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Interview with Avi Adhikari

📷 Avi Adhikari

Journalist: Luke Peterson

Luke: Welcome to SciSection! My name is Luke Peterson and I am a journalist for the SciSection Radio Show broadcasted on the CFMU 93.3 FM radio station, and we are here today with Doctor Avi Adhikari. Thanks for taking the time to meet with me Dr. Avi.

Avi: Thank you for having me

Luke: Would you mind starting off by telling us about your role at UCLA and what your research interests are?

Avi: So I am an assistant professor at the department of psychology at UCLA; and I teach undergraduate and graduate courses with neuroscience, and my main activity is leading a neuroscience lab that studies how the brain controls fear and anxiety by using mice and animal models.

Luke: Can you tell us a little about your most recent research with these neural circuits, and what you’ve been able to infer from what you’ve found?

Avi: We’ve been studying anxiety for may years and we’ve found that there are different circuits that control distinct symptoms related to high anxiety states, so for example, you might have noticed from your own experience that when you are in a high-fear state, you notice many different changes. One change might be that your respiration rate goes up or that your heart rate goes up or that you avoid going to places that seem riskier to you; then we found circuits in the brain that control the different types of symptoms, and those are controlled by somewhat different circuits. Now we are studying more about how the brain controls escape from very potentially lethal, dangerous threats. And those would be things like someone attacking you or someone with a gun firing, or asphyxiation, or a predator biting you. And sort of the normal kind of healthy response in those situations would be to escape, which is what the brain is very well at identifying threats quickly, and then initiating an escape response; that all makes sense. But the same circuits that initiate these escapes from threats become overactive inappropriately, they can lead to very overwhelming and devastating panic attacks in people. And so we are studying the neural basis of these escape patterns and bc they’re implicated with panic attacks they have this clinical relevance as well, and more specifically, we are looking at how the brain controls these more versatile types of escape, and what I mean by that is that in your life you might have some dangerous situation that you encounter such as playing with fire or something like that, then you will try to escape but you will have to very quickly evaluate the layout of the environment and figure out how to escape, like where the door is or where the fire exit is. You have to very quickly understand where to go, not just to run around and jump in random directions. These things are important to us and they happen in real life. But in the lab, people are studying escape-related behaviors by doing it in relatively simple environments where the animal doesn’t have to do anything particularly complicated to escape. It doesn’t require this quick compilation that has to be integrated with spatial navigation or memory of the context. We try to look at which brain circuits control that type of behavior. Then we found out surprisingly that all of the brain regions that had been studied as being important for generating escape motions so far that have been in the literature, they did indeed cause escape as reported by other scientists. But they were not able to induce escape from a more complicated environment where an animal has to figure out what is a more reasonable escape route where they must jump and go here, which is more similar to trying to escape from places where you need to know how to escape from. We found a circuit in the brain that can control this more complex and versatile kind of escape. It was surprising that this brain region was located in the hypothalamus, which is a part of the brain that is very evolutionarily old and is typically not thought to be involved in very complicated types of behaviors and has been generally thought to be more important for hard-wired types of inflexible behaviors. We found that it can generate this complicated escape motion that integrates the geometry of the location to trace a more optimal escape route.

Luke: So do you think that; the brain is a very complicated organ, and there are a lot of substructures that interact with each other. Do you think that the brain is a lot more integrated than most people think? Or that parts of the brain that we think were intended for specific functions are meant for much more? I think that’s what you were getting on to when you were taking about the hippocampus or hypothalamus.

Avi: That’s not a yes or no answer, that requires a more nuanced answer. It is clear in thousands of published reports that there is a specialization of function in the brain but it is not true that all the brain functions affect all of the processes that the brain controls. It is also not true that each region or circuit has only one very specific function and that’s it. Each region has some specialization among a few functions, and there are also some functions that the brain is doing that we haven’t found out.

Luke: I read a few of your research papers before we started talking today, and I think the phrase “top-down” organization was used a lot, can you explain what that refers to and how you have applied that to your work or what you found that relates to that?

Avi: Top-down in neuroscience does not refer to directions like up and down but rather refers to a brain-function hierarchy, where in neuroscience, typically, we classify different parts of the brain as being more near the top or bottom, and what that means is that we conceptualize the brain as having these modules that intercommunicate and the more “top” modules are thought of as being primarily the cortex which is more outward and our “human brain” which is responsible for these actions like planning and conceptualizing different options and deciding what to do, or other cognitively demanding actions. The more “bottom” of the hierarchy are these structures that are more directly related to movement generation like the spinal cord is very directly related to moving beyond the arms and the legs and creating movements, but it is not related to planning what to do or evaluating among different circumstances or comparing what you should do with your memories. Those are more “top” functions and are not more directly related to perceiving what’s happening in the world through your skin senses like heat and temperature and also generating movements. One way to think of that in more concrete terms is something like a hierarchy within a corporation where the CEO is at the top of the hierarchy; they’re usually not responsible for directly doing things like cleaning the floors or ordering supplies or dealing with customers directly, but they’re more involved in higher-scale broader actions like what the company should be. That’s equivalent to the cortex in the top of the brain, and then the people that will be in a store or are selling something or answering questions or box and unbox things to put them in shelves which is more directly related with what is observably happening to the company, those are more equivalent to what the spinal cord would be doing in the nervous system. That’s what these hierarchies are: those are the two extremes with the top and bottom, but most of the activity is somewhere in between. The amygdala is a region of the brain that is somewhat in between, not in the cortex but not at the very bottom of the hierarchy. It’s a part of the limbic system, and it’s been very well studied for its role in controlling fear-related reactions and then what we found is that in the moment where there is something threatening happening, there is also some inhibition of the behavior that is happening because there’s usually some competing force whenever behavior is observed. You can see that from your own experiences; for example, when you get into car accident your first reaction might be to get very angry and get into a fight with the other driver, but most of the time people don’t fight with the other driver, but that also doesn’t mean that it also isn’t there. That means it’s being suppressed, and that usually happens when you hold yourself back from getting into fights. That is also what happens with fear reactions, and that when there is something fearful happening, there is a module in the brain that is trying to produce a fear reaction, but there is also some module that is trying to inhibit it, and we found that in this fear-type behavior, the one part of the cortex called the basomedial PFC was inhibiting the fear-related behaviors that were being produced by the amygdala, and that was the paper that we published about the top-down control of fear, the top being the cortex that was inhibiting the down-part which was the amygdala which was more of a middle-manager type of position in a corporation, and it’s inhibiting this fear-related behavior that the amygdala was trying to produce. That’s what the paper is about, and this top-down interaction again exists in most of the behavior we do; and the cortex often inhibits a lot of these parts from the older brain regions that are near the bottom of the hierarchy. To make another point, in neuroscience, when we say there is a region more near the bottom of the hierarchy, that doesn’t mean they’re less important necessarily, which is the case in the company either, where people would say that the CEO is more important than the janitor, but in neuroscience, the bottom regions are the more important regions for survival, but they’re just less important for long-term planning and things like that. Regions in the brainstem or more bottom, older part of the brain are the regions that can control the very important, vital actions like breathing and things like that. Breathing is clearly more important than lets say playing chess, and for solving differential equations, but those kinds of things are controlled by the cortex, while breathing and heart-rate and flow of the blood are more controlled by these areas at the bottom of the top-down organization.

Luke: I think that you mentioned before that most of your research involves mice; can you talk a little about what methods you use with mice and why the brain of a mouse is good for implying things about the human brain?

Avi: So we use mice as a model for several reasons. A few of them is that they’re good for practical reasons and that they’re small animals and they breed reasonably fast so you can study several generations of mice somewhat quickly, and another important reason is that a lot of genetic tools have been developed in mice that are not available in other mammals like cats and pigs or dogs or gerbils or other things, and those genetic tools allow us to make more sophisticated measurements than possibly for other mammals. For example, maybe we’re interested in understanding what the role is of this particular gene in this brain region, so it’s relatively easy to use mice to knock out the function of that gene in that brain region and then you can see what the effect is on the behavior that we’re interested in. In that same experiment we can apply to other mammals. Similar to that there are many other genetic tools available to mice that are not available to other animals like monkeys. To your second question of what we can learn from studying mice, mice are also mammals like humans so their brains are going to be similar in terms of how the basic modules are interconnected and what their functions are. So the question of what we can learn about humans by studying mice is also not a yes-or-no question where you need a little more nuance. First it depends on what the question is. Mice and humans have some problems they have to solve that are virtually identical problems. For example, most mice and humans really don’t want to asphyxiate; it’s very important for both animals to quickly detect if they have a problem in their oxygen supply so they can initiate a gasping reaction which happens. That isn’t a species-specific action. The circuit that controls that type of behavior is extremely similar in mice and humans, but they don’t solve the exact same problem without any significant differences. Then you can look at something else the brain controls but has more species-specific differences. For example, one thing that the mice do that the humans don’t do is that mice use their whiskers to navigate the world; they feel the surroundings with their whiskers and they know what’s ahead of them. We don’t have that system at all, using mustaches or whiskers to navigate the world. So if you want to study that in mice, you can’t directly transpose that to what humans are using to compute their surroundings. But, you can still find things about mice that are still applicable to mammals and humans also. For example, there is this part of the brain called the whisker-barrel cortex in mice which computes the information from whiskers and those same types of circuits are used in the human-visual cortex, so the same types of interconnectivity between cells and internal computations are somewhat similar between this part of the brain that uses whisker information from brain and the part of the brain in humans that uses information from the eyes, even though those are different things. In our case, we are studying fear which is something that makes animals be able to avoid threats which is clearly important for mice and humans. But it’s not as identical across different animals as it may seem. For example, the things that mice and humans consider threatening are somewhat different; for example, mice are very scared of cat odors and people are not super scared of cat odors, and mice are also very afraid of bright, open spaces because they're more vulnerable to predators finding them in those locations. Humans are the opposite, they’re more scared of dark locations because they can’t see as well so humans have more fear of the dark compared to brightness. And there are some things that are obvious that both mice and humans are afraid of. Both are afraid of very high or low temperatures, or painful things like stepping on nails, so there are some things that are scary for both animals, but what we guess is similar between mice and humans is that the brain regions that get activated during exposure is reasonably similar between mice and humans even though the actual threat source might be different, like a mouse or a person with a gun. So the source of the fear could be different, but it is activating many similar circuits in the brain. We can see that both using human imaging studies, such as when the brain lights up when humans are scared and we can see that in mice by measuring it more directly. In mice you can make inactivations of those brain regions and see that inactivation does cause a decrease in the fear behaviors. You can’t directly do brain inactivation in humans, but there are some rare people that have lesions in various brain regions due to either strain, diseases, strokes, or wounds of various sorts that maybe happen to affect the regions thought to involve fear, and then we can see that the humans then display decreased fear if they have lesions in those regions. In humans although it is hard to inactivate brain regions, there are things to learn from electrically activating those regions artificially and by causing fear-related behaviors in a person that just went through a surgical sweep and nothing actually dangerous is happening. It is pretty similar for fear, but again, not as similar as for something more basic like detecting oxygen or controlling respiration.

Luke: Towards the beginning of our conversation, you talked a little bit about how when the regulation of these circuits goes awry for some reason that these cause behavioral disorders or something along those lines. Have you been doing any work, or do you think there is any potential to apply your work, to try to develop any therapies or pharmacological methods that can help people with those behaviors?

Avi: It’s possible because, again, just like you said, a large portion of psychiatric symptoms as well as other conditions, are created by changes in the activity of brain circuits that have some useful functions in normal situations. It is useful in a normal situation to be able to detect the threat and avoid it and display the appropriate reactions so that you’re not in danger. That’s really important for survival, and then when those senses get overactivated then it would lead to pathological anxiety disorders. So if we can identify the circuits that control those behaviors, then that is the first step in developing a pharmacological method to address the disorder. So it is important that we do that. Also, it is equally or even more important to be aware of circumstances that we know are strongly associated with causing those sorts of psychiatric symptoms. For example, we know that not having a strong social support network makes people much more susceptible to developing an anxiety disorder. So a lot of the development of the disorder happens after having some sort of traumatic experience, but not everyone develops pathological long-term disorder after having the trauma. Some people don’t and then we know a lot about the differences between people that do and don’t, and one of those differences is that, for example, if the person has a strong social support network and close friends and family, then those people are much less likely to develop a problem after a traumatic experience. Another thing that is very protective in general, not just for anxiety but for memory and concentration and focus, is exercise which is extremely beneficial for brain function. There are all these other life circumstances that are not real treatments, per say, but have very important roles in preventing the emergence of these problems to begin with.

Luke: So I think that might be a good place to stop. Is there anything else that you’d like to say or add?

Avi: Yeah, what I’ll say is something that is related not jut to neuroscience but just to science more broadly, which is that a procedure that may appear very expensive at times would seem that there are a lot of other more pressing situations in the world to solve that would need those resources to be allocated to produce an immediate result, but even though that reality might be there, it is important to be aware that it’s really not a good question to say exactly what will come out of this project that is taking place at this moment because by definition, it is always looking at the frontier of knowledge. So we’re not very good at predicting which scientific projects will lead to which particular important improvement in the population eventually. And you can see that if you look at things that clearly are very important now. Now, electricity is very important. Electricity saves millions of lives and it is used in medicine, engineering, all sorts of activities and all of these things that have been unimaginably improved by electricity. If you look at what people were doing with Physics let’s say in the early 1700s or something which is when they first started studying static electricity and how electricity going through a wire changes the needle of a compass or things like that, and you ask them “why are you studying this electricity thing?” then they would not have answered that in the future the people would use it to power every sort of machine in the world, they would make computers or be used in cars. They would have said it is an incredible phenomena which might be useful for something. That’s easy to see now because we’re two-hundred years removed from that, so you can see what it is used for, but we have the same problem now, where the science that we are doing now, we’re not very good at predicting what will come out of it in the future, but what is very clear historically is that it is a worthwhile investment of resources in the long-term because you can imagine that in the 1700s, instead of developing electricity, if all of the resources were allocate to something else like building a bridge or building better houses, then it would appear that those things would make a more concrete impact in that time, but clearly in the long-term that would be a short-sighted action. What I’d like to say in the end is that if scientific enterprises are just allowed to flow more freely without lots of inhibitive constraints, then what we may or may not generate in the near future, it is clear in the long-term that where the innovation comes from that drives economic growth and development in people’s conditions. That’s what I want to end with.

Luke: Ok, sounds good. That's it for this weeks SciSection! Make sure to check out our podcast available on global platforms for our latest interviews, and I’ll talk to you later!


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