PODCAST TRANSCRIPT

Karel Svoboda  
You know, I’m, I’m new here. I lived in the suburbs, and this is different, right? You know, when I go past someone who seems to just lie on the sidewalk, I’m sort of tempted and I tend to check if they’re still alive. A month or so ago, just walking down 2nd street, there was someone lying essentially just barely wheezing. Sometimes with opiates, especially — so one of the key, one of the most abused drugs in Seattle right now is fentanyl, which is a synthetic opioid. One of the side effects of opiates is depression of breathing. And that’s often one way people die and overdose. And sometimes it’s, you really have to wait a while to see a breath. You know, if there are a few breaths a minute right it’s usually okay, but then this person just was barely wheezing and clearly had some other comorbidity, maybe asthma or something like that. And I have to say, I was very impressed by the emergency services. So I called in and they told me what to do. And they were there within three minutes, then the Naloxone came out. The whole thing was, was over in like maybe 10.

Rachel Tompa   
That was Karel Svoboda sharing the story of the time he came across someone overdosing in downtown Seattle. He likely saved their life by calling an ambulance and performing CPR.

Rob Piercy   
Karel moved to Seattle not that long ago from the suburbs of Virginia. He’s the director of the newly launched Allen Institute for Neural Dynamics. Karel studies a lot of different aspects of the brain. One of these is the brain circuits that are involved in reward. These circuits also underlie drug addiction.

Karel Svoboda  
Having come to Seattle and living downtown, I’m also getting increasingly interested in the problem of addiction, because Seattle is, as you know, is a hotspot in the sense that it has a very visible addiction problem. And there’s this scourge of addiction and deaths of desperation, right, that is plaguing this country. And this is a disorder of reward dependent behaviors. Habits gone wrong, in the most extreme ways.

Rob Piercy   
I’m Rob Piercy.

Rachel Tompa   
I’m Rachel Tompa.

Rob Piercy   
And this is Lab Notes, a podcast from the Allen Institute.

Rachel Tompa   
On today’s episode, we’re talking with Karel about the basic biology of reward.

Rob Piercy   
In some sense, it seems like at the most base level, without reward, there would be no life.

Karel Svoboda 
There would be no life, yeah.

Rachel Tompa  
We’re also talking with two other scientists: Hongkui Zeng, Executive Vice President and Director of the Allen Institute for Brain Science, and Greg Scherrer, a professor at the University of North Carolina. Hongkui and Greg are working together to better understand the neuroscience of opioid addiction. Their ultimate goal is to design less addictive pain medications and better treatment for addiction.

Can you just say what do we mean when we say reward? I mean, it’s not just like a trophy, right? Like it’s bigger than that.

Karel Svoboda  
Yeah, so reward is a loaded term, right? As we learn, much of what we learn, we think, is driven by reward. Ultimately there are of course, strong evolutionary pressures, right, to learn from reward, to find mates for sex, very importantly, you know, food for survival, and sort of the basic needs. This goes back hundreds of millions of years in evolution.

Rob Piercy 
We really need extra motivation to just not die, right?

Rachel Tompa   
Yeah, we need some other reason to eat and sleep and stay warm, other than the fact that we have to do these things just to survive. But reward does other stuff for us too.

Karel Svoboda  
Over evolution, how the brain kind of if I may say so thinks about reward is much broader. Right? One of the key aspects of mammalian nervous systems is information seeking, which is sort of at the very other end of rewarding things. So for example, we are curious creatures, but so are mice and primates and all kinds of mammals. We find information very rewarding.

Rachel Tompa 
So, Rob, you know that while I was working on this podcast, I have also been trying to learn audio editing software for the first time. I should explain to our listeners that Rob is our audio guru, and I’m a complete noob at audio stuff.

Rob Piercy   
Is that my official title, audio guru?

Rachel Tompa  
Yep.

Rob Piercy   
All right, that works.

Rachel Tompa  
And I just kept thinking about this moment in our interview with Karel like, isn’t my brain supposed to enjoy learning this new complicated software? I can tell you that it did not.

Rob Piercy  
Well, it took me 15 years to learn it, so you’ve got a little bit more time in front of you. It’s also interesting to think about the fact that learning is rewarding to us. At a basic level, learning is triggering the same kind of feel good chemicals as eating, or sex.

Rachel Tompa   
We’re learning about learning right now during this conversation. So what’s actually happening in our brains if we’re finding this rewarding?

Karel Svoboda
So many things, of course, happen. And lots of these processes we don’t understand, I should say, but reward processing is one of these things that has actually received a lot of attention in neuroscience. So I would say, for reward processing the glass is about 10% full. In neuroscience, that’s a lot. You know, usually we’re sort of at .01% for in many other kinds of aspects of brain function. So one of the key things that happens, there’s sort of this classic pleasure circuit or pleasure loop that involves, at its core, dopaminergic neurons. Dopaminergic neurons are some of the first neurons that were identified.

Rob Piercy  
Let’s talk dopamine for a second.

Rachel Tompa   
It is really the classic feel good chemical.

Rob Piercy  
Dopamine is a chemical messenger in the brain that’s the driver for this reward circuitry that Karel was talking about. It does a lot more than just make us happy. The neurons that produce dopamine, the dopaminergic neurons that Karel mentioned, are key for so many behaviors that we take for granted.

Karel Svoboda  
These neurons have fibers, axons that go all over the brain, and they kind of control the state and learning in the brain and our moods. And they kind of set the tone of the brain. And so what these dopamine neurons do is they secrete dopamine, that dopamine binds, then, this small molecule binds to other neurons, changes the properties of these neurons and information processing in the rest of the brain. Very importantly, for dopamine, it’s also a teaching signal. And this is very important, because when something good happens, that was the result of certain pattern of activity or neural activity. If you move a limb, for example, to grab your coffee, that’s the result of neural activity, then you get that sip of coffee, the dopamine kicks in from these dopamine neurons. And it actually strengthens the connections of the neurons that produce that action. So that action is reinforced, not just at the behavioral level, but now at the level of neural circuits that produce that action.

Rob Piercy   
All I can say is, thank goodness my brain is so good at reaching for my coffee cup.

Rachel Tompa  
Right? If dopamine helps strengthen rewarding connections, my coffee drinking circuit has got to be just super beefed up by now.

Rob Piercy  
All right, getting back to the dopaminergic neurons.

Karel Svoboda 
These neurons are key for processing all of the rewards that we discussed, from the very basic ones to the highly cognitive ones. And so one thing that happens is we receive a reward when these neurons are active. These neurons are also active when we anticipate a reward. So there’s sort of a learning component to this system, it drives learning and it’s also plastic. You’re learning, you know, stimuli that predict reward, or predict sex or food or, you know, an interesting movie, already activate this reward system. How the brain builds complex models of the world using this reward system, how it allows you to make plans about where to go and how to, in very complex dynamic environments, find your way towards rewards.

Rachel Tompa  
So it’s kind of like your brain is mapping the world with like a pleasure typography.

Karel Svoboda 
That’s, that’s great. I love it. Yeah.

Rachel Tompa
So we need reward and dopamine for pretty much everything that keeps us alive. But for some people, this very natural kind of reward seeking can go wrong.

Rob Piercy 
We know that addiction rewires the brain. But those struggling with addiction might have also had different brain wiring all along.

Karel Svoboda  
Over-activation of dopamine produces the euphoria that we experience with drugs of abuse. And these individuals that are prone to addiction actually have downregulated expression of these dopamine receptors. So their dopamine system is kind of underdeveloped in some sense. So they need more of that stimulation. And then that stimulation itself has similar kinds of effects. It further, ultimately, depresses the kind of compensatory effects that decrease the strength of the dopamine system.

Rob Piercy   
Okay, so dopamine is key for both reward and addiction. But as we know, the brain is really, really complicated. The cost of addiction can’t possibly be as simple as just having the wrong amount of dopamine.

Rachel Tompa 
Of course not. And now we get into the territory Karel was talking about where the glass of knowledge is more like .01% full. The neurons that produce dopamine are involved in addiction. But these neurons are involved in so many things. Aiming addiction treatments at dopamine or dopaminergic neurons might not get us very far, because it would have such widespread effects in the brain.

Rob Piercy  
Hongkui Zeng, who leads the Allen Institute for Brain Science is working on some of these unknowns.

Hongkui Zeng 
I think it’s very important to study how opioids activate the reward system and basically, you know, hijacking the normal reward system, right? Make it — desensitize it, you know, make the patients crave for the drugs and you know, wanting to have more and more and, you know, in the end becoming compulsive drug seekers. We want to understand that process, you know, how those drugs can hijack the reward system so that yeah, we can find ways to actually blunt that effect, while not preventing the normal, natural reward process.

Rob Piercy 
Hongkui is an expert in categorizing the healthy brain into different types of cells. She’s now collaborating with Greg Scherrer at the University of North Carolina, to find out what happens to these brain cells in opioid addiction.

Rachel Tompa 
Opioids are a class of drugs that were originally developed as painkillers — like a lot of other drugs of abuse, morphine, fentanyl, of course, oxycodone, these are the drugs you hear so much about in the headlines about America’s addiction crisis. Unfortunately, in some cases, some of these drugs are necessary because we just don’t have better pain medication. I asked Greg, a neuroscientist who’s an expert in opioids, to explain a bit more about their history and their current use.

Greg Scherrer 
Opioids originally, were used because they were extracted from a plant, the opium poppy Papaver somniferum. And so it’s a beautiful plant that makes beautiful flowers, but at a different stage of the plant growth during its cycle it produces, it makes a capsule that at an immature state produces a latex. And so humans noticed that if you lacerate these capsules, you can collect the latex, and if you let it dry, you obtain opium. So opium is very easy to produce. And so this substance, opium, contains alkaloids that include morphine, for example, that’s the most active ingredient, I would say, in opium. And so because it’s been easy to obtain, humans have used it since a very long time for pain, but also because they noticed that it created an euphoric state, pleasure.

Rob Piercy 
That pleasurable state is just the beginning of the addiction cycle.

Greg Scherrer  
These are the real rewarding properties of opioids that drive the addiction disease. This is, you know, you have two aspects in addiction. You have the first pleasure that you get when you experience the effects of opioids, and then you have habit forming, you become dependent. And so the first phase, the addiction is sort of driven by the positive reinforcement, so the pleasurable properties of opioids, and then you have a switch as individuals become dependent. Then you have the negative aspects of addiction that kick in; that is called negative reinforcement. And so if you were to stop taking the drug, now they experience the opposite. It’s a very strong aversive state; you don’t feel well at all. And because of that they need to take opioids again. And so it’s this vicious cycle that is causing the problem of addiction.

Rachel Tompa 
In the 1970s, scientists discovered the molecules in the brain that let opioids do their work. These molecules, called opioid receptors, are like little locked doors on neurons. Opioids are the keys that unlock these doors. One of these receptors, called the mu opioid receptor, is especially important.

Greg Scherrer  
A number of researchers generated mice that lack this opioid receptor, the mu opioid receptor, this is called a knockout mouse. And so simply by removing this single gene from the mouse genome, morphine essentially has no effect. It’s no longer analgesic, it’s no longer addictive, it doesn’t cause respiratory depression anymore.

Rob Piercy 
These experiments showed that the mu opioid receptor is responsible for everything that these drugs do: their analgesic, or pain killing, effects, the euphoria and their effects on breathing. That respiratory depression Greg mentioned, that’s what actually kills many people who overdose on fentanyl or other opioids. The drugs affect the brain’s control of the lungs, as well as the muscles themselves. And people just stop breathing. Separating out these functions is really critical for managing and treating addiction.

Hongkui Zeng 
The brain circuits that are involved in pain control, in respiration, for example, and in reward, the reward system, are all very distinct. The problem here is that the opioid receptor, especially the mu opioid receptor itself, is expressed in all these different systems. But if we are able to separate the effect of opioids on those different centers, then we can try to selectively activate, for example, the pain suppression center, or suppress the pain center to control pain, while not affecting the reward system at the same time, or the respiratory system at the same time. So it is actually critical for us to dissect, to understand the difference among the different circuits so that we can develop approaches to differentially target them.

Rachel Tompa  
Even though opioids are so addictive, why do we still need them? Like why do doctors still prescribe morphine and other opioids to their patients?

Greg Scherrer  
That’s a great question. And this is why my lab works not only on opioids, but also on pain. Because I am convinced that the two problems are really combined in what is in fact, not one epidemic, the opioid epidemic, but there’s another epidemic, which is the chronic pain epidemic. About 20% of the general population, at some point, will experience chronic pain. And we just don’t have that many drugs to relieve severe pain. And so, of course, medical doctors do know that opioids can cause addiction, that some patients may be at risk to transition to addiction. But it’s also not acceptable to let somebody be suffering from pain for months to years. And so, one of the problems with the opioid epidemic is that we do not have good alternatives for management of severe pain. So, by understanding how opioids relieve pain, we can also perhaps discover novel targets in the same cell that could relieve pain just as well as morphine, maybe more efficiently, but without acting on the reward or breathing circuits, for example.

Rachel Tompa 
Even though scientists know a lot about opioid receptors, they don’t know all the types of neurons that carry these receptors. They also don’t know which types of neurons are important for these three different branches of opioid biology: painkilling, pleasure and addiction, and respiratory depression. This is the problem Greg and Hongkui are trying to solve.

Hongkui Zeng 
We now have an opportunity to crack the cell type code of the opioid effect using the cell-type taxonomy on a brain-wide scale that we have generated. We want to do an unbiased screen of how the drugs affect the different cell types in the brain and identify potentially new target cell types for discovery, for investigation, and for intervention. Our hope is that through characterization of gene expression changes in cell types, we can identify, first in animals, but in the future in human brain tissues as well, identify cell types that are affected during specific phases of the drug use. And we hope that, you know, by identifying in a systematic way, the cell types across the brain that are affected, then we can begin to understand better how the drug affects the brain, you know, at a whole brain level.

Rob Piercy  
Right now, this work is happening in mice. But the researchers plan to study the same cell types in human brains very soon. Hongkui has worked in basic, foundational research for most of her career. It’s been really rewarding for her to branch into a project that could directly impact a human health crisis.

Hongkui Zeng 
We very much want to apply our basic research, foundational research, into a benefit to people’s everyday lives. Drug addiction, in particular, opioid addiction is a prevalent societal problem that we hope to be to help to contribute to solutions to.

Rob Piercy  
And she’s also just plain excited about the science.

Hongkui Zeng 
The brain is very plastic. The brain learns new things, can change, can adapt to new conditions. Drug addiction is an extreme form of brain adaptation, plasticity or maladaptation. So I’m very curious to see how it happens and also, in what ways we can reverse that, you know, really strong, persistent maladaptation. I think it’s, in some way, it’s an amazing manifestation of how the brain can be sculpted, and how nature, you know, how nature created those compounds, chemicals that can affect the brain in such a powerful way. And it is, I think it’s, of course, it’s extremely important for understanding and improving human health. But by itself, studying drug addiction is also a very powerful way of understanding the brain itself.

Rachel Tompa  
Does that kind of incredible plasticity of the brain, does that give some extra hope that the problem can be reversed?

Hongkui Zeng 
Yes, absolutely. Absolutely. I think we will definitely be able to find a way to reverse that process given the brain’s capacity of plasticity, you know, changing in the bad direction, but also, you know, changing back in a good direction.

Rachel Tompa  
I’m Rachel Tompa.

Rob Piercy  
I’m Rob Piercy.

Rachel Tompa  
For more lab notes episodes and other science news, visit our website at alleninstitute.org.

Rob Piercy  
Thanks for listening.