14. Limbic System


Stanford University. OK, and– is this audible? No. It’s really quiet. Really quiet. Something’s wrong with
the sound system today. How’s that? No. How’s that? [LAUGHTER] Placebo? Maybe that would have worked? OK, well, I guess I will
just have to shout out. But– OK, help? [INAUDIBLE] [INAUDIBLE] falling off. Was I doing it–? That’s fine, yeah. OK. Good. So let’s see. That is an event you
probably should check out. I’m still irritated you didn’t
want a signed football for me, but nonetheless– OK, so, starting off, as the
large numbers of empty seats imply, not only is
Monday the midterm but today’s not a topic that
we covered on the midterm. So, in case you want to flee
right now, here’s your chance. I won’t be upset. But what we do here is
a look at our last topic of our buckets– in this
case, our neurobiology one. And the whole
premise for this one is to cover the most
wonderful, interesting parts of the brain, which you’re
going to hear squat about when you wind up in medical school. Again, from the other day,
what they will teach you about endlessly
is stuff that goes wrong with your
spinal cord or stuff that goes wrong with
parts of your brain that regulate your bladder and
your balance and motoric stuff. How come– because– Yes? You can’t hear a thing. No. No. Um– [NOISE OF HELPLESSNESS] He’s going to try to
find the sound guy. OK, somebody’s off to get sound. But in the meantime, I will
pantomime bladder problems. So what you’ve got– I will
try– maybe in the back, just start waving each time
I start hypoventilating and run out of volume. But what you’ve got here is not
the part of the nervous system that’s easy to find
out about, because it’s right on the surface. Not the part that
people focus on, because there’s a lot
of spinal-cord injuries and you can tell exactly
what’s wrong by which toe is no longer moving. This is, instead,
focusing on the part of the brain most
centrally involved in emotion– the limbic system. Now– obvious why that
should be of interest to us, more so than spinal pathways
controlling movement. And, in terms of making
sense of the limbic system, this is going to be the most
horribly, multisyllabic, diagram-laden class
of the entire class. But, in terms of making
sense of it, what we will see is there’s some very,
very logical things going on– very logical strategies. OK. Originally, the
limbic system was not known as the “limbic
system” but instead had a name reflecting the
fact that people started off studying it in rats. And you take a rat
brain, which looks kind of like this from
the side, and you’ve got your spinal cord and
cerebellum and cortex. And what is this thing,
at the way front, there? This is the olfactory bulb. This is the olfactory
system of a rodent brain. And this is drawn exactly to
scale, down to the millimeter. This is huge. This thing is huge. The olfactory bulb
and its projections are 40% of the
brain of a rodent. And when people began to
understand where the neurons in the olfactory bulb were
sending their projections, it was an area of the brain,
the underside of the brain, which people very quickly
began to call this region the “rhinencephalon”–
the “nose-brain.” Because, obviously, this
is what was processing all this whomping great amount
of olfactory information coming in. And this area that
we now know and love as the “limbic
system” at the time was called the “rhinencephalon.” This dominated, early on,
with the neuroanatomists, which is to say the people
who just sat there and said, gee whiz, that’s an awfully
large part of the brain, there. And where does it
send its projections? As people instead,
in the ’30s and ’40s, began to understand the function
of this part of the brain, what emerged was a very
different viewpoint, from a different
school, which is, it’s doing all sorts
of stuff with emotion. And this picture of
this region of the brain as having that role. For reasons I don’t
completely understand, somehow the people who liked
the, it’s all about emotion, started calling it
the “limbic system.” And thus you had one of
the most central conflicts of the 20th century, which
was whether this thing should be called the “rhinencephalon”
or the “limbic system.” And thousands of innocent
people were slaughtered before it was all over with. Brother pitted against
brother savagery. And what we’ve got– much
of Picasso’s paintings were about some of the
atrocities committed by the rhinencephalon people. But what wound up
ultimately happening was a completely
logical resolution. “Rhinencephalon,” “limbic
system”– is it about odor? Is it about emotion? And all you have to do is
think like an ethologist, and you’ve got your answer. Which is, if you’re
a rat, there’s not an emotion on earth that’s
not intertwined with olfaction. The rat’s emotional
world is utterly driven by olfactory information. And thus, for a rat, the
rhinencephalon, the nose-brain, is the part of the brain
getting all the information coming in that has
any relevance to the good, interesting, emotional
stuff going on in a rat’s life. So there’s massive resolution. Peace in their time. Suddenly, this recognition
that, of course, a rhinencephalon is going
to be sending projections– is going to be all a part of
the part of the brain that’s doing emotion for you. Now, of course, as
well-trained ethologists, you should immediately be having
a relevant thought already, which is, well,
so what’s up with the [? rhinencephalon-fame ?]
nose-brain limbic system in a species that’s not
some smelly rodent thing? In a species, for
example, that’s paying attention to an enormous
amount of, say, auditory stuff. How about all those
birds, with the birdsong business going on, or auditory
displays of territoriality, or things of that sort? And you look in those
brains, and the limbic system is not the rhinencephalon, in
terms of what part of the brain is disproportionately enlarged
and what part of the brain is sending projections
into the limbic system. Look at a bird brain, and
it is not a rhinencephalon, it’s an ear encephalon
or something or other. And you’ve got to think
like an ethologist. And suddenly you’re
in a world where something as bizarre as electric
fish, who communicate socially through electricity,
have electroreceptors which are sending a
lot of information to this part of the brain. It is not the nose-brain, it
is the, among other things, “getting whatever
sensory information is most pertinent to
my emotional life” part of the brain. So the limbic system,
initially utterly viewed as intertwined with olfaction,
now instead recognizing, as good neuroethologists,
what it’s really about. OK. So, as an introduction
to it, we need to start off with a very
simplified, quick overview of large parts of
the nervous system. You got bits of this last week. But, just to give
an initial overview, here, just to orient
what’s happening. And what we see, here–
and, again, a very accurate, technically drawn diagram–
you see the brain comes in three different pieces. And each one has
a different color. And this reflects the work of
a guy named Paul MacLean, one of the giants in the field. And everyone is required to
say his name, at this point. And this model that he came
up with in the 1950s or so– the triune brain– the
three-layer model of what brain function is about. So what you have is the most
central, ancient, archaic, most phylogenetically
conserved– which is a fancy way of saying that, all sorts
of vertebrates out there, this part of the brain
is basically the same. This is the hypothalamus,
talking to the pituitary. This is the pathways going
from the hypothalamus down the spinal-cord
areas called “brain stem,” “mid brain.” This is what MacLean called the
“reptilian” part of the brain, reflecting the fact
that our section, here, is a whole lot like the type
you would find in a reptile. This is the ancient stuff that
does the purely automatic, regulatory things. You’ve got neurons, here, that
have to tell you something about temperature regulation. Ooh, back to that
endocrinology stuff. Let’s see. What’s a hormone
that’s got something to do with metabolism, body
temperature, thyroid hormone? So you remember the hypothalamus
being part of that cascade. The hypothalamus has
a relevant hormone for the pituitary, which
then tells your thyroid gland all of that. So how does the hypothalamus
need to know what’s going on? That same feedback information
stuff from the other day. There’s got to be neurons
in the hypothalamus that can tell your temperature. And– too cold? Let’s get some more
thyroid hormone out. Great. That makes complete sense,
in terms of regulatory loops. Totally boring. OK. So this is a part of the
brain that keeps your body temperature right. It keeps your blood glucose
levels sort of modulated in some ways. It talks a lot to the pancreas. It does stuff like– it’s
monitoring your blood pressure in various places,
it’s remembering that you’re running hard,
so let’s tell the heart to beat a little bit faster. Completely boring stuff. Just robotic, regulatory
circuitry and loops, there. So this ancient, reptilian
part of the brain. Totally boring
part of the brain– until you get something wrong
with that part of the brain, and suddenly it seems
mighty interesting. Remind me– how many
of you were in Biocore? OK, lots of folks. People in there will
remember, I told you about one of the
all-time creepy diseases that you do not
want to get, which is called “Ondine’s
curse,” which is where you get some
lesions, some stroke damage, to one of these midbrain areas. This part of the brain that
does something very boring, until it doesn’t do
it for you anymore. Ondine was apparently some
Greek nymph or something that Zeus was hitting on
unsuccessfully at some point and greatly frustrated. He put this Olympian
curse on her, which was that she
had Ondine’s curse. Or maybe Ondine’s
curse was what she had to say about him in return. But what this was about
is, she lost the capacity to do automatic breathing. Whoa! That’s a drag! Automatic breathing,
in that you’re just sort of going along,
there, breathing now and then. And we do that pretty eptly,
as opposed to ineptly. And what you don’t have
to do is stop and say, whoa– this would be a good
time to expand my diaphragm, or whatever it is you do there. But you’ve got a lesion
in this part of the brain, and you lose the capacity
for automatic breathing. OK, somebody who’s
not in Biocore, tell me what do you die of,
if you have Ondine’s curse? Oop– who just mumbled that? [INAUDIBLE] asphyxiation. Asphyxiation, good. OK, and at what particular time? When you fall asleep? Yeah. Or, you actually don’t
die of asphyxiation when you’re falling asleep. How come? Because you keep waking up. You fall asleep, and
30 seconds later you wake up because you’re on
the edge of asphyxiation. You die of sleep deprivation. How’s that for one creepy
thing to have happen to you? So you can start obsessing over
that, as an eventual problem. Here’s the boring part of the
brain, this reptilian stuff. We do this part of the
brain exactly the same way that lizards do. Sitting on top of it
is the area that we now put all of our
attention and love upon, which is the limbic
system, this emotional part of the brain which we will
soon see in sickening detail. The limbic system is mostly
a mammalian invention. Birds, reptiles, fish do
not have especially complex emotional lives. Uh-oh– there’s people from
Russ Fernald’s lab in here. Do not tell him
I just said that. But– [LAUGHTER] Yeah. Not a word about it. OK. But it is mostly a
mammalian invention, greatly expanding
the limbic system, emotional complexity–
stay tuned. The next hour and a
half is about what is much more subtle
than saying ooh, this does emotions for you. Sitting on top is the
cortex, the gleaming, analytical machine of cortical
function and cognitive expertise that we have. This is something that all
sorts of species out there– fish and birds and– not bees,
but birds and almost bees. And what you got there is one
that nonetheless is greatly expanded in
vertebrates and mammals and greatly expanded,
even more so, in primates and even more so than in us. And, as we will see, one
area of the cortex which is really very uniquely
human and very intertwined with the limbic system. As we’ll see, what is critical
in making sense of the cortex, with respect to all this
stuff– this limbic, emotion, behavior
stuff, and everything coming for the rest
of the course– is the rumors of
the cortex being this rational, independent,
analytical part of the brain that goes about its
business while all this hormonal-emotional muck
is going on south of it, is completely wrong. All sorts of aspects
of cortical function are being influenced by
hormones and thus, indirectly, under the regulation
of here, all sorts of aspects of cortical
function are being influenced by the limbic system. And all you have
to do to appreciate that is think back on times
of extreme emotional duress and arousal where you made some
incredibly stupid decision that seemed like a brilliant
idea at the time. Therein is proof that
your limbic system is able to influence
decision-making going on up in the cortex. And, as we will see, of
great relevance to us as a fancy species– the
cortex has vast ability to influence stuff
going on below there. And all you need to do to
prove that is sit and think about the fact that you are
not going to live forever. And suddenly this
part of the brain is going to be kicking out
CRH and things like that. And you’ve just done
it with thought. There’s bidirectionality
that completely does in the notion that–
here’s the emotional part of the brain, here’s
the cognitive part. And that’s completely,
completely wrong, that they’re separable. Major figure in the
field– a guy named Antonio Damasio, who’s probably
the best thinker about any of this stuff, had a
book a number of years ago called Descartes’ Error. Descartes, who
saw that there was this great potential separation
between thought and emotion. And that’s complete nonsense. So, starting off merely on
an anatomical level– which is to say, which neurons where
are sending axonal projections where else– tons
and tons of cross talk between the limbic
system and the cortex. OK. So we now have this
utterly undefined mass of limbic system. And we also have a
tabula rasa there. But– here it is. OK. But what you’ve
got is, of course, subparts of the limbic system–
subparts out the wazoo. There are people who spend
their entire lives arguing about whether this subsubnuclei
of this part of the brain should logically be
considered as having seven subparts or eight subparts. Extremely complicated
part of the brain. And what we’ll been looking
at, here, is the circuitry. The circuitry, and what
each individual subregion of the limbic system does. All of this got sorted
out in the 1930s or so by a neurologist
named James Papez. And I think there remains
enormous controversy over whether his name is pronounced
“papes” or “pap-ez.” But probably neither is correct. But what you wound up getting,
as a result of his work, was the first person
to begin to think in a systematic way of,
hey, all of these structures in that old rhinencephalon
part of the brain– all of these structures are sending
projections to each other. There seems to be some organized
module of interconnected function. And it was around
that time that people began to be seeing what
some of the effects were, what some of the roles of these
were– behavior– and suddenly out comes the– this is the
emotional part of the brain. And the circuitry that’s
since been delineated is known as the “Papez circuit,”
or the “Pap-ez” circuit, or the whatever the
guy’s name was circuit. And we will see that shortly. He was the first person
to begin to see, just on the level of
connections, that this is an area that
seems to be doing a lot of interrelated functions. Quick definition. What do we mean by
“doing connections”? Again, back to last
week’s introductory stuff, a connection, a
projection– neurons in this part of the brain
are sending their axons to that part of the brain
and forming synapses there. This area projects to that area. So where are the projections? Where are the
connections to translate this neuroanatomy
concept into sort of the most accessible level? What parts of the brain
are talking to this region? And what parts of the brain
is this region talking to? Where are the axons coming from,
and where are these neurons’ axons heading off to? So, circuitry, in that regard. So this is going to be an
enormously complicated circuit. But, at the end
of the day, there is one way to think about
it, which is unifying, which clarifies
everything, which is the thing that every
single nucleus and subnucleus and subsubnucleus in the
limbic system– the thing that everything in the
limbic system wants to do is tell the
hypothalamus what to do. The entire limbic
system is structured around trying to influence
hypothalamic function. There’s all those connections
going to the cortex and other areas, as well. But, for a first pass,
the way to conceptualize the limbic system is,
it tries to influence what the hypothalamus is up to. Why would that be interesting? You know that, from last week. Hypothalamus is the
central hub for all of that neuroendocrine stuff. And thus the entire
world of your brain wanting to influence behavior
and emotion in any sort of endocrine
context– you’re going to have to be talking down here. From earlier last
week, hypothalamus also playing a pivotal role in
the autonomic nervous system coming down the spine. The whole world
in which emotions change how your body works is
all about the limbic system telling the
hypothalamus what to do. And thus what you see is,
all the circuitry in here is built around
trying to influence hypothalamic function. In a certain way, as follows–
which will make perfect sense. Which is, what every single
area of the limbic system wants to do is tell the
hypothalamus what to do. And in addition, the other
thing that it really wants to do is make sure no other
part of the limbic system is telling the
hypothalamus what to do. And thus you’ve got
all sorts of areas with means of stimulating
regions of the hypothalamus and inhibiting the activity
of other limbic regions. So you’ve got all
these patterns, here, of stimulating down
there, inhibiting here– all built around these different
regions wanting to influence hypothalamic function. So amid it being a total,
complete mess of circuitry, one rule helps you begin
to sort out the details. Which is, OK, so you’ve got
this area of the limbic system, and it wants to influence
the hypothalamus at the end of the day. How many synapses away
is the hypothalamus? How many neurons are
intervening between this part of the limbic system
having something to say, getting action potentials,
and influencing something [INAUDIBLE] hypothalamus? This winds up being a
pretty good rule of thumb, in terms of looking
at influence. You send a projection straight
into the hypothalamus– in other words, you
are one synapse away– and you’re going to be having
a lot more control over what’s going on there than if you
have to send a projection here, which sends one there and
there and bouncing around, and 14 synapses later
you’re influencing hypothalamic function. How come? Well, for one thing,
one synapse away you’re going to be a lot faster. And the other reason being, if
there’s 14 synapses in between, everybody downstream
of you is going to have their own
opinion about things and it turns into a
game of Telephone. The most direct
way of influencing hypothalamic function is
to have as few synapses in your projection as possible. And thus what you see
is, most limbic regions have a number of different ways
of getting information down to the hypothalamus,
and they differ in the number of
synapses, and thus they differ in their power. And what we’ll see is
just one example, here. Ah, we’ll do that later. OK. So, lots of examples of that. Just to give you a sense about
something interesting in us, in terms of this rule of
how many synapses away. So we’ve got this limbic
part of the brain. And back to that rhinencephalon
business– that, you know, rodents are super olfactory
and fish do whatever they do. And, again, don’t tell Fernald. And all these other
species have their– And we’re not a particularly
olfactory species. Here’s something interesting. Every single one of
your sensory modalities has to go through a minimum
of three or four synapses to first plunk
down any influence in the limbic system– except
for our olfactory systems, which are one synapse away
from the limbic system. So even us, we are not
terribly olfactory, and we’ve got atrophied
olfactory bulbs. That’s a rat. Our olfactory system takes
up less than 5% of our brain. Nonetheless, olfaction
is one synapse away from the limbic
system, telling you something about
that whole world, that visual information
can tell you a lot about calculus equations. Olfaction is the thing
that flashes us back to some emotional setting. That’s the reason for it. Great example of this “counting
the number of synapses” strategies. The fewer synapses,
the more influence. So, what are the structures
of the limbic system? First pass–
unfortunately, it is going to make sense to
learn all the details of these different subregions,
because you will be hearing about all of them again. You won’t be hearing
about them Monday night, but you’ll be hearing about them
all in the next month or so. And so learn the stuff. OK. So, what’s going on
in the limbic system? What is inside here? What we’ve got are
the major structures of the limbic system. Sitting in there, you
recognize the pituitary. And thus sitting right on top
of that is the hypothalamus. And here we have all
these other regions. First off– the amygdala. The amygdala– I have
already mentioned it a number of times in class. We will hear details
soon about what it does. You’ve already heard
some intimations of it. So the amygdala is this
cluster of neurons– beginning to get another
anatomical concept, here. You’ve got nuclei– clusters
of neuronal cell bodies– and you have projections–
areas of lots of axons. So you will have a whole
lot of cell bodies here and sending their
projections off there. You will wind up seeing this as
a densely packed area of cell bodies. Each one of these areas
I will be mentioning now are areas where the
cell bodies are nuclei. Interesting elaboration. As you also learned
last week, one of the things that makes action
potentials go really fast is that business about
myelin– myelination. These are very membranous
wrappings-around. Membrane– very fatty,
membrane lipid stuff, which happens to
be white in color. Cell bodies tend to
be grey in color. And this is where
the dichotomy comes in brain science between
grey-matter and white-matter parts of the brain. Grey matter are nuclei–
cell bodies, packed in there. White matter are cables of
axons going from one place to another, wrapped in myelin. So, just translating
that into sort of terms that we’re familiar with. OK, so, starting off– the first
nucleus of the limbic system, the amygdala. The amygdala– if you
study neuroanatomy, most of these places
come with some terms derived from Latin or Greek
or something or other. And the amygdala–
“amygdala” means “almond.” It means “almond.” A number of years
ago, I reported that it means “peach pit,” and
that turned out to be wrong. And I was also wrong as to
whether it was Greek or Latin. And I probably
should have written that down from two years ago. But, from some stupid
old classic language, this means “almond.” And it looks like an almond. OK. Next, we have, in front
of it, the hippocampus. Hippocampus, which we will
hear lots about, as well. And you will see
the hippocampus is a big structure spanning over
there relevant to its function. “Hippocampus,” Latin
for “seahorse.” But if you look at
the hippocampus, it doesn’t look at
all like a seahorse, suggesting neuroanatomists
don’t go out to the beach anywhere near as
often as would be a good idea. It actually looks
like a jelly roll. But people who spoke Latin
didn’t know about jelly rolls, and thus they had
to– seahorses. So you’ve got the
hippocampus, here. We will shortly be seeing
how these two communicate with each other–
where the axons are going between these nuclei. Next, an area
called the “septum.” And there’s a number
of septums in the body. “Septum” is a term for
a midline structure. You have a septum separating
the two nostrilly parts of your nose. The center of the four chambers
of your heart is a septum. “Septum,” here, is
a structure that’s right at the midbrain– at
the midline of the brain. Then we have, just tucked
behind the hippocampus, something called the
“mammillary bodies.” Yeah, you gotta
know these terms. You will eventually
be so, so grateful for having all this stupid
terminology under your belt. It will make the rest of
your life far, far richer. OK. So you’ve got
mammillary body here. Sitting on top of that is a
remarkable structure that you probably could have
intuited was there, because you know about
the hypothalamus. “Hypothalamus”–
what does that mean? It means it’s the thing
that’s under the thalamus. I bet you there’s something
a little bit north of there called the thalamus. And here it is. Which is possibly also known as
the “hypersuprahypothalamus,” but instead it’s known
as the “thalamus.” And we will see some
stuff that it does. Next are two very
interesting areas, which we will hear tons
about in lectures to come– in particular the lectures on
depression– a region called the “ventral tegmental area”
and a region called the “nucleus accumbens.” Every one of these
is in the handouts. Don’t freak out about trying
to get down the terms, at this point. Just at least get
the abbreviations. Here are the major players
in the limbic system– with one addition. And this is one that bedeviled
the field for a long time and reflected a very, very
great piece of insight. A neuroanatomist back– who
sort of was in his prime in the latter part
of the last century– a guy named Walle
Nauta, a Dutch guy who was arguably the best
neuroanatomist of the last half of the 20th century. And in the 1950s, studying
neural connectiveness, what he came up with was
a totally nutty idea. Because, at that point,
we were about 20– “we”– were about 10, 20 years
into the limbic concept. These are subcortical
areas involved in emotion, and they all send
projections to each other. And Nauta, based on looking
at the anatomy– what parts of the brain were sending
projections where, what parts were getting projections
from where– Nauta said, one part of the cortex
should actually be classified as part of the limbic system. Oh, this was heresy! He was driven out of
the neuroanatomy club. And he was insisting that
this made sense, anatomically, and predicted it would
make sense, eventually, functionally. And he was totally right. The most interesting area
of the cortex– a region called the “frontal cortex.” Also known as the
“prefrontal cortex.” An obviously real
distinction there. We will ignore that distinction. An area– the frontal
cortex, including a subarea called the “anterior cingulate.” This is a part of
the cortex which is intimately
interconnected with all these subcortical regions. It is arguably the cortical
component of the limbic system. Why is that the case? We will see, amid lots of
cortex [INAUDIBLE] stuff, like, telling you, is it here
that you were just stimulated, or was it there? Did somebody just play
an A or an A flat? Which limb do I want
to move right now? All sorts of
nuts-and-bolts stuff. How do I do long division? All those things. The frontal cortex has this
world of utterly un-cortex-like things that it’s interested in. Emotional regulation, impulse
control, long-term planning, gratification postponement. It is, without question,
the most interesting part of the brain. And I say that as
someone who’s just spent, like, the last 30
years of my life just obsessing over the
hippocampus, and I was wrong. I mean, the hippocampus
has done well by me. I have been faithful to it. But nonetheless it has
struck me, more and more, that this is where I should
have been sitting, because this is oh so much more
interesting part of the brain than some dumb old area that
remembers stuff for you. Frontal cortex is what makes
us most definedly human. It is proportionately
larger in humans than in any other species. It is the most recently evolved. Something that we will
hear about in coming weeks is, it’s the last part of
the brain to fully mature. Most of you in here
do not yet have a frontal cortex which
is fully online– which is an amazing thing. Frontal cortex isn’t
fully myelinated until in your mid-20s,
on the average. This is not– oh, you
were born with all these neural connections. This is a part of the brain that
does impulse control for you. And it is not working yet very
well, in most of you guys, for a while to come. I don’t know what this
explains, but it no doubt explains a great deal. This is an incredibly
interesting part of the brain which has
nothing to do with– oh, let’s turn that
sensory information into a three-dimensional
map, and I could recognize whose face it is. And this instead is a cortical
area utterly intertwined with what’s going on
in the limbic system. One interesting
measure of it, which is looking at this frontal
part of the cortical brain. And an interesting
measure, worked on by a guy named Ian Dunbar some
years ago, looking at, by now, about 150
different primate species. And, in each one, asking,
what percentage of the brain is made up by this
prefrontal cortex? How much of the brain
is devoted to it? And what he showed, across 150
different primate species– the single best predictor of
how big the frontal cortex was going to be was, how large
is the average social group for this species? In other words,
you sitting around in some species where
you’ve got to keep track of three other people in
there, or you live in a species where there’s 150
individuals in your troop. And the latter species is
going to have proportionally a far bigger frontal cortex. What this suggests,
on a certain level, is, this utterly defining
part of the brain evolved for gossip
and social relations and appropriate behavior
and social intelligence and all sorts of
stuff like that. Truly interesting
part of the brain, utterly intertwined with the
traditional limbic regions. So this Nauta guy was
completely correct. OK. So, now adding in the
next layer of miserable factoids you need to have, which
will show the same principles I’ve been talking about. Which is how these areas
connect with each other. At this point, it
has basically been shown that every limbic region
projects to– sends axons to– some other limbic region. I’m just going to put in some
of the main pathways, here. First one, called the
“amygdalofugal pathway,” which carries information back
and forth between the amygdala and hippocampus. Amygdaloid neurons projecting
to the hippocampus, hippocampal neurons
projecting back. And, as we will
see, an awful lot of what the amygdala is
involved with– I think I’ve mentioned
already– fear, anxiety, learning to be afraid
of particular stimuli. A lot of what the
hippocampus does is help you remember stuff. This connection between
them is critical when you are learning that every
time the guy– the Russian guy with the beard–
puts the light on, you’re going to get
a shock, and then you’re going to have to salivate
when he tells you there’s food coming. What the amygdala is doing there
is hijacking the hippocampus at that time to have hippocampus
do some memory formation for you about a
fearful stimulus. So, interconnections there
that are extremely important. Next we’ve got hippocampus
needing to talk to the septum. And it does so with a series
of projections– bidirectional, again– called the “fimbria
fornix.” “Fornix”– here’s showing just how much fun
neuroanatomy can be. “Fornix” is from Latin or Greek
or whatever for “arch,” and apparently it comes
from referring to the Roman Colosseum. And supposedly this is the
origins of another word. That, during
classical Roman times, this is where
prostitutes would be. So people who would say
they were going off there would be going off to the
arches– off to fornicate. That’s the origins of that. So isn’t this such
a cool subject? So here we’ve got the fornix,
there, completing this arch. Hippocampus talking to septum. Septum then sending
a huge projection, coming down to the
hypothalamus, back on to the mammillary bodies. And projections going
back this way, as well. A major, major limbic pathway
called the “medial forebrain bundle.” OK. Just to make things
more complicated, now, we now have
another projection from the amygdala that goes
straight to the hypothalamus. And this is a total pain. This is a pathway called
the “stria terminalis.” And, by all logic,
what it should do is go from here to there. No, that’s not what it does. Here’s what the stria
terminalis does. It starts in the
amygdala, and it goes looping just on the
outside of the hippocampus, around this way, and
lands back there. What’s up with that? That is ridiculous. What you see, here,
is a principle about a lot of this
neurobiological wiring stuff, which is, you get
totally nutty, inefficient, you know, going out through
left field projections. How did that happen? What that tells you is, at
some point, embryologically, these two structures were
not so close to each other. And part of the
embryonic development involved flipping
over like this. And suddenly the amygdala
is right next door, long after it made the most
efficient possible connection by way of this. And now you’ve got this
completely nutty way to get around there. So often you see really
inefficient pieces of wiring, here,
telling you something about embryonic development. Some of the time, you also
see nutty pieces of wiring telling you something about
the evolutionary history of this nervous system. Here’s one example–
and this is one outside of the limbic system but
great demonstration of this, having to do with some
motor systems in the brain. OK. You’re here, and you
decide what you would like to do is bend this one finger. What would be the logical thing? Some part of the cortex up
here involved in motor control that we’re not
interested in should send a message down to
this finger saying “bend.” No. That’s not what happens. One part of this
motor system called the “pyramidal nervous system”
sends a message to all five of your fingers
saying “do this.” Meanwhile, there’s another
motor system called the “extrapyramidal system”
that quickly sends down a signal and says, if you happen to
hear the pyramidal system tell fingers 1, 3, 4, and 5 to bend,
don’t pay attention to it. And suddenly you’ve
got this going on. Like– what is
this– a committee that came up with this? This is totally crazy,
inefficient wiring– until you think about the
evolution of the system. As follows, there’s not a
whole lot of species out there that have a need, in terms
of reproductive success, to play trills on the piano. There’s not a whole
lot of species that have to do independent
movement of fingers. The basic wiring of
this motor system is one of this crude, pyramidal
system of just sending messages down the line, there. Extend claws, retract–
all that sort of thing. And along come primates and
raccoons and a few other things that suddenly get
it into their heads to move fingers independently. So you’ve got a
choice, at that point. You can either renovate
the entire pyramidal system and rip it out and rewire so
that each finger is controlled independently. And that’s never going to
work, because, you know, the contractor doesn’t show up,
and it’s been a million years. Or what you do is,
you have to come up with a second, newer system
that’s superimposed on top. Totally ass-backwards,
inefficient way of doing– what
does that tell you? The extrapyramidal system
is more recently evolved. It is more of a primate system. And that’s where you
get the fine control. What you often see is bits
of really clunky wiring and regulation– tells you
things about embryonic life, and it tells you
about evolution. Back to this
classic quote, which is “Evolution is
not an inventor, evolution is a tinkerer.” It is just playing with
what’s already there and trying to come up
with something better. That was the idea
from lectures ago. Which, all things
considered, squid do not swim anywhere near
as fast as barracuda. But for something that
used to be a barnacle, they’re pretty good swimmers. You have to realize
where things started and where the
adaptations came from. OK. So, more wiring. And now we’ve got the mammillary
bodies talking to the thalamus. The mammillothalamic tract. And then you’ve got the
thalamus talking bidirectionally with the frontal cortex. So you begin to see
the starts, here, of kind of a looping circuit,
and going bidirectionally– all of that. Two additional areas–
this ventral tegmental area and this nucleus accumbens. Ventral tegmentum sends a
lot of information here, and from on there it goes
to every single place. And we will eventually
see great relevance of that bidirectionally. OK. So, horrible circuitry. What you should already
see is one example of what I was telling you
about, before– counting number of synapses. So you’re the
amygdala, and you want to tell the
hypothalamus what to do. You’ve got a choice. You can do it by way of this
stria terminalis thing, which is one synapse away. Or you could do it by talking
to the hippocampus, which talks to the septum, which
talks to the hypothalamus. Where’s the most important
stuff coming out of the amygdala to the hypothalamus? By way of this stria terminalis. What’s this communication about? A lot of the time,
it’s the amygdala trying to get the hippocampus
to shut up so the amygdala can dominate hypothalamic events. That begins to show
this principle of, how many synapses away? So we have all of this
incredible wiring, here. And, again, every
single one of these, there’s other minor
ones there, as well, and they all interconnect
with each other. But these are some
of the major ones. Does this make sense? How about now? [LAUGHTER] OK. So, that’s the limbic system,
in terms of basic wiring. So what everyone
needs to do now is spend the next five
minutes filling in what those abbreviations were for. And then we will finally get
past this stupid A sends to B and begin to look at function. OK, so, five minutes. OK, so, pushing on. Good question that just came
up, relevant to Biocore people. So what I just
said– that business about the olfactory
system is one synapse away from the limbic system–
isn’t it hopefully amazing? Remember Biocore stuff– that
business– the visual cortex, the first layer that does
dots, the second layer does lines, at certain
angles– that’s where you’re getting
all the synapses coming in which delay you from
getting information into there. Auditory system has the
same multilayer processing. Tactile– all of those are like
that, except for olfaction. That drops its first signaling
right off into the amygdala. So very, very
different circuitry. OK. So, now, finally
getting to function. So how do you figure out the
function of the limbic system? A bunch of different
techniques– bunch of different
experimental techniques. First, you have
the greatest thing that has been most
helpful in all of the history of
neuroscience in understanding how different parts of the brain
work, which is endless warfare. Because what that
gives you are people who have had parts of their
brain blown out of the water, there. You have– nice
jargon– missile wounds. So, after every big,
good, fun, energetic war, all sorts of neuroanatomists
get their careers, like, jump-started
for years afterward, studying people who have had
parts of the brain lesioned, damaged, destroyed by
circumstances like that. But, you know, any old
time, neuroanatomists are delighted to get
ahold of somebody who’s had a brain region damaged. There’s one guy, in fact–
everybody has heard of HM, I suspect. Anybody not heard of HM? OK. So you’ve all heard of HM. There’s another guy– NA. NA his septum taken out. And what happened to NA? All that it ever says
in the literature was that he was at a wedding
and his septum was destroyed by a miniature fencing foil. [LAUGHTER] That’s it! That’s the literature
on what happened to NA. So NA, you know,
was a draft dodger in endless different
wars, and then he gets done in by his,
like, sister-in-law’s wedding kind of thing. But lesions–
lesions are critical. So human studies, where you
have had accidental damage to brain regions. Or the rare,
horrifying world where there was damage done to
human brains intentionally. Back to class 1– the
frontal-lobotomy business. Just to clarify–
frontal lobotomies, in its classic form,
was not lesioning the prefrontal cortex. It was just putting
a big-ol’ cut somewhere through there that
took out limbic structures. Given the fact that most frontal
lobotomies were being done, I kid you not, with
an ice axe– that was the tool of choice
for the neurosurgeons– this was not a very
precise surgical technique. But it was taking out all
sorts of limbic structures. So the rare world of
intentional lesions in humans, HM being the rare version
of that, where it was done for a valid clinical reason. Much more often in
the lesion world is taking experimental
animals, where you go in and you selectively
destroy some region. And the strategy, whether
in humans or animals, is absolutely
obvious, which is, OK, if we destroy this part of the
brain, what doesn’t work right anymore? Ooh, we’ve just found
out something about what that part of the brain does. Next strategy– classic one. Now, instead of
lesioning a brain region, you put down an electrode where
you stimulate that region. You artificially generate
action potentials there. This is a brain region that
gets projections from here, and this region is not
saying anything whatsoever. There are no activity here to
send action potentials there. Nothing’s happening. And what you’re
doing instead is, by sticking an electrode
in there and stimulating, you are simulating
an input, there. Stimulate, and now
see what happens. Ooh, we’ve just
learned something about that part of the brain. Rarely done with humans,
except for epileptics with severe types of
intractable epilepsy where a certain
type of neurosurgery is done to correct it. And it’s often quite effective. On the way down, the
electrodes, going down– often, the neurosurgeons
stimulate on the way down, to be assured that they’re
in the right place. OK. Next version. Now, instead, you put down
an electrode, and that one’s a recording electrode. What that one is telling you
is– so you’re down in here– when are these neurons
getting electrically excited? Or, putting it in here, when
are action potentials pulsing through this part of the brain,
picking up what’s going on? And what really
winds up being fancy are people who, for example,
can put a stimulating electrode down here and a
recording electrode there– that sort of thing. There’s a whole world of
incredibly adept people who could record from one
single neuron at a time. Or how’s about this? Back to those
neurotransmitter receptors coupled to an ion channel,
an ion channel that opens up, and stuff goes in or out. There is a technique
called “patch clamping,” where people can record from one
single ion channel at a time. Which is just madness,
that people could do this. But, in terms of the resolution,
all of these techniques artificially get neurons
excited, electrically. See what happens next. Put in a recording device to
tell you what’s happening. And thus you begin to
do things like, ooh, every time I do
this with my hand, these neurons get
action potentials. We’ve just learned
something pertinent, there. What else? Another realm of techniques
you’ve already heard about, which is this plain
old, boring anatomy. Which part of the
brain sends axons to this part of the brain? How many synapses away? All of the means of
deriving information that we heard about before. So that’s the whole world of
just looking at the circuitry, telling you about
function from that. Then, of course, there’s a whole
world of biochemical stuff. You are measuring
levels of things. You are measuring levels
of neurotransmitters. Molecular biology– seeing
where different genes are being expressed. If you see genes that
are only expressed in this part of
the limbic system, under some circumstance,
you’ve just learned something about its function. All that sort of thing. Finally, a world where you
could do really interesting, trendy stuff with humans,
in terms of seeing what’s up in the limbic system. Where what you do is, you
can image brain regions. And this is now a whole
world of– instead of sitting around, waiting
for somebody to die, and slice their
brain up afterward, instead you could do imaging–
CAT scans, CT Scans, MRI– where you see the areas of
different parts in the brain– how big or small they are. You can look at
the metabolic rate in certain areas of the brain. Which is sort of the
equivalent of recording. Stick in an
electrode, and you can tell what’s happening
here by when there’s electrical excitation. Use functional brain
imaging, and you can tell what’s
happening here by, when suddenly there’s more
oxygen or glucose being consumed, here– Same sort of information. With the imaging,
though, you’re getting a picture of the entire
brain all at once. And one of the
cool things that’s come out of those
studies is showing that some regions of the brain,
particularly the limbic system, will change their
size over time. One example which
I think we’ve heard about already, which is that
the amygdala gets bigger in people with posttraumatic
stress disorder. Severe, severe traumatic
history, and this part of the brain expands. People with PTSD–
amygdalas are larger. You look at the metabolic
rate in the amygdala. People with PTSD, it is
more metabolically reactive than other areas of the
brain or than in people who don’t have PTSD. So that’s just told you
something interesting. Nice cellular basis of that. Periods of severe
stress cause neurons in the amygdala to grow
more dendritic processes. That’s probably why the
amygdala gets bigger. So that’s the sort of
thing that gets picked up on humans, with brain imaging. Another version, over
in the hippocampus, just as pertinent to some of
the stuff we will hear about. People with long-term,
major depression. Their hippocampus gets smaller. Their hippocampus
atrophies a bit. And the same sort of
information being picked up. You see an area
of the brain that is plastic enough, that is
malleable enough, that its size will change in response to
certain types of experiences or emotional states. You just learned something about
what that part of the brain does. So that winds up being
extremely informative, when there’s differences in
the size of different brain regions, in response
to experience. OK. So that’s generally
the set of tools that are available to people
trying to figure out what’s going on in the limbic system. And all of these tools come
with some important limitations. These are limitations if
what you’re trying to do is figure out what this
part of the spinal column does instead of that
part, because you need to figure out– all
sorts of caveats in there. If that’s hard, it is a
gazillion times harder to use some of these
techniques to make sense of emotion and
emotional memories and things of that sort. What are some of
the difficulties in interpreting data from
all the results we just heard about? Here is one problem. OK. Every day, unbeknownst
to you guys, there are two to three
dozen huge tractor-trailer trucks that start
at dawn from Gilroy and bring us our garlic that is
used in all of the dorm dining rooms. Every single morning,
that happens. Thousands of pounds that
are consumed in the dorm. And you are trying
to understand where in California is the
garlic-generating center, the garlic nucleus. And what you’ve been
selectively doing is carpet-bombing certain
areas in Northern California. And, as a result of
a direct hit on 101, no more garlic shows up
at Leland Stanford Junior University. So what have you just concluded? 101, somewhere right
around Laser Quest, is exactly where the center
is for producing garlic in Northern California. And that’s the only plausible
scientific conclusion you can reach. What we have here is
the problem of centers versus fibers of passage. Have you just, in
a lesion study, found out something
about a region? You’ve destroyed
it, and something doesn’t work normally. Is that because you’ve taken out
the neurons, the cell bodies, in the true center? Or have you inadvertently
cut a fiber passage? Have you blown out 101– And endless mistakes
made over the years. Early on in neuroanatomy,
people failing to distinguish between
lesions of nuclei versus lesions of pathways. What really winds
up being hard is when you have nuclei with cell
bodies and, at the same time, fibers passing through
from someplace else. That’s what this medial
forebrain bundle is about. Cell nuclei all
over the place, but, at the same time,
fibers passing through. When you do a lesion
in a place like that, you can’t tell whether it’s
the cell bodies, the nucleus aspects, the center
that you’re taking out, or whether you have just
taken out a fiber of passage. Enormously difficult
stuff to do. OK. So that’s one constraint. Once you get through that,
and you’ve figured out, ooh, this really is the
center– this really is the cell bodies, rather
than just the axons– then you deal with
this issue of, what does a “center”
mean in the brain? Yeah, this may be
the center– the part of the brain that moves this
finger instead of this one. That may be a pertinent concept. Ooh– this is the center of
the brain for feeling depressed amid a bittersweet gratitude
for the unexpected pleasures of life, which are felt
in a poignant context, making you smell memories of
the kindergarten classroom you were in. Oh! That’s the center of the
limbic system for that. By the time you’re getting
to a part of the brain that’s doing all this emotional
stuff, intermixed with sensory information,
intermixed with memories, even the concept of, oh, this
is the part of the brain that does fear for you, this is
the part of the brain that does aggression–
as we’ll see, these are some pretty flimsy concepts. OK. More qualifiers. The next thing you
need to be, in order to be a good neuroanatomist
and make use of the information from these techniques, is
to also be an ethologist. We already heard
a version of that. The rhinencephalon–
that’s what’s going on a species that’s
all about olfaction. You can’t understand the wiring
going to the limbic system unless you have interviewed
an animal in its own language. Classic need for ethology. OK, so here would be
another demonstration. You have found a part
of the brain which you think is interesting. It’s a limbic structure. Nobody quite knows what it does. And you have now just stuck
a stimulating electrode down in there. And the strategy
is, you’re going to mildly stimulate
there, and you see what happens in the organism. So your first study
subject is a lion, and you’ve stuck your
stimulating electrode down in there. And you mildly stimulate
this part of the brain. And what the lion
does is it does this. It extends its claws. Now your next
subject is a human. So you sit down, you plunk down
your stimulating electrode, and you stimulate mildly in
that same part of the brain. And the human says “Shit.” So what part of the brain
have we just found, here? We have found a part
of the brain that plays a role in expressing a
certain degree of irritation. And if you are a
lion, you’re sort of extending your claws, there. You probably want to
stop messing with me, because look what
I’m doing right now, and look how sharp they are. With the human,
another ver– you’ve got to know your species. Another example of this. So here’s a part of
the brain, and you’re wondering what’s up with this. You do the same strategy. You stick in the
stimulating electrodes. And you do this to a rat. And what she does is proceed to
run around her cage like crazy and take pieces of newspaper,
rip into little pieces, and stuff them in the corner. OK, that’s an interesting
center of the brain. Then you do the exact same
thing to a rhesus monkey. And what she does is grab any
sort of cylindrical object around and hold it in
her arms, by her nipples. Oh– maternal behavior. First case, you got
a rat making a nest. Second case, you were
stimulating nursing behavior. Ah! OK, you’ve got to
translate it into what it looks like in the species. And here’s one domain where that
went utterly, utterly wrong. Part of the hypothalamus
which people used to think had everything to
do with aggression. Because, for example,
here you would take a stimulating
electrode in a rat. And you put a mouse in
the same cage as the rat. And you stimulate that part
of the brain of the rat. And the rat leaps on the mouse,
trying to rip it to shreds. Now you take a human,
and you stimulate that same part of the brain. And they leap up and run over to
the cereal box and rip it open and start eating. What’s up with– oh! Rats eat mice. That’s what the– that
was not a rat being angry, that was a rat getting
something to snack on. And you had to recognize
the difference between what does aggression look like
in that species versus what does food acquisition. And if it’s a
predatory species, it could pass for looking mighty
aggressive and not actually be. A whole generation
of people, thinking they were understanding the
neurobiology of aggression, inadvertently made this
mistake and wound up studying the neurobiology
of predatory behavior. So you gotta know your species. Ethological principles. Next, you’ve got to
know your individual. So here, now you’ve
got two lions, and you stick in your
stimulating electrode into the first one. That same region, again. And you stimulate, and he
does the same deal again. Or suppose you even
stimulate it more, and he does this
a bunch of times, and then he roars savagely. Meanwhile, you stimulate the
same area in the second lion and nothing happens at all. You take two baboons. You stimulate that
region in the first one, and he gives this big threat
yawn, displaying his canines. You stimulate it in
the second individual, and nothing changes
in his behavior. What’s the difference? Any speculations? Dominance. Yes! Dominance! Here, in the second
case– in the first case, you’re doing it to a
dominant individual. And they do their
fixed action pattern for their species of
expressing aggression, dominance, whatever. But you do it to
some subordinate guy, and that’s not part of
his repertoire right now. And even though that’s the
part of the brain that “does” that behavior, it is tightly
inhibited in that individual, because that’s not
an individual who goes around
displaying his canines to a whole lot of his buddies. You have to know the
individual, as well. So, given all of
those constraints, that tells you, if you’re
going to understand what’s up with this part of the
brain, and the difference between fibers and
nuclei, and don’t get overly impressed with the
notion of centers of function. But you gotta do
the ethology stuff. Here, more than any
time that we’ve seen, you gotta understand the
species and the individual that you are interviewing
with your electrodes. OK. So, given all of that, what
do some of the limbic system structures do? This is a first, insanely
simplifying pass, because every one of
these areas you’re going to hear about oh so much more. But a very first pass. And you notice, as
part of the first pass I’m going to be violating
the caveat that I just gave two minutes ago, in that,
on this first pass, here, I’m going to be presenting
these as the center. This is the part of the
brain that does this. We’re going to see how
totally wrong that is. Nonetheless, on a first pass. Amygdala. Amygdala is centrally
involved in fear and anxiety. You know this already. Of tremendous
significance, telling us something about why this world
is such a messed up place, the amygdala also plays a
central role in aggression. Not messed up just because, ooh,
this is the part of the brain that generates aggression,
but what it tells you is, you cannot understand the
neurobiology of being violent without understanding the
neurobiology of being afraid and being anxious. And the fact that this is
the same part of the brain that “does” both
of those functions, suggesting on a certain
neurobiological level in a world in which no
neurons need be afraid, you’re not going
to be generating a whole lot of aggression. Also very interestingly,
what we will hear about is, the amygdala also plays a
role in male sexual motivation. What’s that doing, going
through the amygdala? Not sure whatsoever,
but what that may begin to explain is the
subset of the individuals who will confuse aspects
of aggressive behavior and sexual behavior in all
sorts of pathological ways. First pass of what
the amygdala is about. Meanwhile, next door we’ve
got– OK, not “next door,” but two synapses away–
we’ve got the septum. Showing a first
important example of this theme in
the limbic system, amygdala mediates aggression. Caveats, all of that, we
got the fine print now. The septum inhibits aggression. It does exactly the
opposite, beginning to present a theme
throughout the limbic system of different subareas
working in opposition. What would you be logically
betting the farm on right now? When the amygdala is activated,
it tries to silence the septum. When the septum is activated, it
tries to silence the amygdala. Cross-inhibitory projections. So what would these
things look like? You destroy the
amygdala of an animal, you never get aggressive
behavior again. You record from it when it’s
smelling some scary rival. The amygdala activates,
you stimulate, and it does an
aggressive behavior. You could begin to see
how you figure this out. Next, hippocampus. Hippocampus, famous
for being involved in learning and memory. Important for us,
as well, hippocampus plays a role in turning
off the stress response. You remember that
negative-feedback stuff from two days ago. Every endocrine
system, there’s got to be a part of the
brain that measures the hormone in the bloodstream
to figure out what should the hypothalamus be doing. The hippocampus measures the
levels of glucocorticoids. Why should a part of the
brain that does memory be so intertwined with stress? Very logical in two ways. Number 1, here’s a stressful,
horrifying, scary circumstance. Remember what you did to
get out of this, if you do manage to get out of this. File this away very,
very emphatically. Second thing that it’s good
for is, stressful circumstance coming up. What did I do last time to
get out of this circumstance? So, an intertwining between
a memory part of the brain and a relationship with
stress hormone regulation. Next, mammillary bodies. Has aspects relevant
to maternal behavior. And that’s not why it was
called the mammillary bodies, but they’re shaped by,
like, mammary glands. If you, once again, don’t
spend a whole lot of time or look too much at seahorses,
but the mammillary bodies. Next, prefrontal cortex. You’ve heard all
about, and we are going to hear tons
more about it, because it is incredibly
interesting, in terms of maturation and learning
appropriate sexual behavior, learning not how
to be aggressive but when to be aggressive. The notion that
there is a problem with this part, the anterior
cingulate, in people with clinical depression. Anterior cingulate. I think I may have
referred to this already. Sit somebody down, poke
their finger with a needle, and areas here are going to
light up in spinal pathways, telling you it was
this finger and not that one and areas making you
breathe faster and all of that. And, in addition, the anterior
cingulate is going to activate. Take somebody now and have
them watch their loved one get their finger poked
with a needle, and nothing’s
happening down here. But the anterior
cingulate activates. It’s doing something
along the lines of empathy and feeling somebody
else’s pain. And suddenly it becomes
real interesting that there’s stuff going wrong
in it in clinical depression. Easily translated
into, that that is a disease of pathological
hypersensitivity to the pains of life and the world. OK, so, frontal cortex. Finally, lurking around in
here, the ventral tegmental area and the nucleus accumbens. Really pertinent to
depression, as well. This is the part
of the brain that has all the neurons
that release dopamine, having to do with pleasure. This is the part of the
brain that cocaine works on– that, indirectly, all
addictive drugs work on. This is the part– stimulates
dopamine release here, stimulates dopamine release at
all the interesting places– frontal cortex,
amygdala, hippocampus– central to
understanding everything about appetitive
behavior– behavior driven by an appetite for something. That tells us an
elaboration we’ll be learning about, in terms of
what the dopamine system, here, does. People used to think
this is the system that activates when you
are feeling pleasure. Turns out it does something
much more interesting. This is the part of the brain
that activates when you’re anticipating feeling pleasure. It’s not about
getting the reward. It’s about anticipating
that you will get a reward. And what it’s most
about is not only anticipating that
you may get a reward but powering the behavior
you need to do in order to get the reward. Standard paradigm
showing this– you take a monkey that’s been trained. Every time a light comes on,
at that point if it presses a lever 10 times, five-second
delay and out comes some food. That reward system. Initially, the
very first time it stumbles into just happening
to hit this out of boredom 10 times and out
comes some food. Ooh, up go dopamine levels
when the food comes out. But pretty soon,
what you get instead, the dopamine levels go up
when the light first comes on. This is not, ooh, I just
got some pleasurable food, this is, I know this one. I’m on top of this. I’m all over this one. This one’s easy. This is one of those
10-lever-press deals. This is going to be great. I got this under control. Elevated dopamine,
you go hit the lever and along comes the food. Now, instead, you
flash on the signal, telling you we’re entering one
of those “press the lever 10 times, you get food” sessions. You turn that on, and you
block the rise in dopamine. And the animal doesn’t
press the lever. What this pathway is
about is giving you the energy, the motivation,
the depolarization of neurons for carrying out
the pursuit of pleasure. And that’s really
informative, as we’ll see. Because stimulating
the pursuit of pleasure is far more of an addictive
process than the pleasure itself, in terms of making
sense of some of the circuitry. OK. So all of this eventually plunks
us down into the hypothalamus. The hypothalamus has
a gazillion subareas, all these separate
little nuclei that have a variety of
functions, all of which have boring, vegetative,
just keeping track of body temperature type
functions, all of which are also profoundly affected
by the whole world of emotion and thought and memory. First area. Ventromedial hypothalamus. We’re going to hear tons about
that, starting next week, along with a cognate area,
the medial preoptic area. These terms will
become familiar. Do not freak out. These areas are very
pertinent to sexual behavior. And what we will see
is that one of them is more involved in
male sexual behavior, one more in female sexual
behavior, on the average. There are gender differences
in the size of these areas. There is one landmark study
that everybody learned about, about 15 years ago,
showing that there’s a difference in the size
of one of these regions, depending on your
sexual orientation. There is an amazing
study that was shown that people
who are transgender have differences in the size
of some of these regions as a function not of what
their sexual phenotype is but of what they’ve always said
“I have always felt like a” whatever. They have the region the
size of the “what I always felt like I was” rather
than what they actually are, bringing in
this possibility that what transgender is
about is not somebody thinking that they have the wrong
sex, but it’s somebody who’s gotten the wrong body. So these areas, we’re going
to hear lots about next week. Next region– SCN–
suprachiasmatic nucleus. And once Julie Andrews says that
as loud and fast as possible. The suprachiasmatic nucleus
is about circadian rhythms. We’re mostly going
to ignore that. And anybody who has anything
to do with Craig Heller’s lab, don’t tell him that
I said that, either. But it’s like– stupid
circadian rhythms in fish, sort of doing two of
my colleagues at once. Next– moving on. Another part of
the hypothalamus. PVN– paraventricular nucleus. What’s made in there? CRH. That’s the part
of the brain that initiates the backbone
of the stress response. And what areas are
sending projections to it? Everything. Everything ranging from pathways
that tell you that you’ve just burned your toe, to
pathways telling you are very, very hungry,
to pathways telling you that you’ve just smelled a
terrifying territorial rival, to pathways telling you you have
just thought about, oh my god, only four days till the
midterm, or whatever it is. By the time you
get to species that can be stressed by very
abstract cognitive states by thinking about the
suffering of somebody on the other side of
the planet, what do we know about the neuroanatomy? PVN is getting projections
from all over the place. Next, arcuate nucleus. Arcuate nucleus is the bottom
of the hypothalamic funnel. That’s the part where all
of the hypothalamic hormones come out and get into the
circulatory system there. There’s actually another
area on top of that. I will not mention it,
but that’s its function. Lateral hypothalamus has
something to do with hunger. And that’s the area
that people wasted years on thinking they were
studying aggression when they were instead
studying predatory behavior. Lateral hypothalamus
has to do with hunger. Boring version of
it, it does things like measure your
blood glucose levels and your insulin levels–
all sorts of logical things. Really interesting
level, evidence that the lateral
hypothalamus has something to do with hungers
in the broader sense. Hungers for types
of information. Hungers for other
rewards other than food. It’s an area having
to do with hunger. OK. So this very, very fast
pass here over all of it. One additional component
to think about, which is, everything
I’ve just said has been oriented around all
this limbic-system stuff, built around eventually
influencing the hypothalamus and thus eventually influencing
the entire world of hormones or of the autonomic
nervous system. This is this
unidirectional picture. Stuff starts in the
brain, and you have outcomes throughout the body. What is just as important
is, all the ways in which stuff
going on in the body will influence limbic function,
completing this circle. And an awful lot
of that information is the autonomic nervous system
not going in this direction but going in this direction. Now what this brings
up is a classic theory that’s been in psychology
since around 1900 or so called the James-Lange
theory of emotion, named for William James and
Lange– whoever that was. That may have been his puppy. But the James-Lange theory
of emotion goes as follows. Here’s how you feel an emotion. It is not the case
that your brain decides it’s feeling an emotion based on
sensory information coming in, memory, whatever. The brain decides it’s feeling
an emotion and tells the body, let’s speed up the heart,
let’s breathe faster, let’s sweat– whatever it is. That’s not how emotion works. Here’s how emotion works. Stimulus comes into your brain,
and before you consciously process it your body
is already responding– with heart rate,
with blood pressure, with pupillary
contractions– whatever. How do you figure out what
emotion you are feeling? You are getting information
back from the periphery, telling you what’s
going on down there. In other words, how do you
figure out you’re excited? Whoa! If I’m suddenly
breathing real fast, and my heart’s
beating fast, it must be because I feel ex–
oh, I feel excited now. Ridiculous. Totally absurd way in which
you could process stuff. Completely inefficient. And over the years,
after decades of being wildly discredited,
more and more evidence that that is some of how emotion
is based– your brain being influenced by your bodily
state to decide what emotions it’s feeling. A number of examples. First one. Ones of those hormones that
just has “emotion” written all over it– adrenaline. Adrenaline, epinephrine. Epinephrine,
associated with arousal of the sympathetic
nervous system. So what happens when you
dump some epinephrine into the nervous system? What does it do to the brain? What does it do to
the limbic system? What does it do to the sort
of behaviors influenced by it? And, greatest demonstration–
this was a classic study in the ’60s– guy named
Stanley Schachter doing a study that you could
not do again on humans, with current rules. But here’s what he did. He gave people
epinephrine, adrenaline, without them knowing it. OK, less paperwork
in those days. But here’s what the one version
of the classic experiment was. Somebody comes in,
and they believe what they’re doing is some
study of, you take this vitamin and does it change the way
you do Sudoku or something. Like, that was just the teaser. That was the distracter. You’ve taken this pill
which actually contained long-acting epinephrine. Then you’re going to go
into the study, where you’re going to get tested
or whatever the task is. And please sit down in the
waiting room for a while. And the actual experiment took
place in the waiting room. Sitting there in
the waiting room was another individual,
a confederate of Schachter– somebody
working on the experiment. In half the cases,
what the person sitting there was supposed to do
was say, I can’t believe it! I was supposed to go, and they
said I would have a 1 o’clock appointment for this. It is 1:30 already. I’m going to miss my class. My car is going to get towed. I’m totally pissed off. I can’t believe these
people are doing it. Meanwhile, half the
time the other person is sitting there saying, god,
I love these psych studies! Do you do a lot of them? I love doing these ones! I had such a cool one last week. Which dorm are you in? Let’s– and off it goes. The key thing being, totally
different emotional states and each case being
exposed to someone in a very emotionally aroused,
agitated, expressive state. And what did Schachter show? Does epinephrine make
you get more angry? Does epinephrine make
you get more friendly? It doesn’t do either. It’s modulatory. What epinephrine
does is it kicks up the fevered level
of whatever emotion you are socially
being brought into. And thus what you got was the
subject sitting there, soaked in epinephrine, while
somebody is, like, going on about how late it is, and these
people– before you know it, they’re up there, banging on
the counter at the receptionist and saying, this is an
outrage, and this is unfair, and all of that–
getting caught up in it. Meanwhile, the other
one, within, like, five minutes, he’s
singing frat songs with this person
[INAUDIBLE], and they’re going to get
together for dinner, and they’re hugging each other. And what does epinephrine do? It does not cause a behavior,
it exaggerates, it magnifies, emotional states that have been
provoked for other reasons. It modulates. The exact same concept
as the other day– what does GABAA do to that neuron A? It does nothing whatsoever. What GABAA does is it
modulates the ability of this glutamatergic
neuron to talk to A. What does epinephrine do? Does it create any emotions? Not at all. What it does is jack up the
intensity of whatever emotions your social circumstances
have generated. Another example of
James-Lange sort of stuff. OK. So you were sitting around,
and you were terribly anxious, and you go to a clinician. And the person decides to
give you– what class of drugs do we know endlessly by now? Benzodiazepines. They give you some Valium
to decrease your anxiety. Meanwhile, across
town, there’s somebody who has a big gymnastics
competition on Sunday– whatever. And they’ve pulled a muscle. They’ve been having
muscle spasms, and this is really a problem. So they go to their
clinician, who gives them a muscle
relaxant– Benzodiazepines– the exact same dose. So, wait a second. Here’s somebody taking
Valium for anxiety, and here’s somebody taking
Valium to relax their muscles. What’s up with that? It’s the exact same thing. And it is a very
James-Lange moment. What’s part of anxiety about? It’s monitoring the level
of tension in your body. It’s getting feedback
from muscle tone. And that’s one of the ways
in which antianxiety drugs like benzodiazepines work. Because you’re sitting there,
and you’re saying things are just as horrible as
they were an hour ago! But I am so relaxed. I’m, like, dripping out
of this chair, here. It must not be so bad. Part of you deciding is
monitoring the muscle tone in your body, coming back
with autonomic information. That’s where you
break the cycle. That’s why the same
drug decreases anxiety and is a muscle relaxant. More examples of this. One is, what’s going
on with meditation? That’s what
biofeedback taps into. So you’re sitting there,
and you’re suffering from high blood pressure. Translated into our
terms, something here is driving blood pressure
to be increased too much. It’s not necessarily that. It could also be blood vessels. But we’ll put it on a brain
basis, here, for the moment. So you’ve got a choice
between taking drugs or doing some meditational
something that you want to hook up to biofeedback,
to make it more effective. Here’s what you do. They sit you down,
and they wire you up so that they can monitor
your blood pressure. And you sit there. And they say, OK, I want you
to relax and focus, and focus on the best day of your life. Let’s see what happens
to blood pressure. Nothing much. OK, focus on your
favorite piece of music. Nothing much. OK, focus on your favorite
piece of music that’s kind of slow and dreamy– And suddenly the
monitor goes this way. The person’s blood pressure
has just dropped 10 points. And then you say,
stop, wait a second– what did you just think about? Think about it again. And it does it again. And what the person begins
to learn at this point is, what aspects of
meditative states, what aspects of
memory– whatever– suddenly allow the brain to
be regulating blood pressure. What’s going on there? You’re using this machine
to send the signal up there. Part of what’s also going
on is feedback that way. So, another version
of one of these loops. More versions of loops. Here’s one that
probably accounts for 90% of the arguments
between significant others on this planet. OK. So you and your
significant other are behaving, interacting in a
primate social biological way. And one of you
does something that totally outrages the other one. And they’re furious at
you– he says, personifying. And they’re furious. And what’s going on– and
they convince you readily that you’re at
fault and, in fact, this was a horrible
thing you did. And they’re all agitated. And you apologize, and you make
it sound like you really mean it, because you really mean it. And you apologize, and great. And they finally say OK,
OK, I accept your apology. Don’t do it again. It’s all sorted out. It’s over with. It’s done. And then you begin
to think, OK great, we’re out the other end
of the woods, there. Things are just fine now. Things are– And suddenly they remember
something miserable you did to them in 1968! And they suddenly remembered
in every possible detail and want to argue about
it all over again! What’s going on there? What we have is another
James-Lange moment, when you get into
aroused, angry state, and then it’s all
over with, afterward. That’s great, because the
person has apologized. So, cognitively, you
have just adjusted things– yes, they recognize
they did the wrong thing. Good, I’m vindicated,
that’s great. It’s settled now. It’s perfect. And you could do
that in a second. The trouble is, it
takes a long time. It takes minutes, now, for
your sympathetic nervous system and its consequences to
completely coast back to baseline. So you’re sitting there, and
the problem has been solved, but your heart is still racing. And what do you have? A James-Lange moment, there,
sitting there, saying, OK, well, I was really
upset about that. But that’s just sorted out,
and that’s all taken care of. Except I’m still feeling
totally agitated! It must be for some reason. Oh! It’s what that person did to
me in the second Roosevelt administration! And suddenly out it comes out. It’s this James-Lange
loop, there, of the physiological
information coming back there, prompting one into
trying to find a cognitive explanation for it. There must be a reason why I
am still hyperventi– oh, this must be the reason. This thing we need
to go over, also. OK. I am going to give
you one factoid, here, and you can do with
it what you will. But there is a pronounced
gender difference in how long it takes after strong
sympathetic arousal for things to go back to baseline. [LAUGHTER] OK, let’s just get a
show of hands, here. [LAUGHTER] Who guesses that it
takes longer to get back to baseline in males? [LAUGHTER] OK, well, unless there’s a
lot of abstainers here I think we’re– OK, females? Yeah. Yes! There is a pronounced
gender difference in that. And there’s another
realm in which you have that same pronounced
gender difference, which is after orgasm. Males go back to baseline a
lot faster than females do. And that explains a whole
world of, like, you know, he wants to go out and get
noodles in peanut sauce, and she wants to
cuddle and talk to him and all that sort of thing– [LAUGHTER] –and [INAUDIBLE]. And it’s James-Lange’s damn
fault that that sort of thing goes on. OK. So we, there, have
another example of these feedback loops. A couple more. Here’s an amazing thing. You take somebody with
clinical depression, and you force
them, mechanically, to take a somatic state that
mediates different emotions and signifies other emotions. What am I talking about? You take the person
with depression, and you say, you are
going to mechanically go through the process,
with your facial muscles, of smiling– again
and again and again. And you force somebody to do
that for a half hour or so, intermittently. And they feel better afterward. The world is just as depressing
as it was 30 minutes before, but there’s something
going on here, saying, if I am getting
feedback saying I’m doing this thing with
my muscles, here, and I’m doing it a lot,
it must not be so bad. Other studies showing
you take somebody and either they are
slumped in a chair or you have them
sitting up erect, and you tell them the score
that they got on a test that you just gave
them before that, and it’s a very good score. And what you see is, the more
straight upright the person is sitting, afterward,
the more they will assess themselves
as being made happy by the result they got, and
being made to feel proud. What’s up with that? The posture of your spine
is doing something up here. What this shows us is, amid
this whole orientation– the brain controlling hormones,
the brain controlling spinal, autonomic stuff, the
limbic system telling– all of this outflow from there,
completing this big circle back to the very first class– That business of, think about
something really emotionally laden, and suddenly your
body works differently. Think about the people
who have committed murders in the context of a brain
tumor, a period, their hormone levels, their nutritional
history, here. Junk-food murders and all
of that– Twinkie defenses. What that is, is the
other half of this loop. OK. So now you should sit straight
up and be proud of yourself, because you now have
all of the buckets necessary under
your belt. So that’s the first piece of good news. And that now transitions
us to the latter half of the course, which will now be
to use all of these approaches in looking at
specific behaviors. Here is a sexual
behavior, first off. As a good ethologist,
do we actually understand what we’ve just
observed for this species, this individual, et cetera? What went on in the
brain one second before that caused
that behavior to occur? What’s up with the neurobiology? What sensory stimuli caused
those neurons to generate– The world of ethological
releasing stimuli. What hormones in
the bloodstream, in the last minute,
in the last hour, made the individual
more or less sensitive to that sensory information,
blah blah– all the way back to understanding
the evolutionary legacy of the species of which
this individual is a member. That’s going to be our
strategy in each one of these, now, working our
way back in time. So there’s that great news that
you are in that position now to take it on. The other piece of
good news is, we’re not going to do it on Monday. We won’t have class on Monday. So you can all get
all James-Langey and freaked out for
the exam Monday night. But quick survey among the TAs. So, what do you guys think? Should we have a
review session then? Should we show a David
Attenborough movie? Show the Attenborough. Attenborough. OK, David Attenborough. So which one are you
going to bring in? We’ll watch Life,
the BBC version, with David Attenborough. I don’t think it’s really
available in the US very much yet, so it’s
kind of a cool oppor– For more, please visit
us at stanford.edu.

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