Chapter 3: Neurophysiology: Neural Signal Generation & Transmission

Welcome to Last Minute Lecture.

This free chapter overview is designed to help students review and understand key concepts.

These summaries supplement not replaced the original textbook and may not be redistributed or resold.

For complete coverage, always consult the official text.

I want you to picture a hospital room.

It's in Montreal, maybe the mid -20th century.

Okay.

And the air, you know, probably smells like antiseptic and maybe some stale coffee.

And in the bed, there's a woman, her name is Deidre.

And Deidre is in a, well, a really bad way.

She is suffering from epilepsy, but we're not talking about, you know, the occasional tremor.

This is the severe stuff.

These are severe life altering seizures.

We're talking full loss of consciousness, body convulsions, the kind where you can't drive, you can't work.

You can't live a normal life.

Not really, no, because you just never know when the ground is going to completely fall out from under you.

And the usual treatments, the drugs, they aren't working.

So her doctors, they propose something pretty radical.

They say, we need to find the short circuit in your brain.

They want to literally open her skull and implant these very fine wires deep into her brain tissue to listen in.

To find the electrical storm.

It's basically a search and destroy mission, right?

Exactly.

If they can find the specific cluster of neurons that are starting the fire, they can go in and surgically remove it.

So they're in the middle of this procedure and Deidre,

she's awake.

Which sounds terrifying, but the brain itself has no pain receptors.

Right.

So you can be conscious for this.

Right.

And the surgeon is stimulating these wires one by one, setting these kind of pulses of electricity into different spots to map out the territory.

Okay.

So zap.

Nothing.

Zap.

A muscle in her arm twitches.

Zap.

And then they hit one specific wire and Deidre starts laughing.

And we aren't talking about a light chuckle.

She is genuinely truly amused.

Right.

And the surgeon, he stops, he waits a moment, and then he hits the exact same wire again.

And she laughs again.

It's consistent.

It's like flipping a switch.

But here's the part that just stops me cold.

The part that, you know, keeps me up at night.

Deidre doesn't say, wow, that electricity feels really weird.

No.

When the doctors ask her why she's laughing, she doesn't mention the wire at all.

She actually points at the guys in the lab coats and says, you guys are just so funny standing there.

That is the moment.

That's the like unplug from the Matrix moment.

She rationalized it.

Her brain made up a story.

It did.

Her brain experienced a purely physiological trigger, a surge of electricity, and her consciousness herself, it immediately fabricated a story to explain that feeling.

So she felt amusement and just assumed the world was amusing in that moment.

It implies something so unsettling, doesn't it?

It really does.

We all like to think of our sense of humor, our personality,

our soul, even as this kind of ethereal ghost in the machine.

But Deidre's story suggests that the ghost is the machine.

You push the button, you get the laugh.

And that is the core insight we are going to be chasing today.

Yeah.

I mean, everything you are thinking right now, the fact that you're listening to this, the fact that you might be feeling bored or interested or whatever, it is all the product of a biological machine.

And like any machine, it can be reverse engineered.

So that is our deep dive.

We are going to be looking at the wiring diagram.

We are tearing down chapter three of behavioral neuroscience, the eighth edition.

The chapter is called neurophysiology.

Which I know, it sounds a little dry.

It does sound dry.

But as we just saw with Deidre, it's actually the instruction manual for being human.

We're going to go from the micro all the way up to the macro.

We'll start with the literal salt water inside a single cell.

And then we'll look at how that generates a spark.

And how that spark jumps between cells.

And finally, how billions of those sparks create the symphony, or in Deidre's case, the cacophony of human behavior and experience.

Okay.

So if we're going to claim the brain as a machine, we have to start with the power source.

Every machine needs power.

And the brain is an incredibly hungry machine.

It consumes something like 20 % of your body's total energy.

Despite being only, what, 2 % of your body weight.

Exactly.

It's an energy hog.

And a huge, huge chunk of that energy goes toward one single task, maintaining a battery.

You mean a literal battery?

In every sense that matters, yes.

I mean, what is a battery?

It's just a separation of charge.

You have positive stuff on one side, negative stuff on the other, and a barrier in between.

And if you connect them, current flows.

That is precisely how a neuron works.

Okay.

So let's build this battery from the ground up.

What are the materials we're working with?

We're working with ions, which are just atoms that have either lost or gained an electron, giving them an electrical charge.

And we're working in water.

The brain is, for all intents and purposes, a salty soup.

So who are the main characters in this soup?

Okay.

We've got four big players.

First, you have what are called anions.

These are large protein molecules, and they are negatively charged.

I like to think of them as the luggage.

The luggage, that's perfect.

They're big, they're bulky, and most importantly, they are trapped inside the neuron.

They cannot get out.

So the inside of the cell has this baseline negative charge, just because it's full of these anions.

It has a negative personality, yes.

Okay.

Inside is negative.

Who else is in there?

Potassium.

K+.

This is the VIP of this whole operation.

Potassium is positively charged, and there is a ton of it inside the cell.

So we have negative proteins and positive potassium ions all hanging out together inside.

That's right.

Then, stuck outside the club, sort of peering through the window, you have sodium,

Na +, also positive.

Okay.

And usually accompanying sodium is chloride, key L-, which is negative.

So to summarize, inside is potassium and proteins, outside is sodium and chloride.

And separating the inside from the outside is the wall.

The cell membrane.

And it's what we call a lipid bilayer, which is really just a fancy way of saying a layer of fat.

And ions can't pass through fat.

They just bounce right off.

They do.

So if the wall is solid, how do we ever get a current?

I mean, a battery is pretty useless if the charge is permanently stuck on either side.

Right.

Well, the wall isn't completely solid.

It has doors.

We call them ion channels.

Okay.

These are specialized proteins that act as tunnels through the membrane.

But, and this is absolutely critical, they are very, very picky.

We call this selective permeability.

So they have a balancer at the door.

A very strict one.

In a resting neuron that's just sitting there, not firing, just, you know, chilling.

The potassium channels are open.

So potassium can come and go.

It can walk in and out as it pleases.

But the sodium channels, they're shut tight.

Sodium is locked out of the club.

Okay.

So potassium is free to move.

Sodium is stuck outside.

But why would they move at all?

What's the force that's pushing them around?

There are two fundamental forces at war here.

And this tug of war is basically the engine of the entire nervous system.

Force number one is diffusion.

Which is just the tendency of things to spread out, right?

If I drop a bit of ink in a glass of water, it spreads until it's evenly distributed.

Precisely.

Molecules always want to move from an area of high concentration to an area of low concentration.

Now, remember, we have this packed bance floor of potassium inside the cell and almost none outside.

So what does diffusion tell potassium to do?

Get out of here.

It pushes potassium out of the cell.

Correct.

But then you have force number two, electrostatic pressure.

Opposites attract.

And like charges repel.

Now let's look at the charge inside the cell.

The inside is full of those big negative anions we talked about.

Right.

Potassium is positive.

So while diffusion is pushing potassium out the door, the powerful negative charge inside is screaming, don't go.

We love you.

Come back.

It's sort of a toxic relationship.

Yeah.

Diffusion is saying, go be free.

And the electrostatic pressure is saying, no, you complete me.

And the resting potential is simply the stalemate between those two forces.

It's the equilibrium point where they perfectly cancel each other out.

Potassium flows out just until the negative pull from inside is strong enough to stop any more from leaving.

And if we were to stick a tiny voltmeter into the cell and measure that balance point.

We would get a reading of approximately negative 65 millivolts.

That is the magic number for typical neuron.

The inside of the neuron is 65 millivolts more negative than the outside.

The source material actually describes this experiment in a lot of detail.

It refers to, figure 3 .1.

It does, yeah.

They take what's called a microelectrode, which is this glass tube drawn to a super, super fine point, and they physically insert it into the axon of a neuron.

It's an incredibly delicate procedure.

When the electrode is just floating around in the fluid outside the neuron, the voltmeter reads zero.

There's no difference in charge, but the instant that tip pierces the membrane and enters the intracellular fluid,

it swings all the way down to negative 65 millivolts.

And that's the proof.

That proves the neuron is polarized.

It proves the battery is fully charged.

So negative 65 millivolts.

That means the gun is cocked.

The bow string is drawn back.

Exactly.

It's stored potential energy.

But there's a small problem.

The system isn't perfectly sealed.

The membrane is a little bit leaky.

So a tiny bit of sodium always manages to sneak in and some potassium manages to escape for good.

So over time, the battery should die or it should just neutralize and go to zero.

It would, yes, if we didn't have a maintenance crew working around the clock.

And this is the sodium potassium pump.

This is the energy hog you mentioned earlier.

This is the real worker bee of the cell.

It's a protein that physically grabs three sodium ions from inside the cell and kicks them out.

And at the exact same time, it grabs two potassium ions from outside and drags them back in.

So it's constantly bailing out the boat.

Constantly.

247.

Three sodiums out, two potassiums in.

And notice the math there.

You're pumping out more positive charges than you're bringing in.

Which helps maintain that negative charge on the inside.

It makes sure that 9 to 65 milliv charge stays locked and loaded, ready to go.

Okay.

Let's just recap the state of the board.

We have a neuron.

It's sitting there at negative 65 millivolts.

The inside is negative and sodium is desperate to get in.

It's being pulled by fusion because there's way less sodium inside.

And it's being pulled by electrostatic pressure because the inside is negative.

It is banging on the door with both fists.

And the door is locked tight.

That is the resting potential.

It is pure tension, just waiting for a release.

Okay.

So how do we pull the trigger?

How do we turn all of that stored tension into an actual signal?

We need to talk about that action potential, the spark.

This is the binary one in the computer code of the brain.

It absolutely is.

But to get there, we first have to nudge the voltage a little bit.

Neurons are constantly getting signals from other neurons.

Some of these signals make the inside of the cell even more negative.

We call that hyperpolarization.

So that's moving the voltage down to like negative 70, negative 80, negative 90.

Right.

And that moves us further away from firing.

It's like an inhibitory signal.

It sedates the neuron.

But other signals make the inside less negative.

They bring it up closer to zero.

So negative 60, negative 55.

That's depolarization.

Exactly.

Now imagine you're slowly pushing that voltage up.

You hit negative 60 millivolt.

And nothing really happens.

You hit negative 50 millivolts.

Still nothing.

But then you hit the threshold.

And for most neurons, that's around negative 40 millivolts.

And that is the point of no return.

That is the all or none property.

I love the toilet flushing analogy they use in the book because it's physically pretty accurate to the actual mechanism.

You can jiggle the handle a little bit.

That's a small depolarization.

And nothing happens.

But if you push it just past that click point.

Woosh.

The whole tank empties.

The flush happens.

And you can't stop it halfway.

You can't have a small flush or a big flush.

It's just a flush.

The action potential either happens completely or not at all.

So if I were to punch you in the arm versus just lightly tapping your arm, the neurons in your arm are firing the exact same size of explosion.

The individual explosions, the action potentials themselves, are identical in size and shape.

Then why on earth does the punch hurt more?

Frequency.

The punch triggers more action potentials per second.

It's the difference between a drummer hitting the snare drum once every few seconds versus doing a full -on drum roll.

The brain interprets the frequency of hits to determine the intensity of the stimulus.

Okay, so we hit the threshold.

We're at negative 40 millivolts.

The toilet is flushing.

What is physically happening to those ions?

This is the phase.

Remember all those sodium ions that were banging on the door?

The ones that were so desperate to get in.

At negative 40 millivolts, a new set of doors, the voltage -gated sodium channels suddenly pop open.

They literally detect that change in voltage and snap into a new shape.

And the floodgates are open.

Sodium rushes in like a dam breaking.

Remember, it's being driven by both concentration and charge.

It is a massive influx.

And since sodium is positive, the voltage inside the cell must just skyrocket.

It does.

It goes from negative 40 millivic, shoots past zero, and goes all the way up to positive 40 millivolts.

A total reversal of polarity.

The inside of the battery is now positive.

But this state is incredibly unstable.

It can't last.

Which brings us to act two, the falling phase.

The sodium channels, they have a built -in timer.

After about one millisecond, they snap shut and they lock.

Sodium is cut off.

But the cell is now positively charged at plus 40 millivic.

Which poses a huge problem for potassium.

Remember, potassium is positive, too.

Right.

Before, the negative charge inside was holding it in.

But now, the inside is positive, like charges repel.

So potassium is being pushed out by diffusion, and it's being electrically repelled by all the sodium that just invaded.

So potassium flees the scene.

It's a massive exodus.

A different set of channels, the voltage -gated potassium channels, open wide, and potassium pours out of the cell, taking all its positive charge with it.

And this causes the voltage to just drop like a stone.

And act three.

The after potential, or the overshoot.

The potassium gates, they're a little bit slow to close.

They stay open a little too long.

So much positive charge leaves that the cell actually dips below the normal resting potential.

It might go down to, say, negish 80 millivie for a moment.

It overshoots the mark.

Just briefly.

Then the sodium -potassium pumps kick back in, everything normalizes, and we're back to negish 65 millivie.

Ready for the next round.

The text mentions a really, really cool technology that they use to figure all this out.

The patch clamp.

Oh, this is Nobel Prize -winning stuff.

NARA and Sackman.

Before this technique, we just had to infer that these channels even existed.

So how does it work?

Imagine a glass pipette.

A tiny glass needle.

With a kip that's only a few micrometers wide.

You gently touch it to the surface of a neuron, and you apply a tiny bit of suction.

Kind of like sucking a tiny piece of skin into a straw.

Exactly like that.

You isolate a tiny patch of the cell membrane, and if you are incredibly lucky and precise, that patch contains just one single ion channel.

Wow.

That's an amazing level of precision.

It is.

And it allows researchers to record the electrical current flowing through a single protein molecule.

They can literally watch the channel snapping open and snapping closed in real time.

Incredible.

It proved that these channels are binary.

They're either open or closed.

There's no in between.

The smooth curve of the action potential we see is just the sum of thousands of these little guys snapping open and closed in a coordinated way.

We're basically eavesdropping on the machinery of life at the molecular level.

Now, there's a safety feature built into this whole flush cycle, right?

You can't just fire the gun again immediately.

Yes.

The refractory period.

And it's absolutely crucial.

For a brief moment after the sodium channels close, they are physically inactivated.

They're sort of bricked.

So even if I shock the neuron again with a huge stimulus.

Doesn't matter.

The door is jammed shut.

This is the absolute refractory phase.

And it ensures that the action potential is a discrete single event, not just a continuous seizure -like state.

And then there's a relative phase after that.

Right.

After a millisecond or two, the sodium channels are reset and ready to go again, but the cell is still hyperpolarized from that overshoot we talked about.

So it's down at negative 80 millivy.

Exactly.

So you can fire again, but you need a much stronger stimulus to get it all the way back up to the negative 40 millivy threshold.

Why does this matter so much?

Why do we care about this kind of traffic control?

Because of direction.

Think about the axon like a fuse on a firecracker.

When the spark travels down the fuse, why doesn't it also travel back up the fuse it just came from?

Because the part of the period leaves a wake of burnt out inactivated membrane behind the signal.

It ensures that the information only travels one way from the cell body down to the axon terminal.

Without that, our brains would be a mess.

It would just be a static feedback loop.

We'd probably be paralyzed.

Okay.

So we've got the spark.

We understand how it's generated, but a scark in a vacuum is useless.

It needs to travel.

We need to move this signal from, say, your spinal cord all the way down to your big toe.

That's a meter of distance.

In biological terms, that's a cross country road trip.

And if you just rely on the raw wire, the uninsulated axon itself,

it's shockingly slow, isn't it?

It is.

The text uses a great analogy comparing it to a fire hose versus a leaky garden hose.

Right.

Without insulation, the electrical current just leaks out of the membrane as it travels.

It fades away very quickly.

To keep it going, the neuron has to constantly regenerate full action potential at every single millimeter of the membrane.

It's like having to stop at every single gas station on the highway to refuel.

It works, but it's incredibly slow.

We're talking maybe 10 meters per second.

And that sounds fast, but for a critical reflex, if you touch a hot stove, you need to know about it now, not a tenth of a second from now.

So evolution came up with a better way.

Insulation.

Myelin.

Myelin is a complete game changer.

It's a fatty sheath that's wrapped around the axon, provided by glial cells,

and it does what any good insulation does.

It prevents the ions from leaking out.

But wait, if it's fully insulated, how does the signal get regenerated?

You can't get any sodium in if the whole thing is wrapped in electrical tape.

And that is the genius of the design.

The insulation isn't continuous.

There are tiny gaps.

The nodes of Ranvier.

I always thought that sounded like a location from Lord of the Rings.

The armies will meet at the nodes of Ranvier.

It does have that ring to it.

But they're real.

These are tiny exposed sections of the axon wire spaced out every millimeter or so.

And guess what is packed shoulder to shoulder into those nodes?

It has to be the voltage gated sodium channels.

Thousands and thousands of them.

So the electrical signal zips through the insulated myelinated part at incredibly high speed.

That's passive conduction.

And then it hits the node.

The voltage has dropped a little bit, but it's still way more than enough to trigger the channels at that node.

Boom.

A fresh full strength explosion of sodium.

The signal is boosted back up to its maximum.

And then it zips to the next node.

So it looks like the signal is literally jumping down the axon from node to node.

We call this saltatory conduction.

Which comes from the Latin Salterre to jump or to leap.

Right.

And the speed difference is just, it's massive.

We go from maybe 10 meters per second to up to 150 meters per second.

That is the evolutionary difference between being eaten by the saber tooth tiger and climbing the tree just in time.

You know, it's interesting.

The text points out that this is precisely why a disease like multiple sclerosis is so devastating.

Yes.

MS is an autoimmune disease where the body's own immune system attacks its myelin.

It basically strips the insulation off the wires.

So the signal tries to jump from one node to the next, but the bridge is gone.

The bridge is gone.

The current leaks out into the fluid.

The signal fades before it can reach the next cluster of channels.

The message, the command to move your leg or focus your eyes.

It literally gets lost in the mail.

It really highlights how fragile this whole system is.

It's an incredibly high performance machine, but if you strip away one key component, the whole thing can fail.

But when it works,

it works beautifully.

The signal races down the axon, jumping from node to node until it reaches the very end of the line, the axon terminal.

And this is where the plot really thickens because up until this very moment, we've been talking about electricity, ions moving, voltage changing, but electricity cannot jump across empty space.

Not easily, no.

And neurons don't actually touch.

There is a physical gap between them called the synaptic cleft.

It's tiny, maybe 20 nanometers wide, but to an electron, that's a canyon.

So we have to change languages.

We have to switch from an electrical language to chemical language.

This is the heart of synaptic transmission.

A handoff.

So walk us through the mechanism here.

The spark, the action potential hits the end of the wire.

What happens next?

When that wave of depolarization, the action potential, invades the terminal, it triggers the opening of a new type of door.

Not sodium, not potassium, but voltage -gated calcium channels.

Calcium is the trigger man.

It rushes into the axon terminal.

Now, inside this terminal, waiting patiently in the loading dock, are these little bubbles called synaptic vesicles.

And inside these bubbles are the chemicals, the neurotransmitters.

Things like dopamine, serotonin, glutamate.

They're all prepackaged in these vesicles.

When calcium floods into the terminal, it binds to a specific protein on the vesicle.

The text gets into the details of the snare proteins.

The T -snares and the V -snares.

Right.

You can think of them like a docking clamp on the International Space Station.

The V -snare is on the vesicle.

The T -snare is on the cell membrane.

Calcium causes these proteins to twist together, like a winch, pulling the vesicle down until it touches the membrane.

And then they fuse together.

Pop.

The vesicle opens up and spills its entire contents out into the gap.

The neurotransmitter floods the synaptic cleft.

Okay, so now we have a chemical messenger floating in the space between the neurons.

It swims across that tiny gap and it finds the other side.

The post -synaptic membrane.

And embedded in this membrane, there are receptors.

The lock and key model.

It's the perfect analogy.

The receptor is a protein with a very specific, unique shape.

The lock.

The neurotransmitter is the key.

It fits perfectly into that slot and only that slot.

Now this is a crucial distinction the text makes.

The key itself doesn't actually go into the cell, does it?

It just fits into the lock on the outside of the door.

That's exactly right.

The neurotransmitter is what we call a ligand.

It binds to the outside of the receptor.

When it binds, it causes the receptor protein to change its shape.

And usually that shape change opens an ion channel.

So we are back to ions.

The chemical key opens an electrical door.

Precisely.

We converted electricity to chemistry to cross the gap.

And now the chemistry on the other side converts back to electricity to continue the message down the line.

But here is where it gets really complicated, right?

Because not all keys open the same kind of doors.

No.

This is where the brain actually starts making decisions.

Some neurotransmitters are excitatory.

When they bind to their receptor, they open sodium channels.

Sodium rushes in.

That makes the inside of the cell more positive.

That leads to a depolarization.

Exactly.

We call that an EPSP.

An excitatory post -synaptic potential.

You can think of it as a yes vote.

It pushes the neuron closer to that negative 40 millivie firing threshold.

It's saying fire.

Fire.

But other keys do the opposite.

Others are inhibitory.

They might open a chloride channel.

Remember chloride.

CL.

It's negatively charged.

So if a channel for negative ions opens up and they rush in, the cell becomes even more negative.

It goes down to negative 70 or negative 80 millivie.

This is an IPSP.

An inhibitory post -synaptic potential.

It's a no vote.

It moves the neuron further away from the firing threshold.

So the receiving neuron is basically a little polling station.

It's getting thousands of inputs at any given moment.

Some are saying fire.

Some are saying don't fire.

Yes.

No.

And it has to do the math.

We call this process integration.

The textbook calls it neural algebra.

I love that term.

The neuron is literally adding and subtracting all these tiny voltage changes.

It sums up all the EPSPs and it subtracts all the IPSPs.

If the total final sum at a critical region called the axon hillock, the trigger zone, reaches that negative 40 millivie threshold, the gun goes off.

A new action potential is born in that neuron.

And this happens through two main mechanisms, right?

Spatial and temporal summation.

Right.

Spatial summation means you have inputs arriving from many different locations all at the same time.

It's like three of your friends shoving you from different angles simultaneously.

And temporal summation.

That's inputs arriving very quickly.

One after another from the same spot.

Like one friend shoving you three times in a row.

Really fast.

Both methods can be enough to push you over the edge, or in this case, the threshold.

This explains so much about how drugs and poisons work, doesn't it?

The text brings up the example of curar.

The South American arrow poison, a classic example.

Indigenous hunters use it on their blowgun darts.

Curar has a molecular shape that's almost identical to acetylcholine.

Which is the main neurotransmitter used to make our muscles contract.

Right.

But here's the trick.

Curar is what we call a blocker, or an antagonist.

It fits perfectly into the acetylcholine receptor, the lock, but it doesn't turn it.

It just sits there jamming the keyhole.

So the real key, the real acetylcholine, can't get in to open the door.

Exactly.

The muscle never receives the signal to contract.

The animal or the person becomes completely paralyzed.

They can't even move their diaphragm to breathe.

It's a truly terrifying demonstration of how dependent we are on these specific little chemical keys working just right.

It really is.

You jam the lock and the entire machine just stops.

But speaking of the machine, we can't just leave the neurotransmitter sitting in the lock forever.

That would be like pressing a doorbell and then taping the button down.

The signal would never end.

You'd have a permanent muscle contraction or permanent seizure.

Yeah.

So the brain has a very efficient cleanup crew.

Two main types of janitors.

Degradation and reuptake.

Degradation is pretty brutal.

There are enzymes that just float around in the synapse like sharks.

Acetylcholinesterase, for example, finds any free -floating acetylcholine and just chops it in half.

It literally breaks the key so it doesn't work anymore.

And reuptake is more like recycling.

It is.

The presynaptic neuron, the one that sent the signal, has these little vacuum cleaners on its surface called transporters.

They actively suck the neurotransmitter back up out of the gap.

To be reused.

To be repackaged into new vesicles and used again.

It's very sustainable and very efficient.

And this is actually how many modern antidepressants like Prozac work.

They are SSRIs.

Selective serotonin reuptake inhibitors.

So they block the vacuum cleaner.

They block the vacuum cleaner for serotonin.

Yeah.

Which means the serotonin that gets released stays in the gap for longer.

Banging on the doors of the receptors again and again.

It amplifies the original signal.

Precisely.

It's amazing how we can tweak the entire machine of mood and emotion just by messing with the cleanup crew.

Now, we've been talking about this whole chemical handoff as if it's a settled fact.

But historically, this was a massive, massive debate.

The war of soups and sparks.

Oh, yeah.

The early 20th century was wild for neuroscience.

You had the sparks.

These were the physiologists who swore that transmission had to be purely electrical.

It was fast.

It was clean.

It made sense.

And on the other side, you had the soups.

The pharmacologists who said it had to be a chemical process.

Drugs worked, so chemicals had to be involved.

And the whole thing was settled by a dream.

It's an amazing story.

Otto Loewi, a German pharmacologist back in 1921.

He falls asleep and has this incredibly vivid dream of an experiment that would settle the debate once and for all.

He wakes up, scribbles it down on a piece of paper, and goes back to sleep.

A classic mistake.

A huge mistake.

The next morning, he looks at the paper.

It's complete chicken scratch.

He can't read his own writing.

He spends the entire day miserable, trying to remember this brilliant idea.

And then the next night?

The dream returns.

This time, he doesn't risk it.

He gets up, goes straight to his lab at 3 a .m.

Okay, what's the experiment?

He takes two frog hearts.

He keeps them beating in a saline solution.

Now, the vagus nerve is still attached to heart number one.

And the vagus nerve is known to slow the heart down.

Right.

So he electrically stimulates the vagus nerve of heart number one.

And as expected, the heart rate slows down.

Okay, that's good to know.

Then, and this is the genius part, he takes the fluid, the soup, that heart number one has been sitting in, and he carefully drips it onto heart number two.

And heart number two has no nerve stimulation at all.

None.

It's just sitting there, beating.

Yeah.

Heart number two slows down.

That's the smoking gun.

It's the absolute smoking gun.

It had to be a chemical.

The electricity from the first heart didn't get transferred.

The fluid did.

He called the mysterious substance vagustof, or vagus stuff.

We know it today as acetylcholine.

So the soups won the war.

Mostly.

It turned out later that the Starks were partially right in some very specific cases.

We did eventually discover gap junctions.

Electrical synapses.

In these rare instances, the neurons are so close together, only about two nanometers apart, that their membranes are physically bridged by giant protein channels.

Ions can just flow straight from one cell into the next.

So there's no neurotransmitters, no delay, none of that.

It's instantaneous.

It's used for things where speed is the absolute only thing that matters, like escape reflexes and invertebrates, or synchronizing large groups of neurons in our own brains to fire at once.

But for the complex, nuanced, decision -making kind of thinking we do, it's all chemical.

It's all soup.

Okay, so let's zoom out a bit.

We've built the neuron, we've fired the spark, we've crossed the gap.

Now we have billions of these things all talking to each other at once.

We have neural circuits.

And the simplest one of all is the reflex arc.

The classic knee -jerk reflex.

The doctor taps your knee with that little hammer, and your leg kicks out.

It is a model of pure efficiency.

A sensory neuron in your thigh muscle feels the stretch.

It has an axon that goes straight to the spinal cord, where it connects directly to a motor neuron.

That motor neuron fires, and the signal goes straight back to the muscle telling it to contract.

And your brain isn't even invited to the meeting.

Not at all.

By the time your brain even registers the thought, hey, someone just tapped my knee, your leg is already kicked, the decision was made for you.

But then you have more complex arrangements, like convergence and divergence.

Right.

Convergence is the funnel.

In your eye, for instance, you have millions and millions of photoreceptor cells.

They all talk to a smaller number of bipolar cells, which in turn talk to an even smaller number of ganglion cells.

You're condensing a huge amount of data down to its most essential features.

And divergence is the opposite.

It's the megaphone.

Exactly.

One single neuron in your brain stem that detects a potential threat can send out branches to the visual cortex, the amygdala, the motor cortex, the adrenal glands.

It's broadcasting one simple message to many different departments.

Wake up.

Pay attention.

Run.

And when you have enough of these neurons firing in sync, we can actually hear the hum from outside the building, so to speak.

This is the EEG.

The electron cephalogram.

We paste a cap of electrodes onto the scalp.

And we're not measuring single neurons anymore.

We'd need that glass pipette for that.

We're measuring the roar of the crowd.

So -called brain waves.

That's all they are.

Alpha waves, beta waves, delta waves during deep sleep.

These are just different patterns of synchronization among millions of neurons.

It's crucial for sleep studies, but it's most famous for diagnosing what happens when that synchronization goes horribly wrong.

And we are right back to Deidre.

Epilepsy.

Epilepsy is an electrical storm in the brain.

Normally, brain activity is this incredibly complex asynchronous conversation with different groups of neurons talking about different things.

In a seizure, it's like everyone in the stadium starts shouting the exact same word at the exact same time.

Synchronization is usually a good thing for the brain, but here it's catastrophic.

It's too much of a good thing.

In a grand mal seizure or a tonic -clonic seizure, that wave of synchronization sweeps across the entire brain.

The motor cortex fires all at once.

That's the convulsions.

The consciousness centers in the brain stem get overloaded.

That's the blackout.

But Deidre didn't have that.

She was awake.

She was laughing.

She most likely had what's called a complex partial seizure.

Partial means the storm was localized.

It was contained in one specific area of the brain, maybe just in her temporal lobe.

And the temporal lobe is involved in emotion and memory.

And hearing and language.

So the storm hits the specific brain circuit for amusement.

The surfeit fires uncontrollably.

She feels the powerful emotion of amusement.

But because the storm didn't spread to the rest of her brain, she remained fully conscious.

So she was left with this bizarre, unexplainable experience.

I feel incredibly happy, but I have no idea why.

And her brain's interpreter module, which is usually in the lanch hemisphere, stepped in to fill the gap.

It looked for a reason and said, uh,

it must be those doctors.

They look funny.

It just shows how fragile our grip on our own reality really is.

You change the voltage in a few million cells.

And your entire reality changes with it.

It does.

Now, the EEG is great for seeing these big storms, but the text admits it's a bit of a blurry picture.

It's like listening to the roar of a football stadium from the parking lot.

You know a touchdown was scored,

but you have no idea who caught the ball.

That's the big limitation.

It has great temporal resolution.

We know exactly when something happened, but it has terrible spatial resolution.

We don't know exactly where it happened.

So how do we get more precise?

If we want to really understand and control the brain, the kind of electrical stimulation they used on Didri is a sledgehammer.

It hits everything in the area.

We need a scalpel.

Enter optogenetics.

This is the real sci -fi stuff.

This is the future of neuroscience.

This is the section that just blew my mind.

We are using light to control brains.

We are, and we stole the technology from algae.

From pond scum.

Literally.

Scientists discovered that certain types of algae have these proteins in their cell membranes called opsins, and they are light -sensitive ion channels.

So they're like the voltage -gated channels we talked about, but instead of voltage, they're opened by light.

Exactly.

One of them, channelrhodopsin, opens up when it gets hit by blue light, and when it opens, it lets sodium ions flow in.

Sodium ins means depolarization.

It means fire.

It's an on switch.

It's a light -activated on switch.

So if you can take the gene for that protein from the algae and use genetic engineering tools to insert it into a specific type of neuron in, say, a mouse's brain.

You can install a light switch on that specific neuron.

A remote control.

You can implant a tiny fiber optic cable, shine a blue light, and only that type of neuron will fire.

And there's another one, halorhodopsin, that responds to yellow light.

It's a pump that forces chloride ions into the cell.

Chloride is negative, so that hyperpolarizes the cell.

It turns it off.

Blue for go, yellow for stop.

And because we use genetic targeting, we can be incredibly specific.

We can choose to control only the dopamine neurons, or only the neurons in the amygdala that are connected to fear.

So unlike Diedre's doctors, who are just poking around blindly with an electrified wire, we can now sit down at the piano and play the keys one by one to see what they do.

We can trigger a specific memory.

We can turn off a specific craving.

It is completely revolutionizing neuroscience, because for the first time, it allows us to prove causation.

I turned this exact neuron on, and the mouse did X.

There's no more guessing.

It's a very, very long way from Diedre laughing in that hospital bed in Montreal.

It is.

But the fundamental principle is exactly the same.

We are machines.

We're incredibly complex, beautiful, miraculous machines.

But we are machines nonetheless.

That's a pretty humbling thought, isn't it?

We started this hour looking at a woman who couldn't even trust her own laughter.

We walked through the basic physics of ions, the chemistry of the synapse, and the biology of the neural circuit.

We kind of stripped the magic away, layer by layer.

But does that really make it less special?

I don't think so.

I really don't.

When you realize that your love for your partner, or your favorite memory of childhood,

or your ability to simply understand this sentence,

when you realize all of that is just sodium and potassium and calcium dancing across a thin membrane of fat, to me, that makes it infinitely more incredible.

We're just a galaxy of little batteries, all sparking in the dark.

And somehow, out of that electrochemical darkness, comes the light of consciousness.

Well, I think I'm going to go recharge my own batteries.

Literally, I need a sandwich.

My sodium and potassium pumps are working overtime after all this.

Definitely get some electrolytes in you.

A huge thank you to the Last Minute Lecture team for helping us compile all this research.

And thank you to you, the listener, for plugging in with us.

Keep those neurons firing.

We'll see you in the next Deep Dive.