Thank you very much for
having me I'm excited to be here and

in fact you're right it is overdue I've
spoke at Georgia Tech and I've interacted

with lots of you both academically and
socially so I'm glad to be

here to tell you what I do in the basement
of Rollins over on the Emory campus.

So what I'm here to talk to you about
today and what I'm interested in is why

and how we remember what we remember both
from the psychological perspective and

from the neuro science perspective and
I've picked this picture of my son

from last year our summer vacation
at the beach to kick it off and

that I was going to use this
picture as a way to say that to him

it was clear that this was
memorable episode because

look at how much joy is on his face and
this must have been you know worthwhile

memory at least for us to pay all
the money to go to the beach and

when preparing this lecture I showed him
this I said Hey are you impressed I'm

going to talk about you in
front of a bunch of people and

I said What do you remember from
this picture and he said nothing.

So now the example is going to be from my
perspective I'm the one that actually took

the picture and the point is that I
remember this relatively well and

my having a stroke or
is it getting dimmer? OK.

I usually don't get nervous
when giving a talk and

I don't think it's but
it is possible I was stroking out on you.

I don't know I guess that.

I have to wiggle occasionally they're
all right so no remember this but

the reason I remembered that was less
you know the you know fun splashing

in the waves but that as I saw the memory
through his eyes that to me this was

remember remember a ball
memorable because I.

Experienced loss of emotions about
this as a father that this was both

like it was a nice breeze warm
water pleasant sunset but

also it made me think that you know I'm a
good father I provide these choice moments

from my side and I use that memory as
part of what psychologists will call

their autobiographical narrative and
is that me OK.

He has thrown curveballs at me left and
right.

I thought the tech part stood for
technology.

Technical difficulties Georgia Institute
of technical difficulties.

Right so there's a reason why
the both the kind of emotional aspect

that it conveyed to me as you
know that I feel pride in and

in and satisfaction all of those
things wrapped together and

that that's part of why I remembered this
particular event even if my son did not.

But that of course we talk about
these moments that we cherish and

we think about those that how important it
is to hold on to those important memories

but I think that we often forget
how important it is to not remember

some memories that forgetting is just as
important as remembering because without

prior to zation of the important memories
you really don't have a good memory and

to make that case show you this
picture of this woman Jill Price

who in a report by Jim gone others
was referred to as case A.J.

She has since gone on to appear on
Oprah Winfrey and twenty twenty and

wrote her own book but by all accounts
as far as these memory experts could

tell she can remember just about
every episodic detail from her life

starting around one thousand nine
hundred eighty and that the way you can

assess that is by asking about some
things that might intersect with person.

Public events like when did this
plane crash or when did J.R.

get shot for those people here or
more my age and

that every time I ask her what she
answers is accurate now we can't

assess the extent to which having
a bagel and cream cheese for breakfast

on September sixteenth one thousand nine
hundred eighty five is accurate or not but

the things that we can assess were
accurate and that you might think wow that

would make you know graduate studies much
easier if I could remember everything but

the point here is not what how impressive
this is but what a burden she sees

it as and in fact she describes in this
quote most could have called it a gift but

I call it a burden and
it's that she's feels

besieged by the remembrances
of every day Monday and

details that she can't sort out
what's important from what's not and

it's everything to her and
that that's bad not good.

So then to go further than to ask how what
is that means and I've been told I'm only

allowed to pace on this side of the room
because that's what's in the field of view

so I'm not ignoring you I'm
just mugging for the camera.

That to ask what is important and
what's not I don't I don't think that

we can stop that you know the things that
tug at our heartstrings as parents or

any emotional events that I think we have
to ask it from his perspective as well and

I'm sorry for what.

I did was that I had to lead I didn't
think you guys would be eating.

Trigger warning gross stuff coming this is
a tree shrew eating the head of a cricket

and that I think that to ask the question
of what's important to this tree shrew

might be different from what's
important to me as a parent or

what's important to you as going
about in your day to day lives.

And the reason I bring this up is that I
think that we need to think about memory

prioritization not just from
the anthropocentric view of humans but

from the perspective that might apply to
a broader evolutionary perspective and

more so what I'll tell you and this
might be a little bit disappointing that

the fundamental memory mechanisms in this
guys like vampire looking squirrels brain.

It's pretty similar to yours so
here is closeup of a cross-section of

the hippocampus from several different
species including sorry this.

Tree shrew here and what we see
here this is the hippocampus of

the tree shrew mouse ten are akin to
human and you can see the I'll just

pick the tenrec here why not you can
see the densely packed the cell layers

pyramidal neurons of the CA
fields in the hippocampus and

that goes from the CA one there's
a transition Area CA to ca three and

this other densely packed layer of
granular cells in the dented Charis and

that to the extent that we've
looked at these details and

different species we found pretty much
the same thing and I say we I mean day and

animists and it might be
disappointing to you to know that

the anatomy allows you to remember
those cherished memories is not so

different from the ten Rick I'm sorry from
the tree shrew remembering that delicious

meal of his crickets head again apologies
to those of you eating sandwiches

so to me understanding what the how
we remember what we remember the how

memories become memorable prior to
zation I think we have to take into

account what might be an explanation that
would apply to some extent at least at

the neuro biological level across
the mammalian tacks on because those brain

mechanisms are very similar so
the last thing picture I'll show you.

To set up why it's important to
study memory is this picture

of a young gentleman who happens to be me.

Graduating from high school and to
the left and right on my grandparents and

then I show you this picture not so
much to say that this was an important

memory to me though it was it's to
point out the fact that my grandfather

was diagnosed with Alzheimer's
disease at the time of his death and

if you want to know about the importance
of memory don't ask a patient with

all Summers disease because some point
they become blissfully unaware of

their memory condition ask the spouse ask
my grandmother what it felt like to be

forgotten by her spouse of fifty years I
think that goes to a long way to showing

in a simple demonstration how important
memories are and what remembering what

important what things are important means
to us so that that's the set up for

my talk and what I'll try to do
is get through some of that and

I won't get through all of it now that I
understand that some of you have classes

to get to perhaps as early as noon but
that what I'll try to do is

talk about setting up also
disease in a rat model to again.

Set the stage set the stakes so

to speak of understanding these
mechanisms are important not only for

just understanding how you
remember your vacations but

also what goes wrong in disorders that
impact memory like all summer's disease.

Also talk about then what we know about
what are what marks good memory States and

healthy at the campus and then talk
about more recent work that we've used

to stimulate them to try to artificially
prioritize some memories over

others as a window into what makes
good memories over bad memories and

then if there is time which there may not
be talk about work with Scout based E.G.

recordings from humans doing
autobiographical memory retrieval in both

emotional and neutral conditions so jump
in with all Summers disease bottle and

this is a rat model that Robert Cone
developed when he was at U.C.L.A.

in Cedar Sinai and brought here
with them to Emory to Atlanta and

it's a rat model not
a mouse model in which

it was a double transgenic
they used the human genes that

are from particular humans that
are known to come down with adult onset

Alzheimer's disease I'm sorry early
onset Alzheimer's disease and

the two genes are particular priest
in IL and one in the A.P.A.P.

the Swedish variant from those individuals
in Sweden that they got it from so

that this rat model is
detailed by Robert Cohen

in this paper in much detail and

one thing from that they project show
you is that like the neuropathy all A-G.

in human also means disease the neuropathy
all the G in this rat model is aged and

that is some early age and
what we're seeing here is a side view of

the rat brain and as zoom in there of
the hippocampus and this here this dentate

gyrus I think you can see in the red
stain for Red Cell bodies and

both at the time point of six months and
fifteen months and

on this six month period you can see
that there is not much more staining for

amyloid deposits but it fifteen
months there is quite a bit and.

In fact as the rat ages to twenty
four months at a cumulative more but

just to make the point that this
rat model develops the human

similar type of path ology as in humans an
age dependent way including these amyloid

plaques and the neural February tangles
that are shown here we wanted to know then

where we entered into this then was to try
to understand somewhere between these two.

And both of these are before
there's any neuronal loss or

sin APIC loss these are markers of amyloid
bird not necessarily of cell death but

we wanted to know at a very relatively
early age what might constitute

the hippocampal dysfunction in
these rats with all summers

like disease and so the first thing we
did with former graduate student my

lab what Claire Galloway was to
ask At what age do they become.

Memory deficits and so here at that run
that six month age from five to eight

months these rats also miss rats and
gray compared to the wild type and

white showed a memory performance
that was relatively normal and

this is a discrimination
index of a type of memory and

I'll just say That point five represents
chance performance in point six six

represents pretty good performance on this
type of measure but then very quickly by

the time they reach nine to twelve months
the eighty rats had developed a profound

memory impairment in the wild type
we're still performing pretty well and

that's we wanted to know then not
necessarily just at the behavior level but

what was going on in
the hippocampus see these rats and

like a lot of what we do in my lab we
use in people electrophysiology to and

Tara great function and dysfunction and
brain circuits as they relate to memory

and in this particular picture you're
seeing a rat that we're recording from.

Wires implanted in its brain as it
locomotives on this track in fact to

come back and get a little piece
of chocolate for every lap and

show you a video of that of
some of these also Murs rats.

So what we can record from that
are spikes from individual units

using tetrodes like several of the folks
here at Georgia Tech already do.

And here is one way to look at that data
and in this fast forward video of a rat

completing laps on the circle track what
I've done is superimposed with red dots.

Marker on the screen to show you
every time this one example neuron in

the hippocampus and it in actual potential
as the rat was completing its lapse and

that I think what you can see is that all
of the spikes from this example neuron

are occurring in this particular X.

Y.
location on the track and

that these are well known they've been
well known since John described them and

then eventually won the Nobel Prize for
the discovery it's neuron with a receptive

field defined by spatial landmarks
that then are in the name place

feel the receptive field and that the
neurons then are called place cells and

then we use these then as a way to
look at the hippocampus in these rats

to see is it acting normally is it
showing normal looking place cells and

here is a more typical way to plot these
place fields rather than the video.

And looking here across for
the wild type animals you can see

that the black path is just
showing you where the rat ran and

then now and color coded with cool
colors representing lower fire and

rates and hot colors representing higher
firing rates you can see that for

the wild type rat these different
example neurons from CA one and

from the CA two and three regions
are quite circumscribed a nice tight

place feels representing one place and
that that wasn't surprising that's exactly

what we expected from these healthy wild
type littermates But then in eighty rats

the surprise was that at least for
the neurons in the permanent Ahrons and

see one they also looked perfectly
normal even at an age and

this was at least twelve months of age
that these rats we know showed profound

spatial memory impairments the CA
one neurons looked pretty good and

it was only the C three in CA two neurons
that showed us kind of spread out in

the play cells they weren't firing any one
particular place particularly well thereby

kind of raw being that area of the brain
information about the location of the rat.

And that one of the most classic ways
to quantify place cells is what this.

Standard widely used
information theoretic approach.

Measure called spatial information
score and it's just a way to try to ask

how much information could you get in
kind of bits per spike from a neuron

as a rat's local money about and
what you're seeing here in gray for

the eighty and white for
the wild type pretty normal for

the CA one neurons no difference there
between the wild type and eighty but

specifically here for the eighty you
see a deficit in the C A two three

and it wasn't necessarily the fact that we
saw a deficit it was that the deficit was

specific to one area of the brain and just
a kind of making a cartoon here as I talk

in part because you know I can see that
this is while typing eighty for C.

one and C.

A three and it's specifically the C
three neurons that didn't have these

new Ronal landmarks these place
fields that were nice and

tight to give that rat sense of where
it was and instead this little cartoon

rat is obviously lost in these
spatial representations and

that now then what do we do with this and

I think that the answer of course what
also numbers diseases don't let the brain

get to that state in the first place
that we need to develop a cure or

a disease modifying treatments to impact
the trajectory of Alzheimer's disease so

that you don't get there
in the first place but

that there until we have that cure and
even after we have that cure

there is going to be a great need for
treatment of symptomology and

also members disease because probably for
those of you like me who are already in

your forty's even if they came out with
a cure it's probably too late for us we

probably would have need to be taking that
medication now to prevent that trajectory.

Yes ma'am.

That's a great question and

so that had our twenty one not
been in our twenty one and

run out after two years the next step
would have been to record from those rats

as early as three four five months of age
however early you know was feasible to do

to ask where they add normal all along or
did they develop this dysfunction and

so the answer is I don't know the path
ology in the memory is age dependent and

so my best guess is that these
are the dysfunction in the CA two and

three neurons is also age dependent but

that at this point is a guess thanks and
feel free to.

Throw out questions and
I was forgot to ask.

Repeat the question but yes.

Yes I do have.

Yes the data were from it's.

So that then though that the question
isn't like what to do about all Simers

disease that answer is you know cure
it but they suggest that we try for

the treatment of symptomology when there's
dysfunction in this part of the circuit

it leads to questions about how we
might ameliorate that dysfunction and

that the answer is from that of even
now we don't know we've the hippocampus

is one of the most studied brains one
of the most likely brain areas and

of all of neuroscience I mean we
have our own journal for godsake but

that we still don't know
exactly what it means for

ca three to be dysfunctional and see it
wanted to be normal we don't actually

quite understand what
the ramifications of that or

even what kind of treatment
we would want to bring about.

So that no I think that that makes
the point then that also misses these bad

don't get Alzheimer's disease
give money for treatment but

then also we need to understand
the healthy brain a bit better so

that we can better understand other
areas of dysfunction and so that's now

what I'll switch and talk about a bit more
leaving behind all Summers disease and

start talking about the hippocampus
in healthy rats and

we do the same thing that we
do with also Murs disease

rats except that now we focus a bit
more on the actual memory performance so

this is a similar video of a rat
completing laps on a track here but

now I've put objects jump novel objects
the rats never seen before in its path and

it has the opportunity to stop and
sniff the roses so to speak and

I think what you would see on
the first path the rat stopped and

momentarily sniffed the objects but
on laps two and three he ran right by

them because they were boring to him and
we have fur from the reduction in

exploration and subsequent repetitions
memory for the objects and

the ideas based on lots of
testing in this task and

other tasks like it in monkeys and humans
this based on spontaneous preference for

novelty but then we don't stop here
because I think if you looked at this in

the similar plotting of a from a different
example neuron a red spike every time.

The neuron emitted an action potential
from here it's unclear is this neuron.

Activity correlating with location or
with that particular object or

some combination of both I don't think
you could tell from that type of.

Short session so that in fact we record
rats running around for an hour or

so lots of different objects and lots of
different locations and here it's there's

still no answers from one single video
that we know it's not firing over here but

it seems to be firing for something to
do with objects and something to do.

Locations and in fact that we
don't even stop with this but

then instead go on to record in lots
of different neurons simultaneously and

in this video a color coded action
potentials from different neurons

with different colors that there is
potentially a rich opportunity there to

interrogate this by trains to ask what
are the memories is there information in

the activity in these action potentials
about remembering this tin can hear

versus remembering that hairbrush there
and the answer is of course yes but that's

not what I'm going to talk about today
because one of the classic approach in.

Vivo electrophysiology in the hippocampus
has been to record from action potentials

and try to decode the memory correlates
from the spike trains and that it's had

lots of success I mean it's had
Nobel worthy levels of success but

that there is also another approach
rather than you know bringing

out the all the Georgia Tech folks to
try to use their machine learning and

whatnot to squeeze everything
we can from there and

that the other approach Well
let me say I'm not this is.

Not me saying that I think that recording
actual test was a bad thing in my former

career with Howard I combine this
is everything that I did right and

that it's the whole reason Emory hired
me so of course I think it's great and

the idea that one idea that that
I played a small part in but

that was the kind of field why it is that
from asking about the different correlates

of neurons for example grid cells from the
Mosher in the middle and around of cortex.

That we know that the hippocampus sits at
this confluence of spatial and non-spatial

information such that the hippocampus
seems to be positioned particularly

well to integrate spatial information
with non-spatial information so items and

their locations for example but what this
doesn't tell us at least not particularly

well is what might be the dynamical
system here within the hippocampus those

sub regions of the hippocampus that are
already told you are conserved from you to

a donkey to to a tree shrew what's
going on within those local

connections to mark good memory States
compared to bad memory States and for

that we have taken another complementary
approach and in fact this is an even older

approach than the approach of recordings
by trains its record in local field

potentials from those electrodes rather
than the activity of action potentials and

that the local field potentials really
just represent the sum to activity of

lots of the P S P's and I.P.S. bees waxing
and waning to lead to these oscillations

that you can record in the local field
potentials and that has been recent

efforts our effort to try to ask as
we record in different sub regions of

the hippocampus what might be
the oscillatory interactions

between those sub regions and how might
that convey information to us about

good member states versus
poor member states.

So here's just an example
to say what I mean.

So now instead of trying to get from
individual action potentials record from

as it can be one electrode in CA one and
can be one electrode and see three

and this is an example of one
recording from one period of about

four seconds as a rat approaches and
initiate onset here at time

zero exploration of a junk novel object
that it's never encountered before and

from this you can already see even those
of you have or are not used to looking at

local field potentials there's a clear
oscillation in this that it's going

to about eight times a second that's
the classic data rhythm that you can see

in the hip right hippocampus and
as technologies have progressed and

recording humans as they
Lokomotiv out also in humans.

And that there's going to be a good

correspondence between that
they don't see one and

they say that they to and simultaneously
record it ca three and that's you know.

That's true and that's been known for a
while what we wanted to focus on here was

this period of novel object exploration
and what I'm going to do now is just zoom

in on this section and show it to you kind
of superimposed on top of each other for

both see it one and see a three and
red and blue respectively and

you can see that overall theta now for
this shorter half second period but

the point that I wanted to make is
that you can also see alignment here

at a faster what is often
called gamma oscillation and

we've come to know that there's not
necessarily just one type of gamma there's

multiple potentials sub bands of gamma
that have her names like slow gamma and

fast gamma I'm going to be talking about
particularly slow gamma today something

that's about forty per forty cycles per
second and so instead of just asking

you to look at the squiggles and see
the through the squiggles wiggle together

there's a way that we can quantify that
and there's lots of different ways but

the one way that I focus
on today is a metric called

coherence which not only looks at

the phase alignment between two
oscillations but also the covariance and

amplitude of any particular frequency
band between those two and so

here is one way to plot coherence
again with time being on the X.

axis and zero being the initiation of

exploration of a novel object and
but now on the Y.

axis is frequency and going from
zero to about one hundred hertz and

what is color coded then is coherence with
cooler colors representing lower coherence

or lower synchrony between C one and
ca three and hotter colors

representing higher coherence and that
what you can see and I'm really sorry for

those of you I keep wanting to like
give you some over here but then.

You know that.

One guy sitting on his couch
watching me hey one guy.

He would be able to see that.

That this most maxed out thing happening
around eight hertz that's the theta and

that seems to be going on very strongly
basically when the rat is going on about

an awakened like investigating the world
not just investigating objects but

hopefully what you can see is there's not
much here in that gamma range prior to

the onset of exploration but then there's
a dramatic increase from about thirty to

fifty five hertz in that slow gamma
range and that in this particular study

that was from before a graduate student
my lad John Tripper found that four C one

in CA three coherent specifically that
the extent to which there was an increase

in the slow gamma coherence during the
exploration of a novel object predicted

subsequent memory for that object I'm
going to dig into it with a more recent

study because what John
subsequently did after that for

a study was to record not just from C one
and ca three but from all four sub regions

with my apologies to CA two that
we recorded from dentate gyrus ca

three CA once a pic of them simultaneously
to try to get a bit more about

what's going on in the dynamical
interactions between all of the all four

of those sober regions and
that this is basically the same plot but

with different animals that I showed
you before where zero is the onset

of exploration showing this increase in
the slow gamma oscillations when the rat

initiate sex were rationed and
you can see the same thing actually

between dentate gyrus and ca three but in
fact it was kind of going on all along and

it goes from a lot to our whole lot
rather than not much to a lot and

that that isn't universal necessarily an
aspect of what's going on in hippocampus

in fact there's not a lot of
gamma synchrony at least at

this kind of color coding
level between C one and

so so something about a particular
aspect of this portion of.

The circuit.

And so to ask more about that I mean we
had some basic questions like Is this

increase in slow gamma oscillation is
it really about forming a memory for

the object that was our hunch and
that's what I'm telling you but

it could be something as simple as this
is what happens when a rat stops and

maybe succession of
locomotion rather than.

Forming a memory it could be the act of
exploration itself there may be one or

two of you that are interesting and things
like whisking in the audience and so

maybe this is more about a behavioral
state of investigating an object rather

than the memory state of making a memory
for that object and one way to ask that is

to then take what's going on here
during sniffing of a novel object and

ask again how does that do to
predict subsequent memory and

so here's one version of the task and
John did several but

that we have rats sniffing objects
on a brand new jump not a logics

that it's never seen before on as
a complete slaps on the circle track and

that on the very next lap we repeat them
we actually repeat duplicate it's just

to remove the possibility of scent marking
but we treat those objects again and

what we should see and what we did see is
rats reduce their exploration and that's

more to make sure that the rat formed
a memory from that initial encounter and

then there were several different
conditions just shown here is as

this could be trial won this could be
trial two three four different conditions

and so one condition was
we took those objects and

duplicate swapped out locations so
if a rat remembered and

reinitiated exploration of the toy
hamburger it wasn't a real hamburger.

That it would mean that the rat
not only remembered the object but

also the objects Parlow cation because we
put in their control conditions in which

the object got repeated for example and
the exact same place what the same object.

And then the other kind of comparison
condition was what happens when you

put in a brand new novel object and
through something that I won't.

You know the kind of flow chart of
how do you say from this that is

there good memory for the object and
or good memory for the object and

its location it's an inference on
what goes on on laps two and three

to try to predict back was this a good
memory in coding here at the beginning but

so now on the next slide I'm going to
show you neural activity from here but

split by conditions determined
by those behaviors and

that now what we can see
in those memory conditions

in this kind of orange red when a rat

was sniffing a brand new novel object
split by whether it was going to

show good memory in the future for
both the object and the object location or

in blue just the object or
in black no evidence of memory for

either the object or its location and
that this is now shown just as actual

power of oscillations across
dentate gyrus ca three C.

once of the Killam and they just the grand
average because a bit unlike and its.

Baseline subtracted that's why
everything's zero to emphasize kind of

what differs between the conditions and
what differed between the conditions was

this slow gamma range some hair between
thirty and fifty five hertz and it did it

mostly for a dent eight in CA three
somewhat more for C one it's a big but

that one of the most statistically reply
Both thing was just to take the average

slow gamma power in the hippocampus and
that was one of the best predictors of

whether or not the rat was going to
show us good memory in the future and so

we were expecting complication and
in fact one of the rare times we got

something a more simple answer an answer
at least from this data was the slow gamma

oscillations in the hippocampus state
a kind of generic generically like that

was a marker of a good memory state and
so that that was.

A nice one of those times where you get
clarity rather than asking more questions.

And.

Then answering any and I don't want
to say that everything was cut and

dry that the questions of distant big
you waiting in memory state memory

state here from behavioral States was what
a lot of the manuscript focused on and

that it wasn't as if slow gamma is the end
all be all in the hippocampus it was

just that that particular memory network
state correlated best with them and

they inferred memory state of making
a good memory for the object is location.

Talking really fast so
I'll stop Yes record.

Use.

This is where you.

Want to.

So the question is.

It could be the case that gamma
was going on all along but kind of

unsynchronized in different regions of the
hippocampus is it the fact that there was

going on a long and then just snapped
in together during exploration or

was it the fact that you were getting a
little bit of gamma and then when the Rat

started sniffing object and was going to
remember that object you got gamma and

it was locked together we found the latter
rather than the former there wasn't

a lot of low gamma power
consistent low gamma power

going on during baseline Now that's not to
say that it's not there it just tends to

happen when these little sporadic moments
here and there that if you look for it you

can find it outside of object exploration
but if that becomes really most prominent

during novel object exploration then
perhaps other things that you know we

haven't investigated but that's one
way to make it trigger and about.

It was the question was Was there really
clearly from a behavioral standpoint

an obvious good memory and
an obvious bad memory or

was it a continuum of memory that we did
a median split something like that it was

latter we artificially partition
the performance into these states and

what I can say is that it doesn't matter
exactly how you partition them you still

see the general finding that obviously
it's not as if you either get memory

you don't have memory you have better or
worse memory and gradations between and

the only way for us to be able to
partition into these states was to pick

something artificial and to reassure
ourselves that it wasn't just a quirk of

how we partition that we picked this first
went with it but then in our neurotic

moments we did it a couple different
ways to make sure that when somebody

has this we can say it doesn't matter
exactly how we partition it question.

So now.

Switched to talk about in terms
of thinking about good memory and

poor memory or something that is memorable
for something that's forgotten one of

the big lessons that we can take from the
psychological literature is that emotional

memories tend to be remembered better
than neutral memories not always and

that there's extreme
versions that lead to.

Dysfunction such as P.T.S.D. but
in general emotion moderately emotional

modder emotional Rao's all
leads to better memories and

that what we know from lots of work
from folks like Jim a gall here is that

the particular the base a lateral complex
of them into seems to be a key hub in

mediating those emotional Rouse
will influences on memory and

ideas that you have some experience
in that that experience here

record can be made of that experience in
different ways in different locations but

one in four in terms of declarative
memory in the hippocampus and

associated structures in the media
of some fellow than humans but

then there's an opportunity through
emotional Rao's all activating

either directly or through peripheral
hormones indirectly they make and

the outputs of the make to have
the opportunity here shown by McGaugh and

read to through Gronow projections
modularly memory processing and

other areas so as to be able to
prioritise some memories the and

this case those with emotional
salience over others.

And we were interested in this but but
all admit that we're less interested

in the emotion part and more so interested
in the memory unhandsome it part and

so I do know that set forth
a collection of the studies in my lab

was the idea that we could directly and
at first electrically stimulate the image.

To try to prioritize memory for
some junk nuchal neutral no motional

content objects over others and so
the basic set up is the same that

I've kind of been showing you before a rat
comes up and sniffs a novel object and

then later in the future we ask that rat
to show us doesn't remember the object or

better and then one wrinkle is
in this line of work is that at

the offset of exploration we took
the law with a little bit of electrical

current We're talking small twenty micro
lamps and you can see it's in a particular

pattern here that's kind of was meant to
be a guess at mimicking they to modulating

gamma but this is just a small
amount of current delivered for

one second at the offset of
expiration of that neutral object and

the question was then when we brought
the rats back later when they remember

the object that previously was followed by
it made the list immolation better than

a control object and we have course have
to have novel objects here as a reference

for asking just in general can the rats
remember the neutral I'm sorry

the repeated objects more so
than the novel objects.

And this is a complicated schematic and

I'm not going to walk you through it other
than to say we didn't just use three

objects we use lots of different objects
counter-balance in different locations and

that the other part is that after
the rats are in the study phase when

the stimulation was delivered on some
after some of the objects for half of

the objects we tested memory immediately
for the other half one day later.

The point is that the point we did then
the point I'm telling you is that even

from just looking at Jim Acosta work we
predicted that the benefit would be most

prominent here one day later and in fact
over several experiments that's exactly

what we found that here
in the red stimulation

in blue no stimulation on the immediate
test again this discrimination index where

point buy was chance and point six
six would be really good memory that

there was not a difference between the two
conditions on the immediate test but

then when we looked on the one day test
that the objects that were previously

followed by McGillis stimulation were
remembered as bed as good as the objects

that were tested immediately and in
contrast there was very little memory for

the objects that had not been on
a one day test had not been followed

on the initial study by
mental stimulation and we and

our series of experiments the first being
just could we get that behavioral effect

then the next one was does that
depend upon the hippocampus and

for the sake of time the short
answer was using Musim Yes that

in experiment three The question
was what might stimulation of the.

What kind of network state might that
induce in the US in the hippocampus and

show you a little bit about that and
I should say that then first.

Because we're using electrical stimulation
it's always tricky to record electrical

activity at the same time and so for this
we took advantage of the fact that they

have got connectivity from the BE
a way they make to the hippocampus is

almost exclusively It's a lateral And
so if we were quoting from here that we

should expect only artifact from here and
artifact plus actual and around all

something going on here about this one
brain area back in the other and so

just in this little time lock thing we do
find that there are some small artifacts

from the electrical stimulation shown each
pulse here at one of those triangles and

just basically clean it up subtracting
the two makes this look even better

and so there's a way that to help us
understand that we're not just recording

the electrical lack artifact
of electrical stimulation and

what we found was that
stimulation of the lateral

led to robust increase in CA one c three

slow gamma coherence not so much on
the other side and you might ask me well

isn't it obvious that if you stimulate
the somewhere around fifty Hertz and

you record in the hippocampus and
you see something around fifty hers

isn't that you just popping what you
want to see and the answer could be and

we did another condition in which we
stimulated the eighty Hertz just picking

something that's not in
the slow gamma range and

we did see that in it was able to do
something around eighty Hertz but

we still also recorded this
increase in the slow gamma range in

the hippocampus for the EPS lateral
not for the Contra lateral and

this suggested that there's a possibility
that activating outputs from

the at least within some range

induces the hippocampus to go
into whatever its residents.

Oscillation might be and

at least on one front that residents
state is that slow gamma state.

Now excitingly enough that or
depressing enough that it's

not only the hippocampus looks the same
between you and rats I mean the law to.

This the use of electrical stimulation
a rat studies opened up the possibility

in collaboration with
neurosurgeons at any rate and

under the good fortune that patients
hanging out in the epilepsy monitoring

unit with informed consent volunteered to
participate in these studies we were able

to replicate the rat studies basically
do it exactly the same in humans.

And so instead of allowing humans to
sniff or whisk junk objects because

well you might not know but
you don't have active whisking in your

sense of smell is pretty bad but
in patients with electrodes for

clinical reasons implanted into the media
temporal lobe we're able to target those

that happened to be centered around
the base a lateral complex and

deliver that same type of one second
worth of stimulation that had

the same pulse train frequency and
the same kind of

experiment now in the humans it was
seen pictures of novel objects and for

half of them it was followed by
electrical stimulation of the make for

the other half it was not and
weekend tested half immediately and

half the next day and what we found in the
humans was basically what we found in rats

that there was not a consistent effect
between the stimulation and read and

no stimulation and
blew on the immediate test but

that there was a very consistent effect
across the patients despite the overall

variability in their memory performance
that was a consistent effect

of stimulation leading to improved
memory and to kind of crystallize this

a bit better than this plot just
shows this plot but subtracting

no stimulation from the stimulation and so
zero means no effective stimulation and

greater than zero is a memory benefit and
you can see on the one day test

there were a couple participants that
showed no difference but on average

there was a reliable statistically
significant effect of stimulation and

it was somewhat specific to that one day
test just like it was in the rats Now one

thing that we could do in the humans that
we could not do in rats was to ask them so

would you feel so we did and.

As a separate little side experiment with
every participant we put the you know

the button you know and
said OK I just pushed it.

Did you feel something and in fact half
the time the button we pushed delivered

nothing and half the time it actually
delivered the same stimulation that we use

in the experiment we thought that we would
need to try to sort out false alarms

from real hits but
in fact in this completely ridiculous

graph that I insisted we put in
the manuscript because I LOVE IT hundred

percent all fourteen of the patients for
all of the trials and no I did not feel

anything because from the beginning that
we started this experiment people like But

I fear conditioning aren't you know
doesn't that do fear numbness and

that's not true but that the outputs of
the it may have the capacity to prioritize

memory even if upon direct activation
outside the scope of emotional

experience can prioritize memory even
when the participant feels nothing and

so that that's why the system upon this
ridiculous figure whether you know there

can be no error bars because ALL hundred
percent said no I can't feel it.

Work.

Yeah so what I should say is that this
was done with John Williams Korean men

at Emory and that in a separate paper
that Cory did I mean this sounds.

These are all what I'm going to say
because it's within the context of

patients that these
are all within the healthy

normal ranges of the levels
of stimulation this was tiny.

But kind of parallel the rats they
did ask in the patients in a separate

experiment Well what about now what about
now what about now what about now and

eventually if you got it about five to
ten times high of a current as we used to

hear some say I think I think I felt
something in one patient that patient said

not again not in this way higher
levels that we used here said

I feel terrified like I was blinding but
only on the left side of my body

I don't know what did to make of that but
to make the point that it's not as if

every you know it's not as if everybody is
wrong the McGillis has nothing to do with.

Fear it probably just isn't that
conscious appraisal until you ramp

up the stimulation so
much that you're probably stimulating

like neocortex wide kind
of phenomenology OK so.

The this is now all three of the studies
the rat studies and the human data plotted

on the similar scale to show not
only is that look the same but

the effects ises were so
close to one in each and Collins cones D.

that it was almost too good to be true and

maybe it is I mean maybe subsequent
experiments will pull the rug but for

now it looks as if the mechanisms of the
middle of prior to zation of declarative

memory to the extent that you can find it
through electrical stimulation look pretty

similar Now then the question is is
it that the stimulation activation of

the release of glutamate downstream in the
hippocampus triggers the hippocampus to go

into this oscillatory state of slow gamma
and that that's a good memory state and

that that promotes synaptic plasticity and
snap transmission and it's that

mechanistic thing in the hippocampus and
related structures that makes good memory.

It could be that or it could be lots
of other potential explanations and

we're trying to track that down to ask
really is it is it something akin to this

and one approach that.

Graduate student and my lab Nathan all
Graeme is following up is to use up

to genetic stimulation now we're kind
of breaking paths with what's possible

to do in parallel with the humans
at least now but when we.

Transfer gloom a target neurons in the B.

away with Channel adopts and
verify that the terminals are there in

the downstream hippocampus and then China
light and recorded both and they do and

the hippocampus one question can be
what's what's the best way to induce

oscillations in the hippocampus make
the lactation and that this is just.

Don't worry a little color.

Right it's a couple of different efforts

of picking some types of up to
genetic stimulation of the B.

a way and a control condition in which we
shine a light that's outside the spectrum

are the option that we're using And

essentially what we found is that
no matter how you pulse they may.

At least within these constraints will
happily bounce along with you the question

then is to what extent is that
optimally optimally or effectively

transmitted to downstream hippocampus and
to our surprise is actually that.

Stimulating the big at that they have
an oscillation isn't very effective in

inducing increased power in that
they range in the hippocampus.

Not much more so

than what should be the control near
infrared light but things with.

Fifty Hertz as part of
the pulse train do and and

we're moving towards trying to understand
then what what what are the kind of

more in dodging this oscillatory
interactions between the make blood and

the hippocampus to try to push
that forward to understand using.

Stimulation as a window into good
memory states in the hippocampus so.

What I'm going to do is
tell you that I'm not

going to tell you about this last thing
in that it is that we were interested in.

For humans at least when information
that was initially formed

by declarative memory one feature of that
is that it then is subsequently available

to what we often subjectively
perceive as conscious recollection.

More less theoretically described
here as post ritual monitoring and

that was an interest to us and that that
then gets us into this range of areas

of the neocortex that really
are different across species

this part very similar across
species not so much here and

so we wanted to then use Scout based E.G.
recordings and

this was done in collaboration with
my colleague Patricia Bauer and

that we did not a biographical memory
retrieval we found out oscillations like.

Bird are found and
that's why that's the first.

And that we made really neat

animations that was going to make
you go wow and that there were.

Differences between males and
females in the extent to which they did

post ritual monitoring but
you have to go to class so.

Bring this.

Here then say what I've
done is to set up something

that I haven't given you a payoff for
it's like how is it why is it and

how is it that I remember that thing
that event with my son out on the beach

a year ago and and I imply that
that's important to me and but

what I have not really said is what
is important what makes a memory

worth remembering and I think that the
answer is that that is going to differ.

And so.

I actually was going to bring
back another picture of my son to

highlight the differences across
species in terms of well to us

maybe you know that that beach thing
makes sense to remember but for

the tenrec it's like where did I find the
tasty cricket and then as searching for

my own pictures of my son I swear
I didn't make him pose for this.

It occurred to me maybe some of those
difference is even at that psychological

phenomenon logical level aren't all that
different between humans and trees fruits.

So I can tell you for sure even though
he doesn't remember Hilton Head my son

definitely remembers where to get the good
noodles at that place near Emery's campus.

But that thinking about
it there will be species

specific priorities used to
prioritize information and

that that I won't I
can't answer what makes

a memory memorable because that
is both species specific and

idiosyncratic among us what I would
have said is that there are sex affects

even within humans to influence
memorability of different memories

but I'll leave you with these two
creatures eating their food to then

say this last part here that there's
lots of when we think about the.

Neurobiology behind it this.

Evolutionary tree of of
the million neocortex

has to make the point that there's the
extreme diversification of the neocortex

across the diversification
of a million species but

that the point that keeps bringing me back
to study hippocampus dependent memory is

this point the point that at some level
at some thing that we can understand

at the network at the computational
algorithmic level that makes super super.

Porton differences for how you experience
it as a human as you experience it

as a tenor but that no biological
mechanisms should be conserved

across the million tax on and
then the question is exactly what was

did evolution stumble upon two hundred
million years ago that was so good

that in the course of the diversification
of the million tax on and then

the million new cortex every opportunity
looked at the hippocampus and said.

Looks pretty good.

I think I'll keep it there so
that idea then it's not about remembering

everything it's some compromise of
remembering what's important and

having good memory States and
poor memory States and the capacity for

other structures intervene I've talked
about the middle of today to help with

that prior to zation based upon other
things that what is intriguing to me and

what will continue to push me forward so
with two minutes

to spare I'll say they are coming and
acknowledge the folks some of you were in

the audience some of the former graduate
students whose work I talked about

that then here my collaboration's for
some of the work I talked about and

with that I'll stop and see if there are
any remaining questions and I know that

hanging out with some of you afterwards
as well but thank you very much thank.

You.

Yeah.

The question was about printers for
the electrical simulation and

that there was a condition where.

Fifty hurt and Katie hurt both were
modulating by and eight hertz.

But yeah go ahead.

So the question was did we try something
like trickle simulation pattern that did

not itself contain period in a city and
for

the electrical stimulation we did not for
the up to genetic stimulation that

I didn't show you this work we tried two
things to try to get at that question and

one was random pulses matching
the number of pulses within a second and

that was not as effective at inducing
downstream oscillations and so

that that could be that it could you can
interpret that a couple different ways

the other that we tried was
constantly lumination the B.L.

a neuron is to try to ask just if we just
get them to dump glutamate willy nilly

might just the presence of extra
glutamates from those terminals in

CA fields be enough to induce that
residence and no the answer was No but

there could be other reasons that
that was an interesting like for

example saturation of the options that but
so we

tried different things didn't have period
to city and they weren't as effective at

inducing period as city in the downstream
hippocampus So there are constraints.

Thanks for having me.