Neuroscience of Social Behavior, Pain, Empathy, Emotion, Brain Mechanisms of MDMA | Monique Smith | #159

About the guest: Monique Smith, PhD is an assistant professor of neurobiology at the University of California-San Diego, where her lab studies the neuroscience of social behavior, pain, and emotion.

Episode summary: Nick and Dr. Smith discuss: the neurobiology of pain perception; social & empathy-like behavior in animals; emotion; brain mechanisms of MDMA; serotonin; and more.*This content is never meant to serve as medical advice.

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* Episode transcript below.

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

Monique Smith 2:28

Sure, yeah. My name is Monique Smith. I'm an assistant professor of neurobiology and Neurosciences at the University of California, San Diego. And my lab is very interested in looking at how social behavior impacts pain, emotions, and basically internal state. So we do a lot of work to understand how these things intersect, for example, how does having social partners around you impact your experience of pain after injury? Or another example would be by being around somebody in pain? How do we experience empathy? And how does the brain encode that? But when I say we, we actually use mice as models? And yeah, and yeah, so that's pretty much it. And we're working on some human collaborations. But we primarily use mice to model things like emotions, which some people think is a little wild or out there. But I would argue that most mammals, including mice, and other rodents experience emotional states and are affected by social partners and things like that. So yeah.

Nick Jikomes 3:43

What, you know, in your mind, like what, what is a good working definition of emotion? And how do you approach that in an animal that can't speak to you?

Monique Smith 3:54

Yeah, so interestingly, we depend as humans upon language to talk about our emotions talk about things like pain, and obviously, animals can't do that. But when you think about our behavioral output, in distressful situations, or painful situations, or situations in which we're experiencing some emotion, the behavior that you can see, that we engage in might be very similar in our roadmap. So in terms of defining something like emotion, there's, you can think of it as an umbrella term that involves sort of arousal on the y axis, if you were to put this on the graph, and then negative to positive effect. And so emotions kind of lie on this graph, or you can think about it circularly in that we can have a high arousal, highly negative feeling, or emotion. Something like rage, let's say, or we can have a low arousal was all really negative feeling. And that would be something like feeling depressed, or, like lethargic because your emotions are bad. And so that's how I like to think about emotions is this sort of intersection between arousal and negative or positive effect. Though with human emotion, we do talk about it as lasting a little bit longer than sort of a really brief state. But I would argue that the emotional state is quite short. And that feelings are what lasts longer. But you can have really rapid changes in emotions, even as a human and I argue we can look at that in animals by measuring their behavior. Does that make sense? Yeah,

Nick Jikomes 5:42

so So basically, animals will display characteristic behaviors in certain emotional states or when they're exposed to stimuli that we know elicit emotional states and us, they exhibit behaviors that are akin to the ones that that we display. And what you're saying is, you can think of emotion as having two components. One is this arousal component. So like, when you prick your finger, with a pin, it hurts you, you become aroused, right? You you get like a jolt of energy, you know, your nervous system is excited. But it's also painful. There's a negative aspect to it. So there's these two components, arousal and effect or valence?

Monique Smith 6:22

Yeah, yeah. Yeah, exactly. So positive or negative and highly aroused, versus less aroused. And I think if you start to break down emotion into those component parts, then you can see it in terms of behavioral output. Exactly. in lots of different animals. Yeah, I'll say really quick, like, I don't think anyone has an any question that their dog experiences some form of emotion. So I think it's kind of interesting that we think, you know, a dog is that much different than a mouse, which they're different. They're different species, for sure. But yeah, anyways, go on.

Nick Jikomes 6:58

So when you study emotion in mice, if you study something like pain, how do you how do you study that? How do you measure it? How do you quantify it?

Monique Smith 7:08

Yeah, good question. So I'll start with the human, which I'm sure everyone knows, we asked, how much pain are you in a scale of one to 10 one being the least, you're not in any pain at all, and 10 being the most painful experience of your life. And so the first part of why I'm starting with the human is, the way that we ask about pain and measure pain in humans is pretty bad. Because it's highly subjective. It doesn't always relate to injury, per se. Lots of pain conditions happen without injury and persist long beyond any healing, right. And they're impacted by psychological and social factors and all these things. And one person's four on the pain scale, is not somebody else's, right. So your four might be my eight, for example, let's start there. The way we measure pain in humans isn't very great. But the way we measure pain in animals is also not super great, but this is the way we do it. So essentially, we will look at what we call nociceptive hypersensitivity. So we'll measure reflexive responses to pain. And so you have these mechanisms in your spinal cord that will lead to a reflex. And an example of this is touching a hot stove, and your hand will snap back before you've even felt the stimulus on your finger. Right. And so that's controlled by the spinal cord. And so what we do in the animals is we will place something hot or a little poke on their paw to look at their spinal reflex. And what we know is if you're in a state of ongoing pain, or some kind of induced pain or injury, your hypersensitivity to pain is increased. So your reflexes, you'll respond sooner. So we're looking for that earlier response to either a normally non painful or normally painful stimulus. So that's, and we do this with thermal, mechanical, so like pressure, or touch, and chemical stimuli. And then the other things that we'll do are to try to get at the emotional component of pain. And that will ask the animals to conduct some kind of choice to avoid a painful stimulus, for example, or we'll place them back into an environment in which they've experienced pain. And if they if they try to escape or avoid being in that environment that suggests that they have a memory of experiencing something they didn't like. And so these are a little bit of our roundabout ways of asking them whether or not they liked something. And then finally, the other things that we'll do or related to other types of effects that we think we can measure. One is to look at other changes in behaviors related to despair behaviors, or anhedonia, I can talk about how we measure those things. But it's kind of taking all of these behaviors together, in addition to the reflexive, nociceptive response, which is controlled primarily, you know, by pain pathways in the spinal cord, and then adding it on with all these other measures of effect.

Nick Jikomes 10:21

And a lot of these things sound pretty common sensical. You know, if an animal is exposed to some painful stimulus, if it's mildly painful, it might run into the next room. And then it'll maybe go back after a few seconds, if it's three times as painful, it might run away quicker, and or avoid going back in for longer. And that's exactly what you'd expect a human to do as well. Right? Yeah,

Monique Smith 10:43

exactly. And so that's sort of my argument is it? It makes sense that animals have pain because, and it makes sense. It's aversive to them, because pain is essentially a conserved mechanism for us to learn and protect ourselves and survive, right? So why wouldn't other mammals and even non mammals have that? And so I think where it gets a little tricky, or where we have questions about it is, are they suffering? Are they feeling the same level of emotional distress that we feel. And my point going back to the human is that we can't even say, between humans who suffers more, even with language. So there's a little bit of a problem of the way we define these things, and how we measure these things, and what we're capable of doing at this point. So yeah, so there's the emotional component to pain and the physical component to pain, and they kind of go hand in hand, but they can diverge as well. So and what we really care about is the emotional component, because that's the part that really messes up people's lives is the the despair and the distress caused by pain.

Nick Jikomes 11:52

And I would imagine that when you decompose some of these things, you know, when we think about something like the reflexive arousal that happens at at the very beginning of a painful stimulus. So again, if we go back to the hot stove example, you know, you mentioned and we've many of us have experienced this firsthand, you pull your hand away before you've actually consciously registered the emotional part of it. So there's things happening at different speeds here. And so I would imagine there's different circuits that happen, that subserve, that sort of reflexive very quick response, that that physiological arousal that initiates the behavioral reflex, and then there's probably other circuits maybe more centrally located in the brain, that are presumably going to be more closely tied to the the emotional feeling of what just happened? Yeah,

Monique Smith 12:41

no, that's precisely so that reflexive component can be controlled completely in the same segment of spinal cord that receives the information. So if you went, let's say, it's your hand, and you went above that to your cervical spinal cord, and transected, it, you would still have reflexes as long as you have muscle tone. So it's all controlled within one segment of the spinal cord. And these sensory nociceptive neurons synapse, essentially, in different ways onto motor output neurons before the information even gets to the brain. And then we know quite a lot about that. But once the information gets to the brain, we know a bit, but then things get more murky in terms of sensory discrimination versus the emotional component of pain. And there's a lot of theories about where these are encoded in the brain and, and how things go awry. But that's definitely something that the field is very much trying to work out still.

Nick Jikomes 13:40

And what about different types of pain? So for example, you can have, you can have a discrete external stimulus, trigger pain, like like a pin prick or something like this, or put shock to a mouse, something that's that's commonly used experimentally, you could also have, like internally generated pain from say, some kind of inflammatory process. Are those fundamentally different in terms of the the nociceptive circuits and how it's detected? Or is it sort of all running through the same pain pathway? Yeah, so that's a

Monique Smith 14:12

great point, I think, hopefully, no, really, hardcore neuroscientists, pain neuroscientists, that have maybe been in the field for a bunch of years will come after me for this. But um, I would say my, my understanding is that we used to think that we used to think that these types of pain are fundamentally different. And so people would study like inflammatory pain, which would be Yeah, some kind of inflammation, like you mentioned, or, and that's different than neuropathic pain, which is induced by nerve damage, and like maybe some improper healing after the fact, which might be different than chronic headache. And so we've been sort of individually studying each of these by modeling them in animals and studying them as individually We'll types of pain disorders and categorizing them. And for sure in the periphery, and the peripheral nervous system, there are definitely differences in how they're initiated and what signaling molecules they use and how they engage the central nervous system. But once we get to the brain, it I think is starting to become more accepted that maybe it doesn't make so much of a difference. And maybe the the sort of nuances between how neuropathic pain differs from arthritic pain, once we get up to the brain, if it's equally distressful, that's the component we need to try and fix, right, we need to try and help people with the distress that they feel because we were not doing a very good job at fixing the location of the problem. And a lot of these pain states are beyond healing, there's no there's no look no sort of precise location of the pain. And it doesn't seem like there's either even a precise location in the brain, it's very much more distributed. So now the idea is if we can help people feel less distressed by their pain, they might lead better lives. And I'll give you one good example of that. There's a brain region called the anterior cingulate cortex. And activation of this region correlates really nicely with the emotional response to pain. So if someone says that feels really, really bad, and I don't like it, you'll have high activation of anterior cingulate cortex. And for a variety of reasons, people have had lesions of this cortex either purposefully or because of a stroke or an injury. And when they lesion this in, in patients with chronic pain, when they bleed in the anterior cingulate, these patients can still discriminate pain, they can tell you, where they're experiencing pain, how much intensity is there, but they don't, it doesn't bother them. They're not bothered by it, they don't care. And so they're no longer distressed by their pain, and they can live with it just fine.

Nick Jikomes 17:09

And so that would start to say that, okay, they're registering the pain, they still have the sensory neurons and the spinal cord circuitry that can detect and respond to that pain. They can discriminate between painful stimuli. But then once that information gets up to the brain, something about that region, the anterior cingulate is governing how much they actually care about it, or dwell on it. And yeah, yeah, which is

Monique Smith 17:30

a little backwards to think about until like, I've spent a lot of my time thinking about this. At some point, too, we don't want to completely inhibit pain, right? Because this is a dangerous signal for us. And so on the opposite side, the flip side of chronic pain, there are people that are born that are congenitally insensitive to pain. And they often live very, very short lives, they don't always make it into adulthood, because they will break bones or injure themselves and have infections that they're unaware of. worse things that I won't talk about, but like, bad things happen to people that can experience pain. So the the goal isn't to alleviate our ability to feel pain, right, but it's to help people with chronic pain, live their lives without distress and suffering.

Nick Jikomes 18:19

And how much is known about so so on the subject of chronic pain, so the sort of the cartoon summary here would be okay, something happens to you, you might know that something is might be a discrete painful stimulus or not. But when we talk about chronic pain, it's really something's happening, presumably in the up in the brain, although not necessarily, I suppose that's causing the pain to linger or causing someone to dwell and think about the pain longer than someone who experiences it and then shuts it off. So, you know, maybe there's some kind of recurrent pattern of activity that gets triggered and just doesn't get shut off up in the brain. And so what do we know about that in terms of chronic pain, or any signals that enable pain to persist longer than it's actually useful?

Monique Smith 19:10

I mean, I think you might have summarized it better than me. But yeah, so what do we know? Not enough, unfortunately, we do know, there's this circuit, that's that can be initiated via ascending spinal cord projections. So a circuit in the brain, or it can be initiated in the cortex. And this pathway is sort of this reciprocal loop that goes from the spinal cord all the way up to the cortex and then back down all the way again, and it sort of engages slightly different brain regions on the way up as it does on the way down. And what we're starting to think, which is sort of what you alluded to is sometimes that pathway can get engaged in the periphery, right and sort of out Activate things and maybe sensitize things along that pathway. And sometimes you can engage that pathway all the way from the cortex. For example, as you mentioned, by paying attention to it, you can cognitively engaged what they call this descending facilitation of pain, or D hint, descending inhibition of pain, you can choose, in certain certain choose, I say in quotes, because sometimes you can literally choose, but there are expectations, there are things that you can do that can either make the experience of pain better or worse. And so one example of this is the placebo effect. So if you have a very high expectation that an analgesic or a pain relieving substance will work, it will literally work better. And it will literally lead to the release of endogenous opioids circulating in your body in your brain to physically relieve the pain and bind to those new opioid receptors. So it's

Nick Jikomes 20:57

all in your head, but it literally is in your head. It's nothing.

Monique Smith 21:01

Yeah, yeah. So when people say it's all in your head as like a weird insult to dismiss it? Yeah. It's like, no, no, no, everything is in your head. It's all created by your brain. Right. And so yeah, there are lots of ways you can engage those pathways, but how they go awry, and why we can't sort of stop that facilitation of the pain we don't know, and are desperately looking to figure out.

Nick Jikomes 21:27

And so another thing that you study that I want to get into, I mean, it's something that all humans are familiar with that is that we can to different degrees, experience emotions via other people, we can experience other people's emotions to some extent. This is where we get into discussions of empathy. So you know, we see someone that we usually someone we know about or care about that sad, and that makes us sad, we see them happy, that makes us happy. So somehow, these emotions can be triggered, at least in humans, in response to sensory stimuli, but instead of you know, something impinging on our body, like like a pinprick of skin, we can just see someone or hear someone in a particular emotional state, and that's sufficient to generate emotions in ourselves. Do we know anything about just Do we know anything about the very basics of the brain regions involved in that, or how that's possible are the same brain regions, say, like the anterior cingulate that are involved in sensing, you know, physical pain to the, to the surface of the skin? Also involved in that kind of empathetic response? Yeah,

Monique Smith 22:32

yeah, that's a great, great question. And definitely something we're very interested in, in the lab. And I'll say, Yeah, starting with some human research, dating back decades now, there's been some really clever studies to look at the brain regions involved in empathy behaviors. And so when we feel pain, I did mention the anterior cingulate on purpose, because it is involved in both our own pain, and watching somebody else in pain, or understanding that somebody else is in pain. And so if you put there was a bunch of work by Tanya singer and her group back in the early 2000s, that show and a bunch of other people now at this point, but if you put somebody into an fMRI, and you give them a painful shock, or some type of painful stimulus, it activates this pain pathway that I mentioned, which involves a whole bunch of different regions, like the thalamus, and the amygdala, and the anterior cingulate cortex and anterior insula, and the somatosensory cortex, there's a handful that are activated. And if you put that same person back in the fMRI, and they are then meant to watch their loved one that they brought in with them to the appointment receive the same electric shock, some of the same regions are activated, including the anterior cingulate cortex, and the anterior insula. And so those two regions, now over decades of work have shown up over and over again, in this empathic response. And so even if we think about somebody having a bad time that we care about, or if we sort of engaged these, like feelings for somebody else, those are two of the regions that are almost always activated.

Nick Jikomes 24:18

And, you know, for some people, this is a stretch, but I actually don't, I don't think this way, that probably comes from years of thinking about this stuff. Rodents, you know, rats, and even mice, to some extent, are social creatures. They have to interact with each other. There's, you know, there's the there's some mice that that the mice, like in some ways that they don't like they might attack them, they might want to mate with them, they might care for them. So they do have these social interactions. Do they display anything akin to empathy? Do they start to behave in certain ways when they see say a litter mate or a cage mate get hurt or or get a treat or something like that?

Monique Smith 24:56

Yeah, yeah. So great question. So this is like a big bulk of what we Do in our lab here. And so I'll start and say that yes, rodents of all kinds mice, rats, Prairie voles, we can talk about if you want, all show different types of empathy like behavior. Obviously, we can't ask them how they're feeling. But we can break empathy down to these component parts that seem to be evolutionarily conserved. And so at the basis of this level of empathy is like, things like motor mimicry. contagious yawning, maybe. And then above that, you get something that's slightly more complicated, like emotional contagion, which is, you know, feeling for someone else at the same time as they're feeling it. And then you get a little bit more complicated. And we have things like constellation, I'm going to come and touch you on the shoulder and console you while you're feeling bad. And then we have pro social behavior, well, maybe I'll help you up if you feel down. And then at the highest levels, you have, you know, understanding someone else's perspective and things that get into morality that are sort of conserved for humans. But let's go back down to the basis of this little pyramid, let's say that I'm making animals and rodents will show mimicry, emotional contagion, and also pro social behavior. And so and now, this has been shown in mice, rats, and voles and other rodent species, that if a mouse so in our lab, I'll say we have a model of emotional contagion. And what we do is we take a cage of four mice that are all familiar with each other two of them, they go, and they have a social interaction in a separate cage for an hour or so. And then we test their pain sensitivity. And unsurprisingly, they look very normal. These are our control mice. And then we take the other two mice from that same cage, and one of them gets an injection into its pa of some kind of inflammatory stimulus. And the other one hangs out with it in another cage for about an hour or so.

Nick Jikomes 26:57

And once we so they're physically separated, but they can see each other

Monique Smith 27:01

Nope, they're now they're fully interacting. Okay, okay. Well, we have done the physical separation if you're curious, but um, so they're fully socially interacting in a cage together, just not their home cage. It's like a new cage. And what we see is that this partner of the pain mouse, which we call the bystander actually looks like they're in full on pain. So every single way in which we can measure their pain behavior after this one hour social interaction, they are displaying pain, they have really hypersensitive reflexes. They show aversive avoidant behavior, I see.

Nick Jikomes 27:37

I would imagine, they're like walking on that Paul less. So

Monique Smith 27:40

the bystander mouse doesn't actually show any localized behavior in the paw is more of a widespread pain. So they show pain, hypersensitivity all over their body.

Nick Jikomes 27:53

They're just even more jumpy and reactive,

Monique Smith 27:55

jumpy and reactive. And yeah, let's say if you put them on a plate that's hot, they'll try and escape from that, or, you know, etc. But what's just really wild is they are almost exactly the same level of a mouse that was given an injury, like a physical injection, which is wild to me that some social cue has engaged this descending pathway to lead to a state that looks like pain in these mice. So

Nick Jikomes 28:25

basically, if a mouse has an inflammatory insult to its paw that's somewhat painful, it's going to react to that behaviorally, obviously, but if another mouse that's familiar with that mouse sees that mouse, even though it doesn't have the same injury, it displays behaviors that clearly indicate or it would suggest that it's in some kind of pain. So it's somehow picking up on something. And and displaying basically pain behavior.

Monique Smith 28:53

Yeah, you definitely nailed it. Yeah.

Nick Jikomes 28:56

Do we have any sense of what that something is? Is it sufficient to see the other mouse? Is it a smell thing? Is it all the above?

Monique Smith 29:02

Yeah, so we do know for sure that olfactory cues, so smell is sufficient to induce this. So we did some experiments where we gave a mouse the same pain injection into the paw. And we let them live by themselves, or actually with other partners who also had injections for 24 hours in a cage. Then we took the bedding from that cage, and we placed it into clean cages with mice that were just naive. And within an hour, those mice develop the same hypersensitivity to pain.

Nick Jikomes 29:38

Is there a requirement that the mice are familiar with each other? Or is this some sort of nonspecific pheromone or something in the urine or something like that? Yeah. So

Monique Smith 29:48

it works with stranger mice, they do not need to be familiar with each other. And we are currently looking at the whether or not the level of familiarity will modify how robustly they show this effect. And we don't have the answer to that yet.

Nick Jikomes 30:01

Okay, so So mice, mice can get injured and feel pain, other mice can sense that they that has happened to the other mouse and will display pain like behaviors, even though they haven't experienced the same insult. This seems to depend largely on olfaction. So they have they're smelling something. But it sounds like we don't know exactly what that something is. Yeah, so

Monique Smith 30:23

my, my grad school advisor followed up on some of this work, Andre riot Binion to look at what it was in the bedding that exists. And I'll say I'm not an olfactory neuroscientist, there were a whole bunch of different chemicals that were changed in the bedding. And so that gets to a level of complexity with olfaction that I'm not super great at. But I'll say, it's interesting for me to think about it more like this, I like to think about all of these things. translationally. And like, how does this translate to humans? How does this translate to how we perceive somebody else in pain, when we usually use vision and language as our two main modes of sensation and perception? And what I think is that, regardless of the sensory modality of the information, there's got to be some level of convergence, right. And so mice, their primary sensory modality is olfaction. So it makes sense that olfaction is the most important for them. But for humans, I think it's pretty obvious that, you know, as long as we are capable of using our vision and language, that those would be the two that are most important for us. Sorry, I went off on a tangent there. But

Nick Jikomes 31:44

it makes sense. It makes sense. They're picking up on smells. And it's not like, it's not a subtle difference. There's a bunch of smells that sound like they change a bunch of different. The chemistry is totally changes.

Monique Smith 31:53

Yes, yeah, the chemistry totally changes. And I think they are sort of chemo sensory cues that are meant for social communication in a lot of ways, like alarm cues, things to let their social partners know that potentially there's danger or injury, right. Yeah,

Nick Jikomes 32:09

I mean, it makes sense. There's, I think there's lots of examples of that nature, from from plants to animals, like, you know, things get secreted into the environment, they serve as cues to to, you know, warn warn others. Yeah,

Monique Smith 32:20

that's true. Like the trees and they're your meiosis allele pathways or whatever. Yeah. But yeah, like emotional contagion of trees. I'm not gonna horrifies them.

Nick Jikomes 32:33

Okay, so So there is this empathy, like behavior in mice? Is it limited to pain? Have you looked at it in other ways? I would imagine it was probably possible. Yeah. Yeah,

Monique Smith 32:45

we definitely have. So I'll say there's a couple of things. With this exact paradigm. We have also looked at pain relief. And so what we found here is now take your four mice, again, we have all four mice. Now we inject them all with the painful inflammatory soup, they all have swollen paws, they're all in pain. And the two mice that are controls, they have a social interaction, they look like they're in pain, because now they have a chronic pain condition. But the mouse that is with our bystander mouse gets an injection of morphine, and it's an analgesic dose of morphine, so they're no longer feeling pain, they experienced pain relief, and the bystander hangs out with them for an hour. And what still blows my mind till this day, is the bison or mouse demonstrates pain relief to the level of the mouse that got an injection of morphine?

Nick Jikomes 33:41

Yeah, that's that seems very much akin to the placebo effect, instead of instead of giving the other mouse, well, I guess you probably are injecting it with a with a saline control. But it sees the other mouse, who gets the morphine and feels that pain relief from the pharmacological

Monique Smith 33:57

Wild Thing is placebos usually based on our expectation of what should happen? Or what Yeah, yeah, none of these mice have had morphine. So what are they communicating to each other?

Nick Jikomes 34:07

Yeah. And it's not like they know what's about to happen?

Monique Smith 34:10

Exactly. They have no idea what's happening to them. So that's a really wild one that we can see this transfer of pain relief. And then the other one that a lot of people use is called observational fear, or social transfer of fear, whatever you want to call it. And what we do here and so sort of a different modality of information, fear instead of pain, is that one mouse gets electric shocks. You mentioned, this is something that we use in behavioral paradigms, and the other mouse watches. And when mice get electric shock, they do this very stereotyped freezing behavior. That is sort of innate to them when they're in fear, which makes their prey animal and a lot of their predators eat them because they they see movement. Right. And so if they're afraid they freeze. And what you see is the mouse observing the mouse received the shocks will freeze to the same degree as the other mouse, suggesting that they are sort of taking on this behavior that's more indicative of what the other mouse is experiencing. And what's really interesting is, if you put that mouse back into this experiment, this experimental box the next day with no other mouse, they'll freeze a whole bunch, because they remember watching another mouse be shocked. And so you've got this cool observational learning, based on this observational fear paradigm. And so, yeah, so we have pain and pain, relief and fear. And those are some of the most widely used measures of emotional contagion. But I did mention this other prosocial level of empathy, like behavior that we see in rodents, and there's some really cool ones that they will, that rodents will do. So the first one is, if you put a familiar mouse with one of their friends, that got a stressful shock, or even a pain stimulus, they'll come over and allo groom and groom that mouse, and that relieves the distress in their friend. So that's pro social, allo grooming. And that's one way we measure pro social behavior. And then the second one, which is really cool. This is based on Peggy Mason's work, and some others, if you the original work with lists rats, but now it's been done in mice, too. If you trap a rat in a little tube, they really don't like this, the restricted, it's not fun for them. But you place a lever on the outside, one of their friends will come and press the lever to get them out and release them from the tube. And they'll even they'll even do this and four go like a chocolate tree and things like that suggesting that they understand their friend is in distress, and they will go and help them get out of that situation.

Nick Jikomes 36:58

So they're actually foregoing a reward in order to do that, I would presume, are they completely separated? Like, can you rule out that they're just letting them go? Because they want to play and smell and interact or something like that? Yeah, so

Monique Smith 37:09

they have done? They've done lots of experiments to sort of adjust the state in each mouse and rat or mouse. So one question is, yeah, is this really to help the other mouse or rat? Or is it Yeah, just because they want to play or just want to get a social, whack the lever and whatever. And what they'll do to test that is if you give an Anzio, lytic, like dyads, a PAM, something that relieves anxiety and distress and dampens down your sort of stress response to the one in the tube, the one on the outside will not readily release them. So

Nick Jikomes 37:48

they're picking up on some kind of anxiety like behavior, while they're while they're restraint. So if you if you use a drug to take that anxiety away from the one that's restrained, they don't see a signal of distress.

Monique Smith 38:00

Yes, exactly. So they need that distress signal from their partner. Additionally, they won't release a stranger, right? It's not some curiosity or just something else, they'll only release a familiar partner. Interesting.

Nick Jikomes 38:13

And for for any of these types of empathy, like behaviors? Do we know that there's critical brain regions involved here that are necessary for these behaviors? Have you looked at people lesioned parts of the brain and seen these effects go away? Yeah, so

Monique Smith 38:28

I will say I'm, we're pretty early in this field. When I was when I was in grad school, I'm aging myself right now. But a little over 10 years ago, there was the only model people really use to study empathy, like behavior was the observational fear model. And there was one other paper titled The Social modulation of pain by Jeff moguls group that had been used to explore empathy, but wasn't widely used at that point. So I would say we've only had about 10 to 15 years of work in which people started to really trust and believe and replicate that these behaviors exist. And the behaviors must be well validated, as I'm sure you know, to start to look at the neural circuits. So let's say we do know a bit though there's been a handful of studies, I can tell you first about our own, and that that which has been done about with the observational fear. So we know again, back to apparently my favorite brain region is the anterior cingulate cortex is required for both the acquisition of observational fear for that freezing behavior, as well as the social transfer of pain and the social transfer of analgesia. So if you inhibit the ACC, if you inhibit it with drugs, or you inhibit it with optogenetics, and sort of dampen down the signaling in that region, the animals will not display any of that emotional contagion in addition, but what's interesting is what I showed in some of my work in my postdoc is Is the anterior cingulate cortex sends projections down to a region called the nucleus accumbens, which is a region that's very important for reward and receives a lot of dopamine as well as serotonin and other non neuromodulators as well. And what we found is if you inhibit specifically only the neurons from the anterior cingulate cortex that project to the nucleus accumbens, this will prevent the social transfer of pain, and it will prevent the social transfer of analgesia, but it will not prevent the social transfer or observational fear, indicating that even though the anterior cingulate cortex is necessary for all three of those behaviors, it's sort of gating where that pathway projects to based on the type of information and then conversely, the anterior cingulate cortex also projects to the basal lateral amygdala, and others prior to me, K Ty, and he ception had done a lot of work to show that the anterior cingulate cortex to the basal lateral amygdala are required for observational fear. But now if we did the experiments, where we inhibited that pathway during a social transfer of pain and analgesia, and it had no effect. So it really truly looks like there's this convergence in the anterior cingulate cortex, but it's using these different output pathways, depending on the type of information

Nick Jikomes 41:28

and the type of information because that's gonna necessitate a different behavior, presumably.

Monique Smith 41:32

Yeah, yeah, it does. Yeah, it necessitates a different type of behavior. And it's engaging. Yeah, probably different downstream mechanisms and how they respond, right. But what's interesting to me, I truly thought when we were starting those experiments, it would be based on the valence thing we were talking about negative versus positive. I thought pain and fear would engage one pathway and pain relief would engage in another pathway. But that wasn't the case. So valence must be encoded somewhere differently. But yeah,

Nick Jikomes 42:04

I see. When we think about the anterior cingulate or when researchers who study humans think about the anterior cingulate, what is it most famous for? I guess, in other words, was it surprising that this brain region came up in your field looking at these types of behaviors? Is that region also known for other things? Or did it did it all make sense? It

Monique Smith 42:25

didn't make sense, there was enough work to show that this would make sense I'll say it's probably most known for attention. Basically, anything you pay attention to, that is salient or important to you will likely involve the anterior cingulate cortex activation. I'm just

Nick Jikomes 42:45

gonna ask, are there any human psycho pathologies that that are characterized by abnormal into your cingulate activity? Yeah,

Monique Smith 42:53

so psychopathy is one where you'll see really dampened response and like social social personality disorders used to dampen responses in the anterior cingulate cortex. If you want me to go off on a tangent, I'll tell you about a really cool study by Christian Kaiser's group, where they went into a prison. And this was a grad student that did this project with I also think is just like a whole other level of hardcore that I am not. But um, they put prisoners who scored very high on a level or sorry, a questionnaire for psychopathy, and they didn't tell them what they were doing. But they just scanned their brains while they watched photos of somebody receiving painful stimuli

Nick Jikomes 43:40

before before you describe more. For those who don't know, can you just describe what psychopathy is? Oh,

Monique Smith 43:45

sure, sure. So it's a personality disorder that is signified by a lot of like sort of personality abnormalities or atypical behavior, where you don't have a lot of empathy for other people. It kind of ties a lot with narcissism and more self serving behavior, and things like that. And so it also correlates with violence a lot of times, but apparently, a lot of CEOs also have high levels of psychopathy. So that tells you a little bit about what type of personality this is.

Nick Jikomes 44:19

So I mean, at least roughly speaking, is it fair to call this disorder? It's, in some ways a disorder of your ability to model other people in your own mind. So they're very self centered, but they don't have a lot of empathy. They can't really sort of imagine themselves in someone else's shoes.

Monique Smith 44:37

Oh, that's what we thought. I think maybe psychologists have known this for much longer than me. But when I tell you the results of this study, it's kind of wild. So I would have thought that they aren't able to engage this empathy. They just don't feel for other people. They aren't able to understand what other people are feeling or they don't care or something. But What they did is so yeah, they didn't prime them. And they just showed them pictures of someone receiving pain. And this did not activate the anterior cingulate cortex or the insula, or any regions, we would think would be involved in empathy very strongly, it kind of was just like engaging like different attentional pathways, and that's about it. But if they put them back in the FMRI said, We're or they took a different group of people, I can't remember, but they said, We are studying empathy. And we're going to show you pictures of people in pain, and we want to see how you react, then they engage the anterior cingulate and the insular cortex, so they can choose to engage the quote, unquote, correct regions, for feelings of empathy.

Nick Jikomes 45:40

So I could correct me if I'm wrong, a natural interpretation of that would be that they understand how to engage in that in empathy if they want to, but it's not automatic, it's not reflexive. They don't choose to turn it on by default, they only choose to do it if they think it's going to be useful, somehow,

Monique Smith 46:04

or Yeah, so I don't know how far we could go with like the interpretation of that. But very interesting. And sorry, that was a total tangent, but I just think it's a cool thing to think about. So anterior cingulate cortex is, there's also dampened activity and empathy like behavior in the anterior cingulate cortex and dementia, and dementia. Interestingly, in autism spectrum disorder, there can be a dysregulation of activity in a cingulate cortex, but there can be changes in empathy, like behavior in both directions. So they're all deficits, and there can be increases in certain types of empathy behavior. Interesting.

Nick Jikomes 46:45

Okay, so I guess, lots of stuff there. But the anterior cingulate is very important for these types of behaviors, the empathy like behaviors that we talked about in mice, empathy and, and other things in human beings. So this brain region has come up over and over again, it's connected to multiple other brain regions that I think we'll probably talk about a little bit that are involved in things like reward and fear, learning and all of these things. Another hot topic right now related to things like empathy, things like pro social behavior, and emotional distress, especially the treatment of emotional disorders, is MDMA. It's a topic I've covered on the podcast quite a bit. So I don't know how much we need to dwell on the basics. But let's just go very, very concise. What is MDMA? And what do we know about its behavioral effects in rodents in particular, for

Monique Smith 47:40

sure, okay. So MDMA, methylene, deoxy methamphetamine, which is also known as ecstasy, which the generation before me used to call a rave drug, which I think it's funny, but is a drug that was developed, you know, many decades ago, and actually, before it was made a schedule one was used in couples therapy, and, and was actually used in medicine before that was made illegal. And so lots of people use MDMA, in party situations, and have reported over the years that this increases pro social behavior, as well as empathy behavior, and it's even been labeled in in pathogen. And so as you mentioned, it is used as a treatment for PTSD along with psychotherapy, and that has gone through clinical trials and has been extremely successful, which along with this sort of revolution of all these other psychedelics has ignited interest in the use of MDMA as a potential treatment for other types of social dysregulation. So back in 2016, I was in my postdoc, and I had this model that no one quite believed me yet, but I thought was related to empathy. I told my postdoc advisor, I think we should give them MDMA. Because if it's a pathogen and humans, maybe it's an in pathogen mice, and this wasn't by accident, it wasn't just my wild idea. There was another amazing postdoc in the lab named Boris Heifetz, who is just really a leader in the field of psychedelics. Now, he was working on some studies that showed MDMA and mice does increase pro social behavior and, and social interaction. And they related that to social reward. So I took the dose that he was using for pro social behavior, and I gave it to the bystander mice before the social transfer

Nick Jikomes 49:32

of pain before you go on when you say MDMA effects, pro social behavior in mice. What are some examples in mice? Sure, sure. Sure.

Monique Smith 49:38

So what Boris was doing at the time, there's some pretty simple assays. Honestly, we'll just ask mice, how long they like to hang out together. We'll put them in a cage together. And then we'll measure all the amount of time they spend sniffing each other grooming each other following each other around and being in the proximity of one another. And then another one is called a three chamber assay where You can put two mice under little cups, like little pencil cups. So imagine they can stick their noses out and they can see and hear and smell. And then you put a mouse in that can roam around freely, and you ask who they want to hang out with. And most of the time, they'll go to the chamber and sniff the mouse that they're more familiar with, or that, you know, they prefer to hang out with. And so if you give one of those mice, MDMA, they are both of the mice, the one who's roaming around and one of the ones under the cup, they'll spend more time with the other mouse on MDMA. And then they'll display sort of preference for environments in which they experienced MDMA with a social partner. They've actually a distinguish that from just the rewarding properties of MDMA, because obviously, it also causes euphoria and things like that. But yeah, so that is the pro social behavior. So kind of like approach hanging out around another mouse when you're on MDMA seems to be more rewarding.

Nick Jikomes 50:58

Okay, and then the experiment that you were about to describe?

Monique Smith 51:01

Yeah. Okay. So, as I mentioned, Boris was doing these pro social studies with MDMA. And I'll just throw a nugget in there that he determined it was also serotonin signaling in the nucleus accumbens, that brain region I mentioned before, that was an

Nick Jikomes 51:17

icy so it had been MDMA. We know that it increased the serotonin levels in the brain, among other things. But what they showed is that some of these pro social behaviors were related to serotonin in this reward region, in particular, yes,

Monique Smith 51:29

but typically, if you took out serotonin signaling, or increased serotonin signaling and the nucleus accumbens that was responsible for those pro social effects, and others that had previously been in my lab. Well, Dolan had also shown this was true, and shown that oxytocin and serotonin signaling might coordinate so