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Unraveling anxiety and OCD with Nobel Laureate Mario Capecchi


A pandemic, social media, climate change—these are just some of the factors behind a dramatic rise in anxiety and depression in recent years. Now, in this conversation with host Julie Kiefer, Nobel Laureate Mario Capecchi shares exciting new research in mice that may shed light on mechanisms that control anxiety and obsessive-compulsive behaviors and lead to better treatments.

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Julie Kiefer: Welcome to U Rising, where we share stories about interesting and often groundbreaking research and innovations taking place at the University of Utah.

I'm Julie Kiefer, associate director of science communications at University of Utah Health and host of this episode.

In recent years, cases of anxiety and depression have increased dramatically for a variety of reasons. The World Health Organization found, for example, that anxiety and depression increased globally by 25% in the first year of the pandemic. Climate change, social media, world events—all have been suggested as contributing to the rise. But the root causes of these conditions are still unclear and understanding them is the first step toward developing better treatments.

There's exciting news on this front at the University of Utah, where scientists working with mice have found that a type of immune cell in the brain controls anxiety and obsessive-compulsive behaviors.

My guest today is Mario Capecchi, a Nobel Laureate and distinguished professor of human genetics at the Spencer Fox Eccles School of Medicine and of biology in the School of Biological Sciences.

Professor Capecchi is going to tell us what their study found and what it could mean in the future. Welcome to U Rising, Mario.

Mario Capecchi: Thank you, Julie. It's a pleasure to be here and to be able to have a conversation with the U community as well as its students.

Julie Kiefer: Well, thank you. Anxiety, depression and obsessive-compulsive disorders are debilitating conditions that affect about 30% of adults. This spring, you published research on a gene in mice that may shed light on the root causes of these conditions. Can you tell us what you found?

Mario Capecchi: Well, first of all, we generated a mutation in mice in a gene called HOXB8. And what did we find, which was very surprising, was they had chronic anxiety as well as pathological overgrooming. That is a condition that is very similar to OC spectrum disorders and where the patients actually remove body hair and compulsively do so.

Mario Capecchi is a Nobel Laureate and distinguished professor of genetics at the University of Utah.

Julie Kiefer: And so how do you study this phenomenon in mice?

Mario Capecchi: Well, we use a technology that was also developed in our lab—that is, gene targeting. We can change any gene in an organism such as a mouse and then see what happens to the mouse to infer its function. For example, if a little finger disappears, we're in the program for making a little finger. In this case, we knocked out HOXB8 and we got chronic anxiety and pathological over-grooming—a surprise.

Julie Kiefer: And so tell us a little bit more about how you understood what exactly that gene was doing and how it worked.

Mario Capecchi: So, the first thing that you do, you see what we call the phenotype. That is the effects of the mutation and what we see, for example, in terms of grooming, we see that the mouse removes body hair on the chest compulsively until it actually has lacerations, and that makes it pathological. They also show high levels of anxiety and we have multiple ways of measuring anxiety.

We have, for example, two platforms up in the air. One platform has walls on either side and the other is completely open. So, a normal mouse would explore both platforms, but, again, an anxious mouse will stay away from the one that doesn't have supporting walls. So, they can look down and it looks way down there and it's scary. So, it's anxiety increases.

Julie Kiefer: And so you were able to turn these behaviors on and off by manipulating this gene. Can you talk a little bit about how you did that?

Mario Capecchi: Sure. And this is a very new development. It's called optogenetics. Bacteria in the ocean do photosynthesis. It doesn't make sense to do photosynthesis at nighttime because there's no source of sun. So, they have channels, channels that allow ions to go in and out from the cell that are dependent on light. So, in the absence of light, they're closed and as soon as the light turns on, the sun comes up, then the lights open.

And a couple of researchers in Germany, as well as in Stanford, decided, wow, this is quite something because opening a channel and allowing in cations can activate neurons. So they said, well, we'll use gene targeting to put these channels inside a mouse brain into specific neurons, then open them up and those neurons are activated and they fire signals to other cells. And then you can tell what the neuron is doing. If the mouse starts all of a sudden running around, you turn off the light and it stops, turn on the light, it starts running around in circles. So you're in a program that says run around in circles or go forward or back or whatever.

Julie Kiefer: And so you were able to use this optogenetics technology to turn on and off this gene and control these anxiety behaviors.

Mario Capecchi: So the new addition was that nobody had thought of doing the same thing to microglia. People looked at microglia as scavenger cells. They're there to clean up messes. If a cell dies, they remove the dead cell and so on.

They didn't think about microglia controlling the neural circuits and yet our data suggested that they are controlling neural circuits because we inactivate a gene in microglia and all of a sudden we see specific behavior—grooming or elevated anxiety. So that suggested that these cells are somehow involved in the neural circuits in the brain because they're controlling the actual behavior. It's not that the microglia are responsible for the behavior, they're simply controlling the neural circuits that affect the behavior.

And so we knew there has to be a link and this was an opportunity to see whether optogenetics would work in microglia. And nobody had thought of that experiment because they thought it wouldn't work. But we were wild in a sense and put our channels not in neurons, but in microglia, so that when we turn on the light, now only microglia are activated. And then we look at the response and  voilà, we saw all of a sudden behavior, the same behaviors we saw by inactivating gene, turning on anxiety or turning on grooming in response to light. We turn on the light in specific regions of the brain, only in microglia, and then all of a sudden we have these behaviors.

Julie Kiefer: Right. And so you were able to take this optogenetics technology, target the gene in these different populations of microglia and that affected the behavior of these mice. And that was a surprise.

Mario Capecchi: Right. A real surprise and we were very excited. And we've just published that and scientists seem to be quite excited about the paper.

Julie Kiefer: So explain that. Why is everyone so excited? Help us understand that.

Mario Capecchi: I think because it all of a sudden it says . . .  people always knew that microglia were important. There were a lot of them in the brain, but they certainly didn't think about them controlling neural circuits. And here we're showing a direct link between microglia and neural circuits to control behavior.

Julie Kiefer: And it's not just microglia, right? There are different populations of microglia that seem to be doing different things. Can you explain that?

Mario Capecchi: That's the other part. I mean, when we got into this game, in terms scientifically, there was only one population of microglia, and we knew quite a bit about them and they simply called them microglia. Then along we came and we knocked out HOXB8 and then we saw that it was also affecting microglia. But when we looked in detail, they were a different population.

It took quite a while to convince other scientists that there really are two populations of microglia. And here's an example of where these two populations are doing different things. One is increasing anxiety and grooming, and the other is acting as brakes and decreasing anxiety and grooming.

Julie Kiefer: So, it's interesting that there seems to be all this control to fine tune these anxiety behaviors. Can you talk about that a little bit? I mean, we think of anxiety as being so debilitating, but there actually might be some advantages to being a little bit anxious.

Mario Capecchi: Anxiety is actually has . . . and also grooming. It's interesting that these two systems have this in common. That is, in small amounts, it's good. A small amount of anxiety spurs you on, puts you in a new situation, and all of a sudden you say, I can, I can handle this. So it's positive. It is a positive force. It says I can do something about what's happening to me. And that's what happens under small amounts of anxiety.

Similarly with the grooming, small amounts of grooming are comforting. Moms groom their children for comfort and the children receive it as comforting. So, for small amounts of grooming and similarly, if we groom ourselves, we make ourselves look a little better and that makes us more attractive to society and therefore happier. So, in small amounts, it's terrific. In large amounts, it's debilitating. So, what we want to do is be able to control the levels of anxiety, levels of grooming, that are good and not allow it to go beyond that to pathological levels.

Julie Kiefer: So, there are really a lot of groundbreaking ideas here that your lab has been able to uncover. I mean, microglia are controlling behavior through the neurons. That's the major brain cell type. And there's different populations of microglia that are controlling these levels of anxiety in mice. So, what implications do you think this could have for people?

Mario Capecchi: Well, I think what we have to do now is really the nitty gritty. Find out which neural circuits and neurons microglia are interacting with and what is the conversation? Who's saying what to who and how the neurons are responding.

And then once we're there, then we have to figure out the molecular language that they're using to communicate. And then finally, can we modulate that level? Can we control it so that when it becomes pathological, we can put on the brakes? Or if it's not enough, raise the level of anxiety a little bit to be effective to the patient. So, I think it's the more we understand the system, the more targets we have that we can then apply drugs, for example, that are specifically developed for that purpose—to modulate levels of anxiety, maintain them at good levels and similarly grooming, maintain it at good levels and not pathological levels.

Julie Kiefer: So, you're finding that microglia have control over anxiety and anxiety-related behaviors. Do you think they have control over other types of behaviors, too?

Mario Capecchi: I'm not sure whether other behaviors. And why they chose these particular behaviors, I still don't know. But hopefully our research will start giving us clues as to why they were picked out of multiple behaviors.

But I think there's lots of information, for example, that microglia involved in Alzheimer's disease. And, unfortunately, there's evidence for both ways, that they're doing good things and doing bad things.

And so, again, it's an interesting system in a sense. It's a yin yang system, which is what we see with behavior. So, I think that's going to be an interesting system. And so it's being looked at in terms of many pathologies.

And the other thing that's interesting about microglia is they work in timescales that we're familiar with. Normally, neurons are working, what, in milliseconds, that is thousands of a second, really fast, faster than we can imagine, and yet most behaviors are in seconds. So, it's a thousand-fold difference in scale. And so the question is how do you go from one system working at one time period, whereas the others are working at very different time periods. And so that's also going to be interesting to establish that kind of communication.

Julie Kiefer: And so what are the next steps for your lab with this?

Mario Capecchi: Find out which neurons, find out what the conversation is and then develop targets that would allow us to manipulate those targets in a good way to reduce levels of anxiety or increase levels of grooming to levels that are comforting but not pathological levels.

Julie Kiefer: And what makes you excited about this research?

Mario Capecchi: I think it's always surprises. I love science when, you know, you're doing something and then all of a sudden you get something unexpected. And further, the science we do is really at the basic level. We try to understand the biology and then the application will simply fall out from that knowledge and who are good at that? Drug companies are good at that. I'm not good at making drugs. I'm good at studying biology. And so as soon as you develop a target, then they will be very anxious to then develop the drugs.

Julie Kiefer: Dr. Capecchi, do you have undergraduates and other students in your lab?

Mario Capecchi: I'd love to have undergraduates of chemistry students in the lab. I think they're excited. They work hard and that's what I love. So, the opportunities there. When I was an undergraduate, I was very lucky to go to MIT and worked in labs and started all sorts of projects while I was an undergraduate. So no,  I'd love to encourage undergraduates to come. All they have to do is call my secretary, set up an appointment, and if I have money, I mean, the next thing I have to do is get money!

Julie Kiefer: Well, I love your research and thank you very much for sharing it with us.

Mario Capecchi: It was my pleasure. And hello to the U community as well as students and I hope we have further opportunities to interact.

Julie Kiefer: Listeners, that's it for today's episode of U Rising. Our executive producer is Brooke Adams and our technical producer is Robert Nelson.

I hope you'll tune in next time when my co-host Chris Nelson we'll be talking with Nicholas Witham, who won the Wilkes Center Student Innovation Prize.

I'm Julie Kiefer. Thanks for listening.