[MUSIC SWELLING] Stanford University. Can you hear me like this? Is this better? Yes. Yes. OK, great. So yeah, so like Tom said,
feel free at any point to interrupt us with questions. Just raise your hand if
something's confusing, stuff like that. Also, just like with
the other lectures, feel free to email
us after class. Our emails are on CourseWare. You can find us that way. So today, we're gonna provide
a little bit of background context introducing sort
of [INAUDIBLE] place in the context of the other
sort of buckets of this class, or I guess sort of think
about it generally. We're gonna talk
specifically then about peptide and
steroid hormones, different types of hormones. Then we're gonna see some
specific interesting things about them that you
might want to know. Then we're gonna talk about how
the brain controls hormones. So hormone release, and
then eventually feeding back to how hormones
influence the brain. Sort of this dual communication
system that's pretty neat. But we're gonna touch on
all those things today. So Tom's gonna start out
with some background context. OK. So way back when, when life
first arose, things was-- were inside single cells, right. Individuals were
single cells who had to interact with
their environment. They had to get food, they
had to get rid of waste, they had to make sure they were
in the right pH and temperature so that they could do
well for themselves. And as a single cell, it seems
like a simple enough task. But as things got
more complicated and multicellular
life arose, there arose a really big,
important issue for life, which is how
cells talk to each other. Cellular communication, OK? And you don't have to
worry too much about, like, the jargony
words like paracrine. But it's kind of
worth thinking about. There are four main ways that
cells can talk to each other. The first one being
cell-cell contact, where you actually have one
cell physically touching another cell. And that seems pretty
understandable. It's got to be really,
really short range. And it's just gonna be this
cell talking to another cell. We've got paracrine, which
is a little more short range. And you guys have heard
about neuronal and endocrine. And I'm gonna try to put these
examples of communication in the context of us, as a
giant, multicellular organism. This class, right now, OK? So who wants to be the pancreas? No one wants to be the pancreas. OK, we've got a
pancreas right there. Thank you very much. No, we don't have to
be specialized cells. But the point is that
a cell-cell contact in our organism would
be actually someone physically handing you
a note during class, OK? You actually-- and it's just
one to one, short and easy. Not gonna-- not a lot of people
are gonna know about that signal. Paracrine is more
like kind of you whispering to a bunch
of neighbors, right. A couple people can hear you. It happens pretty quick. But it's not widespread. Neuronal is something that is
really important to this class, and it's something you've
heard about already. This is the equivalent
of texting your friend during class, OK? I saw Bill Loundy
texting someone earlier. I was a little offended. So if you could put your phone
away, sir, that'd be great. And the key to
neuronal transmission is that it's really about
electrical movement, OK? That's why it happens
so fast, because I've got neurons that span
all the way from here to through my spinal
cord, or from all the way from my spinal cord
out to the tips of my fingers, and that's just
electrical transmission via action potentials, which
you've learned a lot about. Now, granted, when one neuron
talks to the next neuron, it's kind of a relay. It's got to use a
neurotransmitter to communicate that. But you can really focus, for
the purposes of this example, on that fast electrical
action potential thing. And the fact that it's a
lot more specific than what we're about to see, which is
endocrine, which is long-range. It's all about
chemical messengers traveling through
the bloodstream. Hormones in the blood. That's what endocrine
signals are about. This is a lot more like Steven
sending you guys an email to the entire class,
but it takes a long time to get there, right? It's gonna take a
little bit longer, but it's gonna
enable us as a class to coordinate our
behavior so we all show up to the right place at the right
time, wearing the right thing, whatever. OK. So you guys get that. Questions about those different
mechanisms of communication? OK. So endocrine clearly
the focus of today. Things are traveling
through the bloodstream. It's gonna take a
while to get there, but it's gonna be--
allow us to coordinate a lot of different things. Now, what would we
want to coordinate? Two kind of really exciting
things that we can coordinate. One is these giant
transformations that occur during life. Things like
metamorphosis of-- good, I see some mimicking back there. That's very good. I want everyone to do
this with me right now. Metamorphosis. Good. So basically, you want all
the cells in that organism to kind of change in
coordination with each other. Same thing for a
couple other things which I'm about to talk about. That's in contrast
to-- it doesn't have to be an adult
organism, it just has to be a functioning
organism who is in a certain environment. And in that
environment, oh, crap, I need to get all my
cells on the same page, because we've got to address
this particular environmental thing. So I'll give you
a couple examples. One really great coordinated
developmental transformation was the transition
from young Harry Potter to Daniel Radcliffe, right. He was in that weird horseplay
thing, got a lot of publicity. And you can see, like,
a lot of his cells had to change kind of
all at the same time. And you get the point. Same thing, I've kind
of mentioned these. As opposed to a kind
of coordinated response into a specific
environmental thing, which might be a
stressful situation. We're gonna hear about
that a little bit later. You want to make sure
all your organs and cells are doing the right
thing for stress mode or sexual arousal
mode, whatever it is. And we're gonna hear a little
bit more about that later. So Will has the mic. All right, so that's sort of
the background context putting that stuff into play for today. So there's some very
important things that you have to know
about hormones overall. We wrote here peptide
versus steroid. There'd technically a
third kind of hormone, which is single amino
acid [INAUDIBLE] hormones. But we're basically gonna
talk about the distinction between peptide and
steroid hormones today, and sort of
structural differences and what that means in
terms of their transport in the bloodstream, the effect
they have on target cells. And then we'll see
different things about their duration and
other cool things like that. So the structure generally,
as you can see here, we put up a picture of
insulin in peptide form. We wanted to make it
look like a protein. Peptides, of course,
and amino acids being the precursors
to proteins. We see sort of here this is a
typical peptide hormone made from amino acid precursors. And a key term
associated with this is the notion that
it's hydrophilic. So this idea that
it's water-loving. This plays into the sort of
transport mechanisms involved with it, and other things which
we'll talk about in a moment. So peptide hormones
made from amino acids, hydrophilic, water-loving. We'll see some examples. You've heard of some already. Insulin, vasopressin,
oxytocin, ACTH, CRH, and more. And then we also
have steroid hormones So these are made from
cholesterol precursors. They're hydrophobic,
water-hating. Another term we associate
with this is lipophilic, liking of lipids. When we talk about the
cellular membrane being made of a phospholipid
bilayer, steroid hormones are hydrophobic or lipophilic. They're able to pass through
this phospholipid bilayer. Ends up being very important for
their mechanism inside target cells. So some examples of this. Classic example,
glucocorticoids. We're gonna see those
all over the place. We already had talked
about them a bit. Androgens, estrogen,
things like that. Something really interesting
about the structure of the hormones. So if we take a
steroid hormone-- OK, so I'm not gonna
draw [INAUDIBLE]. I'm gonna draw a single amino
acid, which this actually is nothing-- looks nothing like
a single amino acid hormone. But you sort of bear
with me and pretend here. So a lot of these
hormones, steroid hormones, single amino acid
hormones, peptide hormones, they come from similar
precursors, right? You have peptide hormones,
it's amino acids. And single amino acids,
it's often from tyrosine, and steroid hormones is from
these cholesterol precursors. Why is this interesting? It's interesting
because, when they come from the same
precursor, they end up looking very similar. So one might have this here. So this might be one hormone. And then we might have an
identical-- a newly identical one underneath. But now it has just
another sub-chemical shift. Chemical structure
doesn't really matter. The point is that, if you're
familiar with some organic chemistry, you have just
subtle chemical shifts leading to different hormones. Interestingly, from an
evolutionary standpoint, this suggests the
need for basically having receptors specialized
for these subtle chemical differences in the hormones. norepinephrine and dopamine
have just a slight difference like this. But the effect, if
the receptor wasn't able to distinguish
those-- between those, it would have a drastic effect. So it's very important, from
an evolutionary standpoint, to have receptors
that can distinguish these subtle differences in
the hormone chemical structure. That sounded really technical. Any questions on that
sort of general idea? Is that cool? OK. That does remind me
of one thing that I didn't make a
distinction between when I was talking about neuronal
versus hormonal transport. A lot of times, we will kind
of throw out these words, and there's a lot
of jargony words. Norepinephrine,
blah, blah, blah. And it's kind of
good in your mind to be able to separate
between hormones, things that are really these
classic things that travel through the blood as
signals, and neurotransmitters. Neurotransmitters being
they're also chemicals, and they also need to
communicate cell to cell, but they are gonna be
just in that synapse, OK. From one neuron to the
next in the synapse that you've already heard about. And just to make your
guys' lives awesome, there can be overlap. There can be neurons that
release their neurotransmitter into the blood, at which
point they become hormones. So things like dopamine
and epinephrine, right. Things you might associate
with neurotransmitters can also be hormones, depending
on what context and all that stuff. So just something
to really focus your attention on when you're
distinguishing these signals. OK, cool, thanks. So yeah, so we talked about
the structure very briefly. From that structure, we can talk
about sort of the differences in transport. We talked hydrophobic
versus hydrophilic. The images-- should have done
an animation-style pop-up. So our peptide hormones
are gonna be water-soluble. They're gonna travel freely
through the bloodstream. We have-- I guess
our example here is people riding a roller coaster. These monks are just
riding free, looking good. You can imagine
the monks as sort of examples of these
peptide hormones traveling freely, dissolved
through the bloodstream. Not really dissolved,
but that's OK. So peptide hormones traveling
freely through the bloodstream. Steroid hormones,
however, they're not water-soluble, so they need
to be bound to a chaperone. This is our example of a
chaperone guiding this hormone through the bloodstream. So this is-- it's just sort
of an interesting thing to note about their transport. We may talk about this a
little later in other contexts. Other interesting things we
can learn from the structure. So, interaction with
the target cell. When Thomas was talking
about the context here, it's really that we
understand how hormones interact with cells, right? They require a specific receptor
for each individual hormone. We talked about
the importance sort of the specificity of that. Peptide hormones and
steroid hormones sort of have generalized
mechanisms that we're gonna talk about,
ways in which they interact with target cells. Peptide hormones
on the left here. So peptide hormones, because
they can travel freely through the bloodstream-- or
I'm sorry, let me step back. They can travel freely through
the bloodstream because of their structural properties. However, those same
structural properties, the fact that
they're hydrophilic, prevents them from
being able to travel through the phospholipid
bilayer of a cellular membrane. So the receptors
for peptide hormones are on the surface
of these cells. They're surface receptor
cellular membrane sort of-- the receptors are
on the cellular membrane. Because of that,
they're typically associated with these what
are called secondary messenger responses. The details of this-- I
think a lot of you guys have been exposed to this
in all sorts of biology or human biology. But if you haven't,
generally what happens is a peptide hormone binds to a
receptor of the cell membrane, and then sets off what we always
call this cascade response. The secondary messenger
cascade response. This is actually
really interesting. It can lead to a number
of different effects. One thing it can
do, which we'll talk about when this
is a neuron, is it can activate ion
channels, sort of helping ion channels to open or close. We'll talk about that in terms
of membrane potential later on. Another thing it can do-- and
this is the classical example with peptide hormones--
is it sets off this secondary
messenger cascade that affects proteins within the
cell, directly within the cell. So we can think of
peptide hormones generally as having action
on proteins within the cell. And that's sort
of the end effect of the secondary
messenger cascade. They also technically
can go into the nucleus and affect transcription. However, that we tend to
associate more with steroids. And we'll look at some of the
complexities and complications of this later on. You'll hear about this. But I would say generally,
it's important to note that we tend to associate
peptide hormones with these secondary
messenger cascades affecting the proteins existing within
the cell at the moment. The onset tends to
be relatively quick, and the duration is
relatively short. We're gonna talk about this in
comparison to steroid hormones. And we can see why the relative
onset duration is different. So because it's
affecting proton-- or proteins that exist, it's--
we can say that the duration is relatively short. And as we said here, it may
affect protein activity. Steroid hormones,
by contrast, they travel through the blood
on these chaperone protein carriers. And then when they
get to a cell, they're able to diffuse
through the membrane and actually bind to receptors
located within the cell. Classically, we talk
about steroid hormones passing through the membrane,
binding to a receptor, and then going
directly to the nucleus to affect transcription. So this is sort of
our classic example. Main effect, transcription. The onset, then, slower,
and the duration longer. It takes longer to start these
transcriptional processes, and it's lasting a lot longer. We're changing the rate
of synthesis of proteins, rather than changing the
proteins that currently exist. OK. As always, feel free to
interrupt if anything seems sort of confusing. So those are sort of some
of the generic examples. We-- insulin would be a classic
example of a peptide hormone. Glucocorticoids is
our steroids hormone. We may-- we'll see this
coming up again and again. We may touch on this again
today in the lecture. Cool. So just to recap-- does anyone
have questions off the bat? Yes? For the steroid hormones,
it's like a receptor floating in the middle of a cell. Like, would that be on the
nuclear envelope, or is it, like, on something else? Great question. So the question was,
for the receptor for this-- and this
image, by the way, courtesy of Professor Sapolsky. Thank you, wherever you are. So the receptor is located
within-- the question is where is that
receptor located for the steroid hormone. Is it on the nuclear membrane,
is it within the cell. Classically, we're gonna talk
about basically receptors being located in the cytoplasm. There are examples you'll see
if you look-- even if you did a Google images
search, you might find examples of steroid hormone
coming in, binding a receptor, floating in the cytoplasm that's
then taken into the nucleus. Basically, we
associate the receptors as somewhere within the cell. Perhaps on the nuclear
membrane, perhaps somewhere else in the cytoplasm. And the steroid hormones
bind within there, and sort of carry out
effects from that. And you could
easily also imagine there being a receptor
protein that's already sitting on the DNA
just waiting to be activated. And then when the steroid
hormone travels the entire way into the nucleus, that's
when it hits the receptor. So yeah, both work. Other questions? Yeah. What are cholesterol made of? What is cholesterol made of? So cholesterol-- I have
no clue what it's made of. I know generally what its
chemical structure looks like. If you look at the
steroid picture from the other page,
the chemical structure, cholesterol precursors are sort
of similar ring structures. You can look it up. I think-- it's an
interesting question. In my mind, what I
tend to associate as a relevant
question, or something that I'm trying
to get across more would be that the
steroid hormones come from cholesterol precursors. And so I sort of consider
that the baseline, rather than trying to think
about what cholesterol is made from. Interesting question. Don't know off the
top of my head. And maybe the most
important thing would be that cholesterol
is hydrophobic. So if you're gonna
make stuff from this hydrophobic beginning,
it's gonna be hydrophobic also. And I just want to make sure
people are completely-- those are some really jargony terms. Hydrophobic, hydrophilic. There are a lot of
synonyms for those terms that are equally jargony, things
like lipophilic and lipophobic. Lipo means lipid, so
something that is hydrophobic is lipophilic. That hurt anyone's brains? OK. So just kind of
maybe spend some time thinking about those words. You can kind of logic
through them pretty easily. You might also hear
people use the terms polar versus non-polar. Water is polar. So water-loving things,
hydrophilic things, tend to be polar. And hydrophobic things
tend to be non-polar. Don't worry too much
about that vocabulary. I just want you to
know that there's a lot of different words
people might throw around that all essentially are
getting at the same thing. Any other questions about
this basic setup so far? No? All right. Onto chapter two, which is
how does the brain control hormone release. We've established that
it'd be a good idea to release hormones in response
to certain environmental cues. How can we control that? And as this picture shows, there
are many, many different sites in our body where we can
release hormones from. We've got the
pancreas right there. We've got the testes. We've got all these
different glands. These are just
specialized structures that can just pump this
hormone into the bloodstream, because that's what
hormones are all about. Some that will come
up will definitely be the testes, the
ovaries for females. I don't know why they're
drawn on the same guy here. Kind of interesting. The pancreas, which is-- we
keep talking about this thing called insulin. That's released
from the pancreas, and it's gonna have something
to do with food and sugar and things like that. The thymus is another great
little endocrine gland. It releases thyroid-- no,
thymus releases-- oh, thymus is where-- what endocrine
signal does the thymus release? T-cells. Thymus-- t-cells? I'm not sure those
are hormones, though. So anyway, the thymus is
involved in the immune system. Let's ignore that for now. And blah, blah, blah. You guys get the point. There are many places throughout
our body that secrete hormones. And they tend to secrete
a certain signal. Now very excitingly, you'll
notice that the brain itself has some endocrine glands in it. The hypothalamus. We've heard this word
hypothalamus a few times. The hypothalamus is
an endocrine gland, meaning it can secrete
things into blood. The pituitary, right
next to the hypothalamus, separated by a
little blood maybe, maybe not, the pituitary
also can release hormones into the blood. And these other kind of
lower-down peripheral endocrine glands often are regulated
by those big master endocrine glands in the brain. I don't know if you guys have
been reading your zebras yet, but I think Professor
Sapolsky referred to these as the brain is the
master of these witless organs. These guys are
just kind of, like, doing whatever the
brain tells them to do. And it's the brain controlling,
via the hypothalamus and the pituitary,
is going to be able to control how much
testosterone is coming out of those testes. Does that make sense? The brain controls these
peripheral endocrine glands. OK, so let's zoom in on
that hypothalamus pituitary situation. Will really didn't want
to include this picture, but I thought it was hilarious,
and I can't explain why. Maybe it's the ponytail. I'm not sure. But we're just
kind of focusing in on these two different parts. And you'll notice maybe that
with-- something to take away from this picture is
simply that the brain is kind of feeding into
the hypothalamus, which is feeding into the pituitary. So when we see something,
that information is processed in our brain, can tell our
hypothalamus oh crap, oh, crap, it's stressful. It can tell the pituitary. And we get this-- eventually,
we can tell the rest of our body what to do via hormones. Awesome. Goodbye, ponytail lady. OK. Here's another just classic,
classic Sapolsky image here that we were able to borrow. And this is zooming
in, once again, on just the hypothalamus. And now we're really, really
looking at the pituitary. And this is where
things are gonna kind of hit the
fan a little bit, so I went everyone to put your
A-game on, to mix a metaphor. OK. So the pituitary. The pituitary are these
two kind of things dangling below the hypothalamus. A lot of weird pictures of them. This one's nice
because it clearly divides the anterior pituitary
from the posterior pituitary. And we're gonna make some
really, really important distinctions that hopefully
you can grasp from this image. And if you can't, let me know. OK. So first of all, the anterior
pituitary secretes hormones. It secretes these
things over here. I'll talk about
them in a second. The posterior pituitary secretes
a different set of hormones, these ones over here. That's one distinction. Another really
interesting distinction is how the hypothalamus
regulates that secretion. OK? On the anterior side of
things, the hypothalamus, being an endocrine
gland, can actually drop some hormones into that
little red river of blood right there. So the hypothalamus is
actually releasing a hormone into the blood, and that travels
down to the posterior pituitary and tells those-- sorry, the
anterior pituitary, sorry-- and tells those
cells to then release another hormone into the blood. And once they're
in the blood, they can go all the way down
to those other target organs we talked about. So that's one system. You've gotta actually
travel through the blood in the anterior pituitary. The posterior
pituitary is actually directly innervated, OK? So the hormones that are
released by the posterior pituitary are actually
coming out of those neurons. And the cell bodies
of those neurons are up in the hypothalamus. So a couple examples. Let's go through the examples. You absolutely do not
need to memorize this. We only did this because
Will teaches MCAT, and those kids really
like their acronyms. They like things that you can
say out and put around and put them in bold. So FLAT PEG is the
acronym that people use when they want to
memorize a lot of stuff to memorize the posterior--
or sorry, the anterior pituitary hormones. Some that will be
relevant to us that you might want to keep in mind
are, particularly, ACTH. Don't worry about it quite
yet, but just kind of plug it in your mind to something cool. And a couple of these
other ones might come up as well, but whatever. On the posterior
side, we were upset because there was
no cool acronym-- is that the right word, acronym? Yeah. For the vassopressin
and oxytocin. And we decided that since
these are the two hormones that are always being shouted
out in these vole studies, we put some voles on there. And we thought they were cute. They've kind of got some Rudolph
things going on with the noses. So yeah, whenever you're hearing
about vasopressin and oxytocin, those are hormones
that are released from the neurons in-- that
go from the hypothalamus to the posterior pituitary. Now, questions
about any of that? That's kind of
some neuroanatomy. You're probably not super
excited and interested in about that. But it's useful to know. It might come up a little bit. So, questions? Clarifications? None at all. Oh, there's one. Oh. Yes. So I guess the
neurotransmitters [INAUDIBLE] or are they released
[INAUDIBLE]? Oh, my, that's a great question. So I don't know how much
we got into kind of-- Why don't you
repeat the question. Oh, sorry. The question was the
neurotransmitter slash hormones like vasopressin
and oxytocin that are released in the
posterior pituitary, are those just kind of
like sitting there waiting to be released, or do those
have to be manufactured and then sent over there. Is that the question? Yeah. Or, like, if they're released
from the [INAUDIBLE]. Are they released when needed,
or are they, like, created and then sort of sit there-- OK, so yeah. I would think about this based
on your typical understanding of a neuron, which just has a
cell body, an axon, and then the axon terminal, which
is where it releases neurotransmitter, right? In that axon terminal where
it releases neurotransmitter, it's got vesicles. It's basically got these giant
balls full of neurotransmitter. Same thing here. You've got these giant
balls full of oxytocin and vasopressin just
waiting to be released. But aren't those made
in the hypothalamus? Those-- like any other
neuron, those are synthesized, produced in the cell body
of that neuron, which exists in the hypothalamus. And if you're interested
in how that works, you've got to go on
this crazy journey where stuff--
proteins, whatever, made in the cell body of that
neuron, which you can see up there-- has to be carried
by these motor proteins down the cytoskeleton. They walk like
this, I'm serious. I'm not making this up. And they have to walk all
the way down the cytoskeleton to get there so that they can
just wait for the right signal. That's an excellent
question, also getting at a deeper issue,
which is what is it that leads to this hormone release. And we are gonna cover that in
our chapter three coming up. Yeah. Yeah. So yeah, clearly
there are neurons telling the hypothalamus
neurons when to be activated, when
to release vasopressin. Other questions about this
slide that's-- is anyone totally confused as to what it
is even talking about? Or you guys feel OK? You feel OK. All right. One last thing on
this one is I'd like to contrast it to
Dana's excellent talk on the autonomic nervous
system, where you guys learned a lot about a lot
of different things, including the fact that
the brain can control the autonomic nervous system. And the brain actually sends
neurons with their cell bodies in the hypothalamus and,
instead of sending them to the pituitary, it sends
them some other route down your spinal cord and out. And when we were talking about
the autonomic nervous system and it being also controlled
by the hypothalamus-- this is just kind
of a reminder, OK? The brain and the hypothalamus
are really, really important for regulating a lot of things. In the case of endocrine
systems, this is how it works. Cool. Awesome. Now we're gonna look at just
one example, kind of zoom back out from the lady
with the ponytail to the dude with the
ovaries and the testes to remember kind of how
all this works together. And I could have done many
different systems, right, because we had all those
different peripheral organ-- peripheral endocrine glands
that needed to leak juice out into the blood. I chose this one because it
comes up a lot in the class, and it's often referred to. So it'd be the hypothalamic
pituitary adrenal axis. The adrenal gland is one
of those several glands. It is regulated by
whatever hormones are in its environment. And whether that
hormone is there is thanks to the
pituitary and so forth. There's this kind
of cascade of events that allow the brain to
control a peripheral gland. And in terms of exactly
which hormones do that, we see that the
hypothalamus is gonna have to leak some CRH
into that portal vessel that we saw for the
anterior pituitary. So those neurons
on the upper left would leak, leak, leak some CRH. I might even choose not to
tell you what CRH stands for. And let's just say it's CRH. And then CRH travels
through that blood until it gets to those neurons
where it activates ACTH. It activates neurons--
or sorry, not neurons, it activates endocrine cells
to secrete ACTH into the blood. And then that travels through
the entire body's bloodstream. So it's gonna go
all over the place. But it just so
happens that the cells that really like to respond to
ACTH are in the adrenal gland. So the adrenal cortex,
it's kind of chilling right on top your kidneys,
having a good time. And when ACTH is present, it
will release glucocorticoids. And that's a big, scary word. It's a very important word,
because it's involved-- this is the stress hormones. And for those of you guys who
have started reading zebras, you will have read a lot
about glucocorticoids already. They are gonna be a
really important hormone throughout the second
half of the class. So glucocorticoids,
stress hormones. One specific one that often gets
referenced is called cortisol. And we don't have to worry
about it too much right now, but just remember
stress hormones are getting pumped out. So we kind of understand these
first two positive arrows, I hope. Brain sends an arrow
to the pituitary sends an arrow to
this via hormones. Now when cortisol
comes out and it travels through the
systemic blood circulation, it's kind of knocking on all
the doors of every single cell in the body saying, like,
yo, yo, yo, I'm cortisol, I'm here to party. And if that cell
has a receptor-- this is a theme coming
up-- then it will respond. OK? And some of the cells that
have receptors for cortisol are in the pituitary, and
some are in the hypothalamus. And what that allows for,
it allows the pituitary to know how much cortisol
is in the system. So when it kind of realizes
oh my god, yay, the ACTH made it there and
cortisol came out, now that I hear the cortisol
is in the pituitary, I'm gonna stop. I'm going to slow
down on the ACTH and I'm gonna
relax a little bit. And that's something
called negative feedback. Negative feedback, big term
in biology and all this stuff, just means that
the more cortisol you get it to send
out, the less ACTH. It's kind of a
balancing mechanism. Brings us back to baseline
so that we stop secreting so much dang cortisol. Same thing exists,
there's a whole other area for negative feedback,
in the hypothalamus. And I think that, in the more
advanced endocrine lectures, we'll learn about another
site of negative feedback, OK, other parts of the brain
that, when they hear cortisol, can slow this cascade down. So any questions about
negative feedback, what is the HPA
axis, why does it represent everything
we've been learning. OK. OK, great. Thank you, Tom. So Tom pointed out my
least favorite slide of the day earlier. This happens to be
my favorite slide. This is one of
those slides where it looks like it's
fairly simple, but actually a lot of
thought went into this, so much so that we
probably spent, like, two hours with the
original slide, scrapped that, and then about
an hour ago changed it to this. So here it is. Very important question. Stemming from the things
that Tom just talked about, this hormone being released
and feeding back to the brain, we're gonna investigate
that a lot more closely now. We're gonna look at hormone
action on the brain. We're gonna talk a lot about
the hormone and receptors for hormones. We mentioned very
briefly earlier sort of a generic cellular response
to having a hormone bind to your receptor, either on
the surface or inside the cell. Now we're gonna talk about
specifically in the brain. So we have hormone to the
neuron, an epic journey. The reason this slide
took so much work is we were trying to come up with the
perfect analogy for a hormone returning to the brain. Something historically that
had to go on an epic journey to deliver a message where there
were sort of proper receptors to receive the message. So we thought about sort of
sticking with the Harry Potter theme and going with Kingsley
Shacklebolt's Patronus to Bill and Fleur's wedding. And Tom was a part of this. But I decided that
that didn't quite work. We thought about Phidippides,
the ancient Greek god who went from Marathon to Athens to
deliver the message that Greeks had defeated the Persians,
which was, like, the route-- or why the marathon is 26 miles. Also didn't work. So we stumbled
upon this, which is a picture of Paul Revere,
the guy who supposedly said the British are coming. The reason this is such a good
example-- well, or at least we can stretch it
to fit here-- is that a hormone secreted
from an endocrine gland-- let's say we're starting sort
of from a target organ here. And we-- Tom just
mentioned cortisol coming from this adrenal cortex
and going back to the brain. It has to travel sort
of through-- a hormone has to travel through
the bloodstream. Interestingly, in
order for cortisol to be secreted in
the first place, it received a signal, right. In this case, from ACTH. ACTH binding to receptors,
stimulating the release of cortisol. Paul Revere was
sitting out one night. This is the guy back in
1775-- actually a week ago today, and like 325 years
ago or something like that. 1775, so that math
is probably way off. But you can figure it out. He was sitting outside waiting
to see these light beams. He was waiting to
receive a signal. And we can think of Paul Revere
as sort of a group of hormones here. And when the signal came
in, these two light beacons, he set off on this path
through the bloodstream-- him on horseback through the
roads-- with this message. And he didn't actually say
the British are coming. He said-- boy, what was it. Something like the normals. Something like that. I may have written it down. No, I didn't. OK. Well, he said some code word. And basically, this
code word, if there were proper receptors for
it, they knew how to respond. So it wasn't just the
British were coming, it was some other word. And if there were receptors
for it, they could respond. The relevance in this
case is we're talking about going back to the brain. So Paul Revere was
going to Lexington, sort of the central hub, this
central nervous system brain. We can sort of
stretch it that way. And has to find the
proper receptors there to initiate this
proper response. So I don't know, I
just like that analogy. So what we're gonna talk about
is hormone back to the neuron has to get through the
blood brain barrier. Those are the neurons. It's going through the neuron
or the group of neurons. Do they have the
proper receptors for this hormone signal. And once it binds, how
does it influence activity in the brain. What is going on there. Questions so far? Did I confuse
significantly with that? OK, cool. So we're gonna move on. Starting with the
blood brain barrier. So, the blood brain barrier. On the left, we have this
picture of just blood vessels in the brain. This is here because Tom sort
of has a personal mission. He and I both have been confused
about what the blood brain barrier is, what it looks like. He used to envision--
you can tell them. It's just really embarrassing,
so I'd rather say it myself. I used to think that, like, the
brain was in this barrier that protected it from, like,
the evil blood supply, when it obviously can't be like
that because the blood has to get inside the brain
and tell every single cell in the brain what to do. And I'm confessing
this to you today that you actually have to
picture the blood vessels' access to the brain in a
much more complicated way. So the barrier itself is much
more complicated, as well. Right. So the barrier is
constructed by basically these epithelial cells lining
the blood vessels, right. The blood vessels extend
throughout the brain. Just sort of an
image of it there. And we have this
blood brain barrier created by these tight
junctions in epithelial cells. Sort of a bunch of details
that aren't necessarily super important. However, it's interesting
because this barrier, this blood brain barrier,
basically tightly regulates what type of things
can go inside and outside the bloodstream in the brain. It's very important that
we have a lot of control over what's going on in terms of
our blood supply in the brain. So hormones, the
question comes up, can hormones pass through
the blood brain barrier. We did a bunch of
research on this, and basically because of
their epithelial cells, phospholipid
bilayer, same story, steroid hormones are lipophilic. They can pass
through this blood-- this phospholipid bilayer. Not much of a problem there. Peptide hormones,
generally we know that they can't pass
through just on their own. But we looked this
up, there doesn't seem to really be a problem
with peptide hormones getting to the places they need
to get in the brain because they have these
carrier transports. They have the ability to get
through the blood brain barrier when they need to. So just sort of an
interesting point there. First step getting through
blood brain barrier, it's helpful to know it exists. It might come up in
other contexts later on. Things like alcohol, alcohol
can go right through the blood brain barrier. And that has certain
effects on behavior. We're gonna-- it might
come up later on. Here's this blood
brain barrier, what can get through it, what
can't, what does that mean, what are the implications for
that in terms of behavior. Something just to sort
of know about generally. So next step, receptors. So hormones, when they're
traveling back to the brain, there have to be appropriate
receptors for these hormones. Tom talked about cortisol, an
example of a glucocorticoid. Glucocorticoid is
a steroid hormone. This is an image of a rat brain,
and glucocorticoid receptors in the rat brain. We also have mineral corticoid
receptors, which we're not really gonna focus on, in blue. An example would be, like,
aldosterone for my MCAT, you know what that is. But we'll-- thanks
for the nod, Nate. But we're not gonna
focus on that. So glucocorticoid receptors. As you can see, there are
glucocorticoid receptors throughout the rat brain. Interestingly, however,
we see them sort of clumped in certain areas. What's going on there? This might suggest
a particular area that's particularly sensitive to
these glucocorticoid hormones. So these glucocorticoid
hormones come into the brain, diffuse
through the membrane, and bind to these receptors
located in the brain. We see here that one
area is the hypothalamus. Tom already mentioned
one effect of what's going on there, potentially
sort of these negative feedback mechanisms, right. Glucocorticoids coming back and
helping to regulate, or down regulate the release--
maybe I shouldn't say down regulate, but basically
suppress the release of CHR and, eventually, ACTH and other
things affecting cortisols released in the first place. We also see these receptors
clumped in the hippocampus here. So another interesting potential
other type of negative feedback thing going on there. Stay tuned. We may hear more
about this later on. Interesting point, though, is
that for every single hormone, we're gonna have unique
receptors throughout the body. But we're looking at
the brain right now. So we're gonna have unique
receptors for these hormones in the brain. We're gonna want to
be paying attention to when we're
looking at behaviors, we're gonna want to look--
we're gonna want to think about, basically, where are these
receptors in the brain, what types of receptors are
they, that sort of thing. On this slide, we
wrote receptors location, type, and how many. So I briefly just
talked about location, the location of receptors,
how that can matter. Type of receptors. You can have, within
an individual, you can have different
types of dopamine receptors, for example. You can have multiple
different types of receptors for a particular hormone. And this can lead to
different effects, depending on what type this is. We also heard about this on sort
of the population level, right. A variation in the type
of vasopressin receptor, and how that can lead to sort
of monogamous versus tournament species type behavior. I guess maybe stay
tuned for this, but we've also heard
about these things before. So types of receptors
are interesting, location of receptors. How many receptors. This is another question
that becomes very important. If we have a lot
of receptors, we can basically
predict that there's gonna be a higher sensitivity
to the hormone in that area. The low amount of
receptors, not as sensitive. When we look at
sort of-- when we talk about [INAUDIBLE]
rats, epigenetic mechanisms, this is supposed to
be basically affecting the expression of receptors
in certain parts of the brain. And then we can see the
behavioral impacts of that. So another thing briefly related
to how many receptors we have. We have the level
of hormone, and we have the level of receptor. And both of these
things basically impact the behavioral output. And the interesting effect
we can begin to see happening is that the level of
hormone can affect the up regulation or down
regulation of receptors. You might start out with a
certain amount of receptors. And then if you're flooded
with tons and tons of hormone, these receptors then might
start to down regulate. The cell might sort
of down regulate the amount of
receptors expressed on the surface of the cell, and
you might see down regulation. Conversely, we might
see up regulation if it's not receiving
enough of this hormone. Stay tuned for more of
this, complexity of this, complications with
this, et cetera. Any question so
far on this stuff? OK. Cool. So hormone action on the brain. Next we turn to basically
looking specifically at a neuron. As I mentioned before, we
talked about sort of the effects on cells. We talked about peptide hormones
and the secondary messenger cascades. We put the image back up,
talked about steroid hormones and generally affecting
transcription. Now we basically want
to zoom in on a neuron and see what types
of effects could be happening on these
cells, these brain cells. So we wrote down here, we
summarized it very nicely, potential effects of
hormones on neurons. Once the hormone
binds to a receptor, we can have it change
the membrane potential via ion channels. So maybe secondary
messenger cascade, if basically some
molecule of some sort bumps into another
channel, opens it more, now you've changed the
membrane potential in the cell. It either becomes easier or more
difficult to start an action potential, something like that. We can change
transcription of genes. So it can go in-- like we saw
this with the steroid hormone, going in and basically
binding to DNA, affecting
transcription of genes. In this case, the genes,
they could be receptors. This might be sort
of the mechanism for up regulation
or down regulation of receptors,
something like that. We can also have, of
course, change in protein activity in transport. This, of course,
is crucial, right? Proteins could be involved
with tons of things. Neurotransmission,
formation of new synapses, the things listed there. Basically, hormones
can have impacts on all of these different areas. Protein activity, transcription,
membrane potential, all these different things. And so at an individual
cellular level, we can begin to see sort of
the wider array of impacts on hormone binding,
what that can do. If you step back
and think about this as sort of networks of neurons,
not just individual neurons but networks of
neurons, now you can begin to see how hormones can
start to shape behaviors more overall, just these
networks of neurons, these-- and those behavioral
outputs being sort of the output
of these networks. Yeah, question? When you talk about
impact on neurons, do you mean cells
that are in the brain and the central nervous
system, or are you just talking about the brain? Great. So question-- actually,
can you repeat that for me? Are we talking the whole central
nervous system, or just, like, just the brain? Whole central nervous
system or just the brain? Yeah. So in this case, I'm
talking about neurons that are in the brain. But these might
project anywhere. As Tom said earlier, neurons
can project to other areas within the brain,
can project down the spinal cord and elsewhere. So the impact could be
essentially anywhere that these neurons
could project when we're talking about the
effect of hormone input on neurons in the brain. The key is the neurons,
where they project, they'll have a certain
impact on-- they'll have some certain output
wherever they project to. But in the first
place, they have to have a receptor for
this hormone to bind. So it's just something
interesting to note. Other questions? I saw a question. OK. Cool. Good, thanks. So I think that's-- kind of
summarizes my thing on that. Tom, did you have
anything to add to that? I'd say the more
interesting things that-- when we're talking about
neurons changing activity, neurons in the brain is where
the interesting stuff is happening. Maybe the lower doses reflex
has more of the, you know, how hormones might
influence how likely you are to your little back
arch raise, but who knows. OK, cool. So yeah, so we talked
about in the nervous system lectures how behavior is
affected by the nervous system. Now we've talked
about how hormones can affect the nervous system,
and therefore sort of affect behavior as an output there. We're gonna do a little
preview of some areas we might see hormones
interacting in future lectures. So, stress. We're definitely gonna see
glucocorticoids associated with stress response. Here's Harry and Sirius,
looking sort of stressed. Sexual behavior. Testosterone, estrogen,
vasopressin, oxytocin. We're gonna see these things
as players in sexual behavior lectures. Aggression. Testosterone again. Glucocorticoids,
estrogen, epinephrine. Depression. OK. There's something
about that picture. All right, depression. Glucocorticoids, thyroid
hormone, estrogen, progesterone, melatonin. Great. So some things [INAUDIBLE]. Just something to
add for this slide is we're kind of throwing
a bunch of random hormones at you that you might
not be familiar with yet. Something to think about
is how every single thing we've told you thus far
regarding receptors and hormone levels and room for individual
variation and all these things, levels, where they are,
what type of receptors might influence these things. That's gonna be
kind of how we walk through a lot of
these behaviors. And then I think the
last slide is just take-home points, things that
are really excellent for you to try to walk away with. So don't walk away if
you don't understand most of these things. But steroid versus peptide
hormones and the importance of what it means
to be hydrophobic. Pretty much a lot
of the consequences for how we distinguish
between these two things depend on whether you're
hydrophobic or hydrophilic, so it makes it
pretty easy to logic through if you know
that basic thing. Whether you need the chaperone
or not, and what-- how, where your receptor
is going to be. The nervous system control
of hormone release. You guys-- I kind of hit
that into the ground. The HPA axis as one example
of how the brain could control peripheral or endocrine glands. And then finally, when
those hormones are released, how can they influence
behavior via neurons. Kind of the long trials and
tribulations of Paul Revere. A really excellent
analogy, I think. I think you guys
would all agree. And yeah, basically that's it. So if you guys
have any questions, you can shout them out, or
just come down here and ask us, because you guys have
fun things to do today. Thank you. For more, please visit
us at www.stanford.edu.
