With more than one in three people worldwide living with a neurological condition, the stakes couldn't be higher in enabling brain repair…and these researchers are tackling the problem from the inside out, literally - starting with the brain's own cells.
What if the brain could repair itself all along, and we just needed to learn how to help it? In this debut episode of Bold Minds, host Fiona Sanderson sits down with three of Canada's bold early-career neuroscientists to explore the cutting edge of brain regeneration, including stem cell and myelin biology, the support cells in our brains that might be responsible for stress regulation, and the surprising mechanisms behind what might just be the next generation of antidepressants.
With more than one in three people worldwide living with a neurological condition, the stakes couldn't be higher…and these researchers are tackling the problem from the inside out, literally - starting with the brain's own cells.
Featured guests:
Dr. Anastassia Voronova, Associate Professor in the Department of Medical Genetics at the University of Alberta
Dr. Argel Aguilar-Valles, Associate Professor in the Department of Neuroscience at Carleton University
Dr. Ciaran Murphy-Royal, Associate Professor in the Department of Neuroscience at l’Université de Montréal
This work is supported by the Azrieli Foundation and Crabtree Foundation.
[theme music]
Dr. Anastassia Voronova 00:00
How do you think about the community and how do we now, in our positions now, train next generation of scientists? Because we were once in those shoes.
Fiona 00:15
This is Bold Minds: Future Leaders in Canadian Brain Research. I’m your host Fiona Sanderson. I work at Brain Canada, where our mission is to bring together funders and researchers to enable health innovations for Canadians. The Future Leaders program is made possible thanks to an anchor gift from the Azrieli Foundation and matched by Brain Canada through the Canada Brain Research Fund. Come along with me as we journey into the bold minds and labs of researchers who are redefining our understanding of the brain. [music continues then ends]
[rousing music] According to a Global Burden of Disease study published a few years ago, over one in three people are living with a neurological condition, making it a leading cause of illness and disability. Many of these disorders cause various parts of the brain to deteriorate or stop functioning the way they’re supposed to. For most of human history, we’ve believed that damage to the brain is permanent. The brain you’re born with is the brain you have throughout your life, just a little worse for wear. But we know now that isn’t fully true. Science has shown us that repair is possible and it’s something our brains have been doing all along: quietly growing new cells, rewiring connections, calling in molecular reinforcements. We just didn’t know how to help it do that. Today we’re going inside the frontier of brain repair, where the line between damage and recovery is being rewritten by researchers hailing from a wide array of specialties. This is Bold Minds. [music continues then ends]
Today, I’m joined by….
Dr. Anastassia Voronova 01:57
Anastassia Voronova.
Fiona 01:59
Her lab at the University of Alberta is investigating how a small population of stem cells in the adult brain can become activated to regenerate mature functional brain cells and treat neurological disorders like multiple sclerosis.
Dr. Argel Aguilar-Valles 02:12
[whooshing] I’m also joined by….
Dr. Argel Aguilar-Valles 02:15
Argel Aguilar-Valles.
Fiona 02:17
His lab at Carleton University is interested in how a non-hallucinogenic variant of LSD affects myelin, the protective coating that surrounds brain cells, and whether this mechanism is essential for its lasting antidepressant effects, as it could help to develop safe and effective therapeutics.
[whooshing] And last but not least….
Dr. Ciaran Murphy-Royal 02:37
Ciaran Murphy-Royal.
Fiona 02:38
His lab at l’Université de Montréal focuses on a type of cell in the brain called an astrocyte, and whether fine-tuning its activity in a specific region called the amygdala can control anxiety states and stress response, which could uncover therapeutic targets to help individuals with mental health challenges. Anastassia, Argel, Ciaran, thank you for joining us on Bold Minds.
[theme music]
Okay, let’s dive in. Ciaran, let’s start with you. Your work centers around a brain cell called an astrocyte and how it’s involved in our brain’s response to stress. I think most people are familiar with neurons. We know how they form these connections, these synapses, they can fire off electrical signals to each other, and I know we’re all very familiar with stress. Can you explain to us what is an astrocyte and why might it be important in stress response?
Dr. Ciaran Murphy-Royal 03:31
So, yeah, astrocytes, I guess they’re somewhat less studied than neurons in the brain, but they’re just as present, right? We’re thinking that there’s as many astrocytes as there are neurons in the brain, so quite an important cell. The reason that they’re less studied and less understood is the fact that they—as you mentioned, they don’t fire these electrical signals called action potentials. So, for a long time, we actually couldn’t measure the activity of astrocytes, and so we didn’t really know what they did. And so, in the last decade or so, we’ve started to get new sensors, new ways of listening to astrocytes and understanding what they do. And so, since these technological breakthroughs, we’ve been able to see that these cells are highly active in the brain. That they’re actually helping neurons do their job. So, they do a lot of different things like control the neurotransmitters that are in the synaptic cleft, they ensure that the neurons have enough energy to support their metabolic demands. And now in my lab we’re kind of thinking how they might even be upstream of neurons in the context of stress and behavior. So, one of the big questions in my lab is asking whether astrocytes actually transmit the stress signal from the body to the neurons and actually cause the changes we see with behavior.
Fiona 04:45
Okay. So, like, really important middlemen in this stress response process. That’s super interesting. And Anastassia, you study another type of cell in the brain. This one much rarer, the neural stem cell. Tell us about neural stem cells. Why is it important for us to understand the functions of this relative handful of cells in the brain? What can we do with that information?
Dr. Anastassia Voronova 05:06
I remember my grandmother used to tell me, “Don’t stress too much because your neurons will not regenerate,” and luckily now we know that that’s not true. In fact, every one of us has a pool—actually, a couple of pools of neural stem cells in our adult brain, and those are there to ensure that we have some regenerative capacity. Unfortunately, this process is highly inefficient, especially as we age or if we have a neurological disorder, like for example, a neurodegenerative disorder, whether it be multiple sclerosis, Alzheimer’s, Huntington’s, Parkinson’s, et cetera. And so, what we try to do is we try and sort of, so to speak, wake them up. We call them dormant or sleepy stem cells. They know in principle what they’re supposed to do, which is to replace damaged or lost cells in the brain, but they just quite don’t want to do that without nudging. And so, what we study in the lab is how to provide that pharmacological engagement or waking up of the stem cells using drugs that would enable the molecular switches in the stem cell to actually go on and replace the cell type that we’re interested in. And in my lab, that’s a cell called oligodendrocyte.
Fiona 06:21
It just means ‘the cell that has several feet’. [laughs]
Dr. Anastassia Voronova 06:26
And these are the cell types that are lost in multiple sclerosis, but now we’re realizing they’re also lost or dysfunctional in a variety of other neurological disorders as well.
Fiona 06:36
Wow! That’s really amazing. So, really, you know, you’re trying to flip the switch on, turn the light on, get those cells moving and doing what they’re supposed to be doing. Argel, that brings me to you. Because in addition to also working on understanding neurodevelopment and neurodevelopmental disorders, you also research the mechanism of action of some not so new drugs that are getting newly—getting some traction as clinical antidepressants—so, these are things like ketamine and psychedelics—and how another cell type in the brain, like oligodendrocytes, are involved. So, maybe you can walk us through what is an oligodendrocyte? Why is it important to understand the biology of how antidepressants work?
Dr. Argel Aguilar-Valles 07:14
Oligodendrocytes are another of these cell types of the brain that we don’t hear a lot about. However, they’re crucial for brain function and structure. They have a lot of functions. The most well-known is the formation of this insulating sheet around axons, these protrusions of neurons that allow them to communicate from one region to another, or even within the same region from one cell to another. And a portion of these axons are surrounded by this myelin sheet that allows a neurotransmission to be faster in certain circumstances. Not every axon in our brain is myelinated. Not every signal in our brain is to move fast, but some of them do. And we know of their importance because we have very disruptive disorders, brain disorders and illnesses where the myelin is destroyed by our own bodies and then we see the tragic consequences of these processes. But reduction in myelin function can also be found in other brain disorders such as depression. Particularly, it’s been well characterized in those individuals that suffer from childhood abuse or other forms of early life stress and the myelin sheets in their brain don’t develop as comparable as those that don’t suffer these events. And in those cases, we think that the drugs we’re studying may offer a new mechanism. A new hope through which they act and provide some recovery.
Fiona 08:44
That’s so interesting. So, there’s a common thread here, this myelin, this protective coating around these cells. So, is there a difference between failure to develop that myelin early in life versus the loss of that myelin through, like, neurodegenerative conditions like multiple sclerosis?
Dr. Argel Aguilar-Valles 09:04
Yeah. I mean, there is, and probably there’s some connection as well. You know, when the brain develops there is a program that sort of dictates where these myelin sheets are being acquired, in which neurons and so on and so forth. But now we know that even in the adult brain this process is quite dynamic, the same as what Anastassia was referring to regarding the birth of new cells in the brain of the adult brain. We now know that the myelin nodes can grow or diminish depending on their circumstances. Things like certain types of stress or psychological stressors or physical stressors can change certain levels of activity when we’re learning something. For example, there’s evidence that the myelin changes restructure to accommodate this sort of like storage of information in the brain.
Dr. Anastassia Voronova 09:52
Something just to add to that, while we understand the importance of myelin in neurodegenerative disorders, especially multiple sclerosis, there’s new research that’s highlighting that how myelin develops is just as equally important. And we now recognize that myelin biogenesis, or making of myelin, mistakes during that process contributes to pathobiological mechanism of neurodevelopmental disorders like autism. And in fact, we’re now recognizing that the drugs that we develop for multiple sclerosis to repair the adult myelin might be just as applicable to neurodevelopmental disorders as well. And there is at least one clinical trial already ongoing that is repurposing a drug that was developed for multiple sclerosis to see if they can help kids with a particular neurodevelopmental disorder, which is called the Williams syndrome. So, I think it’s just important to highlight how whether you’re studying brain development or brain homeostasis or repair, that different fields can inform each other and we can only succeed together.
Fiona 10:59
That’s—yeah, I couldn’t have said it better myself. We always try to learn from each other and learn from each other’s fields. Ciaran, what do you think?
Dr. Ciaran Murphy-Royal 11:09
Yeah, I agree with that. I mean, it’s nice to see that we’re all studying some sort of glial cell, right? All of these different cell types that we’re studying, right? They kind of fall into this non-neuronal family, and I think that’s where the future of these fields are, right? So, even when I’m studying astrocytes, I might try to isolate the astrocytic contribution to stress, but there’s a lot of research showing that astrocytes and oligodendrocytes communicate together, right? I mean, there’s some work that’s shown that—mentioned that astrocytes can feed neurons, support their metabolic demands. Well, the same can be said for oligodendrocytes. Astrocytes can also shuttle metabolites in that direction too. So, I think, you know, we’re all going to take separate parts of this puzzle and hopefully we can come together and maybe—I mean, as part of this conversation as well, maybe we can think about ways to work together on kind of overlapping projects, right?
Fiona 11:58
Along that same sort of vein, we know that research can’t happen in a vacuum, and more and more we see the value in sharing our ideas and collaborating like you’ve just been talking about. All three of you are doing really fascinating, cutting-edge research, and your focus is, really, on understanding the fundamental biological mechanisms of the brain. So, it’s a back-to-basics angle as a pathway to answering big questions. So, from your point of view, why is that important? Why should we be investing time, energy, money into this research, and what impact will it have on the average Canadian?
Dr. Ciaran Murphy-Royal 12:32
I think that’s a really important point, that we’re all really fundamental-focused and that’s, I guess, because we actually don’t know a lot about these fundamental processes. So, the way that I kind of got into this was to try to understand astrocytes at a fundamental scale I’d need to perturb them somehow. So, that was kind of my initial introduction to stress. “Let’s just stress the brain and see how astrocytes stop working, and I’ll learn more about what they’re actually doing in the physiological state.” So, that was my first introduction. But then once you dive into that field, you kind of expand, “Okay, let’s get into disease models. Let’s do these things,” and you continue to realize that we know so little about how the brain functions on that scale. So, I think for me they’re the fundamental questions that keep me awake at night, and I do hope that with a long career ahead of me that we can hopefully transition some of these observations into the clinic.
Dr. Anastassia Voronova 13:22
I would follow up on that saying that—I like how Fiona you said that, “One in three people will experience some kind of neurological dysfunction during their lifetime,” and yet the drug programs for neurological disorders have a very high-risk profile, and it’ll be the academic labs that will come out with the next drug for any neurological disease. Because of this high risk, pharma is withdrawing a little bit, and so I think it’ll be down to us to figure this out, really, and to de-risk it, really, so that, you know, sort of, I guess, do—like, create a path for how this translation can happen. But what are we going to translate if we don’t have the fundamental discoveries? How can we repair a dysfunction of a particular cell type if we don’t understand what the dysfunction is? So, I think we really need to understand how a cell typically functions and how it starts to dysfunction in any disease before we can figure out how to repair that dysfunction, which is why fundamental science is so important. And we also don’t know what we don’t know. How are we going to come up with a drug if we don’t understand the fundamentals of what we’re trying to repair?
Dr. Argel Aguilar-Valles 14:39
I completely agree with my colleagues. Like, basic research allows you to dig deep into the mechanisms that you couldn’t do otherwise in patient sense. So, it’s really important that we, you know, sustain a healthy and rich basic neuroscience research community in Canada, because this is the type of research that, as Anastassia here mentioned, will allow you to investigate mechanisms that you can’t necessarily test for different reasons, ethical to technical. But it’s also important to recognize that obviously there will be limitations to some of our conclusions, so that’s where the translational work is important to recognize what mechanisms apply. There’s a lot in common between rodents, for example, and humans at the level of basic biology, but there are fundamental differences, particularly thinking of mood disorders. We can’t think of treating a mood disorder in humans without the social aspect of the disorder, like the isolation that characterizes a lot of people with chronic illness—chronic mental illness, that cannot be modeled. Or sometimes it’s very difficult to model or impossible to model in other species.
Dr. Ciaran Murphy-Royal 15:50
And if I can jump in, I think you’re completely right. I speak to some clinicians here, right? We’re trying to think about—[who 15:55] work with people with mental health disorders, and the social aspect actually is key, right? The kind of therapeutic with a psychiatrist, these kinds of things, these are hard to model in our work, right? But nevertheless, I think some of the drugs are working. Like what you’re working on, the psychedelics—novel psychedelics,
we still don’t know how they’re having their antidepressant effects at all, which is crazy, right? Because people are taking them, right? So, this kind of back-and-forth dialogue is super key.
Fiona 16:23
So, stem cells, the concept of regenerative therapy, harnessing the body’s own processes to repair it from within, even the use of psychedelics to treat illnesses. Those are all very much hot topics right now, but in the case of the brain it can be extremely complex. So, what do you think is the biggest mystery in this field that you’d like to see answered, or the biggest roadblock you’d like to see shattered?
Dr. Anastassia Voronova 16:48
I think in my field, there are a lot of different questions that people are trying to answer. The questions that fascinate me are grand questions, like how neural stem cells build and repair the brain? Because our brain is in large part derived from neural stem cells. There are other cell types as well, like blood vessels and immune cells and whatnot. But then there are rudimentary terms we can think about, you know, the main signaling cell types, neurons, as well as glial cells, astrocytes and oligodendrocytes, all arise from neural stem cells. So, how do they really build the brain and how do they repair the brain? The other question that I am particularly interested about is how does the niche—so, the niche is this context of, you know, your immediate environment. And so, you can think about it, you know, we’re communicating right now, we’re all communicating, and the cell types in our brain are also communicating. It’s vital for them. And so, how does that communication shape the response to injury? What are the key players in that closed environment? And that’s, really, what our Brain Canada grant is actually on. And the last question that we’re starting to think also is, what about individual genetic mutations or, like, the typos in your DNA? You know, some of them will predispose you to disease, but some of them will alter how you respond to drugs. And so, should we really be now thinking about how does that alter the cellular function, especially when we think about drug development or future clinical trials? Will everybody respond the same way? Should we be stratifying the potential patient population based on what typos in the DNA they have? So, these are the questions that fascinate me. [chuckles] Those questions will probably differ based on everybody that you talk to, but I think that’s the beauty of it. Is that there’s such a diversity in ideas and thoughts. And again, I’ll say that it’s, really, working together and coming together where I think we’re going to reap the rewards as, you know, the brain community in Canada and beyond.
Dr. Ciaran Murphy-Royal 18:52
If I think about the astrocytes and what they do, I really want to understand how these cells pass on contexts to the other circuits of the brain. So, that’s what I think astrocytes do and I really want to try and design experiments to figure this out. Because let’s say we can have a disease context and astrocytes become a certain type of astrocyte with a certain molecular program that they’re doing, and in one context it might be completely different, and I think that that’s what these cells do. They adapt to experience and context and provide that information. So, for example, you can have just normal astrocytes in anxiety. Everybody gets a bit anxious now and again. Doing an interview or podcast, you might get a bit anxious. But there’s also then the pathological anxiety, right? Which is a completely different state. And so, I would love to figure out what that state looks like. Can we roll back the clock? And we can also think about that in terms of a disease. Maybe there’s a disease state, like in multiple sclerosis or things like this, where astrocytes arrive into one context. And maybe we can shift them into, you know, an anti-disease context. Not necessarily just back to where they were at the beginning, but maybe we can use those cells and push them in a specific direction to help other processes kind of recover as well. So, this is kind of the big question that I want to do. Can we use these astrocytes, which are highly dynamic cells—across the whole lifespan? They can become toxic, they can become anti-inflammatory as well, and so can we start to program these cells to kind of repair all different types of disorders? That’d be really interesting, I think.
Dr. Argel Aguilar-Valles 20:22
For us, specifically regarding this project that was funded by Brain Canada, it has to do with really broadening our understanding of how psychedelic drugs and other related drugs like the non-hallucinogenic derivatives that we use work in the brain. Since we found that they have the ability to perhaps regulate the myelin sheets in the brain, we’re trying to understand whether this is a consequence of the crosstalk between neurons and oligodendrocytes, or perhaps a direct effect on different oligodendrocytes populations promoting maturation and production of myelin in the adult brain. And then perhaps, given this ability, we can think of applications beyond just mood disorders, neurodegenerative or neurodevelopmental disorders, where there are certainly deficits not only in neurons but also in different cell populations such as oligodendrocytes and myelin formation as well. So, this—broadening this scope, and not only in mechanism but then potential applications, it’s what is driving us right now for this specific project.
Fiona 21:31
Well, thank you. And, you know, as you guys were talking, I couldn’t help but think about sort of the extreme value you add to this tapestry of Canadian neuroscience. And it occurred to me that all three of you have mentioned coming into Canadian neuroscience from elsewhere, all different parts of the world. And so, I have to ask, like, why Canada? What drew you to come to Canada and stay in Canada and develop your research program?
Dr. Anastassia Voronova 21:58
I came to Canada because I really wanted to do stem cell science, and stem cells were discovered in Canada. It is a no-brainer to be a stem researcher in Canada. I did my postdoc at the Hospital for Sick Children asking how the brain develops, and then for my own program at the University of Alberta I was really interested in translating these developmental discoveries to brain regeneration. And so, that’s in a nutshell of how I came to Canada. I loved it and so I stayed.
Dr. Ciaran Murphy-Royal 22:28
Yeah, Canada’s kind of, I guess, discovered a lot of things too, right? Because in the stress field, you could argue that is also a Canadian discovery, right? There’s Hans Selye who was a neuroendocrinologist or endocrinologist, I guess, at the time at the University of Montreal in the 1960s, and he set up, you know, an experimental stress program. And was the first one to think about, you know, regardless of the type of stressor, whether it’s a physical or physiological stressor, he suggested that you get the same stress reactivity mechanism that occurs. And he had all these great and grand ideas and really nice papers from the 1960s that actually have held through till today. So, yeah, Canada’s really pulling its weight, I think, in a lot of domains, and, I mean, that must be—I guess, there’s something special in the water here.
Dr. Argel Aguilar-Valles 23:16
Absolutely. I arrived in a more random, for lack of a better word, reasons to Canada. Because I was looking to find some PhD training outside my country and just because of the funding situation back in 2005, when I came in, that was relatively good in Canada and allowed a lot of recruitment of international students. So, I was offered a position and I accepted it without hesitation. [chuckles] I was just happy that I was able to go into a PhD program. I was at McGill University, obviously, that’s—you know, that’s made a huge contribution to science and neuroscience in particular, and then I stayed. I’ve been here for over 20 years now. [chuckles] The level of research and the generosity of the people working in research, their willingness to collaborate, their willingness to help you, it was just something that really, really kept me going here, and then I decided to start a family here. And then, yeah, now we’re here. We’re here to stay. [chuckles]
Fiona 24:23
I love it. It’s a surge of Canadian neuroscience pride here. [chuckles] Well, Argel, Anastassia, Ciaran, and to our listeners, thank you all so much for joining us today on Bold Minds.
[theme music]
Dr. Argel Aguilar-Valles 24:35
Appreciate it. Thank you very much.
Dr. Ciaran Murphy-Royal 24:36
Thank you.
Dr. Anastassia Voronova 24:37
Thank you for having us.
Fiona 24:41
Bold Minds is a Brain Canada production with support from the Azrieli Foundation. Our executive producers are Jillian Donnelly and Kate Shingler. Our lead producer is Jess Schmidt, with editing by Morgane Chambrin. Thanks for listening. If you enjoyed this episode, we’d appreciate it if you could send it to a friend. If you want to learn more about Brain Canada and our Future Leaders program, please visit our website at braincanada.ca. [music ends]