Isabel Nieves: The way in which we operate is defined in large part by our memories. Memory is a core component of the human identity. In this show we hope to explore the nuances of this fundamental aspect of our brains. These conversations aimed to illustrate the strengths, weaknesses, and mysteries surrounding remembering and forgetting. I'm Isabel Nieves and I'm Tanner Chaille and this is Remembering and Forgetting, a podcast by Themester. Stress is an unavoidable part of life. Every day we are presented with the new stressor. And if you are a college student, this is probably something you know all too well. But how can too much stress affect us and our memory. I sat down with Dr. Cara Wellman to find out on this episode we have in the studio, Dr. Cara Wellman, the director of the Center for Integrative Study of animal behavior and professor of psychological and brain sciences at Indiana University. Dr. Wellman's research is the neurobiology of stress, more specifically as an important variable in the development of an expression of many psychological disorders such as schizophrenia and depression.

Isabel Nieves: Um, how are you today?

Cara Wellman: I'm fine, thanks.

Isabel Nieves: That's good. That's good. Um, so let's get started with some of the questions. Um, I thought you could explain some terms for our student listeners and any other listeners who aren't familiar with some of these psychological terms and scientific terms. So could you explain neurotransmitter systems and the brain structures thatou study that are affected by stress so that our listeners can kind of get an idea, um, as we go on and as we ask more questions and dive deeper into that conversation.

  

Cara Wellman: Okay, sure. Um, this is, uh, so I'm gonna try to just focus just on the neurotransmitter systems and structures that are relevant to our conversation. Um, but just to sort of lay a very basic groundwork. So, um, brain cells, neurons communicate with each other by releasing chemical messengers called neuro-transmitters, uh, onto each other, um, where they interact with receptors and influence the activity of the receiving neuron. Um, for our purposes, the, uh, two of the critical neurotransmitters and, uh, other chemical messengers that, that, uh, we'll be talking about are, um, actually I guess three norepinephrine, epinephrine and cortisol. Uh, also, uh, have, um, alternative names and in one of those you may have heard of. So epinephrine is also called adrenaline, so it's not just a neurotransmitter. It's also released by the adrenal glands, um, which are critical, the activation of which is critical for your stress response. Cortisol is also released by the adrenal glands and you may have heard that also referred to as a glucocorticoid. So glucocorticoids are a class of, of hormones and cortisol is one example, one important example of that class of hormones. So, um, that's what you need to know about neuro-transmitters going into this conversation. Uh, lots of structures in the brain. Many, many structures in the brain are influenced by stress. Um, three structures that you hear about a lot in terms of the stress response are, uh, the hippocampus, which is important in acquiring new memories. Uh, the amygdala, which is important in orchestrating learned fear responses, uh, and the prefrontal Cortex, which is important for emotional regulation, um, personality and, um, what's called executive function. So, um, sort of cognitive flexibility. And those are the three main structures. I'm going to be talking about. Okay. All right. That definitely gives, at least me. Um, I'm not a psychology major or have anything to do with neuroscience, but it's really interesting, but that really clues a lot of things up. Um, when it comes to what we are going to be talking about, how stress affects these parts of the brains and affects these neurotransmitter systems and can potentially cause these, um, psychological disorders.

Isabel Nieves: So can you talk a bit about the effects of stress on, um, what does it do to the neurotransmitter, um, systems first and then we could talk about what does stress due to these brain structures, especially the hippocampus in terms of memories?

Cara Wellman: Okay. So, um, what I'll do is describe what happens when you're in a stressful situation. So when you're in a stressful situation, say you're walking in the woods and use a cougar out there, um, probably pretty scary, right? So when you're in that stressful situation, you perceive something, some stimulus out there in the environment as threatening or dangerous. Um, you have a stress response. And one thing I think it's important to emphasize that a lot of what's out there, sort of in the popular press gets wrong, is that the stress response is not a simple unitary response. There are at least two major components of a stress response. So one component of the stress response, and this is the component that you're, you're aware of in the moment, right? So you see that scary thing and you have what's called a flight flight or fight response. You get, um, maybe a little shaky, you, uh, your palms start to sweat, your heart rate increases, your breathing increases, um, you're getting ready to either run away or deal with this problem. That's the result of the activation of your sympathetic nervous system. And that activation of the sympathetic nervous system increases, um, epinephrine release from the adrenal glands and it increases the release of norepinephrine in the brain among other neurotransmitters. But those are two, two key components of the sympathetic response to a stressful situation. And that's getting you, that that is providing the, the increased arousal that you need to deal with the threatening situation at the same time. That increased arousal, um, uses up a lot of energy. And so the other important component of the stress response is, um, the release of cortisol from the adrenal glands. Cortisol is a hormone. It's intimately involved in the stress response. It's also involved more generally in, in metabolic processes in your body. Um, so for instance, cortic cortisol release increases when you wake up in the morning as you need more energy to need to use more energy to start your day. Um, it's also increased dramatically when you're in that stressful situation. And, um, the effect of that release is to mobilize sources of energy to provide the energy you need, um, for the stress response. And it also has a lot of effects on the brain. In addition to that sort of, uh, energy mobilizing function, uh, the, you can have an increase in cortisol. Like if I were to just give you some cortisol, you wouldn't have that fight or flight response at all. You wouldn't have that increased respiration, et cetera. It doesn't have those kinds of facts. So what's your, what you're aware of your body doing when you're, um, in a stressful situation. That's the sympathetic nervous system. What the cortisol is doing is regulating metabolic resources. So that's OK. So that's more of like the, what's happening with your neurotransmitter when you're in these stressful situations.

Isabel Nieves: Um, what's happening to these brain structures when you're in that, uh, in any stressful situation?

Cara Wellman: Well, so, um, one of the effects that the combination of cortisol and nor epinephrine have is to actually, um, facilitate certain kinds of learning and memory. And specifically what they do is, um, increases in cortisol and norepinephrine. The brain can, um, help to stamp in a memory more strongly, um, that's called consolidation memory. That's laying down the memory trace. And you facilitate that with these, uh, with the stress response. Um, so for instance, um, a lot of people may have had an experience where, um, they're in some sort of stressful situations or you get in an, uh, you know, a car accident, a fender bender at a certain corner, at a certain intersection, say Jordan and 10th Street by the library. And what you may notice is like the next few times you go past that, uh, intersection as you, as you're coming up to the intersection, you start to feel a little nervous, a little anxious, a little scared. And the reason for that is that you've learned to associate the cues at that intersection with that accident you had, which freaked you out. Um, eventually. And, and the reason you've formed such a strong association is because the increase in epinephrine, norepinephrine, cortisol that was going on during that stressful situation helped to stamp in the memory, the association between the cues on that corner and that bad thing that happened to you. Okay? That's called fear conditioning. And one of the classical effects of, of the changes you undergo during a stressful situation is that it facilitates that fear memory.

 

Isabel Nieves: How does stress, uh, play a role with depression and schizophrenia? How does it go into depression and influencing depression and also influencing the schizophrenia?

Cara Wellman: So, um, many, many, many disorders, depression, schizophrenia, post traumatic stress disorder, um, lots of anxiety disorders are influenced by stress. So stress in combination with a variety of other factors that, uh, leads to these disorders. Um, and one of the sort of, uh, frustrating things is that we actually don't know for sure yet exactly how stress contributes to a lot of these disorders. But we do know that, um, a history of stress, a stressful life events, uh, early life stress, uh, is a risk factor for disorders like schizophrenia and depression. And we have some ideas about, um, some of the mechanisms underlying that. Schizophrenia is characterized by dysfunction of the prefrontal cortex. Uh, it's also characterized by, uh, some hippocampus dysfunction. So for instance, in the long run on the average, someone with schizophrenia has a smaller hippocampus than someone who doesn't. Um, depression is also characterized by dysfunction of the prefrontal cortex. So, um, if we understand something about how stress influences the structures that might help us to understand some of the contributors to these disorders. And we know from work with, um, experiments involving, um, animal models, rats and mice that exposure to chronic stress. So daily stressors over a long period of time of time can produce, uh. okay. Shrinkage of the hippocampus and shrinkage of the prefrontal cortex. And specifically if you look at the individual neurons in those structures, you will see that, um, in animals that have been exposed to chronic stress, the dendrites are shorter. In those animals. The dendrites are the parts of the neurons that are receiving information. There. It's sort of the information processing units of these neurons. And so if you change the length of the dendrites, you're changing how those neurons process information. Um, and those changes are associated with, um, changes in, um, the behaviors that those structures are critical for. So for instance, um, that the shrinkage of dendrites in prefrontal cortex is associated with, um, deficits in, um, behaviors in cognitive processes like, um, behavioral flexibility, cognitive flexibility, being able to, um, switch, um, winning strategies. Over time when the, when the rewards change or um, working memory, being able to hold one bit of information, sort of in your conscious memory, in the service of solving a problem, um, extinction of conditioned fear. So extinction of learned fear, that fear memory that got stamped in. If you exposed to those cues long enough you or repeatedly eventually you'll stop responding with fear. That's called extinction. Prefrontal cortex is critical for that process and prior exposure to chronic stress impairs that extinction process. So many, many of these behaviors and cognitive processes that are uh, um, critically controlled by the prefrontal cortex are, um, impaired after a prolonged bout of stress and they're also impaired in these disorders that we know are very sensitive to stress.

 

Isabel Nieves: Yeah. And, um, I wanted to talk about also PTSD as another disorder. As you said, PTSD is influenced by stress among other things. Um, and so can you talk a bit about that because you know, um, PTSD, uh, caused by traumatic stress from traumatic memories. Um, how does stress play within PTSD? Does it play any role at all? Does it have some influence to that disorder? And with our memories?

Cara Wellman: Yes, absolutely. So, um, well, so post traumatic stress disorder gets its name because, uh, it, one of the sort of basic ingredients of this disorder is having experienced some sort of specific traumatic stressor. Um, so you don't get PTSD if you haven't been exposed to stress the symptoms of PTSD. Actually, and let me back up a minute. So, uh, you have to be exposed to a traumatic stressor to get, uh, to have a diagnosis of post traumatic stress disorder. Um, but even setting that aside, again, a history of chronic stress of early life stress is a risk factor for later PTSD when you're exposed to a traumatic stressor. So again, there's a link between that ongoing stress earlier and a problem later. Um, the diagnosis of posttraumatic stress disorder, um, comes, um, not immediately after you're exposed to a stressor. And that's because everybody, or the vast majority of people who are exposed to a traumatic stressor have certain symptoms. They will, uh, have hyper vigilance. There'll be like more responsive to loud noises, et Cetera, and be, you know, sort of monitoring their surroundings more carefully. They have, um, avoidance, you know, they tend to not want to be exposed to the, the reminders of that event. Um, they have a re-experiencing when they are exposed to the reminders. They have a, you know, a vivid memory of the event and again, that re-experiencing is likely to do due to the strong stamping in of the fear memory because you have this, the stress response. When you wonder when that stressful event, um, most people will have those symptoms for a month, six weeks or so, and they'll eventually go away. Uh, for some someone with PTSD, those symptoms don't go away. And so it's at that point when they would have gone away, but they're sticking around where a person gets that diagnosis. One of the critical, one of the hallmarks of PTSD in addition to those symptoms is impaired extinction of learned fear. Um, again, that involves the prefrontal cortex and we know stress, uh, impairs the functioning of prefrontal cortex and specifically produces deficits and extinction.

 

Isabel Nieves: We've been talking a lot about how stress, um, you know, it can help us remember those, I don’t know if help is the, but it can influence how we remember stress can help us. Uh, it can influence how we remember, um, certain traumatic memories. Um, how can it can stress possibly make us forget any traumatic memory or any, um, stressful type of memory, finger to stressed, um, any certain type of levels of stress?

Cara Wellman: Well, so I'm not sure you can say that, uh, high levels of stress would, would help you forget a stressful memory. But, um, it is the case that um, not all stress is bad. There's a certain optimal level of stress, too little stress and your performance is going to suffer too much stress in your performance is going to suffer, but a moderate amount of stress does in fact facilitate memory. Um, and so you wouldn't want to be absolutely completely relaxed and calm, right? When you are learning something, studying for a test, you're not going to do as well as if you're a little, if you have some sort of moderate level of arousal. Um, so from that point of view too, little stress can actually impair memory. Um, it's also the case that, so I've been focusing on how stress can facilitate an acute stressor a one time. The stressor in this moment can facilitate the laying down of a memory trace, but that can vary depending on the amount of stress. So if you get too much stress, you can get some impairment and um, it can also vary depending on the type of memory, um, you're talking about. And the same time that it can facilitate these sort of emotional memories, it can end in some non-emotional mare memories, like simple memories for facts, et Cetera, things that are going on in that situation. Um, it can also impair some sorts of cognitive functions. Again, access stress. Yeah. When I was doing some research, um, I read about like the bell curve as you were saying, that represents the level of stress and it's affects where like if there's, um, you know, a good amount of stress, then that's where you're going to be, you know, the most productive. Um, but if you have like too much stress, then that's when it really can affect you because then, you know, the amount of stress can I read about like the fight or flight response and how that can go into overdrive. And then we stopped, um, filtering in like finer details, um, which can, yeah. Impair our memory. Um, so I, with that I wanted to kind of talk about, you know, um, college as a stressful environment, um, and possibly, um, a stressful, um, or one of these stressors for college students. Um, how can, you know, students maybe manage this stress so that, you know, it can, they can be somewhat proactive about prevention of such disorders like depression, um, possibly schizophrenia, but I feel like, you know, depression, um, and anxiety, those are some of the bigger disorders that, um, college students face. And with college being a stressful environment, um, it's just going to happen, you know, with test courses, um, jobs. How can you know, students try to manage this stress? Excellent question. Um, and luckily I think there are lots of things you can do to manage stress. Uh, and there are lots of, uh, studies out there. There's lots of experimental evidence that suggests a number of factors that, um, that you can think of as, as making stress less stressful than mitigate the effects of stress. So for instance, and in fact it's probably important to point out what I've been talking about is uncontrollable stress, right? Stress you can't influence. Um, but there are lots of, of, uh, things that can make a stressor controllable, right? You can plan, you can schedule, you can make decisions about your coursework, how much you're doing and when. Um, and so anything you can do to make the stressful situation more controllable, we'll make the situation less stressful. Um, in fact, there are data to suggest that if you can control a stressor, if a rat can control a stressor, it prevents some of these negative effects of stress. Um, you don't even necessarily have to be able to, to control it completely. If you can predict it. That makes the stressor less stressful. It makes the, it, it mitigates the effects of the stressor. So, um, you know, we, again, we can schedule, we can look at, we can plan and know when our exams are coming up and so on. Um, so that can be very helpful predicting the stressor, controlling, doing something about it. Um, and then there are some ways in which you can avoid stressors, right? You can navigate your environment in such a way that, that you're not setting yourself up for a stressful event. Um, so by being proactive and, um, sort of looking at, at what's going on in your life and planning accordingly, it can be very helpful. One thing I forgot to ask earlier when we were talking about, um, what you study, I wanted to talk about, um, the models that you use to study stress. You talked about, um, using mice, um, because you do a lot of work with animal behavior, um, in determining these effects of stress on our brain, um, and our, uh, behavior.

Isabel Nieves: So can you talk a bit about those models that you use, the mice as the models and why do you use mice?

Cara Wellman: So, um, I have used mice have been mostly what I use as rant. And, um, the reason I use those animal models is because for two reasons. One is your able to experimentally manipulate the stressor in the long term in ways that you can't ethically do in humans. Um, and the other reason, um, is that I am interested in, uh, how stress influences the, uh, structure and function of the brain on a cellular level. And so if you're interested in studying these things on a cellular level, you really need to use animal models so that you can actually do in depth analysis of those, those neurons. So, um, one thing that I read about is that you, um, researched the stresses influence on, um, psychopathology. Can you talk a bit about that? Well, so, uh, what my research has focused on is in, is the effects of stress, um, in the absence of psychopathology. So I'm using animal models, um, and so most of what I'm studying is in the long run. On the average. How do these, um, unusual situations, how did these stressors affect the function of brain structures that we know are involved in these psychological disorders like depression and PTSD? Um, and the idea there is that if we understand how stress affects the brain, then we can apply it to, um, other, uh, potential models of psychopathology and look at how stress might interact with some other risk factor to produce psychological disorders. Um, one example of that is that, uh, in collaboration with a colleague, um, we've looked at the effects of, um, early life stress, um, interacting with, um, a genetic variant, um, that affects the serotonergic system. And that genetic variant that affects the affects Serotonin, uh, has been implicated as a risk factor in pathological aggression. So one of the features potentially of sociopathy, um, or a psychopath psychopathic disorders. Um, and, but that genetic variant alone isn't enough to produce the risk for pathological aggression. It's the genetic variant combined with a history of early life stress. And together that interaction is what increases the risk for this, this pathological aggression. And so what we've done is in mouse models that where that gene has been manipulated, we can compare, uh, parts of the brain that are involved in aggressive behavior, impulsiveness, et Cetera, in these animals that have had the early life stress and have this genetic risk versus animals that haven't had that early life stress or, um, who do and don't have the genetic risk. And so we can sort of tease apart, um, the independent contributions of those two factors in there, uh, how they combine to produce this aggressive behavior and what brain structures are actually involved in. Now I have one more question. So we've been talking, um, I mean one of the questions is how we can manage stress as students and that was more so, um, being able to deal with controlled stressors.

Isabel Nieves: Um, but I was really curious about, you know, we've been talking about, um, uncontrollable stressors that can influence, um, certain abnormal behaviors that lead to disorders such as depression and schizophrenia. Um, what are ways to manage those uncontrollable stressors after they happen, after the fact? Would it be therapy? Um, or is there some other type of solution to kind of alleviate those uncontrollable stressors?

Cara Wellman: So, um, one sort of final ways. So yeah, sometimes you can't avoid this stressor. You're exactly right. And so, uh, what you can do at that point potentially is change your response to it, right? You can change the way you think about that stressor. Um, change, uh, how you are following up after the fact. Um, when you're thinking about it, the meaning you ascribe to it and sometimes that, uh, it requires therapy. Maybe it doesn't require therapy, but cat can very often help to have somebody working on that, that sort of changing the way you're thinking about these stressors with you. Um, I think a lot of students also probably do that on their own or with the help of friends. Um, but um, that's a really critical component of what comes after the stressor. You can change the way you think about it. You can, you can really help, um, ameliorate some of those effects of stress.

Isabel Nieves: Yeah, because you said like the stress, um, you know, it affects those neurotransmitter systems and then those brain structure systems, you know, like it, there can be some impairment to the prefrontal cortex or to the hippocampus when those abnormal or not have know. When those, um, uncontrollable stressors and uncontrollable stress affect or influence those parts, um, is it irreversible or is it just some kind of short term influence or damage on those parts? Is it fixable?

Cara Wellman: Excellent question. So, uh, we have done some work that suggests that, uh, the effects of stress on a pre-frontal, uh, structure and function are not permanent. Um, so, uh, eventually if you wait long enough, uh, the neurons sort of, uh, remodel. Um, the interesting thing is that, um, what those neurons may do is not exactly go back to their sort of unstressed state. They change sort of in a new way. And for some animals that may though those changes may then make them more resilient to the next stressor, whereas for other animals, it may actually make them more susceptible to the next stressor. And so that, that, uh, leads to a big question about wealth.

Isabel Nieves: So do individuals who say have a stressful event and go on to, uh, get a diagnosis of depression or PTSD, are they, um, are their neurons changing in a way that makes them more susceptible versus more vulnerable?

Cara Wellman: Um, and that's an excellent question that we don't know the answer to yet, but what we do know is that the neurons that, those, the remodeling that we're seeing right after this stressor isn't permanent. The neurons continue to change.

Isabel Nieves: Remembering and Forgetting is a podcast produced for Themester at IU. Special thanks to IU’s College of Arts and Sciences, Tracy Bee, Ken Smith, and The Media School for today’s episode. Music for this episode by Jack Brown. For more discussions on memories of dance forms of commemoration and more, check out the rest of remembering and forgetting. Thank you for listening.