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Using Zebrafish as a Model for Opioid Addiction with Dr. Gabriel Bossé (University of Utah)

In Episode 67 of 17 Minutes of Science, we are joined by Dr. Gabriel Bossé. Gabriel Bossé is currently a postdoctoral fellow with Randall Peterson at the University of Utah. Prior to joining the Peterson lab, Gabriel did his graduate studies at the University of Laval in Quebec City with Martin Simard, where he studied the regulations of the micro RNA pathways with the nematode C. elegans. After completing his PhD, he was interested in developing novel behavior based assays to study neuronal function and disease modeling. He chose to join the Peterson lab with the hope of combining such assays with unbiased screening approaches such as small molecule screening. Given the ongoing crisis with opioid abuse, he set out to develop the first self administration model using the zebrafish model. This unique assay allows him to study the impact of different small molecules on opioid seeking and to investigate important biological pathways regulating this behavior.

Hannah Huston: Hello and welcome to 17 Minutes of Science, our show that explores the world of science and how it affects both the starting academic and the seasoned professional. I am Hannah Huston, and today I am joined by Dr. Gabriel Bossé. Gabriel Bossé is currently a postdoctoral fellow with Randall Peterson at the University of Utah. Prior to joining the Peterson lab, Gabriel did his graduate studies at the University of Laval in Quebec City with Martin Simard, where he studied the regulations of the micro RNA pathways with the nematode C. elegans. After completing his PhD, he was interested in developing novel behavior based assays to study neuronal function and disease modeling. He chose to join the Peterson lab with the hope of combining such assays with unbiased screening approaches such as small molecule screening. Given the ongoing crisis with opioid abuse, he set out to develop the first self administration model using the zebrafish model. This unique assay allows him to study the impact of different small molecules on opioid seeking and to investigate important biological pathways regulating this behavior. Welcome, Gabriel. What an interesting area of research that you’ve chosen.

Gabriel Bossé: Thank you. Thanks for inviting me.

Hannah Huston: So can you tell us a little bit more about your research? It’s very fascinating.

Gabriel Bossé: Yeah. So really the goal of my research is to use zebrafish as a model to study both like how the brain works, but also to model neurological disorders. So first of all addiction is one of those disorders, but also interested in anything particularly relevant to impulse control like depression and things like that. These symptoms are part of different disorders, including addiction. And really the goal is to use zebrafish both to understand the biology controlling these events. You know, what are the pathways involved in aggression and impulse control? But also, why do we have symptoms of like hyper aggressive person or somebody who has a lack of impulse control or in the case of addiction, what are the pathways that regulate self-administration. By understanding the biology, we can then understand and perhaps create new treatments, and by using small molecule screening as one of these approaches that you can have molecules that modulate that behavior. So for example, you have a molecule that can affect how much an animal consume an opioid and then it can give you a lead for potential treatment.

Hannah Huston: Wow. What a fascinating area of research and so important, especially right now. Can you tell us a bit more about why Zebrafish are particularly well-suited for researching opioid addiction?

Gabriel Bossé: I think a zebrafish is an emergening model for logical processes, and I think it brings a set of tools that are not necessarily present in existing models, like rodent models being the primary model to study drug addiction. And they’ve been making great progress in understanding how the brain works and how the circuits are changes and implicated in addiction. But I think zebrafish brings a set of tools, like I mentioned, that are different. It’s really a strong genetic model. For example, you can easily do mutants using techniques such as CRISPR/Cas9, and then you can then study how that affect process, process of addiction, for example. And really, one of the key point, too, is the ability to do large scale assays and large scale approaches. So my assay, for example, you can train fish very quickly to acquire the self-administration conditioning and you can train a lot of animals in a short span of time. And then again, when you talk about small molecule screening with zebrafish, you can put molecules directly into water. So no need for injection. So it’s fairly fast. And then you can test a lot of molecules fairly rapidly. That is a key strength of zebrafish, the ability to do those large scale assays that it’s much harder and more importantly, very expensive to do with rodents. So you can do these assays in fish. So for me, in my view, I see fish as a complement to existing models. It brings a different set of tools.

Hannah Huston: Yeah, we are really big fans of the multi-model approach as well and believe strongly in the fact that every model can provide different benefits to your research.

Gabriel Bossé: Yeah, I think so, definitely.

Hannah Huston: So in your research, do you use larva or adults? And is  there one you prefer over the other for your research?

Gabriel Bossé: Yeah, that’s a very good point. And I think it comes down to what you want to do. Exactly what do you want to study? What are you trying to measure? As both adult and larvae have sets of strengths that are different. So if we think about larva, you know, it’s simple small animals. So doing large scale approaches are much easier. You can think about, for example, if you just want to look at locomotion, let’s say you can use like a 96 well plate and test, like different mutants, different molecules, and very rapidly you can go through thousands of molecules, dozens of mutants. You can study a lot of different parameters or changing different conditions. And again, if combining that with CRISPR/Cas9, for example, looking at the development of the animal, looking at how these different mutants affect other animal behavior are very, very well suited for that. And the other aspect is that larvae are translucent, meaning that you can image anything, almost anything in the larvae, whether it’s like the heart, how its feeding, how different cells might be expressed in the heart, but also you can go down to brain activity. There’s some very cool experiments that has been done over the years to look at how the brain is reacting to changes in light and changes in the environment in real time. So in an animal that is living and you can see the entire brain how it’s lighting up, how the neurons are communicating in a live animal. So larvae are great models for that. But adult brain, like the aspect of complexity, you know, adults can do much more complex tasks with complex behavior. For example, I know you think about social interaction like memory formation and things like that, or in my case, the appearance of administration that larvae don’t have the sets of skills to acquire these more complex paradigms. So, you know, you can still do high throughput assays, which with the adult animal, not quite as much or as large as larvae, but really it depends on which type of experiment you’re trying to do. What are your take away you’re hoping for? So larvae at seven days old, for example, are not social animals. This is not something that they have acquired yet. So if you’re interested in social interaction, then you go with a bit older animal. It comes down to the biological question that you’re asking.

Hannah Huston: No, that’s such a good point about the visualization aspect of the larvae that it makes everything so much easier when you can see it with your own eyes. What assays do you use in your studies?

Gabriel Bossé: Yeah, so the main assay that I’ve been using is an opioid  self-administration. So basically we have a rectangular arena with two platforms and then we train fish to swim towards one particular platform that we call the active platform. And if they go to this platform, they receive a dose of opioid. So we use the opioid hydrocodone. So it’s one of the most commonly abused opioid. It’s used in clinic extensively. So fish essentially train to go back to this platform to get a dose of drugs. And then we can measure the number of time that these animals swim at this platform. And then it gives us a readout of opioid intake or consumption if you want. So this is the main assay we do that with adult. You know, I was talking about the complexity. They have to learn that they have to swim to that location and then they have to form associative memory so associated that this particular platform with receiving a reward. So that’s something that that larvae could not do to that extent. So this is the main assay I’m using, but on this side I have also developed more optimized assays to look at memory. So like novel objects for example, so we can look at memory, stress and anxiety, we can look at social interaction.

Gabriel Bossé: All of these with adults, for example, with larvae. You know, as I mentioned earlier, you can do large scale approaches with like simple behavior, but you can still look at like sleep. You can look at stress, anxiety, you can look at like baseline locomotion. And also you can do something like non-associative learning that we’ve called habituation. So if you repeat the stimuli like they’re going to stop responding to it as they get used to it if you want. So that’s one of the assays I’m using. So it’s really a battery of assays like a platform that you can use after that to understand how a compound, whether it’s a natural molecule, whether it’s a molecule used in a clinic, how is it affecting behavior? So you’re going to get that signature of the behavior and try to understand how does this change so? And after that, you can also use such platform for mutants as well, understanding what sets of behaviors are affected by the treatment of mutants so that these are very useful tools.

Hannah Huston: Wow. Yeah, I know that sounds like a really interesting approach. So can you tell us a little bit more about why you choose a small molecule screening approach in your research?

Gabriel Bossé: Yeah, so that’s one of the key strengths of the Peterson lab. So Randy has been a pioneer of small molecule screening in zebrafish. And for me, what interested me initially was the unbiased aspect. Let’s say you take a library of 1000 molecules, could be, let’s say, natural compounds. These are compounds that we don’t know necessarily what they’re doing. And really they’re going to maybe lead to the discovery of first new biology. They can target a pathway that you have nobody suspected that it could be involved in this particular biological process. But also it could tell you that this molecule could be useful to treat this condition or to improve a particular mutant, something like that. So for me, the bias aspect was the key. In my PhD, I used a mutant that was isolated from a genetic screen. So it’s a different bias approach. In that case, it was generating random mutation. And I identify mutants with this particular set of phenotype. So really I got interested in small molecule screening as an alternative to genetic. It brings different sets of again, and different tools at genetic screening. But really the aspect that you can treat sets of molecules. So it’s not that you can have a hypothesis driven but fully unbiased as well. Then I think it can lead to exciting discoveries, exciting new biology that really were unexpected.

Hannah Huston: Right, yeah. Removing biases from our research can be difficult, but it is crucial. What are the next steps for your research?

Gabriel Bossé: Yeah, so one of the next steps and it’s something that we did with the latest discovery. So we identified a compound in zebrafish called finasteride that affects opioid consumption. So we treated fish with this compound and they reduce opioid intake. And one thing that we wanted to do is to validate these findings in rodents. So that was one of the steps moving forward. Is it conserved in rodents? So that’s something that is interesting to validate. Again, you mentioned multi-model approaches, so that’s one way to do it. And really now that discovery, with finasteride then opened the door as well to study the role of neural steroids in opioid addiction. So this is a molecule that affect neural steroids production. So we are investigating downstream pathways affected by finasteride finoglyscase, what is the biology of it? How is finasteride reducing opioid intake? So that’s something I’m interested in studying. But also we’re looking at potentially small clinical trial even. Can we use the discoveries that we made in fish and in rats and could we improve quality of life of people, of patients affected by opioid addiction? So that’s one of the key things. What can we do with those discoveries but also know how could we improve the assays? How can we improve zebrafish as a model both for addiction and also as a platform for studying surgical disorders?

Hannah Huston: Wow. Yeah. I mean, opioid addiction is such a such a huge problem right now. And your research really could have a huge impact there. So it’ll be really exciting to see where it goes in the future.

Gabriel Bossé: Yeah, we’re very hopeful that it could. Even if you improve the quality of life of a subset of patients, it’d be amazing.

Hannah Huston: Right.

Gabriel Bossé: That’s kind of like the dream for a scientist.

Hannah Huston: Oh, absolutely. Well, your work focuses on zebrafish. You validate in rats. Can you speak more on the benefits of a multi-model approach and why you choose to include this in your research?

Gabriel Bossé: Yeah, and I think we already discussed briefly about it. I think different models have different strengths and it can complement each other nicely. And also there are zebrafish to study addiction. It’s still like a new field of research and it’s still something that we’re trying to establish as a robust and validated approach. And as I mentioned, rodents, especially rats, have been the gold standard in addiction research. I mean, obviously, you can use non-human primates, but there’s a set of complexity there as well. But rats have been really huge over the years and extremely powerful model to study that addiction, or addiction in general. And really, our goal was to use validated approaches like rat self-administration. There’s established protocols that establish ways of doing it that has been used for years and years. And really by validating that a compound that we identified in fish also works in rats gives strength to the story. We know that finasteride can reduce opioid suffering registration, for example. And different models, animals treat condition with different protocols. And I think it really shows that there are potential for translational research. And any research that has a translational aspect often goes through rodents in the steps of understanding. There is more and more molecules that are going from fish directly to clinical trials. But in the field of neuroscience, which is still an emerging field for zebrafish, I think it’s still often people go to rats with validated approaches. So for us, that was important to confirm that what we found in fish was conserved in mammals.

Hannah Huston: Yeah, I know. That’s really unique and wonderful that you’re choosing to take that approach. Now for our final question. Zebrafish have been slow to gain popularity in drug discovery research compared to other models such as rodents. Do you think the field is changing towards more adoption of the zebrafish model?

Gabriel Bossé: Yeah, I think so. And I think fish is being, like I said, validated more and more, so meaning that the field is accepting fish as a solid model to study in neuroscience, let’s say. And I think it comes down to appreciating that fish can have a complex range of behaviors. There’s the old saying that goldfish has a two second memory that they get right and it’s not true, you know. Zebrafish in particular are showing that they can establish memories. They can, you know, they react to the environment. They show signs of anxiety. They are social animals. So there’s a complexity of behavior there that is being more and more appreciated, like I mentioned to it brings a set of tools that is different from rodents. And there’s also a push to more cost effective methods to study different disorders and to do research in general. Right. And also to try to reduce our use of animals, especially in mammals model. And I think zebrafish can bring a lot of extremely powerful methods that can complement and in some cases replace rodent model. But it’s also tricky to say replace because I think it’s really complementing what’s existing. But I think it’s a cost effective method to study some of these disorders, bringing a different set of tools. And I think that people are starting to appreciate and understand the validity of using zebrafish and also how powerful that can be.

Hannah Huston: Right? Yeah. And I mean, we at InVivo love zebrafish, so we are very excited about that and the trends towards more zebrafish adoption and popularity.

Gabriel Bossé: Yeah, I think it’s a great model.

Hannah Huston: Well, that’s our time. So thank you so much for joining us today, Gabriel. It was wonderful to hear more about your research and about zebrafish in general.

Gabriel Bossé: Anyway, it’s my pleasure. It was great to be with you again. Thanks for the invite.

Hannah Huston: Well, thank you so much. And to everyone, tune in next time for 17 minutes of science. Bye.

Gabriel Bossé: See you. Bye.

About The Author

Hannah Huston

Hannah is the Marketing Manager at InVivo Biosystems. She received her Bachelor of Science in Science & Management specializing in Biotechnology from Scripps College in 2017. She has been with InVivo Biosystems since June of 2018. Outside of work Hannah coaches youth soccer and enjoys being active and outside with her dog, Siri.

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