We've got our if/then clause.
If and only if this
steroid hormone shows up,
then you go and you
activate that gene--
our conditional clause.
But what turns
out to be the case
is all sorts of steroid
hormone receptors
have various other proteins
that they bind there.
Co-factors is the
term given for it.
And you get different arrays
of co-factors in different cell
types.
And as a result, when
you activate this,
it will do different things
in different cell types--
cell-type specific coding.
And of course, the
exact same theme
here-- under some
circumstances, cells
will change which
cofactors they have
holding onto those receptors.
So what we see here are
these additional layers
of potential regulation.
More complexities--
next one-- now
we've hurdled past the
notion of only one type
of neurotransmitter per neuron.
We have hurdled past the
notion of the same action
potential will be manifest in
every single axon terminal.
Now we see all sorts of
additional information built
around changing the
number of receptors,
changing the composition of
them, regulating those ways.
One additional complication
here with these receptors,
which is a lot of them can
bind more than one thing,
can bind more than one ligand.
And we see an amazing example
of this at the neurotransmitter
end of the world.
You guys heard about the
neurotransmitter GABA.
GABA is the main inhibitory
neurotransmitter in the brain.
It is the workhorse
for doing that.
The GABA receptor-- no
surprise-- binds GABA.
Its ligand is GABA.
It is found on the
dendritic spines
of GABA-responsive neurons.
And the neurons
just upstream of it
will release GABA in response
to its action potential,
and just goes about its thing.
So what does the
GABA receptor do?
It binds GABA.
And when it binds GABA,
something or other
happens so that this neuron
becomes less excitable.
It's an inhibitory
neurotransmitter.
It turns out the GABA receptor
is insanely complicated.
It is, instead, a
receptor complex
of a whole bunch of
different proteins.
And what the GABA
receptor does is
it binds some other
things as well--
three different classes, all
of which are very interesting.
The first class of additional
things that it binds
are things called
major tranquilizers.
What does the GABA complex bind?
And here we have
our GABA receptor.
And GABA fits right in there.
And it turns out the
GABA receptor also
has another binding site
here for major tranquilizers.
What are major tranquilizers?
Barbiturates-- this is how
barbiturates work in the brain.
There are not
barbiturate receptors.
They bind to the GABA receptor.
There is a side complex on it.
There is a minor binding
site on the GABA receptor
for barbiturates.
OK, so GABA, inhibitory
neurotransmitter-- when
barbiturates are around, does
that increase or decrease
GABA signaling?
OK, who says increase?
Who says decrease?
Who says, what?
OK, me, too.
I wasn't listening either.
I'll tell you, lurking
around in the back
during those TA's
lectures, you really
do get a sense of what
interesting, non-academic
things are going on
people's computer screens.
But I digress.
So what barbiturates do is they
make GABA more inhibitory--
inhibitory enough
that you keel over.
And now they can slice
you open for surgery.
This is how one of the main
classes of surgical anesthetics
work.
Then there is
another binding site
on the GABA receptor complex.
And what that does is it
binds the minor tranquilizers.
And what are those?
We've heard about those
a bunch of times already.
Those are the benzodiazepine,
the valium, and the librium.
And they work there as well.
And we've already
heard about how
anxiety disorders
in some rodent lines
are related to
different versions
of the gene for the
benzodiazepine receptor.
We've just defined
what that gene is.
That gene codes for one of the
subunits of this massive GABA
complex.
So there's another domain there
that binds benzodiazepines--
the minor tranquilizers.
What do they do?
They increase the force
of GABA signaling as well?
Do they do it as much as
the major tranquilizers?
Of course it's not the case,
because you wouldn't call
them minor tranquilizers then.
These guys potentiate GABA
signaling a moderate amount.
These guys potentiate
it enormously.
So now we have these additional
factors binding to these GABA
receptors.
A third class-- and
this is, in lots of ways
the most interesting
one of all, which
is an additional
binding site there.
That responds to a hormone
or a derivative of a hormone.
What is it responding to?
Derivatives of progesterone.
Progesterone has a binding
site on the GABA receptor.
Progesterone is a
steroid hormone.
It's normally doing
its thing here.
And now we have, instead, having
a minor slot there on the side
there that responds
to progesterone.
What does progesterone do?
It also potentiates
the effects of GABA.
What's that about?
Two implications--
one is, in the 1950s,
one of the most common
surgical anesthetics used
was a drug called
Althesin, and it was
a derivative of progesterone.
People in the '50s
would be anesthetized
with this supposedly
reproductive steroid hormone,
because it has this effect
on the then undiscovered GABA
receptor.
It potentiates inhibitory
GABA signaling.
That's weird.
So progesterone--
clearly, this relationship
did not evolve so that
people could do surgery
on people who didn't want
to get major tranquilizers,
and instead deal with
the progesterone route.
Where is this relevant?
It seems to have something to
do with some of the mood shifts
over the course of the
reproductive cycle.
There are reasons, and
pretty good evidence
in lots of domains, where
perimenstrual syndrome--
pre-menstrual
syndrome, PMS-- which
is more accurately
called perimenstrual--
both before and after.
What that involves,
clearly in some women,
is a shortage of
progesterone having
some of these minor
tranquilizing effects
by way of the GABA
receptor complex.
So this is incredibly
complicated stuff
going on here, as you can see.
Final domain-- final
interesting elaboration,
which is now bringing in a
whole additional concept--
and deserves a board
all of its own.
So here we have
circular neurons.
And what we've got is, this is
the neuron we're interested in.
What's it up to?
And this is neuron
A. And just to force
some cognitive flexibility,
this is neuron B,
going in the wrong direction.
So we've got neuron B releases
an excitatory neurotransmitter,
and thus, excites A. OK,
this is not earth shattering.
It's probably releasing,
say, glutamate for example.
So remember GABA-- that
inhibitory neurotransmitter
we just heard about.
So GABA does inhibitory stuff.
So maybe there is a GABA neuron
here sending its projection,
and this one is inhibitory.
Notice what we've done by
turning neurons into spheres.
We've lost all the
little dendritic spines.
So translate that into back to
what it actually looks like.
This is just schematic.
So we've got two inputs.
We've got an excitatory
input by way of glutamate.
We have an inhibitory
one with GABA.
What does that imply?
Dendritic spines in this
neuron contain both receptors
for glutamate and
receptors for GABA.
That would be straightforward.
That would be simple,
if that's how it works.
That's not what you see.
Instead, GABA neurons
never send a projection
onto what would
be neuron A. What
they do is they send a
projection onto neuron B.
What's that about?
What's that about is
what GABA is doing
is making this neuron
less excitable.
It's working as an
inhibitory neurotransmitter.
It's making this
neuron less excitable.
What's happening
here-- this neuron
has just started
an action potential
that's coming down the axon.
And thanks to a heavy
GABA signal coming out,
it silences it.
It never gets to the end, and
dumps the neurotransmitter.
This is totally weird.
This is completely different
from all the wiring
you've seen already.
What's bizarre about it?
Number one, this is a
neuron forming synapses
not on the dendrites
of this neuron.
It's forming a synapse
on the axon of this.
And thus, we have what is
termed an axoaxonic synapse.
What does that also imply?
That there have to be GABA
receptors sitting there
at the pre-synaptic
end-- just as
bizarre as the
pre-synaptic autoreceptors.
Remember, those are for
measuring the amount
of release-- bookkeeping stuff.
But here, this is
perfectly conventional
neuronal responding
to a neurotransmitter,
but coming at the
completely wrong end
with this weird
axoaxonic projection.
But what's most important here
is seeing this implication.
So what is it that
this neuron does to A?
What does this GABA neuron
do to the excitability of A?
And the answer is,
it does nothing.
It has no effect on
the excitability of A.
What this GABA neuron does is
alter the ability of neuron B
to do something
to A. This neuron
has no direct effect here.
What it does is it modulates
the activity of this neuron.
And thus, you have a whole new
class of type of communication.
Technically, rather than
working as a neurotransmitter,
it would be termed
GABA typically
serves a neuromodulatory
role in the nervous system.
And that's this wonderful
conditional clause
yet again-- yet
another if/then clause.
GABA decreases
excitability if and only
if this neuron is trying to
send an excitatory signal.
All that GABA does is snuff
out an excitatory signal
coming down here-- so
modulation in that regard.
We've already seen another
example of that writ small.
Back to the GABA complex here.
What do the major
tranquilizers do there?
What do barbiturates do?
They do not make this
neuron less excitable.
What they do is, if and only
if there is GABA coming in,
it makes the GABA
work even better.
The tranquilizers do
not inhibit the neuron.
The tranquilizers
modulate, potentiate,
the activity of GABA.
The minor tranquilizers the
same thing, the progesterone
the same thing.
So this is a different
level of this concept
of neuromodulation--
if/then clauses
all over the place here.
So if and only if GABA
is doing its thing,
any of these minor ligands
will potentiate it.
If and only if this neuron
is trying to stimulate here,
GABA will have an inhibitory
effect on the whole system.
So you see lots and lots
of this modulatory stuff.
Final example, seeing the
same principle of modulation,
now occurring in an
endocrine system.
OK, so now we're measuring
the amount of ACTH coming out
of the pituitary,
and back to that deal
that we've got all
these different ways
in which the brain can
cause the release of ACTH.
And starting off, we saw CRH.
So suppose you throw in some
CRH on top of the pituitary
there, inject it
into the circulation.
And this much ACTH comes out.
OK, that's good.
Now, instead of putting on
CRH, you put in both CRH
and vasopressin-- a
second one of those.
And what do you see?
That's perfectly logical.
You've got two things
driving ACTH secretion.
Now you put on vasopressin
just by itself.
And what you get is this.
You get no secretion.
Does vasopressin stimulate
the release of ACTH?
No, it doesn't.
What vasopressin does
is it potentiates
the activity of CRH.
It modulates CRH's activity.
Vasopressin does
nothing by itself.
If and only if
there is CRH getting
to those pituitary
cells, then vasopressin
will potentiate its actions.
All of those other
releasors-- the vasopressin,
the oxytocin, epinephrine,
norepinephrine-- none of them
are direct releasors
on their own.
They all are modulating,
potentiating CRH's effects.
So what we've got here
is this enormous realm
of complexity of
all of these if/then
clauses, various hormones
that are not directly
causing anything,
neurotransmitters that are not
directly causing anything,
ligands for receptors
that are not, either.
What they're all
doing is, if and only
if something else is happening,
something else is going on,
there's an additional
ligand, they
do their thing-- lots and lots
of these conditional clauses.
More complexity there.
OK, so what does all of
this get us here at the end?
Obvious-- lots of
individual variability,
lots of ways in which
these systems are changing
in response to experience, all
that subunit changing business.
Something happens and you
get rid of one subunit.
Replace it with another,
and you've changed
the excitability of the system.
All sorts of over and over
conditional if/then clauses,
tremendous increase
in the complexity.
These themes will come
through again and again
in the second half
of the course.
So let's stop at this point.
Are there any questions, since
this was a major download?
Check the extended notes.
Are the extended
notes posted yet?
Not yet.
They will be some time or other.
OK, any questions?
OK, so go read those notes
as soon as they're up.
For more, please visit
us at Stanford.edu.
