[MUSIC PLAYING]
JOE SISNEROS: Good evening.
My name is Joe Sisneros.
I am the associate chair of research in Department of Psychology here at the University of Washington,
and I have the distinct honor of welcoming you to our 13th Annual Edwards Public Lecture
Series.
I'm pleased that you could join the psychology department as we celebrate this year's lecture
series titled Optimizing Human Potential.
Tonight's lectures are part of a three-week series exploring how psychological science
improves-- provides insights into the mind, brain, and behavior, resulting in improved
outcomes for people in society.
Before we begin this evening's lectures, I'd like to address a few housekeeping items.
Please note that this evening will consist of two lectures with a 10-minute break between
them.
And we will hold a question-and-answer session at the end of the second lecture at about
9:15.
During that time, we'll have microphones brought up, so you could address your questions to
the speakers.
And then, finally, please remember to silence your cell phones.
Now, I'd like to share with you how this series came about.
This annual lecture series is the result of the generous support of Professor Allen Edwards,
who made a substantial gift to establish an endowment that ensures that we can share our
latest psychological science free of charge to all of you.
Professor Edwards was a member of our department for half a century.
From his arrival in 1944 to his passing in 1994, he was an outstanding teacher, researcher,
and writer, who is credited with changing the way psychological research is carried
out by introducing modern statistical techniques to this field.
The Edwards family contribution exemplifies the impact that support from members of the
community can have on psychology's ability to educate the public.
Thank you to those of you in this room who are already supporters of our department.
Your generosity is critical to creating opportunities for UW Psychology's ability to solve some
of the most important issues facing our society today and to supporting and training our students.
Without further delay, I would like to introduce our first speaker, Dr. Sheri Mizumori.
The goal of UW Psychology professor, Sheri Mizumori's, research is to understand how
healthy brains mediate memories and decisions so that we can employ specific evidence-based
interventions that improve memory and decision processes.
Early in her graduate training, Dr. Mizumori researched how targeted changes in brain chemistry
can selectively impact components of memory, such as short-term and long-term memories.
To study why signaling between distant parts of the brain is essential for learning, memory,
and decisions and how this changes with age.
Her laboratory currently studies the brain's communication system under different memory
and decision-making conditions.
Specifically, Dr. Mizumori's lab and her research investigates the role of internal and motivational
states in cost benefit neurocomputations that are essential for adaptive goal-directed decision-making.
Over the decades, her experience with integrative neural systems and methods has provided a
strong platform from which to train over 70 undergraduate, graduate students, and post-docs
to become the next generation of leaders in neuroscience and psychology.
Dr. Mizumori is also involved in NIH efforts to broaden the participation of under-represented
groups in neuroscience careers.
Please join me in welcoming Dr. Sheri Mizumori.
[APPLAUSE]
SHERI MIZUMORI: Thank you, Joe, for that wonderful introduction.
And I want to thank all of you for being here tonight to allow both my colleague, Dr. Yassa,
and I to share some of our ideas and recent results concerning aging research.
Now, many of us, myself included, as we're going into the second half of our life, we
often wonder about whether or not and how we can best maintain our cognitive abilities
into old age.
And this really requires-- really, an answer to this question requires the work of a number
of different researchers, researcher types, different disciplines, and so on.
And so I'm hoping to impress upon you today what some of the outcomes could be and what
can happen when all of these different folks work together.
Now, our goal, the long-term goal is to be able to facilitate healthy cognitive aging.
And so when I talk about that, what I'm talking about, really, is our ability to maintain
our memories, because when we maintain our memories, the memories really are the support
process that allows us to make good decisions throughout our lives for our family, for ourselves,
for our work, and for society.
And so really, when you think about all the work that needs to be done to try to understand
cognitive aging, we have to look at the brain.
And the reason is that the brain aging really is what determines cognitive aging.
And the field of neurocognitive aging, then, is a field that seeks to understand the mechanisms
of brain aging so that we can develop targeted and, hopefully, noninvasive interventions
that result in a healthy what we call mindspan that allows us to age gracefully.
And by mindspan, I'm talking about the ability to retain good cognitive skills over your
lifetime.
Now, as a neuroscientist, one of the first questions that people had asked in this field
is, well, we know that the human brain shrinks when you get older.
Does that mean that you're just losing all kinds of cells?
Well, surprisingly, again, for many decades we have known that in non-pathological aging--
that is for individuals who do not have some sort of a neurodegenerative disease-- that
aging is not usually accompanied by great losses in the numbers of neurons, at least
in brain structures that are responsible for processes such as decision-making and memory.
But yet when you ask individuals who are older whether or not-- what kinds of changes in
their minds and mindful operations they might be experiencing, a very common comment is
they have maybe problems making decisions.
It takes them longer.
They have more difficulty with their memories.
So clearly, there's a significant functional loss.
So what's going on here?
How can this happen?
Well, what I'm going to do for the rest of this evening is to first talk to you about
how we think of memory and different components of memory, and then how some of the memories--
these memory processes can change with age.
And then I'm going to talk about what we know about some of the underlying brain changes
that occur that might mediate some of these memory effects.
And really, I'm going to-- I think I'm going to talk about all this research within the
context of an effort to work towards healthy cognitive aging.
So the first question is, simply put, what is memory?
Well, this is actually not so easy to define, as you might imagine, when you think about
your own memories.
So currently, for example, you in your life-- right now, you exist at this point in time.
And it's because your brain automatically records the events in your life that you can
look back in time to sort of recreate your life in the past.
And in doing that, of course, you have to recall memories.
But your memory system also allows you to look forward into the future to make plans.
And so just from that description, you can tell that your memory functions in your brain
are very complex.
So it allows me to look into the past as well as plan for the future.
Now, let me just give you an example of how memory might be studied in a very simple illustration,
because as you'll see, as the talk goes on, you'll see that memory processing is actually
very complex.
But in this simple picture, I might say, you might look at this image, and because you
are all here in this particular auditorium, I know you recognize this image, because it's
just right outside.
But if I say, so what is this image?
What is the name of this place?
Hopefully, you will not take long and say, Red Square, right?
It seems simple.
But really, a lot of things had to happen in order for you to be able to say this.
You had to look at the image, and that visual information had to go into what's called a
sensory memory.
It's this buffer in your brain that lasts maybe only on the short order of a few seconds.
And this is where, again, environmental information comes into your memory system.
And by paying attention to particular parts and elements of the sensory memory, you can
then bring information into the short term or what's called, oftentimes, a working memory.
And this is a memory buffer that lasts maybe tens of seconds.
So it lasts a little bit longer, and you can see there's some filtering and selection happening
here.
Now, over time, some of this short-term memory gets placed into long-term memory via a process
called encoding.
And then when you want to retrieve a name, that information goes back into your short-term
working memory, and you're able to verbalize what the name of the place is.
And if you want to keep that information active, there's a process called rehearsal that allows
you to keep information active in your head so that you can use it for whatever the ongoing
task is.
And now, what happens if you're shown a picture like this?
Now, not everybody would have seen Red Square with snow.
In fact, it hasn't happened like this for quite a number of years.
So you probably will still be able to recognize this as Red Square, but it might take you
a little bit longer.
And the reason is that when you look at this image, again, you go through the steps of
putting information into sensory memory, short-term memory, and then it goes into long-term memory
to see if there's a match, to see if there's something in there in your long-term memory
store that matches this image.
But if you've never seen Red Square with snow, you might pause.
And so as a result, information-- there'll be a message that is sent back out to the
short-term memory stores, and through more attention to the image, you can start to abstract
out more information, like, for example, the geometric angles of one building relative
to another.
And then with enough iterations, your memory system is capable of making some inferences.
And it will say, well, gosh, I've never seen this, but there's enough similar and familiar
items in this image that it undergoes this process called pattern completion, where it
just sort of takes its best guess and says, well, it's probably Red Square.
And of course, that's correct.
And the fact that it's correct, then that information goes back into your long-term
memory stores, and it helps to strengthen the memory that then was existing there.
And now this image of the snow-covered Red Square becomes part of your long-term memory.
But what I just described suggests that the process is very linear with a few cycles and
a few iterations along the way.
But I just want to point out that if you think of a memory in your past, you, yourself, know
that memories are not linear.
So for example-- and they're not all the same.
And so for example, if I ask you to recall a memory, chances are that a memory that you
recall is one that has high emotional content or something that was recent.
And so that suggests that your memory system in your brain uses emotions and emotional
types of information to stamp what's really important.
And also, it uses time to stamp when things happen, and that helps the brain to organize
information in the brain.
Now, there's a structure in the brain called the amygdala.
As the arrow shows here, it's shown there in purple.
And that's a structure that's thought to provide the sort of emotional stamp on your memories.
So when you're now then shown a stimulus-- we'll say a familiar stimulus like this flower--
you're able to-- you smell it, and then in your brain, then you recognize this as a particular
flower.
But in addition, that re-activates the emotion that was associated with that stimulus, and
so that's what you end up recalling.
So already, you can tell that the memories are actually, like I said, multi-dimensional
and have many different components.
So what's happening in old age?
So this is what I consider sort of a typical slide.
I don't know if you've seen it before, but when I've studied aging many decades ago,
I remember looking at slides like this.
And what this shows is that over time, over years on the x-axis, and on the y-axis is
performance on a memory task, where low-- down on the bottom, that means that you're
not doing as well.
And if you're up high, that means that you're getting more correct.
And this is-- what you do is you can't help but notice that there's this downward trend
across age.
But I do want you to pay attention to some of the details.
One is that there is, of course, if you're in your 20s, you're the peak of performance,
so to speak, or peak of memory performance.
And then it kind of plateaus off, and then about 50, which happens to coincide with about
the time your reproductive system starts to go down, and your hormones start to change,
that you start to see this change in the memory for at least these kinds of items.
And it ends up that across all animal species, when the reproductive system starts to age,
you start to see changes in the memory abilities of these different animals.
Now, in this case, what this is, is at a test of, for example, you go in, and they give
you a bunch of words and say, remember this for a certain amount of time, and then you
have to repeat it back.
Or they give you some pairs of some random words, and you're supposed to remember these
pairs over time, and then repeat it back.
And so in one sense, I considered these sort of laboratory tests of memory.
And this happens even without, again, in the absence of neurodegenerative types of diseases.
But I also wanted to show these figures, because what this illustrates is that aging does not
affect all memory equally.
So even though you sort of gasped at the last slide, hopefully, when you look at this one,
you realize, yeah, OK, there are some functions that go down.
But there are some functions-- for example, if you look on the left side there-- that
show that across your lifespan, there are certain kinds of skills that you retain--
for example, more or less, your verbal abilities and, also, your ability for abstract-- to
answer questions that require some sort of abstract analysis.
That ability tends to persist.
And again, if you look on the right figure, again, they just-- there's a whole list of
different kinds of tests.
Again, the details are not so clear.
It's just that the-- are not so important.
The main thing is that there's a number of tasks, which will show declines in performance,
but there's others where there may actually be an increase in performance.
So don't despair.
Not everything is going downhill.
There are things that-- there are systems that are working, and this actually is good,
because we can take advantage of those systems.
So one question that we often have in this field is, how do lab tests of memory, such
as the ones that I just described, how do these really compare to our real world experiences?
Because we're not going around our lives trying to remember arbitrary word pairs and so on.
And if you just take sort of a random poll of a number of elderly folks, the two most
common kinds of memory problems that people describe are ones that are shown here.
That is there's this type of memory called episodic memory, which is the kind of memory
that you need to remember events that happened in your life-- to remember, for example, what
you did a week ago versus a month ago and so on.
And there's another type of memory that a number of people say is a problem for them,
and that is problems in their working or short-term memory.
So let me just give you some examples of these now.
So this is a case that-- I don't know if you've had this experience, but I certainly have
had this experience many times, where someone comes up to you, and you say, I know this
person, and I can't remember where I know them from.
And they totally-- and they think that you know them, and they treat you like an old
friend.
But you just don't remember.
So what you do in your memory is you go back-- it's as if you go back in time.
Say, well, was this a year ago?
Was this through work?
And then you start to go back through different contexts where you might have known the person.
And the fact that you're going through in this orderly fashion, I think, gives us hints
as to how memory organizes information.
We know from lots of work, now, that there's a structure in the brain called the hippocampus,
shown here in the sort of orange-y color.
This is a structure that's very, very critical for the ability to process episodic memories
in a very functional way.
Now, what's working memory?
Working memory is that short-term buffer that I mentioned earlier, and this is where you
can bring information online so that you can do things with it.
So for example, you keep this information online, active in your consciousness for a
few seconds.
It's considered, therefore, temporary storage.
And it's a place, where if you're, for example, solving a math problem, and you need to keep
a number of variables in your mind at once, you keep it active in your working memory.
If you're focused on attention on a particular problem, or you're reading, there's a very
strong activation of your working memory.
And it ends up that a different part of your brain seems to be really critical for your
working memory skills, and that's the frontal cortex, shown here in red.
So now I'm going to talk a little bit more about hippocampus and frontal cortex and what
happens in what I call non-aging memory and then aging kinds of memories.
So the question is, why is hippocampus so important and so critical for episodic or
event types of memory?
We don't really have a complete answer for this right now, but nevertheless, I think
there's some very important nuggets of information that's worth letting you know about.
So here's the hippocampus again.
It's the one in red, and that's just a side view of the brain versus more of a top-down
view of the brain.
And what you can do is you can look at slice-- what you might imagine as a slice of the brain.
And that would be illustrated in this next slide here.
And in this case, you see that it looks like there's two inter-digitated Cs.
And what that really is, is just a whole layer of cells that form that shape.
And what we're interested in is putting down some kind of a probe, an electrode, into the
hippocampus to listen to the conversations that are happening between neurons in the
hippocampus during learning, because if we can understand how information is being processed,
maybe we can understand how hippocampus mediates episodic memory.
And so here's just a little cartoon illustrating how that might happen.
From the top, there's a number of electrodes coming down from the top of that slide.
And those little triangles represent the existence of cells around the electrode tips.
And again, we have different ways that we can now identify the messages of these individual
neurons.
Now, what's interesting is that in the people who are suffering from intractable epilepsy,
oftentimes, electrodes are implanted in the brain so that the surgeon can identify the
focus of the epilepsy before surgery happens.
And in a number of those individuals, then, we sort of subject them to and test their
memory.
And so this is just an example.
If you're interested, there's a very-- it's an old Nova series and movie, but it's very,
very informative, very fun.
And this was focused on Itzhak Fried's lab, who is a neurosurgeon at UCLA.
And so this is just an example of someone who's looking at doing some kind of a cognitive
test.
And what this person is actually doing is the following-- is that they are looking,
or she is looking at a series of scenes, as this, and these are scenes of familiar TV
series-- depends maybe on which generation you are.
They may be familiar or not.
So I don't want to call anybody out, so this is Jurassic Park, The Simpsons.
Now, the other one you may not know.
I know, because in our family, we watched this a lot growing up-- The Wizards of Waverly
Place, and then Star Trek.
And so the point is that when a person looks at a scene, you can record the activity of
the neurons.
We normally just kind of pop along in a dit-dit-dit-dit-dit kind of pattern.
And it's almost like a code that the next cell reads, and then that's how they communicate.
And so just imagine across time, you're looking at Jurassic Park, and the cell that you happen
to be recording from just kind of goes dit-dit, pause, dit-dit.
When The Simpsons come on, they go crazy, right?
[SIREN NOISE] It just loves The Simpsons.
And then The Wizards of Waverly Place come on, not too interested in, and also Star Trek.
So what's really interesting is that you can record from lots of cells at once, and what
you find is that there are certain cells that always fire to one scene or another.
Let's say it's The Simpsons-- that not only does this cell fire a lot, but there are other
ones as well.
But there's a lot of them that don't.
But when you see the Star Trek, a different set of cells will become active, while those
initial sets of cells might be quiet.
And then the same for each one.
So for every different scene, there's a different pattern, a network of cells that become active.
And you might say, OK, well, that's fine.
It just means that they're sensitive to that visual input.
But if you then ask the person to close a laptop and say, OK, now think of The Simpsons--
there's no input coming in, just thinking about it-- you get exactly the same pattern.
The cells that responded before when the person was looking at The Simpsons will now start
to fire when that person is thinking about reactivating the memory of The Simpsons.
And the different set of cells that fire to Jurassic Park will now come online when that
person thinks about Jurassic Park.
And so what that tells us is that the hippocampus replays-- that's sort of the term that we
use-- neural activity during memory recall, that it reactivates, replays a pattern of
neural activity that was there during learning.
And this is really an important thing to understand, because this helps us to think about what's
happening during memory recall.
And so another point to take away from this is that your memories are not housed in a
single cell or even a couple of cells.
But it's really housed, you might say, and processed by networks and groups of cells
that work together.
So this is just sort of a cartoon illustration of what I was describing.
Imagine each one of those little diamond-shaped things are cells, and just focus on the ones
that are filled in.
And in the middle section, I show that, oh, when new learning comes in, those three cells
start to fire together.
And so as the person is still looking at this picture, you still see those three cells firing.
And then-- oops, sorry-- and then on the far left, if you ask the person to remember what
they just saw, you see the same pattern being activated.
And now on the bottom, this is just a different pattern that's being activated by a different
scene.
And one thing to notice is that-- in this example, anyway-- that those three cells on
the top, they overlap by one cell relative to the three cells in the bottom.
Sometimes they do overlap.
And that's actually quite good, because that allows, we think, allows you to generalize
from one type of scene to another, because there is some overlap in the networks.
And the other important thing to point out is that the stronger the connections between
these neurons, the more readily you will be able to recall that information, because you're
more quickly to reactivate the circuit.
So what happens in aging?
That's sort of a quick run-through in what happens, we think, in what we call normative
episodic memory.
Well, again, it's kind of surprising.
When you look at, in the top left there, that's in the hippocampus, and then on the right,
I just indicated there that there's different subregions of the hippocampus that we think
process information a little bit differently.
And so it was of interest to these researchers back in the '90s to go and count the number
of cells in these different subregions to see if it changes as a function of age.
And in this particular example, what they did was they sort of-- this was conducted
in rodents.
And what they did was they separated the old rats into ones that were memory impaired versus
ones that were not, thinking that there might be a difference in cell counts between these
two.
But it ends up there were no differences-- no difference across age and no differences
based on memory ability.
So that's kind of surprising.
And now this has been replicated in other studies as well.
So what else could be going wrong?
Well, I mentioned that the connections are really important for determining how quickly
you can recall memory and, really, the efficiency of memory.
And so here's, now, just another cartoon that illustrates three cells, but now we have those
processes, those connections.
And I show in the middle up there in the pink is maybe the growth of new connections and
growth of new processes when there's information available.
And when we recall that information now, those pink ones become blue, meaning that it's part
of a normal structure for that cell.
And in this little movie down here, I just want to show that when there's different proteins
that are in the cells at the ends of the connections, and there's some fancy staining and fluorescence
on microscopy, you can see that that, over time-- and this is sped up a little bit--
but over time, you can see that they are changing.
And the greens just highlight the tips, so you can see them better.
But you can see that they actually are changing over time.
So the fact that you are here, you're listening to me, almost regardless of what you take
away from this, your brains are changing.
And so when you leave, your brains will never be the same, because there will be at least
some of these connections that have been made.
So what happens with aging?
So this is a different way to view these connections.
Just imagine you took one of these processes, and on the left, what you see is what looks
like a line, but you also see these little nubs on the sides of this line.
So that's one of the dendrites.
Imagine that's just one of those connections.
And it ends up that the neighboring cells talk to each other through these connections
between these little nubs or synapses.
And so the more you have, the more information you can process.
The more a cell has, the more information that cell can process.
And so on the left, that's really an actual photo microscope-- photomicrograph of the
actual dendrite.
And then the next line, B there, that's actually the scientist's-- the drawings of it so that
you can see the processes more clear.
The main thing I just wanted you to take away from that, if you just kind of-- sometimes
you've have to kind of squint your eyes to take away the big image-- but the old dendrite
is thinner than the young.
And it has fewer ones of those spines, fewer of those connections.
So that supports the idea that maybe it's the connections that are deteriorating in
old age, not the numbers of cells.
What about frontal cortex?
Does this have the same problems?
Should we look at the number of cells in frontal cortex?
Remember, frontal cortex is important for working memory, and it is really important,
because it is really a bridge of communication across many different parts of your brain.
So here's just an illustration that shows-- of data-- that shows that across age shown
on the x-axis, and then the y-axis is numbers of cells, roughly, in billions, that over
time, there is a slight decrease, but it's really not impressive.
That is the amount of decrease in the number of cells probably cannot really account for
the change in working memory that we see.
And it seems like the amount of decrease is about the same, proportion of decrease is
about the same for men and women.
And so again, that's not a very impressive explanation for the working memory problems.
So again, let's look at the connections.
So here's an example of, on the left, a young frontal cortical cell, and on the right, one
from an old animal.
And underneath, you can, again, see the dendrites with the spines.
And you can also see, I think, on the left that there are many more longer spines than
the one-- than the dendrite on the right, again, showing that with age in your frontal
cortex as well, you lose some of those structures, which makes connection and connectivity between
these cells and communication a little bit more difficult.
So this may contribute to some of the memory problems.
And indeed, in this figure, this just shows that on the x-axis, if the number of cell-to-cell
connections is listed.
From the left is a low.
On the right is high.
And on the y-axis is memory performance skills.
In this case, good is at the bottom, and poor is at the top.
And the fact that there's this negative relationship shows that when you have higher, more cell-to-cell
connections, you do better on your memory tests.
And again, this is true for young and for males and female animals.
So a question is, then, well, if these cortex cells are there, are they processing this
information, the same kind of information in young and old brains?
And so in this case, these are data taken from frontal cortical neurons.
And what you'll see across time there-- you see time, and there's a time 0 up there.
I don't have a point-- well, maybe I can do it with this pointer.
OK.
But here at time zero, this is when a tone might come on.
And then what the animal is instructed to do is to pay attention to the tone for some
length of time.
And then when-- because when the tone comes off, they get food.
And so what you see in the younger frontal cortical neurons is that this cell will ramp
up its activity, will stay high until the animal gets its food, and go down.
And we see this kind of response, again, in a number of different vertebrate animals.
And this is just the baseline to say well, if there was no cue, then the cell is there,
and it would just kind of pop along fire adding some kind of normative rate.
But in the middle aged, what you see is that when the tone comes on, that there is a difference
between these two conditions, but it's not as extreme.
So this is definitely a much larger increase than in the middle age, and certainly much
larger than in the older age.
So what this tells us is that frontal cortex may process the same kind of information and
help you to remember information over time over this delay.
But for some reason, the activity is lower as you get older.
So that may contribute to the problems in working memory.
So this is just a summary of what I've already described that the number of neurons don't
typically change.
The connectivity between neurons may be what's affecting your memory.
I believe that's based on or dependent on hippocampus and frontal cortex.
So really the big question is, can we increase the plasticity, the flexible processing in
the brain, to improve the connections between neurons?
Can we make the cells make more connections, in other words?
And then can this help to improve our memories?
This is a problem that a number of research labs are working on.
Because if we can, as I said, perhaps we'll have more flexible memory processing.
So let's look at the concept of neuroplasticity, this ability to change the structure and function
of neurons across the life.
Well, it ends up that-- you probably already know this maybe in a different way-- that
even in the younger age, your brain's always changing the patterns of connections.
So when you're really very young-- for example, at birth-- you do have a number of cells that
don't seem to be so highly connected yet.
But at about 6 years old, you have maybe-- in this example, anyway-- about the same density
of cells.
But they're highly interconnected, OK?
That's why you see all those lines.
By the time you're 14, there's this what's called pruning that happens.
That is the dendrites and processes are not used and kind of withering away making space,
for more elaboration, of these remaining dendrites here.
And it ends up that during memory processing-- and this is just a schematic taken from one
of the old Golgi drawing.
Golgi was a very famous neuroanatomist who had beautiful drawings of neurons.
And this is just an example of what might happen during learning.
So for example, here is a cell that has many different dendrites.
But then maybe after learning, these dendrites grow.
There's more connections.
So can we get an older brain to become like something more like this?
This is really a goal.
Now as you can tell because I said it that way-- I don't have a clear answer.
But again, there's indications that this might be able to work.
So one thing I wanted to point out is that even though we're growing processes-- for
example, doing new learning-- that as you get older, that some of these processes may
not be able to grow as much as when you were younger.
But yet that doesn't mean that when you're older that processes can't grow.
There's definitely clear evidence that neurons do continue to grow.
The question is how do they grow?
And it ends up that maybe they grow in slightly different patterns and configurations than
they do compared to young, and maybe that also contributes to the fact that the working
memory's a little bit different.
But what that suggests then is that perhaps if you have different patterns of connections
of neurons, your memory may be using different strategies for remembering information.
And so one question that has come up is whether or not young and old subjects use different
strategies to remember information.
And this is-- I'm just going to just run through a quick experiment that illustrates that,
indeed, this happens.
So basically the experiment is the young and old subjects were asked to learn eight different
surnames by saying each one out loud, but in different ways.
So in one group-- there it is-- the individual is asked to just basically state the first
letter of each name.
So this would be B, J, M, and H.
And then another group, they were asked to come up with a rhyme so that there's some
sort of a phonemic help in aid to try to remember the names.
So in this case, if it was Bill, instead of B, you would say Bill, maybe Will.
Jane, Pain.
Mary, Fairy.
And so on.
OK?
So you have this little mnemonic to try to help you to remember.
There's another kind of trick.
And that is to associate this name Bill with some kind of meaningful association.
So in this case, this could be Bill, my father; or Jane, my neighbor; Mary, my doctor; and
so on.
So you have now meaning associated with that word.
And then finally, in another group, it was mainly just the individual's asked to basically
rote memorize what they call intentional learning with no other association.
Just Bill, Jane, Mary, Harry, and so on.
So the question is which strategy is better for your memory, and does this change with
age?
So in this first set of graphs here, this represents a proportion correct for the young
group as a function of these four different memory strategy conditions.
And so this is where the just remembering the physical letter B, for example.
And you can see that as the processing became more deep, there are more associations with
that word, that the memory, the retention got better.
OK?
So again, this is a finding that is pretty well known in the human memory literature.
What happens with older persons?
Well, what you find is that they also show this effect-- that is, the deeper the processing,
the better the individual remembers compared to just more the superficial memory.
But you can tell that there's some impairment here, that they definitely don't remember
as much as the younger group.
Now remember, in this case, the subjects are asked to self-generate the names.
That is, to just say, OK, now tell me what the names were.
They just have to do it.
OK?
But if you give them this list and ask them to recognize the name instead, then something
interesting happens.
The younger individuals do benefit, and they do better on recognition tasks.
I mean, most students would probably attest to this.
And you can see that this performance here is better than what you see over here.
But what's interesting is that the older individuals also improve their performance when they have
this recognition, this little tip.
And in fact, there's no difference up at this point right here.
In other words, the older individuals disproportionately-- or they benefited greater, I should say, by
having the names there.
And all they had to do was identify whether they recognized it.
So what that tells you is the information got in, but maybe they just had a problem
with the recall.
And that ends up being important because then this starts to now dissect down memory, this
complicated process, into different kinds of sub-processes.
And then we can identify more clearly which component needs attention and intervention.
So this is just the same slide.
And so this now just summarizes some of the findings from the study.
That is deeper levels of processing are important, environmental support improves memory, and
more so for older subjects.
And the other point was that retrieval seems to be particularly difficult for the older
subject compared to young.
So what can we do to improve recall?
So we talked about neurons.
They're connections.
Well, then the connections are mediated through chemicals.
There's connection between cells.
One idea was whether or not the recall deficit that we just saw in the previous study, is
that related somehow to the nature of the interactions between cells?
That is, to this chemical environment.
And we ask that because we know from other work that the chemical environment between
cells is very important in regulating the plasticity between cells, the extent to which
they're going to connect.
OK.
And if we're trying to come up with some sort of intervention, that's where we really want
to focus.
So here's just an example, again, of the cell, the synapse.
Here's an example of the connections.
This would be one of those spines that we looked at.
Here's another spine from another cell.
And it ends up that we now know that there's a number of different chemicals that are located
in the synapse between those connections.
And some chemicals make it so that these communicate well-- those are called the strong connections.
And some chemicals make it so that those two connections really don't talk very much.
The connection is weak.
OK?
So there can be weak connections, there can be strong connections.
In this illustration, this just shows, again, here's one cell, here's another cell that
sending out a message.
And you might say that well, when the cell becomes activated, it causes our second cell
over here to generate one signal, one what's called an action potential signal.
But it might be that in a strong synapse-- if it were stronger, what would happen is
that same cell would generate a signal.
But now, our second cell here will respond by sending many messages.
OK?
That would be an example of communication at a strong synapse.
And it just so happens that we now know that there's two chemical transmitters-- acetylcholine
and dopamine-- that are very important for determining the strength of those connections.
So of course, then the question is, well, what if we focus on those two?
If we can increase our dopamine or increase our acetylcholine, can we strengthen the connections
of the ones that continue to exist in an older brain?
And so here's some data that suggests that maybe we can.
So this is just the actual data taken from a rodent study.
And this is a top down view of a maze where these are little boxes, and these are little
alleys that connect the boxes.
You can see it's a maze, right?
There's many different paths.
And what happens is if you put the animal-- in this case, this is a rat-- in one of these
boxes, it will run out here and just run up and down randomly on these maze arms.
And then what you can do is say, OK, now let's put the animal in a box, for example, here.
Let's put these barriers along different alleys, and that's these little black dashed lines
here.
And then we're going to put food way over here.
So what the animal has to do is when they come out of this little box here, they have
to find the most efficient path to the food.
Now, if you can see it, if you look at it, you can see well, if they go here, oh, they
run into a wall.
They have to back up.
If they go on here, they run into a wall, then they have to back up.
And eventually, they find their way to the food.
And what you can do it in a naive animal-- so one that hasn't learned this-- it will
make a lot of mistakes, and it'll take a long time for the rat to get to the food.
And that's shown here that in the early trials-- these are numbers of learning trials in the
early days of training that the path length from the start to the goal is quite long.
OK?
But that over days, the animal gets better and better, and you see that the path lengths
get shorter and shorter.
And then pretty soon, later on-- for example, in trials 17 and 18-- the animal's let loose
at this one box, and they can make a pretty direct shot-- let's see if I can do this--
over here to the goal.
OK?
And they get very good at it.
So what's interesting is that there are some amazing techniques out there now where one
can-- while the animal's roaming around behaving like this-- you can go in and selectively
ramp up the dopamine system to the cells in the hippocampus or completely eliminate it,
but just for the time that they're in this maze.
So you could turn on D for dopamine.
You can have the dopamine in the hippocampus-- this is one of those subareas of hippocampus--
you can have it on or off.
Well, it ends up that it doesn't matter during this acquisition period here.
It didn't matter if the dopamine was on or off.
So that suggests that maybe dopamine's not so important for the initial learning.
So is it important at all for memory?
Well, later on-- let's say a week later-- you can bring the animal back in after they've
had a break.
And again, you start them in the same start arms.
And you say, well, how long did it take the rat to find the goal?
And what you find is that with the dopamine turned on-- so there's more dopamine than
normal-- during this learning period, you find that at retention, the recall is much
better than when the dopamine was not available during learning.
So what that suggests is dopamine has a specific effect on recall.
Well, that's kind of interesting, right?
Because I was just saying recall is one of the specific problems that older folks have.
OK?
So hopefully the wheels are turning in your head about, oh, what should we do about dopamine?
[LAUGHTER]
I'm coming to that.
I'm coming to that.
[LAUGHS] So again, this just shows that altering the chemical environment can alter the plasticity.
This is reflected in behavior.
Now, I do want to show that dopamine neurons normally-- let's say this is just a function
of time at time zero-- this is when an animal might go into-- it's in a box, and they put
their nose into a hole to get food.
They just go in there and pull it out.
And what you find is that this is the activity rate of the dopamine neuron.
And this, you can see that it's firing along all the time at some rate.
And then just about the time the animal's going to make the nose poke, it goes up if
there's going to be food there, right?
If there's not food there, then you see that this red line just continues and nothing happens.
So this is just one example, but there are many examples to show that dopamine seems
to be ramped up naturally under rewarding conditions.
OK?
What happens in older animals in this same situation?
Well, what you find is that in the same task-- you can see that visually, these look very
different-- that the animal knows what to do.
They go in there nose poking.
But you don't see the same kind of dopamine response, OK?
What that suggests is that the dopamine cells are there in the older brain, but perhaps
they're not responding to the reward as much as the young, annulling that the baseline
rate is kind of low.
So there's just kind of low activity dopamine neurons.
But they're there.
So can we take advantage of this?
OK, so again, the question is how do we increase the potential for neuroplasticity?
Well, let's hijack the brain's dopamine system.
That is, I had just alluded to the fact that dopamine cells increase rewarding experiences.
And now we know that, again, there's lots of other data out there that shows when something
new happens, that novelty often is considered rewarding, and you get strong dopamine responses.
OK?
And so a question is-- oh, these are just some data from our lab that shows that this
is the case.
So in this case, an animal receives either a small reward or a large reward.
And you can see where this arrow is that there's a large dopamine response to the larger reward.
So this is actually interesting because it suggests that manipulating the environment,
manipulating the reward can alter the level of dopamine.
Hmm.
Maybe in aging, we want to do this more.
OK?
And so this translates then into ideas that I'm sure you've heard about, right?
It's that you should exercise more when you get older.
Do you know why?
Well, clearly, we know blood flow-- there's more oxygen to the brain.
But I think in the context of our discussion, more importantly, you want to get that dopamine
going, OK?
And it ends up that by exercising, by keeping yourself more mentally challenging, by experiencing
new things, then you get more dopamine going.
OK?
So now, what about acetylcholine?
Well, it ends up-- again, there's this huge body of work that shows acetylcholine increases
during working memory.
And this is just one example of this.
In this case, again, there's a function of time on the x-axis here.
And on the y-axis, this reflects the amount of acetylcholine that's released.
And I don't know if you can see, but this actually just shows that they're measuring
in the frontal cortex.
OK?
And so as a function of an experiment, they're trying to see what makes acetylcholine go
up.
And what they find is that in this case, when there's a tone that comes on, let's say, right
about here-- and again, the animal has pay attention because they know that after some
2, 5, 10 seconds, that as long as they're paying attention, they get food.
OK?
They don't know how long it's going to be.
They know it's going to be one of those.
So that encourages them to always pay attention.
And indeed, what you see is that acetylcholine jumps up right away, and it stays high until
the animal gets its reward.
Now what's interesting is that in this experiment, they introduce what's called a distractor.
So in this case, there are certain-- I think this was a light that came on that told them
that they're about to get reward.
And then another light came on, what they called the house lights came on.
So something got really bright.
But the animal knew they still had to pay attention, right, to this little light over
here, because that's what's going to tell them when they're going to reward.
And so they ended up paying attention to two things.
And what's interesting is that the more attention energy, you might say, that you spent, a greater
the acetylcholine release.
OK.
So again, the same logic then is what can we do?
Well, let's hijack our natural acetylcholine system in the brain.
OK?
And it ends up that doing challenging attention type tasks may be a way to increase acetylcholine
that maybe then can turn into an increase in the strength of working memory.
And so your question might be how can we do that?
Well, this is a test-- now I'll let you participate in this test.
And this is where I am going to show you a string of objects.
And I want you to just-- you could raise your hand, or just think it to yourself, about
when you see an object, is it the same as the one that was presented two objects before?
OK?
Two, not the one before.
Two.
[LAUGHTER]
So here's-- OK, one.
I'm just going to go through these.
How many times did you see something twice?
AUDIENCE: Two.
SHERI MIZUMORI: Two.
Oh, OK.
This is one, and that's one.
You guys are good.
But it ends up that you can take more of these tests, and you can make them more difficult.
Instead of two back, you have three back, and so on.
OK?
But it ends up that when individuals took this test, that they found that some-- now,
this is a training session here, and this is correct, and this is with good performances
on top.
And you can see that there's some-- and these are human subjects.
They only made modest advances over this amount of training.
Now, maybe with more training, it would go up.
Don't know.
And then there's another group that showed a large increase over here.
And what's really interesting is that if you take the group that showed the large increase
versus a small increase and test them on other kinds of memory tests, what you found is that
the performance generalized.
So if they did well on the working memory test, you can see they did better on a different
kind of memory test when tested right after their training.
But what's even more surprising is if you wait a week later, this persists.
OK, so this suggests that perhaps continuing to exercise your working memory can help you
with other kinds of memory skills.
OK.
So one of the last things I want to mention is that your brain, the certain parts of the
hippocampus has a potential to grow new cells.
And I just want to illustrate that these green cells here are new cells that were shown to
be able to be grown in both young, and this is from an older brain.
And so this shows that, again, you have the potential for plasticity.
It may not be as fast as in the young brain, but it's there.
And so, again, the neuroplasticity continues across the lifespan.
There's different types of neuroplasticity that maybe we could take advantage of, including
strengthening the connections, growing new neurons.
And it's also the case that it can be encouraged by activities.
For example, the mental exercise.
That can allow you to stimulate growth and allow more flexible processing and learning
to take place.
When you engage in physical exercise, it ends up that the physical exercise creates these
chemicals that are needed for the growth of your neurons.
And of course, I didn't mention this, but I just want to put out good nutrition because
you all hear about that as well.
And that's really important too because it gets out a lot of the toxins in your cells
that have built up over the years.
And that allows for more flexibility as well.
OK.
So in the last 30 seconds apparently I have, I just want to point out that, again, just
putting a little plug for a new UW interdisciplinary initiative that a number of us here at UW
are putting together.
And it's because we think that it's time, that we have all this data about what happens
in the old brain, in old cognition, and so on.
But we need more efforts to try to come up with inventive sort of methods to go in and
increase resilience so that you can come up with strategies to combat the age changes
that you see in your brain and your body.
And so these are just an example.
We think that stress is a real important determinant of cognitive aging.
And so in this initiative, we're going to focus on understanding better the interactions
at intersections between stress cognition and aging, to forge new frontiers in research,
train the next generation of leaders, and again, we're going to try and get out in the
public more to engage the public with their ideas, with their support.
And hopefully, then we can make great advances in this area.
And again, you can just contact me if you're interested.
There's my email.
OK.
So again, I just want to thank-- I have a whole host of students, and many of them are
here.
Thank you for coming-- to thank for all the many decades of research that I have been
doing, and lots of different support, different agencies.
I belong to different groups.
Here's an example of a number of the folks that were in my lab at one time, along with
their partners.
And I mentioned that's really important too because they're part of the lab as well.
And I do want to say that--
[LAUGHTER]
--when you get older, you may have different strategies.
And that's OK, as long as you can function.
OK.
Thank you for listening.
[APPLAUSE]
[MUSIC PLAYING]
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