How your brain chemistry rewards hard work

0:23Welcome back to the Nature Podcast. This week, why going the extra mile might make you feel good. And how extreme weather events could threaten malaria elimination efforts in Africa. I'm Benjamin Thompson. And I'm Nick Pertrich Howe.

0:45Why bother doing hard work? It may seem like a silly question, but it is a question that has puzzled scientists. After all, given the chance, we often avoid hard work. If we can do something easily, we will. So why would we bother doing something difficult? Well, partly as it was probably necessary for our survival. Life isn't always rosy, especially for our evolutionary ancestors. Maybe there's little food around, but we need to find it in order to survive. If we didn't do hard things, then we probably wouldn't survive that long. And so there has to be some mechanism that guides our behaviour towards trying hard.

1:26And now researchers have uncovered the neurological basis of this paradox in nature, how the brain chemistry of mice changes in response to hard work. Despite the efforts, I reached out to one of the authors of the new study, Nir Eshel, and he started by telling me a bit more about this counterintuitive process. So what to me is so fascinating is that effort is a paradox in some ways. So we usually try to avoid it. You know, if we can get something easier, then usually we'll take that path. But there's this converse thing that's also true, which is that if you get something good after having worked really hard for it, that thing feels better to most of us than that same thing, that same reward that came easily.

2:15So take, for example, the view from the top of a mountain. If you climbed up laboriously that mountain and you look at that view versus if you drove up or you took a gondola or something that was pretty low effort, I think the view actually looks different. So that concept, that idea that we value things more if we worked hard for them, I think is really interesting. And you can see that across the animal kingdom. So every species that has been tested seems to have some concept like this in which we value things more if we've worked harder for them. It's been shown in ants, of all things. It's been shown in pigeons.

2:52It's been shown in rodents. It's been shown in birds. It's just amazing. I think it's something that many of our listeners can relate to as well. So what is actually understood about this from the sort of neurological basis? The neural basis for that effect in which we tend to value things more if we've worked harder for them, very little was known before the study that we published. So last year, we had a paper come out that showed that when an animal, in this case a mouse, worked harder for a reward, that reward evoked more dopamine release in the brain. And that was really exciting because dopamine is this chemical in the brain that's been associated with rewards and with effort, with drive, with motivation for many, many years.

3:39And yet the idea that the same reward can evoke substantially more dopamine release just because you worked harder for that, that was not very well studied or understood. But what wasn't known is how that happens. What is the kind of circuit basis in the brain for that effect? How did dopamine know how much effort we actually put into the reward that we And that's the main finding of this new paper in Nature, is that it's another brain chemical called acetylcholine that actually does the magic, that teaches dopamine how much effort the animal has put in, and then augments or boosts the amount of dopamine that's released when the reward is delivered.

4:21And so how did you go about uncovering this magic? You mentioned that you use mice as your study animal here. What sort of things were you getting them to do and how were you trying to look at their brains while they were doing it to understand this magic? So what we did for mice is that we had them poke their noses in a little nose poke, it's called, appropriately enough, in a box in the laboratory. And they had to poke their noses sometimes just once or a handful of times in a specific nose poke to get the reward. And mostly what we use for reward is food. So sucrose, something sweet and delicious that the mice would really be motivated for.

4:57The effort is usually just poking their nose a certain number of times. And what we do is we keep the reward the same, but we vary how many times the animal has to poke for it. So sometimes they just have to poke once or five times, but sometimes they have to poke almost 50 times for a single little squirt of sucrose. And while they're performing this task, we're recording from their brains using these amazing new tools. So one of the most important tools that we use are sensors that allow us to look second by second at the ups and downs of dopamine release or acetylcholine release in specific regions of the brain as the mice are actually working for reward.

5:40So do a compare and contrast for me. What did you see in mice that had done like one poke, which I guess is low effort, versus the ones that done 50 pokes, which I guess is very high effort? In terms of dopamine release, there is a little bit of dopamine release when the mouse get a reward, regardless of how much effort it took. So even if they just had to poke their noses once, which is super easy, super quick for them, you can see a little blip in the dopamine release very consistently every time. But if you make the mouse work hard, they have to poke 50 times for that same reward, that blip is five times bigger, or sometimes even more than that.

6:14So it is an extremely large change for the same exact reward. And we were wondering why? What causes that increase, especially because we could see the same increase even for the brain stimulation reward itself. So even when we were using another amazing new tool in neuroscience called optogenetics, in which we can use light to actually activate neurons. So here what we were doing is we were using light to activate neurons. That was the reward that they were working for. and we kept the light exactly the same. But what changed is simply how much the animals had to work for that light. And what we found is that when the animals worked really hard for that little burst of light, the burst of light somehow became more efficient at activating dopamine release.

7:06That really surprised us because it means that there must be something happening really powerful at the level of the dopamine release mechanism itself that takes into account how much effort the animal had put in. And it turns out that that mechanism, that really strong mechanism, is this other modulator, acetylcholine, that is released in the same area. So what's happening then with the acetylcholine to sort of modulate this response? Is it building up? Is it changing things? What's happening with it? So what's happening that we've observed so far is that when the animal is working for the reward, during the time that it's working, the acetylcholine is building up slowly, slowly building up its levels in this region deep in the brain called the nucleus accumbens, which is this key region for reward and motivation in the brain.

7:59And then when the reward comes, if the animal had worked really hard for it, the acetylcholine release is enormous. It's really fast. It's faster than dopamine. And it's really big. And what happens is that big burst of acetylcholine binds to receptors that exist on the dopamine axons. So the dopamine neurons use their axons to release dopamine. And what happens is the acetylcholine binds to receptors on those dopamine axons. And those receptors are called nicotinic receptors because that's what nicotine binds to. And that augments or boosts the amount of dopamine that is able to be released from those dopamine axons.

8:43And that only happens after high effort. That was really amazing and surprising to all of us when we saw these results because you might imagine that the acetylcholine is always able to boost the amount of dopamine that's being released. Maybe that's just a mechanism that's evolved, regardless of context. But what we found is that it is very context dependent. The amount of dopamine that's released only depends on acetylcholine when the animal is in a high effort context. Only when the animal works really hard for reward does this interaction between acetylcholine and dopamine actually seem to happen.

9:22And you know you mentioned that this effortful behavior has been seen in a range of different animals including humans. So do you expect that this same mechanism exists in other animals or will there be more studies to confirm that? I expect that it will be, but I can't say for sure. You know, one of the things I really want to do is to understand how this interaction between dopamine and acetylcholine plays out in people. And especially, I want to know how it plays out in people who are in the midst of a depressive episode in which even small amounts of effort can seem overwhelming or impossible, and also how it looks like in people who are in the midst of an addiction in which a particular drug is motivating them so much that they're willing to endure almost any consequence to seek that drug.

10:10To me, those types of motivations are almost like opposite ends of the same spectrum. I'm really curious if one or both of those that I see in clinic on a weekly basis might be related in part to a dysfunction in this interaction that we've identified between dopamine and acetylcholine. So I don't have the evidence yet, but that's where we're going next. And so what would you like people to take from this paper? I'm sure many people will be interested to learn more about it. But if they can just take one thing away from it, what would you like them to know? I suppose that there is something really beautiful about hard work.

10:46The work itself can actually increase your appreciation of the outcome and that there's an actual brain chemistry that we can now describe that underlies that feeling. So to me, it makes me even more motivated to continue the kind of work that I'm doing. And I hope it has that sort of effect on others too. So you think your acetylcholine and dopamine response was quite big in publishing this paper? I think so. And for my graduate students as well. That was Nir Eshel from Stanford University in the US. For more on that story, check out the show notes for some links. Coming up, modelling the effects that extreme weather events might have on malaria control in Africa.

11:30Right now though, it's time for the research highlights with Dan Fox.

11:38In the early 2000s, astronomers spotted what they thought was a dusty planet orbiting a distant star. But new observations have revealed that the planet was actually a dust cloud, the result of a distant collision. Astronomers using the Hubble Space Telescope to make observations of the formal Hout system found the dusty planet identified in the early 2000s has almost completely disappeared. and that a second cloud of reflective dust had formed in the area. They say the most likely explanation is that both the original and most recent observations show the fallout of collisions between rocky bodies called planetesimals, which are often thought of as the building blocks of planets.

12:22This is the first time these impacts have been observed directly in another solar system. Studying other planetesimal smashes could help researchers to understand the dynamics of planet formation. You can observe that research in science.

12:42Buying up shares in a company would be expected to drive up the price for other investors. And now researchers have their best idea on how much. Econophysicists have long observed that price changes are, under many circumstances, proportional to the square root of the size of a stock trade. So, for example, buying 1 % of a company's shares traded on a given day would account for about 10 % of their change in price. But debate has raged about how universal this effect is. Now, researchers have analysed data from all trading accounts on the Tokyo Stock Exchange from January 2012 to November 2019, and found that the square root relationship holds both for individual stocks and for individual traders' actions.

13:26This finding boosts the idea that other processes in the economic and social sciences follow similarly exact power laws. You can read that research in Physical Review Letters.

13:43Malaria is one of the great scourges of humanity. Each year, the disease results in the deaths of hundreds of thousands of people, and sickens millions with the majority of the burden felt in Africa. The first 15 years of the 21st century saw significant progress in reducing levels of the disease in Africa. However, progress has stalled in recent years. One thing that is unclear is the effect that climate change will have on future levels and distribution of the disease, and that's something that a paper published this week in Nature is looking to shed light on. Specifically, the team behind the work are looking to bring together information on how climate change could affect the interplay between Anopheles mosquitoes and the malaria parasite, as well as information on how extreme weather events, things like floods or cyclones, could affect people's access to preventative measures like bed nets or medical treatment for the disease.

14:44Their results suggest a potentially staggering number of additional malaria cases and associated deaths on the African continent by the year 2050, an exercise that they hope will highlight the need for climate-resilient malaria control strategies as part of efforts to ultimately eradicate the disease. But the team's work doesn't just include climate and health data, it also uses anecdotal evidence from folk on the ground who have experience of extreme weather events in Africa and their effects on malaria control. One of the study authors is Tasmin Simons from Curtin University and the Kids Research Institute Australia.

15:22I gave her a call and she laid out why this information was important. So we, as a general rule, approach enumerating malaria burden in a highly quantitative way. We have access to cross-sectional surveys of infection prevalence in the community. There are a number of well-validated mathematical models to understand how that translates through the immune dynamics of the disease. But when we reach trying to estimate what the impact of extreme weather events are on access to malaria controls, by which I mean access to a bed net, access to a health facility that can treat you if you do get sick. That's never, ever observed for two good reasons.

16:04One, it's incredibly difficult to get to places that have been damaged by floods or cyclones, especially in already very remote and challenging places. The second is the moment you observe it, you do something about it. And a lot of the people we interviewed are the absolute heroes that orchestrate these kinds of response efforts to damaging weather events. They're people who are going in and making sure that these people still have access to bed nets, that these people still have access to effective antimalarial medication. And so what we were trying to aim to estimate was what would happen if we didn't have access to any of those fantastic efforts.

16:41What could we expect to see purely by isolating the impacts of climate change? And that led us to this mixed methods approach to get some insight into the expected impact and for how long that impact would last from people with lived experience, who've been on the ground, you know, programme managers, people from NGOs. So you've pulled together all your data then, this climate data and data on how this could affect the insects and the parasites and the data on how potentially severe climate events could break down the structures designed to protect against malaria. What did your results kick out?

17:17What was the headline finding? The headline finding for us was that the overwhelming majority of what we would expect to see as the impact of a changing climate on malaria abedment in Africa was in fact due to this factor that nobody had really considered before, which is that if you remove control from communities that are already highly susceptible to transmission, that transmission comes back very quickly and in fact accounts for far more of the overall anticipated change that we would have even with changing temperature and changing rainfall affecting suitability on top of that. This, I think, was qualitatively unsurprising.

17:57We have unfortunately observed several times throughout history in other places, areas where malaria control has been suspended or removed and malaria itself has rebounded back remarkably rapidly. And that is what we see manifest here, that fundamentally, climate change over the near future, so over the next 25 years or so, is not going to so dramatically shift the environmental landscape that supports transmission in Africa. And that's partially because so much of Africa is already really highly suitable for transmission. So a small percentage change in that translates into a fairly marginal change in disease burden, whereas all of the efforts that we have put in to make sure that people living in those places have access to life-saving interventions are actually really fragile.

18:46And what are some of the numbers your results suggest then? So up to 2050, we are looking at approximately 500 ,000, so half a million additional malaria deaths due to climate change, and around 125 million additional malaria cases. Those numbers are obviously highly uncertain. We have a projection range around those numbers, which encapsulates a range of different sources of uncertainty. As I say, we find the majority of those, so around 80 % of additional cases and around 90 % of additional deaths, are in fact due to what we call the disruptive effects. So that is the impact of reduced access to malaria control interventions, specifically due to this increased risk of extreme weather events of climate change.

19:33And the risk isn't necessarily the same across the continent? Yes, we found huge heterogeneity across the continent, as well as huge heterogeneity in the type of risk that people will be exposed to. So one place that has been very well studied in the context of climate change and malaria are the fringes of transmission, particularly around highlands in East Africa. so in Ethiopia, in Kenya and there we find that increases in temperature are potentially going to lead to the expansion up elevation slopes of the mosquito and therefore to increase transmission there being the dominant driver. Elsewhere however we do find that particularly along river basins in West Africa an increase in flooding will lead to a decrease in the amount of control that is able to be offered and therefore an increase in transmission.

20:23And this is a modelling exercise, of course. What assumptions have you made? I mean, you've looked at one scenario of how the world could change heading into the middle of the century, for example. We've made several really key assumptions. One major one that I would highlight is that we have anticipated that over the next 25 years, the baseline amount of intervention coverage that could be expected. So that is, if you are not exposed to any extreme weather events, what sort of access could you expect to a bed now? What sort of access would you have to healthcare would remain constant. And that obviously is highly unlikely to be the case, we would all hope that it would actually dramatically increase over the next 25 years.

21:03I mean, as you say, the future is, of course, very difficult to predict. What questions do you think remain? And what does this research not do? We do not attempt at any point to understand the role that mitigation could play in reducing this impact. We have very exciting new tools against malaria that are either now in the process of being rolled out or on the precipice of being so. So one that I find very interesting is the role of the vaccine. An incredible thing about a vaccine is that it lasts for a period after you've received it. So there is potentially a role in areas that we identify at being most at risk of these disruptive effects that you could target people most in danger in advance of a wet season, and they would be much more insulated from the impact of, for example, losing access to healthcare, because if they're vaccinated, they may never need it in the first place.

21:53And your paper is out now. I'm sure folk are eagerly reading it. What questions do you think they'll have for you? An obvious candidate for a question that I think anyone would ask when faced with the numbers that we're projecting over the time period that we're projecting it is, what can we do about this? It's an enormous number of lives that could potentially be lost. And the fact that we identified in this study that those lives are being lost because of things we're already doing, being disrupted, suggests that there should be a way that we can mitigate it. Another follow-up would be, well, how do we increase the certainty in these results?

22:29And we are just attempting here to model a scenario. It is not a forecast. I should be really very clear about that. What we're trying to do is to produce a scenario with a set of very clear assumptions that are laid out in the study around what may happen to the climate, about what may happen to extreme weather, about what may happen to intervention coverages, which as I say we're holding constant, and saying holding all of that equal and allowing the only thing to change to be this rigorous climate scenario, what potential impact could that have? And with that in mind then that this is a suggestion as to one potential future.

23:06What do you hope your work achieves now it's out there? I would hope that it crystallises something the malaria community has known for a really long time, which is that the interventions that we have funded, that we have deployed, that we have put huge amounts of effort into optimising, really do work, and that they can continue to work in the future with the right level of investment and of mitigation of climate change. Tasmin Simons there. To read her paper, head over to the show notes for a link. that's it for this week's show don't forget to look out for the briefing show on friday that'll be on the same feed as the wednesday show so it should just appear in your podcast player of choice in the meantime you can reach out to us on social media we're at nature podcast i'm benjamin thompson and i'm nick percher ciao thanks for listening