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 somehow within the nucleus accumbens to promote pro social behavior in the influence of MDMA. So
Nick Jikomes 51:56
if MDMA does these things, and MDMA isn't a pathogen, and it does all these pro social things. If I think about the experiments you told us about before, with the social transfer of pain and stuff you might imagine, are you you'd imagine that MDMA would tie into that and probably enhance that ability?
Monique Smith 52:13
Yes, exactly. And so back in the day, I decided to inject a bunch of these bystanders with MDMA. We weren't quite clever enough at that point. And we just still did an hour long social interaction. And what we found was, and I'll get back to why it wasn't very clever, it's just it was a very annoying experiment to do. What I found was after the one hour social interaction, normally we'd see bystanders recover within 24 hours, they'd go back to normal. But if they had been given MDMA during the social interaction, they didn't recover for one to two weeks. So they maintained that pain response for one to two weeks. But as I mentioned, that's a very long, annoying time course to to as an experimenter in the lab that also is very difficult to look at the neural mechanisms using the techniques that we have on a time course that long. So we designed a study where we shortened the social interaction to 10 minutes long, what we wanted was an amount of time where a normal bystander mouse without MDMA, just injected with ceiling would not acquire any pain behavior. But if we gave them MDMA, then maybe they would. And that's exactly what we found. If you give MDMA and just give a 10 minute social interaction with a pain mouse, the bystander mouse will acquire the pain. And it will last for about 24 hours.
Nick Jikomes 53:37
Okay? So the MDMA makes it easier for them to acquire acquire the pain by by witnessing it in another mouse. Yeah,
Monique Smith 53:44
yeah, exactly. And so one reason why this is, this is interesting for so many reasons, like, how does it work? What is it doing? But one reason I like to mention that this is interesting is we think that increasing empathy is always a good thing, right? We want to increase empathy, we want to be more empathic,
Nick Jikomes 54:01
but in this case, it was more painful, more painful. And
Monique Smith 54:05
I actually think if you want to come back to it, I can relate that back to humans, but I'll say, we showed the same thing was true for the social transfer of analgesia, so you can shorten that interaction to 10 minutes. And a bystander interaction with MDMA would acquire the social transfer of analgesia as well.
Nick Jikomes 54:24
Now, all of that sort of makes sense. That would be I guess, my what I would have expected to happen from something like MDMA, based on what's known about it in the literature, and also what's just sort of the reputation as from people's anecdotal experiences with it. I want to sort of parse something here that I think is interesting that I know that you know about but I don't think most people know about, which is, like you said MDMA, as it's called. It's marketed if you will, as an pathogen. It's sort of known for the the pro social side of things people like to take it, it feels good. They want to hug people and hang out Do you even see the mice wanting to hang out with each other? But does it? Is it really an pathogen? And what do we actually know there? Let's start with a human literature.
Monique Smith 55:10
Ah, yeah. So this is there's definitely a lot of argument there. Right about what exactly is MDMA doing? Does it always increase empathy and pro social behavior? Can we think about it strictly in that way? I would say that there's conflicting research, there's even some research to show that in male humans, it will increase pro social behavior, but not in females. But without just citing a bunch of literature that's out there that sort of conflicting, this is what I think. I think that MDMA acts on serotonin and oxytocin and these neuromodulator systems, which can have very, very different effects, depending on the circumstance, depending on the circumstance that the person is in, including their social, psychological and environmental circumstance, depending on the other hormones they've already got. So cycling, depending on their internal state and their mood, do you know what I'm saying? And so I think that MDMA, and a lot of these other psychedelics can and just sort of influencing these neuromodulator systems depends on the context. If you want example, oxytocin with that, this is the love drug, we're going to fix everything, we're going to get people to intranasal oxytocin, and it's going to fix all these social deficits. And then there were some clinical studies to show that intranasal oxytocin can actually increase violent behavior. And this is because of the context in which it was given. And so I'll stop rambling there, but I think the context is really important. Yeah,
Nick Jikomes 56:54
yeah, I think you're alluding to the literature on oxytocin, where, you know, just to reiterate what you said, for listeners, you know, oxytocin is sort of known as the the love hormone, or the cuddle hormone, or whatever, and you're doing deeds, see it correlate with those types of behaviors. But as you mentioned, it also can instigate other types of behaviors like violent behaviors. And I believe there's some literature out there that shows that it modulates basically things to do with in group out group discrimination. So you might act more pro social towards those in your perceived in group but actually the opposite way against others.
Monique Smith 57:30
Right? No, yes, you're Precisely right. And thank you for clarifying that. And that's important, right? Because if we just give this broad neuropeptide, we can't expect it to have a very specific effect. And I think if we go to like across every sort of situation, and I think if we look at the success with MDMA, that's been with psychotherapy, in addition, right, and I think that textual environment of the psychotherapy, and maybe talked about this on the podcast, is important for its positive effects, this sort of setting that expectation, and properly engaging the environment that you need for the outcome that you want. These expectation ideas.
Nick Jikomes 58:12
Yeah. And one more wrinkle. I want to get into here before I ask you to describe some of the results you were involved in. Not too long ago, we talked about the potential sex difference here. We're talking about context and how important that is. There's also two, MDMA isomers. And sometimes you get a racemic mixture that's given to patients or two subjects, sometimes you get one way or the other. I believe there's at least one or two studies out there showing that some of the classic effects, quote unquote, of MDMA, are dissociable. Based on which isomer you're using one of them might instigate more of the pro social behaviors, the other one might have more stimulant like behaviors. Is that your understanding? Is there anything we know about there?
Monique Smith 58:54
Oh, wow. I'm going to say that You surprised me with that I wasn't actually thinking about the racemic mixtures. But it's definitely a possibility. I'll say some really good evidence. I don't think the evidence is there for MDMA yet, but I think that the evidence is definitely there for ketamine. Absolutely. The Case for ketamine. And this is sort of a drug that's been used to treat depression. And we know that one of the isomers is much better than the other. Right. And so I wouldn't be surprised that we find the same thing to be true for MDMA. Interesting.
Nick Jikomes 59:27
So you had a paper come out not too long ago, that was really interesting. I took a look at it. Can you can you set up the basic design here and what you guys were trying to get out?
Monique Smith 59:38
Yeah, sure. So first, I'll say I sort of told you my involvement in in actually conducting the experiments of those that was in this paper. And then the first author is Ben Ryan, and he's an amazing science communicator, and he was a postdoc that I co mentored with Rob polenka, and then a bunch of other really Amazing students and trainees in both of our labs mine in Rob's lab. So I want to say that first. So when I sort of moved on to my faculty position, Ben took over this project and was just really amazing and brought like a lot of energy and excitement for the project. And so we started off with that basic set of pilot studies that I had done looking at the 10 minute social interaction with MDMA. And we were wondering, you know, where's this happening in the brain, we know that MDMA releases serotonin, but as we mentioned previously, the anterior cingulate cortex is important for social transfer, but also the nucleus accumbens is important for social transfer. And the main source of serotonin in the brain comes from the dorsal Rafi and we know that the dorsal Raphe, Ace and serotonin to both the nucleus accumbens, and the anterior cingulate cortex. So our next question is, which of these regions might be responsible for this increase in empathy, like behavior that we see with MDMA? And so, Ben, and some others did some really clever experiments, looking at brain activation patterns in both the anterior cingulate cortex and the nucleus accumbens following an injection of MDMA during the social transfer of pain. And essentially, what they found was that there was a big increase in activity in the MDMA injected bystanders in the nucleus accumbens specifically. And we didn't see that in the anterior cingulate cortex. So that indicated to us that maybe it was serotonin acting in the nucleus accumbens, and that, in addition to Boris Heifetz data will Dolan's data, you know, it was pretty convincing that we should look at the nucleus accumbens as a target for this. And so then been really fully characterized the social trend, the MDMA enhancement of social transfer of pain and analgesia. And he decided to micro inject, which means like to put directly into the nucleus accumbens, a tiny dose of MDMA to see if it would work. And what that does is it sort of takes out all the other brain regions that might be involved when you give an injection and it goes throughout the entire brain. So
Nick Jikomes 1:02:13
if you could just give an animal MDMA, it's getting into the bloodstream going everywhere in the brain, more or less, everywhere that it can go. But in this case, you're going to compare that to putting it in this one brain region, and it's going to be limited just to that spot. Exactly.
Monique Smith 1:02:27
That's exactly it. And suffice it to say that that was sufficient to enhance the social transfer of pain and analgesia.
Nick Jikomes 1:02:34
Okay, so this this effect where they they see the other mouse in pain, they display indications of pain themselves that replicated when you put MDMA just in the nucleus accumbens?
Monique Smith 1:02:46
Yes, exactly. That's precisely right. And I'll also say that MDMA has actions on serotonin, it may influence oxytocin non directly, but we also know it acts on dopamine and transporter, so another drug that acts on dopamine is methamphetamine. And so Ben did a really clever control and gave methamphetamine to the animals to see if that would similarly enhance the social transfer of pain, and it did not. So that did suggest to us that it's probably not dopamine that's driving this effect in the nucleus accumbens. It's more likely to be serotonin. So then we started to chase down how serotonin might be involved. And by the way, sort of interestingly, and uninteresting ly everything we found to be true for the social transfer of pain was also true for the social transfer of analgesia. So MDMA directly into the nucleus accumbens was also sufficient to enhance the social transfer of analgesia.
Nick Jikomes 1:03:46
Okay, so you've got the nucleus accumbens. It seems to be a key brain region here MDMA, if you put it just in that brain region, you you get it does what systemic MDMA does, you get the social transfer of pain and analgesia or pain relief? It seems like it's serotonin going into the nucleus accumbens. That's key for this effect. We're able to show that directly.
Monique Smith 1:04:08
Yes, exactly. Thank you for setting me up so nicely. And so next, we essentially put some inhibitory options, which it allows us to target specific neurons and we took the serotonin neurons from the dorsal Rafi which I mentioned, and we shined light to inhibit with this hilar rhodopsin or no, I'm sorry. excitatory opsins rewind, let me re explain. Okay, so we put channel rhodopsin, which is an excitatory optogenetic virus into the dorsal rafting and we shine light over the nucleus accumbens core and this essentially just activates all the serotonin release coming from the dorsal Raphe Bay into the nucleus accumbens. And we found that this was sufficient to also enhance that social transfer of pain and I don't know, Arizona and all by itself.
Nick Jikomes 1:05:03
I see. So you put MDMA into this brain region, it's going to elicit serotonin release and do other things, and you get the social transfer of pain and pain relief. But then if you do a separate experiment where you just directly stimulate serotonin release in the absence of MDMA, in this brain region, you get the same effect.
Monique Smith 1:05:21
Right. And that's fascinating for two reasons. One, because it's only serotonin, we thought maybe oxytocin might be involved or something like that, too. And then two, because we were engaging sort of, you know, super, super threshold firing of these neurons, but firing of actual neurons in our brain instead of adding a drug. And that doesn't normally exist, right. And so we show that our normal neural pathway is capable of producing this effect, and that it seems to primarily use serotonin. And we
Nick Jikomes 1:05:54
mentioned previously that there's some stuff in the literature suggesting that men and males and female humans might respond to MDMA in somewhat different ways. Can you explain the interesting sex difference that you found in this experiment? Yes.
Monique Smith 1:06:08
Okay. So some of I don't know if all of this is published in this paper, because it got very confusing. So I'll get to tell you that T behind the scenes, okay. So when we started these experiments, then I had done it in males and females, then started with males. And then he did the female experiment, and we're talking all the way just the injection systemically of MDMA. And it didn't work. It didn't work. And he tried it several times, and he couldn't get the enhancement of the social transfer of pain or analgesia to work in female mice. And so we're like, well, apparently, it doesn't work. Let's just do the experiment in the males and figure out the mechanism. And then we're going to come back to the females and see if we can find out what is different. And so fast forward, he did a lot of these experiments in the females and nothing worked. I think he did MDMA directly into the nucleus accumbens, he did the channel rhodopsin serotonin release, and nothing worked. But he and I were chatting, because he's as up on the literature as I am. And there's this paper by Jeff mogul who did one of the original empathy studies in mice, that shows that the sex of the experimenter can impact the outcome of different pain behavior assays in mice. And so what we did is we had a female experimenter run the study in the lab, because I was no longer in the lab, remember,
Nick Jikomes 1:07:41
run the study. So the piece that you're seeing right now is not published yet. They did
Monique Smith 1:07:45
not publish. Okay. Okay. You have no mechanism to explain. Yeah, okay. Okay, interesting. So this is not in the paper. But it's interesting that you asked about it. Yeah. So spoiler alert, when the female experimenter ran the experiment, it worked.
Nick Jikomes 1:08:03
So you don't see social transfer of pain in female mice injected with MDMA? If a male experiment a human male experimenter, does that experiment, but it works just like you described earlier. If it's a female experimenter, yes,
Monique Smith 1:08:18
that is correct. And the idea behind this, which was put forth by moguls group and very nicely shown was that there are some chemo sensory cues. So something about sweat or the way that we smell that the mice detect and respond to and in male mice and female mice respond differently to cues from male and female human experimenters. And these cues can engage a certain level of HPA axis. And like stress response, basically,
Nick Jikomes 1:08:49
is the basic result here that in general, female mice get more stressed out in response when they're around a male human compared to a female human.
Monique Smith 1:08:57
So that is not what Jeff mogul found, he found the opposite to be true that mice would show this big stress response to male experimenters. And then they wouldn't show pain behavior. But they would show it if they had a female experimenter. So this is where it got really confusing. We were like, We don't know what to make of this right now is that we don't know why the females didn't show this. And it could be and I'm getting a little bit into the weeds here. But there's this theory that with empathy, you have this inverted U shaped response of activation, stress activation that you need. If you have a very low level of stress, stress activation, watching someone else in pain, maybe you're not going to do anything. It's not going to bother you and you just go about your day. If you get sort of a moderate level that might engage a lot of things in you to feel distressed enough to want to go help them to do something. If you're too stressed out, like you're too, too overwhelmed, your own life is in threat, right? You're not going to engage them But the behavior because it doesn't serve you. Interesting.
Nick Jikomes 1:10:03
That's actually an interesting tie into the imaging studies you talked about earlier with the prison inmates, because my understanding is that psychopaths tend to have very low baseline sort of stress and anxiety. Yeah,
Monique Smith 1:10:15
yeah, no, that's a, that's a really good point, it could just be that they don't engage the stress response in the same way when they see somebody else in distress, and that just doesn't drive. Or they don't even have the ability to get to that threshold that would then drive the empathy, like behavior. That's really interesting.
Nick Jikomes 1:10:32
Anyways, okay, so, you know, this is very much still in the works, you don't know exactly what's going on. But that phenomenological result is robust. The sex of the mouse matters and the sex of the human experimenter, doing the experiment matters.
Monique Smith 1:10:47
I mean, yes, 100%, what we need to do more is run. So it got a little complicated, too. And this is how sciences. That was, we ran a lot of these experiments at two institutions. And we were just trying to get the project wrapped up. So we need to try and replicate that basic finding in male and female experimenters at my new institution and make sure it holds up. But one thing is sure that, as a male experimenter, Ben only saw effect in male mice. And we figured out the mechanism of that, and he was unable to figure out the mechanism and females.
Nick Jikomes 1:11:21
Got it. Yep. So the papers out is that guy doing those experiments on the males. And you Okay, and just to summarize, for people that result is MDMA enables mice to do this social transfer of pain and pain relief, male mice, at least when a male experimenter is doing it, and that involves serotonin release in the nucleus accumbens, which is very important in brain region for reward learning, drug addiction, all sorts of stuff like that. I want to go back real quick. See, she mentioned that he did in a controlled experiment where he used methamphetamine as opposed to MDMA, which is methylene deoxy methamphetamine, and they're both psychostimulants, but they're done. Nonetheless, different drugs. The methamphetamine did not elicit the social transfer of pain effect. Given what you guys figured out here, the involvement of serotonin release, in particular in the nucleus accumbens. Does that say anything about you know, what MDMA is doing in the brain region? And whether or not that might tie into its addiction liability, or its abuse potential and things like that?
Monique Smith 1:12:27
Oh, that's a really good point. Um, yeah, I think, well, we get into some sticky water here. Water, sticky mud, I don't know what I like to be very careful when I talk about abuse potential, and addiction, because drugs aren't innately you know, they aren't addiction themselves. That's a behavioral disorder. That's like very complicated. But I will say, with regard to dopamine, pretty much all drugs that become that lead to addiction and addiction, like compulsive seeking behaviors, lead to a huge increase in dopamine, right? And particular brain region right? In the nucleus accumbens, right in this pet, same pathway. And so, but and so do other rewarding things, which may or may not be addictive, like food and video games, and all that kind of stuff. So we do know that dopamine is integral and very important to addiction. But that doesn't mean that everyone who takes a drug that leads to a large release of dopamine will become addicted. And that doesn't mean every drug that acts on dopamine is addictive, if that makes sense. But with that said, I would actually say that in terms of the liability for abuse, the evidence just isn't there that MDMA is as troubling or concerning as things like methamphetamine or heroin or fentanyl, right? Like people aren't seeking it in the same ways and using it in the same ways, as methamphetamine or drugs that primarily act on dopamine. And
Nick Jikomes 1:14:10
does that basically fit with what we know about the neuropharmacology? There is MDMA, causing less dopamine release than something like methamphetamine? Yes,
Monique Smith 1:14:18
that's true. That is definitely true, that there's a less degree of release because methamphetamine actually has a couple mechanisms to increase dopamine at the synapse. And, and yeah, MDMA causes sort of less overall dopamine and then more serotonin.
Nick Jikomes 1:14:38
One last piece to this paper we've been talking about. So MDMA, super interesting in many different ways. A lot of people know about the clinical trials that have been going on with respect to PTSD. But another major area of concern that has to do with social behavior and social deficits, is autism and you guys did another A group of experiments that speak to that. So what happened there? Yeah,
Monique Smith 1:15:04
great. So this was the last part of this paper. And I'll actually throw in some unpublished data to for fun. So a student in my lab, Sabrina toy was doing experiments in mouse models of autism. And we have a couple different mouse models of autism. And she was very interested in this and came to my office and said that she really wanted to look at the social transfer of pain in different mouse models of autism to see if it was altered in any way. And essentially, we have a couple types of models, we have genetic models, where we can knock out some gene that we know is altered in human patients with autism spectrum disorder. And then we have what we call phenotypic models, which are mouse models that aren't missing just a single gene or something that we can target in humans, but they show all these behaviors that look like behaviors we see in patients. And so what Sabrina did is she looked at these different mice, btbr, mice, biopsy mice, and shank three knockout mice. And she found that none of them displayed the social transfer of pain, which was really fascinating to us. And right at the same time was when Ben was working on the DMA project. And so he replicated the finding that shank three knockout mice do not show social transfer of pain, which is interesting in itself. Because it suggests some deficit in acquiring this behavior through social cues, right?
Nick Jikomes 1:16:38
This genetic model, so you knock out a gene that encodes something called the shank three protein, what is that protein? Do we know what it's doing? In the brain?
Monique Smith 1:16:45
Oh, um, you know, I think we only know sort of the dysfunction, what happens when we knock it out? I think that's mostly what we know about it. And we do know that that human patients have different disorders show dysregulation is gene. Okay. Does that make sense?
Nick Jikomes 1:17:04
Okay, so there's a tie to human autism, because we've seen that in people. And we know that it leads these behavioral changes and things in mice, but we don't really know the molecular details of what this thing does.
Monique Smith 1:17:15
Yeah, yeah, for sure. Um, okay, so but to say that it's one of the best genetic models we have, because it's not a huge proportion of patients, but I think it's about 3%, show some changes in his gene function, which is actually a pretty good for a mouse model. And so it's one of the most robust that we can say is translationally. Relevant. And so this mouse does not show the social transfer of pain around us. Yeah, if they interact with the familiar wild type littermates that they grew up with, who's in pain, they don't acquire any of that pain. But then Ben wanted to see if we give these mice, MDMA, and, again, give them MDMA in the nucleus accumbens, would this be sufficient to rescue the social transfer of pain. And that's exactly what he found. And so he put shank three knockout mice with a wild type partner, so a mouse that doesn't have this chain deficit, but grew up with them was born in the same litter. And the wild type mouse is in pain, the shank three knockout mouse gets an injection of MDMA. And guess what, after an hour long social interaction, they acquire the social transfer of pain, which to me, is pretty incredible. Because it's, it's, it's allowing for a behavior that didn't normally, you know, exist or wasn't, didn't happen in these circumstances in these mice. And he did show that this was due to nucleus accumbens activation, and this also happened for the social transfer of analgesia. And then very finally, the same thing was true if you activate serotonin signaling so via dorsal Rafi stimulation into the nucleus accumbens core in the shank, through knockout mice, you see this social transfer of pain?
Nick Jikomes 1:19:11
Wow, in a lot. Yeah. No, I mean, yeah, there's just a lot of interesting results here. What, what are you guys working on next? Like, is there something directly that follows this workup?
Monique Smith 1:19:21
That's a good question. So we're we are working on some sort of tangentially related things. We're not directly following up on serotonin at this moment. But what we are doing is looking at oxytocin as well. And a graduate student in my lab recently found that oxygen intranasal oxytocin, similarly enhances the social transfer of pain, and maybe even more robustly than MDMA injection. So that's very interesting to us because we show that this MDMA effect, you know, could be replicated with serotonin signaling Hang. But it appears now that we're sort of moving forward that that's not the only neuromodulator involved, the oxytocin might be involved as well. So we're actively pursuing that. And then additionally, we now have started looking at this pro social allo grooming behavior. We hypothesize that the sort of brain mechanisms responsible for the emotional contagion might be slightly different or overlapping, but divergent from those that initiate pro social action. And that's something we're very interested in. So maybe the serotonin signaling drives this emotional contagion, and maybe the oxytocin might be engaged more during the prosocial constellation behaviors. So that's something we're looking at. I could go on, I could go on for a little while. But that's what we're looking at directly related to this project. Yeah,
Nick Jikomes 1:20:53
I'm on a different level two, I think a really interesting concept is this notion of emotional contagion. And one thing that's kind of interesting about empathy and emotion to me, as you sort of touched on this, at the very beginning, I think, we normally think of empathy as being like a good thing. We want to be empathetic people, I want to feel your happiness, I want to be able to help you and you're sad. We talked about psycho pathologies like psychopathy, these are bad things that tend to lead people to behave in bad ways. But Can Can we have too much empathy? Can you have too much of a ability to feel others pain? And what would that look like? Do we actually maybe see that in our world as humans?
Monique Smith 1:21:35
That is a fantastic question. And I think about this a lot. So I have some evidence to back this up. But I'm sure I could get in some heated debates with people. But I believe that things like caregiver burden, physician burnout, I actually think these things are basically an overload of emotional contagion. That's unregulated. And that there are physiological reasons why continually witnessing someone or being around someone in pain, can have physiological actions that are outside of the things that people usually blame that on, right, like caregiver burden, people say, Oh, is increased stress, it's lack of sleep, it's financial pressures. It's all of these things. But I think that there's a physiological mechanism that we might be able to tap into when thinking about emotional contagion. And there's some evidence for that in humans, such that like spouses of chronic pain, patients actually have more hypersensitivity to pain, and in similar regions as their spouse, which is interesting, and people haven't really looked into, especially the localization, like how does that happen? And why? Right. So I think this increased emotional contagion is something we need to pay attention to. And I'll say, you know, if you look at the DSM, or ways in which we categorize different conditions, and mental illnesses and pathologies, there's no sort of hyper empathy. But if you go ask people, and you go search around on the internet, there are lots and lots of people, that people that say that they have so much empathy, they can't function. Like I heard, it was either a podcast, or maybe I read an article about a woman who reports this, and she can barely leave her house, because she has like, such a intense reaction to other people's emotions. And so I think it's out there, I think it's just something we haven't been paying enough attention to, or didn't really know existed until recently.
Nick Jikomes 1:23:48
Is this also potentially something to think about? You know, as things like MDMA assisted psychotherapy become more mainstream, where you know that, you know, in theory, right, the MDMA could actually push you in too far in one direction? Yeah,
Monique Smith 1:24:02
no, I think that's a fantastic point, right, is that we really do need to pay attention to the circumstances of the person's life, their expectations. And, and yeah, sort of, do they meet the criteria that might be improved by this, right. And if on the sort of mouse side, we can figure out the different mechanisms for emotional contagion, and pro social behavior, then we might be able to only increase pro social behavior without increasing emotional contagion. And then it might be a little bit less risky. But until we're there I think it takes like a careful design of the studies and, and I hope that people will, you know, take this for what it is and not just think, Oh, I'm gonna take MDMA and it's gonna solve all my social anxiety or something like that. Do you know what I mean?
Nick Jikomes 1:24:58
Is there Anything you want to reiterate? Or any final thoughts you want to leave people with before we sign off today?
Monique Smith 1:25:04
Okay, let's see. Um, I don't know, I guess no, no, it was it was a joy talking to you, I sort of went off on some cool tangents, I hope that everyone enjoys reading the paper. And anyone that's interested in talking more about it or doing research themselves can definitely reach out to us at UCSD and see what we're up to. Because we do have, I'll just say we do have other projects related that are sort of outside of the scope of this, but I'll mention that are really cool looking at a traumatic birth injury and maternal health and how caregivers and social partners might actually influence pain and healing in mothers, as well as outcomes in offspring. We're looking at the role of the microbiome in empathy, like behavior, and then basically the basic neurobiology of empathy and pain. So those are all the things we're doing. And then if you want to put this in, but I'll pitch then again, he's got a really great eye. I'm on Twitter. I'm sure you can link me there, but then also is on tick tock. He's clearly younger than me. And he's got a great tick tock called Doctor brain spelled br e i n because that's his name. So I'll say that and that's it.
Nick Jikomes 1:26:29
All right. Dr. Monique Smith, thank you for your time. Yeah, thank
Monique Smith 1:26:32
you so much. It was a pleasure.
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