Chapter 17: Learning & Memory

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Welcome back to the Deep Dive.

You know, I was looking at an old photo album this morning.

Yeah.

And I found this picture of myself at a birthday party when I was maybe

26.

I don't know.

And I'm looking at this kid.

He's blowing out candles.

And I logically know it's me.

Right.

I know the date on the back of the photo says it's me.

But I don't feel it.

I don't remember the cake.

I don't remember the people.

And it just hit me.

We think of ourself as this, you know, solid, continuous timeline.

But biologically, we are just a collection of fragile electrical impulses holding on to a story that is constantly, constantly fading.

That is the terrifying beauty of it, isn't it?

We feel like we are the authors of our own autobiography.

But really, we're just the editors.

And as we're going to find out today, the editing room floor is messy.

Very messy.

Today, we are strictly following Chapter 17 of Behavioral Neuroscience, the 8th edition by Breedlove and Watson.

And we are tackling the big one, learning and memory.

It's a massive chapter.

We're going to go from the tragedy of a man who basically lost his future all the way down to the actual molecules, the literal proteins that hold the memory of your first kiss.

It's an incredible journey.

But before we get to the molecules, we have to talk about the man.

The text introduces him as Patient HM.

Henry Molaison.

For 50 years, he was, and this is not an exaggeration, arguably the most famous research subject in the history of brain science.

His case is the absolute foundation upon which all modern memory research is built.

To understand memory, you simply have to understand Henry.

Okay, so let's set the scene.

It's the mid -20th century.

What was going on with Henry?

Henry suffered from severe epilepsy.

It started in his adolescence, likely after a bicycle accident.

And by the time he was a young man in his late 20s, it was.

It was completely out of control.

It's debilitating, I imagine.

Completely.

The seizures were just relentless.

He couldn't work.

He couldn't maintain a social life.

The doctors at the time determined that the seizures were originating in the temporal lobes of his brain.

So in 1953, a neurosurgeon named William Scoville made a really drastic decision.

1953 neurosurgery.

That sounds intense.

We are not talking about lasers and robots.

No, not at all.

Scoville performed what's called a bilateral medial temporal lobectomy.

Which means?

He removed most of the anterior temporal lobes on both sides of Henry's brain.

We're talking about the amygdala, most of the hippocampus, and some of the surrounding cortex just removed.

Which, looking back with what we know now, that sounds like trying to fix a computer virus by ripping out the hard drive.

That is a perfect analogy.

But did it work?

I mean, for the seizures, did it stop them?

And that's the tragic irony.

In that one regard, the surgery was actually a success.

It relieved his epilepsy significantly.

He could finally function without those violent convulsions.

There's a huge butt coming.

A huge butt.

That relief came at a terrible, unforeseen price.

Henry woke up with severe, anterograde amnesia.

Okay, let's unpack that term.

Anterograde amnesia.

Anterograde comes from the Latin, meaning forward.

It means the inability to form new memories, starting from the onset of the disorder.

So he could remember things from before.

Yes.

So Henry could remember his childhood.

He knew who his parents were.

He remembered events from before the surgery.

His retrograde memory looking backward was mostly intact, although he did lose some memories from the time immediately leading up to the operation.

But going forward,

nothing, nothing stuck.

The text has this quote from him recorded in 1970 by Brenda Milner that just, it just breaks your heart.

He described his state as waking from a dream.

He said, every day is alone in itself, whatever enjoyment I've had and whatever sorrow I've had.

It's the eternal now.

Imagine walking into a room and meeting Henry.

You could have a pleasant, intelligent conversation with him.

He was polite, articulate, mild -mannered.

But if you left the room for just five minutes and came back in, he would introduce himself to you all over again.

As if he'd never seen you before.

He had zero recollection of ever meeting you.

And the really fascinating thing or maybe the confusing thing for doctors at the time was that he wasn't, he wasn't dumb.

He didn't lose his intelligence.

Exactly.

This is what the text calls the IQ paradox.

Henry's IQ remained a little above average.

In fact, it actually went up slightly, probably because he wasn't having seizures anymore.

Right.

He could solve problems.

He could hold a conversation.

He retained his general intelligence.

And this was the first major, major clue that memory is not the same thing as intelligence or perception.

They're separate functions.

Completely distinct functions in the brain.

Before Henry, there was this kind of unitary view that memory was just a property of the whole brain working together.

Henry proved tragically that memory is a specific function localized in specific tissue.

So Henry becomes this, this living window into the brain.

Researchers spent decades studying him.

And one of the most famous experiments involves a mirror and a star.

This is figure 17 .3 in the text.

Walk us through this because this is where things get really, really interesting.

This is the mirror tracing task.

So imagine you're sitting at a desk.

In front of you is a drawing of a five -pointed star.

Okay.

But you can't look at your hand or the star directly.

You have to look at their reflection in a mirror.

Your job is to trace the outline of the star with a pencil, staying within the lines while only looking at the mirror.

I think I've tried this out of a science museum or something.

It's incredibly hard.

Everything is reversed.

You want to move your hand left, but in the mirror, it goes right.

It's a total mess.

It is very, very difficult initially.

So they had Henry do this.

On day one, just as you'd expect, he makes a ton of errors.

His line is wobbling all over the place, just like anyone would.

But he keeps practicing.

He does it over and over.

And then they come back on day two.

Right.

They sit him down.

They ask him, Henry, have you ever done this before?

He says, no, never.

He has absolutely no conscious memory of the task.

But, and here's the kicker.

When he sits down to do it, his hand knows what to do.

No way.

He makes fewer errors.

By day three, his performance is almost perfect.

He's tracing that star like a pro.

That is absolutely mind -blowing.

He has no memory of ever learning the skill, but he has the skill.

It's like a ghost is guiding his hand.

It was a revolution in neuroscience.

It was the first solid proof that memory is not just one big filing cabinet.

There are different types of memory.

Henry lost his declarative memory.

The things you can declare, like facts or events.

I had eggs for breakfast or I traced a star yesterday.

That was gone.

But he kept his non -declarative memory.

Correct, which is also called procedural memory.

This is the how.

How to ride a bike, how to play the piano, how to trace a star in a mirror.

These are memories that are shown by performance, not by conscious recall.

So the text uses figure 17 .5 or break this down right.

Declarative is things you know that you can tell others.

And non -declarative is things you know that you can show by doing.

And because Henry's basal ganglia, a totally different part of the brain was intact, he could learn the skill.

But because his hippocampus was gone, he couldn't form the memory of the event of learning it.

Precisely.

The system for what was broken, but the system for how was still working.

So we have this fundamental split.

But you know, we can't just rely on human patients with accidental injuries.

We need to look at animals to really map out the anatomy.

Right, for controlled experiments.

But here's the problem.

You can't ask a monkey, hey, do you remember seeing this key yesterday?

They can't talk.

So how in the world do we test declarative memory in animals?

Well, researchers developed this really brilliant test called the delayed non -matching to sample task.

It's a mouthful, I know.

But the concept is actually pretty simple.

It's designed specifically to test object recognition.

Okay, walk me through it.

You present a monkey with an object.

Let's say a key.

The monkey learns to pick up the key and finds a food treat underneath.

Easy enough.

The monkey thinks key equals tree.

Right.

Then a screen comes down to hide the objects.

This is the delay period.

It can be a few seconds or it could be several minutes.

Then the screen goes up.

Now the monkey sees two objects.

The original key and a new object, say a wooden block.

To get the treat this time, the monkey has to pick up the new object, the non -matching one.

Ah, I see.

So the monkey has to look at the key and think, I remember that key.

That's old news.

The treat must be under the new thing.

Exactly.

By choosing the new object, the monkey is essentially declaring through its behavior that it recognizes and remembers the old object.

It's a very clever test of object recognition memory.

So what happens when they perform a similar surgery on monkeys removing the amygdala and hippocampus like in HM?

This is where the anatomy gets very specific.

And figure 17 .7 in the text is really crucial here.

What they found was removing the amygdala alone didn't really hurt performance much.

Okay, so the amygdala isn't the key player for this task.

Not for this, no.

But removing the hippocampus caused deficits.

And this is the really important part.

If they damage the cortex surrounding the hippocampus.

The neighborhood, basically.

The neighborhood, yes.

The entorhinal, parahippocampal, and perianal cortex.

When that was damaged, the deficit was severe.

Much worse than with just hippocampal damage alone.

So it's not just the hippocampus soloing this.

It's a team effort.

The whole region is critical.

Right.

And this led to what the text describes as a two -process model of declarative memory.

It seems that the perianal cortex is responsible for the sense of familiarity.

That vague feeling of, I've seen this before.

Okay.

Meanwhile, the hippocampus itself seems to be responsible for recollection.

The specific context.

The where and the when of the memory.

So if I see a guy at a coffee shop and think, I know that guy from somewhere.

That's my parahinal cortex firing.

Yep.

But if I then realize, oh, that's Bob from accounting.

We met at the holiday party last year.

That's the hippocampus kicking in with the details.

That's a fantastic way to put it.

And Henry, of course, lost both.

Which is why his amnesia was so incredibly profound.

Now, Henry isn't the only famous patient in the text.

We have to talk about Patient NA.

And honestly, his story is just, it's bizarre.

It sounds like something out of a pulp fiction novel.

It is a tragedy, but of a very, very different kind.

Patient NA was a young man in 1960.

He was a radar technician in the Air Force.

And he had this just freak accident involving a miniature fencing sword.

A miniature fencing sword.

Just like, you can't make this stuff up.

You really can't.

He was sitting in a chair, and a roommate was behind him, sort of, playing around with this little foil.

The friend tapped NA on the shoulder.

NA turned around suddenly.

And the fencing foil went into his brain through his nostril.

Oh, that is horrifying.

It is.

The foil penetrated the criperiform plate, that's the thin bone at the top of your nose, and went right into his brain.

But here's the key difference from Henry.

NA didn't lose his hippocampus.

So what got damaged?

The damage was to the deencephalon.

Specifically, the dorsal thalamus and the mammillary bodies.

Figure 17 .9 actually shows the path of the injury.

And the result?

Profound anterograde amnesia.

Just like Henry, he couldn't form new declarative memories.

Wow, so that was a revelation, right?

A huge one.

It showed that the hippocampus isn't an island.

It's part of a larger circuit.

You need the hippocampus, for sure.

But you also need these connected structures, like the mammillary bodies and the thalamus.

They're all linked up.

You break the circuit anywhere along the line.

Memory fails.

Speaking of breaking the circuit, the text brings up Korsakoff syndrome.

This is something we often see in people with chronic alcoholism.

Yes.

This is a very sad condition.

It's caused by a severe deficiency in thiamine, or vitamin B1.

Alcoholics often get most of their calories from alcohol, and neglect their diet, which leads to this deficiency.

And it damages the same areas?

The same circuit, yes.

It causes damage to the mammillary bodies and the dorsal medial thalamus.

If you look at figure 17 .10 in the book, you can see these tiny shrunken mammillary bodies in a Korsakoff's patient compared to a healthy brain.

The damage is just stark.

And the symptoms are similar to NA and HM.

They have the enterograde amnesia, but they also have a really unique symptom called confabulation.

Confabulation.

That's when they make stuff up.

Yes, but it's really important to understand they are not lying.

They aren't trying to deceive you.

They have gaps in their memory, and their brain just automatically fills in those gaps with falsifications that they genuinely believe are true.

So the brain is just trying to create a coherent story.

It's trying to make sense of the world.

It abhors a vacuum.

If you ask a patient what they did yesterday, and they can't remember, their brain might pull a memory file from 10 years ago and just paste it into the yesterday slot, and they'll report it with complete conviction.

That really shows how much our sense of reality is just.

It's constructed by our memory.

If the memory fails, the brain just invents a reality to keep the story going.

It's the powerful and sometimes frightening illustration of that.

There's one more patient we have to mention in this sort of hall of fame of amnesia.

Patient KC.

Right, KC.

This was a motorcycle accident.

And he had damage to his cortex.

Yes, extensive damage to the cortex.

And KC was instrumental because his case helped researchers distinguish between two subtypes of declarative memory.

Episodic and semantic memory.

Okay, let's define those clearly.

Semantic is just facts.

Semantic memory is generalized knowledge.

Knowing that Paris is the capital of France.

Knowing the rules of chess.

Knowing the definition of a word.

It's the encyclopedia in your head.

And episodic memory.

Episodic memory is autobiographical.

It's personal.

It's remembering the specific episode of your life when you learn the capital of France or remembering a specific memorable game of chess you played with your brother last Christmas.

It's the story of you.

Exactly.

And KC had this incredibly strange split.

What was it?

He could play a perfectly good game of chess.

He knew all the rules.

His semantic memory was intact.

But if you asked him, he couldn't remember a single specific time he had ever played chess before.

He couldn't remember who taught him how to play.

He had the general knowledge, but zero personal history attached to it.

It's like having an encyclopedia but no diary.

That's the perfect analogy.

And because KC's damage was so widespread in the cortex, it strongly implies that these long -term episodic memories, the diary of your life, are stored all over the cortex.

But there's another fascinating detail about KC in the text that says he couldn't imagine his future.

Yeah, isn't that incredible?

If you asked him what he might do next week or even tomorrow, he was just blank.

So what does that tell us?

It tells us something really profound.

The same brain machinery we use to recall the past is what we use to construct or imagine the future.

Without a past, you can't simulate a future.

You are just completely stuck in the present moment.

That's heavy.

Okay, so we've covered the what of memory facts versus skills, episodes versus semantics.

Now let's circle back to the where for skills in space.

We mentioned Henry could learn skills like mirror tracing because his basal ganglia were okay.

Right,

skill learning, whether it's sensorimotor like mirror tracing, perceptual like learning to read mirror versus text, or cognitive like solving a complex puzzle relies heavily on the basal ganglia, the motor cortex, and the cerebellum, a completely different circuit from the declarative memory system.

But what about navigation?

I am personally terrible with directions, so I just assume my hippocampus is taking a nap most of the time.

But for rats, the hippocampus is basically their internal GPS, right?

It absolutely is.

This is one of the coolest discoveries in all of neuroscience, the idea of the cognitive map.

You know, back in the day, cartoons used to show scientists in white coats watching rats run mazes.

Yeah.

Well, it turns out those rats weren't just learning a simple sequence of turn left, then turn right.

They were actually building a mental map of the entire space in their heads.

And we know this because we found specific cells that do it, right?

Place cells.

Place cells, yes.

These are incredible neurons in the hippocampus that fire only when the animal is in a very specific location in its environment.

So like one cell fires for the corner with the food.

Exactly.

Imagine hooking a tiny speaker up to a single neuron in a rat's brain.

The rat is wandering around a box.

For a while, it's just silence.

Silence.

Then as it walks into the northwest corner, pop, pop, pop, pop, the neuron fires like crazy.

Wow.

The rat moves away.

Silence again.

It goes back to that same corner.

Pop, pop, pop.

It's literally a you are here dot lighting up in the brain.

It is.

And it gets even more complex.

Researchers also found grid cells and border cells in the nearby entornal cortex.

Grid cells seem to map the space in a repeating triangular grid pattern, almost like latitude and longitude lines.

And border cells.

They fire only when the animal is near the wall or boundary of the space.

So the hippocampus and its neighbors are constantly actively drawing a detailed map of your environment.

That explains why damage there makes you feel lost, both in time and in space.

Exactly right.

It's a spatial map and a temporal one.

Let's shift gears to time.

We've got these different types of memory based on content.

But what about duration?

The text breaks it down into three basic stages.

Right.

First, you have the sensory buffer.

This is super, super brief milliseconds.

It's like the ghost of an image that stays in your vision for a split second after you close your eyes.

It's raw sensory data, sometimes called iconic memory.

And then if you pay attention to that sensory data, it moves into short term memory.

Right.

Short term memory or what we now often call working memory.

This lasts for seconds, maybe up to a minute.

This is like when you look up a phone number and you keep repeating it to yourself until you can dial it.

Perfect example.

Yeah.

You are actively working with the information.

You're rehearsing it.

Yeah.

But if you get distracted, if someone asks you a question, poof, it's gone.

And finally, if you rehearse it enough, it can move to long term memory.

The vast storehouse, days, weeks, years,

a lifetime.

The text has a great way to show this distinction with the serial position curve.

This is figure 17 .19.

This is a classic experiment.

Imagine I read you a list of 10 or 15 words.

Apple, boat, cloud, all the way to xylophone, zebra.

If I ask you to recall as many as you can, you are most likely to remember the words at the very beginning of the list.

Apple, boat.

That's called the primacy effect.

Right.

And you're also very likely to remember the words at the very end of the list.

Xylophone, zebra.

That's the recency effect, the ones in the middle.

You'll probably forget most of those.

And the explanation is that the primacy effect happens because you've had time to rehearse those first few words and start pushing them into long term memory.

Exactly.

But the recency effect happens because those last few words are still fresh.

They're still sitting right there in your short term memory buffer.

And here's the connection to HM.

Here's the smoking gun.

Patients with amnesia, like HM, when they do this task, they have a normal recency effect.

Their short term memory works fine.

They can hear and repeat the last few words, but they have a greatly reduced or absent primacy effect.

They can't transfer those early words into long term storage.

Which brings us to the three core processes of memory laid out in figure 17 .20, encoding, consolidation, and retrieval.

HM's problem was consolidation.

Precisely.

He could encode information into STM, but he couldn't consolidate it.

He couldn't turn that volatile short term stuff into durable long term stuff.

OK, but there is a major twist here.

For a long, long time, we thought once a memory was consolidated, once it was in long term storage, it was permanent,

stable, like a book on a shelf.

You file it away, and it stays there, unchanged.

But that's not true, is it?

And this is the part of the chapter that actually scares me a little.

No, it's not true.

And it should scare you a little.

This is the concept of reconsolidation.

It turns out that every time you retrieve a memory,

every time you take that book off the shelf to read it, the memory becomes unstable again.

It becomes plastic, malleable.

And to put it back on the shelf, you have to reconsolidate it.

Wait, wait, wait.

So just by remembering my 10th birthday party, I'm making that memory vulnerable to change.

Yes.

In order to read the file, so to speak, your brain has to unlock it.

And while that file is unlocked, it can be edited, and then it has to be resaved.

That's reconsolidation.

That sounds like a massive design flaw.

Why would evolution build a system where the very act of looking at the data can corrupt the data?

That's a great question.

And some evolutionary biologists think it's actually a feature, not a bug.

It allows us to update our memories with new relevant information.

How so?

Well, say you learn that red berries are delicious.

But then one day you eat a specific red berry and get violently ill.

You need to be able to open that red berry memory file and add a big flashing tag.

Correction, some red berries will make you vomit.

Okay, that makes sense for survival.

That's useful.

But for my autobiography, that's terrifying.

The text talks about that famous experiment with the car accident video.

The Loftus studies.

They are foundational.

They showed people a video of a car crash.

Later, they asked some of them, how fast were the cars going when they hit each other?

Okay.

They asked others, how fast were the cars going when they smashed into each other?

And just changing that one word made a difference?

A huge difference.

The smashed group gave much higher speed estimates.

But that's not even the creepy part.

A week later, they ask everyone, did you see any broken glass in the video?

There was no broken glass.

Let me guess.

The smashed group said yes.

A significant number of them remembered seeing broken glass that was never there.

The word smashed was so powerful that it inserted a false visual detail into their memory during that reconsolidation window.

So I tell a story about a fight I had with my spouse five years ago, and I'm still a little angry about it.

You are likely resaving that memory with more anger and justification for your side every single time you tell it.

You might be exaggerating the other person's tone or slightly changing their exact words to better fit your current feelings.

It's like a game of telephone with yourself.

It is.

After five years, you aren't remembering the original fight.

You are remembering the last time you told the story of the fight.

That explains why emotional memories feel so vivid but are so tricky.

We all have these flashbulb memories of huge events like 9 -11 or a car accident, and we feel like they're perfect, like a photograph.

But study after study shows they aren't.

We remember the emotion with incredible vividness, but the factual details are often wrong and change over time.

And that brings us to the chemistry of emotion and memory.

Why do we remember stressful or emotional things better in the first place?

The short answer is adrenaline.

Right.

When you are stressed or highly aroused, your adrenal glands pump out epinephrine, which we commonly call adrenaline.

This hormone, along with norepinephrine in the brain, acts on a key emotional structure, the amygdala, to basically say, hey, pay attention, this is important, save this memory, boost memory consolidation.

And the text describes a really clever experiment with a drug called propranolol to prove this.

Yes, the beta blocker study.

It's fascinating.

Researchers told participants an emotionally arousing story.

I think it involved a boy getting into a terrible accident.

Half the people took a placebo, and the other half took propranolol.

Promolol is a beta blocker.

It blocks the effects of adrenaline.

And the result?

The people who took the drug still rated the story as emotionally sad.

They felt the shock.

They understood the tragedy.

But when tested later, they didn't remember the emotional parts of the story any better than a neutral story.

Wow.

Without that chemical kick of adrenaline acting on the amygdala, the memory boost that normally comes with emotion just didn't happen.

It really shows that the feeling of the memory and the durable storage of the memory are chemically distinct processes.

Absolutely.

The emotion is the signal, but the adrenaline is the engine for enhancement.

Okay, we've been talking about systems in psychology.

Now I want to get into the real meat, the cells, the nuts and bolts.

How does the brain physically change?

Because if I learn to speak French, my brain after learning is physically different than it was before.

This is the entire concept of neuroplasticity.

The idea that the brain is plastic, that it can be molded and changed by experience.

And one of the first really solid proofs of this came from looking at rats in enriched environments.

This is the classic rats with toys experiment, right?

That's the one.

It's a foundational study.

Researchers put some rats in a standard boring cage, just food and water.

They put others in an impoverished condition alone in a small cage.

And then they put a third group in an enriched cage.

The rat paradise.

Basically, lots of other rats to socialize with, toys, ladders, little tunnels, things to explore and interact with.

And the enriched rats had smarter brains.

They had physically different brains, significantly so.

Their cortex was heavier and thicker.

They showed more cholinergic activity, which is an important neurotransmitter system.

And most importantly, when you look at their neurons at our microscope, they had more dendritic branches.

So if you imagine a neuron is like a tree, the enriched rats were growing more branches.

Exactly.

More branches mean more connections, more synapses, more places for information to be exchanged.

And this isn't just for rats, right?

The text mentions human parallels.

It does.

It mentions that professional musicians have larger motor cortex areas corresponding to the hands.

It even mentions a study showing that adolescents from more advantageous socioeconomic environments, you could argue a type of enriched environment,

have on average thicker cortexes.

Experience physically sculpts the brain.

But to understand the mechanism, how a single synapse actually strengthens scientists had to go even simpler than a rat.

They went to a sea slug.

A plesia californica, the unsung hero of neuroscience.

Why a sea slug?

Because it has a very simple nervous system and its neurons are huge, which makes them relatively easy to study.

And they just squirted water at it.

Science is very sophisticated, isn't it?

Yeah.

Yes.

If you squirt a gentle puff of water at the slug's siphon, it has a defensive reflex where it retracts its gill.

Okay.

But if you do it over and over and over again, the slug learns that the puff of water is harmless.

It stops retracting the gill.

This is a simple form of learning called habituation.

So what changed inside the slug's brain or ganglion?

What Eric Kandel, who won the Nobel Prize for this work, found was that the sensory neuron that was sensing the water started releasing less neurotransmitter onto the motor neuron that controls the gill.

So the synapse got weaker.

The synapse got weaker.

It wasn't just that the muscle was tired.

It was a physical chemical change in the strength of the connection between two neurons.

It was the first direct evidence that learning is a change in synaptic strength.

Which leads us to the absolute holy grail of memory research, long -term potentiation or LTP.

Cells that fire together wire together.

The famous Hebbian rule.

Right.

And LTP is the physiological demonstration of that rule.

In the 1970s, researchers discovered that if you take a slice of a hippocampus and stimulate a pathway of neurons with a brief high -frequency burst of electricity, a pattern called a tetanus, the synapses in that pathway become supercharged.

They become potentiated.

For a long time afterward, hours, days, even weeks, they produce a much, much stronger response to a normal single pulse of stimulation.

The connection is strengthened.

Okay, listeners, we are going to go deep here.

This is the heavy lifting section of the chapter.

We need to visualize molecular dance happening at a single synapse.

We can do it.

Let's simplify it.

Picture a nightclub.

A nightclub.

Okay, I'm with you.

This nightclub is the postsynaptic neuron, the cell that is receiving the signal.

The music pumping outside is the neurotransmitter glutamate.

Glutamate is the message and it's screaming, activate.

So glutamate is banging on the doors of the club.

It is.

Now, this particular club has two different types of doors.

The first door is called the AMPA receptor.

It's a standard regular door.

If glutamate knocks on the AMPA door, it opens, sodium ions rush in, and the party inside gets a little bit louder.

The cell gets a little more excited.

Simple enough.

Glutamate knocks, AMPA opens, party starts.

Right.

But there is a second very special door.

This one is called the NMDA receptor.

This is the VIP entrance, and it is blocked.

Who's blocking it?

A big bruley bouncer, a magnesium.

He's a positively charged ion, Mg2 plus cello, and he is sitting right in the middle of the NMDA doorway.

So even if glutamate is knocking on the NMDA door, magnesium, the bouncer says, nope, you're not getting in.

OK, so how do we get the bouncer to move out of the way?

You need a riot inside the club.

You need the party to be already going absolutely crazy.

If there is a massive amount of stimulation coming in, like that tetanus burst we talked about, so much glutamate is being released that all the AMPA doors fly open, and a huge rush of positive sodium ions floods the cell.

So the electrical charge inside the cell skyrockets.

It becomes very positive.

This is depolarization.

And because magnesium, the bouncer is also positively charged, and the inside of the cell is now strongly positive.

It charges repel.

Boom.

The electrostatic pressure literally boots the magnesium bouncer out of the channel.

The VIP door is now unblocked and wide open.

And who walks in through the VIP door?

Calcium, the VIP guest.

Cantu plus Wunter.

And calcium's not just there to party.

Calcium is the general contractor.

Once calcium rushes inside the cell through that open NMDA receptor, it sets off a cascade of chemical reactions.

Calcium triggers the long -term changes.

It activates a whole crew of enzymes called protein kinases, like one called CAM -MKII.

These kinases go to work.

They signal a protein called CRA, which travels into the cell's nucleus and actually changes gene expression.

It tells the cell's factory to start building new things.

And what's the result?

What does it build?

One of the main results is that the cell builds more AMPA receptors and inserts them into the membrane, into the doorway.

The club builds more regular doors.

Exactly.

The synapse is now physically stronger and more sensitive.

The next time a little bit of glutamate comes along, there are way more doors for it to open.

The connection is solidified.

That is LTP.

That is absolutely incredible.

A memory at its most fundamental level is just a rush of calcium telling a cell to build more parking spots for neurotransmitters.

At a molecular level, that's a huge part of the story.

And we can even pre this genetically.

The text mentions the Doogie mice.

Named after Doogie Hauser, the boy genius doctor.

Yes.

These were mice that were genetically engineered to over express a specific subunit of the NMDA receptor, the NR2B subunit.

This basically made their NMDA receptors more efficient.

Their VIP doors were easier to open.

A great way to put it.

Their brains were primed for LTP.

And were they smarter?

They were.

They showed enhanced long -term memory in various tasks.

It's a powerful validation of this entire molecular theory.

So if we can boost memory, what about the other end of the spectrum?

Losing it as we age?

For a long time, the idea was just that your neurons die off, right?

That's a common myth.

And while we do lose some neurons, normal cognitive aging doesn't seem to be about massive widespread neuron death.

The decline in memory that many people experience correlates more with the loss of synapses and a reduction in neural plasticity.

So the connections get weaker?

The connections get weaker.

And the brain's ability to induce LTP becomes less efficient.

There's also a decline in some neurotransmitter systems, like the cholinergic system that originates in the basal forebrain.

But there is good news.

The chapter talks about adult neurogenesis, the sort of upended dogma for a long time.

It really did.

For decades, the central dogma was the brain you're born with is the brain you die with.

Meaning you don't grow new neurons as an adult.

We now know that's wrong.

So where does this happen?

We now know that new neurons are born throughout life, primarily in a specific part of the hippocampus called the dentate chirus.

This is shown in Figure 17 .31.

And these new baby neurons are important.

These seem to be very important.

They are more plastic or excitable than older neurons, and they integrate into the existing circuits.

And guess what?

Boosts the survival of these new neurons.

Let me guess.

Exercise and learning.

Exactly.

Use it or lose it.

Quite literally.

An active, engaged brain that is constantly learning paired with physical exercise helps these new neurons survive and contributes to maintaining cognitive function.

We're almost out of time, but we absolutely have to touch on the cutting edge section at the end of the chapter.

This is straight out of a science fiction movie.

Octogenetics and the artificial activation of an engram.

This is truly mind -bending stuff.

This is Figure 17 .34 in the text.

Researchers used mice.

First, they identified the specific population of neurons in the hippocampus.

They were active when a mouse was in a fearful context, let's say a specific box where it got a mild foot shock.

So they found the physical address of that specific fear memory, the collection of cells that holds that memory, which we call an enneagram.

They found the enneagram.

Then, using some clever genetic tricks with a virus, they labeled only those specific active neurons with a protein called channel rhodopsin.

Channel rhodopsin is a protein that reacts to blue light.

Exactly.

It's a light -gated channel.

So now those specific fear memory neurons, and only those neurons, have a light switch installed in them.

This is wild.

It gets wilder.

They then put the mouse in a totally different, totally safe box.

Context A.

A place that's never been shocked.

The mouse is just chilling,

exploring, perfectly happy.

But then, the scientists shine a blue light into the mouse's brain through a fiber optic cable, which activates only those neurons that were part of the fear memory enneagram.

And what happens?

The mouse instantly freezes in terror.

No!

Yes.

It is physically in a safe place, but its brain is being forced to remember the scary place.

They artificially retrieve the memory.

They successfully reactivated a specific memory trace.

They literally played the memory like a piano key.

It's one of the most stunning proofs that the enneagram is real.

It's a physical network of neurons that holds a specific memory, and it can be manipulated.

It is absolutely wild.

So let's try to wrap this all up.

What does this all mean?

We've gone from HM waking up every day in a blank slate, to the mirror tracing, to the molecular dance of calcium and magnesium at the synapse, all the way to shooting lasers into mouse brains to trigger fear.

I think it means that you, your identity, your history, your personality, your skills are at a biological level, a collection of synaptic weights.

You are a pattern of connection strengths between billions of neurons.

And that pattern is not static.

It's dynamic.

It is constantly being updated, reconsolidated, and physically remodeled by every single experience you have.

It just makes you think about that final provocative thought.

If retrieving a memory really does make it vulnerable to change,

if every time I remember my childhood, I'm essentially opening the file and leaving it open for editing.

It forces you to ask a really fundamental question.

How much of your certain past is actually just a reconstruction of the last time you thought about it?

Are you remembering the event itself, or are you just remembering the memory of the memory?

That is something I am going to be thinking about for a very long time.

Thank you for listening to this deep dive into Chapter 17.

It's been a pleasure.

This is the Last Minute Lecture Team signing off.

Keep those synapses firing.