This is the Convergent Science Network podcast.
Leading researchers in the domain of neuroscience, brain theory and technology
are interviewed by Paul Verschoor and Tony Prescott.
This is Paul Verschoor with the Convergent Science Network podcast.
And in this episode, that's also part of our CSN Barcelona Cognition Brain Technology
Summer School. I'm talking with Donald Pruf.
And Donald, you were giving a very elaborate talk, in some sense, focusing very much on,
let's say, how the arousal system is really very much, let's say,
a core engine of brain, mind, and behavior.
Because in some sense also in the psychological literature, arousal is often
seen as some sort of non-specific, an input to a steam engine and we don't think about it too much.
So why do you believe that arousal is such a core ingredient of what makes us what we are?
It used to be thought that the word non-specific is the worst possible word
in behavioral neuroscience. science.
And I've tried to turn this coin over and look on the other side and say that
beneath every act, beneath every cognitive ability, beneath every emotional state is a primitive.
Impetus, which is essential and powerful.
It's necessary for any motivated behavior, and it's the place to begin.
It's like starting at zero.
Instead of studying the brain, if we were getting together to study the planet,
the Earth, we would say, what's in there? What's making the whole thing work?
And it's the magma of the Earth. It's deep, it's complicated, and it's unknown.
And those things appeal to me. It especially appeals to me because it's been
discarded, this subject, for about 60 years.
The great Italian neurophysiologist Marozzi, working together with the American Horace Magoon,
in the 1940s, really began to break the subject open.
But then we lost our way, partly because we were interested in,
quotes, more specific abilities,
especially in the visual system, close quotes, and also because the tools of
neuroscience became so detailed that we could indeed study the third dendrite
from the left or the second nucleotide of DNA from the right,
and therefore we thought we should.
And in doing so, I think that we lost the ground substance of the nervous system.
The substance, the reticular formation, which in any vertebrate nervous system,
from the fish to the philosopher, is necessary for all motivated behaviors.
I like the universal aspect of it, and that's why I'm studying it so hard.
Right. But now, so you started with saying that That both when we talk about,
let's say, emotional aspects of the brain or cognitive aspects,
it's all sort of predicated on a basic arousal system.
It starts out with arousal. Right. So how should I interpret that?
Well, arousal is necessary but not sufficient, as we were saying a few minutes ago.
What's necessary, what's sufficient. And in the case of cognitive abilities,
we know that arousal is necessary for alertness and attention,
which in turn are necessary for everything else.
And so it starts with arousal, and it's good to begin at the beginning.
With respect to emotional function, whether we are talking about temperament,
whether we're talking about feelings or the emotion of the moment,
the arousal is necessary for the strength of the behavior.
And so it could be that we're just mildly annoyed or it could be that we're enraged.
And the difference between those two is the great arousal necessary for an enraged act.
But now, so you distinguish different layers of organization,
both for emotional processing and cognition, each predicated on the preceding layers.
And at the bottom of that, we then have an arousal system, right?
But that's still, also earlier I alluded to sort of steam engine metaphor.
I could look, okay, arousal could be the steam that you pump into this vat.
But it still doesn't tell you a thing about what you're actually driving with that steam engine.
So how do I get to a specific insight about what brains are up to?
Well, in the first place, you're absolutely right. And so we may have one track
of things which we're going toward cognition and another track of phenomena
which we're going toward emotion.
But we both know that I was giving, and now I'm talking about a minimalist description,
and things are infinitely more complicated than that.
That's what keeps neuroscientists fully employed.
All over the world. Right. And so...
How shall I say, how do we get to those specific abilities?
I think the proper answer is, it's difficult. And let's talk about learning
ability, depending on what kind of learning we're talking about.
Are we talking about the hippocampus? Are we talking about the cortex?
Are we talking about the frontal lobes of the cortex? It could be all of the
above. of with respect to emotion.
Are we talking about the emotional history of the individual?
Are we talking about the drugs that the person is taking at the moment?
The person's state of need with respect to hunger, thirst, and so forth?
All of those will come into play, and it's as complicated as the human mind.
And so I would never pretend to be able to chart for you on September 7th of 2012. 12.
Among human abilities, I would not pretend to be able to chart for you any fully
described task from my primitive arousal, my powerful and essential arousal
function on the one hand, to the end game,
that is, the finished behavioral act on the other.
I would say even in Aplysia, the great Eric Kandel,
Nobel Prize winner for the work on the Gill withdrawal reflex of Aplysia,
who mapped out a minimalist circuit, but other people who study aplysia say
that that minimalist circuit is not really the only way to do things.
It's much more complicated than that.
Now, I don't know how long since you've seen an aplysia, but they're stupid. Oh, really?
And even there, things are more complicated than they seem.
And so I think the task of neuroscience these days is to keep one's mind wide
open as opposed to those minimalist descriptions of the mechanisms that go into
every cognitive ability or every emotional expression,
there are always likely to be mechanisms available to us that haven't been discussed yet.
But you and I have been working in this field long enough that we remember the
neuron-centric idea of the brain.
But now, functioning in 2012, we know full well that the glial cells are doing
very complicated things, especially with respect to glutamatergic action.
That the brain is protected by the blood-brain barrier, We know that there are
immune cells in the brain.
When we were little, when you and I were kids, we could talk about the microglia
in the brain, which are immune cells.
But now we can talk about dendritic cells and we can talk about mast cells in
the brain, accounting probably for neuroimmune phenomena, including depression,
maybe the fatigue states like chronic fatigue syndrome.
So things can be seen as infinitely complicated when we talk about the end goals
that you were asking me for.
I'm trying to start at the beginning I'm also
following the dictate of Albert Einstein Albert Einstein said that every scientific
theory should be as simple as possible but not simpler and that's why I'm starting
at the beginning right so now we've wandered into this pretty complex jungle of around arousal.
And things are getting indeed hairy. But on the other hand, you have sort of,
if you want, compensated for that jump into the deep end. Yes.
With also developing a highly specific, high-throughput behavioral essay for this.
Yes. Right? So how does such a behavioral essay now help me to get the handle
on this very complex notion of arousal? So here's what we needed.
We needed a concept, which we've been talking about. out. We needed a precise
operational definition,
which would be that any animal or any human being is more aroused if he or she
is more alert to sensory stimuli, more motoric activity.
And more emotionally reactive.
And you and I both know people who are off the scales at one end or the other.
Consider the hyperthyroid individual, the person has too much thyroid hormone.
He or she is responding alertly to every sensory stimulus.
He or she is twitchy, can't stand still.
My daughter-in-law is like that. You sit in her kitchen, she is never standing still.
And he or she is very reactive emotionally, able to weep or able to laugh readily.
At the other end, let's consider the hypothyroid individual.
The person clinically does not have enough thyroid hormone. that person will
be not reactive to sensory stimuli, sluggish, not moving around very much,
the ultimate couch potato, and also flat emotionally.
We know folks who are flat emotionally.
So there's the operational definition and human examples. But I work on animal
brains, and so we have this assay where the mice are closed off from the world.
They're on their own little world, about one meter long and one meter wide and one meter tall.
And we present to them sensory stimuli by computer.
We measure their motion 50 times per second, 24 hours per day,
seven days per week. And we measure their fear responses.
That's what stands in for an emotional response.
So it gives us an objective measurement, the way a physicist would want,
of this global behavioral concept arousal.
So we have the concept and the assay, and now we want to study the neuronal mechanisms.
Right, exactly. So now that we have this assay and you have this high-resolution
measurement, first is what are now, for this mouse, for this setup,
what are the operational definitions for arousal?
Greater response to olfactory stimuli, greater response to a very gentle touch
stimulus, a tactile stimulus, and a greater response to a vestibular stimulus which would be shaking.
The animal standing on something which is shaking.
Also the animal's moving more. Also the animal, when presented with a conditioned
stimulus for fear, for the shock,
The animal will freeze. The animal will stand still. That's moving less.
And moving less in response to the conditional stimulus for fear.
That might be contradictory because moving more was the operational definition of high arousal.
It's opposite but not contradictory because it's under very specific conditions.
The conditioned stimulus for fear. Then the animal has to move less.
The animal behaviorist would call it risk assessment.
The mouse, which almost everything can eat a mouse, and the mouse is freezing,
trying to be invisible against its environment, saying, oh my god,
what is happening here? I'm not going to move.
Yeah. But then that would mean the better definition might be just,
let's say, the intensity with which the response is executed.
Otherwise, we would have a potential inconsistency between the freezing behavior
and exploratory behavior. The intensity and the situational dependence.
When the animal is just wandering around, it's more activity. but
when the animal has been given the condition stimulus for fear it's
saying whoa let's stop let's let's let's
not do anything until we find out what's going on sure yeah or the cat might
get me yes so now or the hawk or or the hawk or or don himself yeah right and
it's not healthy for a mouse to be in my laboratory right but then um so what you said is that.
You could account for 30% of the behavior in this essay from this perspective of arousal.
So how should I interpret that? What does that really mean? It means that the
animal's behavior is varying, is changing all over the place.
And when you put the animal in a large number of tests, all of which have something
to do with arousal, you then find out what's correlated with what.
The fancy word would be that it's a covariance matrix. tricks.
What that really means is, is the animal who is the most aroused in this test
also most aroused in test number two, most aroused in test number three,
and so forth, and so forth, and so forth.
When you do that for a large number of tests and a large number of mice,
you can say, aha, there are certain forces beneath all of these tests that are
regulating the animal's behavior, And these arousal-related tests.
How much can I account for by one big, massive, let's call it generalized arousal?
And the answer was about 30%. Now, our colleagues this morning in our meeting
pointed out that there must be many other determinants of behavior in addition
to generalized arousal.
And so when the animal is responding to any individual reason for getting excited,
let's say it's fear, let's say it's food, it's hunger, it's sex,
anything that arouses a human being.
For you and me, it could be a scientific exam.
I find them very arousing. I always did too.
Then we say, what percentage roughly of our overall excitement is due to this generalized arousal?
Maybe 30% but then the other 70% are due to all the other complex causes of
behavior specific causes to one situation or another but would you be willing
to consider let's say as a second source a,
two nonspecific arousal specific forms of arousal. Absolutely. Okay.
And so we could talk about the arousal of the male approaching the female.
We could talk about the arousal of an animal or a human being which has woken up because he is hungry.
And so the orexin neurons in the hypothalamus are receiving the input that the
animal is hungry, causing the animal to wake up or the human being to wake up.
I wake up in the middle of the night and I head for the refrigerator.
And then one reduces the hunger drive by eating and then one can go back to sleep.
Right. Yeah. Okay. Yeah. But then, so how much would that add to the 30% if
we take specific arousal into account as well? I don't know.
Okay. What would be your bet? If you just have to bet. Think of the, okay.
Think of the, is the prize a good glass of wine perhaps?
If you want, sure, no problem. Okay. So let's say that every behavior is like an equation.
If we neuroscientists are trying to go away from philosophy,
we as young people knew that very smart guys and women, going all the way back
to the Greeks, were talking about the causation of behavior.
And they could elaborate very great philosophical theories about behavior.
And we read about these century after century after century.
How can we go away from that and turn this behavior into a science?
And the way we do it is to have precise definitions and to think of behavior
as quantitative equations.
Now, for the equation of the rat who was hungry, or the human being,
the guy who's hungry in the middle of the night, let's say on the left side
of the equation is the behavioral result, getting up and going to the refrigerator.
On the right side of the equation are many terms.
The generalized arousal term is just one of them.
Now, you're asking me, what about the rest? What about the other 70%?
For that glass of wine, I'm going to bet for the simple act of eating that maybe
the hunger drive accounts for another 50% perhaps.
And so now we're up to 80%. And now you're going to ask me, what about the other 20%?
And I'm going to say that there are other facts about the person's personality
which make him either, maybe he feels sorry for himself.
And that accounts for another 19%. Now, in a way, you could say,
well, this is pretty good, because if we're right about this as scientists,
we're accounting for a motivated behavior.
On the other hand, I'm certainly going to have, at least as I explain in this
fictitious manner, at least 1% to 5% due to slop.
I'm not going to know. No. And you, as a realistic scientist,
are going to say to me, yes, we're going to give Don one to five percent.
But this is embarrassing in a way as a scientist, and especially a scientist
who wants to achieve the precision of physics. And here's why.
Suppose you were a judge, and you were deciding about an American judge,
where there is a capital punishment.
A person can be put to death, let's say, by lethal injection for murdering somebody.
And you're a judge who's deciding about capital punishment. Do you want to have
a five percent chance of error?
That as a mature judge out of every 100 individuals whom you sentence to death,
did you sentence five of them to death by accident? I don't think so.
And so we're really still striving hard.
We're trying hard to reduce that error.
But it's clear that you want to go for the full bottle of wine and one glass is not sufficient.
I want to go for 100%. Right. But on September 7th of 2012, I'm sure about the 30%.
Percent and i'm guessing pretty well about the 50 percent and
i'm pretending uh that we're just
guessing about the other 20 right but now but now there's
there are historical examples where people try to develop let's say a physics
of behavior yes right in a comparable i'm thinking about clark hall for instance
with the most elaborate theory of this kind absolutely yeah which in some sense
also collapse under its own weight right and then he had to he had to as soon
as a new paradigm was discovered,
let's say eye blink conditioning was one of his difficult cases,
he had to start to add ad hoc parameters to keep the whole thing afloat,
and so on. I'll tell you a secret.
The secret is that he started too complicated.
As an ambitious and arrogant scientist, he and other people said,
we're going to explain learning.
We're going to take the behaviorism of B.F. Skinner and we're going to make
it into an elaborate theory, not like B.F. Skinner, and explain learning.
The secret is to start much simpler. Start with behaviors that the animals don't have to learn.
Start with behaviors that have the simplest possible sensory determinants.
The simplest possible motor outputs, and the simplest possible regulatory elements.
And so that's what I did. I started this a long time ago, an embarrassing number of years ago.
And as a chemistry student, I had figured out that these steroids are actually
hormones, and they're very simple chemicals.
A steroid hormone is a rigid, flat piece of carbon atoms, which you can draw
on a piece of paper. If we were doing this in video, I could draw a steroid
hormone for you in about 30 seconds.
And it turns out that these steroid hormones regulate simple behaviors,
not learned behaviors necessarily, but simple behaviors. And the simplest of all is sex.
And among the simplest sex behaviors are behavior where the animal doesn't even have to locomote.
Locomotion is pretty hard, actually. But before we go to the sex behavior,
I think there's a step in between, right? Because I think there's another really
important difference between what you're doing and what Clark Hull is doing.
Because by simplifying the behavior you explain, you do not necessarily insure
yourself against failure.
The complexity can still be too high to come to a physics of behavior.
Oh, yes. It's easy to fail. Exactly. There's no certainty.
Yeah. But you, I think, have added a new ingredient in this equation,
which is a neuroscientific one.
Yes. Right? You have been mapping this functional interpretation of behavior
and arousal also back onto the brain.
And now things start to become, I think, it becomes a very different game and
a game that Hull couldn't play because now we have new constraints.
Yes. Now we have the neural substrate. Yes. So I think that really distinguishes
what you're doing from these more traditional approaches.
So how has this helped you to look at the substrate?
What are the insights? Well, first, let's talk about the tools that compared
to the behavioral neuroscientists, or shall we say the behavioral scientists
of 60 years ago or 50 years ago.
On the neuroanatomical side, we know so much more about nerve cells connected
to other nerve cells than people did 50 years ago.
Techniques that map cell-to-cell connectivity and discriminate individual cell
types and say, where do these cell types go?
This is available to us now. Now, in terms of the physiology,
the function of neurons, we have electrical recording techniques that we didn't used to have.
We can record from single nerve cells, whereas people couldn't do that so well 60 years ago.
We can also not only record the cortical electroencephalogram,
EEG, with precision, but we can analyze it with mathematical detail.
We can get nerve cells into the dish. And instead of having it mixed up with
all the other nerve cells in the brain, And I did this on Tuesday.
We're now talking on Friday.
On Tuesday, I was looking at individual nerve cells and a so-called nerve cell line.
And I could bring my pipette in, a tiny pipette, which has a tip of one micron,
which would be one millionth of a meter.
And bring that next to the nerve cell and record the nerve cell's activity.
So on the physiological electrical side, we have tools.
Let's talk about the chemistry. We have the chemistry of neurotransmitters now
that weren't so much known then.
And we now know that there are these neuromodulators called neuropeptides,
which are tiny pieces of proteins, which are now not fully described necessarily,
but compared to 60 years ago, I mean, we're in heaven compared to 60 years. We're in nirvana.
And now we have molecular biology. The genes expressed in the nervous system
and the regulations of those genes by transcription factors.
Clark Hull didn't know about DNA and he didn't know about transcription factors,
but now we know these things. Sure, exactly.
About the other 349 degrees or in some cases we collaborate with guys and teams
who know about the other 349 in order to make a story and sometimes we succeed and sometimes we don't.
You choose your problem right if you're surrounded by people who are smarter
than you are and work long enough then you can succeed.
Right yeah that's very good but now of all these possibilities you have have
in the arsenal, you highlighted two in particular. So on the one end, it was to map,
a functional notion of arousal to neuromodulation, right? And the other one
then to map it to very specific ascending, descending neurons in the brainstem.
So let's first look at neuromodulation.
So how does a neuromodulation view on arousal help us to sort of get a better
grasp on this functional notion?
Well, we're starting with the more complex part of it, but let's talk about it.
Neuromodulators are typically hormones or small pieces of proteins.
And so if we think about neuromodulation of the animal alerting because there's
danger in the environment,
chances are we're talking about a little piece of a peptide called CRF,
corticotropin releasing factor.
The guy that discovered that died just about six years ago, I mean six months
ago, and his name was Wiley Vail.
And many years ago, maybe 20 years ago, he described these, it's about 40 amino
acids in a row, which is CRF operating through three types of receptors.
And the neurons, which are most essential for turning on the rest of the brain, have CRF receptors.
And so that would be one way in which a neuromodulation could tell the individual,
oops, you are in a situation where something bad has happened.
You're in a part of town where you were robbed, or you're in a situation with
your girlfriend where she's going to get angry at you.
In these cases, you're made alert in order to not do the wrong thing,
in the wrong part of town to avoid getting killed, with your girlfriend to avoid
losing her, or boyfriend to avoid losing him.
And so there's an example of how a specific chemical could set up the arousal
system to say, whoops, let's be careful about this.
Now, what about the pathways that are being acted upon?
The neuroscientists will quickly start talking about pathways that go from lower
parts of the brain, like the brain stem above the spinal cord,
to upper parts of the brain, like the forebrain, the cerebral cortex in a human being.
And those pathways, their chemistry is known.
Norepinephrine and dopamine, anybody that's used cocaine or methamphetamine
is operating on norepinephrine and dopamine systems, probably with disastrous complications.
Serotonin, anybody who's taken his antidepressant today, selective serotonin
reuptake inhibitor, SSRI, has been manipulating the serotonin system.
Histamine, well, if you took your allergy medicine today, and if it was an old
type of allergy medicine, it made you sleepy.
And the reason it made you sleepy was because it blocked histamine receptors.
And acetylcholine, if we're talking now about, let's say, an 85-year-old person
who's succumbing to Alzheimer's disease,
his doctor is giving him a drug which will slow the breakdown of acetylcholine
so that the acetylcholine can come to that guy's cerebral cortex and try to
keep him functioning a little bit longer. So those are five ascending systems.
But it also turns out there are systems going from the upper part of the brain
to the lower part of the brain. And those are more complicated to talk about.
But I think rather than talking about their chemistry, what I'd like to say
is that part of arousal is the autonomic nervous system.
You and I know that the James Lange theory of emotion was that a person gets
a sense of fear partly because his guts and his heart and his breathing are
telling him that he's afraid.
Well, what about those controls? The autonomic nervous system controls.
Sympathetic nervous system and parasympathetic nervous system are controlled
by systems going from the upper part of the brain to the lower part of the brain.
And of course, I'm especially excited about nerve cells that could contribute to both.
Right, exactly. Exactly. And we're going to get to those, right?
Because in some sense, if we look at this neuromodulatory view,
you can talk about, let's say, what you also call the high and the low road
towards controlling arousal.
So how should I think about that with respect to these neuromodulatory systems?
Well, let's consider the evolution of the brain from the simplest vertebrate
animal, which would be a fish or even a simple fish like a lamprey,
I don't know what the Latin word for lamprey is, up to the most complicated
individuals, which I would still think would be human beings.
In the simplest individuals, we have the low road to arousal,
and that would be the systems that go from the spinal cord through the lower
part of the brainstem, down where our neck is,
along the roof of our mouth, which would be through the hypothalamus,
to the basal forebrain, which is quite primitive,
and that's what we call the low road to arousal.
And in fact, some cholinergic neurons are at the target of that low road of arousal.
But as we move into higher forms of vertebrates, even mammals,
we're developing that thalamocortical system.
So that would mean that perched on top of the brainstem is something called the thalamus.
And the thalamus is the Greek word for antechamber. And the reason it's called
the antechamber, the thalamus, is because it is the doorway to the cerebral cortex.
All of these high roads to arousal go through the antechamber to the crowning
glory of the mammalian brain, the cerebral cortex.
So, the high road would go from the lower brainstem into this thing called the
thalamus, and then certain thalamocortical pathways would wake up.
And when we're lucky, both of them are working, the high road and the low road.
But all the neuromodulatory systems you alluded to earlier would completely bypass the thalamus.
They are directly tapping into the neocortex.
I think they do, yes. I would agree with that.
So then this high road seems to be more based on, let's say,
glutamatergic transduction, probably conveying signals from the periphery, memory, etc.
Into neocortex. Is this really the distinction you would agree with?
You have to be correct in the sense that one of the important inputs to the
medial part of the thalamus is a glutamatergic input from the midbrain reticular
formation, also called mesencephalic reticular formation.
So, when the neurologist Nicholas Schiff, S-C-H-I-F-F, stimulated the brain
of a vegetative state patient in the central thalamus, and he woke up that patient
so that patient could be conscious.
He lays the success of his electrical stimulation to the fact that he was stimulating
glutamatergic inputs to the medial thalamus. Right, exactly.
Okay, so now, so we have this high and low road. And then what you also mentioned
earlier, in some sense, of course, we can now start to think about,
okay, but how could these systems possibly be coupled in some way, right?
And what you were talking about, there was a very, very unique category of cells
that you found in the brainstem that might be, let's say, some sort of mediators
between this high and low road of arousal, possibly.
Okay, this is my interpretation right now. So what makes these cells so special?
Their size and their location. You and I both know that the name of the game
in neuroanatomy and in the brain research is just like real estate in New York City.
Location, location, location. Probably real estate in Barcelona as well. I think so.
I think so, yeah. And so these cells have the right connections, so to speak.
If you're a politician and you talk to your sister, you may not be too influential.
But if you talk to William Clinton, the former president of the United States,
and he talks to everybody, well, then you're going to be influential.
Talking to these nerve cells, which are called nucleus gigantocellularis,
these nerve cells, they're huge.
Let's call them giant nerve cells, nucleus gigantocellularis.
Talking with them is a little bit like talking with Bill Clinton,
because they talk in turn,
not only to systems ascending the nervous system up in the midbrain, for example,
but also down in the spinal cord.
And so I believe that they have a unique role.
Okay, but now, so what makes them gigantic? So in terms of, if you would compare
them to your standard, let's say, layer five pyramidal cell in terms of their,
let's say, cell body, their dendrites, their axons, how are they,
why are they gigantic compared to those? Honestly, the answer is I don't know.
Within the past six months, I've gone to people smarter than me.
James Darnell, the great cell biologist who's a molecular biologist at Rockefeller
University, and several other people like him, and said, what about these huge cells?
Is there something about their gene expression which is likely to be unique,
which automatically would know that I'm dealing with nucleus gigantocellularis
neuron because it expresses the X factor?
And all we can think of is, no, there is no X factor. It's simply more of the same.
Now, if you were to say to me, why is there more of the same?
I would have to get very nervous and say, I just don't know the answer to that.
I want to find that out. And within, I would say within the next six months,
we'll be doing molecular biological experiments attempting to answer your question. Right, exactly.
But now, okay, let's try to understand this a little bit better,
right? So if we talk about how they're organized in the reticular formation,
the brainstem, how distributed are they?
Are they very clumpy and clustered or is it sort of diffuse in the structure? They tend to be diffuse.
And first I'll be literal and then I'll reflect on our state of knowledge in
neuroscience at the moment. Okay.
Uh, the reticular formation comes from the word for reticule.
And a reticule is like a grid. And so if we were to look, let's say,
through a microscope, and we see a bunch of vertical lines crossing and a bunch
of horizontal lines crossing them, then we're talking about a reticule.
When you look at a cross-section of the reticular formation,
that's what it looks like.
You see these cell bodies in their separate little boxes, so to speak,
but you see these fibers zooming back and forth, vertically and horizontally,
and that's why it was called the reticular formation.
And so going all the way from the brain just above the spinal cord up into,
but not including the thalamus, we have this kind of pattern.
Now I might say that a couple of the questions that you're asking are touching
on the very frontiers of neuroscience.
And you and I hope that many people, not just our friends, our colleagues,
our students, who are already in the know, so to speak, we'll listen to this
but we also hope that many many people in many different countries.
Who don't exactly know what this
neuroscience is all about are going to listen to all of your podcasts.
How many did you say you have at the moment? Well we should have about 50 by now or so.
Yeah 50 and going right? 50 and growing. Do I hear 51? Do I hear 52?
Oh yeah you will So and by one year from now you'll probably have 60 and so
we hope that large numbers of people one, people who are deciding what to study And two,
citizens who are paying for this, because we both know that good neuroscience
and good science of any sort is dependent upon good economy.
And good economy is dependent on governments collecting taxes and knowing that
the scientists are doing the best possible thing with the money,
either to push back the envelope and push back the frontiers of knowledge with
respect to what we know about ourselves,
or for that matter, what we know about the universe.
So in that spirit, what I'd like to do is to say that there will be free in
economically developing countries coming from the publisher Springer.
So this would be the formerly German medical publisher.
It used to be called Springer Verlag, but now it's just Springer.
They worked at cost, and all of the editors and the authors worked for free,
to produce an online text called Neuroscience in the 21st Century.
And while it will be sold as a regular electronic text to universities in developed
countries like Germany or the States or Japan.
In large numbers of economically developing countries,
which are identified by low gross domestic product per capita,
and there's a specific list of 78 of these countries and another 28 where they
get this list of Springer things for a very, very small amount of money.
This electronic text will be published and we hope that people will make use
of it. Besides our talking on this Friday afternoon...
There are two organized ways of getting this out, and one would be the International
Brain Research Organization.
You and I call it Ebro, International Brain Research Organization,
headquartered in Switzerland.
And the other would be the Human Frontiers Science Program, headed in Strasbourg,
France. And both of these organizations are devoted to the neuroscience as an
international enterprise.
And so all the university librarian in Zimbabwe, let's say, or in Sierra Leone
or in Sri Lanka, the university librarian just has to tell Springer what the
IP number of their computer is.
And then automatically they not only get this text that
i've done neuroscience in the 21st century 106 chapters
including a chapter about how to set up a
neuroscience program in a developing country the great canadian uh richard brown
great sense of humor uh i wrote that chapter how to send how to set up a neuroscience
program in a developing country with the order of things to do the problems
you're going to have and so forth 106 chapters and the university librarian will get Get that text,
and then everybody associated with the university,
the students and faculty, get it for free.
So we hope that this effort, which we're doing with podcasts here in Barcelona.
Will be supplemented by Ebro's efforts and by Human Frontier's science program
efforts. Well, that will be excellent.
And I say that because now your questions, although we'll maybe not continue
in that vein, are touching on the frontiers of neuroscience.
Neuroscience what makes that large cell the
way it is don uh nucleus gigantosalers how did it get to be that way and the
answer is i hope to start studying that within six months right that's very
good and so now this is an excellent initiative and then we definitely support
that um but in some sense i would i would still i would like to go back to the
frontier of neuroscience.
And think a little bit more and discuss a bit more about about these these cells
Because you said you estimate there might be around a thousand of them,
let's say, more or less. Good guess.
So they're embedded in this sort of matrix structure of the particular formation.
They have both ascending and descending projections. Precisely.
That extend over millimeters, I assume, because they have to touch… Depending
on the size of the brain. Right, exactly.
And you called them then the first responders. A fashion model with a long neck,
a supermodel may have a long axon. Right, exactly.
So now the question becomes, what are they really responding to?
So you showed some physiology of these neurons, right?
What do these guys like? What do they respond to? Well, your question during
our discussions this morning was right on.
And that is that these cells have dendrites.
Dendrite comes from the Greek word for tree branch, which are very unusual.
If we take the first segment of the dendrite as it emerges from the cell body,
it has a certain length. Let's call it L.
The next segment after that branching point will be longer than L.
It'll be LL. And the next segment after that, going farther away from the cell
body, will be longer than that, LLL.
And you can picture, therefore, that these birds have very big wings.
These nerve cells have a very large spread.
And therefore, they're beautifully attuned to be able to pick up large numbers
of signals from sensory neurons, sensory stimuli.
And we know that they're capable of responding to every sensory stimulus we
could give them. Right. Vision might be the worst.
But since these are on the hindbrain, it was rather surprising that they responded
as well as they did to olfactory stimuli, because the olfactory stimuli come in the nose.
But they did respond to olfactory stimuli. So even though these are not sensory,
these cells we're talking about are not out in the skin, or they're not in the
eye, or they're not in the nose,
they seem to be central for telling the rest of the central nervous system that
something just happened.
Right. Right, but now, what are their ascending targets?
Ascending targets in, I'm not going to name all of them, because I might make
somebody ill, and I probably would forget some.
But they're going forward in the brainstem to the higher up parts of the particular formation.
They're going to the hypothalamus, and they're going to the central thalamus,
where you can stimulate in order to wake up the individual.
Right, exactly. Are they also targeting structures like this periaqueductal
gray, for instance? Yes.
That's an incredibly important target. Yes, absolutely. Because there you would
have more behavioral output, right? Oh, yeah.
Because if you want to make an animal attack another animal,
I mean, it's quite sad, actually, and quite vicious.
Then stimulating the periaqueductal gray, that's called the central gray because
it's right in the middle of the midbrain.
And remember that the aqueduct is filled full of cerebrospinal fluid.
It. It's like a land locked lake, uh, which is in the middle of the brain and
people don't exactly know what it's doing.
Is it, is it, is it just a pressure absorber to protect the brain from a,
from a traumatic injury or is it a vehicle of communication?
I think that many people would say that it's a vehicle of communication.
They would speculate that the nervous system has a Navy, uh,
and, and that signals can go up and down and it's people are just working that out now.
But again, that's on the frontiers of neuroscience. Sure. Yeah.
But on top of that, you found that, interestingly enough, some of these neurons
are coupled rather directly, both to the circulatory system and to each other.
Yes, to each other for sure.
We don't know how quantitatively important that is.
If we were to say, if this is an important part of the brain,
this reticular formation, and its output is a certain amount,
let's call it 100, what portion of that 100 units of output is due to them talking with each other?
We're not sure. We're sure that it would make signaling faster, but how much faster?
We think that some of these neurons can pick up signals from the blood,
and we're excited about that because we know that some mental illnesses have
something to do with the immune system.
And if these nerve cells are picking up proteins in the blood,
if they're receptive to proteins in the blood which reflect infections,
for example, or even HIV, AIDS, then that would be very important.
But right now we're in the realm of speculation.
Although you did show in the morning that you have data that shows that these
neurons can actually absorb substances that float around in the blood, right? It is possible.
It is possible. But is it a small story or a big story? Sure.
Shall we spend this weekend in the laboratory trying to find out?
That's a good idea. But then, what's the transmitter they use?
Glutamate. Glutamate. Some of them use GABA, and I can't figure out why. Okay. This is a puzzle.
Glutamate is what we were expecting, and many of them do use glutamate.
Some of them use GABA. And as you pointed out, and as Nick pointed out in our
discussions this morning,
even as it is important to figure out what makes these nerve cells fire their signals,
their action potentials it's equally important to
understand how to keep them quiet when nothing is happening right
exactly because their their output would be meaningless if
they're chattering away all the time sure it's like you when certain
people can't stop talking you stop listening to them whereas another person
he hardly says anything but when he says it we all listen right uh so how do
we keep them quiet and it was pointed out in the morning uh discussion that
That small nerve cells nearby the giant nerve cells might use the transmitter GABA,
gamma-aminobutyric acid,
in order to keep these cells shut up and quiet when there's nothing important to say.
Yes. Very good. So then, what is their descending target?
The entire spinal cord is the safest thing to say. Right. Both motor neurons
directly and interneurons indirectly.
And are there any specific patterns to these terminations they have in spinal
cord? Not really. Not that I know of.
The best way to study about this would be to study the work of the really accomplished
Dutch neuroanatomist, Geert Holstege, who's in Groningen.
Would you say? Groningen, yeah. Oh, there you are. and then in the United States
there's a wonderful physiologist by the name of Barry Peterson with an S-O-N
Peterson and you put his neurophysiology together with Herod's neuroanatomy
and you have a picture of a whopping massive.
Signal to the spinal cord but it's hard to figure out any specificity so here
we have these neurons fairly clusters of them, they're coupled through these
inhibitory local neurons,
having both these ascending and descending projections,
if you want, regulating lots of subsystems in the brain, right?
And in some sense, you started to look at these as these neurons after you had
been trying to dissect also these subsystems in a more complete way.
So you were describing how you took very specific sexual behaviors,
for instance, to try to understand how, let's say, this kind of behavior regulation could take place.
And these first responders we just talked about, these large neurons in the
brainstem, could be like a substrate
that helps with this kind of behavior regulation. Yes, I think so.
So to understand on the other side of that story, so how should I think about
the regulation of a very basic behavioral pattern?
So I think that so many neuroscientists are interested in how the body informs
the brain of what needs to be done.
After all, I think it was the talk….
Nick's talk yesterday had the quotation from Theodosius Dobzhansky,
a geneticist who incidentally worked on my campus at Rockefeller University,
who was quoted as saying, nothing makes sense except in the light of evolution.
And therefore, we have to say that the brain, and Ernhard Holstege would say
the same thing, really has two functions, to keep the individual alive and to prolong the species.
And so all of these motivated behaviors, which are meant to make life longer and more worthwhile,
so to speak, longer in the case of a laboratory rat and perhaps more worthwhile
in the case of a citizen of Spain or the citizen of the United States and so forth.
And among those things would be the hunger and the thirst motivations,
the fear to avoid danger.
But what I chose to study was a very simple system, which is triggered and modulated
by a hormone whose chemistry is very, very well known.
These steroid hormones, the same kinds of steroids that athletes are not supposed
to use, are simple, flat molecules.
And it turns out that sex behavior in these lower animals absolutely depends upon them.
Estrogens in the female and androgens in the male.
So androgens would mean from the Greek, what is it that makes a male? The androgen.
And estrogen, what is it that makes a female?
And the estrogens and the androgens circulate in the blood from the ovaries
and the testes, respectively.
And because the brain is looking for lipid molecules, like the hormones,
these hormones go right into the brain and they flood the entire brain,
estrogens and androgens.
But in certain parts of the brain, there are proteins and certain neurons that
soak up these steroid hormones, and they're called hormone receptors.
So an estrogen would bind to a protein called an estrogen receptor.
A testosterone, an androgen, would bind to an androgen receptor.
Let's stick with the estrogens.
It turns out that this protein, which is called estrogen receptor alpha.
Is manufactured by nerve cells in the primitive part of the forebrain,
which is called the limbic system, the amygdala, the hippocampus,
the septum, and so forth, and also in the hypothalamus.
So it is a limbic hypothalamic system.
And again, from the fish to the philosopher, the limbic hypothalamic system
is well and thriving, working to receive hormones and to regulate behavior.
So that was the first step of making a big advance and explaining how sex behavior
happens is to know where the receptors are.
Secondly, the receptors are at the top of a behavior-regulating loop.
Now, let's think of the loop from the sensory stimulus, which would be being
touched by the male on the flanks of the animal, and the signals go into the spinal cord,
up the spinal cord, to the nucleus gigantocellularis, and also to the midbrain
central gray, which you mentioned, the periaqueductal gray.
And there, if the animal's ready to mate, If the estrogens are circulating and
have turned on the estrogen receptor alpha, which in turn turned on certain genes,
then a signal will come from the hypothalamus to tell that midbrain periaqueductal gray,
yes, this is a go.
This is ready. We are ready to mate. and then the descending side of the circuit
goes back down through nucleus gigante cellularis back down to the spinal cord
and it says to the spinal cord when you are touched on your flanks by the male the male.
If dorsiflex, your spinal cord, that would mean lift your rump so that the male can fertilize.
If and only if the female quadruped, the female with four feet,
does that, then fertilization will occur and mating will occur.
So we have the entire circuit. And by the way, if I can pat my colleagues on
the back, it was the first circuit for any mammalian behavior,
any vertebrate behavior for that matter. Now, at that point,
as you know, we got lucky.
Because when I started this work, the phrase transcription factor was not even
a phrase. Nobody had that idea.
But a transcription factor is a protein that tells a gene either to turn on
or to turn off. It can work either way.
And it turns out that the estrogen receptors that we had discovered are transcription
factors which are regulated by the hormone.
So if and only if the hormone like estradiol in a female comes from the blood
and touches that estrogen receptor and binds to it, if and only if that happens,
the estrogen receptor will bind to DNA,
to a specific sequence of nucleotide bases on the DNA, and will turn on genes.
Genes, and we know what several of those genes are.
And then that affects the activity of that cell, it gives an estrogen-dependent
signal back to the midbrain, and the behavior occurs.
So at this point, we know the neuroanatomy of this behavior,
simple behavior, we know the electrophysiology, and we know some of the functional
genomics of the behavior.
Right, so this is a really very complete description of a very specific behavioral.
But the question that it raises is that, so do you believe this generalizes
to any type of behavioral subsystem?
Like the philosopher might not only engage in reproductive behaviors,
they might also read a book.
Yes. And reading a book might be on less hormonal control than reproductive behavior.
So will it generalize to the ability of philosophers to read a book?
The answer is I don't know. No.
Probably, we talked about ripple analogies in one of the talks in this meeting.
And what's probably going to happen is that my behavioral system,
which we've explained, is like throwing the rock into the water.
And it shows how to explain a simple man behavior, and the ripples will spread.
And so from this example, we'll learn how to study other simple motivated behaviors,
And we'll start approaching even more complex behaviors,
like let's say the philosopher is a graduate student in philosophy and he would
like to pass his test in order to get his PhD.
And we could call that mastery motivation. What's the word?
It's a motivation for accomplishment. And it used to be studied by something
called a thematic apperception test.
Mastery, there's a word...
I'm not a native speaker, so I have an excuse. There's probably a good Dutch word for it.
I know all the Dutch words for it. And probably the Dutch words are better than the American words.
But you could measure people's motivation to do complicated things.
And this philosophy graduate student, this fictitious student whom we're talking
about, is going to have that kind of motivation.
Now, will that sort of behavioral regulation follow the same kind of simple pattern?
I would not bet on it. But for instance, to make it easier, would you believe
that even in that behavior, also in that behavior, the hypothalamus would be
playing a coordinating role as it does in the sexual behavior?
I suspect that the hypothalamus will be down at the core of it,
even as the magma is down at the core of the earth.
But the magma doesn't explain everything about the earth. There are many things
about the mountains and the oceans and the caves of the earth and the weather
of the earth that the magna cannot explain.
This is very important, right? Because you are saying whatever behaviors we
observe, they're all driven by motivation.
There's a motivational driver of this, which comes back to your arousal system in some form.
Yes. And the core structure that is setting it up is hypothalamus.
So in some sense, I would imply without hypothalamus, you will have no motivated
behavior, whether they're abstract reading of books or the reproductive behaviors
that occurred just before it. I think that's right.
And so I think you and I are very interested in striving forward into forms
of behavioral regulation, notably social behaviors, which are not likely to
subsume, to be subject to this very simple model that I've worked out for sex behavior.
They're likely to have equations that are of a different sort.
I would make the analogy of the difference between arithmetic and calculus,
or perhaps the difference between arithmetic and fractal geometry,
maybe nonlinear equations.
And they're both mathematics, but understanding arithmetic may be necessary
for understanding more complicated forms of mathematics, but not sufficient.
Right. But aren't you a little bit….
Let's say, holding back too much here, because in some sense,
if we would just pursue this line of reasoning, if you place,
let's say, the hypothalamus always at the center of this, or these neurons,
these gigantic neurons in the brainstem.
You could say this is an invariant substrate of any motivated behavior.
These guys always have to be involved, and if they're doing arithmetic,
there's always arithmetic playing a role here.
And they will, I agree with you, they absolutely will be involved,
but it's going to be a lot more complicated than that.
And so as we strive forward, I think on the one hand, the reason I'm being so
shy about it is I don't want to be presumptuous and say, oh,
what we discovered is going to be the Bauplan for pretty much everything there
is. Well, that would just be silly of me to say that.
On the other hand, as scientists, we have to be optimists and we have to be proactive.
We have to say, yes, there is a reality out there. There are sequences of behavior
that we want to explain, and we have the faith that they are explainable.
And so you have robots downstairs and you already know how to regulate some
of their behaviors and you're about to study their ability to regulate social behaviors.
And so even though you don't know all the formula yet by which the social behaviors
will be regulated, you have the faith that sooner or later you're going to be
able to figure it out. Am I right? Sure, absolutely.
But at least in my case, the robots will have to do something.
So it's an easy test. But now, in case of the rat,
let's say, how many of these behavioral subsystems do you think are implemented
in these circuits and would this map onto these clusters of gigantic cells? else.
It's easier to state an inequality than it is to guess an exact number.
And so, for example, if we were in a guessing game and you were the great neuroscientist
in the sky who knew the exact answer, you could say, how many of these systems
are involved? And I would say seven.
And you would say, wrong, you do not win the trip to Las Vegas.
So you do not win the trip to.
Monaco. But it's easier to say it's greater than.
And so if I, as a person who's a sophisticated and well-educated and well-read
neuroscientist at the moment, I would say that there's probably greater than 10.
Greater than 10. How much greater than 10? I'm not going to say.
Right. Okay. Very good. No, because what I, so my contention would be also,
so having taken on to these kinds of concepts of behavior regulation, right?
If you now start to generalize this towards more complex behaviors like social
interaction, you very quickly see actually you have to even decompose those
overall behavioral systems in all sorts of subsystems.
And it's very difficult to get away with, let's say, getting to plausible social
interaction just relying on a single kind of arousal-based drive.
So I think it will start to fragment very rapidly.
This will be an interesting problem to address in the future.
I think so too. So it's dynamic.
In the sense that everything that you're going to be studying,
that I study with animals and are also interested in human beings,
studying autistic children, it's dynamic in the sense that it's a flow of behavior through time.
And on the other hand, it's things working in parallel, one system,
a second system, a third system, all working in parallel in order to govern the behavior.
Maybe sensory systems, motor systems, regulatory systems, all working at the same time.
And so the equations are not going to be simple. The great British physiologist,
Sir Charles Sherrington, he not only was maybe the best of the 20th century,
but he trained the great Australian physiologist,
Sir John Eccles, both Nobel Prize winners, and then they trained other guys.
And Sir Charles Sherrington said that the job of the neuroscientist is to explain
the flow of behavior through time.
And so it's not just the individual reflex, the cat taking its paw away from
the source of the damaging heat.
But it's the sequence of behaviors, whether we're talking about simple behaviors
like avoidance reflexes or complicated behaviors like social interactions.
Okay, so Don, after this exploration of, let's say, arousal systems and behavior,
two questions to finish up.
So you've been around the blog quite a while in this business, right?
Over 50 years. Right. And also now you've produced this marvelous book,
Neuroscience for the 21st Century, that I hope will find many readers in your target audience.
You've also taken a very, let's say, you're trying to develop this physics of
behavior, but using modern neuroscience tools.
So if you would have to give us the law, Don's law, the law we should adhere
to in trying to understand brain and behavior, what would that law be?
Don't be shy about it, okay? The law would be to say, don't say a law.
And the reason is that even as we strain to accomplish the explanation of behavioral
regulation in the simplest possible way,
and again, we shared the idea that Einstein said every theory should be as simple
as possible, but not simpler,
that the temptation to do the shortcut is something that we should avoid. And so...
I would never say that any substantial fraction of human behavior is going to
be encompassed by a very simple lawful statement.
It's going to be encompassed by large numbers of complex lawful statements,
which I have the faith that neuroscientists will indeed explain over a period of time.
But on this particular Friday afternoon, it would not only be false to try to state the law,
but it would be discouraging because we hope that many people listening to this
podcast will be people who are about to become neuroscientists,
who are thinking about becoming neuroscientists.
And if they think that it's already done, that's what I thought about physics
when I was, therefore I went into the neurobiology.
We want people who hear this podcast to get some sense that neuroscience is
alive and kicking and that we're now, we're about to enter the golden age of neuroscience.
And so if I had a law, it would be to say that we are entering the golden age
of neuroscience. And why do I say that?
It's because our science of how behavior is regulated has reached a stage of
detail and sophistication, such that on the one hand, we can make use of the
tools of physics and chemistry and mathematics,
as you and I have talked about, to try to bring it to the service of behavioral explanation.
Maybe simple behaviors, but we're getting there step by step by step.
Thousands of neuroscientists across the world are getting there step by step by step.
On the other hand, as sophisticated individuals and scientists,
we know that as well as coming from bottom up,
that every form of complicated human behavior is also governed by the lawfulness
of society, that there are well-described social laws that we're all conforming
to as civilized individuals.
Let's call that from the collective on down to the individual.
And so I believe that social scientists are getting more sophisticated than
ever, and therefore we who are trying to study individual animal behavior, human behavior,
robot behavior, can take advantage on the low side of the physical sciences
and on the high side of the social sciences.
And I think we're going to be doing that big time, all 216 countries and territories.
How do I summarize that law now? What's Don's law?
It's make use of all the tools of the physical sciences, all the tools of the
social sciences, and that will keep you busy for 50 years. Like be inclusive and take the challenge.
When I think of all the places this could be going on, the reason I said 216
is because that's the numbers of countries and territories that took part in
the Olympics in London in 2012.
If you look at the UN right now, I think it's 196.
And out of those 196, about half of them are in miserable economic shape.
And so we really want the brilliant people in those countries to go to Springer
and through perhaps Ebro, International Brain Research Organization,
or perhaps through the Human Frontier Science Program and look for this text
called Neuroscience in the 21st Century.
Because we've got great scientists from all over the world. How many different
countries contributed to that?
Oh, I would guess inequality again.
Certainly greater than 20 countries. Right. Greater than 20 countries.
And they worked their hearts out to produce great stuff. Right.
For neuroscience students all over the world. Excellent. Now,
I'm looking forward to it.
So, the last question then is, so five years from now, I'm going to go find
you there at the campus of Rockefeller University.
Yes, I'll be there. And I'm going to ask you, like, look, listen,
Don, five years back you made this prediction.
Yeah. And today it's pay up time, you know. You're going to lose your wine or you're going to gain it.
What is one prediction you feel most strongly about today?
I'd like to know what are the rules by which these giant neurons,
nucleus giganticellularis, neurons in the reticular formation just above the
spinal cord, what are the rules by which they operate?
And the answer is going to come in two parts. One will be, what are the internal rules of governance?
Is there something special about them? Is there really a factor X that we haven't conceived yet?
Or is there a new channel? Or is there a different protein expressed?
Or is there a different kind of mitochondrion, a fundamentally different kind
of mitochondrion to use energy by those neurons that makes them great?
And I would like to be able to tell you, if there is a factor X,
and if so, what is that factor X? Right.
Especially if there's not a factor X, then I'd like to go to the second part
of the equation, which is to say, how are they managing their inputs?
As you pointed out, there are many sensory surfaces that have started to receive
these signals, somatosensory signals, olfactory signals, you name it,
auditory signals, coming onto these dendrites.
How exactly does that happen? If I could tell you that, then I would be able
to tell you what is the rules of operation of these nerve cells,
which are at the center of arousal, which I believe is at the beginning of the
execution of every behavioral response.
Right. So what's the specific prediction, the specific one?
The specific prediction is going to be that there is no factor X.
I hate to say this. I really hate to say this. This is no fun.
That there is no factor x it's more of the
same okay more of the same a bigger cell body more
mitochondria more dendrites and therefore
a greater integrative capacity and that they
operate in groups in a fish they operated one by one but in some way i want
to know how they operate in groups we're dealing with teamwork here exactly
excellent well donald prof thank you very much for this conversation this is
a great series of podcasts i hope that uh people People will listen to all 100. Very good. Thank you.
The CSN podcast was produced by the Convergent Science Network of Biometrics
and Biohybrid Systems, a project funded by the European Sevens Research Framework Program.
Music.