Translator: Angelica Teal Reviewer: Denise RQ
When we look at this picture of the September 11 attacks,
I'm sure any of us in the room could remember where we were,
what we were doing when we heard the news that day.
To neuroscientists and psychologists
this is a great example of a flashbulb type memory
where you're confronted with a very, very powerful event,
and all the inconsequential things that you normally wouldn't remember,
like where you were, what you were eating, what you were wearing.
All of those things get caught in the flash, if you will,
and come along for the ride.
So the question of how the brain achieves these types of associated memories,
and how it gives you your sense of self location
- that would be where you were when you heard about the attacks -
these have been and continue to be
very intensive areas of research in neuroscience.
But understanding how memory formation happens in the brain
is no small task
because the brain contains approximately 86 billion neurons.
Each of these neurons makes connections
with between 1,000 and 10,000 other neurons.
This makes for a staggering 100 trillion synapses in the brain.
We can see the nerve cell on the left
passes neurotransmitter onto the cell on the right.
This is a synaptic junction.
While we've learned a lot about
the biochemical and molecular mechanisms of synaptic transmission
over the many decades,
the discipline of neuroscience itself
is really just more than about 100 years old.
So, although this image looks pretty similar to the one we just saw,
it was actually drawn in about 1900.
It is some of the earliest detailed drawings of nerve cells
any human ever made.
The neuroanatomist who drew this was named Santiago Ramon y Cajal.
He is considered by many
as the father of modern neuroscience as we know it.
He applied the most current, recently developed techniques
for staining neurons and for imaging them with microscopes.
He also was a talented artist,
so he could go and do
very, very detailed drawings of what he saw.
One of the things that really, really stood out to Cajal
is, if you look at the nerve cell up here on the right,
shooting up at the top of it,
it's a tree-like structure that's called a dendrite.
It's on the dendrite of the nerve cell
that input from other nerve cells talks to it.
What struck Cajal was that the dendrites of all the nerve cells that he saw
were covered in these structures that now we call dendritic spines,
these little protrusions that stick out from the dendrite.
Well, he thought this clearly is the basis for memory formation in the brain.
It's the connection points between the nerve cells.
This is what stores information.
As it turns out, Cajal was exactly correct;
but it wasn't until more than 70 years later
that it was actually confirmed;
so if we zoom in now, and we look at an individual spine of Cajal's
we have cell A and cell B just like a couple of slides ago.
So cell A sends its neurotransmitter to cell B;
they communicate with one another.
But a couple of researchers, Tim Bliss and Terje Lømo,
in the laboratory of Perry Anderson,
were working in the late 1960s and the early 1970s
and they placed stimulating and recording electrodes
into the brains of anesthetized rabbits.
What they did was they applied Patterned Electrical Stimulation.
They had a well-defined anatomical pathway
and they placed in a tetanus of about 10 to 20 hertz, and applied this,
so that cell A persistently drove cell B to fire.
What they found was
even in response to very brief patterns or pulses of electrical stimulation,
the strength of the evoked response or the synaptic connection
was much, much stronger.
This effect lasted many, many hours.
So the jingle, that this is known by
that cells that fire together, wire together.
In light of our previous TEDx speaker's talk,
we know that the statement must be true.
But the more technical term for this is Long Term Potentiation, or LTP.
So one of the more exciting things about Bliss and Lømo's discovery
was that it took place in a structure called the hippocampus.
So, in humans, the hippocampus is about as big around as your pinkie finger;
it sits in your temporal lobe just in the midline of your ear,
and as we'll see in a few slides,
indeed this structure is very critical for learning and memory.
The structure is common to all mammals and many other species.
It's not just in humans.
So shown on the right is an example of the hippocampus in a rodent.
It has a dorsal half and a ventral half.
And it's quite good that lower species have a hippocampus for us to study,
because it's not very ethical
to just take people off the street and stick electrodes in their brains.
We can't really do that.
So, as it turns out, one of the most intensely and well-understood models
for learning and memory is the lowly rodent hippocampus.
Just as a case of this, as an example of this, for my own graduate work
I had placed stimulating and recording electrodes
in the hippocampi of freely behaving rats.
They were placed in the light side of a two-chambered box
with a light side and a dark side.
The natural tendency of the rats
is to avoid the light and to walk into the dark.
They feel safer there.
But when the rats went in, they got about a two-second footshock.
It's a mild footshock.
They just got it one time, but based on this one learning episode,
the animal would remember for days and weeks
to avoid the dark side of the box.
So the animal has its own flashbulb type memory going off
and it learns to avoid this bad place.
What I found was
that a subset of the recording electrodes in the animal's hippocampi
actually showed increases very similar to what Bliss and Lømo had described
more than 30 years before.
This isn't a very unique study;
other researches have looked in other brain areas
following different types of learning
and seen that these types of changes happen all over the brain.
If you have the right training paradigm,
you will probably going to see plastic-related changes going on
as a consequence of learning.
If you put in chemicals that prevent synaptic enhancements from happening,
often times this blocks memory formation.
And this is even crazier. This was done more recently.
You can put in drugs that shut down recently-enhanced synapses.
They knock the synaptic weights back down
and the animals actually lose their memory.
So, a really profound demonstration of how bad it is
when you can't make a new memory
can be seen with the example of an individual named Clive Wearing.
He had a case of herpes encephalitis;
a virus that ate away his hippocampus completely.
He lost both hippocampi on both sides,
and he ended up with one of the worse known cases ever of amnesia.
He could only make memories that lasted between seven and thirty seconds long.
So shown here is his wife interviewing him about what his life is like
when he can't make new memories, and he can't recall his past.
(Video starts) Wife: Because...
CW: I have nothing to say about it. It's just like death.
No thought of any kind, no dreams, no sight, no sound,
no thoughts, no taste.
It's just like death. No difference between day and night. No thought.
Nothing. No dreams, nothing at all.
Wife: I...
CW: Any question you have, the answer is, "I don't know!"
There's nothing to say.
No dreams, no sight, no sound, no taste, no smell.
Nothing at all. Nothing. Not a thought. Nothing.
Wife: How long has it been this way?
CW: A few years. That's all I know.
The whole time we've been in here, nothing at all; no thought, nothing.
Wife: What's like now?
CW: I could see. First time. First time I had any of these...
Wife: Did you feel sort of normal now?
CW: Yes, since I've sat down here. I don't remember sitting down here.
Wife: You don't remember sitting down?
CW: No. I'll see any human being now. I could see yo, right now.
No touch, no smell, nothing at all. Wife: Do you know what happened to you?
Wife: Any idea? CW: No idea at all. It's just like death.
Wife: Do you know how long you have been like this?
CW: No idea. Just three or four years, that's all.
Wife: Do you have any idea what year you got ill?
CW: No. Wife: Have a guess.
CW: Sometime in the 80s.
Wife: Sometime in the 80s. Early 80s, mid 80s, late 80s?
CW: No Idea. Wife: Guess.
CW: Middle 80s. Wife: Middle 80s, yeah. That's correct!
Wife: Do you know what year it is now? CW: No.
Wife: Have a guess. CW: It's in the 90s, I suppose.
Wife: Yeah? How far would you say?
CW: Could be anywhere between 91 and 99.
Wife: No feeling for that? CW: No.
Wife: But it is now 1998. CW: It could be.
(Video ends)
JW: I think it is safe to say that he has lost more than the ability to just to,
for example, learn how to play golf.
He has no sense of identity, no sense of continuity in life.
This is in fact a very central aspect of our being:
remembering who we are, what we are about, what we want to do.
As it turns out, decades of research have also shown
that the very same circuits that mediate memory formation,
also mediate our sense of self location and spatial navigation.
So, the fact is
memory and navigation are absolutely inseparable functions in the brain.
This is illustrated really nicely by a recently published study
where human patients - epileptic, they were undergoing brain surgery,
their skulls were open -
and a very privileged group of researches
were able to go in and place recording electrodes
in the hippocampi of these human subjects.
What they had the people do was to navigate around this virtual town.
You can see there is an apartment building at the top, a skyscraper at the bottom.
They could explore their environment and could form a mental map of the place.
Once they had done that,
they were tasked with delivering different items
to different locations on that map.
So the different delivery spots are shown in red on the map.
In this case, the person had to deliver a zucchini to the bakery.
After the experiment was over, the subject was asked,
"What did you deliver to the bakery?"
The person had to recall, "I delivered a zucchini."
But the crazy thing is that the cells which were active
when the person was around that spatial location
also perked up and became more active when he recalled, "Zucchini."
So he wasn't trying to recall the spatial location;
he was recalling the item,
but the spatial content came along for the ride.
It really illustrates the fact
these two things are definitely interconnected.
Like I've said before, human subjects are pretty hard to come by
for doing neurophysiological experiments.
So often times, we neuroscientists have to rely on animal models.
In fact, most of what we know about the cellular mechanisms
for spatial navigation was learned in animal models.
So we'll go back to the hippocampus now. We're back in the brain of a rat.
A researcher named John O'Keefe had lowered recording electrodes
down to the hippocampus of rats
and what he found was a cell type
that he called place cells - place responsive cells.
I'm going to show you a video with one here now.
All I'll say is
anytime you hear the popping sound and see a red dot appear on the screen,
that's actually the discharge of an isolated neuron in the animal's brain.
(Video starts) (Popping discharge sounds)
(Video ends)
So, are there any disbelievers now?
For decades, it was thought
that place cells were the ultimate spatial code in the brain.
But as it turns out, if you change the walls,
the color of the walls in the box,
if you change the scents, or the odors,
if you add an object, or a landmark,
the firing rate and the location of the cells
will actually change in response to these stimuli.
So, it's not just the spatial code.
It's actually also coding different aspects of the animal experience
within that space.
So things that actually color the animal's experience in that space.
What we neuroscientists can do is go in and look;
for example, on the top right,
you see the path of the animal in white, and where the cell was firing in red.
Down beneath, you have a rate map, where the hotter colors,
the red color corresponds to higher firing rate,
and the blue color corresponds to the cell not firing at all.
So the pattern of the cell that I am going to show you next
is actually very, very different from this image.
Like I said, for decades,
place cells were thought to be the ultimate spatial code in the brain,
but there are all these other things
that can change the way a place cell fires.
Well, Edvard and May-Britt Moser came along more than 30 years later,
here in Trondheim.
Neuroscience history was made here in Trondheim in 2005.
So two researches in the laboratory of Edvard and May-Britt Moser,
- their names were Torkel Hafting and Marianne Fyhn -
had lowered recording electrodes into the entorhinal cortex.
This is a structure that is one synapse upstream from the hippocampus.
The hypothesis was that spatial signals aren't generated in the hippocampus,
but the actual cortical representation of space is occurring elsewhere,
out in the brain, and then it gets inherited down to the hippocampus.
So I will show you an example now of the cell type they discovered,
called a grid cell.
All I'll say is that as opposed to the previous video
where there's one firing field, here there's a lot of firing fields.
I'll let you guys spot the pattern.
(Video starts)
(On stage) JW: Whenever the cell fires, it shows up as a white dot on the screen.
Maybe it's starting to become clear right now.
(Video ends)
So, far more than just an oddity,
as it turns out, the discovery of the grid cell
represented one of the most profound discoveries
in this field of research in more than 35 years.
Instead of having lines of latitude and longitude
that go across a map, say of Washington, D.C.,
the brain doesn't opt for squares, it opts for triangles
- shown here -
so the fundamental unit of the grid map is equilateral triangles.
The rat has no idea what an equilateral triangle is,
let alone a straight line,
but the brain cells in the animal entorhinal cortex do.
This is absolutely baffling and mysterious,
and there are lots of models that are out there
that seek to explain how this pattern forms.
So it's not just one equilateral triangle,
the entire recording environment that's accessible to the animal
is tiled with equilateral triangles.
Because of the geometric precision,
the triangles add up to make ever bigger triangles.
It's not just in this recording box;
it's in any recording box that an animal is placed in.
The same pattern is always expressed.
This led to the conclusion
that these cells are probably the brain's universal spatial mapping system.
So what's constantly ongoing in our own heads
is we are forming new memories.
Let's say you went to a birthday party;
you remember who you saw, what you ate, what you were wearing, if it was fun.
These types of details of that event may be encoded in the hippocampal system,
something akin to place cells,
whereas where the house was located in Trondheim,
your sense of where you were at that time
is being simultaneously recorded by grid cells in your brain.
So for every memory that you make, it's like your brain is geotagging it,
which is exactly identical to what goes on
whenever you post on Twitter that you had been somewhere,
and you say where you were and do something similar in Facebook.
So I talked a lot about animal models, mostly about rats,
but it's worth noting
that for every species that researches have looked in
to see if the same cell types exist,
they've always found them.
They have been found in mice; they have been found in bats;
they've been found in monkeys,
and then, more recently, they've even been shown to exist in humans.
So what this implies is that place cells and grid cells,
among many other cell types,
originated at least as far back as the common ancestor of all mammals.
So that puts them back at least 100 million years old,
and they are probably much older than that.
So the place cells and grid cells I, as a researcher, would study everyday
are often times older than some of the stones I might pass
while I'm biking on my way to work.
I will just close by saying why do we do this type of thing,
why do we study the cellular mechanisms of memory and navigation?
We will take Alzheimer's disease as an example.
You can see the healthy brain on the left, and the Alzheimer's brain on the right.
The cortex is dramatically atrophied in the case of Alzheimer's.
Some of the earliest symptoms in Alzheimer's
are spatial disorientation and memory loss.
But, as it turns out, the hippocampus and the entorhinal cortex
are two of the earliest afflicted structures in Alzheimer's.
Actually, the disease starts in the entorhinal cortex
and spreads, like a disease, throughout the rest of the brain.
So it's far more than just intellectual curiosity,
because when we study how the brain navigates and forms memories,
we can begin to understand
what goes wrong in diseases like Alzheimer's disease.
And this can help guide the search
not only for treatments but possibly, even cures,
not only for Alzheimer's disease
but for a wide spectrum of neurological disorders.
Thank you very much.
(Applause)