From Our Neurons to Yours

Will work for dopamine: why hard work motivates us | Neir Eshel

• Wu Tsai Neurosciences Institute at Stanford University, Nicholas Weiler • Season 9 • Episode 7

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Today’s episode is about the neuroscience of hard work—or maybe more specifically, the value we place on hard work.

There’s something different about hiking to the top of a mountain versus taking a helicopter. The view from the top is exactly the same, but if you’ve done the hard slog to get there, the payoff is going to be much more rewarding. 

The question is, how does the brain know the difference? To answer this, we need to take a deep dive into the brain’s reward system, and one of our favorite neurotransmitters, dopamine. And it turns out, the way dopamine operates is more complicated than we thought.

Our guest today, Stanford Medicine psychiatrist Neir Eshel, tells us about new research that’s starting to reveal exactly how the brain pushes us to work hard for the things that matter to us. 

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Nicholas Weiler (00:10):

This is From Our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University, bringing you to the frontiers of brain science. I'm your host, Nicholas Weiler.

(00:23):

Today's episode is about the neuroscience of hard work or, maybe more specifically, the value we place on hard work. There's something fundamentally different about hiking to the top of a mountain versus taking a helicopter. The view from the top is exactly the same, but if you've done the hard slog to get there, the payoff is going to be much more rewarding. The question is, how does the brain know the difference? To answer this, we need to take a deep dive into the brain's reward system and one of our favorite neurotransmitters, dopamine. It turns out the way dopamine operates may be more complicated than we thought.

(01:06):

Our guest today has new research that's starting to reveal exactly how the brain pushes us to work hard for the things that matter to us. Let's get right to it.

Neir Eshel (01:17):

My name is Neir Eshel and I'm an assistant professor of psychiatry here at Stanford, where I see patients one day a week and spend the rest of my time running a lab studying the fundamental neuroscience of motivation.

Nicholas Weiler (01:30):

Well, Neir, I'm so excited to have you back on From Our Neurons to Yours. Thanks for joining us.

Neir Eshel (01:34):

Absolutely happy to be here.

Nicholas Weiler (01:36):

So today, we're going to talk about this really interesting new study your lab did in mice that helps explain why something we have to work to achieve can be more rewarding than if the same thing is just handed to us. But before we get into that, as you said, you're also a psychiatrist at Stanford. You help people, if I understand correctly, particularly the queer community struggling with depression or anxiety, trauma, and things like that.

(02:00):

And I wonder, is there a connection between your experience working with patients, the kinds of things you see them struggling with, and your interest in the neurobiology of the brain's reward system and how it shapes our behavior?

Neir Eshel (02:14):

Absolutely. There's a very direct link between what I see in my patients and what I decide to study in lab. When I started my lab, I had to decide what types of behaviors or topics to study. And I chose two, motivation and irritability or aggression. So on the motivation side, I became really interested in trying to understand what is happening in the brain that enables someone to be a really successful software engineer and marathon runner, but then twice a year, maybe they'll have these three-week episodes of really bad depression that they are in bed. They can't get the energy to get up out of bed, put their clothes on, get shower, eat breakfast, go to work, do the things that make them happy for the rest of the year. What's happening that the kind of motivation just goes away?

Nicholas Weiler (03:09):

Right. Same brain, but completely different experience.

Neir Eshel (03:12):

Same brain, same person, same values, same interests, but completely different experience. And on the other side of the spectrum of motivation, I see patients who are in the throes of addiction, who have a particular drug of choice, for example, that they will do anything for, even at the expense of everything else that they actually care about, their relationships, their jobs, their families, everything, their own health.

(03:37):

So in that case, the motivation gets funneled into a single pursuit, which is for the drug. So I see that as another example of how the brain's reward circuitry, motivation circuitry gets hijacked in the context of a neuropsychiatric disease that is also just extremely problematic. And we don't have nearly enough tools in our toolbox to help people who are suffering in that way.

Nicholas Weiler (04:05):

How did you make the connection from that broad interest to the study that you just released about why things that we work harder for actually produce a higher level of reward of motivation than something that's just handed to us?

Neir Eshel (04:21):

So I'm a firm believer that before we understand how things break, we need to understand how they're made in the first place, how they work, what are the fundamentals that allow, for example, brain cells to communicate with one another and control behaviors. And so, in this case, what I really wanted to understand is a phenomenon that's been in the literature now for many decades, and that is this phenomenon.

(04:45):

So, for example, if you're climbing up a mountain versus if you just drive up to the peak, the view from the top of that mountain is objectively it's the same view, but your experience of it is really different. And I think that's the same for classes. If you take a really hard class and you work really hard and you get that A versus a really easy class, or you didn't work too hard, or maybe you use ChatGPT to help you a little bit on the final assignment, I think that A is just worth less. Objectively, it's the same A, but it's different. You value it different. It means different things to you.

Nicholas Weiler (05:19):

Yeah, no, I know exactly what you mean. And I think you bring up AI. I think that's something that's on so many of our minds right now, which is like there's this moralistic side to things, which is like, well, if you didn't work for it, is it really valuable? But there's also a personal side to that, which is sometimes working for it is the thing that really allows you to grow and a thing that allows you to learn and develop and get to where you're going. I'd love to come back to that later.

(05:43):

We should probably focus on your study that gets to some of the neurobiology behind this. How does your brain know that you worked for it? As you said, you get to the top of the mountain, the view is the same. How does your brain know that you worked for it? So to answer that, we're going to dive into the dopamine system. And one of the things I wanted to do just before we dive into it, there's so much conversation about dopamine these days, right? People talk about dopamine all the time. My brain's been hacked by these cheap dopamine hits on my phone. My receptors are shot from scrolling all day. I need to detox to reset my dopamine baseline.

(06:19):

And on the one hand, I love this, because the whole point of the show is to help people think about their own lives like neuroscientists. But I also want to make sure that the way we talk about dopamine in the public discourse actually matches the way you think about it as a neuroscientist. So what's your take on that? As a dopamine expert, what does this public discourse about dopamine get right? And are there ways that we might want to reframe how we think about that now that we're talking about the literal brain chemical dopamine?

Neir Eshel (06:48):

That is a tough question. I also have mixed feelings about it. I love that people are thinking in terms of the brain and how the brain controls behavior and how these neurochemicals in the brain like dopamine have a really powerful place. What dopamine actually does is a complicated question that people in neuroscience have been obsessed with for probably 70 years. I personally have been obsessed with for about 20 years, and I don't have an answer for what it does. And probably there is no answer in the one sentence description. If I were dopamine and I was wearing a shirt that said what I did, I don't exactly sure what that shirt would say.

Nicholas Weiler (07:24):

It doesn't have a good elevator pitch.

Neir Eshel (07:26):

No. Although probably the closest elevator pitch for what dopamine does is something like it induces wanting. In the last show, we talked a little bit about this distinction between liking and wanting, which is something that has been floating around the literature for decades now. And I think still has a lot of explanatory power. The basic idea being that when people think about dopamine as a happy, or a pleasure, or reward molecule, that's partly right, because when you give an animal a reward, you will see dopamine neurons spiking.

(08:05):

But it's more complicated than that because what it seems to be more capable of doing is regardless of whether the thing that you're getting is actually pleasurable or not, it makes you want more of it. And you can see this really clearly in the context of addiction when people often will describe being in a really aversive state of mind and really not enjoying the experience of the drug anymore once they're in the throes of addiction. And yet the dopamine keeps on being released, they keep on wanting more, and wanting more at the expense of everything else in their lives. And it seems like dopamine is more involved in that wanting or what's sometimes called incentive motivation as opposed to the liking or the pleasure making of the reward.

Nicholas Weiler (08:52):

So with that understanding in mind, and I think you make a great point, which is dopamine is produced in one part of the brain and sent all over the brain and does different things in different places. Even in the same place, it does different things depending on which receptor a neuron expresses, right? So it's complicated, it's not just one thing. But in the context of this study, in the context of thinking about why we value things more that we've worked harder for, we're talking about dopamine that gets released in part of the brain called the nucleus accumbens, broadly speaking, this reward center.

(09:26):

And so what you're just saying is dopamine isn't necessarily about how much we like something, it's about how reinforcing it is, how likely it makes us to do that same thing again.

Neir Eshel (09:36):

Exactly.

Nicholas Weiler (09:37):

So the basic observation that you're trying to address is that what I asked earlier, how does the brain know if we worked harder for the same reward? Why is it that we have that experience? And you and others have observed that if you look in the nucleus accumbens in a mouse, if they work harder for a reward, there is actually more dopamine released.

(10:00):

So I don't want to go into all the gory detail. This is an amazing study. You did a bunch of really, really cool techniques here, and I will link to the study in the show notes for all the people who want to geek out like me about triple recordings of dopamine neurons. Excellent stuff. But what was your approach? What kind of hard work were you having these mice doing? How did you go about figuring out why it causes more dopamine to be released?

Neir Eshel (10:23):

So what we really wanted to do was dissociate the reward itself from the effort that the animal puts in for that reward. So the way we did that is in any given day, we would have a mouse ... And we were using mice because, believe it or not, their dopamine system is remarkably similar to the dopamine system that exists in non-human primates and in people. And we have all of these amazing tools at our disposal in mice to record from these neurons, manipulate these neurons in real time while the animals are performing a task that we can teach them to perform.

(10:56):

And what we did is, on any given day, we had a mouse work for a particular type of reward. And by work, I really just mean poke their noses in a particular nose port in a particular part of a box that we put them in for the recording session. So sometimes they just had to poke once or a few times in order to get a reward. And other times, they had to poke, let's say, 50 times in a row to get that same little reward.

Nicholas Weiler (11:24):

Is that like some sugar solution or something, or food?

Neir Eshel (11:27):

Absolutely. So the reward most of the time was a little some kind of juice that the mice really enjoyed, but we have tried other sorts of rewards, too. And it looks like for all the rewards we tried so far, the same system is more or less in place. So other rewards could be, for example, social rewards. So being able to play with another mouse, it could be drug reward, self-administering a drug of abuse, it could be, what I call, brain stimulation reward, which is direct release of dopamine in the brain that is under the mouse's control.

(12:03):

So if they poke the right number of times in the right place, we can use a technique called optogenetics to immediately and directly activate the dopamine neuron so that dopamine is released, and that is the reward that the animal is working for.

Nicholas Weiler (12:19):

Okay. So they're sticking their nose in this little port, and sometimes it activates when they do it once, and they get their little sugar juice, and then other times, they've got to do it over and over and over and over again to get that same juice.

Neir Eshel (12:30):

That's it. That's exactly it.

Nicholas Weiler (12:30):

Okay.

Neir Eshel (12:33):

And it's the same juice every time. What changes is how much they have to work for it. And so while the animals are performing this task, we're recording from their brains and specifically we're recording from this region called the nucleus accumbens, and we're recording the ups and downs of dopamine release on a second-by-second basis. And what we found is that when an animal receives the reward, the dopamine release is substantially higher if the animal had to work harder for it than if it got it for cheap. That was our initial finding, which was really interesting and surprising to us because, again, everything is exactly the same about the actual reward.

(13:10):

The only thing that changes is the context of the animal, basically how much they had worked for that particular reward. And that was true even when the reward that they were working for was direct brain stimulation. So even if we got rid of all of the other brain circuits that are involved in licking, and smelling, and consuming the reward, and we just stimulate those dopamine axons to directly release dopamine, even when we do that, the amount of dopamine that those axons release is substantially higher if the animal had worked harder for it.

Nicholas Weiler (13:45):

And so what that suggests is that it's not the dopamine neurons exactly. It's something in there, something in the nucleus accumbens, because you're stimulating those axons in exactly the same way, and you would expect them to release the same amount of dopamine, right? You're not changing your stimulation, but something about working harder causes those axons to release more dopamine for the same stimulation.

Neir Eshel (14:09):

That's exactly right. And we hypothesized that it must be something local in the nucleus accumbens, something surrounding those dopamine axons. There has to be some other chemical that's probably involved in teaching the dopamine axons, how much effort the mice had engaged in, and allowing the dopamine axons to amplify how much dopamine is released in that context. And it turns out that it's acetylcholine.

Nicholas Weiler (14:53):

What is acetylcholine? I imagine that ... As we said, people talk about dopamine all the time. Acetylcholine gets less attention. What do we know about this other neurotransmitter and what it's doing in the brain?

Neir Eshel (15:05):

So acetylcholine is a essential chemical in the brain and the body. So it's one of the primary chemicals involved at the neuromuscular junction. So the interface between the nerve cell and the muscle that is necessary for us to control our skeletal muscles if we want to walk or run. It's also a key chemical in the parasympathetic nervous system. So the rest and digest autonomic nervous system, what allows us to control our breathing, and our gut motility, and everything that in our bodies allows us to rest and digest.

Nicholas Weiler (15:41):

So just to clarify, so the ... This is like neuroscientists split the nervous system communication with the body into the fight, flight, flee system that's active when you have to do something quickly and this rest and digest system that's all the stuff that you can do when you don't have to worry about fleeing from a predator or what have you.

Neir Eshel (16:02):

Absolutely. So that's sympathetic versus parasympathetic or the fancy terms. I like fight or flight versus rest or digest. In fact, acetylcholine plays a role in both of those, but I would say it's particularly important in the parasympathetic or rest and digest system. But these are all ... We're talking about peripheral body, but it also plays an extremely important role in the brain. It's been studied in many contexts. It's been studied in attention, arousal, memory, but in this context of effortful reward, it's much less known.

Nicholas Weiler (16:38):

So it also doesn't necessarily have a slogan on its T-shirt or a bumper sticker.

Neir Eshel (16:44):

I would say it might be even harder to come up with a bumper sticker for acetylcholine than it is for dopamine. They do a lot of stuff.

Nicholas Weiler (16:51):

Well, what do you ... In this particular context, what have you figured out that acetylcholine seems to be doing? What's triggering the acetylcholine and how is it making more dopamine get released when the animal has worked harder for a reward?

Neir Eshel (17:04):

So in this study, we wanted to understand what is this local chemical that's amplifying the dopamine release in high effort context. And so all we did is we stuck a cannula in the brain, in the nucleus accumbens, and we put a bunch of drugs one at a time that blocked each receptor we could think of that could be responsible for this effect because they exist on the dopamine axons. And we tried about a dozen of them, one at a time, and we found that 11 of them didn't really do anything. And then the last one is the blocker of this acetylcholine receptor. It completely abolished the effect that we saw.

(17:39):

In other words, the dopamine release was still there, but it didn't go up as the effort went up. So if we block the acetylcholine signal, we flattened the dopamine release.

Nicholas Weiler (17:50):

And I think that's an important point. I mean, we were talking about why these neurotransmitters don't have bumper stickers or T-shirts. It's like my job is X. And partly it's because all of these different receptors, not only do they go to different parts of the brain, but there are half a dozen, a dozen more different receptors on different kinds of neurons in different places that cause different effects. So it's all very complicated in there. We're not going to dive into all that, but you did this work to figure out, okay, it's this particular receptor, and it's the same receptor that's involved in, I may be jumping the gun here, that responds to nicotine. Is that right?

Neir Eshel (18:26):

Absolutely. It's actually called the nicotinic receptor. So it's an acetylcholine receptor that is named nicotinic because nicotine actually binds to this type of acetylcholine receptor, and it's been linked in the past to the reinforcing effects of nicotine. So one of the major reasons why nicotine is addictive is because it binds to this particular set of nicotinic acetylcholine receptors on dopamine neurons.

Nicholas Weiler (18:52):

Okay. So you've identified that this effect, where hard work makes dopamine release go up, depends on this particular nicotinic acetylcholine receptor.

Neir Eshel (19:03):

And so then what we went to do is understand the dynamics of acetylcholine itself. So it turns out that acetylcholine in the nucleus accumbens is released almost exclusively by a small set of what's called cholinergic interneurons. So there are neurons that are in that region that are releasing acetylcholine locally and affecting the activity and the function of the other cell types in the region, and that includes the dopamine axons.

(19:31):

So if I record acetylcholine release in this region as the mice are performing the task, what we found is that, just like dopamine, when the mouse is working really hard for the reward and the reward comes, the acetylcholine is released from these cholinergic neurons at a much higher extent. And in fact, if you compare the acetylcholine and the dopamine release, what you find is that the acetylcholine is released first. It's right away. And then about 400 milliseconds later, you see the dopamine peak.

Nicholas Weiler (20:04):

And it's higher because the acetylcholine is released.

Neir Eshel (20:06):

Absolutely.

Nicholas Weiler (20:07):

So that raises the question of like, okay, now we need to take this upstream. Why does hard work make more acetylcholine get released in the nucleus accumbens?

Neir Eshel (20:15):

Well, stay tuned because that's what we're working on right now.

Nicholas Weiler (20:17):

Okay.

Neir Eshel (20:18):

And we have lots of ideas about inputs to the acetylcholine producing neurons. What we think is happening is that the effort is being tracked and stored. What we think is happening is that there are a specific subset of neurons in the cortex that are retaining that information in working memory, in this case, essentially saying that the mouse is working and working and working. You can see a reflection of that effort in the activity of these subset of neurons, which are then relaying that information to the cholinergic neurons, which then relay it to the dopamine axons, which then really help to reinforce the behavior.

Nicholas Weiler (20:55):

It's so cool that we've evolved this system because hard work is hard, right? But in order to get anything valuable, you generally have to work hard for it. And so the fact that work is often unpleasant. We have systems in our brains to tell us not to waste energy on stuff.

Neir Eshel (21:15):

Yes.

Nicholas Weiler (21:15):

But that has to be balanced against, well, sometimes you do have to do that unpleasant thing to get something good. So I love getting this insight into how does the brain balance those needs? Do you have any insights about what the counter to that is? When does the brain know that it's time to stop doing the work?

Neir Eshel (21:36):

We're working on that question, too, trying to understand every individual in any given moment might have a different breakpoint, a different threshold for when the work is too much and it's better to conserve energy. And that will depend on all sorts of things, like, for example, the opportunity cost, what else is available to the mouse at that time or the energy status of the mouse, how depleted, how hungry, for example, is the mouse, might change the decision as to how much effort is worth it to put in for a given reward.

(22:10):

There's all sorts of contextual variables that might play a role in making that choice. And we're looking now to see if we can predict what an animal's choice might be in any given context based on the network activity that we're recording in the brain. Because if we can do that, then I think we'll get some insight into why that threshold changes in the context of depression or in the context of addiction for a particular reward. If we understand how that set point is actually determined in the brain, I think we might be able to come up with ways to manipulate it when something goes wrong.

Nicholas Weiler (22:50):

Well, that's what I'd love to get into next. My one last technical question, just to confirm, so you don't see these acetylcholine neurons active all the time when the animal is working for something. It's only the coincidence of working hard and getting the reward that triggers the acetylcholine neurons to boost the dopamine response.

Neir Eshel (23:10):

Definitely the biggest signals that we see in the cholinergic neurons are at that coincidence point in which the animal has worked hard and then it gets the reward. They're not silence the rest of the time, but there's no obvious signal in other parts of the test that we've observed.

Nicholas Weiler (23:29):

So it's a great transition to talk about what this all means. You're on the trail of this really fascinating system that allows us essentially to put value on the hard work. I mean, what you were saying before is that dopamine is not a signal of how pleasant something is necessarily, but of how likely we are to keep doing the thing that got us there. And so this system that you're investigating is the system that essentially rewards hard work.

(23:59):

And I think I want to get into a lot of the implications that you were talking about for patients, people with depression, and just for us in our everyday lives. But you mentioned earlier that the mouse dopamine reward system is pretty similar to that in humans. And I wanted to dwell on that for a moment because, as humans, sometimes we're very impulsive, sometimes we're very reward seeking, but we also have this capacity to plan and to delay and to work for something over not just 50 nose pokes, but over weeks and months and years. So what do we know about how that might be different between mice and humans? Hopefully the mice aren't working at devious plots to take over the world over weeks and months and years.

Neir Eshel (24:42):

Right. I see that in my kids' storybooks all the time, devious mice or other animals who are working to subvert human society in one way or another.

Nicholas Weiler (24:50):

Right. And we're talking pinky in the brain here.

Neir Eshel (24:52):

Exactly. Less so in the laboratory, but honestly, we have a bias in lab experiments like this to make everything on short timescales because it's convenient to do that, and we have the technology to do that. We can keep an animal working for half an hour, but for many days or weeks or months, that might not be feasible. But that doesn't mean that the systems for long-term behavior haven't evolved and that we can't study them. It's just that it's much harder to study and to understand.

(25:24):

There are some examples, though, even in rodent literature that I think are beautiful showing changes on the level of weeks or months. And you can see this, for example, in mating behavior that a male mouse after having mated is much less likely to do it again for a number of days or a week. And you can see things change at the level of protein expression in the brain that can explain those longer term changes in behavior. So I haven't yet done that, but I'm really interested in understanding exactly what you're saying, which is, what are the time scales at which dopamine is actually modifying brain activity to modify behavior? We know a lot about really short time scales. We know much less about moderately long timescales.

Nicholas Weiler (26:13):

I mean, the thing that still remains so mysterious to me about dopamine and reinforcing behavior, and I suspect it is mysterious to everyone, is what we're saying is release dopamine that reinforces the specific behavior that led to the dopamine release, but where is that behavior? How does that dopamine connect to some brain circuit that is guiding a very specific thing, poking your nose into this hole? That's such a complex thing to try to say, "Oh, yeah, that just got reinforced." But what does that mean exactly? I don't know if there's an answer to that, but that seems like the big question.

Neir Eshel (26:50):

Well, I think the closest we have to an answer is still more of a model than a real experimental verified fact, which is the idea that when an animal is performing a certain behavior, there is a subset of cortical neurons that are projecting to the striatum that are encoding and controlling that behavior. And if dopamine is released at the same time that that particular cortical striatal projection is active, then the dopamine leads to synaptic plasticity, which means that it strengthens that connection between that set of cortical neurons and that set of striatal neurons so that they're more likely to be activated in the future.

(27:39):

So there's something that dopamine is doing that is changing the strength of connections between other neurons in their brain that are the more specific ones about a particular behavior or context that the animal is in.

Nicholas Weiler (27:53):

So the way I interpret that in my mental model is we've got the striatum, which is controlling specific behaviors like initiating doing a particular thing. We've got the cortex, which is monitoring what we're doing and maybe planning what we're going to do next. And that process of which we would call behavior, like what am I doing, what am I going to do? And then actually, how do I move my body? If there's a dopamine hit, whatever the signals that are going through, those pathways just get a little stronger. And that means that the next time you have a similar situation with what am I doing right now, what am I trying to do next, that particular behavior is going to be more likely to be the outcome.

Neir Eshel (28:37):

That's basically the way that I think about it, and I think much of the field thinks in that way. What's amazing to me is that the evidence for it is actually pretty sparse. Even after decades of work on trying to verify this exact model, it's really hard.

Nicholas Weiler (28:54):

Interesting.

Neir Eshel (28:55):

But we're getting there. There's progress being made in terms of what is dopamine doing downstream in the brain, whether it's in the striatum, or in the cortex, or other places that is actually reinforcing that behavior. More to come.

Nicholas Weiler (29:09):

Yeah, exactly. Well, we'll have you back on the show. So what we know now is that when an animal works hard for a reward, it triggers acetylcholine to be released in the nucleus accumbens. That means that the dopamine synapses there release more dopamine, and that is important for the animal to continue working hard for these rewards that maybe they've got to do this annoying task for. That's what we know given your paper. And now we're going to speculate.

(29:35):

So with that addition to your model of how this works, let's come back to the folks that you see in the clinic. How does this adjust or help you understand that patient who you mentioned earlier who maybe is a really high achieving person half the time or most of the time, but then a few weeks a year, they just can't get out of bed?

Neir Eshel (29:55):

I think it's probably different things in different people, which is one reason why it's so hard to figure out a cure for depression because I don't think depression is just one thing.

Nicholas Weiler (30:04):

Right.

Neir Eshel (30:05):

But what this paper makes me think is that we should be paying some attention in addition to the dopamine system a little bit more, also on the acetylcholine system in those cases, which has not really been done to a large extent before in this context. And so it's possible that what's happening at the dopamine system is okay, but there's something malfunctioning in the ability of the cholinergic neurons to fire or for the cholinergic neuron firing to amplify dopamine release in these effortful contexts that we just haven't looked for yet and haven't found.

(30:41):

But one of the things that I'm really excited to do is to take this model that I have, this microcircuit deep in the brain that we've determined seems to be important for promoting effortful behavior in normal contexts, and then put it into abnormal contexts and see what happens. So, for example, if mice undergo chronic stress, you can see that they're less motivated to work for sucrose rewards like they were before. That's a very commonly observed phenotype, and it makes people excited to try to understand what stresses do to behavior across species because we know that that's also the case in people, that exposure to chronic stress can really wreak havoc on your ability to engage with the world. That seems to be the case also in mice.

(31:34):

And so that opens up the possibility of studying what's happening in the brain during that disruption of motivated behavior. And so I'm really curious to see whether one of the disruptions that we can observe in the brain has to do with this interaction between acetylcholine and dopamine.

Nicholas Weiler (31:49):

Right. Depression is many things in different people, and it can have different symptoms. There's the emotional symptoms of sadness that many people experience, but there's also this loss of meaning in regular activities and there's a loss of motivation to do things.

Neir Eshel (32:07):

Yes.

Nicholas Weiler (32:09):

The things that normally feel meaningful to you don't feel that meaningful. So why get out of bed? Why do anything? And this suggests that maybe in this piece of depression where you struggle to get out of bed because most of our lives is just like doing a bunch of stuff to get to somewhere else. That's the nature of existence. We got to get dressed. We got to make the food to eat the food. We got to get the kids out the door to get them to school because presumably that will lead to rewards later in life.

(32:35):

So if that system isn't working, you're not getting those extra dopamine hits to say that was worthwhile. And so what matters? Is that [inaudible 00:32:43] that this hypothesis is correct?

Neir Eshel (32:43):

Yes, that is actually the way that I think about it. There's lots of different interlocking symptoms that come together in the case of depression, but when I see a patient with depression or any other set of symptoms, I usually ask them, "If I could change one thing for you now, because I may not be able to change everything, if I can help you with one symptom, what would it be?" More often than not, people say something like energy, willpower, motivation, get up and go because, as you say, it's just essential for life. People can often work through sadness. It's really hard when you're just in bed, you just can't get up.

Nicholas Weiler (33:19):

Yeah. You also said something about when you were talking about some of the animal studies, it depends a lot on the state of the animal. And that immediately made me think, maybe because I didn't have quite enough breakfast this morning, of you mentioned irritability and the hunger is real. When you're hungry, when you're stressed, when things are not right, when your energy levels are not right, it is really hard to have the patience that you need. And you mentioned earlier that you're interested in this idea of irritability.

(33:47):

So I'd love to have you make the connection there. What do you see as the connection between this system and irritability and ... What did you connect irritability to?

Neir Eshel (33:57):

Well, aggression is how I study irritability in mice because I can't really ask them, are you ...

Nicholas Weiler (34:05):

Are you feeling frustrated?

Neir Eshel (34:06):

... feeling frustrated, angry, irritable, but I see the threshold that it takes to elicit aggressive behavior. And that can vary with all sorts of things like you mentioned, like stress and hunger, sleep disruption. Other things that we can see in people also make us irritable, make other people not want to be around us. So I chose to study irritability in part because I do see it a lot in clinic and we don't have great treatments for it. And it's something that comes up across multiple different diagnoses that essentially people say they're losing their relationships or their jobs because people walk on eggshells around them because they're liable to explode or just get angry for no reason, and no one wants to be around them.

(34:50):

And so they come saying, "What can I do?" And this is often in the context of various stressors of post-traumatic stress disorder, irritability is very common. It can be common in depression. It can be common in bipolar disorder. It can be common in schizophrenia. Most of what I treat can have an element of irritability and it's just very understudied. And so one of the ways that I connect it to the motivation and reward circuitry is this concept of frustration.

(35:17):

So frustration is when you're working for and expecting to receive something good, some reward, and you don't get it, you're blocked from achieving that reward, it induces this negative or agitated emotional state that you can call frustration. And that lowers the threshold for aggression. Well, in the case of people, for yelling, for saying things that you later regret, and sometimes for being physically aggressive, you can see this in vending machines often have dents in them because-

Nicholas Weiler (35:53):

I need that snack. Give me that sugar juice.

Neir Eshel (35:55):

You need that snack. And for whatever reason, you put the quarter in and it doesn't come, people will kick that vending machine. And maybe there's a hunger component to that, too. So these are studies that are ongoing in the lab that I'd be happy to discuss once the data is out there. But I see it as a really interesting interface because you're working for this reward in the same way that we've been talking about this whole episode. And yet what happens if we just block the mouse from getting it?

(36:22):

You can see that they become frustrated. You can see it. They get agitated, they run around more, they try to escape, maybe they make some ultrasonic vocalizations that are very different, and they are more likely to attack another mouse.

Nicholas Weiler (36:35):

And you should study those ultrasonic vocalizations because it's probably mouse cursing.

Neir Eshel (36:41):

And I'm sure it is. It's absolutely right.

Nicholas Weiler (37:00):

The other angle on this that you can take with why is hard work rewarding in a sense, why are rewards more sweet when we work for them, is that there's also a flip side to that, which is that if we've worked for something, it's really hard to stop working for it sometimes. This is this idea of the sunk cost fallacy, right? This is a thing that we all do where if you've put a lot of money into something or you've spent a lot of time working on something and thinking about something, it's sometimes hard to find the point where you need to cut your losses and just say, "You know what? This isn't happening."

(37:34):

So talk about that a little bit. Why do you think this applies to why we do this as humans or as mice?

Neir Eshel (37:42):

So as you said, this sunk cost fallacy is this idea that sometimes we make the wrong decisions based on overvaluing how much effort, or time, or money we've put into something and not being able to let go. You've paid $15 to get a seat in a movie theater and the movie is terrible. You really want to go. We're like, "Well, I paid $15 for this. I'm not going to go." That doesn't make sense. You should leave the theater. Every minute that you spend in there is aversive and there's no reason for you to do it. But a lot of us might because we've paid the money for it, so we're going to get what we paid for.

(38:18):

That is maladaptive decision making that's driven in part by this sunk cost effect. It may be partly explained that the fact that this exists in our brains, that this fallacy can happen, maybe a byproduct of the circuitry that we're studying now, this acetylcholine dopamine interaction, being really important to promote effortful behavior when rewards are scarce or hard to get. There's some reason that evolution has kept this added value of effort circuit online in our brains, and it can do a lot of good, but like many things, in the right context, it can lead to bad decisions.

Nicholas Weiler (39:01):

And it's a tough balance because it's hard to know in advance. Maybe that movie turns out to be great at the end.

Neir Eshel (39:08):

That's true.

Nicholas Weiler (39:08):

And it's all worthwhile. And so it's only a fallacy in retrospect, I guess.

Neir Eshel (39:13):

Right.

Nicholas Weiler (39:14):

So this whole thing has me thinking about AI. I mean, so much of our anxiety about AI is about how easy it makes things. And I think we have a natural suspicion for, well, if everything becomes too easy, then what's the point? Does this suggest to you one of the reasons why we have that reaction to not wanting to just let these computer systems do our work for us?

Neir Eshel (39:40):

I think ... Again, this is a study in mice doing recordings in their brains that probably don't have immediate relevance for the way that our brain [inaudible 00:39:49]-

Nicholas Weiler (39:50):

I know. We've moved from neurobiology to philosophy, for sure.

Neir Eshel (39:52):

But I think there may be some link there that one thing that I'm worried about is that if people rely on AI to perform all tasks, not only will they cease to know, or learn, or develop skills, that might be helpful, by the way, if the AI system shut down or the power goes out. But in addition to just not learning how to do things, I think we also miss out on this incredible experience of having earned something, of having gotten something good that feels even better when we know that we put that effort in.

(40:37):

There is something really beautiful about looking at a piece of work, the satisfaction that you get, and the reinforcing nature of it when you made that cake and ate it instead of if someone else made it for you. There's something really different. And I would hate for people to miss out on that experience because of an overuse of AI.

Nicholas Weiler (41:01):

Well, we've gone from chemical receptors in the brain to AI. So I think we've done a good job with this conversation, and I can't wait to have you back on as more of these findings come out to help us understand this fundamental question of why we do the things we do, why we work for big rewards, and why these systems sometimes go wrong. So Neir Eshel, thanks so much for joining us on From Our Neurons to Yours. I hope to have you back soon.

Neir Eshel (41:27):

Thank you for having me.

Nicholas Weiler (41:29):

Thanks again so much to our guest, Neir Eshel. He's an assistant professor of psychiatry and behavioral sciences here at Stanford Medicine. To read more about his work, check out the links in the show notes. If you enjoyed this conversation, please be sure to subscribe for more topics from the frontiers of brain science. We also would love to hear from you. If you've got thoughts about the show or questions about the brain you'd like to hear us discuss in a future episode, send us an email. We're at neuronspodcast@stanford.edu or just leave us a comment on your favorite podcast platform.

(42:02):

While you're at it, we'd really appreciate if you could give us a rating and share the show with your friends. It might seem like a small thing, and I know that everyone asks this, but it really is tremendously valuable for us to be able to bring more listeners to the frontiers of neuroscience. Coming up on From Our Neurons to Yours.

Cory Shain (42:23):

What we are looking at when we look at an fMRI image is something like a Monet painting where we've stepped far enough back to see this kind of a big picture structure, but when we zoom in, things look quite different.

Nicholas Weiler (42:42):

From Our Neurons to Yours is produced by Michael Osborne at 14th Street Studios, with sound design by Mark Bell. Our social media strategy is by Julia Diaz, additional editing by Nathan Collins. Our logo was designed by Aimee Garza. I'm Nicholas Weiler. Until next time.