Lecture by Prof. Daniela Kaufer

*Automatic generated transcript:


I’m going to try to give you the biology 

of it that’s that’s what my lab does is 

taking those 

big ideas and trying to find the actual 


processes that are behind it so it’s 

very basic world 

but it is informed by the world and i 


this is the way to convince people that 

those things work right it’s 

uh go beyond the epidemiology and say 

and here is how that happens and here is 

how this is actual biology we’re not 

talking about 

choices we’re not talking about it’s all 

in your head 

the the lab so i’ve been at brickley now 

for about 12 years and a professor of 

neuroscience and physiology 

my lab studies uh the this process is 

across the lifespan this is 

my own teenage daughter so now i got 

very interested in teenagers and 

adolescents and their absolute ideas but 

we’re looking at from a very 

young uh we there’s a lot of work that 

we are not doing that look at in utero 

development we’re starting from the 

moment that the organism is born 

early life uh toddler years 

adolescent years in adulthood and we’ve 

now extended that and started asking 

questions about the aging brain as well 

you see that all across that spectrum 

there are trajectories and we can look 

at those trajectories and 

aging and the successful aging 

seems to also track back to a lot of 


we’re looking at social emotional and 


measures in those rats and in the mice 

sometimes we use rats sometimes mice 

depending on 

what we do rats are so much smarter than 

the mice and so 

for behavior that’s always a choice uh 

mice genetics are easier to manipulate 

so a lot of times when we’re trying to 

manipulate a specific gene 

there are models and mice that are 

easier for us to study 

and then we do take that into pathology 

and injury and we’re looking at 

traumatic brain injury 

and we’re looking at epilepsy and i want 

to say that i’m not talking about this 

today but happy to answer any questions 

about that 

um with you guys just to 

get to to not take credit for things i 

didn’t do myself this is the work of 

many many students and collaborators 

that i’m showing today and of course 

nothing can be done without the funding 

i want to start by telling you the 

biology of the stress response 

is that sitting in a day like this 

thinking about what we’re thinking today 

we’re really sort of forgetting 

possibly one very crucial part which is 

the stress response is vital 

it’s crucial you have to have a stress 

response to survive 

right so we’re not talking about the 

evil stress response let’s 

figure out how to take it away because 

if we take it away from rodents for 


the next time that the veterinary 

assistants come in and want to change 

their cages 

half of them are dead because they 

weren’t able to handle the stress of the 

cage change 

so the stress response is vital it’s 

important you have to have it to survive 

it is something that is there to help 

you in traumatic 

situation and in chronic situations and 

actually day-to-day 

so waking up in the morning there is a 

stress response we talked a lot about 

the cortisol there’s a rise in your 


every day right before you wake up and 

it’s actually responsible for the fact 

that you are 

woken up and you can go on your daily 


when it’s really elevated and it’s 

elevated across the 

uh different times and different 

responses like darlene just showed you 


you saw earlier today that’s a problem 


then we start seeing maybe troubles 

falling asleep 

maybe other troubles that we’ll talk 

about so there are 

parts to the response that are 

physiological and crucial and important 

and there are parts to the response 

where it doesn’t work as it should 

that could be detrimental you’ve heard 

already about adrenaline so adrenaline 

and adrenaline 

are right here this is the part of the 

autonomic nervous system that gets 

activated with stress 

so there’s a stress response the 

autonomic nervous system gets activated 

actually sort of shift from one mode to 

another mode 

one mode is called the the 

parasympathetic mode it’s also called 

rest and digest 

and the active mode you might know as 

fight or flight 

would be i think i actually have it here 

fight or flight would be the sympathetic 

mode everything gets activated 

everything gets ready 

to handle something for instance a lion 


gonna run after you or any other 

stressor that comes around right 

and so the whole response is there to 


the organism to deal with whatever it’s 

coming so you need that heart 

to go faster you need to breathe faster 

you need to send blood specifically 

to your muscles to your heart to your 


you kind of don’t need other things you 

may not worry about digestion right now 

so there’s a 

decrease in digestion in the enzymes and 

the intervention to it in the 

uh prayer celtic movement other things 

not really important 

maybe reproduction let’s not worry about 

reproduction right now very urgent 

things are going on 

so there’s a decrease in reproduction we 

study that in another 

part of the lab and in collaboration 

with friends of ours where we show 

that stress what are the molecular steps 

in which 

stress would inhibit reproduction on an 


life term this is very important right 

you need to not worry about reproduction 

when you’re doing something else now 

imagine this goes on for very long that 

means reproductive problems 

for a chronic stressed individual for 


within that adrenaline and noradrenaline 

that are secreted from the adrenal gland 

the adrenal gland is this little gland 

sitting on top of your kidneys you have 

one of each side 

they’re sitting on the kidneys and they 

have two types of cells one 

type of cell will release adrenaline and 

noradrenaline the other type of the cell 

would release cortisol that we heard 


and together they orchestrate the stress 


at the same time that this happens this 

is very quickly this is a neuronal 

response neurons fire and you have this 

response very quickly 

there’s a slower response that takes 


which is the endocrine response the 

endocrine response goes through this 


hpa axis that you’ve already heard today 

the term means the hypothalamus 

in the brain the pituitary 

and the adrenal gland hpa that axis 

gets activated there’s a series of 

hormones that are now released 

from the hpa there’s a hormone that 

hormone gets to the pituitary 

triggers the release of another hormone 

that hormones get released 

sent all the way across the body gets to 

the adrenal gland 

and makes the release of cortisol so 

some minutes after the stress occurred 

so immediately you’re going to see 

adrenaline shoot up 

no adrenaline showed up some minutes 

after that cortisol is going to be 


and released to the bloodstream this 

hormone cortisol released to the 

bloodstream and goes 

around and it’ll get to any cell in your 


now which are the cells that respond 

that depends on the receptor 

receptor would be the molecule the 


that is built to see that one molecule 


the right fit for that molecule so for 


we have two different receptors for 

adrenaline we have two different 


noradrenaline other receptors the cells 

that are going to respond 

to cortisol are the cells that have the 

receptor for cortisol 

turns out and then cells in our body 

have different expression of different 


if i were to look at the kidney cell a 

muscle cell 

a heart cell a brain cell they all have 

different receptors that they express 

which means this is what they’re 

responding to 

what about cortisol turns out each and 

every cell in your body 

has a receptor for cortisol some of them 

have the receptor for all three hormones 

that we’re talking about 

there isn’t a single cell that does not 

have the receptor for cortisol 

some years ago about 15 years ago one of 

our various teams colleague from 


put out a paper about a cell type that i 

will tell you about today some stem cell 

very exciting stem cell that we found in 

the brain and said this is the one cell 

that does not have a cortisol receptor 

it doesn’t res it does not at all work 

for that 

and then it turned out she wasn’t there 

there was some mistake in the way that 

she was quantifying of course the cell 

has that 

so we do not know of today a single cell 

that doesn’t and that tells you about 


widespread that response is all the 

cells in your body 

respond to a stress response to a change 

in the cortisol level 

so of course it’s going to be something 

that affects everything right it affects 

health in all those different levels 

that darlene just showed you 

because it really affects the whole 

organism every cell in us 

and as you already heard alastairs and 

allostatic load 

are important concepts in that right and 

so it’s a good response it’s an 

important response when there’s some of 


when there’s a lot of it there is wear 

and tear to the system 

in a lot of different levels and because 

every cell in our body responds to it 

we’re going to see a lot of those 

effects we’ll see immune suppression and 

reproductive suppression and digestive 


problems like ulcers stunted growth 

cardiovascular problems blood pressure 


osteoporosis metabolism diabetes 

accelerated aging on the cellular level 

right you just heard about how 

those women have an accelerated age this 

is something that you can see 

with cortisol and most importantly to 

what we’re going to talk about today 

the brain the brain is a hub of 

responses to the stress 

the brain is full of those stress 

receptors the picture that you’ve just 

seen from darlene 

is something that shows you all of those 

receptors in the brain so some areas 

have a lot of it 

some less every cell has it 

in the cortex we see a lot of the stress 

receptors in different areas and 

the most of it we see in the prefrontal 

cortex that area of the cortex that is 

important for executive decisions 

so we’re going to see impairment of 

executive function 

with exposure to stress to chronic 


to traumatic stress what that means to 

people it’ll be 

decreases in verbal calculus decision 


right take it back to the talk in the 

morning take it back to students in the 


i could argue that those are a little 

bit important for function in the 


okay there’s a exacerbated neuronal 

death following a lot of neurological 


meaning the way that your brain and your 


at the level of the cells is able to 

deal with any other 

insult that comes along is hampered so 

if a traumatic brain injury comes along 

but you’re in a chronic stress different 

outcome if 

concussions comes along a football 

player let’s say 

different outcome right epilepsy looks 


if there is a stroke for an aging 

individual on a background of chronic 


there is much greater susceptibility of 


cells to that when we look into other 

areas of the brain 

there’s that area that you looked at 

right now the hippocampus 

that area is very very enriched in in 

the glucocorticoid receptor in that 

receptor for the stress hormone 

and this is an area that is very 

important for learning and memory 

and it is much inhibited by the stress 

there’s a huge difference in stress 

there there is 

uh an impairment of memory in permanent 


and there’s increase of incidence of 

depression and psychopathologies that 

seem to be 

important involving that area 

so overall when we look at it there’s 

going to be emotional symptoms there’s 

going to be 

cognitive symptoms there’s going to be 


symptoms i’ll talk a little bit about 

those there’s social withdrawal that 

uh the chronic stress shows in our 

rodents and 

there are long-term effects long-term 

effects would be things like anxiety 


panic attacks and in its extreme 

post-traumatic stress disorder 

i don’t know if we have time to talk 

about that today but there’s a lot to 

say about that 

we could questions and answers or 


the activation of the stress response 

even in animal models even when we look 

at the rodents 

is really dependent on environment right 

so this is not 

genetics this is not a set in stone 

there is a 

stress response and it’s always going to 

look the same it depends on whether they 

were eating and drinking beforehand it 

depends on whether they have access to 

food and drink 

right after the stress response it 

depends on physical activity and 

physical activity seems to really 


stress effects you can stress a rat and 

let them then run on a 

running will and the stress effects 


so that’s a big uh difference in that 


sleep patterns are very important to 

that did they let them did they sleep 

well before do they sleep well after and 

the stress is going to be 

different their social environment 

uh social support and i’ll show you some 

data about that 

and sadly displacement of aggression if 

you stress a rat and then you put them 

in a cage and there’s a smaller rat in 

there and they can beat up on that 

smaller rat 

that is one way to ameliorate the stress 

reaction maybe not the way that any of 

us want to think about 

but that tells you that social context 

matters social support 

also does something very similar to that 

and then sense of control 

which we all sort of understand but 

imagine that for a rat 

so if a rat has a lever there and they 

press the lever 

and think that they have a control over 

the stressor 

versus a rat that has a lever presses it 

gets exactly the same amount of stress 

but they don’t control it they will show 

a physiological difference 

right there’s going to be a difference 

in the hormone 

in the neurotransmitter in the 

physiology of the brain 

if the rat has control over it 

and then having control for all of that 

there’s still individual variability 

we still see differences we can take 


sort of identical animals and give them 

the same environment 

and give them the same stressor and 

there’s going to be a range of responses 

some of them are resilient and are going 

to do just fine and some of them are 

going to show a lot of differences 

and that allows us to ask very very 

meaningful questions that 

really lets us now unpack the biology of 

how that happens 

so i’m going to give you one example for 

how we do that 

um it’s important to to explain that 

in the context of understanding brain 

development right so when we start with 

brain development 

all of our cells in the brain as an 

embryo would start being a stem cell 

the stem cell can uh differentiate into 

it it proliferates it make more of 


and then it can differentiate into being 

different types of cells 

neurons versus glia the support cell 

other cells 

and then about 50 or 70 of the cells die 

depending on which one connected and now 

you have your mature brain 

and for many many years the central 

dogma was just i’ll tell you 

this is it what you have when you’re 

born is what you’re going to have when 

you die 

except for what dies in the middle 

because you drank too much alcohol 

so it’s fixed this is the central dogma 

of neuroscience comes from this 

brilliant person who found out what was 

right for his 

time that said once development was 

ended growth and regeneration 

of dendrites dried up irrevocably the 

nerve paths 

are fixed immutable everything may die 

nothing may be regenerated optimism at 

its best 

but but 

you immediately can tell that this is 

not exactly true right the brain is 


you all know people who got stroke right 


maybe they were paralyzed or they 

couldn’t speak and then some months 

later they can do that 

when i have more time i sometimes show a 

video here of a 

friend of mine canadian friend of mine 

who has a cat 

who had a an injury and a leg was taken 


and then the cat learned to walk again 

and you can’t even tell so there’s 


there is some change in the brain where 

it adapts we learn 

we learn all the time you’re learning 

right now your brain is going to look a 

little bit different when you leave that 


because there are different connections 

that were made right so it’s very clear 

that there is plasticity 

and where does that sit in the brain we 

also know 

uh that plasticity drops across the 

lifespan and so it’s very very high 

in the beginning and across the lifespan 

it drops not a 

not not a happy thought when you’re my 

age however you see that it does not 

drop to zero 

so it continues throughout the life span 

we know that there are critical periods 

of plasticity there are times where our 

brain is 

much more susceptible to different kind 

of cues 

whoever’s working with youth will know 

that social cues are very very important 

to that age less so than they are 

beforehand right 

for instance the team brain is a little 

bit different 

lack of time we’re not going to talk 

about that now and it was mentioned 

before so i’ll 

jump into the actual now cells right 

so we’re talking about the cells where 

does that plasticity 

lie where is that so one thing is the 

connections between 

cells this is called the synapse two 

cells are connecting to one another and 

talking to one another this is a synapse 

they can change 

they can change the uh house how 

strong they talk to one another they can 

change whether there’s a 

connection there at all or not or they 


actually change completely that tree 

that that cell is the neuron is 

meaning what cells do they connect to or 


and we already know that that happens in 


so we know that given a chronic stress 

there’s going to be a difference 

in the connections between different 

cells how strong they connect to one 

another into in the hippocampus 

when you apply chronic stress there’s a 

decrease in that the 

hippocampus is not as plastic to learn 

new things 

when you apply stress we see a 

difference in the amount of those 


and even we see a difference 

in the cell morphology so that’s very 

very profound right the cells actually 

look different in the brain of a mouse 

that was stressed here 

for seven days seven days of stress and 

look at how much this 

cell shrunk and that’s in an area of the 

brain that’s critical for learning and 


and so it is clear that from that we 

will get deficits in learning in memory 

if you look at another area of the brain 

the amygdala this is an area of the 

brain that’s important for fear 

and for threat there the cells are going 

to be bigger 

so it’s not overall everything shrinks 

some areas get stronger and those are 

areas that are responsive to fear and 


that will explain to you why you might 

see a difference in the response 


but the most sort of mind-blowing thing 

of all of this to me 

was that actually this whole story about 

cells are not born in the brain that’s 

not true that’s true for most of the 

brain but there are 

pockets there are tiny little places in 

the brain 

where cells are being generated 

throughout life and one of them is the 


and we already know that the hippocampus 

is so important it’s important for 

activating the hpa axis it’s important 

for depression it’s important for 

learning from memory 

and there is a population of cells in 

that area of the brain 

that is stem cell population and 

continuously makes 

more neurons it makes more neurons and 

those neurons mature 

and it’s not a lot you can see that if 

you’re a new 

a newborn or during development there’s 

going to be 

a quarter of a million neurons that are 

born per minute 

if you’re an adult right now your brain 

is going to create something about 700 

to 1 000 neurons 

throughout today so that’s not a lot 

but they’re very important and turns out 

that they’re important for specific 


they’re very very important for pattern 

separation for 

high level for high level of learning 

for specific learning of details 

so you teach a mouse to do something 

that’s pretty simple 

they can do it without those cells you 

ask them to do something that is more 

complex there’s more details to it 

they’re not able to do that 

without those cells even though they’re 

not a lot it is very important for the 

regulation of this hpa 

axis so they’re going to play a role in 

deciding how much of a stress response 

do you have 

and they’re crucial for antidepressants 

when you give mouse antidepressant they 

do not work 

unless this population of cells is there 

and they’re important in remembering 

fear associated context 

so they put together this information 

from the amygdala and the hippocampus 

and your responses to fear involve 

the activation of those cells and then 

turns out those cells are also very 

heavily regulated they’re not always the 

same they’re things that push up 

the proliferation of them and things 

that push down they’re pushed up by 

environmental enrichment 

by learning right just think back about 

the amount of words that somebody is 

exposed to the amount of 

environmental complexity how complex is 

your environment the more complex the 

more of those neurons you’re going to 


sitting here today you’re going to leave 

with more neurons and they’ll survive 


because you learned something today 

versus if you were to sit in your home 

and watch tv 

physical exercise changes that right so 

physical exercise is a very very strong 

inducer of that 

every time you have a physical exercise 

you see more of those cells born you see 

more of those cells survive and as i 

said antidepressants push that up 

what pushes it down aging not a lot that 

we could do about that 

jet lag maybe we can do something about 

that but not a lot 

stress and glucocorticoids this stress 

hormone cortisol 

are very important for that they are 

depressors of that 

is all stress the same is it always 

being exposed to stress something 

that is stressful well i’m gonna say no 

this is one example that i might not 

have time to talk about right now 

so we’ll put it to the side but just say 

social environment 

super important we see some up 

regulation with stress with a moderate 


and a down regulation with chronic 

stress so but 

let’s put this aside for a minute those 


that we’re talking about those 

proliferating cells turns out 

we found out that acute stress moderate 

stress some amount of stress 

actually pushes up the generation of 

them it pushes up the generation and 

more so it pushes up 

the activation of them and the 


interfere learning and so with some 

amount of stress 

you’re actually doing better this 

moderate stress pushes you to do better 

the data that i didn’t show you the 

moderate stress pushes you to seek 

social support 

there’s a difference in a hormone in 

your brain called oxytocin that pushes 

you to seek social support 

that makes you remember better the fear 

and learn better 

later on but when that stress becomes 

too much 

then we see a decrease in those things 

what we also were able to show is that 

that pushes those cells 

to create another line of cells so again 

i’ll glance over the details but just 

tell you 

that that change that we found 

we could show the same thing in humans 

and in stress rats 

and that explains a lot of the 

individual variability that tells us 

when we look at a population there’s 

going to be individual 

variability and the more of that change 

that we see the more of the cells that 

are pushed away 

in making this other line of cells and 

creating myelin 

the more humans are showing ptsd 

symptoms the more rats are showing 

anxiety a composite of anxiety 

symptoms so starting to understand 

where resilience comes from and why 

giving the exposure to trauma some 

individuals will do well and some not 

we’re at the beginning of those 

understanding we really don’t know 

enough about that 

but it starts to give us a clue one of 

the clue that we found was in 

collaboration with darlene looking at 


rats that you just heard about the 

hylikin and grooming the low ligand and 


what happens to those neurons in those 

brains this is one of the biggest 

differences that we’ve ever observed in 

animals right so we’re looking here 

at the high liquid and the low ligament 

everything that’s different is the 

amount of maternal care that they got in 

the beginning 

and this is an enormous difference right 

and that enormous difference in the 

proliferation of the stem cells 

in the proliferation of those cells that 

create myelin in the amount of myelin 

that we’re seeing 

sort of can explain now trajectories and 

individual variability that follows them 

the rest of their life 

we’re looking here at adult mice that 


different amounts of maternal care and 

are showing profoundly different brains 

at the end of it that are going to be 

much more vulnerable or much more 

resilient to stress 

later on in life so we’re now 

at the point in in this project where 

we’re working together 

to ask questions about mechanism to look 

at what are the hormones what are the 

neurotransmitters what is the 

connectivity what is the network 

process that explains those differences 

in social that i didn’t show you today 

some of the work on cognitive that i’m 

showing today 

anxiety behavior and 

trying to and even put that to get 

towards the the data that we have about 

traumatic brain injury and concussions 

and see how that can explain those 


variabilities it is something that i 


is sort of optimistic in the world of 

that very pessimistic 

neurobiology of stress story right so we 

understand the biology of it and the 

biology of it is pretty depressing that 

means there 

are physiological mechanisms there are 

things that would happen and we can’t do 

much with it 

but the knowledge to me is very powerful 

but it also says that there’s a lot of 


and it also says that there’s a lot of 

context that we can provide 

to then change that and maybe we get to 

the point with that understanding at 


future future uh aim 

where we even know how to change that 

when we know 

who’s more vulnerable and how do we 

switch them on to the trajectory 

of resilience some things that one can 

take from that 

is there our literature to show that 

those types of 

interventions work we know that 

mindfulness works we know that physical 

exercise works 

we know that positive outlook and 

gratitude look works we know that 

control and sense of control work 

and sense of control that’s an 

interesting one right because it could 

be perceived control it could be tools 

to to to decide where your control is in 

the situation 

but a lot of those are tools that we can 

give the people that you guys are 

actually working with 

okay so i’ll end here thank you 


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