Allie Akmal:
Dr. Marga Behrens is a research professor in Salk’s Computational Neurobiology Laboratory. As a neurobiologist, she studies the interplay between genes and environmental influences to determine why some people develop conditions such as bipolar disorder, depression, schizophrenia, or autism.

Dr. Marga Behrens, welcome to Where Cures Begin.

Marga Behrens:
Well, thank you for having me here.

Allie Akmal:
So, you study the brain circuits in the prefrontal cortex, which is an area of the brain responsible for decision making and reasoning.

Marga Behrens:
What’s interesting of the prefrontal cortex is [that it’s] the brain region that develops slower. So in humans, for example, it doesn’t reach maturity until 25 years of age. You really need a long process. Even in animals, this region of the brain has a slow maturational process. When people talk about development, they usually talk about the very early stages when neurons are produced, et cetera. That occurs in the embryonic phase. And what I call maturation is once those neurons become neurons, they go through a very slow process to become what they are in your brain. So they come up as cells that are quite defined in what they are, but they haven’t made the connections they need. They have a long way to go.

Almost like any human being, you know, you have a kid, all it does is open the eyes, cry, poop and sleep. And then slowly it starts reacting. So that is the process of the maturation of your brain and the neurons that can form it. So in humans, there is a, a sprout of a connectivity quite high up until the two years of age. So if you look at a brain, it looks as if it’s growing like crazy.

And then it starts a very sharp pruning off connections that are not useful and cells that are not engaged in any network. And those ones die. So in a sense that 99% of the neurons you have in your brain now, you were born with them. And you were born with more neurons than you have now. You keep on killing them slowly, but you get a pretty rich dowry. And so the reason why this region of the brain is so interesting is because in a sense it’s sort of the central command, and it receives inputs from almost all other regions in the brain. And it sends outputs to a lot of different brain regions. And it’s the one that takes all inputs from your own body and it allows you to make a decision. And so whenever you find an alteration in this brain region, usually your decision making is sort of off.

Allie Akmal:
And that’s happening in the prefrontal cortex.

Marga Behrens:
And that the prefrontal cortex is the hub for this. It’s involved in mentalizing, in decisions, on given a situation, you have inputs, perceptual inputs, and your own state. And it makes you take a decision towards moving towards doing a thing. So it has very strong connections with motor cortex for example, to run away. So all that part is sort of a hub of decision, which is what basically keeps us alive.

Allie Akmal:
So it might be helping determine…you’re at a street corner and you’re trying to decide whether to cross the street and you’re evaluating all of the traffic and the lights and everything…

Marga Behens:
Exactly. Exactly. So the brain in a sense is a machine that allows you to perceive the world and keep yourself alive.

Why it’s so important to me is because usually the workings of that brain region is altered in mental disorders. Subtle changes won’t affect evolution; the species won’t disappear because of that, but the social part of that working of the brain is altered. I make the difference between mental illness and neurological disorders, where there is a very strong alteration in pathways that you can see in an MRI or things like that, but that is a very different situation. For example, in Down syndrome, you have strong alterations, but in mental disorders you cannot observe. It’s the workings that you observe are altered, the reactions towards a certain situation.

Allie Akmal:
How did you get interested in this field?

Marga Behrens:
How did I get interested in neurosciences? Because while I was in college—I did university in Chile—and there I had the opportunity to interact with schizophrenia patients and it just marveled me. [I asked myself] What is going on? Why is this person talking to me, totally normal, and then suddenly is totally off? You know, the same fact is taken in a different way and built up a whole world parallel that you say, what are you seeing? Why do you…? And that thought disorder to me was fascinating.

Allie Akmal:
So as a neuroscientist, you’re not looking at people’s behavior, you’re looking at the brain function and the brain structure and that sort of thing. So how do you find the subtle differences? How do you see them?

Marga Behrens:
So one of the things that started me on this was I started working on the effects of ketamine in the brain. It’s a dissociative anesthetic that is an analog of phencyclidine. Both of those drugs were designer drugs, anesthetics. You know, they were designed for that. But one of the things that they discovered was that they were propsychotic.

So when you give them to a normal person, they do produce the dissociation, but they give a psychotic state. And so I was trying to understand the workings of that drug. And we discovered that it produced sort of long-lasting effects. (We are talking always mice. Which is what we can control—in the adult mice.) And those effects would last about a week. And then the system would recover and produce the state that was similar to the psychotic episode that is schizophrenia in persons. And so in studying this, I realized that, well, you can produce a psychotic state, but the animal doesn’t remain psychotic as, for example, a schizophrenic person is. And so I say, well this is affecting very major cell type in the brain. And when does this happen and can we produce a state that is permanent? And so that’s how I went back, early on to see when these neurons become active, when they start a producing their connections. And that’s what brought me to the early perinatal period. Because during that phase, which correspond to the second, third trimester in humans…

Allie Akmal:
Behrens explains that mice are born less developed than humans. So by studying how mice brains are developing shortly after birth, we can better understand how human brains are developing shortly before birth.

Marga Behrens:
But looking at that period was that we started looking at what are the rules that command the way this system is maturing. And that brought us to what are the genetic networks that guide the maturation of these neurons. And that is what brought us to the epigenome, which is what I study.

Allie Akmal:
Epigenome literally means above the genome. It’s the pattern of chemical tags attached to DNA that control when genes are active; they’re like Post-its that say, turn this gene on or leave this gene off. Although our genome doesn’t change during our life, our epigenome does; and scientists are finding that studying how these patterns change over time can be very useful for understanding, for example, how we age or how a disease develops.

Marga Behrens:
So it is … sort of, we went from the behavior to the brain networks to the neurons to the molecular signatures that are commanding how these neurons develop and how they acquire their identity. Nowadays, we know that each neuron has an epigenetic pattern that is its own. And so it’s so defining that—we are now mapping the whole brain based on those patterns. And those patterns are dynamic as the animal is maturing, up until adolescence. And so all those changes allow you to understand, okay, there are a lot of things happening that lead to these neurons in this region of the brain to behave the way they do.

Allie Akmal:
Not only are neuroscientists like Behrens mapping epigenetic patterns overall, but they’re looking at which specific genes are turned on or off, because those genes make proteins that help neurons and other brain cells function. So the researchers can use molecular tools to turn specific genes on or off in a neuron and see how the neuron’s activity changes or how it connects to other neurons across junctions called synapses.

Marga Behrens:
So you go one step at a time and then you say, okay, you have alterations in this protein—does that lead to alteration in the type of connections the neuron does? So you look at synapses and then you say, okay, the synapses are altered—can we go a step further and see how the working of that neuron is affected? Because sometimes a change in a protein doesn’t lead to a change in the electrical pattern of the neuron. So you go and do electrophysiology and then you see alteration in electrophysiology. Does this lead to an alteration in the system? You go do EEG to analyze how the brain is working and then you finally go, does this affect behavior? Does this lead to an alteration in the way the animal is perceiving its surrounding, is reacting to it? And that’s how you do behavior.

So you go from a behavioral output that you see, and you go walk back—not always is successful—we usually get lost in the middle—but in general that is the way. And from there is that we know in mostly autism and schizophrenia, which is what I try to study, [that] we have certain characteristic alterations in behavior and a lot of knowledge of the workings of the connectivity patterns.

Allie Akmal:
So you’re able to notice behavioral details about somebody with schizophrenia and then connect those back to actual changes in the brain patterns or the epigenetics of their brain cells.

Marga Behrens:
Yes, that’s what we’re trying to do.

Allie Akmal:
How did you get interested in science?

Marga Behrens:
Well, there were, so how would you say it? Both my parents were scientists, so there was a default thing. I was going to be an architect. I did two years of architecture and then decided, nope, and went into science.

Allie Akmal:
Was that because you were rebelling against the influence of your parents?

Marga Behrens:
No. No, because I love it. And I still love it. There were two loves and I had to incline myself for one. And I decided that the challenges of science were more exciting. The excitement of doing science is… is bigger.

Allie Akmal:
Bigger questions, maybe?

Marga Behrens:
Bigger questions and it’s the excitement of, I don’t know. Do you like solving puzzle? It’s that.

Allie Akmal:
So what advice would you give to people who are thinking about a career in science or interested in potentially pursuing science?

Marga Behrens:
In general the advice that I give to the students that come around is: you won’t like it, but, yes, this is a priesthood. You really need to love it because the setbacks are 9 out of 10. It requires an enormous amount of work and resilience because you become emotional, you know. You have an idea and unfortunately you end up loving your idea and then the facts are telling you [that] you are wrong and you have to accept that you’re wrong.

Think about it. Think whether you want to keep learning, the rest of your life, just like a student, and whether you want to get up at three in the morning and go to the lab because you have an experiment that is running. And so it’s a commitment. It’s a true commitment. So in young people, in mostly the students that I get from UCSD, I always tell them that you need an enormous amount of passion because if not…nobody likes torturing themselves.

Allie Akmal:
But it sounds also like, you know, I’ve heard that resilience and grit is something that can be learned. So you don’t have to, think, am I naturally resilient? You can learn to be more resilient, right?

Marga Behrens:
No, yes, of course. But you have to have the drive. If not, it’s—you know, you learn resilience, yes, but what for? To me it’s the drive to keep going.

Allie Akmal:
The curiosity and the interest in finding answers.

Marga Behrens:
Exactly.

Allie Akmal:
Well, it seems like the way you’re going at problems, you see a behavior, like the behaviors of schizophrenia, and then you’re going backwards in mice to cells and then networks of cells and then epigenetic patterns. That’s the work of a lifetime. Because there’s so many brain cells and it’s so complex.

Marga Behrens:
But I am a person that believes—strongly believes—science is teamwork. For example, I would ban the Nobel prize. Totally ban it, because that prizes the individual, and science is teamwork. And so, as you have seen, I don’t work alone. I don’t try to learn everything myself. Okay, we have a problem—which are experts in each of their fields that can help to look at this problem? And so I team up with everybody, because I have a question—or because they have a question. And so that is one of the nicest parts of our work—the ability to team up to go after a question. And that I think if we did that more, it would be much more successful and entertaining.

Allie Akmal:
And entertaining also? To be part of a team, a collaborative team…

Marga Behrens:
Exactly. Yeah. Think of it, any situation you have to do something—if you have a partner, a pal, a buddy, it makes it way more interesting.

I always say it’s like humans are the only species that make the same mistake twice. Not even donkeys make the same mistake twice, we tend to do it a lot. And so when you have a team working all together, it’s more difficult to, you know, stumble into the same mistake twice. And it brings the fresh point of view, which is, for example, one of the things that I tell little kids: Don’t be afraid. Ask the question. If not, you’re not going to have the answer. And it might sound silly, but you don’t understand it, so keep on asking until you do. And in this case, it’s the same: we are grown ups, et cetera, but never stop asking questions, never believe something until you understand it deeply.

My daughter used to come with me to the lab and one day, she asked me to look—she was about six—to look through the microscope and so I put her a plate with neurons. And so she was looking through the microscope, didn’t say much, and on our way back home, in the back seat of the car, she says, “Now mom, how did you manage to put all those mosquitoes in those little wells?”

And I said, “Those are not mosquitoes. Those are neurons. The cells of your brain.” And she says, “Oh, come on, are you telling me that our head is full of mosquitoes now!?!” Don’t accept things as a fact, without really deeply agreeing. And be prepared. It’s a fight.

Allie Akmal:
Science in general, it’s, you know, your ideas are always being challenged.

Marga Behrens:
Ideas being challenged is the basis of science. We need it. It’s as my late husband used to say, “It’s a well-considered guess.” And so if other people get to the same well-considered guess, it starts making sort of sense that, oh, it might be true. But you have to be always aware that the way you look at things…you have an intrinsic bias in the way you look at a fact and sometimes you’re wrong—many times. But be open-minded to that. Don’t marry to your idea, because somebody will come and say, “Well, you didn’t look at it from this angle,” and it turns out that it’s not that way. Because in the end the truth will come up.

Allie Akmal:
I like it! Seems like a good place to end. Thank you so much for joining us. This has been a fascinating conversation and look forward to hearing more about what you’re discovering.

Marga Behrens:
Well, as always, it has been a lot of fun chatting with you, although I chat more than you.

Allie Akmal:
You have more interesting things to say.

Marga Behrens:
No, no, I bet you have, too. Thank you.