E161 | How do Psychedelics Help with Depression? (Professor Emma Robinson)

Professor Emma Robinson is Professor of Psychopharmacology at the University of Bristol. Professor Robinson conducts research with rodents, which can help us to better understand how emotions get formed by the brain and how novel fast-acting antidepressants like ketamine and psilocybin (aka the active ingredient of magic mushrooms) could cause antidepressant effects. 

We discuss how animal research can help us understand human emotions and very human conditions like depression, and why psychedelics might work to treat it.

Interviewed by Dr. Anya Borissova - Give feedback here - thinkingmindpodcast@gmail.com Follow us here: Twitter @thinkingmindpod Instagram @thinkingmindpodcast Tiktok - @thinking.mind.podcast 

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Transcript

Speaker: [00:00:00] Hello everyone. Welcome back to The Thinking Mind Podcast. This week I am very excited to be joined by Professor Emma Robinson. Professor Robinson is a professor of psychopharmacology working at the University of Bristol. She conducts research with rodent, running a research program studying the new brow of emotional behavior.

The brain mechanisms, which were important to rapid acting antidepressants like ketamine and psilocybin. She also runs a program to better understand the welfare and refine the experience of laboratory animals. So our conversation today helps us to better understand what we can learn from using rats to study human conditions like depression, why this is an important part of improving how we treat these conditions.

And we also get a bit of an insight into what research with rats can be like. I really hope that you enjoy. Professor Robinson, welcome to the podcast. 

Speaker 2: Hi. Nice to meet you. 

Speaker: I guess I'm hoping that we can have a conversation today that really gets into the nuts and bolts of, [00:01:00] uh, working with animals and conducting research in neuroscience and mental health.

This is work that you focus on. And so before we take a deep dive into your work, specifically, as this is the first time we're having this kind of conversation, what do you think are the hallmarks of good quality animal research? Do you think researchers doing this should be doing? But also if people are reading about animal research, what should they be looking out for?

What should they be aware of? 

Speaker 2: I think that probably the most important thing to think about when you're looking at papers is when they're published. So our understanding of animals and, uh, the way we do research has changed over time and the ethical framework has changed over time. And so I think sometimes we look at.

Publications that may have come from the sixties and the seventies. And we compare those with publications that are coming out in 2025 and, and we make similar judgements of them. And that's, that's not necessarily a sensible way to do it. So the questions we asked in the 1960s, seventies, eighties were very different from the questions we asked [00:02:00] now.

And therefore, the approaches we use and the way we use the animal models was very different than to what it is now. Um, so the first thing I would say to anyone reading is, is. Be mindful of the date so that you can sort of reflect on when the publications were done, what were the questions that were being asked?

So back in the sort of seventies, we had these, um, these drugs, very exciting drugs that had come to the market, which were treating people with mood disorders. The first time it had ever been a drug psychopharmacology emerged. And we started to ask questions about how did those drugs work? 'cause they came about by chance.

Somebody observed, the clinician observed the drug doing something into people's mood, and they weren't meant for mood. They were tuberculosis drugs, or completely different area. But then the question was how do they work? And so animals were used to answer that question, where in the brain do these drugs interact?

What are the targets in the brain? And [00:03:00] we discovered that they hit the monoamine transmitters and that, you know, the, the monoamine hypothesis emerge from that. Um, and then we asked the question, how do we make better versions of these? Because the tricyclic antidepressants. Caused over, you know, they were very dangerous.

They had a, what we call a narrow therapeutic window. You couldn't take very much over the therapeutic dosing and they were cardiotoxic, so that was very bad. And they had a quite a heavy side effect burden. Um, we used to call them dirty drugs. I think we call them rich pharmacology now. But you know, they did a lot of stuff.

Um, and so the question then came, well, we know that they work on the mono amines and then we know they work on these other things that are not good. Can we make a drug that's going to be more. Targeting the mono amines and not the bits we don't want. And so animal models came in again and they asked a different question here.

Um, and that's where one of the most potentially controversial tasks that came in our field, the full swim test came about. And the way it was developed, it was a task that would measure [00:04:00] for similar drugs. So it was a pharmacological screen. INE Amitriptyline worked in this assay. They changed the behavior of the animal in this assay, and then people looked at other drugs like the serotonin specific reuptake inhibitors, and so those models delivered us the next generation antidepressants, which I'm sure most people would agree, have been a advantage.

And we now have drugs that don't have those high risks of somebody being able to overdose with them. Uh, the cardiotoxicity, they don't interact with food. They're easier for people to take alongside other medications. All of those benefits. And, you know, I'm just looking, the other day, 90 million prescriptions were written in the UK for antidepressants, mostly SSRIs.

So that's what animal models helped us to achieve. More selective, more specific, less side effects, easier for patients to take. And lots of people have benefited, but they're not perfect. We know they're not perfect, and that's always an argument. They don't work perfectly. Not everyone responds. So we are now in another phase, and this is a much more [00:05:00] challenging phase, I believe this is the phase where we need the animal models to ask questions about mechanisms.

We're trying to do things rationally. We are not just screening. Compounds till they do something and then off we go and try them In people, we are trying to be rational. We're trying to say, what is the biology that underpins emotional behavior? That's not easy. That's a tough, tough question to do, and you can't do it in humans.

All of you can ask some questions. We can't do all of it in humans, and so. That's where our work comes in. So we've said, well actually, you know, maybe we need to evolve the models. We need to move on from the models we use to predict and test for novel antidepressants based, but for antidepressants based on.

How we knew they could work to something that works differently, and particularly rapid acting antidepressants. So this is a new type of antidepressants. It works very quickly in people. It lasts for a few days and then in some cases with the psychedelics, it may last for several months, but we have no idea how that is happening.

And equally, just as [00:06:00] the tricyclic antidepressants of the past had cardiotoxicity. Psychedelics have psychedelic effects that isn't suitable for lots of people. It's gonna be very costly potentially to treat people using that route. Ketamine, again, there's abuse potential that worries people and, and rightly, um, you have to go to hospital to have it.

But can we learn from those? So we have tried to move the field forward. So what we've tried to do is say, okay, if we, how can we make a better animal model for studying depression? And that's where we went to the human literature. We can talk more about that sort of aspect and how and how we got there.

Speaker: So from what you're saying is really the key thing now is that the focus of what questions we're trying to answer has, has moved on. So whereas. Previously animal models have helped us get to drugs like sertraline, fluoxetine that people might be quite familiar with by just looking for a drug that does the same thing as another drug in an animal.

We're now at a point where we're trying to see what is it that depression. Is [00:07:00] in the brain and what is it that, or depression, anxiety, such conditions are in the brain. How, how are you looking at this? 

Speaker 2: Yeah. So absolutely that, that, that's, um, the way that I think, you know, we, we've now moved to a different place.

Um, how are we doing that? Well, the first thing we've done is go to human literature. So we've, we. Believe that the tasks that were used in the pharmacological sort of side of this, they have their place, but they are not necessarily helpful for mechanisms. And if you want to know how to get the next generation from here, we need to understand mechanism, ideally, why is it, what is it that that drives the development of depression?

How are emotions processed in the brain? Those sorts of fundamental questions. So we have gone to human. Psychology. Experimental medicine and we've said, what can you objectively measure? People always criticize animal models, but in fairness, how can an animal [00:08:00] model ever be aligned with me sitting down to somebody with depression saying, so how does it feel to have depression?

What does it impact on your life? And they tell me that they feel sad. Um, they think about negative things a lot of the time. They don't have any motivation to do things they used to do. They don't like socializing. How am I supposed to model that in an animal? Because it's subjective. It's very human. So what we do is we can say, well, hang on, what do you measure in humans that we could measure in animals?

And there are people doing some really interesting measures. We call them objective. Sort of tasks. Um, and the one that really stood out for us in, in, in depression related and anxiety actually, is a thing called effective biases. And we all experience them even though we don't probably know we do. And that's like, you know, I wake up, I've had a really bad night's sleep, I've had a bad day, something's been on my mind.

And, and, and things I think about. I influenced by my mood. Equally things I experienced that day when I've had a bad day, something bad's happened at work and I'm grumpy. Things I [00:09:00] experienced in that day are changed by my mood, and when I think back on them, I reflect on them. I think of them less positively.

And those are affected biases. They affect all of our cognition, um, everything we do, and they're normal. They're part of normal biology. Um, but interestingly, when you study people with depression, they have this presence of negative biases. So they are much more likely to interpret things negatively.

They're much more likely to make negative choices. Um, and that we think could be like a bit of a biomarker, behavioral biomarker of. Of depression, um, anxiety similar. You've got attentional biases. You tend to attend to negative information more when you have anxiety. So we took that kind of concept. We agree that rats are nice and no good at facial recognition.

Well, actually they are, but we are not very good at making tasks for that. Um, how, and they're no good at language. So how do we ask them to do effective biases? So we've set up tasks where we, we train them to, um. [00:10:00] Forage and to learn that a queue predicts reward. And then we bias that behavior. So we say you're gonna have a good day and we're going to give you food reward, uh, in a bowl that contains sawdust.

And then we're gonna have a neutral day where we're going to give you a food reward that's contained within gravel. And then we are gonna let you form memories of those, and we are gonna predict that. The good day leads to a positive bias. And we can test that 'cause we can ask you, which do you prefer?

So we do a choice test. Um, the rats that have had the positive affective experience have relatively increased the value they attribute to that experience. So when we say, which of these two things do you like better, even though they're the same value, when they learnt them, they go, actually I like this one better.

So it works in the positive, but it also works in the negative. And this is something where animal models are so important. You can't ethically do some of these things in people, but you can ask the questions in the animal model. So we can do those things where we do [00:11:00] give them a bad day. You know, we put them in a box for 10 minutes, which they don't like, um, and that it generates a negative affective bias.

And then we can look at how antidepressants modulate those biases. And that's been the basis of a lot of what we've done now. I'm not saying that affected biases are the only thing that drive depression, and they're not the only thing I'm sure that antidepressants interact with, but they're much more translatable between humans and animals.

And we have colleagues in Oxford doing human tasks that are so like ours and they are testing the same drugs as we are, and we can then align it with the animal data. And I think we're starting to unravel some really interesting cool biology. I can. Tell you from the work that we are doing, that I've identified parts of the brain that control these behaviors that are very selectively modulated by antidepressants and that, that those mechanisms we're beginning to zoom in now on very [00:12:00] specific circuits.

And by zooming in on those circuits, we are optimistic that we might find novel drug targets, ways in which we can achieve these particularly rapid acting antidepressant effects. We've also learned some really cool stuff about the interaction between these chemical effects. So biochemistry, I give a drug, it changes the chemistry of the brain and how he interacts with the environment.

Um, and those I think, are very important questions for mental health going forward in our society. Although we want to try and obviously improve the drug treatments, I think we also need to try to find a more rational strategy for understanding the impact of our environment. And it may be that by having these more translational models, we can start to ask questions about how does the social environment impact on your vulnerability?

And we've done a little bit of work on that as well. 

Speaker: I'll pick your brains on that 'cause that sounds fascinating. But to go back, uh, to go back a step and just to check that I've understood correctly, so the types of things that you're trying to sort of mimic in animals [00:13:00] are, so, for example, the experience that.

As you say, I've, uh, you know, I dunno. I've had an argument with my partner before I go to work and I'm in a bad mood and, you know, I'm, therefore, I dunno, everyone's in my way on the tube and, um, everyone's a bit rude and the person giving my coffee gives me a dirty look and my boss brushes me off a bit and I take that to mean that they're mad with me.

And so we're trying to see whether we can. Reproduce that kind of thing in animals by giving them the same bit of food that they like, but in two different situations. One where they've had a good day before they have the food, and so they associate that bit of food as being good. And the way that that's done is because the food is like parceled in a different container, but the food from the bad day, although in a different container, is still just as liked by the animals.

All things being equal. They end up choosing the one that is in the more positively associated container because they've kind of got these nice memories of it. 

Speaker 2: Yeah. I mean, what we think is that, that the memory is of the, [00:14:00] it's a digging substrate, so rats are very good at digging in substrates and remembering which substrate has food in it.

That's just a good ratty thing. And we have, you know, several, probably about a hundred different digging substrates available to us that we, I mean, one of, one of the rules of the lab is once you join the lab, you have to go and find five new substrates that we haven't found before. So, um, we have lots and lots of different things and they form a memory.

So it's an associative memory. We've taken exactly what you described that. That complex human thing of, you know, my, our lives are really complicated. We experience so many things, but yeah, fundamentally we are influenced by our, our mood and our mood influences, our memories. Now, in a normal, healthy human, that is a dynamic process.

You have good days and bad days, and that modifies our behavior, and that's a good thing to do if you have experienced a [00:15:00] bad day. There's a reason for that. Continuing to do those things is probably not very clever, so devaluing positive experience you had during that day is probably biologically a good thing to do.

Unfortunately, that same biology may well become the driver of sustained negative mood. We think that may be the case that's potentially where depression is coming from. So yeah, we, we've simplified it. Really, really simplified it to say that that core psychological process, neuropsychological process can be taken down to simple associative memory, digging substrate food reward, and then we can make different associative memories in the wrap by giving them different experiences on different days and changing their effective state on those days.

And then we can say to the rat, which of those do you prefer? So we can put a number on their effective state, and that is translatable because we can do similar things in humans. And it's [00:16:00] not absolute. It's not like the rat suddenly goes, oh, I only like this. It's a bias. So it's 10, 15% shift. That's all it is.

So when they go to the choice stand and we say, which do you prefer? They remember that both of these substrates had food in it. So they go to them both. They just have this bias. There's this subtle preference. The reason it works so well is because everybody does it. I don't know why it's such a powerful thing, but it is, it's, it's very clear.

Every rat pretty much has either a five, 10, or 15% bias. When we ask them that question, which do you prefer? And that works in the positive domain, the negative domain, and they don't really get bigger. You know, you can do bigger or smaller, but they don't massively change. It is dose dependent. So we can see nice dose dependent, but it's, you know, it's not like it's suddenly becomes a 80% bias or anything like that.

It's, it's dose dependent in this quite small window, which is really similar to what you see in humans. So if I was to. Ask you to perform, uh, a task with, [00:17:00] for example, a list of words. Some of them have emotional associations, positive, negative, neutral, and then I ask you to recall those words. If you have depression, you're more likely to recall the negative ones than the positive, but it will be a bias.

It will only be that 10, 15% shift. 

Speaker: And so therefore, because it's mimicked in humans, as you say, in very similar tasks, that you have colleagues doing similar tasks, it means we can have. Uh, it greater certainty that these things are capturing processes that are running. 

Speaker 2: We hope so. I mean, it's, it's always going to be the case that a rat and a mouse or a rat and a mouse and a human is a human.

And we have very different experiences and we will always debate. I don't doubt. Whether human psychiatric disorders are replicated in an animal ever. I think it does depend on the psychiatric disorder, but I am absolutely convinced that there is a animal representation of a depression like state, and I think we all [00:18:00] probably would agree to that.

If we think about zoos and think about different environments that we see animals in, and we know how much effort we've put into changing the environment of a zoo animal, and if you think what they were like in the seventies versus what you see now, it's fundamentally shifted. That's because we recognize that it has an impact on their wellbeing.

And wellbeing is. Affective state in lots of ways. Most animals that are in captivity in the seventies, they had food, they had water. They survived. They didn't die. They didn't really get, they did have an increased risk of disease, but what they really suffered from was abnormal behaviors, stereotypic behaviors, social withdrawal, all of the things that we would probably align with sort of mental health.

So I would argue that there is evidence. They're just manifest differently obviously. 'cause we have language and we have complex social structures 

Speaker: given that we can measure these things in both groups. You were [00:19:00] kind of touching on what the added value of being able to study these things in animals, because clearly it sounds like probably quite a lot of efforts to train rats and teach Russ do these things and sort of, and then the whole ethical process of, of managing animals.

But you were telling me the, the insights that you can get into the brain. Circuits circuit takes us to a level above what we're able to do in, in humans. 

Speaker 2: Yeah. So I mean, the justification that we make for using animals in research broadly is that we believe that, you know, as a society, we believe that we have diseases for which we think we.

Will benefit from having better treatments and, and I'm sure most people probably would agree, be those neurodegenerative diseases which every family is experiencing, mine included. And seeing that you obviously want to see that treated in the future. And the same with mental health disorders. You know, these are com the brain is very complicated and you know, I think, [00:20:00] we think we know more than we probably do about it.

I think we know very little actually at the moment about it. Um. So that then sets you up to how are you gonna move that forward? And, and, and the argument is you, you know, well, we just study humans, which is definitely very important. They set up sort of hypotheses really. So we can do things like, we can scan the brains of people, we can measure blood samples, but.

The problem with psychiatric disorders is there's no brain biomarker. Nobody's brain. You can't scan someone's brain and go, oh, you've got depression, or you've got, it's not like diabetes where you can take a blood sample. Oh, you've got high levels off. And I, I can measure that. So psychiatry doesn't have that.

Even in dementia, you don't see it until people are really quite poorly and probably quite late on in the disease if we could only find earlier predictors. But there isn't a blood marker. There isn't, you know, it's, it's hard. Even where we can image the brain imaging's so cool, but it only gives us a certain resolution.

What we can do with animals is completely different because the ethical framework that [00:21:00] we. Broadly as a society agree to, is that we can do invasive things in animals. In the uk we work under the Animals and Scientific Procedures Act, which says that I can cause pain, suffering, or lasting harm if the benefit to humans.

As a whole is greater than what will be the suffering. And that's the basis of the three Rs. Reduce, refine, replace, and how we do animal research. And I know everyone has different views on that, but, but, but broadly as a society, that's our case. And the reason we do that is because I want to ask really fundamental questions.

I want to ask how does the brain generate an effective bias? How does an antidepressant modulate that effective bias? Can I then find a better target, something that will do this modulation better? Or in my case particularly, I'm really interested in how do these things interact? Can we use these drugs better if we just understand more about how they modulate this?

What I think is a really important process [00:22:00] and the difficulty with humans is that, well, they don't give us their brains. Obviously, which is fair enough, um, until much later when they may, you know, they die for another reason. People donate, which is amazing. We have the biobanks and things very generously.

People do donate, but at that point we were only asking a question at the end. We can't ask those questions. How did it get there? Um, and so with animals we can, we start with a blank canvas and we can do manipulations. We can say, if I do this to you, what happens if I do that to you? What happens? And. We try to integrate then from, you know, thinking about social environmental, so there's a model called Early Life Adversity in Rats, where we just take the babies away from their mom for three hours a day.

It's not a particularly nasty intervention, but the mother gets stressed by it, which is fair enough 'cause we're taking her babies away for three hours a day. And that leads to a long term change in the brains of those animals. It makes them vulnerable to negative affected biases. It makes them more likely to [00:23:00] generate negative biases, stressful events.

It makes them more prone to drugs of abuse. It has a whole phenotype. So that's the sort of thing that you, so we can then say. That, that correlation we see in pe, in human, in, in databases that say there's a relationship between un love diversity and vulnerability to mental health disorders. We can then say, yes, there is.

It's causal. We can show that by doing this manipulation early in life we can, and then we also have a model that we can say, okay, so this happens, which is often happened. We don't find out about it till after it's happened. And then you have. An individual who's had this really extreme level of suffering that is now very vulnerable, but how do we protect them?

Can we identify ways to protect them? So then again, that's where our animal model comes in and we say, okay, so we generate it. Now how do we try to stop it becoming. A mental health disorder 'cause we know it's a risk and it doesn't have to become a disorder if we can work out the bit in the middle. The other thing that also happens is we can [00:24:00] do interventions in the brain.

So we directly manipulate rat's, brains doing amazing sort of precision surgery so that we can manipulate very specific pathways, very specific circuits. And in doing that we can really zoom in on how it works. Now lots of people say, well, what's the point in that? Because it's really just fundamental biology.

But most of the development we have made in medicine comes from a very big foundation of fundamental biology. I'll step away from a moment into COVID 'cause it's always really interesting 'cause people don't really realize why vaccines came about so quickly. It was a brand new technology. mRNA technology hadn't really been used.

Other than an experimental sort of, uh, settings, and it, it was suddenly the right thing and it, and this massive volume of fundamental research suddenly became extremely relevant. And I'm sure the people who did some of those studies looking at how mRNA changes the immune system or how those processes [00:25:00] were studied way back then, they were not thinking this was gonna be the answer to the COVID vaccine.

And, and I'm sure they didn't write that in their grants or their, you know, animal license applications because they were just saying, this is a really interesting thing to understand how this works. And so that's the kind of way we do science. We, we have this big volume of fundamental research that we don't always know what it's gonna lead to, but by building that foundation of knowledge in the future, we then start to be able to put things together and go, ah, okay, so this circuitry is linked to, this is linked to this.

Now we do have the potential to target and, and, and generate a, a new drug or a new understanding of how to treat that, that process. I think neuroscience struggles, as does psychiatry because we haven't done it very well yet. It's, it's a very slow process, I would say. That's fair because the brain is so complicated and I think that, you know, what we expect [00:26:00] is based on other systems of the body where you can get to them easily and get tissue and, and get blood samples, whereas the brain is just this locked in box, making it extremely difficult.

It's also really, really, really complicated. People don't, I don't think you can conceptually realize that. I mean, I always say when I go to schools and talk to in schools, you know, there are 10 times as many neurons in your one brain as there are people on this planet. And you imagine everyone on this planet is broadly interconnected and that processing power of humanity, well your brain, if you took one person and made it one brain cell, you got 10 times that just inside your head.

So yeah, it's a bit complicated. 

Speaker: And I guess one of the things that I've really struggled to get my head round, I guess, when thinking about neuroscience, about thinking about how, you know, for example, like how different parts of the brain communicate, interact with each other, is that it isn't like one follows the other like sort of stations on a train line, you know?

So you might do something to one part of the brain. Uh, you know, for example, it's, [00:27:00] let's say in depression, people say like. The amygdala is o is overactive. Um, and that means that this other part of the brain does something else. But actually what we don't understand and, and almost, I don't even know if our brains can conceptualize it, is it's also doing like five other things to other parts of the brain that then also somehow interact back and forth.

I mean, I guess I'm wondering whether, does it become any simpler in animals to trace those sort of circuits and processes? 

Speaker 2: Well, yeah. I mean, the advantage rats have, I don't know. 270,000 neurons. So a bit less, there's, there's less neurons. And if you go right down to a fly, brainin fly brains are beautiful because you, you know, we, we know exactly how many cell neurons they have, and we can map the, the, the numbers are much lower so we can start to build from these model organisms.

So we kind of go, right, you know, we look at the fly, we see elegance, which doesn't even have a brain. It's, it's, it's just a nematode with a, a simple, very simple nervous system. Flies fish. And we can study that complexity as it changes. Yeah. Um, but yeah, you are [00:28:00] right. I mean, you look back into the kind of era when, uh, the anatomists were looking at the brain and studying people who had had brain lesions or doing studies in animals where they.

Lesioned bits and said, what stops working? You know, that's what told us that the cerebellum's really important in balance and coordination and, and pre-programmed movements. And now we're starting to realize the cerebellum's also really important in cognition and emotion, which we didn't think about then.

And. Prefrontal cortex does all of our decision making. That's comes from amazing, you know, studies where people had trauma or lesions and things happened, and then they lost functions. And that gave us this sort of idea. The brain was in compartments, and that was up until not that long ago. It was very much seen as the amygdala's, the center of emotion, the, you know, per ductal spray is part of your.

Pain responses, your prefrontal cortex makes all the decisions and is the organizer. Um, what I think as we've been able to study the brain and as our ability to look at it in more detail has come about, we now realize that [00:29:00] it's networks. And so yes, the, the, the whole brain is integrated, information comes in, passes through our brain, and, and, and things are tuned into different bits of it, and they respond in different ways to it, and they modulate those signals and it's, um, very much more a network.

So, yes. There are critical elements in those networks. There's critical junctions, there's critical points, and if those fail, then the whole thing can fail. That's why when people have a stroke, you can end up with failure, but also you can get recovery, which I always think is the most exciting part of studying these sorts of things, is you get recovery.

How do you get recovery? You get recovery because the brain's really plastic and dynamic and it says, well, hang on a minute. There's a blockage here. Right? Okay. We can't go that way. Let's go another way. And if you look at brain injury in young children and young people and see how they can adapt, it's quite amazing.

Yes. As we get older. That gets harder. Harder and, and that gets harder physically as well as because the brain is getting older. Um, but the brain is incredibly adaptable. It's not this [00:30:00] preset thing that's blobs that have been put together like Lego and you lose a bit and that's it. And we're only really starting to, I think, get.

An understanding of that. And I would still say that even with the resolution we have now in animal studies, we can measure the activity of, you know, over a hundred neurons all at the same time in different bits of brain and how they're talking to each other and that connection. That's really cool. But it's still only a really tiny proportion of the cells that are there.

And in humans, obviously those invasive things are not ethical. We can't do that. We do when people are having brain surgery or needing recorded for things like epilepsy. Yes, you can get these people to do tasks. We can learn a lot from those, but it's limited. So, yeah, I think the animals are really important in helping us to just understand those fundamental questions about the brain and then from that, hopefully start to move our understanding forward.

But they're not blobs. Definitely not. They're, they're, you know, the networks are phenomenal. I mean, we are even zooming in now on sort of, you know, there's [00:31:00] interest in subpopulations of neurons within regions of the brain. Gosh, 

Speaker: I, it doesn't get simpler, but more we know. 

Speaker 2: No, I think it's definitely gonna get more and more complicated.

Speaker: Um, coming back to the tests that you've developed and the way that you're using these to study drugs, so you've, you've touched on an area of interest, your group now being with rapid acting antidepressants, which obviously are, you know, fascinating I think to everyone, whether you work in psychiatry or, or you don't, and people will have heard about things like psilocybin.

People probably have heard psilocybin, not magic mushrooms. People have probably heard about ketamine being used as well. What are you using animal models to understand about these drugs? 

Speaker 2: So the first question we asked was, why do conventional antidepressants take time to work? Takes several weeks to seemingly have their effects.

If you ask someone, do you feel better? But rapid acting antidepressants seem to work within 24 hours. And then the weird thing is that they seem to last. And that's strange [00:32:00] because most drugs, most people know, you take a medicine, it works. You stop taking it, stops working, takes some more of it, it stop working, you know?

Um, these drugs are a little bit unusual because they seem to have an effect in the acute phase, and then they last. Ketamine probably seven days. Some places are using it once or twice a week. The magic mushroom story, the psilocybin, the clinical study that's recently been published, uh, recently reported there's a published phase two clinical trial with psilocybin that's been really well controlled, well designed, and it shows that after a single dose, some people are still well, uh, better, uh, three months later.

So that's really unusual. So we wanted to ask the question, how could that be? And we have a hypothesis. All good science. You know, we worked to a hypothesis. We had a high prediction. We said, we think that delayed onset antidepressants take time to work because they only can modify your new experiences.

So you've been depressed for some time. Your memories are biased. [00:33:00] Your influence by those past experiences, they're all negatively biased. And you take your antidepressant and we know it acutely does positively bias new experiences. But it's like a bit of a balance, isn't it? So there's all this negative, and then I start getting positive, and it takes time for that positive to build up.

And then after a while, those positively biased memories, particularly people who are well socially supported, they get out, they reengage with the world, they start to have those experiences that can be positive bias, then they start to feel better. Then you've got the rapid acting antidepressants. So we tested the idea that maybe the way they work is different.

So it's not about biasing new experiences, it's more about what happens to those past experiences. So we simplify that right down to a, generate a negatively biased memory. So we still generate the bias memory. And then we give the conventional antidepressant. Nothing happens. So. It doesn't work on those past experiences we give ketamine and it completely and utterly blocks the negative bias and it's [00:34:00] selective.

So it's, it's not just an amnesic, it's not like we've given them a drug, they can't remember who they are, what they are. They can still do other tasks. Perfectly. If we ask 'em to do a really similar task, which is called a reward induced bias, so we make them biased by giving them more food in one of the substrates over another, and the effective bias, we make them prefer it or dislike it based on effective state.

It only affects the effective state one. And then we do the thing that we can do in animals. You can't do people, so we stick the drug into specific bits of the brain and we say, look, it replicates that effect when we only target this bit of brain. We can even go further and we can start to, you know, look at sort of the underlying mechanism so we can say this is dependent on protein synthesis, so it has this weird effect.

So at 24 hours after you've taken, after the, the animal's been given, ketamine. Their negatively biased memories have flipped and they've become positively biased. We haven't made them bad memory good. That's not what we're, what we've done at all. Some people sort of try and see it, that it's not, [00:35:00] we've taken a good memory, a positive memory.

I found food in this place, but it was negatively biased. And the animal has then relearnt it with a more positive, effective evidence. So we think that that is a really potentially important part of how these drugs work in the longer term because. Your mood is a very much a product of your memory. I mean, if you think about where does mood come from?

When I'm thinking about how I feel, it's based on my past experiences, what's happening now, and what the future expectations are, and if those are all negative, then obviously I'm gonna feel negative about the moment now, and I'm gonna feel negative about the future. If I can change the bias of those past experiences so I can modify those now, what we've no idea is whether.

It's 1, 2, 3, 4. How much is it that people are able to modify during that period that they're taking the ketamine? But it looks like it might be, and these are any animal studies. They haven't been replicated in humans 'cause it's slightly difficult to get humans to do our rat task. But that [00:36:00] kind of sets up this novel framework.

So the idea is that there's a neuropsychological mechanism, so we argue that it's not just the drug itself that changes the biology and makes you happy. We argue that the drug changes the neurochemical environment, enabling you to do different things in terms of affected biases, so conventional bias, new experiences, rapid acting bias, those past experiences, and that means that they work quickly.

The interesting thing we discovered with psilocybin is that it does both. So it's able to modify the past experiences very effectively. It does the inversion thing, so you can relearn past experiences with a more positive, effective valence, but it also looks like a conventional antidepressant and positively biases, new experiences.

So our next job is to find out why. So we are now looking at the underlying mechanisms of that. So what is happening in the circuit of interest? In the timeframes that we are looking at. What happens [00:37:00] acutely? What happens at 24 hours? What happens seven days? What happens four weeks down the line? Well, we haven't done the four weeks down the line because we've gotta get funding to do the next bit, but that's where we're heading.

Speaker: Now, I'm not sure if this will be directly related, but I guess something that I'm curious about is your take on a lot of the, I guess, sort of public conversation around neuroplasticity when it comes to these drugs. And my understanding is that whilst people will say things like, these drugs help your brain to rewire, or, you know, these drugs help your brain make new connections, that's really entirely based on animal research at the moment.

You know, we haven't been able to show that there's sort of new brain cells sprouting in humans. I think is, and I guess what, what do you think about the animal research? I dunno how well it links to what you are looking at as well, and also what do you think about the kind of extrapolation that's happening to, to humans at the moment?

Speaker 2: So I think the animal studies are very compelling. There's no question. Um, in the, in the chronic stress model combined with the conventional or rapid acting antidepressants, you [00:38:00] certainly see a pretty compelling argument for a neuroplastic mechanism. It definitely happens in these animal models, and that on the face of it looks pretty good.

Um, but there's a few bits out there that don't align. So one of the big challenges for me was always that if you go to a different animal model than chronic stress. So chronic stress does do this. But if you go to early life adversity, you don't see it. And if you go to Interferon alpha, now that's an inflammatory drug, a pro-inflammatory drug.

It, it was used in the treatment of Hepatitis C and it's well known in people to induce depression. It's quite an interesting model because in humans it was given and, and more than half the people given it would develop. Clinical depression. Now, if you do that to rats, you get a phenotype, but it's not a neurotrophic mechanism.

It's not as compelling. So that's one of the sort of potential caveats. We've been working a little bit on dose and the fact that a lot of these effects are seen in animals at much higher doses. Now that's very [00:39:00] controversial and it's. Potentially not gonna be a very popular kind of way of looking into that, but I think it's important that we do.

So the question then becomes, is this a really beautiful piece of elegant stress biology? Rodents that may or may not link in to what happens in people with depression. It doesn't stand completely different from ours at all. I mean, I think some people sort of thought of them as being very different. I think ours is just slightly changing the, the perspective of it.

So I think neurotrophic factors do play a role. My argument is that they're the other way around. And so what happens is the reason that people with depression show reduced volume in their brains. Because when you have depression, you do less. So why would your brain not react to that? Our brain is plastic.

It changes all the time. You look at the data on taxi drivers with bigger hippocampus, 'cause they do lots of spatial navigation. If you go to the animal world, animals that forage and store food in [00:40:00] the Autumns brains get bigger as they're doing it. So our brains react to what we do. So my argument is that the brain changes because of you being depressed.

So yes, there is a neurotrophic mechanism, but it's a consequence. And then in terms of the reversal, yeah, we are talking about similar stuff. We're talking about changing connections, but we're talking about it very specifically around memory circuits. I don't think it's that kind of large scale plasticity that is being seen in the animals, but I don't think they're miles apart.

This is often what happens with animal studies is there is a. Bit of truth in all of it. It's just bringing it all together. I'm hoping that eventually we can kind of, I mean, science has always got its kind of ideas and its camps of things and I, uh, I do try very much to look at all of it and I think we can bring it perhaps all together a little bit more, but certainly it's a very compelling case from animals.

Sadly, the pro neurotrophic drugs that were first developed, that, that have come through the pipeline now and they've gone into clinical trial and they've completely failed and I think we do [00:41:00] have to ask that very important question. It's all well and good being prone, neurotrophic. What does that mean in terms of bits of brain?

Because just having your whole brain made more plastic doesn't seem like a good idea to me anyway. What we really want is it to be targeted to those right bits. I think that you do get plasticity, but you get it because you behave differently once you have. Had these rapid antidepressants that change your past experiences, et cetera, et cetera.

There's, and there's lots of little bits of evidence that if you pull it all together, you can kind of find issues with those different arguments. Human, and, you know, one thing I've always stood out for me is that a lot of plasticity is driven by excitation. And then the one thing we've seen with certainly the psychedelics is they quieten down the human cortex massively.

So they actually are shutting. It's, it's gotten quieter, it's not exciting it, so that's quite interesting. 

Speaker: So it sounds like. From your perspective, again, the role of the environment, it is key in this. 

Speaker 2: Yeah, I mean, we've just been, our latest [00:42:00] probably quite controversial topic is to suggest that actually perhaps the animal models we have are not the best models for psychiatry and that we should look at more normal.

You know, being a, a rat and being weaned at 28 days and living in lab cages, you know, it's not optimal for their, you know, development. We know that, and as we want to ask questions like. Effective disorders and depression anxiety do, are they the best models? And I would argue they're not. Uh, and that perhaps, you know, one of the problems we have is we may be working with what is effectively a depression like model anyway, because they have grown up in abnormal environments with limited stimulus and you know, all of those factors.

So yeah, we're looking to try to develop. A different way of modeling. So actually taking the idea that actually we can put animals into much more naturalistic settings to create a more normal control from which we can then manipulate and ask questions about environmental and social factors. I mean, in the past we've done social isolation and there's no question you would socially isolate a rat, and they become quite odd [00:43:00] creatures.

Speaker: So the idea, it sounds like moving things forward is, you know, like you talk about the buring, you talk, so kind of working with behaviors that these animals have, but also working with environments. 

Speaker 2: Yeah, and I think there's been a, uh, I guess I'm a very unusual, probably a very unusual neuroscientist in that, you know, most of my life's been around animals and I had rodents since I was four years old and have studied rodents in a.

Not scientific way, but had pet rodents of all different types for all of my childhood. I think by the time I was 12 I had about 120 rodents of different species and things, and that's really unusual, uh, in my world. Most people come into science, wouldn't know anything about mice and rats, and they learn to use them as part of their research.

Whereas I see things much more from, you know, I'm aware of much more of them as a species. And to me it makes no sense to try and make rats and mice look like little humans 'cause they're not, and, and understanding their world. So they live in olfactory world. They live in a tactile world. They don't live in a visual world.

Rats are very sociable. Definitely [00:44:00] live in family groups, complex social interactions. Mice are completely antisocial. They're not the same at all. Mice are not little rats. They're a much more basic species in terms of a lot of what I see in terms of their cognitive effective behaviors. They have them, but they're, they're, they're diff very different.

Um, it's one of the reasons we work a lot with a rat model and they really like working with us, so that's the other advantage. You can handle rats, you can pair your interactions with them, with rewards and things, and it means that they all come and greet you when you come in to do your work in the morning.

You know, they're very, very, very sociable. They like working with us. A lot of what we do might look from the outside to be invasive and cause them suffering, but actually you come in and see them and they will all be there waiting for you to handle them and take 'em off and do tasks. And we, we record a lot of their vocalizations, so we listen to them.

We actually have back detectors so we can listen to what they're saying and understand whether they're in a good mood with us or not. And we hear the positive chi ups and calls from them when we interact with 'em. So we do things that are very different from other labs probably. Um, but I [00:45:00] think it does give us.

A lot more insight into them as a species and then how we develop the tasks that we use to then align with their affective behaviors. Not trying to make them look like us working on little iPads and that sort of stuff. We do have some iPad guys working, but it's, it. 

Speaker: So I guess linking back to what you're talking about, zoos, you know, animals can look sad or sort of look depressed in their own way, and by understanding how it looks for them and how it develops for them, you can actually get a better sense of what's going on.

Speaker 2: Yeah. We see abnormal behaviors in, in animals that can't, that are not living in the environment That's right for them. And we could maybe argue that psychiatric disorders in humans are not dissimilar. We, we we're not coping with the environment we're in. We either suffer with depression, anxiety, we start to show abnormal behaviors.

I mean, stereotypic behaviors in animals are very common. So if you put predators with big home ranges into small pens, they pace. It's a sort of [00:46:00] coping strategy and maybe, you know, some of the sort of OCDs and some of those repetitive behaviors are not. Miles away in, in humans. It's just that animals have a limited repertoire of what they can do because of their physiology and their anatomy.

And you know, ours is obviously humans is much more complex. But no, I don't think they're miles are past at all. And I think this. Need to have a habitat and environment that meets your core biology. And when that doesn't happen, we've, we've known for decades what happens with animals in the wild? Put them in captivity.

You think you've met their needs by giving them food and water, but you haven't. They don't breed. They have abnormal behaviors. They mutilate, they do, you know, it's extreme. And you know, I think that. We can learn quite a lot from that, but we have to remember to think about it as the species. And not a lot of the time we have tried to sort of have rats and mice, just be little humans.

They're models of humans, rather than recognizing them as rodents that we can study to learn about humans. 

Speaker: Professor [00:47:00] Robinson, I'm devastated to say we've run out of time, but thank you so, so much for your insights today. If people want to learn more about your work or learn more about animal research, is there any way you would point people to?

Speaker 2: Yeah, so the animal research side, I'd say, you know, look at the understanding animal research. You know, they do have a really good sort of general resource about the kind of, particularly in the uk, the ethical framework, the legal framework. And I would say, you know, if you are, be a bit open-minded. And read a bit more about it and think a bit more about the ethical kind of side of it and how we use animals in our society, how animal research fits into that.

Uh, and certainly from research point of view, we've got a website that's not a huge amount on there. There's a bit on there. 

Speaker: Well, we'll link to it. Thank you so, so much for your time. It's wonderful to meet you and hopefully speak again. 

Speaker 2: Yeah, thank you.