Welcome to the Huberman Lab Podcast,

where we discuss science

and science-based tools for everyday life.

I’m Andrew Huberman,

and I’m a professor of neurobiology and ophthalmology

at Stanford School of Medicine.

Today, my guest is Dr. David Burson,

professor of medical science, neurobiology,

and ophthalmology at Brown University.

Dr. Burson’s laboratory is credited

with discovering the cells in the eye

that set your circadian rhythms.

These are the so-called

intrinsically photosensitive melanopsin cells.

And while that’s a mouthful,

all you need to know for sake of this introduction

is that those are the cells

that inform your brain and body about the time of day.

Dr. Burson’s laboratory has also made

a number of other important discoveries

about how we convert our perceptions

of the outside world into motor action.

More personally, Dr. Burson has been my go-to resource

for all things neuroscience for nearly two decades.

I knew of his reputation as a spectacular researcher

for a long period of time,

and then many years ago, I cold called him out of the blue.

I basically corralled him into a long conversation

over the phone, after which he invited me out to Brown,

and we’ve been discussing neuroscience

and how the brain works and the emerging new technologies

and the emerging new concepts in neuroscience

for a very long time now.

You’re going to realize today

why Dr. Burson is my go-to source.

He has an exceptionally clear and organized view

of how the nervous system works.

There are many, many parts of the nervous system,

different nuclei and connections and circuits

and chemicals and so forth,

but it takes a special kind of person

to be able to organize that information

into a structured and logical framework

that can allow us to make sense of how we function

in terms of what we feel, what we experience,

how we move through the world.

Dr. Burson is truly one of a kind

in his ability to synthesize and organize

and communicate that information.

And I give him credit as one of my mentors

and one of the people that I respect most

in the field of science and medical science generally.

Today, Dr. Burson takes us on a journey

from the periphery of the nervous system,

meaning from the outside, deep into the nervous system,

layer by layer, structure by structure, circuit by circuit,

making clear to us how each of these individual circuits

work and how they work together as a whole.

It’s a really magnificent description

that you simply cannot get from any textbook,

from any popular book, and frankly, as far as I know,

from any podcast that currently exists out there.

So it’s a real gift to have this opportunity

to learn from Dr. Burson.

Again, I consider him my mentor

in the field of learning and teaching neuroscience,

and I’m excited for you to learn from him.

One thing is for certain, by the end of this podcast,

you will know far more about how your nervous system works

than the vast majority of people out there,

including many expert biologists and neuroscientists.

Before we begin, I’d like to emphasize that this podcast

is separate from my teaching and research roles at Stanford.

It is, however, part of my desire and effort

to bring zero cost to consumer information about science

and science-related tools to the general public.

In keeping with that theme,

I’d like to thank the sponsors of today’s podcast.

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And now for my discussion with Dr. David Burson.

Welcome.

Thank you.

So nice to be here.

Great to have you.

For more than 20 years,

you’ve been my go-to source for all things,

nervous system, how it works, how it’s structured.

So today I want to ask you some questions about that.

I think people would gain a lot of insight

into this machine that makes them think and feel

and see, et cetera.

If you would, could you tell us how we see?

A photon of light enters the eye, what happens?

Right.

I mean, how is it that I look outside,

I see a truck drive by, or I look on the wall,

I see a photo of my dog, how does that work?

Right, so this is an old question, obviously.

And clearly in the end,

the reason you have a visual experience

is that your brain has got some pattern of activity

that it associates with the input from the periphery.

But you can have a visual experience

with no input from the periphery as well.

When you’re dreaming, you’re seeing things

that aren’t coming through your eyes.

Are those memories?

I would say in a sense,

they may reflect your visual experience.

They’re not necessarily specific visual memories,

but of course they can be.

But the point is that the experience of seeing

is actually a brain phenomenon.

But of course, under normal circumstances,

we see the world because we’re looking at it

and we’re using our eyes to look at it.

And fundamentally, when we’re looking at the exterior world,

it’s what the retina is telling the brain that matters.

So there are cells called ganglion cells,

these are neurons that are the key cells

for communicating between eye and brain.

The eye is like the camera,

it’s detecting the initial image,

doing some initial processing,

and then that signal gets sent back to the brain proper.

And of course, it’s there at the level of the cortex

that we have this conscious visual experience.

There are many other places in the brain

that get visual input as well,

doing other things with that kind of information.

So I get a lot of questions about color vision.

If you would, could you explain how is it

that we can perceive reds and greens and blues

and things of that sort?

Right, so the first thing to understand about light

is that it’s just a form of electromagnetic radiation.

It’s vibrating, it’s oscillating.

When you say it’s vibrating, it’s oscillating,

you mean that photons are actually moving?

Well, in a sense, photons,

they’re certainly moving through space.

We think about photons as particles,

and that’s one way of thinking about light,

but we can also think of it as a wave, like a radio wave.

Either way is acceptable.

And the radio waves have frequencies,

like the frequencies on your radio dial.

And certain frequencies in the electromagnetic spectrum

can be detected by neurons in the retina.

Those are the things we see,

but there’s still different wavelengths

within the light that can be seen by the eye.

And those different wavelengths are unpacked, in a sense,

or decoded by the nervous system

to lead to our experience of color.

Essentially, different wavelengths give us the sensation

of different colors through the auspices

of different neurons that are tuned

to different wavelengths of light.

So when a photon,

so when a little bit of light hits my eye, goes in,

the photoreceptors convert that into electrical signal.

Right.

How is it that a given photon of light

gives me the perception,

eventually leads to the perception

of red versus green versus blue?

Right.

So if you imagine that in the first layer of the retina,

where this transformation occurs

from electromagnetic radiation into neural signals,

that you have different kinds of sensitive cells

that are expressing,

they’re making different molecules within themselves

for this express purpose of absorbing photons,

which is the first step in the process of seeing.

Now, it turns out that altogether,

there are about five proteins like this

that we need to think about in the typical retina.

But for seeing color, really, it’s three of them.

So there are three different proteins.

Each absorbs light with a different preferred frequency,

and then the nervous system keeps track

of those signals, compares and contrasts them

to extract some understanding

of the wavelength composition of light.

So you can see just by looking at a landscape,

oh, it must be late in the day

because things are looking golden.

That’s all a function of our absorbing the light

that’s coming from the world

and interpreting that with our brain

because of the different composition

of the light that’s reaching our eyes.

Is it fair to assume that my perception of red

is the same as your perception of red?

Well, that’s a great question.

And that mine is better?

No, I’m just kidding, I’m just kidding.

It’s a great question.

It’s a deep philosophical question.

It’s a question that really probably

can’t even ultimately be answered

by the usual empirical scientific processes

because it’s really about an individual’s experience.

What we can say is that the biological mechanisms

that we think are important for seeing color, for example,

seem to be very highly similar

from one individual to the next,

whether it be human beings or other animals.

And so we think that the physiological process

looks very similar on the front end.

But once you’re at the level of perception

or understanding or experience,

that’s something that’s a little bit tougher to nail down

with the sorts of scientific approaches

that we approach biological vision with, let’s say.

You mentioned that there are five

different cone types, essentially,

cones being the cells that absorb light

of different wavelengths.

I often wondered when I had my dog,

what he saw and how his vision differs from our vision.

And certainly there are animals that can see things

that we can’t see.

What are some of the more outrageous examples of that?

Of seeing things that we can’t?

And in the extreme,

you know, dogs, I’m guessing, see reds more as oranges.

Is that right?

Because they don’t have the same array of neurons

that we have for seeing color.

Right, so the first thing is,

it’s not really five types of cones.

There are really three types of cones.

And if you look at the way that color vision

is thought to work, you can sort of see

that it has to be three different signals.

There are a couple of other types of pigments.

One is really mostly for dim light vision.

When you’re walking around in a moonless night

and you’re seeing things with very low light,

that’s the rod cell that uses its own pigment.

And then there’s another class of pigments

we’ll probably talk about a little bit later,

this melanopsin pigment.

I thought you were referring to like ultraviolet

and infrared and things of that sort.

Right, so in the case of a typical,

well, let’s put it this way, in human beings,

most of us have three cone types

and we can see colors that stem from that.

In most mammals, including your dog or your cat,

there really are only two cone types.

And that limits the kind of vision that they can have

in the domain of wavelength or color, as you would say.

So really a dog sees the world kind of like

a particular kind of colorblind human might see the world,

because instead of having three channels

to compare and contrast, they only have two channels.

And that makes it much more difficult to figure out

exactly which wavelength you’re looking at.

Do colorblind people suffer much

as a consequence of being colorblind?

Well, it’s like so many other disabilities.

The world is built for people of the most common type.

So in some cases, the expectation can be there

that somebody can see something that they won’t be able to

if they’re missing one of their cone types, let’s say.

So in those moments, that can be a real problem.

If there’s a lack of contrast to their visual system,

they will be blind to that.

In general, it’s a fairly modest visual limitation

as things go.

For example, if not being able to see acutely

can be much more damaging,

not being able to read fine print, for example.

Yeah, I suppose if I had to give up

the ability to see certain colors

or give up the ability to see clearly,

I’d certainly trade out color for clarity.

Right, of course, color is very meaningful to us

as human beings, so we would hate to give it up.

But obviously, dogs and cats and all kinds of other mammals

do perfectly well in the world.

Yeah, because we take care of them.

I spent most of my time taking care of that dog.

He took care of me too.

Let’s talk about that odd photopigment.

Photopigment, of course, being the thing

that absorbs light of a particular wavelength.

And let’s talk about these specialized ganglion cells

that communicate certain types of information

from eye to the brain

that are so important for so many things.

What I’m referring to here, of course,

is your co-discovery of the so-called

intrinsically photosensitive cells,

the neurons in the eye that do so many of the things

that don’t actually have to do with perception,

but have to do with important biological functions.

What I would love for you to do is explain to me

why once I heard you say,

we have a bit of fly eye in our eye,

and you showed this slide of a giant fly

from a horror movie trying to attack this woman,

and maybe it was an eye also.

So what does it mean that we have a bit of a fly eye

in our eye?

Yeah, so this last pigment is a really peculiar one.

One can think about it as really

the initial sensitive element in a system

that’s designed to tell your brain

about how bright things are in your world.

And the thing that’s really peculiar about this pigment

is that it’s in the wrong place, in a sense.

When you think about the structure of the retina,

you think about a layer cake, essentially.

You’ve got this thin membrane at the back of your eye,

but it’s actually a stack of thin layers.

And the outermost of those layers

is where these photoreceptors

you were talking about earlier are sitting.

That’s where the film of your camera is, essentially.

That’s where the photons do their magic

with the photopigments and turn it into a neural signal.

I like that.

I’ve never really thought of the photoreceptors

as the film of the camera, but that makes sense.

Yeah, or like the sensitive chip,

a CCD chip in your cell phone.

It’s the surface on which the light pattern

is imaged by the optics of the eye,

and now you’ve got an array of sensors

that’s capturing that information

and creating a bitmap, essentially.

But now it’s in neural signals

distributed across the surface of the retina.

So all of that was known to be going on 150 years ago.

A couple of types of photoreceptors, cones and rods.

If you look a little bit more closely, three types of cones.

That’s where the transformation

from electromagnetic radiation

to neural signals was thought to take place.

But it turns out that this last photopigment

is in the other end of the retina,

the innermost part of the retina.

And that’s where the so-called ganglion cells are.

Those are the cells that talk to the brain,

the ones that actually can communicate directly

what information comes to them from the photoreceptors.

And here you’ve got a case where actually

some of the output neurons that we didn’t think

had any business being directly sensitive to light

were actually making this photopigment,

absorbing light and converting that to neural signals

and sending it to the brain.

So that made it pretty surprising and unexpected,

but there are many surprising things about these cells.

So, and what is the relationship to the fly eye?

Right, so the link there is that if you ask

how the photopigment now communicates downstream

from the initial absorption event

to get to the electrical signal,

that’s a complex cellular process.

It involves many chemical steps.

And if you look at how photoreceptors in our eyes work,

you can see what that cascade is, how that chain works.

If you look in the eyes of flies or other insects

or other invertebrates,

there’s a very similar kind of chain,

but the specifics of how the signals get

from the absorption event by the pigment

to the electrical response that the nervous system

can understand are characteristically different

between fuzzy, furry creatures like us

and insects, for example, like the fly.

I see.

So these funny extra photoreceptors

that are in the wrong layer

doing something completely different

are actually using a chemical cascade

that looks much more like what you would see

in a fly photoreceptor

than what you would see in a human photoreceptor,

a rod or a cone, for example.

So it sounds like it’s a very primitive part of,

primitive aspect of biology that we maintain.

Exactly right.

You know, and despite the fact

that dogs can’t see as many colors as we can

and cats can’t see as many colors as we can,

we have all this extravagant stuff for seeing color.

And then you’ve got this other pigment

sitting in the wrong, not wrong,

but in a different part of the eye,

sending, processing light very differently

and sending that information into the brain.

So what do these cells do?

I mean, presumably they’re there for a reason.

They are.

And the interesting thing is that one cell type like this,

carrying one kind of signal,

which I would call a brightness signal, essentially,

can do many things in the brain.

When you say brightness signal,

you mean that it, like right now,

I have these cells.

Do I have these cells?

You do. Of course not.

I’m joking.

I hope I have these cells in my eye.

And they’re paying attention to how bright it is overall,

but they’re not paying attention, for instance,

to the edge of your ear

or what else is going on in the room.

Right, so it’s the difference

between knowing what the objects are on the table

and knowing whether it’s bright enough

to be daylight right now.

So why does your nervous system

need to know whether it’s daylight right now?

Well, one thing that needs to know,

that is your circadian clock.

You know, if you travel across time zones to Europe,

now your internal clock thinks it’s California time,

but the rotation of the earth

is for a different part of the planet.

The rising and setting of the sun

is not at all what your body is anticipating.

So you’ve got an internal representation

of the rotation of the earth in your own brain.

That’s your circadian system.

It’s keeping time.

But now you’ve played a trick on your nervous system.

You put yourself in a different place

where the sun is rising at the quote, wrong time.

Well, that’s not good for you, right?

So you gotta get back on track.

One of the things this system does

is sends a, oh, it’s daylight now signal to the brain,

which compares with its internal clock.

And if that’s not right, it tweaks the clock gradually

until you get over your jet lag

and you feel back on track again.

So the jet lag case makes a lot of sense to me,

but presumably these elements didn’t evolve for jet lag.

Right.

So what are they doing on a day-to-day basis?

Right, well, one way to think about this

is that the clock that you have in not just your brain,

in all the cells, almost all of the cells of your body,

they’re all oscillating.

They’re all, you know.

They got little clocks in them.

Little clocks in themselves.

They’re all clocks.

You know, they need to be synchronized appropriately.

And the whole thing has to be built

in biological machinery.

This is actually a beautiful story

about how gene expression can control gene expression.

And if you set it up right,

you can set up a little thing that just sort of hums along

at a particular frequency.

In our case, it’s humming along at 24 hours

because that’s how our earth rotates

and it’s all built into our biology.

So this is great, but the reality is

that the clock can only be so good.

I mean, we’re talking about biology here.

It’s not precision engineering.

And so it can be a little bit off.

Well, also it doesn’t, it’s in our brain.

So it doesn’t have access to any regular unerring signal.

Well, if in the absence of the rising

and setting of the sun, it doesn’t.

If you put someone in a cave,

their biological clock will keep time

to within a handful of minutes of 24 hours.

That’s no problem for one day.

But if this went on without any correction,

eventually you’d be out of phase.

And this is actually one of the things

that blind patients often complain about.

They’ve got retinal blindness.

Their retina is insomnia and-

Because their brain’s awake in the middle of the night.

Exactly, they’re not synchronized.

Their clock is there, but they’re drifting out of phase

because their clock’s only good to, you know,

24.2 hours or 23.8 hours.

Little by little, they’re drifting.

So you need a synchronization signal.

So even if you never cross time zones,

and of course we didn’t back on the Savannah,

we stayed within walking distance of where we were,

you still need a synchronizer

because otherwise you have nothing to actually confirm

when the rising and the setting of the sun is.

That’s what you’re trying to synchronize yourself to.

I’m fascinated by the circadian clock

and the fact that all the cells of our body

have essentially a 24-hour-ish clock in them.

Right.

We hear a lot about these circadian rhythms

and circadian clocks,

the fact that we need light input from these special neurons

in order to set the clock,

but I’ve never really heard it described

how the clock itself works

and how the clock signals to all the rest of the body

when the liver should be doing one thing

and when the stomach should be doing another.

I know you’ve done some work on the clock.

So if you would just maybe briefly describe

where the clock is, what it does,

and some of the top contour

of how it tells the cells of the body what to do.

Right.

So the first thing to say is that, as you said,

the clock is all over the place.

Most of the tissues in your body have clocks.

We probably have, what, millions of clocks in our body.

Yeah, I would say that’s probably fair.

If you have millions of cell types,

you probably may have millions of clocks.

But the role of the central pacemaker

for the circadian system is to coordinate all of these.

And there’s a little nucleus,

a little collection of nerve cells in your brain

that’s called the suprachiasmatic nucleus, the SCN.

And it is sitting in a funny place

for the rest of the structures in the nervous system

that get direct retinal input.

It’s sitting in the hypothalamus,

which you can think about

as sort of the great coordinator of drives and-

The source of all our pleasures and all our problems.

Right. Or most our problems.

Yes, it really is.

But it’s sort of, you know, deep in your brain,

things that drive you to do things.

If you’re freezing cold, you put on a coat, you shiver.

All these things are coordinated by the hypothalamus.

So this pathway that we’re talking about from the retina

and from these peculiar cells

that are encoding light intensity

are sending signals directly into a center

that’s surrounded by all of these centers

that control autonomic nervous system

and your hormonal systems.

So this is a part of your visual system

that doesn’t really reach the level of consciousness.

It’s not something you think about.

It’s happening under the radar kind of all the time.

And the signal is working its way

into this central clock coordinating center.

Now, what happens then is not that well understood,

but it’s clear that this is a neural center

that has the same ability to communicate

with other parts of your brain as any other neural center.

And clearly there are circuits

that involve connections between neurons

that are conventional.

But in addition, it’s quite clear

that there are also sort of humoral effects,

that things are oozing out of the cells in the center

and maybe into the circulation

or just diffusing through the brain to some extent

that can also affect neurons elsewhere.

But the hypothalamus uses everything

to control the rest of the bodies.

And that’s true of the suprachiasmatic nucleus,

this circadian center as well.

It can get its fingers into the autonomic nervous system,

the humoral system, and of course,

up to the centers of the brain

that organize coordinated rational behavior.

So if I understand correctly,

we have this group of cells, the suprachiasmatic nucleus.

It’s got a 24-hour rhythm.

That rhythm is more or less matched

to what’s going on in our external world

by the specialized set of neurons in our eye.

But then the master clock itself, the SCN,

releases things in the blood, humoral signals,

that go out various places in the body.

And then you said to the autonomic system,

which is regulating more or less how alert or calm we are,

as well as our thinking and our cognition.

So I’d love to talk to you about the autonomic part.

Presumably that’s through melatonin.

It’s through adrenaline.

How is it that this clock is impacting

how the autonomic system, how alert or calm we feel?

Right, so there are pathways

by which the suprachiasmatic nucleus can access

both the parasympathetic and sympathetic nervous system.

Just so people know, the sympathetic nervous system

is the one that tends to make us more alert,

and the parasympathetic nervous system

is the portion of the autonomic nervous system

that makes us feel more calm in broad context.

To first approximation, right.

So this is, both of these systems are within the grasp

of the circadian system through hypothalamic circuits.

One of the circuits that will be,

I think of particular interest to some of your listeners,

is a pathway that involves this sympathetic branch

of the autonomic nervous system, the fight or flight system,

that is actually through a very circuitous route

innervating the pineal gland,

which is sitting in the middle of your brain.

The so-called third eye.

Right.

So this is the-

We’ll have to get back to why it’s called the third eye,

because, yeah.

That’s an interesting history.

You can’t call something the third eye and not,

and just, you know.

Just leave it there.

Just leave it there.

Right. Right.

Anyway, this is the major source of melatonin in your body.

So light comes into my eye.

Yes.

Passed off to the suprachiasmatic nucleus,

essentially not the light itself,

but the signal representing the light.

Sure.

Then the SCN, the suprachiasmatic nucleus,

can impact the melatonin system via the pineal.

Right.

The way this is seen is that if you were to measure

your melatonin level over the course of the day,

if you could do this, you know, hour by hour,

you’d see that it’s really low during the day,

very high at night.

But if you get up in the middle of the night

and go to the bathroom

and turn on the bright fluorescent light,

your melatonin level is slammed to the floor.

Light is directly impacting your hormonal levels

through this mechanism that we just described.

So this is one of the routes by which light can act

on your hormonal status through pathways

that are completely beyond

what you normally would think about, right?

You’re thinking about the things in the bathroom.

Oh, there’s the toothbrush.

You know, there’s the tube of toothpaste.

But meanwhile, this other system is just counting photons

and saying, oh, wow, there’s a lot of photons right now.

Let’s shut down the melatonin release.

This is one of the main reasons why I’ve encouraged people

to avoid bright light exposure in the middle of the night,

not just blue light, but bright light of any wavelength,

because there’s this myth out there that blue light,

because it’s the optimal signal for activating this pathway

and shutting down melatonin,

is the only wavelength of light that can shut it down.

Am I correct in thinking that if a light is bright enough,

it doesn’t matter if it’s blue light, green light,

purple light, even red light,

you’re going to slam melatonin down to the ground,

which is not a good thing to happen

in the middle of the night, correct?

Right, yeah.

I mean, any light will affect the system to some extent.

The blue light is somewhat more effective,

but don’t fool yourself into thinking

that if you use red light,

that means you’re avoiding the effect.

It’s certainly still there,

and certainly if it’s very bright,

it’ll be more effective in driving the system

than dim blue light would be.

Interesting.

A lot of people wear blue blockers,

and in a kind of odd twist of misinformation out there,

a lot of people wear blue blockers

during the middle of the day,

which basically makes no sense,

because during the middle of the day

is when you want to get a lot of bright light,

and including blue light into your eyes, correct?

Absolutely, and not just for the reasons

we’ve been talking about in terms of circadian effects.

There are major effects of light on mood,

and seasonal affective disorder

apparently is essentially a reflection

of this same system in reverse.

If you’re living in the northern climes,

and you’re not getting that much light

during the middle of the winter in Stockholm,

you might be prone to depression,

and phototherapy might be just the ticket for you,

and that’s because there’s a direct effect

of light on mood.

There’s an example where if you don’t have enough light,

it’s a problem.

So I think you’re exactly right.

It’s not about is light good or bad for you.

It’s about what kind of light and when

that makes the difference.

Yeah, the general rule of thumb that I’ve been living by

is to get as much bright light in my eyes,

ideally from sunlight, anytime I want to be alert,

and doing exactly the opposite when I want to be asleep

or getting drowsy.

And there are aspects of this

that spin out way beyond the conversation we’re having now

to things like this.

It turns out that the incidence of myopia-

Nearsightedness.

Nearsightedness, right,

is strongly related to the amount of time

that kids spend outdoors.

In what direction of effect?

The more they spend time outdoors,

the less nearsightedness they have.

So this is all about-

And is that because they’re viewing things at a distance

or because they’re getting a lot of blue light, sunlight?

It’s a great question.

It is not fully resolved what the epidemiological,

what the basis of that epidemiological finding is.

One possibility is the amount of light,

which would make me think about

this melanopsin system again,

but it might very well be a question of accommodation.

That is the process by which you focus on near or far things.

If you’re never outdoors, everything is nearby.

If you’re outdoors, you’re focusing far.

So this is-

Well, unless you’re on your phone.

Right, exactly.

There’s a tremendous amount of interest these days

in watches and things that count steps.

I’m beginning to realize that we should probably have

a device that can count photons during the day

and can also count photons at night and tell us,

hey, you’re getting too many photons.

You’re going to shut down your melatonin at night

or you’re not getting enough photons.

Today, you didn’t get enough bright light,

whether or not it’s from artificial light or from sunlight.

I guess that, where would you put it?

I guess you’d put it on the top of your head

or you’d probably want it someplace outward facing.

Right, probably what you need is as many photons

over as much of the retina as possible

to recruit as much of the system as possible.

In thinking about other effects

of this non-image forming pathway

that involves these special cells in the eye and the SCN,

you had a paper a few years ago

looking at retinal input to an area of the brain,

which has a fancy name, the perihabenula,

but names don’t necessarily matter,

that had some important effects on mood

and other aspects of light.

Maybe you could tell us a little bit about

what is the perihabenula?

Oh, wow, so that’s a fancy term,

but I think the way to think about this

is it’s a chunk of the brain

that is sitting as part of a bigger chunk

that’s really the linker

between peripheral sensory input of all kinds,

virtually all kinds,

whether it’s auditory input or tactile input

or visual input to the region of your brain, the cortex,

that allows you to think about these things

and make plans around them

and to integrate them and that kind of thing.

So, you know, we’ve known about a pathway

that gets from the retina

through this sort of linker center,

it’s called the thalamus,

and then on up to the cortex.

It’s like a train station.

Exactly, but you want to arrive at the destination, right?

Now you’re at Grand Central

and now you can do your thing

as you’re up at the cortex.

So, this is the standard pattern.

You have sensory input coming from the periphery,

you’ve got these peripheral elements

that are doing the initial stages of the-

The eye, the ear, the nose.

The eye, the skin of your fingertips, right?

You know, the taste buds on your tongue,

they’re taking this raw information in

and they’re doing some pre-processing maybe,

or, you know, the early circuits are,

but eventually most of these signals

have to pass through the gateway to the cortex,

which is the thalamus.

And we’ve known for years, for decades, many decades,

what the major throughput pathway

from the retina to the cortex is

and where it ends up.

It ends up in the visual cortex.

You know, you pat the back of your head,

that’s where the receiving center is

for the main pathway from retina to cortex.

But wait a minute, there’s more.

There’s this little side pathway

that goes through a different part

of that linking thalamus center,

the gateway to the cortex.

It’s like a local train.

Yeah.

From Grand Central to-

It’s in a weird part of the neuroid, right?

It’s a completely different,

it’s like a little trunk line that branches off

and goes out into the hinterlands

and it’s going to the part of this linker center

that’s talking to a completely different part of cortex,

way up front, frontal lobe,

which is much more involved in things like planning

or self-image or-

Self-image, literally how one thinks about themselves.

Views oneself.

You know, do you feel good about yourself?

Or, you know, what’s your plan for next Thursday?

You know, it’s a very high level center

in the highest level of your nervous system.

And this is the region that is getting input

from this pathway,

which is mostly worked out in this function

by Samer Hattar’s lab.

I know you had him on the podcast.

He didn’t talk about this pathway.

This pathway at all, right.

So Diego Fernandez and Samer

and the folks that work with them

were able to show that this pathway doesn’t just exist

and get you to a weird place.

But if you activate it at kind of the wrong time of day,

animals can become depressed.

And if you silence it under the right circumstances,

then weird lighting cycles

that would normally make them act sort of depressed

no longer have that effect.

So it sounds to me like there’s this pathway

from eye to this unusual train route

through the structure we call the thalamus,

then up to the front of the brain

that relates to things of self-perception,

kind of higher level functions.

I find that really interesting

because most of what I think about

when I think about these fancy,

well, or these primitive rather,

neurons that don’t pay attention to the shapes of things,

but instead to brightness,

I think of, well, it regulates melatonin, circadian clock,

mood, hunger, the really kind of vegetative stuff,

if you will.

And this is interesting

because I think a lot of people experience depression,

not just people that live in Scandinavia

in the middle of winter.

And we are very much divorced

from our normal interactions with light.

It also makes me realize

that these intrinsically photosensitive cells

that set the clock, et cetera,

are involved in a lot of things.

I mean, they seem to regulate a dozen or more

different basic functions.

I want to ask you about a different aspect

of the visual system now,

which is the one that relates to our sense of balance.

So I love boats, but I hate being on them.

I love the ocean from shore

because I get incredibly seasick.

I’ll just, it’s awful.

I think I’m gonna get seasick if I think about it too much.

And once I went on a boat trip,

I came back and I actually got motion sick

or wasn’t seasick because I went rafting.

So there’s a system that somehow gets messed up.

They always tell us if you’re feeling sick

to look at the horizon, et cetera, et cetera.

So what is the link between our visual system

and our balance system?

And why does it make us nauseous sometimes

when the world is moving in a way

that we’re not accustomed to?

I realize this is a big question

because it involves eye movement, et cetera.

But let’s maybe just walk in at the simplest layers

of vision, vestibular, so-called balance system.

And then maybe we can piece the system together

for people so that they can understand.

And then also we should give them some tools

for adjusting their nausea

when their vestibular system is out of whack.

Cool.

So, I mean, the first thing to think about

is that the vestibular system is designed

to allow you to see how you’re, or detect,

sense how you’re moving in the world, through the world.

It’s a funny one because it’s about your movement

in relationship to the world in a sense,

and yet it’s sort of interoceptive

in the sense that it is really, in the end,

sensing the movement of your own body.

Okay, so interoception,

we should probably delineate for people,

is when you’re focusing on your internal state

as opposed to something outside you.

Right.

But it’s a gravity-sensing system.

Well, it’s partly a gravity-sensing system

in the sense that gravity is a force

that’s acting on you as if you were moving

through the world in the opposite direction.

All right, now you got to explain that.

You got to explain that one to me.

Okay, so basically the idea is that

if we leave gravity aside,

we’re just sitting in a car, in a passenger seat,

and the driver hits the accelerator

and you start moving forward.

You sense that.

If your eyes were closed, you’d sense it.

If your ears were plugged and your eyes were closed,

you’d still know it.

Yeah, many people take off on the plane like this.

They’re dreading the flight

and they know when the plane is taking off.

Sure, that’s your vestibular system talking

because anything that jostles you

out of the current position you’re in right now

will be detected by the vestibular system pretty much.

So this is a complicated system,

but it’s basically in your inner ear,

very close to where you’re hearing.

I can put it there.

And I don’t know who they is.

I don’t really know.

They’re sort of derived.

I’m just kidding.

To steal our friend Russ Van Gelder’s explanation,

we weren’t consulted the design phase

That’s a great line, that’s a great line.

But it’s interesting it’s in the ear.

Yeah, it’s deep in there

and it’s served by the same nerve actually

that serves the hearing system.

One way to think about it is both the hearing system

and this vestibular self-motion sensing system

are really detecting the signal in the same way.

They’re hairy cells and they’re excited.

Hairy cells?

Yeah, sort of.

Little cilia sticking up off the surfaces.

And depending on which way you bend those,

the cells will either be inhibited or excited.

They’re not even neurons,

but then they talk to neurons with a neuron-like process

and off you go.

Now you’ve got an auditory signal.

If you’re sensing things bouncing around in your cochlea,

which is- Sound waves.

Sympathetically, the bouncing of your eardrum,

which is sympathetically the sound waves in the world.

But in the case of the vestibular apparatus,

evolution has built a system

that detects the motion of, say, fluid

going by those hairs.

And if you put a sensor like that

in a tube that’s fluid-filled,

now you’ve got a sensor that will be activated

when you rotate that tube around the axis

that passes through the middle of it.

Those who are just listening won’t be able to-

No, I think that makes sense.

I always think of it as three hula hoops.

Right, three hula hoops.

One standing up, one lying down on the ground.

Right, one the other way.

Three directions.

The people who fly will talk about roll, pitch, and yaw,

that kind of thing.

So three axes of encoding,

just like in the cones of the retina.

Sort of the yes, the no, and then I always say it’s,

and then the puppy head tilt.

Yeah, the puppy head tilt.

That’s the other one.

So the point is that your brain

is eventually going to be able to unpack

what these sensors are telling you

about how you just rotated your head

in very much the way that the three types of cones

we were talking about before

are reading the incoming photons

in the wavelength domain differently.

Red, green, blue.

Yeah, you can compare and contrast, you get red, green, blue.

So it’s the same basic idea.

If you have three sensors and you array them properly,

now you can tell if you’re rotating your head

left or right, up or down.

That’s the sensory signal coming back into your brain,

confirming that you’ve just made a movement that you will.

But what about on the plane?

Because when I’m on the plane,

I’m completely stationary.

The plane’s moving, but my head hasn’t moved.

So I’m just moving forward, gravity is constant.

Exactly.

How do I know I’m accelerating?

So what’s happening now is your brain is sensing the motion

and the brain is smart enough also to ask itself,

did I will that movement or did that come from the outside?

So now in terms of sort of understanding

what the vestibular signal means,

it’s got to be embedded in the context

of what you tried to do or what your other sensory systems

are telling you about what’s happening right now.

I see, so that’s very interesting.

But it’s not conscious, or at least if it’s conscious,

it’s not conscious, it’s definitely very fast, right?

The moment that plane starts moving,

I know that I didn’t get up out of my chair

and run forward. Right.

But I’m not really thinking about getting up

out of my chair, I just know.

I guess the way I think about it is that

the nervous system is, quote, aware at many levels.

When it gets all the way up to the cortex

and we’re thinking about it, you’re talking about it,

you know, that’s cortical.

But the lower levels of the brain that don’t require you

to actually actively think about it,

they’re just doing their thing, are also made aware, right?

A lot of this is happening under the surface

of what you’re thinking.

These are reflexes.

Okay.

So we’ve got this gravity sensing system.

Right.

I’m nodding for those that are listening,

for a yes movement of the head, a no movement of the head,

or the tilting of the head from side to side.

Right.

And then you said that knowledge about whether or not

activation of that system comes from my own movements

or something acting upon me, like the plane moving,

has to be combined with other signals.

And so how is the visual information

or information about the visual world

combined with balance information?

Right.

So, I mean, I guess maybe the best way to think about

how these two systems work together

is to think about what happens

when you suddenly rotate your head to the left.

When you suddenly rotate your head to the left,

your eyes are actually rotating to the right automatically.

You do this in complete darkness.

If you had an infrared camera and watched yourself

in complete darkness, you can’t see anything.

Rotating your head to the left,

your eyes would rotate to the right.

That’s your vestibular system saying,

I’m gonna try to compensate for the head rotation

so my eyes are still looking in the same place.

Why is that useful?

Well, if it’s always doing that,

then the image of the world on your retina

will be pretty stable most of the time.

And that actually helps vision.

Have they built this into cameras for image stabilization?

Because when I move, when I take a picture with my phone,

it’s blurry, it’s not clear.

Well, actually, you might want to get a better phone

because now what they have is software in the better abs

that will do a kind of image stabilization post hoc

by doing a registration of the images

that are bouncing around.

They say the edge of the house was here,

so let’s get that aligned in each of your images.

So you may not be aware if you’re using a good new phone

that if you walk around a landscape and hold your phone,

that there’s all this image stabilization going on.

But it’s built into standard cinematic technology now

because if you tried to do a handheld camera,

things would be bouncing around,

things would be unwatchable.

You wouldn’t be able to really understand

what’s going on in the scene.

So the brain works really hard

to mostly stabilize the image of the world

on your retina.

Now, of course, you’re moving through the world,

so you can’t stabilize everything.

But the more you can stabilize most of the time,

the better you can see.

And that’s why when we’re scanning a scene,

looking around at things,

we’re making very rapid eye movements

for very short periods of time, and then we just rest.

But we’re not the only ones that do that.

If you ever watch a hummingbird,

it does exactly the same thing at a feeder, right?

But it’s with its body.

It’s going to make a quick movement,

and then it’s going to be stable.

And when you watch a pigeon walking on the sidewalk,

it does this funny head bobbing thing.

But what it’s really doing is racking its head back

on its neck while its body goes forward

so that the image of the visual world stays static.

Is that why they’re doing it?

Yes.

And you’ve seen the funny chicken videos on YouTube, right?

You take a chicken, move it up and down,

and the head stays in one place.

It’s all the same thing.

All of these animals are trying hard

to keep the image of the world stable on their retina

as much of the time as they possibly can.

And then when they’ve got to move,

make it fast, make it quick, and then stabilize again.

That’s why the pigeons have their head back?

It is, yeah.

Wow.

Yeah.

I think I just need to pause there for a second

and digest that.

Amazing.

In case people aren’t, well,

there’s no reason why people would know

what we’re doing here, but essentially what we’re doing

is we’re building up from sensory,

light onto the eye, make color,

to what the brain does with that,

the integration of that circadian clock, melatonin, et cetera.

And now what we’re doing is we’re talking about multi-sensory

or multimodal, combining one sense, vision,

with another sense, balance.

And it turns out that pigeons know more about this

than I do because pigeons know to keep their head back

as they walk forward.

All right, so that gets us to this issue of motion sickness.

And you don’t have to go out on a boat.

Anytime I go to New York, I sit in an Uber or in a cab

in the back, and if I’m looking at my phone

while the car is driving, I feel nauseous

by the time I arrive at my destination.

I always try and look out the front of the windshield

because I’m told that helps, but it’s a little tiny window.

And I end up feeling slightly less sick if I do that.

So what’s going on with the vision and the balance system

that causes a kind of a nausea?

And actually, if I keep talking about this,

I probably will get sick.

I don’t throw up easily, but for some reason,

motion sickness is a real thing for me.

It’s a problem for a lot of people.

I mean, I think the fundamental problem typically

when you get motion sick is what they call

visual vestibular conflict.

That is, you have two sensory systems

that are talking to your brain

about how you’re moving through the world.

And as long as they agree, you’re fine.

So if you’re driving, your body senses

that you’re moving forward.

Your vestibular system is picking up

this acceleration of the car,

and your visual system is seeing the consequences

of forward motion in the sweeping of the scene past you.

Everything is honky-dory, right?

No problem.

But when you are headed forward,

but you’re looking at your cell phone,

what is your retina seeing?

Your retina is seeing the stable image of the screen.

There’s absolutely no motion in that screen.

Or the motion is just, or some other motion,

like a movie or, yeah.

If you’re playing a game, or you’re watching a video,

a football game, the motion is uncoupled

with what’s actually happening to your body.

Your brain doesn’t like that.

Your brain likes everything to be aligned.

And if it’s not, it’s going to complain to you.

By making me feel nauseous.

By making you feel nauseous,

and maybe you’ll change your behavior.

So you’re getting-

I’m getting punished.

Yeah, for setting it up

so your signals don’t conflict, right.

By the vestibular-

You’ll learn.

Visual signals.

In time.

I love it.

I love the idea of reward signals.

And we’ve done a lot of discussion about this

on this podcast of things like dopamine reward and things,

but also punishment signals.

And I love this example.

Well, maybe marching a little bit further

along this pathway,

visual input is combined with balance input.

Where does that occur?

And maybe, because I have some hint of where it occurs,

you could tell us a little bit about this

kind of mysterious little mini brain

that they call the cerebellum.

Cerebellum, yeah.

So, you know, the way I try to describe

the cerebellum to my students

is that it serves sort of like

the air traffic control system functions in air travel.

So that it’s a system that’s very complicated

and it’s really dependent on great information.

So it’s taking in the information

about everything that’s happening everywhere,

not only through your sensory systems,

but it’s listening into all the little centers

elsewhere in your brain that are computing

what you’re going to be doing next and so forth.

So it’s just ravenous for that kind of information.

So it really is like a little mini brain.

It is.

It’s got access to all those signals.

And it really has an important role

in coordinating and shaping movements.

But, you know, if you suddenly eliminated

the air traffic control system,

planes could still take off and land,

but you might have some unhappy accidents in the process.

So the cerebellum is kind of like that.

It’s not that you would be paralyzed

if your cerebellum was gone,

because you still have motor neurons.

You still have ways to talk to your muscles.

You still have reflex centers.

And it’s not like you would have any sensory loss

because you still have your cortex

getting all of those beautiful signals

that you can think about.

But you wouldn’t be coordinating things so well anymore.

The timing between input and output might be off.

Or if you were trying to practice a new athletic move,

like an overhead serve in tennis,

you’d be just terrible at learning.

But all of the sequences of muscle movements

and the feedback from your sensory apparatus

that would let you really hit that ball

exactly where you wanted to after the nth rep,

right in the thousandth rep or something,

you get much better at it.

So the cerebellum’s all involved in things like

motor learning and refining the precisions of movements

so that they get you where you want to go.

If you reach for a glass of champagne,

that you don’t knock it over or stop short.

You know, that’s what you’re good at.

People who have selective damage to the cerebellum.

Absolutely.

And what, like I’m familiar with,

well, Korsakoff’s is different, right?

Isn’t that a B vitamin deficiency from,

in chronic alcoholics?

Right.

And they have a, they tend to walk kind of bow-legged

and they can’t coordinate their movements.

Is that, that has some,

not sure about the cerebellar- Memory bodies,

but also cerebellum.

I’m not sure about the cerebellar involvement there,

but you know, the typical thing would be

a patient who has a cerebellar stroke

or a tumor, for example,

might be not that steady on their feet.

You know, if the, you know,

dynamics of the situation,

you’re standing on a streetcar

with no pull to hold onto,

they might not be as good at adjusting

all of the little movements of the car.

You know, there’s a kind of tremor that can occur

as they’re reaching for things

because they’ll reach a little too far

and then they over-correct and come back,

things like that.

So it’s very common neurological phenomenon, actually.

Cerebellar ataxia is what the neurologists call it.

And it can happen not just with cerebellar damage,

to the tracts that feed the information

into the cerebellum.

Just deprive the structure.

Exactly, or output from the cerebellum.

And so the cerebellum is where a lot of visual

and balance information is combined.

In a very key place in the cerebellum,

which is, it’s really one of the oldest parts

in terms of evolution. Talking about the flocculus.

The flocculus, right.

This is a, it’s a critical place in the cerebellum

where visual and vestibular information comes together

for recording just the kinds of movements

we were talking about, this image-stabilizing network.

It’s all happening there.

And there’s learning happening there as well.

So that if your vestibular apparatus

is a little bit damaged somehow,

your visual system is actually talking to your cerebellum

saying there’s a problem here, there’s an error,

and your cerebellum is learning to do better

by increasing the output of the vestibular system

to compensate for whatever that loss was.

So it’s a little error correction system.

That’s sort of typical of a cerebellar function,

and it can happen in many, many different domains.

This is just one of the domains

of sensory-motor integration that takes place there.

So I should stay off my phone in the Ubers.

If I’m on a boat, I should essentially look

and as much as possible, act as if I’m driving the machine.

Right.

That’d be weird if I was in the passenger seat

pretending I was driving the machine,

but I do always feel better

if I’m sitting in the front seat passenger side.

Right, so more of the visual world that you can see

as if you were actually the one doing the motion,

I would think.

Let’s stay in the inner ear for a minute

as we continue to march around the nervous system.

When you take off in the plane or when you land

or sometimes in the middle of the air,

your ears get clogged, or at least my ears get clogged.

That’s because of pressure buildup

in the various tubes of the inner ear, et cetera.

We’ll get into this.

But years ago, our good friend, Harvey Carton,

who’s another world-class neuroanatomist,

gave a lecture and talked about how

plugging your nose and blowing out

versus plugging your nose and sucking in

should be done at different times

depending on whether or not you’re taking off or landing.

And I always see people trying to unpop their ears.

Right.

And when you do scuba diving,

you learn how to do this without necessarily,

I can do it by just kind of moving my jaw now

because I’ve done a little bit of diving.

But what’s the story there?

We don’t have to get into all the differences

in atmospheric pressure, et cetera.

But if I’m taking off and my ears are plugged,

or I’ve recently ascended, plane took off,

my ears are plugged, do I plug my nose and blow out

or do I plug my nose and suck in?

Right, so the basic idea is that if your ears feel bad

because you’re going into an area of higher pressure,

so if they pressurize the cabin more than the pressure

that you have on the surface of the planet,

your eardrums will be bending in and they don’t like that.

If you push them more, they’ll hurt even more.

That’s a good description that the pressure goes up,

then they’re gonna bend in.

Bend in, and then the reverse would be true

if you go into an area of low pressure.

So if you started to drive up the mountainside,

the pressure is getting lower and lower outside.

Now the air behind your eardrum is ballooning out, right?

So it’s just a question of, are you trying to get

more pressure or less pressure behind the eardrum?

And there’s a little tube that does that

and comes down into your back of your throat there.

And if you force pressure up that tube,

you’re gonna be putting more air pressure

into the compartment.

To counter it.

If it’s not enough.

And if you’re sucking, you’re going the other way.

In reality, I think as long as you open the passageway,

I think the pressure differential

is gonna solve your problem.

So I think you could actually blow in

when you’re not, quote, supposed to.

Okay, so you could hold your nose and blow air out

or hold your nose and suck in the effect.

Either way is fine.

I think so.

Excellent.

I just won $100 from Harvey Carton.

Thank you very much.

Harvey and I used to teach in our anatomy together.

And I was like, I don’t think it matters,

but thank you, Bruce.

I’ll split that with you.

Okay.

This is important stuff, but it’s true.

You hear this, so it doesn’t matter either way.

I’m no expert in this area.

Don’t worry.

Don’t quote me.

He’s not gonna, well, I’m going to quote you, but.

Okay, so we’ve talked about the inner ear

and we’ve talked about the cerebellum.

I want to talk about an area of the brain

that is rarely discussed, which is the midbrain.

Yeah.

And for those that don’t know,

the midbrain is an area beneath the cortex.

I guess we never really defined cortex.

It’s kind of the outer layers or are the outer layers

of the, at least mammalian brain or human brain.

But the midbrain is super interesting

because it controls a lot of unconscious stuff,

reflexes, et cetera.

And then there’s this phenomenon even called blindsight.

So could you please tell us about the midbrain,

about what it does and what in the world is blindsight?

Yeah, so this is a, there’s a lot of pieces there.

I think the first thing to say

is if you imagine the nervous system in your mind’s eye,

you see this big honking brain

and then there’s this little wand

that dangles down into your vertebral column,

the spinal cord,

and that’s kind of your visual impression.

What you have to imagine is starting in the spinal cord

and working your way up into this big, magnificent brain.

And what you would do as you enter the skull

is get into a little place

where the spinal cord kind of thickens out.

It still has that sort of long, skinny, trunk-like feeling.

Sort of like a paddle or a spoon shape.

Right, it starts to spread out a little bit

and that’s because your evolution

has packed more interesting goodies in there

for processing information and generating movement.

So beyond that is this tween brain we were talking about,

this linker brain.

What diencephalon really means is the between brain.

Oh, I thought you said tween.

Well, it is, yes.

No, no, between, between.

I’m sorry, I said tween.

Yeah, it’s the between.

It’s the between brain is what the name means.

It’s the linker from the spinal cord in the periphery

up to these grand centers of the cortex.

But this midbrain you’re talking about

is the last bit of this enlarged

sort of spinal cord-y thing in your skull,

which is really the brainstem is what we call it.

The last bit of that before you get to this relay

up to the cortex is the midbrain.

And there’s a really important visual center there.

It’s called the superior colliculus.

There’s a similar center in the brains

of other vertebrate animals.

A frog, for example, or a lizard would have this.

It’s called the optic tectum there.

But it’s a center then in these non-mammalian vertebrae

is really the main visual center.

They don’t really have what we would call a visual cortex,

although there’s something sort of like that.

But this is where most of the action is

in terms of interpreting visual input

and organizing behavior around that.

You can sort of think about this region of the brainstem

as a reflex center that can reorient the animal’s gaze

or body, or maybe even attention

to particular regions of space out there around the animal.

And that could be for all kinds of reasons.

I mean, it might be a predator just showed up

in one corner of the forest and you pick that up

and you’re trying to avoid it.

Or just any movement.

Any movement, right?

It might be that suddenly something splats on the page

when you’re reading a novel

and your eye reflexly looks at it.

You don’t have to think about that, that’s a reflex.

What if you throw me a ball,

what if I’m not expecting it?

And I just reach up and try and grab it, catch it or not?

Is that handled by the midbrain?

Well, that’s probably not the midbrain,

although, I mean, by itself,

because it’s going to involve all these limb movements,

this movement of your arm and body.

And what about ducking

if something’s suddenly thrown at my head?

Sure, right.

Things like that will certainly have a brainstem component,

a midbrain component.

Something looms and you duck.

It may not be the superior colliculus

we’re talking about now.

It might be another part of the visual midbrain,

but these are centers that emerged early

in the evolution of brains like ours

to handle complicated visual events

that have significance for the animal.

In terms of space, where is it in space?

And in fact, this same center actually gets input

from all kinds of other sensory systems

that take information from the external world,

from particular locations,

and where you might want to either avoid or approach things

according to their significance to you.

So you get input from the touch system.

You get input from the auditory system.

I worked for a while in rattlesnakes.

They get input from a part of their warm sensors

on their face.

They’re in these little pits on the face.

You used to work on baby rattlesnakes, right?

Well, they were adults actually.

Oh, I wasn’t trying to diminish the danger.

I thought for some reason they were little ones.

No.

Why in the world would you work on rattlesnakes?

Well, because they have a version

of an extra receptive sensory system.

That is, they’re looking out into the world

using a completely different set of sensors.

They’re using the same sensors

that would feel the warmth on your face

if you stood in front of a bonfire,

except evolution has given them

this very nice specialized system

that lets them image where the heat’s coming from.

You can sort of do that anyway, right?

If you walk around the fire,

you can feel where the fire is

from the heat hitting your face.

Is that the primary way in which they detect prey?

It’s one of the major ways.

And in fact, they use vision as well.

And they bring these two systems together in the same place,

in this tectum region, this brainstem, midbrain region.

What’s all the tongue jutting about when the snakes?

That I don’t know.

That may be olfactory.

There may be-

They’re sniffing the air with their tongue?

Yeah, there may be a gust of air.

Earlier in our drive,

you told me that flies actually taste things

with their feet.

They do, yeah.

That’s so weird.

Yeah, they have taste receptors in lots of funny places.

I want to pause here just for one second

before we get back into the midbrain.

I think what’s so interesting in all seriousness

about taste receptors on feet, heat sensors,

tongue jutting out of snakes,

and vision and all this integration

is that it really speaks to the fact

that all these sensory neurons

are trying to gather information

and stuff it into a system

that can make meaningful decisions and actions.

And that it really doesn’t matter

whether or not it’s coming from eyes or ears or nose

or bottoms of feet,

because in the end, it’s just electricity flowing in.

Sure.

And so it sounds like it’s placed on each animal.

It always feels weird to call a fly an animal,

but they are creatures, they are animals.

It’s placed in different locations on different animals,

depending on the particular needs of that animal.

Right, but how much more powerful

if the nervous systems can also cross-correlate

across sensory systems?

So if you’ve got a weak signal from one sensory system,

you’re not quite sure there’s something there.

And a weak signal from another sensory system

that’s telling you the same locations

is a little bit interesting.

There might be something there.

If you’ve got those two together, you’ve got corroboration.

Your brain now says it’s much more likely

that that’s gonna be something worth paying attention to.

Right, so maybe I’m feeling some heat

on one side of my face,

and I also smell something baking in the oven.

Right.

So now neither is particularly strong,

but as you said, there’s some corroboration.

Right.

And that corroboration is occurring in the midbrain.

Right, and then if you throw things into conflict,

now the brain is confused,

and that may be where your motion sickness comes from.

So it’s great to have, as a brain,

it’s great to have as many sources of information

as you can have, just like if you’re a spy or a journalist,

you want as much information as you can get

about what’s out there.

But if things conflict, that’s problematic, right?

Your sources are giving you different information

about what’s going on.

Now you’ve got a problem on your hands.

What do you publish?

The midbrain is so fascinating.

I don’t wanna eject us from the midbrain

and go back to the vestibular system,

but I do have a question that I forgot to ask

about the vestibular system, which is,

why is it that for many people, including me,

there’s a, despite my motion sickness in cabs,

that there’s a sense of pleasure in moving through space

and getting tilted relative

to the gravitational pull of the earth?

For me growing up, it was skateboarding,

but people like to corner in cars, corner on bikes.

It may be for some people it’s done running or dance,

but what is it about moving through space

and getting tilted, a lot of surfers around here,

getting tilted that can tap

into some of the pleasure centers?

Do we have any idea why that would feel good?

I have no clue.

Is there dopaminergic input to this system?

Well, the dopaminergic system gets a lot of places.

It’s pretty much to some extent everywhere in the cortex,

a lot more in the frontal lobe, of course,

but that’s just for starters.

I mean, there’s basically dopaminergic innervation

in most places in the central nervous system.

So there’s the potential for dopaminergic involvement,

but I really have no clue about the tilting phenomenon.

I mean-

People pay money to go on roller coasters.

Right.

Well, I think that may be as much about the thrill

as anything else. Sure.

And falling is, the falling reflex is very robust

in all of us. Right.

When the visual world’s going up very fast,

it usually means that we’re falling.

Right, right.

And some people like that, some people don’t.

Right, and kids tolerate a lot more

sort of vestibular craziness spinning around

until they drop.

Well, I’ve friends, it always worries me a little bit

that they throw their kids.

I’m not recommending anyone do this.

When they’re little kids,

like throwing the kids really far back and forth,

some kids seem to love it.

Yeah.

Yeah, our son loved being shaken up and down

very, very vigorously.

That was the only thing that would calm him down sometimes.

Interesting.

Yeah, so I’m guessing we can guess

that maybe there’s some activation of the reward systems

from moving through space.

Well, I mean, if you think about how rewarding it is

to be able to move through space

and how unhappy people are who are used to that

who suddenly aren’t able to do that,

there is a sense of agency, right?

If you can choose to move through the world and to tilt,

not only are you moving through the world,

but you’re doing it with a certain amount of finesse.

Maybe that’s what it is.

You can feel like you’re the master of your own movement

in a way that you wouldn’t if you’re going straight.

I’m just blowing smoke here, right?

Yeah, well, we can speculate, that’s fine.

I couldn’t help but ask the question.

Okay, so if we move ourselves, pun intended,

back into the midbrain,

the midbrain is combining all these different signals

for reflexive action.

At what point does this become deliberate action?

Because if I look at something I want and I wanna pursue it,

I’m going to go toward it.

And many times that’s a deliberate decision.

Right.

This gets very slippery, I think,

because what you have to try to imagine

is all these different parts of the brain

working on the problem of staying alive,

and surviving in the world.

They’re working on the problem simultaneously.

And there’s not one right answer to how to do that.

But one way to think about it is that

you have high levels of your nervous system

that are very well designed to override

an otherwise automatic movement if it’s inappropriate.

So if you imagine you’ve been invited to tea with the queen,

and she hands you a very fancy Wedgwood teacup, very thin.

Wedgwood teacup?

Yes, with very hot tea in it,

and you’re burning your hand.

You probably will try to find a way

to put that back down on the saucer

rather than just dropping it on the floor,

because you’re with the queen.

You’re trying to be appropriate to that.

So you have ways of reining in automatic behaviors

if they’re gonna be maladaptive.

But you also want the reflex to work quickly

if it’s the only thing that’s gonna save you,

the looming object coming at your head.

You don’t have time to think about that.

So this is the interplay

in these hierarchically organized centers

of the nervous system.

At the lowest level, you’ve got the automatic sensors

and reflex arcs that will keep you safe,

even if you don’t have time to think about it.

And then you’ve got the higher center saying,

well, maybe we could do this as well,

or maybe we shouldn’t do that at all, right?

So you have all of these different levels

operating simultaneously,

and you need bidirectional communication

between high-level cognitive centers,

decision-making on the one hand,

and these low-level, very helpful reflexive centers,

but they’re a little bit rigid, a little hardwired,

so they need some nuance.

So both of these things are operating in tandem

in real time, all the time in our brains.

And sometimes we listen more to one than the other.

You’ve heard people in sports

talking about messing up at the plate

because they overthought it,

thinking too hard about it.

That’s partly, you’ve already trained your cerebellum

how to hit a fastball right down the middle.

Right.

And if you start looking for something new or different,

you’re going to mess up your reflexive swing.

Right.

If you’re trying to think about the physics of the ball

as it’s coming at you, you’ve already missed, right?

Because you’re not using your,

all those reps have built a kind of knowledge.

This is what you want to rely on

when you don’t have enough time to contemplate.

This is important and a great segue

for what I’d like to discuss next,

which is the basal ganglia.

This really interesting area of the brain

that’s involved in go type commands and behaviors,

instructing us to do things and no-go,

preventing us from doing things.

Because so much of motor learning and skill execution

and not saying the wrong thing,

or sitting still in class when,

or as you used with the tea with the queen example,

feeling discomfort involves suppressing behavior.

And sometimes it’s activating behavior.

Tremendous amount of online attention is devoted

to trying to get people motivated.

This isn’t the main focus of our podcast.

We touch on some of the underlying neural circuits

of motivation, dopamine, and so forth.

But so much of what people struggle with out there

are elements around failure to pay attention

or challenges in paying attention,

which is essentially like putting the blinders on,

getting a soda straw view of the world

and maintaining that for a bout of work

or something of that sort and trying to get into action.

So of course, this is carried out by many neural circuits,

not just the basal ganglia,

but what are the basal ganglia

and what are their primary roles

in controlling go type behavior and no-go type behavior?

Yeah, so I mean, the basal ganglia are sitting deep

in what you would call the forebrain.

So the highest levels of the brain,

they’re sort of cousins to the cerebral cortex,

which we talked about is sort of the highest level

of your brain, the thing you’re thinking with.

Cerebral cortex being the refined cousins

and then you’ve got the- Right.

You know, the brute. Yeah.

I mean, that’s probably totally unfair, but the point-

I like the basal ganglia.

I can relate to the brutish parts of the brain.

Little bit of hypothalamus, little bit of basal ganglia.

Sure. We need it all.

We need it all.

And, you know, this area of the brain

has gotten a lot bigger as the cortex has gotten bigger.

And it’s deeply intertwined with cortical function.

The cortex can’t really do what it needs to do

without the help of the basal ganglia and vice versa.

So they’re really intertwined.

And in a way you can think about this logically

as saying, you know, if you have the ability

to withhold behavior or to execute it,

how do you decide which to do?

Well, the cortex is going to have to do

that thinking for you.

You have to be looking at all the contingencies

of your situation to decide, is this a crazy move

or is this a really smart investment right now?

Or, you know, what?

Right, I don’t want to go out for a run in the morning,

but I’m going to make myself go out for a run.

Or I’m having a great time out on a run

and I know I need to get back,

but I kind of want to go another mile.

I mean, another great example is that, you know,

the marshmallow test for the little kids.

You know, they can get two marshmallows

if they hold off, you know, just 30 seconds initially.

You know, they can have one right away,

but if they can wait 30 seconds, they got two.

You know, so that’s the no-go

because their cortex is saying, you know,

I really like to have two more than having one,

but they’re not going to get the two

unless they can not reach for the one.

So they’ve got to hold off the action.

And that has to result from a cognitive process.

So the cortex is involved in this in a major way.

Yes, I recall in that experiment,

the kids used a variety of tools.

Some would distract themselves.

I particularly related to the kid

that would just put himself right next to the marshmallows

and then some of the kids covered their eyes.

Some of them would count or sing.

Yeah, so that’s all very cortical, right?

Coming up with a novel strategy.

Simple example that we’re using here,

but of course this is at play anytime someone decides

they want to go watch a motivational speech or something,

just, you know, a Steve Jobs commencement speech

just to get motivated to engage in their day.

Sure, I take this new job.

It’s got great benefits,

but it’s in a lousy part of the country.

Why do you think that some people have a harder time

running these go, no-go circuits

and other people seem to have very low activation energy,

we would say.

They can just, you know, they have a task,

they just lean into the task.

Whereas some people getting into task completion

or things of that sort is very challenging for them.

Yeah, I mean, I think it’s really just another,

it’s a special case of a very general phenomenon,

which is brains are complicated

and the brains we have

are the result of genetics and experience.

And my genes are different from your genes

and my experiences are different from your experiences.

So the things that would be easy or hard for us

won’t necessarily be aligned.

They might just happen to be just because they are,

but the point is that, you know,

you’re dealt a certain set of cards,

you have certain set of genes,

you are handed, you know, a brain,

you don’t choose your brain, it’s handed to you.

But then there’s all this stuff you can do with it.

You know, you can learn to, you know,

to have new skills or to act differently

or to show more restraint,

which is kind of relevant to what we’re talking about here,

or maybe show less restraint if your problem is

you’re so buttoned down, you never have any fun in life

and you should loosen up a little bit, right?

Thank you, I appreciate the insult, yeah.

David’s always encouraged me

to have a little more fun in life.

So basal ganglia are,

they’re kind of the disciplinarian

or they’re sort of the instructor or conductor of sorts,

right, go, no go, you know, you be quiet, you start now.

I wish I knew more about the basal ganglia than I do.

My sense is that it, you know,

this system is key for implementing the plans

that get cooked up in the cortex.

But they also influence the plans that the, you know,

cortex is dishing out

because this is a major source of information

to the cortex.

So it becomes almost impossible to figure out

where the computation begins and where it ends

and who’s doing what,

because these things are all interacting

in a complex network and it’s all of it,

it’s the whole network.

It’s not, you know, one is the leader

and the other is the follower.

Right, of course, yeah, these are,

all the structures that we’re discussing

are working in parallel.

Right.

And there’s a lot of changing crosstalk.

I have this somewhat sick habit, David,

every day I try and do 21 no-go’s.

So if I wanna reach for my phone,

I try and not do it

just to see if I can prevent myself

from engaging in that behavior.

If it was reflexive,

if it’s something I want to do, a deliberate choice,

then I certainly allow myself to do it.

I don’t tend to have too much trouble with motivation,

with go-type functions,

mostly because I’m so busy that I wish I had more time

for more goes, so to speak.

But do you think these circuits

have genuine plasticity in them?

Absolutely.

I mean, everybody knows how they’ve learned over time

to wait for the two marshmallows, right?

You don’t have to have instant gratification all the time.

You’re willing to do a job sometimes

that isn’t your favorite job

because it comes with the territory

and you want the salary that comes at the end of the week

or the end of the month, right?

So we can defer gratification.

We can choose not to say the thing

that we know is gonna inflame our partner

and create a meltdown for the next week.

We learn this control,

but I think these are skills like any other.

You can get better at them if you practice them.

So I think you’re choosing to do that just spontaneously.

It’s a mental practice.

It’s a discipline.

It’s a way of building a skill that you wanna have.

Yeah, I find it to be something

that when I engage in a no-go-type situation,

then the next time and the next time

that I find myself about to move reflexively,

there’s a little gap in consciousness

that I can make a decision

whether or not this is really the best use of my time.

Because I sometimes wonder

whether or not all this business around attention,

certainly there’s the case of ADHD

and clinical diagnosed ADHD,

but all these, the issue around focus and attention

is really that people just have not really learned

how to short-circuit a reflex.

And so much of what makes us different than rattlesnakes

or, well, actually they could be deliberate,

but from the other animals

and is our ability to suppress reflex.

Yeah, well, that’s the cortex.

I mean, or let’s just say the forebrain,

cortex and basal ganglia working together,

sitting on top of this lizard brain

that’s giving you all these great adaptive reflexes

that help you survive.

You just hope you don’t get the surprising case

where the thing that your reflex is telling you

is actually exactly the wrong thing

and you make a mistake, right?

Right, so that’s what the cortex is for.

It’s adding nuance and context and experience,

past association, and in human beings,

obviously learning from others through communication.

Well, I was, you went right to it

and it was where I was going to go.

So let’s talk about the cortex.

We’ve worked our way up the so-called neuraxis

as the aficionados will know.

So we’re in the cortex.

This is the seat of our higher consciousness,

self-image, planning and action.

But as you mentioned, the cortex isn’t just about that.

It’s got other regions that are involved in other things.

So maybe we should, staying with vision,

let’s talk a little bit about visual cortex.

You told me a story, an amazing story about visual cortex.

And it was a somewhat of a sad story, unfortunately,

about someone who had a stroke to visual cortex.

Maybe if you would share that story,

because I think it illustrates many important principles

about what the cortex does.

Right, so the visual cortex is,

you could say the projection screen,

the first place where this information

streaming from the retina through this thalamus,

connecting linker, gets played out

for the highest level of your brain to see.

I mean, it’s a representation,

it’s a map of things going on in the visual world

that’s in your brain.

And when we describe a scene to a friend,

we’re using this chunk of our brain

to be able to put words,

which are coming from a different part of our cortex,

to the objects and movements and colors

that we see in the world.

So that’s a key part of your visual experience

when you can describe the things you’re seeing,

you’re looking at your visual cortex.

And this is-

Could I just ask a quick question?

So right now, because I’m looking at your face,

as we’re talking, there are neurons in my brain,

more or less in the configuration of your face

that are active as you move about.

And what if I were to close my eyes and just imagine,

I do this all the time, by the way, David,

I close my eyes and I imagine David Bersin’s face.

I don’t tend to do that as often, maybe I should,

but you get the point.

I’m now using visualization of what you look like

by way of memory.

If we were to image the neurons in my brain,

would the activity of neurons resemble

the activity of neurons that’s present

when I open my eyes and look at your actual face?

This is a deep question.

We don’t really have a full accounting yet.

Yes, except you’re talking about looking in detail

at the activity of neurons in a human brain,

and that’s not as easy to do as it would be

in some kind of animal model.

But the bottom line is that you have a spatial representation

of the visual world laid as a map of the visual world

laid out on the surface of your cortex.

The thing that’s surprising is that it’s not one map,

it’s actually dozens of maps.

What do each of those maps do?

Well, we don’t really have a full accounting there either,

but it looks a little bit like the diversification

of the output neurons of the retina,

the ganglion cells we were talking about before.

There are different types of ganglion cells

that are encoding different kinds of information

about the visual world.

We talk about the ones that were encoding the brightness,

but are the ones that are encoding motion or color,

these kinds of things.

The same kinds of specializations

in different representations of the visual world

in the cortex seem to be true.

It’s a complex story.

We don’t have the whole picture yet,

but it does look as if some parts of the brain

are much more important for things like reaching for things

in the space around you,

and other parts of the cortex are really important

for making associations between particular visual things

you’re looking at now and their significance.

What is that object?

What can it do for me?

How can I use it?

What about the really specialized areas of cortex,

like neurons that respond to particular faces,

or neurons that, I don’t know,

can help me understand where I am

relative to some other specific object?

Right, so these are properties of neurons

that are extracted from,

detected by recording the activity of single neurons

in some experimental system.

What’s going on when you actually perceive

your grandmother’s face is a much more complicated question.

It clearly involves hundreds and thousands

and probably millions of neurons

acting in a cooperative way.

So you can pick out any one little element

in this very complicated system

and see that it’s responding differentially

to certain kinds of visual patterns,

and you think you’re seeing a glimpse

of some part of the process

by which you recognize your grandmother’s face.

But that’s a long way from a complete description,

and it certainly isn’t gonna be at the level

of a magic single neuron that has the special stuff

to recognize your grandmother.

It’s gonna be in some pattern of activity

across many, many cells,

resonating in some kind of special way

that will represent the internal memory of your mother.

Which is really incredible.

Yeah.

I mean, every time we do this deep dive,

which we do from time to time, you and I,

we kind of like march into the nervous system

and explore how different aspects

of our life experiences is handled there

and how it’s organized.

It, after so many decades of doing this,

it still boggles my mind

that the collection of neurons one through seven

active in a particular sequence

gives the memory of a particular face

and run backwards seven to one,

it gives you a complete, you know,

it could be, you know, rattlesnake,

pit viper, heat-sensing organs,

as we were talking about earlier.

So it sounds, is it true that there’s a lot

of multi-purposing of the circuitry?

Like we can’t say one area of the brain does A

and another area of the brain does B.

So, you know, areas can multitask or have multiple jobs.

They can moonlight.

Right.

But I think in my career,

the hard problem has been to square that

with the fact that, you know, things are specialized,

that there are specific genes expressed in specific neurons

that make them make synaptic connections

with only certain other neurons.

And that particular synaptic arrangement

actually results in the processing of information

that’s useful to the animal to survive, right?

So it’s not as if it’s either a big,

undifferentiated network of cells

and looking at any one is never gonna tell you anything.

That’s too extreme on the one hand,

nor is it the case that everything is hardwired

and every neuron has one function

and this all happens in one place in the brain.

It’s way more complicated and interactive

and interconnected than that.

So we’re not hardwired or softwired.

It’s both.

We’re sort of, I don’t know what the analogy should be.

What substance would work best, David?

No idea there, but you know,

the idea is that it’s always network activity.

There’s always many, many neurons involved,

and yet there’s tremendous specificity

in the neurons that might or might not be participating

in any distributed function like that, right?

So you have to get your mind around the fact

that it’s both very specific

and very nonspecific at the same time.

It’s a little tricky to do,

but I think that’s kind of where the truth lies.

Yeah, and so this example that you mentioned to me

once before about a woman who had a stroke in visual cortex

I think speaks to some of this.

Right.

Could you share with us that story?

Sure.

The point is that you all, those of us who see,

have representations of the visual world

in our visual cortex.

What happens to somebody when they become blind

because of problems in the eye, the retina perhaps?

You have a big chunk of the cortex,

this really valuable real estate for neural processing

that has come to expect input from the visual system,

and there isn’t any anymore.

So you might think about that as fallow land, right?

It’s unused by the nervous system,

and that would be a pity,

but it turns out that it is in fact used.

And the case that you’re talking about

is of a woman who was blind from very early in her life

and who had risen through the ranks

to a very high level executive secretarial position

in a major corporation.

And she was extremely good at braille reading,

and she had a braille typewriter,

and that’s how everything was done.

And apparently she had a stroke

and was discovered at work, collapsed,

and they brought her to the hospital.

And apparently the neurologist who saw her

when she finally came to said,

you know, I’ve got good news and bad news.

Bad news is you’ve had a stroke.

The good news is that it was in an area of your brain

you’re not even using.

It’s your visual cortex,

and I know you’re blind from birth,

so there shouldn’t be any issue here.

The problem was she lost her ability to read braille.

So what appears to have been the case,

and this has been confirmed in other ways

by imaging experiments in humans,

is that in people who are blind from very early in birth,

the visual cortex gets repurposed

as a center for processing tactile information.

And especially if you train to be a good braille reader,

you’re actually reallocating somehow

that real estate to your fingertips,

you know, a part of the cortex

that should be listening to the eyes.

So that’s an extreme level of plasticity,

but what it shows is the visual cortex

is kind of a general purpose processing machine.

It’s good at spatial information,

and the skin of your fingers is just another spatial sense

and deprived of any other input.

The brain seems smart enough, if you wanna put it that way,

to rewire itself to use that real estate

for something useful, in this case, reading braille.

Incredible.

Somewhat tragic, but incredible.

At least in that case, tragic.

Very informative.

Very informative.

And of course it can go the other way too,

where people can gain function in particular modalities,

like improved hearing or tactile function

in the absence of vision.

Tell us about connectomes.

We hear about genomes, proteomes, microbiomes,

ohms, ohms, ohms these days.

What’s a connectome and why is it valuable?

Yeah, so connectome actually now has two meanings.

So I only refer to the one that is my passion right now,

and that is really trying to understand

the structure of nervous tissue

at a scale that’s very, very fine.

Smaller than a millimeter.

Way smaller than a millimeter, a nanometer or less.

That’s a thousand times smaller,

or it’s actually a million times smaller.

So really, really tiny.

On the scale of individual synapses

between individual neurons, or even smaller,

like the individual synaptic vesicles

containing little packets of neurotransmitter

that are gonna get it released

to allow one neuron to communicate to the next.

So very, very fine.

But the notion here is that you’re doing this

section after section at very fine scale.

So in theory, what you have is a complete description

of a chunk of nervous tissue that is so complete

that if you took enough time to identify

where the boundaries of all the cells are,

you could come up with a complete description

of the synaptic wiring of that chunk of nervous tissue,

because you have a complete description

of where all the cells are and where all the synapses

are where all the cells are.

So now you essentially have a wiring diagram

of this complicated piece of tissue.

So the omics part is the exhaustiveness of it,

rather than looking at a couple of synapses

that are interesting to you from two different cell types,

you’re looking at all the synapses of all of the cell types,

which of course is this massive avalanche of data, right?

So in genetics, you have genetics,

and then you have genomics,

which is the idea of getting the whole genome.

All of it.

And we don’t really have an analogous word for genetics,

but it would be connectivity and conomics.

Right.

Excuse me, conectomics.

Conectomics, sure, sure.

Connectivity and conectomics.

Right, so it’s wanting it all.

And of course it’s crazy ambitious,

but that’s where it gets fun.

Really, it’s a use of electron microscopy,

a very high resolution, microscopic imaging system

on a new scale with way more payoff

in terms of understanding the connectivity

of the nervous system.

And it’s just emerging,

but I really think it’s gonna revolutionize the field

because we’re gonna be able to query these circuits.

How did they actually do it?

Look at the hardware

in a way that’s never been possible before.

The way that I describe this to people is

if you were to take a chunk of kind of cold,

cooked, but cold spaghetti.

Right.

And slice it up very thin,

you’re trying to connect up each image of each slice

of the edge of the spaghetti

as figure out which ropes of spaghetti belong to which.

And have a complete description

of where this piece of spaghetti

touches that piece of spaghetti,

and is there something special there?

Obviously.

Where the meat sauce is and all the other cell types

and the pesto, where it all is around the spaghetti.

Because those are the other cells,

the blood vessels and the glial cells.

And so what’s it good for?

I mean, maps are great.

Right.

I always think of connectomics and genomics

and proteomics, et cetera,

as necessary but not sufficient.

Right, right.

So, I mean, in many cases what you do

is you go out and probe the function

and you understand how the brain does the function

by finding neurons that seem to be firing

in association with this function that you’re observing.

And little by little, you work your way in

and now you want to know what the connectivity is.

Maybe the anatomy could help you.

But this connectomics approach,

or at least the serial electron microscopy

reconstruction of neurons approach,

really is allowing us to frame questions

starting from the anatomy

and saying, I see a synaptic circuit here.

My prediction would be that these cell types

would interact in a particular way.

Is that right?

And then you can go and probe the physiology

and you might be right or you might be wrong.

But more often than not,

it looks like the structure is pointing us

in the right direction.

So in my case, I’m using this to try to understand

the circuit that is involved

in this image stabilization network we’re talking about,

keeping things stable on the retina.

And this thing will only respond

at certain speeds of motion.

These cells in the circuit,

like slow motion, they won’t respond to fast motion.

How does that come about?

Well, I was able to probe the circuitry.

I knew what my cells looked like.

I could see which other cells were talking to it.

I could categorize all the cells

that might be the players here

that are involved in this mechanism

of tuning the thing for slow speeds.

And then we said, it looks like it’s that cell type.

And we went and looked and the data bore that up.

But the anatomy drove the search

for the particular cell type

because we could see it connected

in the right place to the right cells.

So that creates the hypothesis

that lets you go query the physiology,

but it can go the other way as well.

So it’s always the synergy

between these functional and structural approaches

that gives you the most lift.

But in many cases,

the anatomy has been a little bit the weak sister in this,

the structure, trying to work out the diagram

because we haven’t had the methods.

Now the methods exist.

And this whole field is expanding very quickly

because people want these circuit diagrams

for the particular part of the nervous system

that they’re working on.

If you don’t know the cell types and the connections,

how do you really understand how the machine works?

Yeah, what I love about it is

we don’t know what we don’t know.

Scientists, we don’t ask questions, we pose hypotheses.

Hypotheses being, of course,

some prediction that you wager your time on, basically.

And it either turns out to be true or not true.

But if you don’t know that a particular cell type is there,

you could never, in any configuration of life

or a career or exploration of a nervous system,

wager a hypothesis because you didn’t know it was there.

So this allows you to say,

ah, there’s a little interesting little connection

between this cell that I know is interesting

and another cell that’s a little mysterious but interesting.

I’m going to hypothesize that it’s doing

blank, blank, and blank and go test that.

And in the absence of these connectomes,

you would never know that that cell

was lurking there in the shadows.

Right, right.

Yeah, and if you’re just trying to understand

how information flows through this biological machine,

you want to know where things are.

Neurotransmitters are dumped out of the terminals

of one cell and they diffuse across the space

between the two cells, which is kind of a liquidy space,

and they hit some receptors on the postsynaptic cell

and they have some impact.

Sometimes that’s not through a regular synapse.

Sometimes it’s through a neuromodulator,

like you often talk about on your podcast,

that are sort of oozing-

Dopamine or something.

Dopamine, exactly.

Oozing into the space between the cells

and it may be acting at some distance

far from where it was released, right?

But if you don’t know where the release is happening

and where other things are that might respond

to that release, you’re groping around in the dark.

Well, I love that you are doing this.

And I have to share with the listeners

that the first time I ever met David,

and every time I’ve ever met with him in person,

at least at his laboratory at Brown,

he was in his office, door closed,

drawing neurons and their connections.

And this is somewhat unusual for somebody

who is a endowed full professor,

chairman of the department, et cetera, for many years,

to be doing the hands-on work.

Typically, that’s the stuff that’s done by technicians

or graduate students or postdocs.

But I think it’s fair to say that you really love

looking at nervous systems

and drawing the accurate renditions

of how those nervous systems are organized

and thinking about how they work.

Yeah, it’s pure joy for me.

I mean, I’m a very visual person.

My wife is an artist.

We look at a lot of art together.

Just the forms of things are gorgeous in their own right.

But to know that the form is, in a sense, the function,

that the architecture of the connectivity

is how the computation happens in the brain at some level,

even though we don’t fully understand that in most contexts,

gives me great joy,

because I’m working on something

that’s both visually beautiful,

but also deeply beautiful

in a higher knowledge context.

What is it all about?

I love it.

Well, as a final question,

I get asked very often

about how people should learn about neuroscience

or how they should go about pursuing

maybe an education in neuroscience

if they’re at that stage of their life

or that’s appropriate for their current trajectory.

Do you have any advice to young people, old people,

anything in between

about how to learn about the nervous system,

maybe in a more formal way?

I mean, obviously, we have our podcast.

There are other sources

of neuroscience information out there,

but for the young person

who thinks they want to understand the brain,

they want to learn about the brain,

what should we tell them?

Well, that’s a great question,

and there’s so many sources out there.

It’s almost a question of how do you deal

with this avalanche of information out there?

I mean, I think our podcast is a great way

for people to learn more about the nervous system

in an accessible way,

but there’s so much stuff out there,

and it’s not just that.

I mean, the resources are becoming more and more available

for average folks to participate

in neuroscience research on some level.

There’s this famous eye wire project of Sebastian Mazzone.

Oh, yeah, tell us about eye wire.

Yeah, so that’s connectomics,

and that’s a situation where a very clever scientist

realized that the physical work

of doing all this reconstruction of neurons

from these electron micrographs,

there’s a lot of time involved.

Many, many person hours have to go into that

to come up with the map that you want

of where the cells are,

and he was very clever about setting up a context

in which he could crowdsource this,

and people who were interested

in getting a little experience looking at nervous tissue

and participating in a research project

could learn how to do this and do a little bit.

From their living room.

From their living room.

So people will put a link to eye wire.

It also is a great bridge

between what we were just talking about, connectomics,

and actually participating in research,

and you don’t need a graduate mentor or anything like that.

Right, so more of this is coming,

and I’m actually interested in building more of this

so that people who are interested,

want to participate at some level,

don’t necessarily have the time or resources

to get involved in laboratory research,

can get exposed to it and participate

and actually contribute.

So I think that’s one thing.

I mean, just asking questions of the people around you

who know a little bit more

and have them point you in the right direction.

Here’s a book you might like to read.

There’s lots of great popular books out there

that are accessible that will give you some more sense

of the full range of what’s out there in the neurosciences.

We can put some links to a few of those that we like

on basic neuroscience.

Our good friend Dick Masland,

the late Richard, people will call him Dick,

Dick Masland, had a good book.

I forget the title at the moment.

It’s sitting behind me somewhere over there on the shelf,

but about vision and how nervous systems work.

A pretty accessible book for the general public.

Right, right.

So that, and there’s so many sources out there.

I mean, Wikipedia is a great way.

If you had a particular question about visual function,

I would say, by all means,

head to Wikipedia and get the first look

and follow the references from there,

or go to your library or, you know,

there’s so many ways to get into it.

It’s such an exciting field now.

There’s so many, I mean, any particular realm

that’s special to you, your experience,

your, you know, your strengths, your passions,

there’s a field of neuroscience devoted to that.

You know, if you’ve got, if you know somebody

who’s got a neurological problem or a psychiatric problem,

there’s a branch of neuroscience that is devoted

to trying to understand that

and to solve these kinds of problems down the line.

So feel the, feel the buzz.

It’s an exciting time to get involved.

Great, those are great resources

that people can access from anywhere, zero cost,

as you need an internet connection.

But aside from that, we’ll put the links to some,

and I’m remembering Dick’s book is called

We Know It When We See It.

Right, one of my heroes.

Yeah, a wonderful colleague

who unfortunately we lost a few years ago.

But listen, David, this has been wonderful.

We really appreciate you taking the time to do this.

As people probably realize by now,

you’re an incredible wealth of knowledge

about the entire nervous system.

Today, we just hit this top contour

of a number of different areas to give a flavor

of the different ways that the nervous system works

and is organized and how that’s put together,

how these areas are talking to one another.

What I love about you

is that you’re such an incredible educator

and I’ve taught so many students over the years,

but also for me personally as friends,

but also anytime that I want to touch

into the beauty of the nervous system,

I rarely lose touch with it,

but anytime I want to touch into it

and start thinking about new problems

and ways that the nervous system is doing things

that I hadn’t thought about, I call you.

So please forgive me for the calls past, present,

and future, unless you change your number.

And even if you do, I’ll be calling.

It’s been such a blast, Andy.

This has been a great session

and it’s always fun talking to you.

It always gets my brain racing.

So thank you.

Thank you.

Thank you for joining me today

for my discussion with Dr. David Bersin.

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of how the brain is organized and how it works

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