#30. Unravelling the Role of Dopamine - Dr. Kate Witt

Dr. Kate Witt, lecturer at Victoria University of Wellington, joins to discuss her research on Dopamine. Dopamine is an integral neurotransmitter, mainly associated with pleasure and motivation. Dr. Witt's work uses a genetically modified animal model to understand changes in behaviour focusing particularly on anhedonia (the inability to experience joy or pleasure), asociality (lack of social interactions) and avolition (lack of motivation).

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Transcript

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Yeah. Yes, quite. I will usually go into a cult or at least I don't know anything about your research. So, okay, I guess the point is that I try to understand it at the same pace that like, you know, a listener is trying to understand it. Yeah, no. Yeah. Anything about it. Yeah. So now that Olivia has given the basic idea, welcome to the Smooth Rain Society. Yeah. So, as mentioned, Olivia would, Olivia will kind of Axe is a person who is coming in completely cold, has no idea what your research is, and we're going to try to see how well Olivia, all the listeners, and myself, because I only know a little bit about it, learn about your work. But first I should introduce you. And this is fun, Kate, because usually when I introduce people, it's the other way. I try to humanize researchers, and now I get to show how cool my friends are. So it's the other end. Let's go. So all right. Let's... So Dr. Kate Witt now as of a little bit ago. Yeah, I guess, I don't know if you can technically say doctors since I haven't submitted to the library, but you know. Yeah. Well, maybe by the time this uploads, you'll be a doctor. Maybe by the time this uploads actually. Um, and yeah, I'm recording from our office and Kate's recording from home. So anyway, um, yeah, so Kate Witt is now a PhD holder, um, in cognitive and behavioral neurosciences. I was also a lecturer at Victoria University of Wellington. And we worked in the same lab together into completely different projects. So Kate's here to discuss her project. The PhD thesis was titled the role of dopamine D1 receptor in the negative symptoms of schizophrenia. Now these seem like a lot of weird words and Kate's going to hopefully break them down. But We'll start off by welcoming her on and she can give us a little bit of a background into how she got into this type of research work in the first place. So welcome, Kate. Thank you. I realized my title of my thesis changed by the time I submitted it, but that's okay. It's different than the website. But yeah, like Sahir said, I have finished my PhD, so I'm just waiting to submit it to the library, to be officially done. and doing some research work in the meantime and lecturing at uni as well. You can probably tell from my accent that I am not from New Zealand. So I'm originally from the States and I actually studied on exchange at Vic many years ago, like over seven years ago now. And just for this termester came over, I actually took one of Terta's papers, Perception and Attention. when I came over, which is funny because I think you just had him on recently, or it was just posted recently. So yeah, I came over and really honestly was like I have to come back to New Zealand, like was just here for the semester. Went back home. I did my undergrad in CB&S in Cognitive and Behavioral Neuroscience, so I went to a really small uni in the States. like a fraction of the size of Vic. And so they had a neuroscience major and I did the CBNS route. And for me, when I was kind of deciding, okay, graduation is coming close and undergrad, you know, what do I wanna do? I really knew that I just, I was really interested in neuroscience still. I didn't ever have like a specific career goal, like, oh, I wanna research or I wanna teach. It was more like, I just wanna do neuroscience and whatever kind of form that is. Um, and so I was like, okay, let's continue studying. Like, how do we do more neuro? We study more. Um, and for me, it was just an easy decision to come back to, um, like Wellington to study, um, for post-grad. So in 2018, um, like I had graduated from undergrad, um, moved over to start my masters in the CBNS program. Um, and I've been here since and the masters obviously. turned into PhD. So I didn't actually finish my masters. I did part one with the courses and lab work and then I got into the thesis part of it. COVID happened and then I just ended up upgrading into a PhD to extend it. I just kept thinking of ideas for experiments. I didn't want to stop with my original idea for the masters. So I upgraded and kept going and now here we are. Very nice. The thing to note about the exchange is when Kate had come over on her exchange, her flatmate at the time was really good mates with me and me and Kate never met but I went over to her place multiple times. We only realized that we were talking about the same friend when she came over again from France to visit. She was supposed to meet me in the afternoon and Kate in the evening and we did not know that we were talking about the same person until... Yeah, that was... it's small. Wellington's small, the world's small. Yeah. Yeah, I can't believe you went to a university that was smaller than Vic. Like, Vic's already small and then it gets smaller. Yeah, my uni, my undergrad experience was probably very different, I think, than New Zealand undergrad universities, but also in the States because you can go to... very small sort of liberal arts colleges, where there's like two or 3000 people, or you can go to bigger state schools, where there is, you know, size of Vic and others. And I really wanted sort of that hands-on experience where there were small classes. And so I went to a really small school. And so I think like my biggest class was probably the Intro to Psych, which there was like 80 people. which was the biggest. And then in like from your first year, you're in the lab doing research, you're like having discussions in class. It's like no big lecture halls and stuff. So it was quite different, but I really liked it. I mean, it was hard, but I liked, I liked that. Yeah. What drew you to neuroscience? I like the idea that you said that you just like neuroscience and you just went with it. You just kind of followed your passion. It's interesting you asked that because I recently I just had an interview for a position like a full-time position lecturing at Vic and it's in educational like psychology neuroscience and I was like oh well my majors neuroscience not education or psychology but when I originally went to uni I wanted to do education in psychology like I wanted to double major and I wanted to be a teacher which I was just so funny looking back because I'm like, oh, now I'm teaching. Like I've come back full circle. Um, even though I didn't do that, but I, um, took the intro to psych paper, but was more interested, like when we got to the brain part, like the more biological part, um, then it's the psych theory. So I was like, Oh, I want to do that. Um, and so then immediately like switched and was like, cool, there's an intro to neuroscience paper. Let's do that. Um, and then jumped into it. So yeah, that was not originally my plan. Um, I mean, psychology is very similar to neuro, so still in the same sort of realm, but really wanted to do early education teaching. Um, and I guess teaching uni students is somewhat similar at times, but, um, yeah, so I guess I'm still like doing the teaching kind of thing, um, which is interesting because yeah, just. Once I got on the path, it was like, oh, neuroscience, we'll see where it takes me. Um, and I guess it's taken me back to teaching. So as of right now, I don't know what it will be, you know, in a couple of months, but yeah. Yeah. Should we get on to your PhD thesis then? The reason you're a doctor. So could you then start us off with, because you said you upgraded from a master's, so could you give us an idea of what the initial project was and what kind of components it had? Yeah. So I originally, I guess like just for people who are iffy that are starting a master's, You don't like when I originally started, I had no idea what thesis idea topic I could have. Like I remember starting part one where it was courses and lab work. And I was like, how am I supposed to come up with a whole thesis idea in a year? Like I haven't, that seems so daunting. Um, and, um, I don't know if other uni's are like this, but I really liked how Vic had the part one set up where you did coursework, but then you also did lab rotations. Um, and that was how like the CB&S masters was set up. And so. In doing the lab rotations, I kind of got to figure out, okay, what do I like? What do I don't like? I don't like, and then also with that, the ideas for theses just sort of slow as you're working in the different labs. Um, and so I had worked in, um, the human behavior analysis lab, which I really liked that, but I couldn't see myself doing it, um, for an entire thesis. And, um, then I worked in Bart's lab. Sorry, my headphones are like. Um, and then I worked in Bart's lab and the ideas just started flowing for things that are projects I could do. Um, which I guess is a good indication of how, okay, maybe you're passionate about this area if, um, the ideas for projects just kind of keep flowing. Um, so originally I was going to look, um, at the role of the dopamine D1 receptor, mainly in social behavior. Um, we have these rats in our lab, um, which we call D1 mutants. So they're genetically modified to have a reduction in a specific dopamine receptor, the D1 receptor. And so you can look at their behavior and say, okay, they're acting differently than control animals, which should be because of the D1 receptor, because it's genetically modified. And so I was like, okay, what can I do with those animals? And originally, yeah, I was going to really look at social behavior and... how they anticipate and then consume rewards. So using social behavior as a reward, like us as humans, we're social animals, so social interaction is rewarding for us, but also for rats, it's very rewarding. So you can use social behavior and interaction as a reward. So I started out as like, cool, just like do a social play experiment and look at how they anticipate that and how they also engage in play. And then that was my original idea for my master's. So I got started on that. Um, and interestingly, like the idea for some of the later experiments, which was looking more at motivation and effort, um, was because of some stuff that I noticed just like with the pups when they were little, the D1 mutant pups, um, were quite small, like they were a lot of runs. And there can be runs when there's a large litter of animals because there's just not enough milk then to go around And they kind of have to compete for it, but these D1 mutants were always They just seemed to be more of the runs than like the ones that weren't genetically modified in the litter And so I was like, oh, maybe you know the D1 receptor is impacting their exertion of effort So like they're not motivated to like compete for the milk And so maybe that's why they're smaller and then I started doing reading and I was like, okay The D1 receptor has been implicated in motivation and effort um, you know, but not a lot with using these genetically modified animals. And so that's where kind of the ideas just started flowing for, okay, how could I add more experiments? Um, and I guess originally, as Sahir read out my title, the, the role of the D1 receptor and the negative symptoms of schizophrenia, that sort of pivoted. So my title now, or like when I submitted was the role of the D1 receptor in, um, abolition and hedonia and asociality, which I can break that down, but. Essentially those are the negative symptoms of schizophrenia. Um, a abolition means a reduction in motivation. So, you know, we're, we're less motivated to, um, engage in goal oriented tasks to complete tasks. Um, a sociality means a reduction in social behavior. So we just like, aren't as motivated to engage in social interactions with people and are wanting to like, um, be more on our own. And then anhedonia is a loss of pleasure. So we're unable to. experience pleasure either when anticipating getting something pleasurable or when getting something pleasurable in the moment. And so originally that was my idea was like looking at those negative symptoms, negative meaning a loss of behavior. So in schizophrenia, we see individuals that have, they have positive symptoms. So in addition of hallucinations, delusions, but then also negative symptoms. So a loss of motivation, loss of social interaction. The more, the reason my title changed, which kind of goes along with how neuroscience is shifting a bit, is those symptoms are also seen in other disorders. So they're not just in schizophrenia. And the more I read, I felt like having my title be the negative symptoms in schizophrenia really, I kind of ignore the other disorders that have those symptoms. So we see those just, those symptoms in major depressive disorder. We see it in anxiety disorders. bipolar disorder, not just schizophrenia. And a lot of that has to do with how disorders are diagnosed, but actually how that really differs from what's going on in the brain or what we think is going on in the brain. So disorders are diagnosed currently based on the DSM. So we look at symptoms that they cluster. So for example, depression, a loss of interest in activities, suicidal mood, like all those. You have to have a checklist of symptoms and then you're diagnosed with depression. But in reality, when we look at disorders, a lot of the symptoms overlap and symptoms can really vary within disorders too. So in depression, you could have someone who has insomnia so they can't sleep. They're not really interested in eating and maybe they have like slowed motor movements, but also you could have an individual. Also, diagnosed as depression on the other side who like is hyperinsomnia, has hyperinsomnia. So like they're sleeping a lot, they're like moving a lot. You know, so like within a disorder itself, you can have a same disorder, but like a variety of symptoms and then those symptoms could also be seen in schizophrenia. And so neuroscience is really like, if we're going to understand, you know, what mechanisms are actually leading to disorders. We really have to break them down to their symptoms and not actually the disorder. Because when you go into a lab and we say, okay, we're going to look at the mechanisms of schizophrenia, it's like, well, you can't model that in an animal. You can't say that an animal has schizophrenia, right? But you can say that an animal has reduced motivation, or you can say, you know, an animal has reduced social interaction. Um, so I guess like my, my thesis kind of pivoted, it didn't pivot in the experiments, um, you know, with the change of the title, but I really just pivoted the theory behind let's look at multiple disorders and those symptoms themselves rather than like clustering in just schizophrenia. I just ranted for a while, but. No, that's good. That's interesting. Can I ask, I'm more like social psych orientated, so I actually don't know. I've only taken a couple of neuroscience papers. So can you explain the D1 receptor and I think you briefly mentioned what it's known for and things like that? Yeah. So all neurotransmitters have different receptors that they can bind to. So people are probably really familiar with serotonin and SSRIs or antidepressants. So antidepressants, they are actually acting on the receptor that serotonin can bind to in the brain. So in the case of dopamine. can bind to five different receptors. And what's important about the different receptors is the function or the action or behavior differs based on which receptor a neurotransmitter binds to. So for example, if one neuron in the brain is sending information to another, so say that information or that neurotransmitter is dopamine and it binds to a D2 receptor, that would impact someone's movement. So that's really involved in movement. But if it binds to a D1 receptor, then that action would more be reward and motivation or social behavior. So really, you know, you can look at neurotransmitters and like dopamine as a whole is involved in movement, rewards, pleasure, motivation. But also each receptor has a different sort of action once it binds to that, if that makes sense. And I guess like kind of with the reason that I use like the animals that have a genetic modification in the D1 receptor is right now there is no pharmacology that is solely selective for the D1 receptor. So a lot of studies in neuroscience will give an animal or a person a pharmaceutical, a drug that affects a certain receptor or neurotransmitter and then see how it changes their behavior. And a lot of the studies have pointed like, hey, it looks like the D1 receptor is involved in rewards and motivation. But any drug that targets the D1 receptor also targets the D5 receptor and also some serotonin receptors. So although the research like points to it that it's likely the D1 receptor, we can't like be certain because it could also be, oh, maybe it's a little bit of a serotonin effect because it is also binding to that. In our lab, they developed, Bart and some other people from the Netherlands, developed a rat with a genetic mutation so we know that it's only the deion receptor being infected and not the subatonin of the D5. So I didn't do any of the modifying. That's beyond my understanding of actually modifying the genetics. But yeah, that's why I use those animals, just because we can look only at that receptor. Right, so my understanding is you kind of... Oh, I can hear a really bad echo. I think it's gone now. My understanding is that you sort of get given this group of rats that have that receptor sort of taken away and then you compare them to normal rats and then look at all those negative symptoms that you were talking about. Yeah, yeah. So like when the rats are bred, some of them will have like a knock... down, so reduced amount of that receptor. We don't completely remove it. I'm not sure like some of the animals in the lab, they have a complete removal of a serotonin transporter, but like when in mine, not mine, but like in the D1 mutants, they have just a reduction. So there's still some function of the D1 receptor. What we see a lot in the research in terms of the D1 receptor is if you completely knock it out, animals... really don't do a lot because it is involved in motor activity a bit. So it's hard to know if it's like, oh, they're not moving because of the motor or because they're not motivated to. So having that just reduction is really important. And yeah, so in a litter, when they're born, the way that they're bred is some have that have that reduction. Some have a little bit of reduction and then some have no reduction. And so I looked at the ones who had no reduction and then the the highest reduction. So to compare, you know, what those control ones, the ones with no reduction, and then the ones with the reduction look like. Yeah. Well, I think I've got it down. I've got it. Yeah. So how did you, I know that you kind of mentioned, but how did you get into that specific area? Was it just you were inspired by what you heard, like in the lab rotations, I don't know, any kind of personal connection to the topic? No, I don't really have any personal connection. I think it was really just being in the lab and our lab and then the lab in the Netherlands where they were created are the only ones with the D1 mutants, with those with reduction. So it was kind of like, and not a lot of people were doing them. Like a lot of people were more interested in working with serotonin. Not that that's not interesting, but for me, I was like, no, I was like, oh, I really want to look at dopamine. I don't like, I don't know, for no particular reason. Um, I was just like, oh, motivation and, um, social stuff seems interesting. So yeah. Yeah. I saw you guys smile. Is serotonin like not as cool to look at? I don't know. I didn't want to offend you. I'm pretty sure Alex looks at serotonin as well. Yeah, yeah. I can't, I can't, yeah. So Kate's the cool one. I wanted to be the odd one out. Okay, can we, now that we've got the kind of concept down of dopamine, D1 receptors, what they do, what the reduction should do, let's talk about the experiment side. So, could you go a bit more into the three things you mentioned, anedonia and I can't remember the other two off the top of my head now. Asociality and a motivation. Okay, so should we start with like a sociality and how you would measure that and then we can go through each one that way? Yeah, so in terms of a sociality, typically rats when they're pups especially are extremely social. So you can isolate them. They're housed, I guess, for people who You know, they're housed in pairs, so rats are very social creatures, so they're housed with another rat. And what you can do, they play like all pretty much from when they're separated from their mom like after weaning, they play up until adulthood. They play a little bit in adulthood, but like when they're juveniles in that pup period, they play a ton. And so you can separate them from each other just for a couple hours and then put them back together and they'll play a lot. Um, cause if you don't separate them, then like they might play a little and then rest for a while and then play a little bit. If you separate them for a couple of hours, it really just motivates them to play a lot when they're put back together. Um, so for experimental purposes, um, you know, you could separate them and then put them back for 10 minutes and look at their play. Whereas if you didn't separate them, um, you know, they might play once in that 10 minutes, whereas, um, just a little bit of isolation really motivates them to play. Um, so typically what you do, yeah, is you isolate them from each other. And then you'll have a little arena set up with some bedding at the bottom because they like to play in like wood chips, kind of like soft wood chips. And then you put it back and we have a camera recording and you just like put them together and then they start playing and you record it and you record it. It's a, you have to go through that and manually analyze their behaviors. So, we don't just say playing, we look at. how often they wrestle each other. So that's like boxing. They'll stand up on their hind legs and box with each other. And then they'll chase each other. So like the one will like be actively chasing while the other one's running away. They also pin each other. So like one will pin the other down where it's laying on its side and the other standing on top of it. And then they'll pounce on each other, which is to initiate playing. So they'll just like grab the back of the neck. So they have very specific. behaviors when we're talking about social play. So essentially, you record while they're playing and you go back and watch hundreds of hours of videos of them playing, slow it down and are like, cool, they're chasing, now they're wrestling, now they're pinning. And then you're able to look at that and you can look at, so the amount of play you can say, overall the mutants played this much. or overall they chased this much versus wrestling. I also looked at the sequence of the play, so because I recorded the time of it, I was able to say like, all this behavior, like chasing is more frequently followed by wrestling, to look at the pattern of play to see if that differed. There's some different like techniques and how people do it, but yeah, it's a lot of like a manual, just the manual watching the videos is a lot, but. I also, I guess I should say is I wanted to combine not only that asociality, but I also wanted that anhedonia aspect. So like anticipating rewards. When we're talking about processing rewards, we often think of just like consuming rewards, right? In the moment, like going to a concert, I'm enjoying this or like eating a candy bar, I'm enjoying this. But we actually, it's like a two-part process. There's the anticipation. Ooh, I'm really looking forward to that concert on Friday. And then there's that consumption. So that in the moment, Ooh, I'm really enjoying this concert. Um, and often it was originally thought of as just one concept, like just rewards, just pleasure. Um, but yeah, in reality, they're two separate constructs. And so when it does come to the D1 receptor, it's implicated in that anticipation of rewards. So, um, you know, um, what they, like people who have, um, schizophrenia, They have actually, we don't see that they have reduced like consumption of rewards or like pleasure when consuming rewards. Um, but it's actually that anticipation. So they're not able to say like, Oh, I'm really looking forward to that concert on Friday, but they might enjoy it in the moment. Um, I've kind of gotten sidetracked a little, but so essentially like what I wanted to look at is typically with those kinds of experiments, what you can do. And with, with rats, especially is you just, um, repeat an experiment. So. rather than having that social play on one day, if you repeat it for seven days, the rats learn to expect that. So they learn to anticipate that play. So essentially what I would do is separate the animals from each other, again, to induce that motivation. And then I put them in a little box where they were by themselves and waiting. And this was called like the anticipation box. So they're sitting there, you record their behavior, and then after 10 minutes they're put in that social play arena. And so what they learn over the 10 days is, I'll wait, when I'm sitting in this box waiting, I get to go play with my friends soon. And so you can look at what their behavior is in that box and amortizing them a little bit in terms of like, they don't actually sing. But yeah, they have an anticipated behavior, so looking forward to that play. So I also looked at that. So not only did I look at how they were playing, but I looked at how they're anticipating playing. I don't know if you want me to kind of, it might be easy if I talk about like the results for each experiment as I go. Because it might get confusing, or I don't know, or I can talk about other. Yeah, I think so too. I think it might be good to talk about the results for each one as we go. Yeah. I guess I'll talk about like the overall findings. So I, the D1 receptor and like dopamine in general has been implicated in social behavior. But what I found is, and what we've seen with the, I guess with those D1 mutants is, when we look at, I was like, what is that? Was it beeping or something? It went back on. When we look at the D1 adults, they have reduced social interaction. So the rats that when they make it, when they're in adulthood, they have reduced social interaction. But what I found is when they're pups and playing, there was no difference between those with a reduction and those without. So what this means is it could mean that the D1 receptor does, you know, it differs over the lifespan. So play is a very specific type of behavior when we're younger to kind of prime us for social interactions when we're older. And you know, sort of serves an evolutionary purpose of like finding a mate and stuff like that later on. So it's possible that like the D1 receptor, you know, it doesn't really have anything or like that much to do with play at that age, that young play, but maybe more that adult social interaction. But I guess like the interesting part of what I found is, it's interesting that there was no difference because I thought there would be, but even though they played the same, so they played the same amount, whether they have the reduction or not, and they played in a similar structure, so their like sequence of play didn't differ. What I saw is that the D1 mutants showed no anticipatory behavior. So they, consumed and enjoyed, like were experiencing pleasure while playing, but they didn't actually anticipate that play. I looked at that in several measures. We can look at their vocalizations, which are indicative of their pleasure. We can look at like how often they stand up on their back legs, which also is indicative of pleasure. And so they didn't show those behaviors. Whereas the ones who had no reduction, you see clear over the days they increase. They increase their vocalizations, they increase their rearing nice as they should. So they're learning to anticipate that and showing pleasure prior to anticipating. So it does support the evidence that the D1 receptor is implicated in that anticipation of rewards. Yeah. Interesting. Maybe this is too early to ask this question. then how, if you could apply those findings to real life, I know it's a bit of a jump going from rats to humans, but if you could just kind of like off the record, you know? You definitely have to write that in your, that's part of it is like, okay, so what? You know, like, what does this mean? Like, it's great to say that, okay, cool, the rats didn't show pleasure, but like, what does that mean? So in terms of what we talked about with anhedonia, so that loss of pleasure, What we see, like I said, in schizophrenia and depression is we don't see that anticipation of rewards. And that anticipation of rewards, like experiencing pleasure and looking forward to it, really is key for goal-oriented behavior. So if you're not really anticipating or looking forward to something, you're not going to put an effort to get it. So we see a lot of functional outcomes with work and relationships stemming from that lack of anticipation. in individuals with certain disorders. And so it is in development, there are targeted pharmacologies right now in development to actually target the D1 receptor. Like I said earlier, the current drugs, they do target the D1 receptor, but also some other ones. So right now they're in pre-clinical trials are some that are specifically being developed just to target the D1 receptor in hopes that maybe an individual with, who's unable to anticipate rewards could potentially have a D1 agonist that is boosting that D1 receptor, which could then help them experience pleasure, looking forward to rewards, and then be more likely to engage in tasks that are goal-oriented and stuff like that. So it's a bit down the road, of course, of like, we don't know if it's solely the D1 receptor as well. That's a hard thing, is like... with this research, right, we're looking at such a specific, like, you know, so here's looking at serotonin, um, or, and, you know, I'm looking at the D1 receptor and it's like, likely it's a lot of different things going on in the brain and like, you know, it can also interact with the environment, but like, that's one aspect, right? You kind of have to chip away at like, what's one potential mechanism. Um, so it could, you know, lead to pharmacological treatment for the D1 receptor, um, there could be other receptors also involved. So potentially, um, down the road looking at, you know, Is something else involved with this? Is it just dopamine? Likely not just because the brain is so complex, but yeah. Speaking of dopamine, I think we should have asked at the start, but because we're looking at D1 receptors, what causes a reduction in dopamine in humans to see these sort of symptoms? Is there any natural reduction? Is it genetic? Is it a bit of everything? Yeah, it is a bit of everything. We do have, there's like a few known polymorphisms. So that's like changes in the receptors that are seen in the D1 receptor. So individuals can have a bit like the rats, like a reduction in those D1 receptors that's just been passed down or somehow become mutated. I guess what's interesting is like, because of now how disorders are diagnosed, we're not necessarily looking at whether individuals have a mutation in a receptor. It's more like they're presenting with these symptoms, we're going to diagnose that as depression and then give the treatment that we have now. Who knows in maybe 20 years or something, rather than looking at, maybe when we look at symptoms we'll say, okay, cool, let's test them and see if they have any of these polymorphisms or these mutations in receptors. and then target the treatment for that. I'm not saying that's like where we're going, but it could, you know, some stuff has suggested that maybe in the future, diagnosing disorders and treatment will kind of be a combination of, because it is happening on a biological basis, right? Like the symptoms are psychological, but what's making them happy, you know, there's something going on in the brain or the body, and so, you know, some people are proposing of like, maybe we'll look at symptoms and then also look at like, oh yeah, let's look at dopamine levels or serotonin levels. And so maybe, you know, down the road, if someone's displaying this anticipatory anhedonia, we could say, okay, it looks like they have anticipatory anhedonia. Should we check out their receptors? Maybe they have a mutation. Yeah. So as of now, like it's not necessarily that people know, you know, like, oh, yes, I know I have a mutation in this receptor. Um, but we know that they are out there, that those mutations do exist. Yeah. That's interesting. I haven't actually heard of this anticipatory... Anhedonia? Yeah. Yeah, I haven't heard of that actually. That would be quite a probable thing to experience, like not really looking forward to something. But then I guess once you do get into it, you enjoy that. I haven't heard of that. That's quite interesting. It's really interesting because it's like originally just called Anhedonia, right? So when you look at the current DSM as well. It doesn't distinguish between anticipatory or consumatory anhedonia. With the disorder, it will just state like it's anhedonia. But you have to go to the research and the papers that will say, you know, actually in schizophrenia that anhedonia is the anticipatory anhedonia. It's not just anhedonia. It's not a loss of pleasure as a whole. And in depression, it looks like it can be both. It can be, you know, loss of pleasure in the moment, but also anticipating. Um, so it kind of differs across disorders, but yeah, that's a big, probably. Something that I guess is missing in terms of, um, not a lot of people know that. Reward processing has to do with the anticipation as well. And that, um, in hedonia or a loss of pleasure could just be that loss of looking of, of like prior to a reward, not actually in the moment. Yeah. It's really interesting. Yeah. Um. And what other results did you get from your study? I think maybe you mentioned there were other aspects that you looked at as well. Oh yeah, I did. I did look, I guess I can walk through some of the other experiments. So yeah, the social, I did the social experiment. I did do experiment just also looking at the anhedonia. But instead of social play being a reward, I had sucrose water as a reward. You know, rats like, they like sugar. So the sugar water was the reward. Um, kind of just to look and see like, okay, do they anticipate, you know, maybe food rewards different than social rewards? Like, um, unfortunately though, like the sucrose water was not rewarding enough. So with that experiment, like I essentially, what I found is like even the normal control animals, um, didn't show any anticipation. Like they consume the sucrose water, but, um, didn't show anticipation and didn't consume a ton. So that experiment was kind of like, okay, cool. I didn't find anything. Um, but then what was it, what was cool is that I was able to see that like, okay, the social play was clearly rewarding enough for, um, the, uh, those control animals to show that anticipation. Um, so that's another thing that's like, we think of rewards as like, you know, they, there has to be sometimes a certain level of reward, that reward value to actually anticipate them, um, like sure. They might've like enjoyed having some sugar water, but not enough to be like, yeah, I really want it. Um. So that experiment didn't show much. I then, I kind of talked to, I guess, a little bit about that effort, like exertion of effort and motivation that I saw when they were pups, they were really tiny. Did that have to do with effort? So what I did to look at effort, so how much effort are they willing to exert, which basically indicates in animals how motivated they are. So the more exertion, or the more effort they will exert for getting a reward, the more motivated they are. And that plays role in A, motivation. So if you're not exerting effort, we look at that as a lack of motivation. So typically what you do for rodent studies with that is you do a lever pressing experiment. So you just teach a rat to press a lever and then they get a sugar pellet reward. challenging experiment in that previously in the lab no one was able to get these D1 mutants to press the lever like wouldn't do it wouldn't press. Lever pressing is probably the easiest thing for to get rats to do like they'll learn it within a day that you know if you turn on a light and then they get a pellet they'll learn oh but if I press that I get the pellet right away like it's this easy it's supposed to be this really easy paradigm. no one had gotten the D1 mutants to be able to do that. And so I was sort of determined to get them to do it. And I originally just tried what the other people had done. Like I did the same experimental setup, but the difference was that I included female rats. So previously there were only male rats, which there's a lot of bias, sex bias in research with only including males because it's like, it's just easier to do males, you know, not having to look at sex differences. Um, and what I found while just, which I, which I think is like probably the most interesting result is the female mutants were able to learn to press the lever completely, and they did not differ at all from the control in animals. The males, the male mutants, um, only a few of them learned. So very, very small and like. whereas in the females it was 75% learned and it wasn't any different from the control animals. And I was like, oh, that's interesting. No one else had ever included the females. So maybe this isn't actually a D1 mutant thing, but it's like a sex and D1 interaction. And so with all of those experiments, so the lever pressing and looking effort, you first have to get them to learn to even press it. And then what you can do is... change sort of the exertion of effort required. So you can make them, you know, normally they'll press the lever once and they get one pellet, but you can make them press it five times and get one pellet or 10 times, you know, and you kind of can keep increasing that to see, you know, when do they break? When do they stop pressing it to get that reward? And that's, you know, an indication of their level of motivation. Unfortunately, because I had such small numbers of D1 mutants that actually like went on to, could acquire lever pressing to go on. there were small numbers of those, but what I did, because the females learned, they were able to learn and go on into other experiments. So even though they learned, they were able to learn to lever press at the same rate, when they actually had to exert more effort, that's where we saw a difference. So those males who did make it on, a few of them made it on, and they didn't differ from the females in terms of they didn't press the lever as much. Whereas interestingly, the control animals, they would press a lever like 150 times for one little sugar pellet. Like they will exert effort for it, which is like a least presence to get like one little pellet. But yeah, the mutants, we saw like the small amount of males who went on and then those females, all they learned to press at the same rate. Like when they actually had to increase their effort, they just, they couldn't exert as much effort. And that You know, that supports the evidence that suggests that the D1 receptor is involved in motivation and exertion of effort. So it does that, that did support that finding. Um, it also though brings up, you know, that big sex difference of like, why were the males, you know, so few of them able, um, to learn to actually press it. And what's interesting is when I kind of was trying to write up these results. there was not much out there. Like no one had looked at the D1 receptor in females. I think every, like pretty much every study on D1 receptors, whether it's pharmacology or a mutation or a complete knockout, males only. And they, you know, will find that like reduce motivation or they won't learn to lever press, et cetera. And I was like, oh, but no one's looking at females. Like, you know, is this a common finding? I don't know. What I was able to look at though is like take a step back and just look at dopamine itself. And what we see is that estrogen, so you know, one of the hormones that are higher in females like biological, if you're born female, or if you're on a hormone replacement therapy, estrogen actually facilitates dopamine. So it facilitates the transmission of dopamine, the sending of dopamine. hypothesize that maybe these D1 mutants, like the females, although they do have a reduction, maybe at certain, because they have more estrogen than the males, that's helping sort of somewhat overcome that genetic reduction. But it's hard to say because I didn't track their cycles. I didn't track their hormone levels because I didn't know what to expect because no one had used the females before. or the female demutants at least. And what's also interesting is like, I didn't see that sex difference across other experiments. So it was really key in that motivation, like in the social play, you know, the male and female mutants didn't play differently. They didn't anticipate differently. So it seems to be really key for that motivation, which it has a lot of unknowns still, you know, why, you know. you know, is it the estrogen was facilitating dopamine, but like really key to motivation, not other behaviors? I don't know. So that's something that I'm still kind of like, I wonder why, you know, what is the why of why I found that? That is really interesting. I like that you've kind of discovered something that other people haven't and yeah, yeah. You have to use both sexes in the in the in your experiments, you know. Yeah. Do you personally have any theories as to why that might be the case? Well, in the sense why by why I mean why it's only for motivation, but not for the others if the D ones seem to perform worse in both? Yeah, yeah. On one or on the other. That's what I think. I'm not 100% sure. I wonder, pardon me, when it comes to, like when we look at the actual experimental setup, learning to press the lever has more to do with learning itself than exerting effort because there's not a ton of effort that you have to exert when you're learning. You're pressing it once, you know? But you do have to learn to associate you pressing it results in the delivery of rules. reward and I tried to do a few other, I did a few other experiments to try and see if what's happening, you know, when they're learning to rest the lever and to see if something was going on there. So I am, you might be familiar with like classical conditioning and operant conditioning. So operant conditioning is when the response is dependent on our behavior. So okay, I have to press the lever to get something classical. conditioning is when a stimulus is associated with a response. So a light might come on in the chamber where they're learning. And then after the light goes off, a pellet is delivered. So in terms of classical conditioning, it's like, you have to learn that, oh, yes, that, that light or that stimulus means I get something in return. With rats, when they're learning to press the lever, the standard really easy for them to get is a light comes on. And if they press the lever when that light is on, they automatically get a pellet. If they don't press it, then the light will turn off and they'll still get a pellet. And eventually, basically over time in that session, they learn that like, oh, light turns on, I get something. And so they move towards that lever and we'll eventually start pressing it. And this happens very quickly. Like within a session, an hour, they can pick that up that, oh, yeah, light reward. But if I press, I get it sooner. I tried to parse out another experiment, that classical versus operant, because I wasn't sure if, you know, maybe the male mutants are having an issue with understanding that when the light comes on, they get a reward and they get it sooner if they press it. Like, maybe they weren't getting that and that's why they didn't acquire it. So I did a few other operant chamber experiments, you know, to kind of parse out what was happening. And in the end, I really wasn't able to figure out like what was happening. I really need to do an experiment or someone needs to do it where they record their behavior with video cameras to see what they're actually doing then because what I saw was like the lever pressing and eating the pellets didn't really tell me much. But I really don't know if when the light came on, if they went to the pellet, if they noticed the pellet was there. And if that's the case, if they do go to it, and they don't press, it's like they're not grasping then that their behavior can result in something or they might not be grasping that the light means something, which again, that doesn't have to do with effort or exertion of effort. It's more like something's going on with their associative learning of, you know, learning to associate that a stimulus means something. I'm not sure if that's the case because when we look at some other experiments that like were done with D1 mutants previously, they were able to learn avoidance behavior. So they were able to learn that like, if they got shocked in one, I didn't do this, but someone else did, but like if they got shocked in a compartment, they learned to not go back there. So they are able to associate of learn in that they know that they can associate a stimulus with a response that was aversive and it was negative. And you know, getting a sugar pellet is positive, but usually that's not different. Like usually. learning about a negative stimuli is not really different than learning a positive one. So I'm not, I really don't know what's happening. I would love to see what they're actually doing in the chambers. Yeah. Do you think that there could be an element of an evolutionary preparation kind of thing? In the sense that the negative stimuli just might be stronger, that's why they remember it as opposed to the positive one? Yeah. The negative... No, you're right, that could be. Because, I mean, typically we're primed to... avoid negative stimuli and avoid harm, avoid harmful things and get what we get, things that we want or things that are positive. So it is possible that maybe for the D1 mutants, normally in learning a positive and a negative, there's no difference between learning with this, but maybe for them, it's easier to learn the negative because it was such an adverse event of getting a shock. maybe like the sugar pellets, you know, aren't that, aren't rewarding enough, you know, maybe to create this sort of like, oh yes, I can learn to associate my behavior with that reward. It would be interesting to see, I think, you can also do different types of effort experiments where you can try and get them, instead of pressing a lever and increasing that, you can have them climb a barrier for things. So you could have them climb a barrier In the past, in the lab, they did this with D1 mutants, where you train them to climb a small barrier to get a sweet reward, and then you increase it. Okay, now you have to climb a little bit more, and then a little bit more. You see where they're like, no, I'm not climbing, not worth it. And apparently the D1 mutants wouldn't climb at all, so no, not climbing. But what I think would be interesting is doing that with social behavior, because we can see that they played right the same amount and it's like, well, maybe social behavior is so rewarding that it kind of would overcome that. Maybe then they exert effort to get it. Um, and maybe just for maybe sugar pellets or the fruit loops that they used in the other experiment for the barrier, aren't it's just like for them, that's not enough to exert effort or to even create those, I guess, kind of associations with the learning. Yeah. There. Yeah. Who knows? I could do a million more experiments to see. I also just wanted to ask why looking at effort and motivation is, I don't know, important to look at or like how that maps on to a human experience? Yeah, yeah. So when I talked about those, like the three behaviors or the symptoms that we see with anhedonia, so that loss of pleasure, and then asociality, so that loss of social interaction or wanting to interact. You also see abolition, which is also known as a motivation. So that's a reduced amount of motivation or exertion of effort. So what we see in individuals with schizophrenia is like when you give them a task that has any physical or cognitive effort. So it's not just physical, but it might be cognitive effort, like completing a task or doing a math problem. to exert effort to obtain a reward. And we also see that in individuals with major depressive disorder and a few other disorders. So in terms of like, and again, it kind of goes all back to the goal-oriented behavior of, you know, if you're not willing to exert effort for a goal, like, or you're not as motivated, maybe you're not gonna exert effort. So in terms of like, that's, I guess, where that importance comes back to the symptoms of. you know, they're kind of the hallmarks of the negative symptoms schizophrenia, but we also see them across disorders where motivation and sort of that motivation to engage in activities, that motivation to complete tasks is really reduced. So, you know, it's possible, it looks like the D1 receptor from the D1 mutants, but also from other pharmacology studies and other knockout animal research in terms of mutations is. The de-onarceptor does play a key role in that exertion of effort. And if you reduce the de-onarceptor or knock it out, then like animals are just like not going to exert that effort. Um, so again, kind of similar with that anticipatory pleasure. It's like, okay, if someone's experiencing a reduction in, um, exertion of effort or reduction in motivation, um, you know, maybe rather than, you know, just giving them something for different issues as a whole, we could treat that reduction in motivation. Um, yeah. Or, or, you know, maybe, um, there are natural ways to kind of, I guess, potentially increase dopamine levels, whether if we know that social things aren't rewarding, so maybe someone needs a little bit different type of motivation to be, I guess, to exert effort. So not everything necessarily has to be pharmacology and medication, but kind of right now, when we look at the treatment for depression, and schizophrenia and bipolar, it's not targeting those, that loss of behavior. So it's really, you know, I guess I should have said that in the beginning. Like that's the key is like current pharmacology doesn't actually help those behaviors. So, or those loss of behavior. So like when you give an individual anti-psychotics for schizophrenia, or you give someone antidepressants or depression, it improves some symptoms, but it doesn't. improve the A-motivation, it doesn't improve an anhedonian, and it doesn't improve A-social behavior. So, those behaviors, I guess the reason I chose them is, you know, not only do we see them leading to functional outcomes, like poor, you know, work outcomes, or relationship outcomes, we have no treatment for them right now. In terms of pharmacology or any type, you know, they're kind of, they're left untreated, and they really... are kind of leading to that poor quality of life in terms of maintaining friendships, relationships, work. Um, we see those sort of outcomes associated with poor quality of life. And right now it's left untreated. Yeah. I definitely should have said that at the beginning with like, why that, why we look at those symptoms, but yeah. Don't worry. I'll turn that into the TikTok and reels for advertising. So people hear it first before they. Yeah. Before they come. Yeah, so I guess it's that's kind of like You know a lot of neuroscience research or like in our lab is kind of looking at things that we currently can't actually alleviate or treat, you know, and for example like It's not that like, you know SSRIs aren't great for depression I mean, well, that's a whole other thing in terms of like how long they take to work and stuff But like they just there's some stuff that they don't target like they don't help improve your motivation you know, like it might help improve your mood, but like that doesn't necessarily mean that your motivation or your desire to engage with other people is improved. I didn't know that. Yeah. It's my key learning for today. Yeah. So at the moment is... Oh, sorry. You go. No, I'm just gonna say it's kind of like, I think like a lot of times especially kind of why I started, why I started with schizophrenia is because there's such a stark contrast between We have this treatment that is really effective for hallucinations and delusions. Like, antipsychotics work for that, but that's half of the disorder, you know. We have these loss of behavior that's normally present, and that's actually what's leading to that poor quality of life is like not being able to maintain relationships, friendships, and work. That's the poor quality of life, but like we have no treatment for that. And, you know, not saying that the treatment isn't good, like the antipsychotics alleviating the hallucinations and delusions is very beneficial and needed, but we are missing a massive, massive side of that. Yeah. It might sound a little bit cheesy, but do you feel like in doing the research that you do, you're sort of, I don't know, getting the world closer to knowledge to treat those three things? I mean, yeah, I guess like it seems so nice so far removed because it's like, I'm only looking at like this little receptor and like working with rems. But I do think I would hope that like we are moving closer to that. I also think like in terms of how neuroscience has shifted to instead of, you know, we might diagnose things based on disorders and like, you know, how we currently have the disorders. But Research seems to be, you know, we're shifting research to kind of target like, okay, we haven't had luck trying to find the root cause of depression as a whole. Because there probably isn't, you know, a root cause. There's a root cause of, you know, some symptoms, but like depression as a whole or schizophrenia as a whole, we're not finding causes for those. And it's almost like, okay, now neuroscience, you know, in the last 10 to 15 years is shifting to, okay, what is causing that symptom and can we alleviate that symptom? And maybe, you know, I don't know, maybe that's where we are headed in terms of treatment as well. And we've had discussions in the lab though also, like, so here you'll, like, with, you know, if we do shift eventually to treating a symptom, right, well, are we going, like, what if, you know, what does a diagnosis bring though? Because for a lot of people, a diagnosis does kind of be like, okay, wow, like, this is why I'm experiencing the symptoms, like, I have a label for it. you know, I can talk to other people who are experiencing this and kind of like having a diagnosis can help people. And so it's like, well, if we ever shift to kind of like, oh, yes, you have a motivation, so now we're going to give you this, like, do we lose that kind of that function of, um, of diagnoses? Um, yeah. So we have like long chats about that and we, there's no, um, you know, there is no answer to it necessarily, but it is kind of interesting to think about. You know, we can come up with the mechanisms and stuff. We also do have to keep in mind like that doesn't mean that we're going to change the way it's necessarily diagnosed or like thought of socially, because maybe the way diagnosis, they do so much form a function, you know, and have a purpose. But yeah, yeah. But maybe we treat it differently. Yeah. Are there any other key conclusions, takeaways you wanted to give as well, which you haven't spoken about yet because we've been recording for an hour? Oh my gosh, we have. I think, yeah, I guess my key takeaways are just like the importance of really breaking down, you know, our research into about disorders into those symptoms, like looking at we're going to look at the root cause of a behavior or a symptom rather than disorders as a whole. Because I even remember like an under guide being like, oh yes, that's the depressive model of, you know, that's the depressive animal model, that's the schizophrenia animal model. And it's like, you know, now we don't really use that. And papers, journals, when you're publishing and stuff, they kind of, you know, they don't want you to use that. And so it's cool to kind of see that shift of like, okay, that wasn't working and now we're already shifting. Um, and I guess the other biggest key takeaway for me is just like researchers, um, addressing the sex bias and like, not in terms of like the researchers of the gender or like the sex of the researchers, but, um, with the animals used, um, the amount of papers like, and I know other people in our lab like Brie have had so many issues where when it comes to serotonin, dopamine, all these things, only male rats are used for simplicity. And it's like, we're missing. so many other factors like hormones play a massive role in how they interact with neurotransmitters and affect behavior and a lot of research is just missing out on that. So when I wrote up the results from the effort, I felt the effort like base learning experiment, it felt quite good to kind of call out people and be like, we need to do better. You can't just include males and say, oh yeah, this is what we found. It's like, what about you're missing half the equation there. Yeah. So that's my other cause, that you look at everything. Yeah. I need to get Breanne to specifically talk about that. Cause she's written a lot. Just on sex bias and research. Yeah. It's, it's massive in neuroscience research, which yeah. No, it's the same when I was, it's the same when I looked at my, the stuff for my research, like a lot of, a lot of the work was done purely on male. mice or male rats. When you're doing it on both, it's very hard to find justifications for why one's doing one and the other sex is not doing the same thing. Do you guys have any other questions, I guess? I don't know if I answered all the questions, but I just went on. No, I feel like those are great answers. Yeah. I'll ask them, because you said you keep getting multiple ideas of what to do next. If we gave you all the funding, like a Marston grant and more, based on your findings now, what do you think the next steps should be? I, okay, so I have two things. Um, I think what's interesting cause this was sort of asked, well, sort of in my defense, a bit of like, what's one thing you would change or one thing you would add if you could, um, and I think one, I would look at hormone levels, um, and, and the female rats and see if, you know, that's associated with their behavior. Like, are, do we see any, you know, across all the behaviors and experiments, even if we didn't see differences, like. in their behavior, looking at, especially though in that motivation and exertion of effort of like, are there fluctuations in their hormones and is that impacting their behavior? Because, you know, I can say there's a sex difference, but I kind of wonder, is it different to a specific hormone? Like, what's kind of driving that? The other thing is I would love if the lab had, at the time we didn't have the equipment, to set up individual cameras in the chambers where they learn to press the lever. So I wasn't able to see what they were actually doing when they were learning, but to really address, okay, why can't the males learn to press the lever? Why can't the male mutants do that? I'd love to just have cameras set up and have that automated the behavior automatically recorded to be like, okay, cool, when the light was on, this is what they were doing. And then I could be like, all right, that's why. Um, they didn't learn rather than like trying a few other operant chamber experiments and not really being able to tell like what exactly it meant. Um, yeah. Can, can I ask on that speculatively? Do you have any reason? Do you think the D1 is also associated with learning in males then if males or, or there has been, or is there some sort of combination affecting learning ability? That's what's really interesting is I cannot find things that look at the D1 receptor and learning and things with the D1 mutants and learning show that they can learn. They can learn associative learning, their spatial working, their spatial memory is fine, their working memory is fine. They seem to be able to learn and have those sort of cognitions just as the normal ones do. So why there would be a deficit in learning in just the operant chambers. Like, I'm not sure. And maybe, I guess, if I kind of look at that and if I see, I guess, kind of the next step for me in the mind is like, if I were to record the behavior and see that like, oh yeah, when the light comes on, they go and eat the pellet. Like, they're clearly learning that like light comes on. I get a reward, but they're just not pressing it. I would guess maybe if I increase the reward, so instead of having a sugar pellet, maybe they need some people use sweetened condensed milk, like as where maybe it's like they need something more, or again, maybe they need social play. I guess if the answer is that they don't have a learning deficit, because it doesn't seem to be that they do in other areas, so why would they have a really oddly specific one for operant chambers? I don't know. It was interesting because in my thesis defense, there was a lot of talk about, well, maybe they just can't learn. And it was like, that could be the case, but in all these other experiments and all the other literature points to that, that's not having an impact that they can learn. And so maybe it is that they need a higher reward, which would be, I don't know how you would... have a lever pressing experiment with social play as a reward when you press the lever, but again, you could maybe set up that barrier where they have to climb over a barrier to play with their friend. Yeah, so I'm convinced it's not learning, but I just wanna be able to prove that it's not learning. That has, maybe it has something to do with that reward itself, and it's not actually the learning because I don't think they're dumb. Like, I think they can learn. Yeah, it's funny, one of my other supervisor called the DOA Immunity was like, well, maybe they're just, you know, the Homer Simpsons of the room. So I was like, no, they're not. Like, they can learn. They're just not putting in the effort. So yeah, I would like to have a kind of a conclusive answer of like, yes, see, they can learn. It's just maybe like, they need a lot of rewards to work. When you interacted with them day to day, did you get a sense that they were different? You felt like they were the Homer Simpson or not? No. What's interesting is in general, the D1 mutants are smaller than the normal rats, which makes them quite...they're a little bit cuter. They stay a little bit small and fluffy sometimes, rather than getting massive and kind of the coarse hair. They kind of look like pups sometimes throughout their whole life, which when we've looked at their motor skills and how much they actually eat for their body weight and stuff like that, it doesn't differ. But yeah, they... All of my animals, because I worked with them throughout their life, and you know, doing different experiments, by the end, like, you know, so here I can probably tell you, like, animals learn, like, your voice, and, right, your scent, like, when you open up the box, like, by the end, they just would jump out onto me. And the D1 mutants would do that just like the other ones, right, like, they would jump out, like, when they heard my voice, just as much as the other ones would. So I don't think, like, I don't think they're dumb, or the homers. I do think though, like, if for them, exerting effort is just like, not something they're going to do just because of the reduced one. And you know, I saw that in the pups of like, the little ones, like the runs would be so tiny and it's just like, they're just in the corner, you know, not getting the food. And even like sometimes after weaning, so you know, they stay with their mom and with their mates for a certain amount of time. and then they're placed with a cage mate and they have normal food, you know? Like sometimes, normally the food is up a little bit higher and they have to like get it out of kind of like a box thing. And sometimes the D1s wouldn't do that. And so I would have to put food at the bottom for them. So like, in terms of like basic kind of like exertion of effort for like food that's right there, you know, they sometimes wouldn't do that. So I don't think they're necessarily the Homer Simpson dumb, I think they just might, you know, they don't exert effort for things. So they need a little bit of... Maybe they're just entitled. Yeah. Like they want you to bring it to them. Yeah, they're like, I was getting a bowl on the floor. Yeah. Maybe that's it. Yeah. Cool. Two things. One, do not insult Homer Simpson, please. The man takes care of a family of five honestly going down. Oh, I should not say that. That was not me. You can help to Dave about that. Oh. that man's a working class hero in this economy. In this economy is taking care of a family of five. Um, but, uh, the second thing, uh, should we get onto the questions and Olivia and wrap up? So, okay. Five questions. Yep. So nothing to do with your work, just general stuff. Let's see. Yeah. Olivia, you want to start? Yeah, they're like quick fire random questions. Yeah. Summer or winter? Summer. Movies or TV shows? TV shows. If your life was a TV show, what TV show would it be? Oh, genre. Oh, what genre? That was the most important. Drama. Nice. Not a comedy probably. Maybe it is. Cats or dogs? Dogs. Nice. Um, dogs or rats? dogs. Those rats gave you your thesis. They put so much on the line for you. What superpower would you have? I think invisibility would be cool. What's your favourite place in the world? I mean New Zealand as a whole compared to the States. Um, what's your least favorite type of music? country? Least, you said least, right? Yeah. Okay. Yeah. Um, what's the ugliest fruit or vegetable in your opinion? The ugliest. Ummm Like maybe ugly mushrooms, I guess, or maybe. Yeah. They come in a lot of different shapes and sizes. Some uglier than others. What's something dumb or stupid someone's tricked you into thinking or believing? Sorry, thinking or doing? Oh see that, I'm really gullible. So honestly, someone could say anything and I'm like, oh really? And they're like, no. You know, so anything like a small thing where someone would be like, yeah, did you hear? And I'll be like, oh my gosh, really? And I fall for it easily. So a lot of things, yeah. What's legal but still feels illegal? for you. Uhhhhhhhhh This is a weird one, but I think I saw this somewhere, someone was talking about it. You know when you pull up to stoplights or you feel like you need to turn down your music? I feel like you have to turn down your music when you're driving, but that's not a thing, you know? Do you mean you feel more conscious that the people next to you can hear it? Yeah, I feel like that's just something you have to do. Yeah, I don't know. Yeah. Especially like the car next when you're next to you when you have your windows down. Yeah, I don't know. It feels like I shouldn't be doing. Yeah. If you- if you wouldn't be doing this, so, your line of work, what would you be doing? Um, maybe campaigning. I do that on the side, like some green campaigning. Oh yeah. Yeah, of course. You're the camp, you're one of the campaign managers for Come of the Fall. Volunteer coordinator. Yeah. I helped her. Oh, you did a great job. She, she won, which is amazing. Yeah. Maybe something like that. Yeah. What is a common phrase or saying that people say that you think is bullshit? Ummm Why can't I think of any songs? It's okay, you can take your time. The magic of podcasting means you can edit out pauses. Oh, okay. So it sounds like you came up with it straight away. What are some ideas? What are some, what have people said for that? Like... I remember someone saying, they said the phrase, like, it is what it is. Just kind of like... I wanna get like, what will be, or like... what's meant to happen will happen or like yeah. No, you know what, you know what now I'm thinking it's the like what doesn't kill you make you stronger that thing. Stronger. Oh yeah because like that doesn't mean that you need to go yeah I don't know yeah you shouldn't have to go through like tough times or traumas right. As I was about to say I don't know I feel I feel a lot weaker if someone like decapitated like my legs or something. Okay, well, I don't think I'd feel stronger after that. Probably won't kill me. But oh, was it? I think Mary, Mary Ann said something like anything about trickle down economics and lost it. And she said that. But yeah, anytime. Oh, wait, okay. I have another one. Anytime anyone's like the US is superior about things. I'm like, no, Like anti-patriot over here. The US bashing. Americans have a very interesting relationship with their nation. Were there any other questions that we I can't remember I can just think of the last one. Yeah, I can just think yeah, ask the last one. Sweet. All right, if you could if you had one piece of advice to leave everyone with, so the listeners ask with, what would it be? I would say find something, like in terms of, I guess, finding something that you're passionate about and continue doing that. Like for me, I had no idea that I wanted to do neuroscience when I went into uni, happened upon it and, you know, entered a psych and then kind of stuck with it. And I guess for those people who might be, you know, early in their uni or like even maybe doing post-grad like. Even if you don't have a specific career aspiration in mind, that's okay. I've, sometimes I've felt like, oh, I really need to have a career aspiration because other people do. Um, but you know, if you're passionate about a field or a topic or an area, that's also okay. And you can kind of, you know, not just like see where it takes you, but yeah, kind of see where it takes you. Like you don't necessarily have to have this career goal planned out or in mind. Like it's okay to just go with what you're interested in. Maybe that's not the best advice, but that's. It's worked for me. So I like it. Well, it's taken you now. You're a doctor. So, yeah, it's worked out. Awesome. Well, thank you so much. Kate, that was hope that wasn't at all. That's good. See, people are nervous for no reason. I know. I was like, I'm not going to have anything to say. So I kept telling here now. I hear I finally say, thank you. Thanks, Olivia. Thanks for joining. Hopefully this one we can actually upload because Olivia has been on a lot of podcasts which could not get up on YouTube for various reasons. So hopefully. Yeah, like we have the audio but then this image, this is the whole point of the riverside to be able to have the visuals. So yeah, for some reason or the other it messed up, but hopefully this time it won't. But yeah, thanks everyone for listening. Until next time, take care. and