Dave Grattan: Prolactin, the hormone that does everything

Dave Grattan, image courtesy of Dave Grattan

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First up, I just knew I had to grab Professor Dave Grattan from the University of Otago after his fascinating talk exploring some of his latest findings about the role of the hormone prolactin in pregnancy. It’s long been known as a hormone that promotes lactation, or the production of breast milk, in mammals - hence the name, pro-lactin - but Dave and his team are finding that it does so much more than that. 

Dave: It's thought of as a lactation hormone, but in fact, it's produced by all vertebrates, apart from jawless fish. The vast majority of fish, amphibia, birds, all have prolactin, none of them lactate.

Dave: Obviously this hormone's been around for a long time in evolution doing something else. My thinking on it is that it's had a role in facilitating reproduction across many different types of species. In mammals, it's added this new function, which is lactation, but overall it's just essentially doing the same thing. It's promoting reproductive processes.

Kat: Getting the body ready to make the next generation.

Dave: Yeah. In the females that's certainly the case, but also in males, helping the males produce appropriate behaviour. The best example of that is in birds. The levels of prolactin in male birds promotes them to sit on the nest. In some species of bird, the male will sit on the eggs and roost them. So prolactin has similar roles in males and females. It just happens that it's more prominent in females because they have pregnancy and lactation.

Kat: Here's an interesting question before we get onto the role of prolactin in mammals that you've been studying. Have you looked at seahorses? Because it's the males that do the childcare there.

Dave: We haven't looked at seahorses but I have had that exact thought. I think there are a number of interesting species where their life history is quite different. I'm always thinking,"I wonder what prolactin is doing in them." But no, we haven't looked at seahorses.

Kat: Okay. You can have that one for free! So let's talk about the work that you're doing. So you are looking in mice at prolactin. Tell me about some of the areas that you are exploring, about how it's acting in pregnancy, on the brain, and what it's up to.

Dave: We started out looking at prolactin purely to understand how its secretion is controlled. Because under most conditions in males and females, prolactin levels are very low. If they're high, that causes problems like infertility. But in pregnancy and then lactation, prolactin levels rise. And so I was interested in that question as to why the feedback control of prolactin changed and why it goes high in lactation.

Dave: So we started looking at the brain, particularly focused on the regions of the brain that we knew were involved in the control of prolactin. But as soon as we started looking at the brain and looking at the prolactin receptor, we found it in all sorts of places. Many, many parts of the hypothalamus in particular.

Dave: So that's the part of the brain that's involved in a lot of control of homeostatic processes. Many of those cells have the prolactin receptor. So we started thinking, why are there so many different neurons that are expressing the prolactin receptor? And I started thinking about it from a wider perspective of when is prolactin high?

Dave: It's high in pregnancy, it's high in lactation, so why would the brain need to be doing anything different under those conditions? And then I started thinking about all of the things that change in a mother during those processes. I thought maybe prolactin is a signal just across the board for the physiological state of pregnancy.

Dave: And so we essentially look at this in two different ways. One is we look at pregnancy and say something is changing. A good example is fertility, the menstrual cycle stops and we think, ok could that be being driven by prolactin? And we do various experiments to look at the pathways that we know are involved in that process.

Dave: We also do it the other way around as just identifying cells that express the prolactin receptor. We've found a number of neuronal cell types that express the prolactin receptor. Then we ask the question, why would that neuron have to behave differently in pregnancy or lactation? Both ways kind of ended up supporting our idea that the high levels of prolactin have a broad effect on multiple different systems.

Kat: You presented some really fascinating data at the Genetics Society meeting today about activity in pregnancy and the role of prolactin there. Tell me about that experiment. Where did that start from and what did you do?

Dave: That was an experiment that actually came as a total surprise. We were interested in the fact that females, pretty much all species, gain weight during pregnancy. That's not just foetal weight and placenta, it's actually laying down additional fat. The idea behind that I think is it seems to be adaptive because pregnancy and particularly lactation is very metabolically demanding. It's almost like in preparation for that, mothers store a bit of energy because...

Kat: Baby is gonna suck you dry!

Dave: Exactly, and if there's not enough food around during lactation, you've still got to be able to lactate.

Dave: This is a very common thing and we were interested in why do the mothers eat more. So we decided to put the animals in a metabolic cage where we could monitor how much they were eating, how much their energy expenditure was and things.

Dave: It just so happened that within the metabolic cages we had, there was a running wheel, so you could measure the voluntary activity of the animals as well. To be honest, we didn't really think about it, it was just part of the equipment that we were using. We were interested in food intake and energy expenditure, but not physical activity.

Dave: But as soon as we started looking at the data, we realised that the pregnant animals really didn't run anywhere near as much as when they were non-pregnant. So as soon as they became pregnant, and this is even before implantation so it's not like there's any physical constraint on it, they just stopped exercising.

Kat: Put the feet up. They've got to make this baby now!

Dave: Exactly. And there might be many reasons. We were originally thinking about it as an energy conservation mechanism, but actually, more recently, there's a range of other things. Is there a change in reward? Normally they find running rewarding. Maybe in pregnancy, it's no longer rewarding because their systems are more focused on the pups or the offspring. But really in pregnancy, it's pretty early and there aren't any pups at that point. So it's a really interesting question and when you see the profile of essentially as soon as they get pregnant, they stop running. They essentially don't run until the pups are taken away. So right throughout pregnancy and lactation, those are exactly the times when prolactin is high.

Dave: Someone like me looks at that and says, "Well that must be prolactin doing that!"

Dave: So we essentially did the experiment where we knocked out the prolactin receptor from specific parts of the brain and under those conditions, the animals kept on running. Even when they were very pregnant, they would continue to choose to go onto the running wheel and run.

Dave: What that told us is that it's actually the prolactin that is causing this change in behaviour. Completely unexpected. There was no prior reason to guess that and we only really observed it by accident. But it was really fascinating, it's such a profound change in behaviour, purely due to the action of this hormone.

Kat: I'm sure people who have been pregnant listening to this will go like, "There's baby brain!" It does something to you. Is this actually starting to get towards the mechanisms of what the baby brain thing is?

Dave: I think for sure it will be. You're exactly right, when we were discussing this in my lab group, in my lab meeting, I have several researchers who have young children and so have recently been through pregnancy and I asked "what happened to your willingness to exercise?"

Dave: Uniformly they said, "I was so tired. First trimester, I was so tired." And I was thinking there's no reason for you to be tired in the first trimester. There's no real additional physical work. I think that maybe there is something going on in the brain and the hormones are actually saying something's different now, you have to change your behaviour.

Dave: But whether that's true or not remains to be seen. There's always the example of the women who run marathons right through their pregnancy and who knows what's different. But I really think that these hormones will be having an effect on our behaviour, as well as the physiology of the mothers.

Kat: You've been looking at the impact of prolactin on female animals as they go through pregnancy. But you said earlier, males have prolactin. What's the situation with males?

Dave: That's a great question. I think for about 20 years of my research career studying prolactin, I would get asked the question almost every month or so. "Why do males have prolactin?" I did a bit of hand waving and we didn't really know. We were involved in a study in collaboration with a Swedish group run by Christian Broberger in Stockholm, where we asked the question of, "what is the role of prolactin in the male brain with respect to parental behaviour?"

Dave: We took advantage of the fact that in mice, virgin mice who have never mated don't show parental behaviour. Actually, they tend to attack pups if anything. But after they've become fathers, their behaviour changes and they will actually be parental. They'll retrieve the pups and nest them and sit over them much like a mother, a female mouse will do.

Dave: So we wanted to see is that change in behaviour dependent on prolactin. Basically what we found is that if we knock out the prolactin receptor in the same parts of the brain where it's acting in the females to promote maternal behaviour, we would also lose the ability of the fathers to show that behaviour.

Dave: So actually prolactin in the male is doing something very, very similar to the females. The really interesting part of that is that the levels of prolactin in the blood are very, very low in males all the time. They don't seem to change during interaction with the babies or anything. It's just the presence of that receptor seems to be important. So even at that very low level of prolactin, that seems to drive parental behaviour.

Dave: And Christian's group were able to show that if you compared a mouse to a rat, rats have even lower levels of prolactin in the male and they never show parental behaviour. Whereas mice have slightly higher levels of prolactin and they do show parental behaviour. So in males, it seems to be a really subtle difference. But prolactin is having a very similar effect from a behavioural perspective as it is in females.

Kat: Are there other things you notice when you start manipulating the levels of prolactin with the kind of genetic systems that you've got?

Dave: There's quite a broad range of effects. Sort of one that caught us a little bit by surprise is body temperature and thermo regulation. We actually did an experiment where we were manipulating the activity of neurons trying to understand this pathway that's involved in parental behaviour. But what we found is that when we activated a particular population of neurons that expressed the prolactin receptor, we caused a profound hypothermia.

Kat: So basically really, really cold little mice.

Dave: Yeah, that's what happened to them. Prolactin doesn't do that. But the cells that have the prolactin receptors, if you activate them, can do that. And so we asked ourselves the question, a bit like I talked about before, that here's a cell type that has the prolactin receptor, why would they have to be different in pregnancy?

Dave: If you think about it, actually pregnancy is a really significant challenge to thermoregulation because the mother has got a whole lot more metabolism going on. She also has to lose temperature for the babies because elevated body temperature is bad for the babies.

Dave: So there's going to be changes in thermoregulation or adaptive changes in thermoregulation and pregnancy. We are really interested now in, having seen that these thermoregulatory circuits are responsive to prolactin, we're starting to look at what is the role of prolactin in controlling them.

Dave: Again, what we've seen is if we knock out the prolactin receptor in these thermoregulatory circuits, it makes the mothers less able to lose temperature. And so they run their whole temperature at a slightly elevated body temperature and under normal conditions that may be okay, they can cope with that. But if they're kept in a warm environment, then it becomes really disastrous and they tend to lose, or just abandon the litters because they're not coping with the elevated temperature.

Dave: I think that given climate change and the various things we're going through at the moment, this is actually quite an important adaptive response of pregnancy and again, something that we've found that prolactin is involved in when we really didn't expect it. But it fits with the overall idea that this is just a broad spectrum adaptive response to pregnancy.

Kat: I love the idea that we have that metaphor if you've got a bun in the oven, and this is like turning the temperature dial down on it when you're getting too hot!

Dave: Yeah, exactly. I think the way that it works is that your body works on a kind of a set point in that once you get to a certain level, you activate the systems that you have to cool off: start sweating, flush blood to the skin, those various things. And what we think is happening in pregnancy is that setpoint is just becoming a little bit more sensitive, so it just activates earlier. That's a kind of adaptive response to make sure you don't get too hot. Mostly that's about protecting the baby from getting too hot because that's bad for brain development in particular.

Kat: What's the next thing that you're interested in? It sounds like prolactin does everything, so there's so many things you could look at. What have you got your eye on next?

Dave: I think the thermoregulation question is one that has opened up to other ideas and one place there we are thinking about is menopause and hot flushes around menopause.

Dave: And then other things, there's many other things that change in pregnancy that we haven't even started to look at yet. There's changes in respiration, changes in the cardiovascular system. We're starting to identify some of the cell types that are involved and we'd like to look at those as well. But I think there's just too many things for our small lab to cover them all. I'm looking for help!