myAir scienceStress

Stress & Brain Plasticity – Prof. Daniela Kaufer

Lecture by Prof. Daniela Kaufer

*Automatic generated transcript:

We’re going to talk about 

plasticity and brain plasticity 

specifically 

and this is what my lab studies we look 

at the neurobiology of plasticity the 

ability of the brain to respond to 

different things around it to change 

according to what’s happening around it 

and we do that in several levels 

of measurements several levels of 

analysis we look at the genomic level at gene 

expression changes 

at neural circuits network level of 

plasticity in the brain 

we look at physiology we use a tool 

called optogenetics that 

changes uh or lets us activate and 

deactivate specific 

neurons we look at behavior we look at 

learning we look at memory 

so we integrate a lot of different 

levels of analysis from molecular to 

physiology to system level to behavior to answer 

our questions 

we also do that across the life span 

you’ll see some of that today we’re not 

going to talk about everything that we 

do in the lab 

but we start from very early on in life 

we actually have a newer project that 

also i won’t talk about but you’re 

very welcome to ask me about we were 

looking even at the 

preconception stress what happens when 

the stress happens in the 

parents before the conception even 

happened and then what happens in stress 

that’s 

early on in life what happens with 

stress is during your adolescent years 

during puberty turns out this is a very 

critical period 

for brain development what happens in 

adulthood and what happens in aging 

how is all of that different in aging 

and i won’t get to all of that today 

but we’ll talk a little bit about 

somewhere around here 

when we’re thinking about stress effects 

and about plasticity and about how the 

brain responds to things we’re also 

thinking about 

the context the environment the social 

interactions that goes on the learning 

uh the memory the how complex the 

environment is all of those things play 

a role in that 

and there’s another project that i won’t 

really get into today 

but tell you that we’re doing in the lab 

which is looking at 

pathology is plasticity always good is 

more plasticity always the best thing 

that you can have and the answer is no 

because sometimes when you have 

hyperplasticity 

there’s that much changes in the brain 

we’re following 

a process that’s called epileptogenesis 

how epilepsy 

develops we’re looking at traumatic 

brain injury or stroke 

and looking at the plasticity that 

follows that all the way 

to how we actually get to an epileptic 

brain 

so not always the more the better 

within all of that we’re focusing on 

stem cells in the brain and i’ll tell 

you a lot about them and this is how we 

are connected to the serm program 

and so we’ll focus on one aspect of the 

work in the lab today and feel free to 

ask about anything else that’s interest 

of you 

i really have to start by mentioning the 

people that actually do the work 

the graduate students and the postdocs 

in the lab in a list 

of many many many undergrads that i 

can’t list here 

those are the people that work in my lab 

currently 

and in the last few years that are 

involved in the project that i’ll show 

you today and you’ll see their names and 

pictures as we come 

specific uh data sets uh 

very thankful for funding agencies that 

let us do it 

and a lot of good collaborators from 

from uc berkeley from stanford and from 

around the world right 

so why do we even look at stress why is 

it interesting 

and i think that’s sort of inherently 

interesting to almost everyone 

so let’s see do you have any personal 

connection to that 

how many of you have used the term 

stress let’s say in the past 24 or 48 

hours 

okay and i’m among you 

and it wasn’t just when i was teaching 

my neurobiology of stress course this 

morning 

it was really a personal thing what did 

you mean by it 

somebody willing to say what was 

stressed to them or how do you 

yep 

i was actually reading right before i 

came here i was reading something about 

how 

whether homework is important or not it 

was a good 

yeah i agree but all right so that’s one 

stressor 

anybody else that is willing to say 

yeah you’re not knowing how to do 

something i know i’ve been taught 

and i’m not understanding and like yeah 

stressing out about that 

i don’t know how to do this i don’t 

understand how to learn the information 

correctly 

yep totally relate to that 

any others 

sorry 

yeah yeah i have a grand deadline coming 

next week i can’t tell you how much i 

feel 

your pain and somebody else was 

answering oh 

we had a kid in the term returns this 

week 

yeah the terms okay 

so sort of common to what everything 

that we’re talking about is 

psychological stress 

right so those are things that we’re 

worrying about those are not 

physical stressors when we think about 

stress and we move to the animal kingdom 

a lot of the things that 

are stressed to us will say a zebra 

that’s running away from a lion 

right the difference here is pretty big 

and the difference between this that we 

have to deal with at the moment and 

something that’s 

chronically worrying us we think about 

it ruminate about it we sit there at 

night and we think about this deadline 

coming up or the midterm that’s tomorrow 

or the homework that i didn’t get in 

time that’s a big difference 

and that’s where a lot of those 

differential 

responses that could be very helpful on 

the short term 

but maybe detrimental on the long term 

come into play 

so basically what i’m saying is that 

stress response is actually a good thing 

right the last thing that i want you to 

take out of this lecture is that stress 

is bad for you 

stress is really good for you stress 

response being able to respond to a 

stressor around us 

that’s actually crucial if we take that 

away from an animal 

they will die with the first thing that 

goes wrong if we take this uh we can 

take away part of the stress response 

system from a rodent and the first time 

that the cage is changed they’re going 

to die 

because they’re unable to deal with that 

little stressor even 

right so the stress response is crucial 

and it what’s let you survive 

through some kind of a threat in the 

environment and what it 

um mobilizes is this fight-or-flight 

response 

so if you are a zebra and a lion comes 

after you you definitely want to have a 

stress response there in place 

to be able to deal with that situation 

and maybe actually run away from it 

there are two systems in the body that 

are involved in that response and 

mobilizing that response 

one is the autonomic nervous system the 

autonomic nervous system sort of has you 

can think about it as two modes 

one mode would be rest and digest 

everything’s fine i can just 

take care of rebuilding my systems 

digesting my food investing in the 

immune system 

investing in the reproductive system 

everything’s chill or fight or flight 

it’s a very alarming situation 

all of the resources that i have have to 

go right now 

into surviving the situation nothing 

else is important 

this is done through activation of two 

modes of the 

of the autonomic nervous system called 

the parasympathetic or the sympathetic 

node so under stress there’s going to be 

a sympathetic drive 

and all of this energy is going to go 

into being 

very alert very much in the moment 

shuttling all the energy that you have 

putting glucose into the bloodstream 

putting the muscles in the heart and 

everything can work so that you 

run away from the situation 

the other system that comes into play is 

the endocrine system 

your hormone secretion system and that 

activates the system that’s called the 

hpa axis the hypothalamus 

pituitary adrenal axis what is this 

system the hypothalamus is this 

nucleus in the brain it’s a center in 

the brain that is responsible 

for controlling the secretion of a lot 

of hormones 

it starts by secreting the first hormone 

in that 

uh in that chain it’s called crh 

once this is secreted it activates 

another part 

which is the pituitary the pituitary 

sort of this neuroendocrine gland that’s 

dangling right beneath the brain 

and that has a second hormone that’s 

activated now this is called acth this 

hormone goes out 

to the general circulation it’s in the 

blood 

it activates a lot of different places 

and one of the places 

is your adrenal glands your adrenal 

glands sit on top of your kidneys 

and they produce two things adrenaline 

and this hormone called cortisol 

which is the stress hormone that we all 

think about when we think of a stress 

hormone 

so now in response to all of this 

activation we will have cortisol 

that’s rising in our blood in our 

circulation 

and goes around all of the body and the 

brain it actually goes 

and passes into the brain and activates 

everywhere that has a receptor for it 

and here lies one of the key 

points every cell in your body have a 

receptor for that 

so there are two receptors that can see 

cortisol they’re called glucocorticoid 

receptor mineralocorticoid receptor 

every cell in our body have at least one 

of those a lot of them have 

two of those receptors and so every 

system in our body responds to stress 

because they have the right receptor to 

see it 

the stress response physiology is such 

that is going to allow you to do the 

fight-or-flight response 

and at the same time suppress 

non-vital functions so we’re going to 

see 

things like mobilizing energy 

mobilizing increasing blood pressure 

increasing ventilation increasing heart 

rate 

immune suppression reproductive 

suppression not really vital 

right you don’t know that you’re going 

to survive the next hour you’re not 

planning 

to mate and generate the next generation 

digestive tract again you’re not going 

to really worry about digesting your 

breakfast if you don’t know you’re 

surviving the next hour so not really 

vital 

cardiovascular when it works that hard 

it’s great 

in the moment but chronically we’re 

going to start seeing all of those 

effects build up right so chronically if 

our cardiovascular system is 

all the time activated there’s going to 

be wear and tear of it 

chronically if we have immune 

suppression that’s a problem chronically 

if we have reproductive suppression 

that’s a problem 

all of these things metabolism right at 

the moment it’s great that we have 

all this glucose that’s running through 

our body and can get into the brain into 

the muscle 

and help everything work but long term 

all this glucose into the circulation 

that’s actually called diabetes 

so all of those things happen with 

chronic stress and that’s an important 

distinction right with acute stress is 

something that’s helpful 

chronic severe stress maybe not so much 

all of the psychological stress that 

we’re mentioning is sort of this chronic 

stress a lot of it is 

worrying a lot of it is not an actual 

threat to our life 

but interestingly the response is just 

the same so it doesn’t need to be 

happening it’s enough that you’re 

thinking and getting and that’s 

mobilizing a stress response what 

happens in the brain 

we talked about all this peripheral 

stuff what happens in the brain at the 

same time 

when we’re thinking about exposure to 

chronic stress in the brain level 

we see a lot of areas of the brain that 

are activated by stress 

as i said every cell every neuron every 

other cell in the brain has the right 

receptors to see those enzymes 

to see those hormones definitely for 

cortisol but also for the hormones that 

come before 

that the crh and the acth and all of 

them have effects 

we see very high density of those 

receptors 

in several key brain areas one is called 

the hippocampus that’s the brain area 

that is involved in learning and memory 

it also is involved in regulating this 

hpa axis 

so mobilizing the stress response itself 

is controlled by this area of the 

hippocampus and that’s a very stress 

sensitive area 

a lot of receptors amygdala that’s 

another area that’s very important 

that’s sort of the fear 

emotion circuitry nucleus of the brain 

and there’s a lot of 

uh responsiveness to stress over there 

and the frontal lobe the prefrontal 

cortex 

for particularly have a lot of the 

stress receptors 

and is vulnerable to stress what we see 

sort of follows that immediately 

there’s an effect of chronic stress on 

executive functions that sit in the 

prefrontal cortex so you’ll see things 

like verbal 

verbal abilities calculus decision 

making 

that are diminished with chronic stress 

there’s exacerbated neuronal death 

following neurological insults 

so if you just hear about you know 

stress kills cells in the brain 

that’s actually not true i can tell you 

that i tried 

for many years during my post-doc time 

to kill 

neurons with glucocorticoids and you can 

put as much as you want on them they’re 

not dying with that 

but they do become more vulnerable such 

that if a second thing is coming over 

like a seizure they’re going to die more 

readily 

in the very extreme there’s memory 

problems and in the very extreme we’ll 

see 

post-traumatic stress disorder so 

complete 

reorganization if you want of the stress 

activity in the brain 

limbic system that are activated are the 

amygdala and the hippocampus that we 

just mentioned 

and we know that stress impairs memory 

and increases the incidence of 

depression 

in psychopathologies 

and i’ll tell you that that’s part of 

the story but that’s not all the story 

right this is not exactly the more the 

worse 

so the more stress that you have the 

worse that the outcome is 

because if you look at cognitive 

functions 

and you’re looking at stress level or 

this could be cortisol level 

this is not a linear line there’s 

actually this 

optimum and the optimum is a little bit 

of stress so a little bit of stress is 

actually something that boosts up 

cognitive function 

and we all sort of know that we didn’t 

really know what would be the molecular 

mechanism for that that’s one of the 

things that we set up to 

to look at can we find what’s the 

molecular mechanism for it 

but then too much is what’s going to 

drive you into poor performance poor 

cognitive 

uh decision making so on 

so when we set up to look at it we said 

let’s zoom in and start looking at the 

molecular level 

and figure out if we can find actual 

molecules actual cells 

that are changing and that are causing 

those gross 

uh physiological uh circuit level 

changes that we’re seeing that people 

are reporting 

so the the shortest primary that one can 

have on the brain 

is there different kinds of cells in the 

brain the cells that get all the 

attention and i would tell you that i 

don’t think 

for the right reason are neurons right 

so neurons are the important ones 

they’re the ones that transmit 

electrical pulses and therefore they’re 

the one 

that create all this activity that we’re 

very interested in 

to do that to to to be able to 

send electrical pulses which is the way 

that neurons talk to one another 

they connect over places where they 

touch each other those are called 

synapses 

and the pulses are sent along uh 

processes 

and the processes have to have some kind 

of insulation around them 

like an electrical wire does this 

insulation is called in the brain 

myelin or we also call it a lot of time 

white matter gray matter would be where 

the cell body is and this processes in 

the myelin around it would be the white 

matter 

and they are created by another cell 

so if this is sort of a cartoon of what 

the brain 

might be there’s your neuron here the 

neuron has a rounded the myelin this 

purple cell is the oligodendrocyte that 

cell creates the myelin 

secretes it and put this insulation 

around the neuron so they can send 

the information properly and there’s 

another kind of cell 

called the astrocytes which were not 

thought to be very important they were 

like support cells glue cells they’re 

around to sort of keep the the brain 

working 

we didn’t really know what they were 

doing the more 

research is looking at them the more we 

think they’re super important 

um the this project that i’m not going 

to talk a lot about today the epilepsy 

this is uh this was one of those 

breakthrough moments for me where it 

became very evident that it’s the 

astrocytes 

that are making all the decisions and 

this isn’t a 

disease that is all about electrical 

information 

right so it’s epilepsy is about seizures 

is about 

the way neurons are firing together but 

the real mind behind it the real 

programmer is the astrocytes and 

more and more we see that they play a 

very important role there’s also 

microglia which is sort of the 

um resident 

immune system of the brain it’s the 

private immune system that the brain has 

and again we’re finding out more and 

more along the time that they play a 

role in other things as well even 

learning in memory 

and so on when the brain 

develops we start with a series of 

divisions of stem cells 

so during embryogenesis there’s a series 

of divisions 

stem cells that are making decisions 

along the way they decide whether 

they’re going to become 

neurons or astrocytes or 

oligodendrocytes 

they terminally differentiate they 

migrate to the right place they 

make all the right processes and 

then start making those connections the 

synaptic connections between them 

and finally you’ll get this mature brain 

about 50 to 70 percent of the neurons 

will actually go program 

cell death so there’s generation of more 

than we actually need 

and then whatever is not connected and 

wired right will 

die off right and then those mature 

neurons are post mitotic 

meaning once the neurons became what 

they’re going to be 

they do not go through divisions anymore 

right so a neuron can’t make more of 

itself you have to have stem cells 

there’s the central dogma of 

neuroscience which was 

different from anywhere else in the 

brain and was 

was something that sort of was set in 

stone if you wish by 

uh ramoni kahal many years ago but all 

of us that 

went through studies in their up until 

maybe the 90s 

learned that as the central dogma of 

neuroscience we were told 

that you’re born with a set amount of 

neurons and from that moment on they can 

only die 

but you never get new neurons because 

you don’t have any more stem cells in 

the brain 

you you only have the neurons that you 

have and they’re gonna 

die or if you use them if you you know 

maybe they’ll die 

less if you drink alcohol maybe they’ll 

die more 

but basically you have what you have and 

now you go throughout life diminishing 

the amount 

of neurons there’s nothing that is 

regenerated in the brain so he said 

everything may die 

nothing may be regenerated really gloom 

idea right 

now consider this i want to show you a 

movie right 

we’ll take a break for a minute and 

watch this lovely cat 

think youtube um 

this is the cat of a friend of mine 

brian kolb he lives in canada he has a 

farm 

and he showed me this movie the cat lost 

a leg to some wild animal 

and you could see that he had difficulty 

walking around 

right and this is in august the same cat 

in november 

much more optimistic story right 

so i was very happy for brian and his 

cat but what that 

really made me think about is plasticity 

second movie 

you can’t even if you do not know that 

the cat is missing a leg you won’t be 

able to tell there’s a huge difference 

right 

there had to be a remapping of a lot of 

cortical areas that control movement to 

to move from that to that right there 

has to be a lot of plasticity to allow 

that level 

of of change and that regeneration 

this happens in stroke we all know 

people who had stroke there is some 

regeneration after that there’s also 

things like learning right we learn new 

things 

there must be some plasticity that 

controls that 

and so what are the different levels 

that we can think about plasticity 

there’s differences in synaptic strength 

the actual connection between new 

neurons the strength 

of transmission could be different 

there’s synaptic remodeling there could 

be 

synapses that come up or go away 

and this is an example from an exposure 

to a stressor 

you look at this neuron in the 

hippocampus and you see that it lost a 

lot of its synapses a lot of those 

little boutons are lost between one and 

two and that’s another level of 

plasticity there’s synaptic 

remodeling there’s dendritic remodeling 

if you look at those neurons a and b 

also from the hippie campus you see that 

the control one has this big branch tree 

and it’s losing it after stress and i 

will tell you that more than that 

in a fairly young brain you will also 

see regeneration of that 

right so if we wait another month and 

that subject 

uh now recuperated from the stress 

there will be regrowth of that so that’s 

a lot of plasticity 

right if you go to a more aged brain 

there might be not as much plasticity 

but the most extreme of all is to think 

that there might be cell remodeling 

maybe there’s cells that are dying that 

will fit with ramoni cacao 

but maybe there’s cells that are getting 

added to the circuit and that’s 

completely against the central dogma of 

neuroscience 

and turns out that there is there 

actually is plasticity on the level of 

the cells there are stem cells 

in the brain they were discovered in uh 

in the brains of songbirds 

that learn a new song every season it 

was uh discovered by 

fernando notabum at princeton university 

and he 

showed that this depends on the 

generation of new neurons 

right so actually those songbirds they 

learn a song 

and there’s a nucleus in the brain that 

grows with learning the song there’s all 

these new neurons that learn the song 

at the end of the season the thing dies 

completely 

and disappears all those neurons die 

come the next season they grow again 

this neuron population 

and learn another song 

and when he it thing people thought it 

was very interesting but then said you 

know this has nothing to do with the 

mammalian system 

uh definitely if it’s in mammalian 

system it wouldn’t have to do anything 

with a primate brain those are birds 

they’re really different 

long story short 20 years later we know 

that there are two areas of the brain 

actually in mammalian systems in primate 

system 

in human brains that generate new 

neurons there are two pockets 

at least two pockets that we all agree 

on there’s other pockets 

or other little populations that 

the community is still out debating 

whether they exist or not but those two 

places everybody agree that occurs 

there is the ventricles right around the 

ventricles 

there’s a population of stem cells that 

continuously makes new neurons 

that go into the olfactory bulb and make 

olfactory neurons 

and only olfactory neurons in a normal 

brain 

this is one place we’re not going to 

talk about that today 

what we’re going to talk about is the 

hippocampus this area that’s important 

for stress and for learning in memory 

and controlling the hpa axis 

that area within the epicampus there’s 

one subfield of the hippie campus called 

the dente gyrus 

one subfield of the dental gyrus called 

the subgranular zone 

where we see stem cells that 

continuously divide 

make more of themselves and also are 

able 

to make cells that make the decision 

whether they’re neurons or glia 

they make those neurons that then mature 

over several weeks make the right 

projections 

and after four six eight weeks they look 

indistinguishable from their neighbors 

we can’t tell anymore that they were new 

newly added to the brain that they’re 

newborn neurons and there’s not a lot of 

them 

but there’s enough of them that we now 

know that they’re very important 

once those are mature they express 

mature neuronal markers that display the 

morphology 

of the cells around them so we really 

can’t tell them apart 

start making those connections and 

receive information and send information 

just as you would expect from any other 

neuron 

interestingly in their maturation 

there’s this 

point in time maybe two three weeks in 

time that they’re immature 

and they’re hyper excitable and that’s 

what makes them so important this is why 

they play such important role in 

learning 

in memory in um in making a difference 

while you 

have not that many of them 

just to give you sort of an idea of 

numbers if you look at humans 

during embryogenesis during development 

between five weeks and five months of 

the pregnancy there’s about 

a quarter of a millions of neurons that 

are born per minute 

right in the adult human brain we’re 

talking about maybe 700 neurons per day 

okay so this is a low rate of generation 

but functionally they are very important 

now again 

just as in development about fifty 

percent of them 

will die within four weeks so most of 

them are born and immediately dead 

however if they’re activated then they 

will survive so 

this is sort of a use it lose it kind of 

situation if you don’t use it 

you’re going to lose it if you use them 

and they’re integrated into the 

circuitry and they get the right 

activation pattern then they will stay 

more you can look at 

animals and follow those newborn neurons 

in situations where you’re 

increasing the need for them like a very 

complex environment and much more of 

them will survive maybe 70 percent of 

them 

will survive now we know that they’re 

very important because we could 

actually ablate them we could delete 

this population we could do that 

pharmacologically with a drug 

or we can irradiate the brain as you 

would like cancer cells proliferating 

cells will die with the radiation those 

cells will die with the radiation 

or you can do a genetic trick to somehow 

only 

manipulate those cells and all of those 

things were done 

and we know that when you do that you 

lose certain types of hippocampal 

dependent memory 

so things that are the hippocampus plays 

a big role 

in learning or in remembering you need 

those cells for it we also know that the 

hpa axis that stress axis is 

acts differently when those cells are 

missing so they’re very important 

for controlling the stress axis and 

we know that when you eliminate them you 

don’t get 

the effects of antidepressants so it’s 

not to say that they’re specifically 

involved in depression 

but antidepressants works through them 

when you administer antidepressants to 

an animal you get more 

generation of those cells and when you 

eliminate those cells 

antidepressants don’t work on those 

animals it’s sort of interesting because 

it 

it may provide an answer to why 

antidepressants take so long to work 

it’s sort of a just so 

story it’s not something that we know 

scientifically but 

there’s always a mystery about 

antidepressants when you give them to 

people 

they don’t start acting right away 

there’s a three to four week 

delay and it doesn’t really make sense 

because what 

we’re told that they do is that they 

increase the level of serotonin in the 

synapse that’s something that will 

happen within 

minutes to hours yet the effect takes 

three to four weeks 

right what does take three to four weeks 

is the maturation of those cells 

so just a correlation but an interesting 

one 

when you look at the activation of those 

immature neurons there are 

times that they’re selectively activated 

that we see more of them being activated 

in a specific environment for instance 

if it’s a very complex environment that 

we’re exposing the animal to 

you’ll see more of those cells being 

activated 

in very taxing complex learning 

situation 

like pattern discrimination we will see 

activation of those cells 

right so think about this for example 

let’s say that there was a maze in the 

middle of this room 

and i’m asking you to find a treat this 

is a fruit loop 

the rats really like fruit loops you can 

imagine that’s actually fantastic 

chocolate 

that you’re trying to remember where i 

hid from you and in this situation it’s 

either here or 

at the other end of the room those two 

ends of the room look very different 

from one another 

the rats can do that with or without 

those cells ablate all of those cells 

they still remember how to find the 

fruit loops if they’re they’re there 

we do the same thing and those are in 

these two arms so now it’s going to be 

either 

here or here now i need to remember 

many more details to be able to 

discriminate between this and this 

and this is something that you can’t do 

without those newborn neurons 

so the more taxing the more fine-tuning 

is where you need those those cells 

here’s another example for pattern 

discrimination if i’m asking you to look 

at this 

remember this remember the details of 

that 

and now i’m going to give you number g 

and ask 

is that the same or not if you have 

really really 

fine details then you’re able to say 

that this object here 

is not like that right corner object 

over there 

but if you remember that in sort of 

vague details 

then it’s very hard to discriminate 

between those two 

right so that’s where we see activation 

of those cells 

we also see activation of those cells in 

remembering fear 

uh context where the activation is 

actually dependent 

on input from the amygdala from that 

fear area of the brain 

right so when we put the animals in a in 

an environment where they give them a 

little shock 

and then we test them afterwards and see 

whether we get activation of those cells 

and they remember that the environment 

was 

frightening they do that with 

super activating of those newborn cells 

that respond or sort of put together 

information from the hippocampus that 

tells us about spatial memory 

and the amygdala that tells us this was 

a scary place there was an emotional 

valence to that place 

if we take away the amygdala we don’t 

see this hyperactivation anymore 

those cells are also very much regulated 

by factors 

environmental enrichment complex 

environments learning situation 

increases the proliferation of those 

cells physical exercise 

running on a treadmill 

boosts the proliferation of those cells 

antidepressants i said 

um there’s a paper that shows uh 

that sexual activity can boost that it’s 

actually an 

interesting one both sex and physical 

exercise are one 

that where we see increase of the stress 

hormones 

yet it pushes us up but when we have 

stress 

and an increase of that stress hormone 

it pushes it down right so it’s context 

dependent so when it’s stress 

that is somehow something that you 

choose or that you have some reward with 

like physical exercise 

or sexual activity it boosts the 

proliferation of those cells 

and if it’s something that’s stressful 

or negative then you have a decrease 

interestingly enough somebody actually 

did the 

the pe experiment where you said 

physical exercise but we’re gonna make 

you do the physical exercise 

you put a little treadmill and the rat 

has to run on that treadmill 

and then you don’t have the 

proliferation you actually have a 

decrease 

right so you really do have to have some 

kind of reward that comes with it 

so stress is something that pushes it 

down chronic stress 

aging jet lag as well 

and we wanted to ask what’s the 

mechanism for that how does stress 

do that to those cells what is the 

molecular mechanism 

those are graduate students 

sundry and erin in a postdoc cherishment 

who worked on this project along the 

years 

asking the question of where does stress 

and glucocorticoid or cortisol the 

stress hormone 

work on that axis interestingly enough 

it could be anywhere right it could be 

the proliferation of those stem cells 

how many more of themselves can they 

make 

it could be how much they’re 

differentiating into 

neurons or astrocytes or 

oligodendrocytes 

i’ll tell you that about 95 of the cells 

make neurons 

in a regular situation or it could be 

the survival of those cells that are 

born 

and the answer was sort of everything 

right so there’s 

a lot of different levels in which it 

did it which did those effects 

one of the first things we saw that 

chronic stress 

decreases the proliferation of those 

cells they make less of themselves 

and they make less neurons and that 

followed a lot of literature there’s a 

lot of other people that showed that and 

knew 

that you start seeing less of this 

newborn neuron 

with stress but what was really 

surprising to us 

is that at the same time we started 

seeing an increase in oligodendrocytes 

it actually pushed the cells and we 

showed the transcriptional reprogramming 

of those cells 

to become oligodendrocytes that’s 

surprising like why would you get more 

oligodendrocytes 

in that little area of the hippocampus 

we had to actually see that those were 

the cells that are doing it 

right how do we know that it’s that stem 

cell that is becoming more 

oligodendrocytes maybe it’s something 

else maybe those are 

dendrites are coming from somewhere else 

and so we did that 

in two ways one was we said let’s 

lineage trace those cells we could 

actually put a genetic marker into those 

cells they’re going to 

rest in yellow and now we’re going to 

follow their fate 

and if we’re correct then we should get 

yellow oligodendrocytes and we did we 

would get more oligodendrocytes if the 

animal was exposed to stress 

or to cortisol so cortisol actually 

pushed away those cells that would 

become 95 percent of them will become 

neuron and now 

many more of them would become actually 

algodendrocytes the other way to ask 

that is to say we could actually take 

those cells out of the brain those stem 

cells and we can culture them in a dish 

and throw the stress hormone on them and 

see what happens 

and when we do that we get a decrease in 

the amount of neurons that they’re 

producing and an increase in the amount 

of oligodendrocytes that we’re 

generating in that dish 

we then moved on to do a lot of work on 

asking what’s the molecular mechanism 

what’s the transcriptional programming 

that they go through and show that 

they’re changing their fate 

at the end of it what we really wanted 

to know is what does it mean 

what does it mean to have a little more 

oligodendrocytes in your 

adult hippocampus and we said what that 

means 

to us is that you’re going to have an 

increased capacity to produce myelin so 

you’re going to have more myelin 

in your hippocampus and he said 

does that even ring a bell you know we 

went to the literature and said do we 

see anything like that 

when you go to the literature you see 

that it turns out that there are changes 

in white matter 

or in myelin in a lot of different 

ways now nobody’s looked specifically at 

the hippocampus but when you’re looking 

at other brain areas people said there 

are 

changes that come in depression in 

schizophrenia maybe adhd 

and early life stress is associated with 

vulnerability to mental illness and 

changes in white matter 

so we decided to look at the human brain 

we are not able as as of yet to look for 

those stem cells in the human brain 

there’s no marker for them we 

need to have a way to to actually have 

the brain so there’s some postmortem 

work but we can’t look at them 

during but what we can look at is myelin 

we can image myelin with mri 

and we did that in collaboration with uh 

ucsf colleagues 

tom nieland and linda ciao and they 

looked at a very specific population 

they took veterans that were exposed to 

trauma and they said let’s look at 

uh veterans that had were exposed to no 

trauma 

veterans that were exposed to trauma and 

did not 

develop post-traumatic stress disorder 

and veterans that were exposed to trauma 

and developed post-traumatic stress 

disorder and what we saw 

is that just as we would predict from 

the animal studies from the my studies 

you get an increase in myelin 

specifically in the hippocampus 

so where you wouldn’t expect it to be 

basically 

which made us feel sort are very secure 

in in 

in continuing to ask those questions and 

thinking that they might actually 

have a clinical significance to come 

with them 

and so we know that they might play a 

role those cells play a role in 

emotional memory we know that that 

is very much changed in post-traumatic 

stress disorder and we know 

that uh those cells play a role in that 

so the next thing that we wanted to 

use the system for is to ask might that 

be the link 

for sort of a trajectory if you have an 

early life environment 

that changes the way that those stem 

cells in the brain behave in the 

hippocampus 

could that be sort of what puts you on a 

trajectory for resilience 

versus a trajectory for vulnerability to 

mental illness 

that might come later on in life 

and to do that we used an interesting 

model 

of early life environment we actually 

did not manipulate anything 

but we recorded the behavior of 

rat mothers and this is not this is 

following a lot of work in the 

literature starting from michael 

meaney’s lab 

in montreal and darlene francis here at 

berkeley 

that we’re showing that when you look at 

a population 

moms they will fall on uh some kind of a 

curvature of how much they’re licking 

and grooming 

their pups right so there would be 

some variation there are some moms that 

are really overlooking and grooming and 

do 

you know play a lot with the rats some 

that are very neglectful if we take the 

two extremes this purple work 

group and this green group the very high 

liquid and grooming the very low ligand 

and grooming 

and we compare them to one another 

they’re big differences between them 

there’s differences in the stress 

reactivity the low ligand and grooming 

one are much more stress reactive 

they’re much more anxious 

they don’t do as well cognitively their 

hpa access is over 

activated and they have less 

glucocorticoid receptors in the 

hippocampus 

and that was shown to be epigenetically 

mediated 

we wanted to see whether those stem 

cells in the hippocampus also look 

different in those populations 

and what we find is that very very much 

so 

so if looking at the here the 

the block ones are the low ligand and 

grooming and the checkered ones are the 

high liquid and grooming 

you can see that there’s a very very big 

difference in 

the proliferation rate and how much 

those stem cells are able 

to proliferate to make more of 

themselves there’s also a 

very big difference in how much they’re 

making neurons so the hyalic and 

grooming animals have much more 

proliferation in their brains 

in their hippocampus when we look at the 

oligodendrocytes 

we see the opposite right so actually 

the low liquid and grooming 

the ones that uh possibly are the 

neglectful mothers so maybe more stress 

in their early life 

they make more oligodendrocytes and that 

carries all the way into adulthoods 

p90 is three months old rat which is an 

adult rat 

so into adulthood those brains are very 

different in terms 

of of the proliferation of those stem 

cells and in terms of 

how much oligodendrocyte they’re making 

are they actually making more myelin and 

the answer was yes 

they’re making more myelin and they’re 

making more myelin specifically 

in hippocampal regions and not in other 

places right so they’re not really 

changing 

white matter as such in other places but 

they’re changing white matter in a 

specific area that’s very 

important for learning and memory and 

stress 

reactivity and that also carries into 

adulthood you can see that this is 

actually 

a very very uh impressive difference and 

you have to remember that we didn’t 

manipulate anything right we only 

recorded 

this natural variation in the animal 

behavior 

so this tells us something about what 

happens with chronic stress and why 

chronic stress would actually impair 

memory 

and impair cognition and all of those 

things 

but remember we started with this 

question that said 

there’s also an optimal amount of stress 

there’s some stress that actually could 

be good for you 

right so what is there a molecular 

mechanism for that can we see what 

happens to those 

cells when we have just the right amount 

of stress 

and that was done by liz kirby and david 

and sandra 

that were working on this project and 

found 

a really really interesting correlation 

in those cells so now exposing the 

animals to a very short 

brief moderate stress it’s not too much 

they’re actually they’re put in a bag 

and they’re unable to move for about 

three hours it’s not painful 

but it’s uncomfortable and 

psychologically stressful for them to be 

in that terror but that’s all three 

hours we look at them 

at the end of this three hours and we 

can see an increase 

in the proliferation of those cells we 

see an increase in 

proliferation of the cells with the 

behavior with the immobilization 

but we could also check what’s the 

amount of circulating cortisol 

or corticosteroid in the in the case of 

the rat and inject that same amount 

and we get the same thing so i can just 

inject the stress hormone for them 

to them wait three hours and i get an 

increase in proliferation of those stem 

cells 

what happens with those stem cells to 

ask this question we used um 

this fear paradigm where we’re 

habituating the animals to 

uh to the context we’re then giving them 

a very short brief 

uh foot shock again not not painful but 

sort of alarming 

the next day that you put them in the 

box we can look at their 

stress response by freezing they’re 

going to freeze in the context 

and then you can teach them that this is 

not 

a threatening context by exposing them 

again 

to the same context and you see how long 

does it take them to extinct the 

response when do they learn to not 

freeze 

in that context and we can 

try different timelines so we can test 

right away after the acute stress if we 

have increased proliferation here those 

cells are going to be too young to do 

anything so i wouldn’t 

actually guess that they should do 

anything immediately after the stress if 

i wait about two weeks 

three weeks those should be this 

hyper-excitable 

cells now there’s more of them if 

they’re so important as i told you they 

should be protective at this point right 

and this rat that has this moderate 

amount of stress 

should be protected from the second 

stressor that comes along 

and indeed that was the case right 

so when we look immediately after this 

brief stressor 

i don’t see any differences in the way 

that they learn how to extinct 

but when i look at two weeks later we 

see 

those animals that got the 

immobilization stress 

they’re protected they do better 

when we look at the activation of those 

cells we can actually mark those cells i 

know when they were born 

and i can look at activity gene that’s 

turned on in them when they’re activated 

and i see there’s hyper selective 

activation of those cells so those cells 

are 

activated during the second stressor and 

sort of participate 

in buffering this the second stressor or 

doing better with the second stressor 

so now came the question sort of can we 

find a molecular switch 

that turns this acute moderate stressor 

that’s actually beneficial for you and 

makes you do better with the second 

stretch as it comes along 

to something that becomes deleterious 

something that’s not good this is 

chronic and too much and now we have 

all this decrease in proliferation and 

increased anal dendrogenesis 

what’s the switch between those two 

and i’m not going to show you this is a 

very long molecular story but i can tell 

you 

the the two endpoints of that 

and interestingly it turned out to be 

all about the astrocytes 

turned out that who actually makes this 

switch is the astrocytes 

those astrocytes that are around the 

stem cells 

they’re very close to them they’re 

actually in very close proximity to 

those stem cells 

receive the stress signal and in the 

case of acute stress 

they secrete a molecule that’s a growth 

factor 

it’s called fgf2 and that growth factor 

goes out and activates those stem cells 

and make them proliferate more 

make them make more of themselves and 

make them more neurons and then 

those neurons are protective when this 

stress becomes 

elongated when it’s much more than that 

the astrocytes 

start doing something else our first 

guess 

was the astrocytes are going to stop 

making that after you have to and 

actually they don’t they continue to do 

that after you have two 

but somehow the stem cells stop 

responding to that 

turns out that what the astrocytes are 

doing at the same time is when that 

stress becomes very elongated they start 

depleting 

another protein so they turn down a 

protein called noggin 

and that protein regulates some pathway 

in the stem cells 

that continues their proliferation now 

it pushes them out 

of proliferative cycle and makes them 

not not go through the cycle anymore 

right 

so they stop responding to those cues 

and they’re not participating anymore in 

that whole 

game of we’re proliferate we’re not 

proliferating we’re 

just pushed out into senescence they’re 

not in the cell cycle anymore 

they don’t respond to the fgf2 and that 

explains 

also that shift so that now they start 

differentiating and they start 

differentiating in the wrong way 

because those transcription factors go 

up so there’s sort of the switch that 

occurs 

through the astrocytes 

so that was interesting we wanted to 

start asking questions 

that do more on the system level 

right so we know now how those cells 

play a role in learning and memory and 

spatial memory 

but what about the social brain right 

could that be 

um some part of it and this is work that 

was done again by liz kirby and 

sandra and i’ll talk also about work by 

uh two post docs fantastic post docs 

snooper 

minion and balbertal that are working on 

a pro-social behavior 

and the reasoning behind that was 

there’s a very close link between social 

environment and stress responses 

so first of all the social environment 

could be a very very potent stressor one 

of the most potent 

stress paradigms in animals is uh um 

something that’s called a social defeat 

and this is sort of a bullying paradigm 

you take an animal and you have a bully 

animal and a bully mouse if you want 

that comes into their cage 

and for 10 minutes is there is bigger 

than them 

he might beat them up he chases them 

really 

bullying them for this 10 minutes that’s 

not a lot right what happens for the 

next 24 hours 

is that they share the cage without 

being able to have physical contact with 

one another 

so now there’s sort of this wire mesh 

in between the two of them he can smell 

them he can hear them he can see them 

but they can’t beat him up you do that 

for 10 days you get 

now the resident mouse the one that got 

bullied 

they won’t they don’t want any social 

contact anymore whatsoever they just 

withdraw 

completely if you put them in any social 

choice kind of thing they would just go 

away they don’t want to interact they 

don’t even want to interact with 

juvenile rats that are smaller or 

juvenile mice that are smaller than them 

and don’t 

so social environment is a very very 

potent 

stressor by itself one thing but also 

stress responses themselves could be 

buffered by a positive social 

interaction 

we know that having a positive social 

interaction reduces the stress response 

in humans and in animal models 

we know that stress can actually promote 

adaptive relationships 

in humans right so if people go through 

a stressor together they would tend to 

actually 

get a stronger social bonds between them 

but on the other hand stress could also 

uh precipitate sort of psychopathologies 

that 

are characterized by social withdrawn 

like depression like post-traumatic 

stress disorder 

so on the one hand social interaction 

positive social interaction 

social affiliation could be the one 

thing that sort of helps you in buffers 

and sometimes stress will make you seek 

those but sometimes stress would 

actually make you 

withdraw completely and go towards 

social withdrawal 

and so can we can we build a model for 

that and so what liz and sandra did 

is they started putting the animals into 

this acute 

immobilization stress just as i said 

before three hours in that bag 

and say let’s look at the home cage what 

happens at the level of the home cage 

can we see 

social interactions in the natural 

environment of the animals they would go 

at night and film the cage and look at 

social interactions and what they saw 

was a lot of pro-social bonding they 

would be huddling the animals that went 

through the stressor during the day 

together would sort of huddle one with 

another 

they looked they would do more aloe 

grooming than self-grooming 

there was no aggression whatsoever other 

cages you would see some aggression you 

would see some social interactions but 

also a lot of other behaviors 

what we also saw that this acute 

immobilization stress led to 

lasting facilitation of sharing what do 

i mean by that 

if we take away the water from the cage 

for a couple of hours and then we bring 

it back there’s one water bottle now 

and the two rats are supposed to share 

it together in a control group 

they would sort of fight over it half 

the time they’re fighting nobody’s even 

drinking half the time someone is 

drinking if there’s a very strong 

hierarchy the dominant one will dominate 

and not let the other one drink so much 

when you do the stress experiment all of 

a sudden they’re sharing it beautifully 

there’s no 

fighting over it a hundred percent of 

the time it’s actually used by either 

one or the other 

there’s much less fighting over it we 

actually see them sort of push away 

the other one in a control situation but 

not after stress 

after stress they become really good at 

resource sharing 

there’s much reduced aggression 

um interestingly but the complicated 

point 

the dominance hierarchy is actually 

steeper 

i can get into that if it’s interesting 

to somebody and you want to ask about it 

at the same time what we see is that 

this acute 

immobilization stress increases a 

hormone in the brain that has to do with 

social affiliation 

oxytocin oxytocin is this uh what’s 

known as this 

love hormone now it’s much more 

complicated than that it’s actually sort 

of a hormone that 

pushes social bonds within group 

so that means you have a strong 

affiliation now with the other 

rat that went through the stress with 

you there you’re in group 

and now you’re more bonded to them 

and that comes with more oxytocin and 

more of the oxytocin receptor 

so that fits all of that human 

literature about sort of seeking support 

and having 

the social support that can buffer the 

stress response 

what happens if we do exactly the same 

thing but now we also add a context of 

odor 

so in one case we were adding peppermint 

odor 

so you’re in your little bag 

and you can’t move for three hours and 

it’s really annoying you and you’re 

smelling peppermint 

very natural very neutral there’s not 

not 

anything special about it the second 

group went through the same thing 

but the odor that we added to them was a 

fox urine 

so a predator right so now you can’t 

move and it’s kind of annoying 

but you’re also thinking that there’s a 

fox that’s right next to you and gonna 

come and eat you right away 

so the context is a little bit different 

we then run exactly the same set of 

experiments and turns out 

that in that case all of the good things 

that we saw before disappear 

there’s no more increased oxytocin 

there’s no more resource sharing there’s 

no huddling there’s no 

none of that right this was too much and 

now you don’t get that 

increase in social effects so that’s one 

way 

that we can think about sort of social 

behavior 

and how can we get those two different 

effects on this on the social world 

in baal and nupur asked an even more 

complicated question 

they actually came with this really 

ambitious idea that they want to study 

not just social behavior but they want 

to study a specific kind of social 

behavior pro-social helping behavior 

they they came in they said we want to 

study empathy the embassy in rats that 

would be interesting 

but um they convinced me 

after a while and we decided to look at 

that 

and um use 

a very interesting model that involved 

developed 

which is looking at a helping behavior 

right so this is 

now sort of an altruistic behavior this 

is a rat that will help another 

rat that’s in distress what she does is 

she puts them in a big arena 

and in that big arena one of the rats is 

going to be in a restrainer 

the other rat is running around turns 

out that the other rat will spend a lot 

of effort 

to try to release that trapped rat 

actually give them 

an hour a day over 12 days they would 

spend the hour 

circling around and trying to help and 

they learn how to open the cage door 

and they become very consistent in 

helping the rats inside 

you can try to tempt them by putting a 

chocolate restrainer there and they 

would actually 

release the rat and share the chocolate 

with the one that was in there 

so very specific 

helping behavior very motivated very 

goal oriented 

they don’t just do it if the restrainer 

is empty they don’t spend the same 

amount of time there 

so they do it because they want to or 

because there’s 

there’s this rat inside 

they don’t do it for every rat they do 

it for a cage mate so if they were 

housed together with that rat they’ll do 

it 

if it’s another rat from the same strain 

as them they’ll do it 

if you take a rat from a different 

strain 

they don’t help they actually are not 

interested they will go around 

they will not help they will help 

only who they know now what happens if 

you take that other rat from this other 

strain 

and you house them together they spend 

two weeks in the same cage then they’ll 

open 

right so now this other rat from this 

other strain become 

their in group and they make a decision 

and they help that other rat 

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