Neurobiology of Stress: Resilience, HPA Axis, Stress Hormones, Sex Differences, Early Life Stress | Rosemary Bagot | #191

About the guest: Rosemary Bagot, PhD is an Associate Professor in the Department of Psychology at McGill University and the Canada Research Chair in Behavioural Neurogenomics. Her lab studies the neurobiology of stress at the molecular, circuit, and behavioral levels.

Episode summary: Nick and Dr. Bagot discuss the hypothalamic-pituitary-adrenal (HPA) Axis, cortisol and hormonal responses to stress; neural circuits related to the perception of threats & stressors; resilience & early life stress; sex differences & individual variability in stress response; epigenetics & transgenerational effects of stress; and more.

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Rosemary Bagot 3:06

yeah, so I'm Rose Bagot. I'm an associate professor in the Department of Psychology at McGill University in Montreal, Canada. I'm also associate member of the department of psychiatry and a primary investigator in the Latimer center for neuroinformatics and mental health, and a member of the Concordia Center for Studies in behavioral neurobiology. And

Nick Jikomes 3:30

so what does your lab do in terms of you guys, study animals? Do you study humans? Are you doing molecular stuff, system stuff? Where do you kind of fall?

Rosemary Bagot 3:39

Yeah. So almost everything we do is in mice, and in terms of what we do, I'd say that broadly, we're interested in understanding the neural bases of affect and effective behavior. But as I said, we're doing this in mice, and sort of the approach that we take is starting with robust behavioral paradigms in mice, and then we use this as a foundation to explore the molecular, cellular and synaptic changes that are induced by things like chronic stress or other kinds of experiences, and to understand how That changes neural circuits to lead to changes in behavior. So we've done a lot of work looking at how chronic stress leads to changes in the brain with sort of differential emergence of susceptibility or resilience, and using this as sort of a window into understanding mechanisms of stress related disorders like depression

Nick Jikomes 4:43

and, you know, starting at a very high level. If we think about just animals, generally, little mouse, a human, whatever, just mammals, birds, like, just animals in general, we all experience stressors in life. It's just part of being a living thing. When we think about sort of the natural, healthy. The ecologically appropriate mammalian stress response. Can you just walk us through sort of the basic, the basic stress response as it should work under normal circumstances in a healthy individual? What are some of the hallmarks of

Rosemary Bagot 5:12

that? Yeah, so I'll answer that directly in a second. But I think the really first thing to say is this idea of like a normal or adaptive stress response. There is no absolute. It's it's really contextually determined. And I think that's just sort of generally an important sort of caveat to keep in mind. But in terms of like, what is the stress response at the simplest level, we can talk about the HPA axis, the thalamic pituitary adrenal axis. And so when an organism, be it sort of me joining a podcast, or a mouse in the lab, encounters some kind of stressor, so something that elicits a stress response, we get activation of the HPA axis, and this leads to release of various hormones that ultimately leads to release of cortisol in humans, corticosterone in rodents. Okay,

Nick Jikomes 6:04

so we can think of the quintessential stress response as being a measure of how much this HPA, this hypothalamic pituitary adrenal axis, gets activated. And when we say activated, we basically mean stuff is happening in that part of the brain such that a certain cocktail of hormones get released.

Rosemary Bagot 6:22

Yeah, in a sense, we can. And so this is what we mean by sort of the classical stress response. Is this HPA Axis activation. But most of what we study in my lab is you could consider it as being sort of upstream of the HPA axis. So we're interested in what's happening in sort of higher brain regions that influence how the HPA axis is being recruited. Yeah,

Nick Jikomes 6:50

yeah. So like, if I'm if I'm out in the wild and a tiger jumps out of me, my HPA axis will light up. I will have a cortisol spike and all that. But, you know, I had to have, I had to see the tiger. It had to go through my retina, get in somewhere, into my nervous system, before that stress response got elicited. And so there's sort of probably multiple things happening in parallel here, from the activation of the HPA axis itself to the object recognition and the sensory perception and

Rosemary Bagot 7:19

all that. Yeah. Yeah. And so the tiger jumping out at you in the wild is a pretty unambiguous stimulus. And so then you really want this sort of, like very acute activation, and there are sort of other systems that are responding to that as well. But a lot of what we're interested in studying is probably more in what you consider the gray areas and so how stimuli that could be threatening or maybe aren't so threatening, how that could lead to changes in behavior. So I'd say that in a sense, like the HPA axis is in the background of a lot of what we do, but it hasn't been the focus of anything I've done since back in my PhD, where we really were looking sort of more directly at HPA access regulation. We did some work that the library did my PhD. We were looking at how just very small variations in experience during the first week of life in rats. And the experience was how much they were licked by their mother, how that leads to changes in specifically how the HPA axis is regulated in response to a stressor. And we can look at sort of the time to the peak hormonal response. And then also a really critical factor in HP access function is the shutdown, because need to have this strong response to a stressor. You need to be able to mount a response. But then when that, when that threat has dissipated, you need to be able to come back to baseline, yeah, yeah. And

Nick Jikomes 8:49

I imagine there's a lot of variability between species and between individuals and that stuff. How quickly it comes on, how quickly it goes off, yeah, whether or not it comes on, response to something that someone else might perceive as innocuous, you perceive as a huge stress Yeah?

Rosemary Bagot 9:03

Because, yes, you can also have disorders of HP access function where you don't mount an appropriate stress response. So there's lots of ways that the HP access can go awry. Yeah,

Nick Jikomes 9:14

yeah. Before getting into some of that and some of the neural stuff, I want to, I want to cover off on a couple other basic things. So you mentioned the HPA axis, and one of the key outputs of that is cortisol. Cortisol is pretty widely known. Most or many people out there have heard of cortisol. We call it the stress hormone, or a stress hormone. What exactly makes it a stress hormone in the sense of like, what is, what is the cortisol doing? What kind of physiological changes does it instigate?

Rosemary Bagot 9:43

Yeah, so, so cortisol in humans, or corticosterone in rodents, binds two different receptors, glucocorticoid receptors and mineralocorticoid receptors, and these receptors are widely expressed throughout the brain, but also throughout the body. And so. What does court do many, many, many things. So acutely, it's really important in kind of reorienting the organism towards meeting an acute challenge. So you get changes in metabolism, changes in alertness, but chronically, you get a lot of sort of negative consequences where you have this continued activation and continued stress response. So you can get, like metabolic disorders. You can, even in extreme cases, have stunting of growth, you have a shutdown of reproductive functions, and you can have atrophy in various brain regions, but also hypertrophy in other regions. So it has very wide ranging consequences.

Nick Jikomes 10:44

But among other things, it sounds like the cortisol it's having hormonal effects that influence how the animal is mobilizing its energy stores.

Unknown Speaker 10:54

Yeah, for sure, yeah.

Nick Jikomes 10:55

That's a cool function, interesting. So, so instead of, you know, so if it's a growing animal, for example, some fairly large percentage of your energy is going to go towards growth and building new tissues and stuff. But if you're stressed a lot, you're going to mobilize that for other purposes, and then therefore you're going to take away from

Rosemary Bagot 11:12

that type of function. Yeah, yeah, absolutely.

Nick Jikomes 11:14

And when we think about this on on the neural side, I'll let you sort of navigate us in terms of some of the experiments that you've done in your lab that are relevant. But you know, when an animal is perceiving a stressor, you know, before maybe even the HB axis turns on, what are some of the major neural pathways that are involved in, you know, if it's threat detection or just the perception of a stressor, that's, you know, before that hormonal, the hormonal effects of the HPA axis actually start.

Rosemary Bagot 11:43

So, yeah, really. So upstream. We're talking about upstream of the hypothalamus. So the hypothalamus is a brain region that's the sort of you could think of it as the start of the HPA axis. It's the H in HBA. And the hypothalamus receives inputs from many different brain regions, and in terms of what brain regions are going to be processing the different threats that would depend a lot on the nature of the stressor, and so you could have sort of direct inputs from the amygdala related to, sort of, like, fairly unambiguous threats. We've done a lot of work looking at, I'd say, sort of less traditional pathways, about uh, prefrontal cortical and ventral hippocampal inputs to the nucleus accumbens. And so it's not they're not circuits that are traditionally thought of in the context of stress response, but their pathways that we found are modified by stress and then coming back to ask sort of what their function is, and what they're doing, we've found that they do seem to be quite important in processing specific aspects of threatening stimuli.

Nick Jikomes 12:47

What would be? What would be some examples of that, like, what aspects? Yeah.

Rosemary Bagot 12:51

So what we found? Yeah. So in our most recent work, we kind of took a very reductionist approach, and we're just looking at which neural circuits process an auditory stimulus that predicts a foot shock. So the threatening stimulus is the foot shock, we can look at just the neural response to the foot shock, and we see that both prefrontal cortical neurons that project to the accumbens and ventral Bucha neurons that project to the accumbens, both of these show an increase, an acute increase, in neural activity to the foot shock. There are some really interesting sex differences there, but maybe let's come back to that in a second. But then, when we can also look at how does the that auditory cue that precedes the foot shock, how is that encoded? And we find that again, both of these circuits encode that. But when we go a step further and we look at what's the response to a different auditory cue that the animals encounter in the same setting, but that's never associated with foot shock, so we can think of it as a non threat cue, and we see that these pathways seem to encode the identity of that non threat stimulus as well, but in these sort of curious sex specific ways. And another sort of nuance to this work that sort of resists simple explanation is that we see that this Neural Encoding is happening when animals are just encountering their stimuli, but when we look at how that relates to behavioral responses to threat, and so remembering that there are lots of different ways that animals can respond to threat and can respond in a stressful or threatening situation, we see that that Neural Encoding doesn't seem to have much to do with these sort of canonical threat behaviors like freezing, but it seems to be really important in how animals kind of use that information to guide sort of ongoing reward seeking behavior. Okay,

Nick Jikomes 14:50

so, yeah. So if I'm, if I'm starting to understand this, basically, something is going to end up being stressed. Which means it's going to end up activating the HPA axis, but depending on exactly how directly stressful it is, or whether it's not stressful, but it predicts something stressful, like the tone paired with the with the foot shock, there are sort of multiple paths in the brain, multiple circuits that can eventually get you to the activation of the HBA axis. And there's probably different. I think what you started to say there is there's differences between animals that affect things like how easily new stimuli are going to end up affecting that, that stress circuitry. So for example, if you pair the tone with the foot shock, the foot shocks. Obviously a stressor. The tone is paired with it, so the tone sort of ties into things. But then it sort of it sounded like you were saying that if you just play like another tone, not that tone, but maybe a similar tone. For some animals, they say, okay, maybe that one's stressful too, but some animals don't do that. So there's this sort of susceptibility issue that seems like it's coming

Rosemary Bagot 15:59

in here, yes, but I think there's kind of a couple of things to unpack here. And the first thing is, sort of these comments about how different brain circuits sort of lead to activation of HP access. One thing to note is, like in our recent work, we haven't actually been looking at this question of how HP access is activated. We're looking more how, say threatening stimuli are encoded, and then one of the the consequences of that encoding, you would imagine, is activation of HP access, but we haven't looked at that directly, so just that aside for a second. But then I think the more interesting thing that came up from from your comments, is thinking about how, like different brain circuits can encode different kinds of stresses. And I think this relates to something that is both interesting and very frustrating about stress as a stress researcher, and that is that it's very, very difficult to sort of settle on, like a definition of what, what's stress what's a stressor? And that's that's really the nature of the experience, that stress is highly subjective. And we can define a stressor, something that elicits a stress response by this sort of outcome, how it changes behavior, how it changes court release, but thinking about sort of how stressors, like the stimuli that elicit stress responses are processed in the brain is going to be highly variable, because the things that elicit stress are highly variable. So you can have a stress response. You can experience threat from a tiger jumping out at you in the forest, but you could be sitting in your lounge room and just imagining something that's never happened, right? And find that stressful, yeah, or even in the absence of any stimuli, just imagining, oh, I have to do this, this exam next week, right? Yeah, yeah. And so just appreciating, sort of how variable the things are that can elicit a stress response. And I think it follows that the neural circuits that encode those kind of stimuli will be highly variable,

Nick Jikomes 18:08

right? So, I mean, we all can think of examples in our lives. You know, some people really lean into stress. Some people are stressed out by seemingly everything. So in other words, the same stimulus can elicit a stress response one person but not in another, or the magnitude could be different, etc. And

Rosemary Bagot 18:23

then I think also how people react to that stress is enormously different. Like, I think some people really seem to thrive on stress and almost aren't get motivated without it. And some people find any amount of stress to be disabling. So there's many levels of individual variability. It's sort of different parts of the process, yeah,

Nick Jikomes 18:41

and so, so all of that sort of it speaks to this idea that the way that stimuli are encoded prior to touching the HPA axis is going to affect whether or not that access lights up or lights up a little bit or a lot, or whatever,

Rosemary Bagot 18:57

and then downstream, once the HBA axis is activated, that will have very different consequences for different people. So thinking

Nick Jikomes 19:05

about like the activation side here, and some of the circuits you were talking about, I'm gonna ask a bit of an intentionally naive question. So you mentioned the nucleus accumbens as being important, an important part here. Normally, when we talk about the accumbens, a lot of people that just associate that with reward, learning and addiction, they don't necessarily associate it with stress. Was it surprising for you that this ended up being a place we were looking at it? Or why do you think that that's a circuit that's relevant here? Yeah,

Rosemary Bagot 19:33

so the way that I came to it was through work that I did in my postdoc, and so there within, within the library, did my postdoc, there was a history of studying the accumbens in the context of addiction and animal models of and stress. And so there was already, like a lot of papers showing changes to the accumbens, which. With with stress. So in that sense, it wasn't so surprising. But I agree with you that generally the accumbens is thought of as this reward center. But one way that we can think about sort of why that might be touched by stress is because when you have this experience of chronic stress, one of the sort of key functions that can be impaired is your ability to to perceive and to use information about reward to guide behavior. And so I think that's one way we can understand the role of the accumbens in these stress related disorders.

Nick Jikomes 20:34

I mean, naturally, I start to think about, you know, when I think about reward and stress, oftentimes the natural response we have to stress, and chronic stress is to engage in reward related behavior. Some people get stressed and they start eating junk food or whatever. So so there is sort of an intuitive tie in, I would think, and

Rosemary Bagot 20:54

actually there's a, this is not my work. This is a this is a published book. I don't remember the group, but there's a really interesting paper showing that just giving mice Sucrose is sufficient to dampen the activation of the CRF neurons in the pVn the Para ventricular nucleus of the hypothalamus, to dampen HB axis activity. So probably not a great long term strategy, but it does suggest that there's like a physiological drive there that consuming sucrose, and this paper only explored sucrose, you could speculate quite likely sort of other hyloric foods might have a comfort food idea, yeah, that it is actually dampening HPA Axis activation, at least acutely. So basically,

Nick Jikomes 21:38

you give mice sugar and the the cells in the HPA axis that release some of these stress hormones are actually less active. Basically, yeah, yeah, yeah, interesting. One of the areas I want to get into is individual variability and susceptibility. I know that there's a lot of work out there on some of this, and I'm only partially familiar, but I think a big tie in here is going to be that a lot of early life experience affects things like the sensitivity of the HPA axis and how much it responds and how quickly it shuts off. You know, whether or not, you know the mother mouse was constantly licking the pup or not, whether there's many, many siblings competing for milk access. All of these things probably tie into this. But what can you say about the origins of variation in the susceptibility that individuals have to stress? Yeah,

Rosemary Bagot 22:32

I think this is a this is a huge question. So I think we can all appreciate that people, individuals show differences in their susceptibility to stress. But why is that so? And I think there are lots of different factors, particularly in humans, we can't discount genetic factors. There's certainly genetic variation that plays a role in this, but definitely life experience is one of the factors. And so, I mean, there's epidemiological work in humans showing impacts of early life adversity, but in rodent models. So I alluded to this work in in my PhD, just this sort of natural variation in the amount of maternal care that rat pups experience in the first week of life leads to quite large differences in HPA Axis function, and so differences in the peak and the return to baseline in court release also ACTH, another stress hormone in the HPA axis, And that then goes on to produce differences in behavior. So differences in anxiety like behavior, I found some really sort of unexpected differences in how animals learn, and in particular, how animals learn under stress that suggested that animals that sort of had the lower levels of maternal care early in life show this paradoxical increase in learning and hippocampal plasticity under conditions of stress, although at baseline they seem to be impaired. So

Nick Jikomes 24:10

is the basic idea there, that because they had more stress early in life, their brain is sort of tuned in to learning better under stressful conditions, or something like

Rosemary Bagot 24:18

that. That's kind of like the explanatory model. There's these ideas about preparedness. I think they fall apart if you push them too far. But the idea is that there's this sort of programming that might happen, that if you sort of are born into a high stress environment, you're going to thrive in a high stress environment. I don't think that epidemiological data holds up so much when you look at that, I think there's also a pretty good argument that, like compounding stresses actually lead to worse outcomes. But yeah, that's that's one interpretation of this idea of why you have sort of stress enhancement of plasticity.

Nick Jikomes 24:56

And you know, at least from the rodent work, it sounds like. You know, again, if we're talking about rodents, right, we're not talking about anything as dramatic as, like, the, you know, the major human stressors. We might talk about it like being born in a war zone, or into poverty, or something just natural, sort of normal variation, like, like a, like a mother mouse has a litter. There's some number of pups in it, I imagine, you know, if she's got a particularly large litter, there's only so much time she can give to each individual mouse, and there's natural variation in how much licking each one gets, how much cuddling and milk suckling each one gets. Those types of things are relevant here. That sort of natural variation in early life experience leads to changes in stress response. Yeah. So

Rosemary Bagot 25:36

actually, one of my colleagues in the Netherlands when I was a grad student, did that experiment. It was absolutely heroic. So not only did she observe the rat, sort of maternal behavior, I think we used to do it like five times a day for seven days, something crazy, she did all of that. But she also, like labeled all of her pups so that she could track exactly which pup was getting the care at each time. And sort of the upshot of that study was that, yeah, it seems that even so, before she did that study, we just looked at the level of the the litter, so that that little rat family, if you will. But she took it one step further and looked at within letter variation, and found that, yeah, it holds up there. So it does seem to be about the amount and quality of care that each individual pup experienced, and

Nick Jikomes 26:31

naturally. I mean, one, one human thing, this immediately makes me think of our birth order effects. You know, those of us from larger families know that even though, even though you all get quote, unquote the same treatment, you know, there's only so much time in the day, and if you're the first born versus the second or third or fourth born, you're just going to get a different level and quality of attention from your parents. And actually, you know, that's going to affect your development.

Rosemary Bagot 26:53

So yeah, as a as a parent of multiple children, I have to say that I am a believer in benign neglect. So not all care is I think we have to sort of see the nuance in this, that it's not just that we should give all of our offspring more care. But I think the other thing to keep in mind, which I think is super interesting, is that you can also have sort of a converse where you have children or individuals that have, like, objectively, the same experience and yet have different outcomes. And I think this speaks to the interplay between like Gene and environment interactions, or perhaps some kind of, like latent differences that emerge from like prenatal prenatal differences.

Nick Jikomes 27:39

Yeah, yeah. And are, you know, are there? It sounded like there are some raw genetic there's some raw genetic variability that might be relevant here. Is there much genetic variability in things like, I don't know the genes encoding the cortisol receptor or whatever? That's a

Rosemary Bagot 27:55

great idea. I haven't looked a lot at this because we're working within inbred mice, and so we really kind of put genetics aside, yeah,

Nick Jikomes 28:08

yeah, yeah. So, I mean, independent of any genetic factors here. The fact that you see variability in inbred mice means that there's lots of other things going on, for

Rosemary Bagot 28:18

sure. And so like, where does that variability come from in our mice. I think that it could be related to, as you say, differences in birth order, differences in utero positioning, for instance, differences in the amount of care experienced early in life. So it could be essentially just the combination of all of the different experiences. But I think there's also an interesting possibility that there could just be stochastic changes in brain development, right, right, kind of start on a path that then becomes kind of canalized by by later experience. Yeah,

Nick Jikomes 28:53

that's an important concept. I've I've covered it before with people like Kevin Mitchell. But Can you unpack that just a little bit more for people, what exactly do you mean by a stochastic developmental effect, as opposed to, say, a true environmental difference between two individuals, right?

Rosemary Bagot 29:06

So we're talking about the effect of an environmental manipulation, or some kind of environmental experience. We we are thinking about the effect of a specific stimulus that somehow impacts the brain, so it has an effect on the brain, but there is an external stimulus, but with stochastic differences, essentially, largely in the absence of the input of specific stimulus, there's just some kind of differences. So we could just think about, say, the normal developmental process is unfolding, that maybe there's just some kind of variation, perhaps in the timing of that, in how different genes turn on and off, or perhaps in the growth rate of different sort of neuronal projections. So there could be all kinds of different biological processes just that are unfolding, and there's sort of some small variation in that that could lead to individual differences. Yeah, it's not something that I've researched, but I think it's, I think it's always important when we're trying to understand a mechanism that we kind of think widely about what it could be that's not what we think it is right, because it's convince yourself, oh, the evidence supports my idea, but I think we should always be thinking about but what else could it be? Because we're generally less disciplined about looking for evidence for our unfavour ideas. Yeah,

Nick Jikomes 30:29

and I think when it comes to thinking about things like developmental stochasticity, you know, our minds as just animals in the world, they're naturally tuned into looking for cause and effect and agency. And A goes to B. What you're saying is, you know, you've got genetic influences, and we all know what that is. You've got environmental influences. Maybe mom was eating a different diet for me than she was for you, etc, etc. But also, there's just random differences that crop up based on, you know, a neuron going this way versus that way, for sort of purely random mechanistic reasons. Yeah,

Rosemary Bagot 31:01

exactly.

Nick Jikomes 31:04

What about so another element to the variability in susceptibility to stress. So there's sort of developmental stochasticity thing. There can be genetic variability between individuals. There can be these sort of birth order and other environmental effects that affect you versus a sibling. What about the role of sex here? I know that there's quite a lot of differences between males and females across species in terms of at the population level, between the magnitude of the stress they experienced, how susceptible they are to certain things eliciting a stress response, et cetera, et cetera. What can you start to tell us about male female differences here?

Rosemary Bagot 31:40

Yeah, I think that there are profound and at least until recently, under appreciated differences. And so in our research, we talk about the effect of sex, because we're studying mice and they have sex, they don't have gender. But when we're studying humans, we also need to think about gender, and that is this additional level of complexity thinking about the social construction of gender identity. So I think the simplest thing to say is that we know that there are interactions between sex and acute stress response, but also intercept ability to chronic stress. And so this is something that we've grappled with a lot in my lab, in thinking about how to study both males and females, and so not even explicitly looking at sex differences per se, but just studying both sexes, and what is immediately apparent is that doing the same thing to males and females doesn't lead to the same outcome. And so this could be say, if we apply like a stress protocol of say, something like chronic variable stress, we know from from work done by Georgia Hodes and Quincy LaPlante some time ago, that females show susceptibility, so they show behavioral change after just six days of chronic variable stress. And this is sort of repeated experience of, say, foot shock, tail suspension and restraint stress. And when you

Nick Jikomes 33:16

say chronic variable stress, you mean so the stress is chronic, meaning it's going to last over a fairly lengthy period of time, but it's variable, so they don't really know when the stress is coming. Yeah.

Rosemary Bagot 33:26

So the chronic is that it's repeated, and the variable is exactly the stress that happens each day It differs. So that particular paradigm is a pretty simple one, where each day, the animals are exposed to a stressor for one hour, and the identity of that stress, of that specific manipulation, varies each day, and sort of just rotates every three days. So after six days of this, females already show behavioral change. So they show like increased anxiety, like behavior. They'll avoid the center of an open field. They show reductions in social interaction, but male mice take 28 days to show similar levels of behavioral change. I see.

Nick Jikomes 34:07

So they get to the sort of same output, but it takes a much different period of time.

Rosemary Bagot 34:11

Yeah, exactly. And so then that, in itself is interesting, and we can study the mechanisms for that. What we've been doing in my lab is asking questions about so we had a paper looking at the state of susceptibility in males and females. We were asking if we can induce kind of similar behavioral levels of susceptibility. Do they have similar or different mechanisms? And so there we use different lengths of stress to induce similar levels of behavioral change in male and female mice, and then we looked in the brains to see, with this similar presentation of susceptibility, do we see the same neural pathways being being recruited in. And and we do, yeah, so this is a paper where we found that neural activity in the ventral hippocampus to the nucleus accumbens. So this the same pathway that we keep coming back to. We found that exposure to chronic variable stress, so we actually use four days in females or 21 in males. Increased activity in this pathway to similar levels in males and females, despite this sort of differing amount of stress, and looking into the mechanism of this. So first we found sort of this increase just using fiber photometry, which is this in vivo imaging technique, but using slice electric physiology to try to understand the synaptic mechanism, we found that it seemed like what was happening with chronic variable stress, be it four days or 21 days, was increased in presynaptic input to these neurons in the ventricular campus that project to the accumbens. So this would sort of lead to the increased activity. But so what was really striking about this is that, I mean, there's a, there's a huge difference between four days and 21 days, right? Yeah, we saw the same mechanisms being recruited, yeah.

Nick Jikomes 36:10

So it's as if, you know, very vaguely speaking, it's as if the circuit is, you know, keeping track of the total amount of stress. And if the stress gets big enough, or, quote, unquote, too much, it kicks in in this way. But you know, how much is too? Much really depends on in this case, if it's a male or a female. Yeah,

Rosemary Bagot 36:26

I think that's an interesting way to think about it, and it also ties into sort of another observation that we made, which is that with this technique in vivo fabric photometry, we were able to do our recordings longitudinally. So we actually recorded activity in this neural circuit before animals ever encountered stress, and then across the course of stress and after stress, and we found that there were actually individual differences in the amount of neural activity in this circuit before stress that were predictive of that sort of behavioral presentation of stress susceptibility post stress, which I think sort of comes back to this idea that you're suggesting that that neural circuit might be kind of keeping track of stress, so you could maybe it's some kind of readout of some kind of integrated susceptibility factor. Yeah, interesting.

Nick Jikomes 37:13

And that would vary between the sexes naturally and also vary between individuals because of, you know, all of the myriad things we talked

Rosemary Bagot 37:20

about before. So another interesting thing about that that neural circuit, so AJ Roberson found, around about the same time we published this paper, he actually looked at the excitability of these neurons in male and female mice, and found that there's the in female mice these ventropic campus to accumbens projecting neurons actually more excitable, so they're more easily activated, and that's something that we've since replicated in our own lab. So we have individual variability within sex, but we also have this considerable variability between sexes.

Nick Jikomes 37:54

And do we have any sense of where this arises? So one thing that starts to come to mind here the fact that we see this individual variability, and we see it at the level of males versus females. You know, one thing that comes to mind here is, you know, I'm fairly familiar with some of the hypothalamic literature on the effects of estrogen, especially across the life cycle of females, like before and after pregnancy. And you know, as many as you probably know as a mother, right? Pregnancy often comes with changes in your sort of overall baseline levels of stress and anxiety. And it sort of makes ecological sense, right? Because now you have to be tuned into potential stressors in the environment, because you have the little ones to look after. Are things like sex hormones involved in modulating the excitability of these circuits. How do we start to think about the origins of

Rosemary Bagot 38:37

this difference? Yeah, so the short answer is yes, yes, they are. So we recently actually got a grant to explore this in detail. So we, we haven't done much work on this as yet, but there's, there's pretty good reason to think that that it will be modulated. So actually, AJ represent the the colleague I mentioned, he did some interesting work where he actually pinned down this difference in excitability in the ventral per capita accumbens neurons. He pinned it down to an effect of testosterone, not estrogen, and that it seems that in male mice, this androgen signaling is actually suppressing excitability. And if you do an orchidectomy so removing the testes, this actually leads to increased excitability. That was an interesting effect, actually, because I think people often assume that all of the sex differences are driven by estrogen, and certainly estrogen does a lot of things, but there's also effects of testosterone. And then I think another really interesting thing that is often kind of overlooked is that there's also estrogen signaling in males, yeah,

Nick Jikomes 39:48

yeah. And it's crucial, like, if you don't have enough estrogen, normally, we think of males as having, quote, unquote, very little estrogen, but if you don't have enough, that can cause serious behavioral issues,

Rosemary Bagot 39:57

yeah, yeah. So in work. A that I did in collaboration with my postdoc lab, we actually found that estrogen, estrogen signaling in the accumbens, the nucleus accumbens, seems to be protective against the effects of chronic stress in both male and female mice, and

Nick Jikomes 40:16

I guess directionally, the effects you just mentioned about testosterone, it reduces the excitability of some of these cells. Yeah, that makes directional sense with how people normally think about testosterone. In general, the higher testosterone levels, the more I guess, impervious to stress the animal seems to be. Is that generally true? Yeah,

Rosemary Bagot 40:32

I don't know. I haven't really done any research on that to have an informed opinion. I think testosterone is going to have complex effects. And I think the other thing to keep in mind is that I think that while some of the effects might be sort of fairly similar in terms of changes in excitability or changes in spine growth or synaptic plasticity, where in the Brain testosterone or estrogen is acting is also going to have a big effect because of how neural circuits work, right?

Nick Jikomes 41:07

Yeah. And I guess one thing that could be relevant there is correct me if I'm wrong. But these things are not just released systemically. They can also be synthesized and deployed locally in certain parts of the brain. Yes,

Rosemary Bagot 41:19

yeah. So you have local production of neuro steroids, which is fascinating, right? Yeah, there's, we need a lot more research into this is what I would say, yeah, yeah.

Nick Jikomes 41:32

So what about So, what do we know about? Okay, so we have individual variability and stress that people have people and mice and all sorts of creatures. There's variability in your susceptibility to stress. How much stress will manifest in terms of like, your behavior from a given stimulus, and there's difference between acute and chronic stress. So obviously, you know, to some extent, some acute stress is normal and expected and potentially even good for you, but eventually there's this threshold you cross where the stress becomes chronic and it becomes unhealthy and maladaptive. It's just too much. One of the ways that can manifest is in chronic disorders like PTSD say, what do we know about how individuals in a species transition from, you know, just responding to sort of regular, normal amounts of stress, to developing something like a disorder where now they're just having this hyperactive, persistent over response.

Rosemary Bagot 42:32

Yeah, I think one other thing to keep in mind that is that the chronicity of stress is important, but also the intensity and so for instance, with PTSD, PTSD could develop with sort of exposure to chronic stress, for instance, in personnel serving in war zones, right? Yeah. But PTSD can also develop from a single, intense, sort of near death experience, right? And so it's about this complexity of the intensity of the stressor, the perception of control seems to be a really important thing, and then the chronicity. And so what do we know about how sort of individuals differently transition? So there's quite a lot of research now, largely in mice, looking at this concept of susceptibility and resilience. And so we can model this in mice, exposing mice to a chronic stressor. So the one of the stresses we use commonly is a chronic social defeat stress. And so this is this paradigm where mice are put into the cage of a bigger, meaner mouse, or a brief aggressive encounter. This is really quite brief, and it's then the experimental mouse is sort of separated from that mouse, but still in the same cage. But there's a Plexiglas divided with sort of holes drilled through it, so that there's this very potent psychological stress of being housed next to this mouse that just intensely bullied you.

Nick Jikomes 44:01

They can see it. They can smell it. It's probably a very stressful place to be, exactly,

Rosemary Bagot 44:05

yeah, but there's no physical harm. So this model isn't primarily about sort of the physical harm. And so this experience is repeated every day for 10 days, and then at the end of this, mice are put into a social interaction test. And so they're put first into an empty arena and they can explore it, and then they put back in when there's a mouse in this interaction enclosure, and that mouse looks the same as the mice that it had these aggressive encounters with, but it's actually a new mouse, so it's the same strain, but it's a mouse they've never encountered. And so what's really interesting about the social interaction test is that you might predict that all of the mice will just avoid interacting, right? Because they've had repeated experiences of getting defeated, yep, but we find that actually only a subset of mice showed this social avoidance, and that there's actually a good third of the population that continues to seek out interaction. And these are termed the resilient mice,

Nick Jikomes 44:56

yeah, yeah. So they're naturally, uh. Uh, they're naturally resilient. They're naturally willing to go explore, uh, the stranger again, even

Rosemary Bagot 45:05

though, like, maybe this time, it's going to be different. Yeah, and I

Nick Jikomes 45:09

would have so I know from talking to other people that this, this idea of resiliency, is very consequential. So there's probably a lot you're going to be able to talk to us about here, but one thing that I learned recently had nothing, you know, this was from studies that had nothing to do with stress per se, directly. But, you know, I was talking to a gentleman from the Jackson lab, and he did these very, very large scale studies looking at calorie restriction in mice. And I don't need to get into the details here. I don't know if you've seen this, but the basic idea was, can you calorie restrict mice? You generally see lifespan extension, but you see a lot of variability between individuals within a strain and between strains. But one of the things they sort of happened upon was that, you know, when you restrict mice with their food, when you pick them up just to weigh them and do things like that, those are all stressors to the mice, right? A giant human monster is coming and picking you up and doing these things. What they found is that the level of weight loss that mice displayed was highly variable in response to just being picked up and weighed and going through all those experimental processes. And what they found is that a good index for stress resilience was how much weight they lost in response to these stressors. The ones that lost the least were the ones that were most resilient. And in those mice, they actually found the largest lifespan extension effects. And so one of the interpretations of this was that stress resilience may have had something to do with things like, in this case, lifespan. So my general question for you is, what sorts of things does stress resilience in mice predict? So when you sort of cohort them from, when you take the highly resilient ones and the ones that are not resilient, do these mice display very different levels of lifespan, other health markers, other types of behaviors we wouldn't naturally maybe think of,

Rosemary Bagot 46:49

yeah, that's super interesting question. We have done more work asking kind of the inverse of what predicts the resilient phenotype because of the sort of opportunity that opens up in that if we understand what sort of predisposes animals to be resilient, maybe we can kind of shape the course of the trajectory towards resilience. But there's a lot of work, and we've done some of this looking at the mechanisms of resilience in terms of things about lifespan. I don't know that anyone has done aging studies. I think super interesting question, but certainly, like, there are people who have done a lot of work about sort of like, neuro immune interactions, that it seems like susceptibility is probably more of a state of inflammation, but let's talk

Nick Jikomes 47:41

about the origins of the origins of the susceptible, of the resilience. So, so basically, you said you this experiment where, you know, the mouse gets beat up for a second, and then they don't have to interact with that mouse against they're not gonna get hurt, but they can see it. They can smell it. And you said about a third of the mice are what you would call resilient. They're willing to go and socialize again. And some fraction are probably, you know, off in the corner, avoiding those mice. What are the resilient ones? What's going on under the hood for them? What's making them resilient?

Rosemary Bagot 48:05

Yeah, so lots of things. We've done a lot of work looking at sort of patterns of gene expression. One thing that sort of I found early on is that it seems like across a variety of brain regions in general at this sort of, if we just look, say, like one day after this social interaction test, so like, fairly soon after the chronic stress ended, in resilient mice, there's actually a lot more changes in gene expression. And one way that we sort of interpreted this is that this is sort of like organized transcriptional response. There's adaptation to the stress, whereas in susceptible mice, there's fewer gene expression changes. And this could be reflecting to sort of like increased variability. And so looked at the gene expression data through another lens, which was co expression networks. And so this is the sort of idea that genes don't function in isolation. In fact, genes don't do anything except make proteins, but it's easier to sort of talk about things at the level of genes, but sort of we have these sort of organized groups of genes that mediate biological functions. And so we can look at how the sort of correlational relationships between groups of genes change with an experience. And we found that in resilient an