This is Paul Verschure with the Convergent Science Network podcast.
And today I'm with one of the regular visitors to our summer school here in
Barcelona, Jerry Haslow.
And Jerry is with us now. He's visiting Barcelona. And he talked about his recent work on the cerebellum.
And um so jerry one thing maybe as an introduction but what i always found fascinating
in in your case is that sort of you moved from psychology and philosophy,
into not just neuroscience but a very sort of hardcore version of of neuroscience
right so so how do you how do you see that transition for yourself well i wanted
when i started psychology I was in a department that was mainly Freudian,
and I wanted to study psychology from a more scientific point of view.
And I looked at various departments and laboratories, and I found that there
was a group in my hometown in Lund working on the cerebellum.
They were doing things that I found extremely boring.
They were looking at pathways through the spinal cord up to the cerebellum.
And I found that very, very boring since I was interested in learning and memory
and stuff like that, physiological psychology.
But the quality of the research was extremely good.
And I've come to the view that this is really, really crucial for probably most of science.
The quality of the research, when things are done in a careful, precise,
painstaking, systematic way, this is much more important than working in trendy
subjects and following fashion and so on.
So even though I found it boring, I found that the quality of the research being
done in that department was just so good.
I felt that these guys know what they're doing. This is what I want to learn.
So I started working on the cerebellum with Carl Friedrich Eckert,
Gert Andersen, and a few others just to learn the techniques and to try and
emulate their way of thinking,
their carefulness, and the systematic way they were doing research.
And then, just by luck, it turned out that a certain form of associative memory,
Pavlovian conditioning, actually occurred in the cerebellum.
So, for me, that was just fantastic because it meant that I could utilize my
knowledge of cerebellar physiology and...
Address a task that I felt was also very interesting, namely the formation of associative memory.
So that's how I ended up doing work on the cerebellum on Poblovian eye-blinking conditioning.
So that's basically what you've been doing for the last 25 years.
Exactly. And it's been extremely difficult.
We've spent a lot of time trying to create an experimental setup that is workable.
There are many constraints when you do research. You have the ethical constraints, for instance.
You cannot do this on any kind of animal. You cannot do it with any kind of anesthetics and so on.
But we found a way to solve these problems.
But it's taken, I would say, it took more than 15 years to almost 20 years to
make the preparation really workable.
Now, finally, results are pouring in. It's been a very long travel to get there.
So how do you map Pavlovian conditioning onto the brain, and in particular onto the cerebellum?
What's the relationship there?
Well, Pavlovian conditioning is a very general phenomenon. There are many response
systems in which you can get it.
I mean, Pavlov used autonomic conditioning. He showed how you could train dogs
to salivate when they heard a sound by pairing the sound with food in the dog's mouth.
We can also use the same learning paradigm to.
How should I put it, to look at how certain immune responses occur,
cognitive aspects of learning, how your heart rate changes when you are told
something frightening.
How asthmatic patients can get asthmatic attacks when they look at pictures
of flowers or smell flowers and things like that.
There are many, many, many applications to this, and we are only studying one
of them, namely Eibling conditioning, which is a motor response.
We know that this is in the cerebellum, but probably the other forms of conditioning,
or many of the other forms of conditioning, involve other parts of the brain.
But it's a very simple and very basic form of learning. There is the Nobel Prize
winner Peter Medawar once wrote a collection of essays called The Art of the Soluble.
And by that he meant that scientists should
not only address the important problems they should also choose
problems that are really soluble and
that often means you should
start with the simple problems and wait with the really huge task like explaining
cognition and consciousness and stuff like that okay but now in pavlovian conditioning
we actually have a very reduced setup right you just have you're talking about
two kinds of stimuli yes in the end one kind of response you're going to get
out of the system, right?
So how do you... And these are also very simple responses. They're stereotyped responses.
Exactly. So how do you map that very reduced learning system now from the behavioral perspective?
Onto the neural substrate, right? So how does something like this conditioned
stimulus, this initially neutral stimulus, now map onto this preparation you developed?
Or how do you map your unconditioned stimulus onto that system and so on?
I'm not sure what you mean by how do I map it. Well, you have a functional relationship.
You know that if you present this conditioned stimulus paired with an unconditioned
stimulus, you will be able to trigger conditioned response over time.
So that means you have to now identify the pathways that actually transduce
this information to the brain.
Yeah, but we know that we can, in our case, we map it on the cerebellum and
there's a lot of experimental work before us where people have showed you can
get these in animals that have no forebrain.
You can remove a huge part of the brain and still get conditioning.
Conditioning, we have developed this into a preparation where we remove most
of the brain, all the parts of the brain that maintain cognitive function and
consciousness and so on are removed,
and we have the cerebellum and the brainstem left intact.
We can still get conditioning, and it seems to follow basically the same rules
that you find in the intact animal. It takes roughly the same amount of time
and training to acquire the response.
They extinguish in the same way and so on. So it looks very, very similar.
And then we have tried to identify precisely which cells in the cerebellum learn this.
And we show that these cells, they have particular properties,
they have particular input characteristics and so on.
So we can, within a few tens of a microns, we can localize the cells that learn this task.
And we can record from precisely those cells. And we can...
The findings we have can account for almost everything you find in the behavior.
So we have cellular responses, responses in the particular group of Purkinje
cells in the cerebellar cortex.
They have the temporal properties of the behavior. They respond in the same
way when you change various conditions during training.
And that means that we we know within
a very very very narrow area very
small area where the learning takes
place so how do these cells learn i mean on on
these cells we have convergence pavlov already talked about looking
for convergence to find the site of the n-gram or the memory trace
so the condition stimulus information comes
up to this perkinia cell through the parallel fibers
there is a granule cells this might tell you something
about the world now we have our climbing fiber coming
in so it conversions on this Purkinje cell so you
could argue well look that seems a fairly trivial setup to
learn an association right well actually the Purkinje cells are ideally suited
to make associative connections they are unique in the nervous system in the
degree of convergence of inputs one Purkinje cell can receive several hundred
thousand different inputs from the so-called parallel fibers.
So a single Purkinje cell will be contacted by maybe a quarter of a million,
maybe half a million parallel fibers.
And the parallel fibers will signal everything that happens to the organism.
All the sensory systems project via the parallel fibers of the Purkinje cell.
Also, everything that happens in In the brain, when you think about things,
when you plan ahead, when you imagine you're seeing things, all of that information
is also sent via the parallel fibers to the Purkinje cells.
So this is a perfect system for generating associations.
And once you've seen this degree of convergence, it's not a surprise that this
is where associative learning takes place.
Well, but it seems a very special kind of associative learning because it's
not that you just associate any idea with any other idea, to use a more Jungian interpretation,
but you seem to associate in a very convergent fashion a large set of possible
states onto one output state.
Yeah. Right, so it's not just any form of associative learning,
but it seems a very specific kind of associative learning. Yes,
but you have many output channels also, small groups of Purkinje cells project to their own targets.
Most of them project to muscles, but there are also Purkinje cells projecting
to the prefrontal cortex and to the parts of the brain we believe are the centers
of various cognitive functions.
And since all these Purkinje cells projecting to small groups of muscles or
areas of the cognitive parts of the forebrain,
they all receive this convergent input from all the other systems.
But what do you then see as the output unit?
Because in the eye-blink conditioning case, which is a standard paradigm that
you also have pursued vigorously, the output is a discrete movement in the end, right?
So now you also say that, but other Purkinje cells would indirectly project
towards the frontal cortex.
Yes. So what's now this output unit of the system? Well, if you go,
some of the projections from the cerebellum goes to the primary motor cortex.
And there you have pyramidal cells projecting also to elementary movements or
small groups of muscles.
So that outward pathway is rather similar to what we're looking at in eye blink conditioning.
But then as you go more forward in the forebrain, you will reach areas that
control more global aspects of actions.
Perhaps you shouldn't even call them movements because they are actions in a more abstract sense.
So the more rostral, the more forward you come, the more complex the movements
will be controlled by that area.
And when you come, suppose that I said that I want to draw a triangle.
Then on my primary motor cortex there
will be commands for holding the pen
and moving your arm
in a certain direction if you go a little bit forward you will have a command
signal controlling let's say draw a horizontal line and if you go even further
forward than that you will have more global commands like drawing a triangle
or even drawing a house or something like that And the more forward you go,
the more global will the commands be, the more abstract will they be,
or the more abstract will the actions be that are controlled from that area.
So it looks as if the cerebellum can control not only the sort of the fine detailed
parts of a movement like squeeze the pen to hold it,
but also more global actions like draw a triangle or things like that.
But would that not mean that, like in the eye-blink conditioning case,
you were describing the output of the system as groups of muscles.
But it actually is, this projection is only indirectly targeting these muscles
because it hits brainstem motor nuclei.
So also there wouldn't be fair to say that you control an action as opposed
to groups of muscles? No.
Well, you might, I suppose.
And I also suppose that if you take eye blink conditioning, which is in some
ways a special case, but it will activate the facial nucleus and send signals out of the eyelid.
If you're looking at other forms, in a rabbit, for instance,
it's retraction of the eyeball and not only the eyelid and so on.
But in any case, the facial nucleus will not only respond then to change in
its input signals controlling the movement of the eyelid.
There must be other mechanisms controlling, let's say, the amplitude of the
movement. That could also be the cerebellum in a different part of the cerebellum.
And maybe that will also be controlled by signals coming from the forebrain.
Like in this particular situation, it's not very good to close your eyes because
you need to have a look at the dangerous environment you're being in at the
moment, things like that.
So, of course, in a certain sense, the facial nucleus will have to integrate
or compromise between signals coming from the cerebellum but also coming from
other parts of the brain and from the periphery.
So now we have the whole setup, right? We have sort of our conditioned stimuli coming in.
This is basically all possible states of the world or internal states of my
brain that come in via the pons over these parallel fibers.
I have these climbing fibers that are much more specifically targeting these
Purkinje cells linked often to very specific events on the body,
like unconditioned stimuli, painful stimuli, and noxious stimuli, and so on.
And now we have this output pathway, which is a strong divergent pathway,
or conversion pathway again, onto motor nuclei or onto frontal areas of the brain.
Okay, so now you could argue, well, and indeed, because of this very almost
clean, what people call crystalline design of this circuit,
its operations, or some people like to call this its computations,
might be fairly trivial.
There have been models of this already by Marr and Albus and Ito since the 70s and early 80s.
You could argue, okay, but given this anatomical arrangement and given this
physiology, the computational principles appear clear because you just learned
to trigger this response.
You have to bridge some sort of little time interval between the onset of one stimulus and the other.
What's really the problem of this system? Why is it so difficult to understand
how this really works? Where are the problems coming in? I don't think it is very difficult. Okay.
I think... Yeah, but still, you're performing experiments every day,
so apparently they're on these old problems.
I mean, we're trying to sort out many of the details, but I think that in some
basic stuff, we understand pretty well now.
We do. I think we do understand that all the sensory information is transmitted
via the mossy fiber and the parallel fibers of the Purkinje cells.
The climbing fibers provide a teaching signal to change the circuitry.
The pre-kinder cell has the ability to output, to generate well-timed outputs that control behavior.
I think this is now pretty clear.
A lot of the controversy surrounding the cerebellum is that a lot of people
who work, perhaps those who are working on different setups,
don't accept the answers that I claim are the right ones.
But there's another complication, And that is that the cerebellum,
as you said, has a crystalline structure.
It looks very similar throughout the cerebellar cortex, wherever you are in the cerebellum.
And that has fostered the assumption
that the cerebellum works in the same way in all different parts.
However, it is known and has been for some time that there are biochemical differences
between different zones in the cerebellum.
And those biochemical differences must correspond to some sort of functional
difference. Like what kind of difference would stand out?
I'm not sure what they are. And this has not been investigated because almost
all the in vitro work has been done in the vermis.
People have taken out slices from the vermis and put them in a dish and try
to explore learning properties and so on.
But a large part of the cerebellum have never been subjected to that kind of
analysis. And if you look at what different parts of the cerebellum do,
it's not difficult to envisage that they might learn quite different things
and respond in different ways.
This is very speculative on my part, but if you take, for instance,
a medial part of the cerebellum that controls posture and axial musculature.
It's difficult to see that the cerebellum would be very useful if it only produced a kind of phasic,
fairly short latency and very short lasting movements that are generated by
a more lateral area that generates eye blink.
So, pre-kinesio-cell controlling eye blink, you would expect it to generate
a short-lasting fast movement or signal.
But if you go to the part of the vermis controlling posture,
you wouldn't want, you want someone to be able to stand still for a while.
And it's not useful then to generate very, very short lasting fast movements.
So my guess is that you would find that those parts of the cerebellum work in
a slightly different way. They may have very different temporal properties.
But look, you could also argue that that transformation is
performed in these downstream brainstem stem nuclei that
they sort of perform some sort of temporal matching
of these output signals to the properties of the periphery you
can but your original question was why has this and why
has it been so difficult to agree on how the cerebellum works
and one one guess that i have is that it has always been assumed that the cerebellum
works in the same way everywhere but people working on eibling conditioning
work in one part of the cerebellum those who work on in vitro on slices work
in a different part of the cerebellum,
and those working on the other main experimental paradigm,
namely the adaptation of the vestibulo-ocular reflex,
they work in a third area of the cerebellum.
And maybe the properties of the cerebellum are different in all these areas.
And that could also be one reason why it's been so difficult to reach agreement.
But these three paradigms, how much of the cerebellum do they really cover?
Well, they cover only a small part of the cerebellum. We are working in the
intermediate part known as the C3 zone.
The slice people work mainly on the A zone. Maybe they get some B zone.
I don't know, depending on how careful they are.
And the vestibular ocular reflex people are working on the flocculus,
a very old part of the cerebellum.
And it could be that there are significant differences between these areas.
So in total, this is not more than 10%, I would guess.
No, less than that. Less, okay. Okay, I was being generous.
Okay. Yeah. So the problem is that if you say, okay, it might not be a uniformly
operating learning system, do you have any physiological or direct anatomical evidence for that?
Or is it only in terms of functional considerations?
Well, it's functional considerations coupled with the fact that we know that
there are biochemical differences. People working with anatomical techniques
have found that there are some clear chemical differences between different
parts of the cerebellum.
One of the most well-known is the zebrin bands, which correspond to an enzyme
called aldolase, which is important for basic metabolism of the cells.
And it's very difficult to understand why should there be bands of Purkinje
cells with different levels of aldolase. Mm-hmm. Um.
If it doesn't correspond to some sort of functional difference between them.
Yeah, that's reasonable.
So you said earlier, which I liked actually, you said, okay,
I know how this system works, but they don't want to listen.
So how does this system then work when we take the eye-blink conditioning example, right?
So here comes the sound, a bit later comes the air puff to the cornea.
Well, of course. What's happening in this system now? We don't know a lot about
the details here, but what we know is that Sketch it out. Yeah,
the Purkinje cell controlling the eyelid is only a small fraction of the Purkinje
cells, but it is a distinct group of Purkinje cells.
They will receive input from tones and light and skin pressure and everything
that happens to the organism all the time.
But now and then, a certain stimulus like a tone will occur and be followed
by some kind of stimulus to the eye,
like air on the cornea or an insect irritating the skin around the eye or something like that.
And that will produce a signal in a particular pathway known as the climbing
fibers going up to the same pre-kinder cells.
And that climbing fiber impulse will change the synapses between the parallel
fibers and the Purkinje cells.
And it will only change those parallel fibers that were just active at the time
we're considering. And those happen to be tone.
So the synapses between the tone carrying signal and the climbing fiber input,
those synapses will be changed by the climbing fiber input.
And that will make the Purkinje cell more likely, the next time this happened,
to generate an output signal in response to the tone, before the clavicle fiber,
before the corneal or eye stimulation.
But how does the Purkinje cell then trigger that response?
That is totally unknown. Okay. And very controversial.
Okay. Yeah. How come? What's the difficulty there? Well, one difficulty is to
account for the timing. if the dominant idea...
In the neurobiology of learning has been for many decades, I would say,
the idea that you can change the strength of a synapse.
Synapses can be depressed or they can be potentiated.
And the terms long-term depression and long-term potentiation are usually used
to designate these two forms of learning.
And this has been the standard assumption in not only the cerebellum,
but in all ideas about learning in the brain.
The difficulty has been that the learned eye blink, the conditioned eye blink, is well-timed.
It reaches, if you have a particular interval between the onset of the tone
and the onset of the air puff, like 300 milliseconds or 500 milliseconds,
the Purkinje cell response is adaptively timed to the interval between these
two stimuli that occurred during training.
And how can you account for the delay? If you use 300 milliseconds,
the Purkinje cell will start firing or change its firing early,
and it will reach a maximum amplitude at roughly the time when the unconditioned
stimulus or the air puff comes on.
If you use 500 milliseconds instead, the response will be delayed and adapted
to the 500 millisecond interval.
Now, how can you account for a timed response if you have only increases or
decreases in stimulus strength?
Just changing the strength of the response to the tone signal could explain
why the Purkinje cell responds to tone, but it doesn't explain how that response
can be delayed by a couple of hundred milliseconds or so.
So this has been the main problem, that how do you account for the timing?
And there have been many ideas about how this could be achieved.
For instance, you could have delays in the input signal.
This has been an idea that goes back many decades. It's called tapped delay lines.
And the idea was that if you had a delay, let's say, in the mossy fibers going
up to the cerebellum or delays in the granule cells and parallel fiber signal into the kidney cells,
then you could have a synaptic change only between those parallel fibers Bruce.
That had the right delay so that the signals would coincide with the input coming
through the climbing fibers from the air puff.
And that would give you an automatic way of timing because then only those parallel
fibers would respond after learning. And that would give you automatic timing.
We have in Lund conducted experiments suggesting that there are no such delays in the input signals.
And even if we circumvent them by stimulating, Well, a few years ago,
we tried to stimulate the mossy fibers, and we got well-timed responses showing
that it couldn't be delays in the mossy fibers because we had delays after the mossy fibers.
So then recently, we have stimulated the parallel fibers instead,
and we still get nicely timed responses suggesting that it cannot be delays in the parallel fibers.
It has to be something closer to the Bikindi cell, either cortical interneurons
or the Bikindi cells themselves.
Well, but what you're invalidating with these experiments is the notion of a
tap-delay line, which would be that you have one spike basically traveling through
this parallel fiber that signals, well, the interstimulus interval is 100 milliseconds.
And it's on that one spike that you have to learn, right? But you cannot exclude
the possibility that you have a more continuous fluctuating response on these
parallel fibers that sort of represents interstem.
This is also a problem for the LTD, LTP story that if you, yes,
when you provide a tone signal,
the mossy fibers and the parallel fibers will go on firing throughout the whole
period that you have the tone.
And you can get if the tone continues well after the air puff.
The tone can continue several hundred milliseconds after the air puff,
but that doesn't produce a continuous response.
The response goes on at a certain time, but it also goes off at a certain time.
Even if the condition simulates continuous of many hundreds of milliseconds,
the response still goes off at the right time.
But wait, I could argue that that is then accomplished by the climbing fiber signal.
Yes, but the same thing happens if you give a C as alone or tone alone trial. the same thing happens.
The response goes off at the time when the climbing fiber response usually comes
in. So it doesn't really matter.
And also you can elicit the response with a brief, if you train with several
hundred millisecond tone, you can still elicit the conditioned response with
just 10 milliseconds conditioned stimulus.
So it looks as if it's only the initial part of the stimulus that matters from
the learning point of view. Right.
Okay, so this whole topic of how is the interstimulus interval represented so that you can learn it.
This is one problem, right? And now you sketch some scenarios how we can think about this.
But another issue might be how you transform this. Yeah, but I have to interrupt here. Yeah, please.
If you have the tone, and the tone goes on for many hundreds of milliseconds.
Then there will be parallel fiber signals coming throughout this whole period.
And that means the first parallel fiber signals, they will
be matched with say if you
have an interval of 300 milliseconds they will be followed after 300
milliseconds by the complex back climbing fibers
in the air path but if they can continue then there will be some parallel fiber
signals will be followed at a shorter interval by the climbing fiber input and
some will be followed even at an even yet shorter period and some will even
coincide with the unconditioned stimulus.
So this also creates a problem for the idea that you just have this long-term
depression of synaptic strength.
Okay. So one riddle, if you want, still in the system is, okay,
where does the trace reside that correlates or that corresponds to the stimulus interval, right?
It's just one problem. And indeed, I think your most recent experiments shed
really an interesting light on that.
But another question I think that's unresolved is really how do you now transform
changes in peritoneal cell firing to actually triggering this eye blink?
Because it's not that this peritoneal cell is directly driving this skeletal
muscle system, right? It has to go through a number of steps.
Moreover, the modulation might be inhibitory. Right.
So you have a sign reversal problem. So how do we map now changes in Purkinje
cell responses to actually triggering that eye blink?
Well, we know that Purkinje cells are inhibitory, and they inhibit the cerebellar
nuclei, and they are tonically active.
That means that if a Purkinje cell that is tonically active has a certain stand...
At a pretty high rate, I might add. At a pretty high rate, yeah.
Tens of impulses per second, and even hundreds of impulses per second.
And the nuclei to which they project also have a spontaneous background activity.
So in order to generate an excitatory output, the Purkinje cell has to stop its firing.
And that is what it actually does. When you apply a Pavlovian conditioning protocol
to the Purkinje cell, it will respond with a pause to the input signal.
Signal, and that pause means that the Purkinje cell, which is inhibitory,
will stop inhibiting the nuclei.
That means the nuclei will be excited and will generate an excitatory signal.
Who excites the nucleus?
What excites the nucleus? Nothing has to excite the nucleus.
This was previously considered a problem, but it's now known that the nuclei
have an intrinsic mechanism for generating a background activity,
so nothing really has to excite So it's a form of rebound, a rebound excitation?
You don't need that either. Okay. If the Purkinje cell stops firing,
stops inhibiting the deep nuclei, they will immediately increase their firing rate.
So that's not a problem. There may be problems, and this, of course,
has to be addressed in a future physiology presentation.
How is this transformation from the inhibitory perikinetic cell signal to the
nuclei, to the red nucleus, to the facial nucleus?
How is this transformation? What does it look like? Is it linear or is it something else?
And this, of course, we don't yet know. And this has to be found out.
And there are, of course, interesting aspects because the system also has to
regulate the amplitude.
The blink has to have, the eyelid movement has to have the right force.
Right. If the eye is a little bit dry, for instance, it will need a larger force and so on.
So that has to be regulated also. And that could well be downstream from the Purkinje cells.
It could be in the nuclei, cerebellar nuclei.
It could even be learned in the cerebellar nuclei. We don't know.
Okay. But now there's another puzzling component of this story,
which is that these deep nuclei.
So now we have an idea of how we transform the pons and the Purkinje cell firing
into triggering an action of the eyelid.
But these deep nuclear cells also receive a collateral input from the pons, right?
Well, no. So does it play any role of significance?
I don't think so. Actually this has been a highly controversial subject.
The nuclei do receive some mossy fabric collaterals from some sources.
It's highly questionable if they do so from the pontine nuclei and from the
mossy fibers arising in the pons.
There have been some claims that they do. Other people have claimed they do not.
And in any case, the number of such collaterals is likely to be very,
very small compared to the convergence of input you have in the cerebellar cortex
with a quarter of a million parallel fibers to a single Purkinje cell.
So how many mossy fibers would collateral to the deep nucleus you think?
I don't know. I mean some people have questioned that there are any at all. Oh really? Okay.
So my guess is it wouldn't be near, I mean it would totally different order
magnitude from what you have recorded.
So we ignore this for now. It wouldn't be nearly enough to explain associative learning.
But it might be enough to explain explain, for instance, a consistent modulation of reflex strength.
Exactly right, yeah. So if you had mossy fibrous collateral,
perhaps not from the pons, but from somewhere else, regulating,
let's say, the background firing rate of the deep nuclei, that could mean that
the eyelid response, the eye blink amplitude.
Could be stronger or weaker.
And that kind of learning could well... And this is a relevant issue, right?
Because what you're conditioning is the amplitude time course of the response.
And the Purkinje cells tell us how we can get the timing, but not this amplitude modulation.
Precisely. And in other areas, for instance, in the vestibular ocular reflex,
the Purkinje cell, or sorry, the cerebellum does modulate the amplitude of reflex.
This has also been a view, if you go back decades, this has been the view of
what the cerebellum does with all our spinal reflexes, that they modulate the reflex.
Gain right so that the strength of
the reflex it always has to be adapted when the
body grows your muscle strength changes the
mechanical properties changes all the time so you cannot these things cannot
be inborn they have to be subject to modulation right as we grow and as we train
as our muscles become stronger and then as we grow older as the muscles become
weaker speaker, they will always have to adapt this.
So you need some kind of adaptation of reflex gain throughout your life.
Or even you could argue as soon as we start to use tools, for instance,
if you talk about posture, posture control with tools, then you have to adapt
very rapidly to that. Oh yes.
But now, so okay, so let's say we're not going to worry too much about these
mossy fiber collaterals, but another aspect of this downward pathway towards the action.
Is that it also has a collateral from the deep nucleus back to the inferior
olive, which seems puzzling, right?
And you actually have been investigating this specific aspect of the whole circuit quite a bit.
Because over the inferior olive, we have, if you want, our error signal coming
in that tells you, okay, you just got a shock or you just got an air puff,
something bad happened to you.
But now in itself, these inferior olive neurons receive an inhibitory input
from the deep nucleus, which we are triggering when we're saying,
okay, close your eyelid now.
So what's the role? How do you see the role of that connection, of that link?
Well, we think that this is a negative feedback pathway for controlling learning,
the amplitude of the learning.
The amplitude of learning? The amplitude of the learned response. Okay.
This was very puzzling initially. We discovered this by chance that this pathway
was inhibitory. It was always believed to be excitatory.
And when it's inhibitory, it's very difficult because Bikini cells are also inhibitory.
And the climbing fibers are excitatory.
The net effect would be a positive feedback system which is unbiological and
and it can never be stable and there are all sorts of problems with that but
if and this so this looked as a problem when it was thought that the effect
of the climbing fibers was the excitatory.
Providing excitatory input to the pre-kindle cells but if the pre-kindle if
the climbing fiber induces a weakening of the parallel fiber to Purkinje cell
synapses or if they produce post-responses in the Purkinje cell,
then it becomes a negative feedback pathway.
And that makes sense because it might control learning.
So the idea that
we have tried to pursue has been that when
the cerebellum the
cerebellum learns to produce an excitatory output
signal generating a learned
movement like an eye blink it will at the same time send a signal to the inferior
olive that is inhibitory and that weakens or turns off the learning the teaching
signal coming from the olive so it means that when the learning has reached
a certain level you turn off the learning machinery So,
you would prevent a kind of overlearning.
And that in itself might not seem to be so important, but it does have important consequences.
And one of them is that if the subject learns to respond to a certain stimulus like a light.
And then, or say, sorry, like a tone.
And then you add. So suppose you learn to blink to a tone. So each time you
hear the tone, you blink nicely, a conditioned blink.
Then you add a light on every trial.
And pair the light with the tone and the air puff.
If you then test learning to the light afterwards, you will find that somebody hasn't learned.
Now, that makes biological sense, because why should it
learn to respond to the light when you already have
the tone and the tone enables you to avoid
the air puff without paying any
attention to the light so it would be just a waste of circuitry
a waste of energy and so on to also learn to respond
to the light but this system this
mechanism will do precisely that because whenever
you have the tone and the air puff the
the subject generates the condition blink an output signal you turn off the
learning mechanism so when the light comes on the subject doesn't learn anymore
it has already learned to respond to the tone so it doesn't need the learning
machinery anymore and it will prevent the animal from forming.
Associations that are of no use but they're like redundant yeah exactly they're
redundant right but then information but the interesting implication of that
is that this learning machine.
Has set itself up to never be a perfect learner
because as soon as you started and block this
teaching signal of the the climbing fiber signal you are creating conditions
for extinction yes right so in some sense the learning plateau is now defined
by by let's say the correct prediction then setting in motion extinction that
forces you again then to learn because you start to make mistakes, right?
Well, my view is if you have a thermostat system, the system will,
when the temperature increases, it will turn off the heating.
The heating, temperature go down, heating will be turned on,
and you will have an oscillation around a set point.
And I guess the same thing happens here. You have a set point,
and you reach some kind of equilibrium,
and you get a little bit of extinction and that
suffices to turn on the learning the teaching machinery
and you will learn and you will
oscillate around a certain certain level
okay but it also means it's always testing the hypothesis is predicting right
yeah by just this this if you want non-specific extinction that it imposes upon
itself yeah okay but now another Another aspect of this circuit is that in turn
the inferior olive also projects back to the deep nucleus.
Right. Is that of any significance in this learning perspective? I just don't know.
My guess is that you can have some other form of learning in the nuclei and
maybe those are also elicited by these collaterals.
I don't know. Another possibility is that when the teaching segment to brachyndosal
will cause the brachyndosal to fire and provide an inhibitory signal down to the nucleus.
And maybe that inhibitory signal interferes with the normal movement.
So if you have a signal coming via the collateral, it would help to cancel that
meaningless inhibitory signal coming from the Purkinje cell.
I don't know. This is pure speculation.
But on the other hand, what is intriguing about this is that the inferior olive
has its own spontaneous activity, right?
Which is about one hertz to 10 hertz, depends who who
you talk to um but now so
it's not the case that that you only have climbing fiber activity when
you actually have this unconditioned stimulus it's actually interspersed with
a spontaneous level of yes and and it looks as if the climbing fabric input
not only teaches the perkin cell to respond to particular specific stimulus
it also regulates the background firing rate of the Purkinje cell.
So normally the olive will fire with around one hertz or so.
If you increase that to just over two hertz, you will silence the background
firing of the Purkinje cell. It will totally silent.
And if you reduce the background firing rate of the olive down to half a hertz or zero,
after half a minute or so, the Purkinje cell will start firing with very increased rate.
But when that happens, when the Purkinje cell background firing goes up,
it will suppress the nucleus.
Which will reduce the inhibitory signal to the olive, which will increase the
background firing rate of the olive, and that will depress the Purkinje cell
background firing rate.
So you have a negative feedback system, not only for controlling learning,
but also have a negative feedback system for controlling the background firing
rate of the Purkinje cell.
But now, in some sense, you could argue that maybe, if you think about eyeballing
conditioning, it's actually a very tiny perturbation on the intrinsic dynamics of this system.
So, maybe this learning system is just trying to keep, let's say the Purkinje
cells are just trying to keep the inferior olive at some optimal level of activity, right?
And tries to regulate it up and down by regulating the deep nucleus essentially, right?
So, it's really homostatic negative feedback. Yeah, this makes it very difficult
to theorize about it because it's not clear to me what is regulating what.
Okay. Is it the Purkinje cells that are regulating the olive or is it the olive
that are regulating the Purkinje cells?
Well, it would basically mean that if you have, let's say, this closed-loop
homostatic system where the Purkinje cells are regulating the inhibition of a deep nucleus,
so you in turn regulate the inhibition onto the inferior olive,
so you can keep it at a fixed rate, somewhere between 1 to 10 hertz.
Now, if I have a climbing fiber of an unconditioned stimulus coming in,
I start to speed up my inferior olive, right? So that would say,
okay, now I have to sort of start to increase my inhibition to an inferior level
to bring it back to this baseline that I want to keep it at, you see.
So this might be, in that context, you could also account for cluster conditioning.
But then what the learning system is still trying to do is keep this inferior
olive neurons at the right level of firing and it doesn't act.
And that you get an eye blink associated with it is something you get for free.
That is how this system is wired up. So the emphasis of the learning system
is on the controlling the fear olive as opposed to controlling the periphery. Is that reasonable?
Well, it's certainly consistent with what we know, and I just don't know.
I find this a very difficult subject to speculate on. Okay. It has puzzled me
for a long time and confused me. Right.
But we have an idea now about what this circuit does, right, how this could operate.
And what is interesting about this, and now we also know that all the data we
have is actually only describing a tiny fraction of that system, right? Right.
So, what's the rest of the cerebellum actually doing?
Well, a large part of the cerebellum will control movements that are in a certain way similar to eyelid.
It will control various muscles like leg withdrawal or finger movements and things like that.
Some parts of the cerebellum will control the forebrain.
You have a huge part of the cerebellum projecting to the forebrain.
And what it does there we don't know but presumably at least to some extent
what it does is it changes the.
Excitability of pyramidal cells controlling movements so that for instance if
you make an error when you try to reach something,
the cerebellum can learn to correct your movements and exciting a little bit
more those muscles that would tend to move your arm in a certain direction and
so on So that is one thing that's happening.
You have all the responses...
Of the this your system of balance that the
cerebellum controls it could operate in
a way the similar type link conditioning but my guess is that there
are significant differences but now a few years ago you also proposed that these
kinds of learning systems could actually underlie our ability to simulate right
to support internal simulation or because now your examples you seem to emphasize
very strongly the motor aspect of this.
Yes, but my view of internal simulation is that it's very similar to actual
motions, just as you turn off the output signals from the primary motor cortex.
And for all we know, it could well be the cerebellum that is doing it.
It could be the cerebellum that turns off or prevents movement from coming out.
We normally think of the cerebellum as producing signals to excite the motor
neurons in the motor cortex. But it could just as well be the opposite.
They could very well be there in order to inhibit or stop movements that could be dangerous to you.
So just as the cerebellum can produce a movement of the eyelid in anticipation
of something that might be harmful,
like an air puff or an insect coming into your eyes or something,
It could very well also project to stop or prevent movements that might be harmful.
For instance, you are walking, you are approaching something that is dangerous,
you should stop walking before you fall off a cliff or something.
Maybe the cerebellum is producing a signal that will enable you to stop the
ongoing movement before something dangerous happens.
Happens and the cerebellum is very good at it because it's
so well timed and it's very fast compared to these signals
coming from let's say the visual cortex to the fore to the forebrain it's very
very slow and you need for quick adaptation anticipating dangerous events you
need a fast system and the cerebellum is good at that but now do you believe that this um that
also plays a role in, let's say, conscious states or conscious processing.
Do you see this kind of simulation that you describe occurring in the cerebellum
or being supported by cerebellar processing also feeding back into conscious
states or do you really see those as completely distinct subsystems?
I don't think the cerebellum in itself could be conscious, But I do think that
the cerebellum is an integral part of what is going on in the cerebral cortex.
And I think that consciousness has to do, well, consciousness is a term that
covers too many different things.
But in my view, the most critical part of consciousness is the fact that we
have an inner reality that we can perform movements and see things and hear things.
Internally in the brain without connection to the external world and that is
what i mean by simulation so the cerebellum would play the same role in simulated
movements as it does in overt movements and it would generate anticipated movements
even if they are not and it would stop.
Continuation of a movement that just incipient and you just started start doing
the cerebellum could prevent that from occurring.
And by doing that, it will always modulate the internal simulation.
It will also, in that sense, modulate what's going on in your inner reality
and, if you want, in your consciousness.
Okay, but then it's more, let's say, an assistive function that then presents
this information to the conscious scene.
It's not really directly, let's say, it's not directly carrying that conscious scene. No, it's not.
But it has a particular kind of importance because one of the important aspects
of consciousness is your ability to anticipate what is going to happen.
And you are aware of something might be dangerous. If I do this, then that will happen.
This is something you're always aware of and it's a very important part of the
function of consciousness, I think.
And the cerebellum is very good at anticipation, and therefore I think that
the input from the cerebellum to the frontal cortex is very important for consciousness.
But I could argue that also unconscious functions have predictive components
to them. Oh, absolutely, absolutely. Absolutely.
And in fact, when you, I don't know if you've ever experienced being subjected
to eye blink conditioning, but
when you, if you do, you will notice how surprised you are when you blink.
Okay. It's not, it's not as if you're aware that, that, oh.
I hear the tone soon there will be an air puff i'd better
blink so that i i avoid the air puff it's actually
when you notice that the movement you're really surprised and i think the same
thing happens when you learn let's say to play the piano or any musical instrument
that that you you train and then suddenly you reach a point where your fingers
move by themselves you're not really.
You don't feel that you are moving the fingers you feel as if they are doing it themselves.
Because of an unconscious process and what has happened is that the cerebellum
has taken over into doing right exactly but so another so now that we solve
the puzzle of consciousness,
let's let's try another one which which i find
very very intriguing with respect to the cerebellum which is the one of causality
because which actually you also studied prior to entering into neuroscience
yes i worked in philosophy for a few years before yes and and so what's interesting
there is in the amount of conditioning we have this debate between contingency
and contiguity being dominant in conditioning.
That means either it has a specific order of events that matters,
or is it just that events co-occur in space and time, right?
So now in some sense, you could argue that the cerebellum is actually wired
up to be sensitive to a very specific order of events, right?
So that would be the contiguity view of conditioning.
But I could also now make an argument. You could argue that from an evolutionary perspective,
what is wired into this learning system is that causal relationships do exist
out there in the world because I have wired myself up to pick them up within
a timeframe of up to one second, right?
So do you feel that this wiring of the cerebellum from a sort of evolutionary
epistemological perspective tells us that causality is actually out there in
the real world and that this is the way of the brain to deal with it?
Well, you are now touching some extremely difficult questions.
I mean, we are really entering deep waters here.
And I can't comment on everything you said here, but let me first say that in
any behavior, the order of different components of your behavior is very important.
I mean, in language it's very obvious that the order of words is extremely important
for the comprehensiveness of the message.
Order can be achieved by a temporal code.
If every component of your speech has a specific time, then order will be secondary.
It will impose an order on it because if
if the first phonemes
are are generated early and the
later phonemes are generated late then the order of the
phonemes become sort of an unavoidable consequence but
of course it's also possible that
the cerebellum and the cerebellum might be
important for that but it's also possible that the cerebellum imposes an
order you can you can imagine for instance either you
have let's say that you play a piano and you have you're moving a certain a
certain finger in a certain number of times on a key and each key press has
a specific time on it so you can
imagine the purkinje cell sending out controlling that muscle sending out.
Temporal signals to to press the key now
and now and now and now but you could also imagine you had a chain of responses
so the first response would cause the second response which causes the third
response right and that is a very different kind of phenomenon and one of the
The difference is that in this case,
you could scale up and down the speed of the movement.
So an interesting thing is that you can talk a little bit slower,
but the order of the various components of your speech will be the same.
This is difficult to understand if you have timed signals coming all the time,
determining the exact time of each component.
It's much easier to understand it if you have a sequence of cause-effect relationship
as if one conditioned response triggers
a second conditioned response that triggers a third one and so on.
But what I was after was also to look at just the anatomy of this system, right?
Because it's very peculiar that you have these widely divergent parallel fibers
conveying states of the world and of the brain itself converging with these
highly specific climbing fibers and really tell you something,
let's say, intrinsically meaningful,
right? Okay, now this was painful, right?
And it is already structured in a way to deal with.
Time, right? That something happens before something else, but they can co-occur, right?
So isn't that one of the necessary conditions of a causal relationship? Yes, of course.
So this is why I was wondering whether we could not argue that really the cerebellum
is really biased towards, let's say, picking up.
Causal relations but in a very permissive
fashion right so it can also pick up illusory i wouldn't
necessarily say causal because i because i think
this would happen whether the whether the relationship is causal or pseudo correlation
from the point of view of the cerebellum it doesn't really matter what matters
is that the air puff tends to follow the tone even if the tone is not even if
the air puff is not caused by the tone so but that's a force in the lab right Yeah,
but from the biological point of view, if you look at it in sort of infunctional terms,
the important thing is that you have a predictive relationship,
which could be a pseudo-correlation that doesn't have to be causal.
So my guess is that the cerebellum would learn a non-causal correlation just
as well as a causal one, and it doesn't really matter.
Okay, the only thing I could then say in my defense is that,
of course, given that the system always learns to extinction,
right, it does with time zoom in on truly causal relations because these will
be the only one that are persistent in an interaction with an environment.
That's true, that's true.
And this is what is, yeah, and this is what often happens with pseudo-correlations.
They break down eventually.
Right, exactly. Because they are, because they're not causal,
it's possible to interfere with them in a different way.
That's exactly right yeah okay great so now that we also solved the causality
problem that's wonderful Jerry we're making great progress here so let's finish up with.
My last two questions so look you're in the business for a long time 25 years
working your way through the cerebellum and I think we made amazing progress
understanding cerebellum.
Also if you have farmed out to issues in consciousness so based on your experience
and your knowledge what would be jerry's law in our study of the brain,
pre-kinder cells learn temporal relationships not only changing strength of synapses okay,
okay that's my punchline all right and then if i'm going to visit you five years
from now at lund and i'm going to say okay jerry you made the prediction five
years ago and i want to see what happened with it what's the one prediction
you would like to sort of commit yourself to today.
That is very difficult to say because I can see before me a lot of some very,
very interesting avenues of research.
You have to give me one prediction. I don't know what they will generate,
but I suppose I can tell you what I think we will have learned.
We will have learned something about the molecular underpinnings of learning
a temperate relationship.
Relationship so i think we will have gone much deeper into receptor physiology
and second messenger systems and so on in the pre-kinder cells but there are
also a number of very difficult and,
at the moment unsolved problems about how the cerebellum interacts with the
cerebral cortex and if you take one very nice example prism adaptation if you
wear prisms that displace the outside world laterally.
Then if you try to point to a certain point at a certain object, there will be an error.
You will point to the side of that object.
And pretty soon, if you train to do pointing, wearing these goggles with displace
the outside world, you can fairly quickly adapt to it and you can point in the right direction.
The same thing happens if you have prisms that turn the world upside down.
Adapt to that also pretty fast.
Now, this is believed to be done by the cerebellum. And given what we now believe
about learning in the cerebellum, it means that pre-kindi cells controlling
the muscles that point your arm and finger,
those pre-kindi cells will send some kind of corrective signals up to the motor cortex.
Now, how do these pre-kindi cells learn to do that? they would need climbing
fiber signals to change their responses and where do the climbing fiber signals come from.
What triggers the learning is the mismatch between the intended movement and the actual movement.
You're pointing not where you intended. There's nothing wrong in pointing in a certain direction.
It's wrong only when you intend to point at something else.
So there must be some way for the brain to detect a mismatch between what you
intend and what you actually do.
And that mismatch has to generate, activate inferior olives so that you get
a climbing fiber signal to the cerebellum.
This is extremely intriguing and we just don't know.
We don't even know how the intended movement is encoded. We don't know really what that means.
And how do we detect the mismatch? Where does that occur?
And it seems to me that this will, if you can answer those questions,
you would have gone a very long way to understanding how the cerebellum interacts
with the forebrain because as you know
the cerebellum takes part in all your movement and probably
also in your cognitive function when you just simulate movement but but
it it takes part in all of it it fine-tunes the
amplitude the precision the timing and so on but it in order to learn it it
will have to to receive climbing fiber input not only when you do something
painful but also when you do something that you didn't intend to do and how
is that signal being generated.
And this is something that I believe we will know perhaps not in five years, but in 10 years.
That's great. Well, Jerry Haslow, thank you very much for this conversation.
Thank you. It's very nice.