cc >> Tom Zinnen: Welcome,
everybody, to Wednesday Nite at the Lab.
I'm Tom Zinnen. I work
of Wisconsin Madison here and the University
Extension Cooperative Extension, Biotechnology Center and for UW
sponsors, Wisconsin Public and on behalf of our other
Alumni Association, thanks again Television and the Wisconsin
at the Lab. We do for this every WednesdayNite
night, 50 times a year. Tonight I'm delighted
to introduce to you Hilary Gerstein.
She's currently in the
here at UW Madison. Her neuinterests focus on usingam
rodent models to explore how
in the brain relate to behavior. cellular and molecular changes
transgenic mouse models of Hilary has done past work with
studied the effect of pharmacological manipulations on
maternal behaviors and
Currently as a graduate student she's studying the function of
certain genes expressed in the
been implicated in hippocampus that have previously
In the Berger lab they use learning and memory.
virus, otherwise known as rAAV, as a gene delivery system to
over-express or knock down
genes in specific funregions of the brain.ate
Hilary will then examine the
variety of behavioral tests rand anatomical techniques.
Whoa, I like that.
Hilary gave this talk at PLATO
last fall. I think Frontiers in Life Sciences
enjoy it. Please you're really going to
Hilary to Wednesday joNite at the Lab.ng
[APPLAUSE]
Hilary Gerstein: Is this on? Yes? Okay.
It's really impossible
Okay, so one of the nice things about the introduction that Tom
gave is it wasn't just what am I
in the past as well, because doing now but it's what did I do
little bit of what there's only going to be a
There's going to be several sections of this talk.
I hope everyone got a chance
cartoons are awesome. There to lwill be more cartoons.ause
So this is where
First we're going to talk about memory, and it's kind of what I
like to think of as information everyone should know about
memory and how the brains works. Just basic overview.
And then when we talk about that, you'll be prepared to talk
about happens in the brain, what
does that relate to changelearning and memory.nd how
And once we have that down then we can look at some different
ways in which aging can affect learning and memory.
And we'll first start off with some theories about how
Alzheimer's disease works. That is perhaps the most famous
example of a disease involving
memory deficits. And then aged lastly we'll look atning
some of the research I'm doing
terms of what changes are going non in the brains of normaln
individuals as they age that
not be quite as good. causSo it's a little bit ofge or
everything, but I think those are the best kind of public
talks so you get a little bit of
detail on any one thing. And everything and not just too much
ask questions as you like. Okay, you can raise your hands and
memory is not all so thjust one thing.s that
There's different types of
really functionally important to memory, and that's actually
different types of memory. know the difference between the
memory or working memory. And this is if someone tells you
on the telephone, oh, you need
call the restaurant to make a reservation, let me tell you the
number. And then you
pen, and you can't see a pen so you start repeating the number
to yourself as you walk around
you can write it down. That's yoa type of working memory, so
short-term memory. It could also be if you sit down
or are cramming for something very last minute and then right
it all down within
Long-term memory is, as it states, long term.
And there's two major types of long-term memory.
First is conscious memory or declarative memory.
And this is facts. So people, places, events, what
year William the Conqueror
your grandmother looks like, invaded Normandy, D-Day, what
these things are facts. That's what your birthday is, any of
memory. Unconscious coor procedural memoryve
is different. That's
bicycle, for example. Once you have learned or
acquired the task of riding a bicycle, when you get on a
bicycle you don't think okay I'm
and I need to stand up straight goand balance, it just sort ofs
happens. It's unconscious.
And these, as you'll see in a bit, are the important in terms
of how they are different.
short-term or working memory and So interestingly, both
show a gradual decline or aren't conscious and declarative memory
that are aged. And that's quitjust a normal event.uals
That doesn't mean there's anything wrong with the
individual. It is something that happens
pretty much across the board. But what's even more interesting
is that specifically the
is greatly impaired in certain conscious or declarative memory
also Alzheimer's disease. So forms of dementia and also in
we're going to be thislooking at today.emory
We're going to be looking at
people, places, events, things. Okay, so something I always like
to start off with is we're going
your memory is going to get worse but first let's talk about
how your memory can be improved.
actually very fortuitous because So memory palaces, this is
think it comes out this week by Jonathan Foer and it's called, I
have it written down on the next
Einstein. It's about slide I think, Moonwalking With
himself using this exact method I'm going to explain to you
right now to become a national memory champion.
And he started investigating
a newspaper article about it. And then he got sucked into the
competitive world of memory games and became a national
memory champion himself not having any previous experience
with it. So it does work.
It can work. Let's explain.
This is a tool by the ancient Greeks.
Not everything was
It was very expensive alto have scribes.n.
So it was very common for important people in the learning
community to memorize works of literature or science.
And the way, one way you can
like a string of numbers or an memorize something very large
memory. So they entirdeveloped this thingatial
called a memory palace, and you think about a building that you
know incredibly well. I like
up in. My husband to ulikes to use therew
Metropolitan Museum of Art in New York because he grew up near
there as a child. Something that you know very
well, you can imagine yourself
three-dimensions in walyour mind's eye.in
And as you go through the palace
the little items that in yoyou need to remember.posit
So if I'm trying to remember a
to think about walking in the front door of my parent's houseg
where I grew up, and
I would take out my keys and put what do I do next?
where we have the keys, and that's where I would leave the
first number in the string I was remembering.
Then I probably take off my shoes, and so I look down and,
look, I would put the number in my mind's eye, number two, on
top of where my shoes are right inside the door.
Then I would probably walk to go
top of the crate I would let the dog out of his crate, on
And you can actually leave a leave the third digit.
objects that you were trying to remember throughout this entire
palace, and all you need to do
same path through to ryour memory palace.e the
And you can train yourself to be very effective at this.
And, in fact, one of the most famous world memory champions
has used this method repeatedly for eight national championships
or eight world championships. And he can use this exact method
to memorize 1,000 random numbers
can commit them all to at over 300 locations, and he
That's pretty extreme but I've memory in half an hour.
to remember, like, eight personally used memory palaces
well for me so I was numbers, and that works pretty
[LAUGHTER] Starting small.
They do that only with numbers?
So, you can do it with
that you have to complete anyto become a world memorysks
championship are often things that don't have a lot of meaning
so they're difficult
So strings of random numbers or the order of a deck of cards are
common things that they use.
salient like JFK being shot, Things that are very emotionally
found out about the buildings falling in 9/11, those are not
things you have to struggle to remember, they are very
emotionally salient. So to
memories they want to use resomething that is note's
emotionally salient at all. So the memory champions are
using an interesting piece of information about the brain is
that they're using
And the hippocampus is important the hippocampus.
for both the conscious for this because it is required
mentioned that's important for declarative memory that I just
numbers. It's also facts, places, long strings of
memory. So when you rare navigating inal
space such as in a house, even
house just walking through the if you're not physically in the
you're trying to remember facts, house in your mind's eye, or if
you're using your hippocampus. strings of numbers in both cases
memory palace would work because So it makes sense that the
conscious declarative memory for it's sort of a combination of
Additionally your hippocampus is facts and memory for a space.
memories and changing them important for taking short-term
And if you have your hippocampus into long-term memories.
you no longer have the ability removed for some reason, then
And you'll talk about to mathat more in a minute.ies.
So where is the hippocampus?
guy right there. It's It'sin your temporal lobe.aped
And so if you were to put your
underneath your skull in your temporal lobes on either side of
your brain. And it's, as you can see, quite
small. It is not a
brain at all, but it's very important.
So the discovery of this
declarative memory owes a great debt to an individual who used
to be known as patient HM, but
we can use his full name he died a few years ago so now
And Henry had a childhood head which is Henry Molaison.
history of epilepsy, and this led to common blackouts and more
than one major or grand mal seizure per week in his late
20s. That's a lot of seizures, and
that made his life very difficult for him.
So as was common at the time and
seizures by removing the part of the brain where the seizurese
emerge from. And for him, that was the medial
temporal lobe which included the hippocampus.
So they removed the entire
hippocampi from Henry Molaison. And, as you can imagine, they
didn't know this at the time but
he came out of surgery and was when testing him afterwards when
discovered that there has been one striking and totally
unexpected behavior result: a grave loss of recent memory.
And I don't mean that he
I mean that he couldn't make couldn't remember his childhood,
So after the surgery, anyone he met he would be able to talk
with them for a brief period of time, if they got up and left
the room for more than a minute and came back in, he would
introduce himself to
And he had no ability to them all over again.
a few minutes, at most maintain memories for more than
So if anyone has seen the movie Memento or 50 First Dates,
that's actually somewhat
memory loss this accurate in terms of the type of
And as you can imagine individual went through.
So to look at exactly what they removed from HM you can see here
the red sections where they've
hippocampus, the medial remoor the inner part. the
It's actually quite a significant amount of tissue
they removed. So
interesting work performed most of the really
researcher named Brenda Milner on patient HM was done by a
this was back in the '60s when at the McGill University, and
understand the role of the they were first starting to
memory. And something hippocthat she reallyng and
ingeniously figured out is that patient HM didn't have a loss of
all memory. He only had a loss of conscious
or declarative memory, that memory for facts, places,
people, events. His unconscious or procedural
memory was still in intact. And the way she discovered it
was this is she had a task
neurological testing called wha mirror tracing task.in
And as you can see on the screen
individual has to do is their hand is placed into a box and
they look forward into a mirror and they can only see their hand
in the mirror and based on the
mirror they have image of their hand in the
So if you've ever done this, to trace the star.
because you move your hand this way but the image moves that
way. And it's really
it's very difficult to control. And if you practice it enough
over multiple times, you get
task you need to learn, like good at it like any other motor
in cursive. If you get riding a bicycle, like writing
good at it. In HM's case, uover the course of
several days she would present
it. And each time they would ask
him, do you remember having done
a similar test before? And this before, have you ever done
done this before. Even he would say no I've never
sat down and did it perfectly, on the third day when he
done this before, I guess I expmust just be good at it.er
So he had no memory of
of performing the task, of the performing the task, of the fact
but he had learned it his evprocedural or unconsciousk,
memory. So the
that we're talking about right hippocampus is this area
little bit more about it. nSo if we zoom into the bluea
C-shaped item over there, and then we take a cross section
through it, what you see is this big image right here.
And you can see it's not
There are parts of the brain just a mish-mash of cells.
structure to them, that just that don't have a lot of
is not one of them. It's a look like a big blob, but this
the brain, and it has specific highly structured part of
arranged in a very layers of cells that are
And the neurons in one part of specific pattern.
and make connections with neurons in other parts of theo
hippocampus. And this way they form a complex
or an intricate circuitry. And
be responsible for how that circuitry is thought to
So how do the cells communicate with each other?
How do the neurons in the hippocampus communicate?
So first we have a sending
sending an electric signal which neuron, and it's going to be
So it's sending its electric we call an action potential.
which we call the axon, and this signal down the long part of it,
wire that reaches out and connects to the next neuron in
the chain. And at the end of the axon it
gets close to the receiving neuron that's going to receive
its signal, but it doesn't
neuron. The space actubetween the sendingiving
neuron and the receiving
And when the electric signal neuron is called the synapse.
in this sort of large area reaches the bottom of the axon
trigger chemicals to be released called the terminal, it will
And these chemicals are called from that sending neuron.
transmit a neurological signal. These chemicals can then flowy
across the gap and bind to
of the receiving neuron. The special receptors on the surface
take that signal and use it to receiving neuron can then
the cell including its own do a whole host of things inside
axon and continuing the sort of whisper down the lane effect.
Okay, so how does this
Well it's thought that new relate to memory?
the pattern of synapses. So mehow much neurotransmitter isng
released by each electrical signal can change.
You can have some synapses
release lots of that aneurotransmitter.at will
You can have some synapses that are very weak and don't, and
this pattern of which synapses
and how much is what we relethink encodes memory.when
So, again, how does this relate to aging?
Well, there is evidence of
certain old people. Not all shrinelderly persons have as in
shrunken hippocampus, but those that do been found to perform
less well on certain memory tasks, especially memory tasks
that involve spatial memory.
the lab I'm going to show you the research for in a minute,
one of the graduate students
Alzheimer's ward, and she would wtake them on a specific routee
around the hospital and then
from that route and ask them show them pictures of landmarks
And individuals with smaller to explain where they saw it.
task compared to older hippocampi are impaired at this
hippocampi. So that's ione clue as to how the
hippocampus could relate
Another one is that there seems to be evidence for changes in
the number of synapses, in the
molecules go into make up ssynapses in elderly people.t
So it's been found that age-related changes in the
expression of certain genes and those genes encode certain
proteins that make up the synapse could be important for
learning and memory. And
show you at the end. But that's the research I'll
to first show you some theories of Alzheimer's disease now that
we have a sort of good overview of what the different types of
memory are, why the hippocampus is important for the type of
memory that is often deficient
And now we're going to talk about the hippocampus and its
role in the most famous example,
example, of an aging in my opinion most famous
Okay, so some people, unfortunately, are not diagnosed
with Alzheimer's disease as early as would be useful in
order to start treating them
behavioral symptoms rightare kind of vague.early
Forgetfulness, irritability,
That could come from a whole depression, confusion.
the later stages of Alzheimer's hwe get changes in personalityin
and most famously the inability to encode new information.
So those are the behavioral problems, but what are the
physiological symptoms? So
include neuronal death, and that the physiological symptoms
the hippocampus which explains neuronal death usually starts at
we'll discuss in a minute. But some of the memory problems that
we have a nice healthy brain on the left-hand side, nice and
full, and on the right-hand side
individual there's a with an advanced Alzheimer's
cortex which is all the dead shrunken-ness of the cerebral
And as you can see where the neurons being sloughed off.
blue is on the healthy hippocampus that I've circled in
there on the Alzheimer's individual, there's just nothing
So you can see how that would affect learning and memory.
Okay, so there's many, many theories as to the cause of
Alzheimer's disease, but these
researched theories. So I thought I would explain ay
little bit about them and how they might relate to each other.
So the first theory is
And it goes like this: so there's a large protein on the
cell membrane in neurons called APP, and it's very large.
And in order for its parts to go off and do their jobs in the
cell, they need to be cut down into smaller pieces.
And one of those smaller pieces is called A beta, and you can
see it in purple. Now if
that needs to get cut down, the enzyme that cuts isn't quite as
accurate. I mean, if
and you are have a lot of work you're being rushed
accurate either. So in to do, you might not be as
APP that it's not cut very this case there's so much
does end up being cut is too accurately, and the APP that
A beta is toxic. And it loaggregates or just formsal
into clumps that we know of as plaques.
So what do plaques look like? So here on the left we have a
slice of healthy brain tissue from a human being, and the
little purple dots are cell bodies and they look nice and
healthy. And on the right we have the
similar cell bodies in purple,
brown plaques and a lot of them. but we also have these large
like with A beta plaques. Now Sthe Tau theory is a littles
bit different. Tau is a very important protein
that allows neurons to communicate.
First we should go over the parts of the neuron.
So we have the cell body which
Like any cell it has a nucleus. And the dendrites are the areas.
where the cell will receive information from other neurons.
Then we have that long axon,
mentioned previously, and that's that long protruding axon I
will go from our cell wherhere to the next cell.tion
So Tau is very important because
physical structure of the axon, itit holds it together the waye
railroad ties hold
And if you've ever, you know, seen an old movie where a train
is going to go off the tracks because someone has sabotaged
the railway and ripped the ties off, it's kind of like that.
So if Tau is not there to do its
break apart. And as is job, the axon will literally
types, if the cell can't do its job, if it can't communicate, it
will die. So this is
of axons, and if there's two an image right here
Tau becomes hyperphosphorylated, many phosphate groups, if the
the axon and it falls off. then it can no longer hold on to
holding the axon together, it just falls apart, it spreads out
and it dissociates and then we have neuronal death.
Additionally, those hyperphosphorylated Tau proteins
cluster together or aggregate into tangles.
And so we can also see this visually just by inspecting the
brains of individuals of a certain age.
So on the left we have
It looks lovely. And on the right we can see that
in the stain that is staining for axons or axonal proteins, we
can see that there's a lot of business there which is the Tau
tangles. So I've just explained a little
bit about the A beta theory, and
about the Tau theory, so the I've explained a little bit
So let me show you some questevidence for each.s it?
So the gene that encodes the
chromosome 21, and many of you protein APP is found on human
Down syndrome occurs if an may realize or already know that
chromosome 21. So those indiindividuals with Downes of
syndrome, besides having Down syndrome, also have 50% more APP
than a normal individual, and people with Down syndrome almost
across the board develop
they are 40. So this Alzheimer's disease by the time
A beta and APP being very important in causing
Alzheimer's. Additionally,
the brains of elderly people, some elderly people that were
starting to get forgetful but they died, some elderly people
that were really just mentally
and they saw differences in the number of Tau tangles in these
individuals. The individuals
very sharp had very few Tau tangles and they had a young
looking brain, according
Whereas individuals that were getting more forgetful, maybe a
little bit of a dementia, had many Tau tangles.
So this is some evidence for Tau.
So which one is it? If you
look at the brains of individuals with Alzheimer's
disease, you'll actually see
So it's thought that both may play a role but many, especially
10 years ago, many researchers
disease tend to favor one over who investigate Alzheimer's
their lab looking at either the Tau or looking at APP.rate
And this brings me to my
one, which is when some scientists say that something is
caused by A and other scientists
B, it's pretty likely that say that something is caused by
scientists are smart people and they probably both have evidence
in both cases. So let's consider both of them
together. But especially
ago this was a delicate matter. People would fight about this
and squabble. So the
started graduate school where I was a research technician wanted
to prove just that, that both of
to you might play a role these proteins I just explained
So this is the title of the paper, but what you need to know
is that we looked at special
However, mice don't get mice Alzheimer's disease.ease.
So we have to give them the human APP gene so that they can
then have Alzheimer's. This is a very common model that
we use for Alzheimer's, and these mice show the same
behavioral symptoms and they also show this same
physiological symptoms in their brain as humans with Alzheimer's
do. So we gave the
certain mice, and, happily for human APP gene to
protein. So that us, all mice expressed the Tau
So the question is, oh, so was already there.
interesting, knocked out the we also, to make things
So we have mice that have APP but no Tau, mice that have Tau
but no APP, and mice
So the question is, do mice with that have both.
memory than mice with just APP and Tau have worse or better
How do these two proteins work APP or mice with just Tau?
these animals? So what together to affect the memory in
investigate this is we used the Morris water maze.
And the Morris water maze is a
dependent on the hippocampus, and it uses that spatial memory
I was talking about that is one of the main roles of the
hippocampus. So what the
and mice are both very good swimmers.s
They don't like being wet,
little cold, but they're especially if the water is a
They can do it very well. And so we put the animals in
this tank of water, and we have a hidden platform somewhere, and
when I said hidden I mean that
surface of the water the platform is just under the
They have to just swim so they can't see it.
The first day or two that we're testing them, that we're
training them on this task, there's a large flag or
something really visually obvious sticking out the top of
the platform saying here it is. So they can just swim directly
to that nice visual cue,
Their feet are still wet but get on to the platform.
they're not soaked in theythe cold water anymore.ing,
And they like that, that's a reward for them.
So they learn to do that. They
cue, and then we take learthe visual cue away.ual
And now they have to use visual and spatial cues around the
room. We tend to
things on the walls to try hang up a lot of
They have to use their spatial to make it easier for them.
platform is, and we can drop memory to remember where that
the edge of the pool. And theby the end they will learnnd
where the platform is and swim
we drop them because the directly to it no matter where
platplace. Okay, a graph. same
I know, I will take you through it.
So on the left we have escape latency.
So what we're learning or what
did the mouse swim. How welong did it take this mouseong
to find the platform and
So that's what we're looking escape from the water.
And then on the bottom it's just at in seconds on the left.
We have five days of what day of training are we on.
And if you can sort of see the training. So this is time.
but there are six different groups, and there's three groups
that are red, and they're sort
groups that are black, and of at the top, and there's three
The groups that are black tdon't have any APP.m.
They don't have Alzheimer's.
top have APP. And for Theeach of those having APPthe
or not having APP we have having
from the mother, one from the father, one copy of the Tau gene
or zero copies of the Tau gene. This is a Tau knockout.
And so what we see is that all
have two copies of the Tau gene, three groups in black, if they
copies of the Tau gene and no APP, they all learn well, and by
learn well I mean their escape
them to find the platform goes latency or how long it takes
fifth day it's quite low, it's down every day, and by the last
quite good. However, 10 seconds or under which is
animals that are expressing APP, when we look at the
see a difference that's caused that do have Alzheimer's, we can
So at the top we have animals that have APP and two copies of
the Tau gene, and they're at the
solid line. And then top with the red boxes and the
better than them are the animals performing a little bit
disease, and they only have one copy of the Tau gene.
And then performing at the
animals with no APP are the lanimals with APP and no Tau.e
So this is very interesting.
animals have, if they have It seems that the more Tau the
So after the last day of APP, the worse they do.
sneaky with the water maze, tand we take the platform out.ly
So now there's no way to solve
but it's important. So the maze, and it's really mean
around for the entire minute, the entire 60 seconds and we
track what path he swims. So
with no APP and two on copies of the Tau gene.mal
So this is a very normal mouse. And a normal mouse by the end of
the fifth day you drop him in the upper left-hand corner and
he'll swim straight to the
and he'll just swim around, qswim around, I know it's here,
somewhere, I know it. And he'll keep doing that very
religiously. However, an animal that has the
APP gene and a full amount of Tau, both copies of Tau, we'll
place him in and he kind of swims haphazardly around the
entire pool. You can
eventually found the platform, see he would have
little platform box at one his little path crosses the
confident of his answer there. point, but he's not very
And then if we look in an animal He's swimming everywhere.
Tau, we can see that he's thatperforming quite well. no
He's really sticking to right near where that platform was,
very similarly to the animal that had no APP.
So, what did we learn here? So
knocking out Tau completely from lowering the amount of Tau or
model of Alzheimer's disease animals with APP who are a mouse
So this is interesting. But sI just said that lowering.
the Tau expression in mice with APP makes them smarter, but it
doesn't change the way their
weird. If you saw braibehavioral changes,ch is
you want to see structural
it, but you don't in this case. cSo if you look at, if you canh
see the top and the bottom, at
have a picture of the cross-section of the hippocampus
similar to the one I showed you before, but now glowing green
are all those little plaques
those clusters of APP. And that we talked about before, all
just that it's not the same thing is in B, it's
I don't really see much of a green, they're brown.
with APP expressing lots of Tau dwho were very stupid and thes
animals with APP expressing no Tau who were smarter.
There's not really
They both have a lot of plaques, any difference.
especially compared to a normal wild type animal in the lower
left-hand corner that doesn't have any plaques.
So what's going on? Let's review.
So mice that express the APP
Okay? Mice that gene express the APP genease.
but do not express the Tau gene,
out, do a lot better have had the Tau gene knocked
Okay, that's cool. And on memory tasks.
plaques even if their memory mice with APP always get
how much Tau they have, iswhich is very interesting.of
So what does this mean? So
Tau need to be present to have it mean that is both APP and
symptoms. They need botto both be there inr's
order to have the plaques and in order to have the memory
problems. Yeah?
Is there a possibility to move the Tau and the plaque
response are a reaction to a
level inflammation of the brain, different level of perhaps a low
Tau just simply respond to that? and somehow the plaque and the
the way over here I heard on the The reason I'm saying this is on
level dose of ibuprofen had a newsignificantly lower level,low
40%, of developing
And ibuprofen, of course, is an anti-inflammatory.
So is there any relationship
response in the brain system in the development of Alzheimer's?
So that's really spot on
So it's totally possible that both of these events might be
caused by a third item that doesn't have a obvious thing to
look at. Like plaques,
they're right there, let's I see them,
probably what causes it. find what causes them, that's
thought to result Inflafrom the A beta.ally
There's been some experiments that show even before the plaque
formation that just the higher
in inflammation which, of course, can change how the brain
is and make it more susceptible to further insults as well.
So it's kind of this beautiful
And, yes, inflammation in vicgeneral can make the brains.
susceptible to a lot of diseases, but then the diseases
can also make the brain more inflamed.
Okay, but so yes so this feeds
So what does this mean? A rbeta plaques are correlated.
with Alzheimer's disease, but they may not be causing the
disease on their own. And this is fairly new.
Like 15 years ago no one
So one of the other things I was was really thinking that.
test a new plaque busting drug, and these plaque busting drugs
were shown to go in and just
everyone thought would be great bbecause there's these big ugly
plaques in the brain, let's just get rid of them.
But actually we found that this made the mice even more stupid.
This made them worse. And that wasn't really expected,
and it depended on how long after the drugs you tested them,
how long a course of the drugs
they had, but we found that it they had, what dose of the drugs
plaques apart released the toxic was thought that breaking those
around in the brain. And A beta so it was free to float
which is that collecting the so there's a new theory
plaques is kind of the brain's toxic A beta protein into these
and just kind of making dust way of gathering up all the mess
trying to condense piles as it sweeps around, like
And so just spreading someone's dust piles all over the house is
just going to make everything dirty all over again and
actually be worse. So the take-home message from
this is my cardinal rule of science number two is that
correlation is not causation and
conclusions sometimes. Dr. that even scientists jump to
severe memory problems, and when Alzheimer's met a woman with
and it was full of plaques. shAnd so scientists have beenin
assuming for many, many years after that that these plaques
must have caused the memory problems, but it may not be
direct causal relationship. And so this is one of my
favorite comics on that topic.
that just because something is So it's important to remember
cause. And everyone correlloses track of thatbe the
sometimes, but it's important to keep it in mind.
Okay, so the last thing that
that we've talked about general ideas of what memory is, we've
talked about how aging can
about one very clear example of adisease in terms of aging andd
memory. We're going to talk more now
about normal changes in memory
course of aging. So here's that might occur during the
what might be happening in a little spiel about
expression. So by gene normal aging in terms of gene
that is being read into RNA and then being made into protein.
And the protein is the
It can go around and tool of the cell.
So in babies and teenagers and perform lots of jobs.
genes are expressed in their young individuals different
And the same is true brains than an adults.
Different genes are expressed in their brains than in adults,
which is very interesting. So we found that certain genes
are expressed more in adults
genes are expressed less in thadults than in the elderly.in
What's also interesting for us
being expressed differently iin the elderly is not just ins
humans. It's also true in many mammals,
for example, rats and mice. There are old rats that are just
very, very old but they still learn and remember just as well
as young animals. And that's great.
And there's some old rats that
they don't have any one particular disease or problem,
they're just really not with it anymore.
And that's kind of
Some individuals age incredibly well in terms of their ability
to learn and remember and some don't.
And so we're interested in what genes are responsible for that.
So my lab previously performed a
what genes in the rat are gechanging or have changed in at
elderly individuals, and we can use that to get a good idea of
what might be changing in old humans because humans and rats
are actually fairly similar.
work on is called Homer 1, So the gene that I personally
of Homer 1. There's andHomer 1B and Homer 1Crms
and Homer 1A. And they're found all over the
brain, but since we're talking
just going to talk about the about learning and memory we're
simple. So we found that after a
learning task or a memory task
just showed you, animals, old srats, had an increase in their
Homer 1C levels if
So we took all the animals that were old that learned the task
really well and looked at their brains and their brains had more
Homer 1C in them. And we
didn't do terribly well on the took all the animals that
well, and their brains did not task, that didn't remember very
Homer 1C. They had have very much more levels of
Homer 1C. So maybe fairly low levels of
learning impaired because they these old rats were
Okay, so we were not the first didn't have enough Homer 1C.
the behavioral effects individuals to think to look at
Actually another lab knocked of the Homer 1 gene.
strain of mice. And they this gene completely out of a
had a whole host of symptoms found that these mice
they're really tiny. including small body size,
coordination. They have Tan enhanced socialr
drive. They are also
kind of crazy, very twitchy. But really anxious and
feature significant most learning deficits.they
And another group took some healthy rats, just totally
normal rats, and injected the Homer 1C gene into the
hippocampus. And they tested those rats
against normal rats, and the
better. So imagine rats with the more Homer 1C did
and crack open your skull and inject something into your
hippocampus and then
That's what they did. That you'd be smarter.
That's really cool. So this raises the question if
we restore specifically the Homer 1C form to the hippocampus
of these knockout mice, will it help their problems that our
hippocampus based, and we know that the hippocampus is
important for declarative memory and spatial memory.
So would it fix their problems in spatial memory?
So that's what
So in this experiment since we're using mice we did not use
the Morris water maze which was developed with rats in mind, we
used the radial arm water mace
the animal is in which is very similar in that
There is a platform that a pool of water.
The platform is always they need to swim to.
First the animals are trained to in the same place.
visible cue sticking swim to a platform with a large
And then we take the visible out the top.
spatial cues around the room to remember where the platform is.
However in this case there's
big open circle, there's arms soor lanes it can swim down.a
And this makes it a little bit
easier for us to record their eabehavior because now we're's
looking at the number of errors they make and each error is any
time they swim down an arm that does not have the platform.
So if he swam into three arms that didn't have the platform
and then swam down the arm with the platform and found the
platform, that'd
So let's look at be three errors.
So on the left-hand side we have some of the data.
or the wrong arms they entered. And on the bottom again we have
the trials that we
So the two groups that I'm performed or time.
knockout mice. However, shothe red ones at the topr 1
have had Homer 1C injected
And we used a viral vector back into their hippocampi.
introduction. We use rAAV asas a viral vector toe
deliver our little gene package into the brain because viruses
are very good are going in and
said, hey, you want injectto do that for us? so we
And they did. So we have animals that, so
these are both Homer 1 knockout animals, and in red we have
Homer 1 knockout animals that we added Homer 1C back in the
hippocampus. And in green we have Homer 1
knockout animals that we've added green fluorescent protein
to their hippocampi. Now you
that? That's not might ask, why did we do
learn, it's just going to make their brains green.
And that's true, but it's very important to have proper
controls. So we wanted
there was a group of animals to make sure that
our animals injected with Homer tha1C that were geneticallyas
identical, they're also Homer 1 knockouts and they've undergone
the exact same brain surgery and
and the exact same experience thof having a virus in theirod
hippocampus, but the gene that
it's not a gene that's going to ichange how their synapses work
which is Homer 1C. So this is a great control.
And if we look at how these animals perform, we can see when
there's a visible platform, which is the first four dots,
both of these animals are decreasing the number of errors
they make each time. So they're maker fewer and fewer
errors. They're getting better and
better at the task. However,
hidden platform, so we take away when we move to the
animals have an uptake in the tnumber of errors they makee
because I just changed
of sneaky, but the animals everything on them, that's kind
flat line. They're expressing the GFP just kind of
better very much anymore. Whereas by the end, the Homer 1
knockout animals that have had
hippocampus are performing Homer 1C put back into their
animals without Homer 1C. signAnd this difference isthe
significant which is awesome. And if you want to see what this
looks like compared to a normal animal, we took the litter mates
or the brothers and sisters of
genetically normal, and our Hwe ran them as well.t are
And you can see that they have a
visible platform, they're not thrown off as much by the change
in the paradigm. And by the end you can see that
Homer 1 knockout animals where
the hippocampus, they're we've added the Homer 1C back to
their wild type brothers and performing almost as well as
So to sort of review what I just sisters, which is super cool.
1 knockout animals where we've showed you, we have these Homer
hippocampus. These mice addperform significantlyheir
better on a task of spatial memory, which we know to involve
the hippocampus, than the Homer 1 knockout animals that were
just expressing GFP,
So basically injecting Homer 1C into Homer 1 knockout mice fixed
their memory deficits. And
course, they were lacking it and you might say, well of
course that would fix youit. No, not of course. of
Not of course at all. In
difficult and rare to be able to fact it is very, very
them back the gene later in life fix a knockout animal by giving
their entire embryological because if you think about it,
childhood and in most of their development, their entire
gene. Their brain adulthohas come up withd this
other methods for doing what needs to get done.
And then you're adding this tool, this protein back in, and
the brain hasn't ever seen that before.
It may not integrate, it may
So being able to do this kind of gene therapy in animals in a
knockout animal and get it to fix the deficits is really cool
and not all that common. So what we can say here is that
if there is a lack of Homer 1C, we added it back to the
hippocampus and it made the animal have a better memory.
So how does this relate back to aging, which we had been talking
about for the entire rest of the
about young animals. So this talk and then I started talking
animals in mid-adulthood that were lacking the Homer 1 gene
and it added the specific Homer 1C form back to the hippocampus.
And this helped the hippocampus recover its ability to make
memories. So previous research in our lab
showed that learning impaired older animals had very low
levels of Homer 1C. So the
to know is can we add Homer 1C next question we wanted
learning impaired animals to and will it help them too?ld
Or maybe it's too late for
We don't know. So stay it to have an effect.
to be starting that texperiment next month.
[LAUGHTER] And that's the end.
This is a picture of me and Brenda Milner who did all of
that really seminal work on HM, and I've been to rock concerts
where there have been fewer people swarming the main event
afterwards. She had body guards, and there
were at least 5,000 people
who had just stood and given swarming this 90-year-old woman
in her nice high heels. an hoAnd she's awesome.feet
So a round of applause for her. [APPLAUSE]