A new neuroscience of pregnancy
We know shockingly little about what goes on in a mother’s brain during pregnancy.
For example, we know only a handful of the hormones involved—out of hundreds scientists think may exist—and very little about how they might impact the brain. This gap in our understanding is one of the reasons we don’t have great treatments for pregnancy-related maladies, whether it’s extreme nausea, or anxiety and depression.
Closing this gap is the mission of the new Stanford Neuro-Pregnancy Initiative, part of the Wu Tsai Neurosciences Institute's Big Ideas in Neuroscience Program.
Today on the show, we speak with initiative leaders Nirao Shah, a neuroscientist who studies sex differences in animal behavior, and Katrin Svensson is an expert in how our tissues use hormones to communicate in health and disease. Together with Longzhi Tan, an expert in gene regulation and 3d genome structure, the team aims to chart the cellular and molecular transformation that occurs in a mother's brain during pregnancy, in hopes of better understanding this fundamental event in a person's life and improving health outcomes for both mothers and infants.
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Learn more:
- Big Ideas in Neuroscience tackle brain science of everyday life and more (Wu Tsai Neuro, 2026)
- Nirao Shah lab
- Katrin Svensson lab
- Longzhi Tan lab
References
- Hoekzema, E., et al. (2017) Pregnancy leads to long-lasting changes in human brain structure. Nat Neurosci 20, 287–296. This is the landmark neuroimaging study discussed in the episode that provided evidence of long-lasting, pregnancy-induced changes in the structure of the human brain.
- Fejzo, M., et al. (2024) GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature 625, 760–767. This recent paper provides strong evidence that the hormone GDF15 acts on the brainstem to cause nausea and vomiting in pregnancy.
- Knoedler J, et al. A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior. Cell. 185, e1–e18 (2022). This is the work from Dr. Shah’s lab mentioned in the episode, identifying a specific circuit in the hypothalamus that changes its connectivity across the estrous cycle to control female mating behavior.
- Ladyman S.R., et al. (2021) A reduction in voluntary physical activity in early pregnancy in mice is mediated by prolactin eLife 10:e62260 This is the research mentioned from Dr. Grattan’s lab showing that the hormone prolactin acts on the hypothalamus to reduce locomotor activity and anxiety-like behavior in pregnant mice.
Glossary
Placenta A temporary organ that develops during pregnancy to support the fetus. As an endocrine organ, it produces hundreds of known and unknown hormones, which are thought to orchestrate massive changes in the mother's body and brain.
Peptide Hormones Powerful signaling molecules made of short protein chains that travel through the bloodstream to coordinate complex biological processes, from appetite and nausea to preparing the brain for motherhood.
Hypothalamus A deep brain region that acts as a master hormonal control center, linking the nervous system to the endocrine (hormone) system and regulating essential behaviors like mating, appetite, and maternal care.
HCG (Human Chorionic Gonadotropin) A key hormone produced by the placenta early in pregnancy (it's what pregnancy tests detect) that is thought to travel to the brainstem and cause pregnancy-related nausea and food aversions.
Estrous Cycle The reproductive cycle in female mammals like mice (analogous to the human menstrual cycle), which serves as a powerful model system for scientists to study how hormones cause dramatic and reversible changes in the brain.
Pregnancy "Fingerprints" A central goal of the Neuro-Pregnancy Initiative, which aims to create a comprehensive map of the molecular (gene and protein) and phenotypic (behavioral and physiological) changes that define a healthy pregnancy in order to better identify when things go wrong.
Episode credits
This episode was produced by Michael Osborne at 14th Street Studios, with sound design by Mark Bell . Social media strategy is by Julia Diaz, and additional editing by Nathan Collins. Our logo is by Aimee Garza. The show is hosted by Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute and supported in part by the Knight Initiative for Brain Resilience.
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Transcript
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.
(00:25):
One of the things I appreciate about working at the Wu Tsai Neurosciences Institute is that we sit outside any department or school at Stanford, and so we're in a unique position to foster new ideas and help forge connections between researchers from very different fields. One of our flagship programs is the Big Ideas in Neuroscience Awards. This is a program we've run since 2014, where we bring together top scientists from different fields to kickstart big, bold research projects that have the potential to transform how we think about the brain. In a moment when support for basic science has never been more important, programs like this have never been more critical.
(01:08):
If you've been following the show for a while, you've already heard about some of these Big Ideas projects, efforts to engineer an artificial retina or to ground addiction policy in the neurobiology of choice or to grow human brain circuits in the lab to study autism. All of these have roots in our Big Ideas program.
(01:29):
Earlier this year, we launched five new projects, and over the next few months we'll be inviting members of these teams onto the podcast to tell us about their big ideas. Today on the show, the neuroscience of pregnancy. Now when you hear that, you probably think about the brain of the developing fetus, but today we're actually going to talk about how pregnancy affects the brain of the mother because it turns out we know shockingly little about what goes on in a mother's brain during pregnancy.
(02:00):
For example, we know only a handful of the hormones involved and very little about how they might impact the brain. Scientists now believe there could be hundreds of hormones released during pregnancy, many of which are totally unknown to science. This gap in our understanding is one of the reasons we don't have great treatments for pregnancy-related maladies, whether it's extreme nausea or anxiety and depression. So today we're speaking with two of the initiative's leaders. Nirao Shah is a neuroscientist who studies sex differences in animal behavior, and Katrin Svensson is an expert in how our tissues use hormones to communicate in health and disease. Nirao and Katrin are also working with Longzhi Tan, an expert in the genomic structure of brain cells.
(02:48):
I started our conversation by asking them to pitch us on the big idea behind their neuropregnancy initiative.
Nirao Shah (02:55):
So I think the big idea here is to really try and understand how it is that the mother's brain is adapting to pregnancy, regulating her physiology and behavior, so to promote her health and also promote the health and survival of the baby. We know a lot about how the mother's body changes, and of course we know a lot about how the baby develops in the womb, but we know very little by comparison about how it is that the mother's brain adapts to the requirements of pregnancy to support both the mother and the baby.
Nicholas Weiler (03:27):
It's amazing because pregnancy is such a huge event and it seems like it must have a huge impact on the brain. I mean, anyone who's been pregnant, or I guess in my case pregnancy adjacent, has heard about the pregnancy brain, the nausea, the changes in appetite, and so on. I know a lot of people experience postpartum or peripartum mood changes, so it's kind of shocking, I guess, that we don't know more about this. How bad is our ignorance on this point? What are the known unknowns here that we really ought to know more about?
Katrin Svensson (04:01):
Yeah, so we understand a lot about the experience, what you're mentioning, nausea, cravings, postpartum depression, what we all know as pregnancy brain, we understand pieces of it, but we don't know a lot about the system at the molecular level. We don't understand the mechanisms of why it's happening and what is actually causing it. So just to take an example, with nausea and appetite changes, my lab studies appetite and anti-obesity agents, and everyone that has been pregnant, they know that you have a tremendous increase in appetite and cravings and also taste aversions, and they clearly change and track with dramatic endocrine shifts in pregnancy, but it's not at all clear where they're coming from, what is causing them.
Nicholas Weiler (04:50):
Just to linger on this for a moment, I remember reading this book Invisible Women several years ago, that really lays out a case that biology has pretty systematically understudied female biology for, well, I guess for most of its history. Is that the case here? Are there other things going on that have made this difficult to study?
Katrin Svensson (05:11):
Yes, it's difficult to study pregnancy. It's difficult to design studies. It's hard to get approval to do clinical trials. And in many of the cases you need to have mechanistic studies done in animals before going into humans, and that is also something that Nirao knows very well. It's extremely difficult to study pregnancy in mice too. It's costly. It's not time efficient. It's very challenging.
Nirao Shah (05:41):
I also think it's been technically challenging in addition to just the variability of handling animals that are pregnant. It's only the last decade or so, pioneers like Katrin, for example, and others here at Stanford and elsewhere have developed the tools that allow us to look at specific genes or specific hormones or even identify genes or hormones that might be changing in response to different physiological events. So those tools are available now.
Nicholas Weiler (06:10):
So there have been some studies on this. I know there's been some brain imaging studies that have looked at changes in brain volume. There's been some work on the hormones that you specialize in, Katrin, and I'd love to dive into those. But before we do, in a way this is obvious and maybe the answers are very clear, but I'd love to hear why is it important to understand pregnancy from a neuroscience perspective? What is the neuroscience of pregnancy specifically and how does that help us understand the experience that a woman goes through during pregnancy and help make sure it's a healthy one?
Katrin Svensson (06:44):
Yeah, sure. It's super important to understand the molecular mechanisms and what is happening during pregnancy. While this is not a disease state, there's a lot of changes, and to be able to treat a condition, for example hyperemesis or postpartum depression, we need to understand what is happening.
Nicholas Weiler (07:05):
When you say hyperemesis, that's sort of a severe form of the nausea many people experience during pregnancy.
Katrin Svensson (07:10):
Right. And even if it's not hyperemesis, most women experience some degree of nausea. I looked into this during my own pregnancy because there's really nothing known about what is causing this tremendous nausea and why is it different in different pregnancies in the same person. The studies that are out there would suggest that it's the hormone HCG that is coming from the placenta, and that is traveling to the brainstem and causing nausea, but it's clearly not the entire explanation. There are a lot of endocrine signals that could maybe explain this phenomenon better. If we knew what those were, we could potentially identify better treatments.
Nicholas Weiler (07:51):
That raises a question that I was wondering about as I was preparing for this conversation. You could imagine that a lot of these could be seen as side effects of other things that are going on during pregnancy, and maybe the body is, you can frame it as sort of a conflict in a way between the placenta and the infant and the mother's body at times in some cases.
(08:13):
So maybe there are places where, well, there are some side effects that affect the brain, but that's just a side effect of things that are going on elsewhere in the body versus are there things that are specifically happening in the brain that are important for regulating and ensuring a healthy pregnancy, preparing someone to be a mother, and so on, that are like these things have to happen in the brain for the pregnancy to be successful? Do we have any idea about the balance between those two sides?
Katrin Svensson (08:40):
We think that is the latter, and that's partly what we're exploring in this grant, how the brain can actually dictate what happens to a pregnancy.
Nirao Shah (08:50):
I mean, there could well be some side effects like you're suggesting, for example, HCG and from the placenta causing nausea, if that's one of the underlying reasons. But also there must be sort of adaptive changes in the brain that regulate the need to eat more, for example, and that regulate other physiological changes in the mother that are going to prepare her for birth and then lactation. So those changes are clearly going to be emanating from the brain. Those are going to be adaptive in response to the needs of pregnancy.
(09:23):
I think one of the interesting neuroscience reasons to study pregnancy, beyond the fact that we know so little about how the brain regulates and is regulated by pregnancy, is that it's an astonishing change in the body of the mother and her behavior and her mood and her weight over the course of pregnancy.
(09:42):
Mice will put on, their pregnancy lasts about 20 days, and mice will put on 20, 30% of their body weight in those 20 days. But then postpartum, after birth and after they wean their babies, they basically revert back to baseline conditions as if they were not pregnant before.
(10:01):
So how do you get this reset to baseline? What is the plasticity flexibility mechanisms that not only govern the bodily changes, but what are the plasticity flexibility mechanisms of the brain that allow the brain to go back and say, "Okay, I'm not pregnant anymore. I can then go on to do other things, and if I decide, I'll just become pregnant again." What are those changes and how is that managed multiple times across the course of a female's lifetime?
Nicholas Weiler (10:28):
And I suppose not everything is going to go back to the way it was before, as every new parent finds out that there are a lot of things that change and a lot of ways in which your lifestyle, your behavior, and so on. There's a lot of things that change. I'm debating a little bit about whether to start with what we know about the hormonal changes that occur during pregnancy or what we know about the neurological changes. Let's start with hormones.
(10:50):
Nirao, you were just saying pregnancy is this huge event that occurs. It affects almost all parts of the body, appetite, weight, there's an increase in blood volume. And Katrin, I know that there's a hormonal side of this. Can you give us a sense of what are a few of the key hormones we know about? And then I'd love to hear the evidence that has been coming up that there may be a lot more hormones than that, that we know almost nothing about.
Katrin Svensson (11:17):
Some of the things that we know going on is early in pregnancy you have an increase in progesterone, estrogen, HCG, and later in pregnancy, there's an increase in prolactin to promote lactation. I think the field in general focus on this small set of well-known hormones because they have been studied for a very long time. They were discovered more than 50 years ago.
(11:43):
So what we quickly found when we started this collaboration with Nirao's lab was when we looked into the expression in the placenta and in the uterus, we actually found that we predict that there are hundreds, more than 300 hormones or secretive peptides or proteins, and the majority of those have never been tested for biological activity.
Nicholas Weiler (12:06):
Secreted by the uterus and the placenta?
Katrin Svensson (12:10):
Secreted by the uterus and the placenta.
Nicholas Weiler (12:11):
Wow.
Katrin Svensson (12:11):
So what we call pregnancy hormones today is most certainly a very incomplete list.
Nicholas Weiler (12:18):
So you're saying we have about what, five, half a dozen or so?
Katrin Svensson (12:22):
Something like that, yeah, that we know have a very particular role in pregnancy.
Nicholas Weiler (12:27):
And your initial read on it is that probably there are actually more like 300 being produced by the uterus and the placenta. I think I read that there was some research suggesting that hormone levels, maybe this is even just looking at the hormones we're familiar with, the levels change a hundredfold, a thousandfold during pregnancy. I know this is an unknown, so what can we say, but what are some of the things that those hormones might be signaling?
Katrin Svensson (12:56):
Yeah, I think there are a lot of hormones that would be there to promote growth and health of the fetus, but also to signal back to the mother that could affect behavior, appetite, aversion. We know very little about hormones that are coming from the reproductive organs that can affect aversion, for example.
Nicholas Weiler (13:18):
So certain foods or tastes or smells just being off limits.
Katrin Svensson (13:22):
Yeah. The cravings and aversion go hand-in-hand. So these are events that typically happen in the brainstem. There are a couple of known molecules or peptides that are known to act on the brainstem to induce aversion, but none of those seem to be implicated in pregnancy.
Nicholas Weiler (13:38):
When we talk about numbers of hormones, tenfold or thousandfold fluctuations, it's hard not being in the field to know what those numbers mean.
Katrin Svensson (13:50):
It's hard to get a number on it, but at least as far as our data would suggest, is that if you look at an organ map of the known peptides, the majority are coming from the brain. That's in the hundreds. The second largest organ that is releasing secreted peptides and protein is the liver. Right after that, it's the placenta.
(14:14):
And what's really interesting about the placenta is that it's a temporary endocrine organ. It's not there normally. It's not there in men. It's not there normally in non-pregnant women. So it sort of overshadows a lot of the normal signals that are there.
Nicholas Weiler (14:30):
Every time I'm reminded of that, it blows my mind, that when a woman becomes pregnant, a new organ is created and then detaches itself and disappears. It's really incredible.
(14:39):
Okay, so that gives us a little bit of a picture of the scope of what might be going on hormonally, that there are probably dozens or hundreds of hormones involved in the uterus and the placenta that we really don't know what they do, but maybe that could link us to disorders like preeclampsia, mood disorders, things that we know happen often to people as potential risks of pregnancy.
(15:23):
I know there has been some work on the neuroscience side of some of the brain changes. So Nirao, maybe you can give us a little bit of an overview of the evidence the field has gathered to date about ways that the brain may be changing during pregnancy. I think there's been some neuroimaging on this. Is that right?
Nirao Shah (15:42):
That's right. There has been an MRI study that followed one woman across the course of her pregnancy, and they did see changes in the brain, as you mentioned. But a lot of the knowledge that we have about changes in the brain actually come from animal models, rodents, for example. And it's known that there's a prolactin regulated increase in de novo neurons, brain cells being born in pregnancy, in the olfactory bulb in mice. The olfactory bulb is part of the brain that processes odors. Another striking finding, again with prolactin, is that prolactin acting on a part of the brain called the hypothalamus, seems to regulate locomotor behavior.
Nicholas Weiler (16:23):
So movement.
Nirao Shah (16:24):
Movement, yes, movement of the animal. So female mice will move about less, they'll locomote less when they're pregnant.
(16:31):
So people have described these changes across the rodent brain, but there's not been sort of a systematic effort to go in with using modern tools to really ask in an unbiased way, what are the changes and what might they mean for the animal and the baby?
Nicholas Weiler (16:46):
Yeah. This is one of the things that I was struck by when I was looking at some of this research. Tell me if I've misread this. I thought I saw some studies by Carmona and her group doing MRI research, and I thought it was more than one woman. Wasn't there some evidence that there are some significant brain density or gray matter changes in the course of pregnancy?
Nirao Shah (17:08):
Right. So their group has done multiple studies, as you just pointed out. What I was referring to was a study that followed one woman continuously across pregnancy, so a longitudinal study.
Nicholas Weiler (17:18):
Oh, I see.
Nirao Shah (17:19):
So that's not been done too often, to my knowledge. So they could see sequential changes in the same brain. And as you pointed out, they do see changes in white matter, gray matter densities in different brain regions.
Nicholas Weiler (17:30):
And combining some of that human work looking at changes in density of the gray matter in I think it was areas of the brain involved in social cognition that they hypothesized might be involved in bonding or in changing the priorities of interactions with infant versus others, and then some of the work that you cited and that your lab has done, for example, looking at changes in the hypothalamus at a more granular level in mice, we can see that there are significant changes in connectivity among cells in this part of the brain that's very much involved in hormonal signaling. What do you imagine about how the brain might be changing during pregnancy to support a healthy pregnancy?
Nirao Shah (18:19):
Right. So my sense is the human data are great. I think they represent the tip of the iceberg in terms of what's actually happening in the brain of the mother. And that's because you're limited to MRI studies in humans, and the resolution there is not great. As compared to in mice, we can use the brain to look at single genes at the level of single cell at any time point in pregnancy.
(18:43):
And going back to the point you raised, we have identified estrogen [inaudible 00:18:48] cells in the hypothalamus that change their connectivity dramatically, threefold, or 300% change across the ovulatory or estrous cycle, which is five days long in the mouse. This is analogous to the human menstrual cycle, which is 28 days long. And we see these dramatic changes in connectivity in the female brain in this part of the hypothalamus every five days. And I'm talking about changes in about, say, a thousand cells, a thousand neurons, and the mouse brain contains 80 million neurons roughly. So we can really go in and pinpoint the very specific cells that are undergoing these changes and then ask, what might these cells be doing to the animal's behavior?
(19:32):
And we've also done that, and this is not in pregnant animals, if we sort of electrically silence them using optogenetics, or if we simply kill those thousand cells, then the females lose interest in sexual behavior. They will not mate. So just identifying these cells, a thousand cells out of 80 million, and then silencing them, you basically lose a very specific behavior that is intimately tied to the estrous cycle because as estrogen and progesterone surge and the female starts ovulating, that's a state of maximal readiness to engage with the mate and have babies.
(20:08):
So these are the sorts of things that we imagine are going on in the pregnant brain, that there'll be changes in very discrete subpopulations of cells that change enough with gene expression that then regulate very specific aspects of maternal physiology and behavior, and perhaps also ultimately fetal or the baby's health.
Nicholas Weiler (20:27):
I think that raises a really important point. Obviously humans are not mice and human pregnancy is not a mouse pregnancy, but this idea that if you're looking in mice and you want to understand how their estrous cycle and their fertility and mating cycle works, you need to be able to find those thousand cells out of, what did you say, 80 million?
Nirao Shah (20:46):
Mm-hmm.
Nicholas Weiler (20:46):
And understand, well, what are the signals? How are those cells affecting that very particular behavior that may be specific to mice? But something similar has to be going on in humans, but you need to be able to find the specific cells and see what are the specific changes that are happening during pregnancy. That's what I find so exciting about the project that you all have put together to try to map out, okay, what are the changes that happen at the level of cells, at the level of genes, and at the level of behaviors?
Katrin Svensson (21:16):
Yeah, I guess one thing that I can add is that we're very cognizant of the problems translating mouse mechanisms and studies into humans. That's something that we think about in every single project. The projects that we have that are outside of this pregnancy related projects where we look at appetite regulation, for example, we run into this all the time where we want to make sure that the peptides that are in the signals that we're looking at are conserved across all the species we're looking at, mouse, pig, in humans eventually. Hopefully it will go to human studies.
(21:53):
And we make sure to look at the sequences so that we know that the peptide could actually be made in a human. So to take an example where we look at appetite regulating peptides, we often use GLP-I or Ozempic as a positive control. And this is the drug, the peptide drug that people use to lose weight, and it works very well in mice. And that's just one example of a peptide that is highly conserved between mice and humans. And so is the model system that we are looking at.
Nicholas Weiler (22:27):
And it comes from lizards, I think.
Katrin Svensson (22:30):
Well, it was discovered in lizards, but it's present in the mouse. It's present in humans. But yes, it's conserved across many animal species. And that's very important because that speaks to the biology of it.
Nicholas Weiler (22:41):
Right. And that raises a really important point. Thank you for raising that, which is, you were talking earlier about we think there are at least 300 peptides, potential hormones, only a handful of which we've studied, involve coming from the uterus and the placenta. GLP-I one, that's of these peptides that has been recently discovered that can have tremendous medical benefits. And so just the very project of trying to understand what all of the active peptides and hormones are in our bodies could have amazing benefits, whether it's for pregnancy specifically or for just our general understanding of our biology.
Nirao Shah (23:21):
Also, all the pregnancy hormones that we've talked about so far, estrogen, progesterone, prolactin, oxytocin, they're also found in the mouse as well. And they seem to play similar roles as well. So at least in known pregnancy related hormones seem to be very similar between mice and humans. And Katrin can speak exactly to the sequence relationships between them, but they're all very conserved. Insulin's another great example.
Nicholas Weiler (23:48):
So before we jump into talking about the project, I would be remiss, several people who I've talked to about this episode and just asking what are some things you'd be curious to know about, have mentioned this idea that I've read some evidence for, but it feels a little bit sci-fi, about cells from the fetus actually becoming embedded in maternal tissue, sort of creating a fetal maternal chimera of some kind.
(24:15):
And the idea I've seen is perhaps these are in some way influencing maternal behavior later, sort of a toxoplasmosis-like situation where there are cells that get embedded in the brain and alter behavior. This may be too far afield from what you all are planning to study, but is there any solid science behind that?
Nirao Shah (24:35):
Well, certainly you can find fetal genes and cells in the maternal bloodstream. People can now, I think, use blood tests, and Katrin can speak specifically about this, but those things leak into the maternal bloodstream. Whether or not they go into the mother's brain, I mean, certainly the blood circulates, so the blood's going to get into the maternal brain as well. But whether the cells embed, as you're suggesting, in the mother's brain to alter physiology or behavior, that I think is an interesting question that we don't have a clear answer on yet.
Katrin Svensson (25:07):
It's interesting, but I think as far as the cell-free DNA from the fetus, it's actually pretty remarkable that 10 to 20% of the total circulating DNA can belong to what can come from the fetus during pregnancy. So it's not a small fraction, it's a substantial fraction, but I don't think there's much evidence yet that there is any functional transfer.
Nicholas Weiler (25:58):
Well, let's talk about your Big Ideas project. So we know that there are a lot of hormones we don't know about. We know there's a lot of hormonal change during pregnancy. We know that there are changes in brain volume in certain parts of the brain during pregnancy, and that other aspects of reproductive biology, like the estrous cycle in mice, there are some very significant changes going on in particular cells that seem to be very importantly related to the mouse's behavior during that cycle. So a lot of stuff is happening.
(26:28):
My question is, why is now the right time to take this on? What can we do now that maybe we couldn't do five or 10 years ago?
Katrin Svensson (26:35):
Yeah, so from the peptide side, we have for decades studied peptide and peptide signaling molecules by literally grinding up tissues and looking for things that we can measure. And often it was guided by a bioactivity assay. So this will bias discovery towards abundant hormones and peptides that are more stable and missing low-level peptides. And there are now more modern tools like mass spectrometry, and they're powerful, but very often they're not sufficient to detect very low abundant peptides in an unbiased way. So we know that we're missing a large space, the [inaudible 00:27:20] peptides, the T-peptides, and very transiently regulated neuropeptides.
(27:25):
So what has changed over the past 10 years, I would say, is that we can now use a combination of genomic information using computational models to predict secretive peptides directly from transcriptomic or gene data. So in our lab, we developed a model, I talked a little bit about that, that can map proteins for signals which can help us to systematically predict previously invisible peptides, and that includes pregnancy neuropeptides, rather to hope to detect them by just try to measure them by mass spec. So for this project, we looked at the placentas in sample and already found some. So this is really fascinating to me that just by taking a quick peek that we can already find new things.
Nicholas Weiler (28:15):
Actually, I meant to start with another question, which I think will lead into what we were just talking about, which is how did this specific group of experts, you, Nirao, Katrin, and Tan come together to launch this project? What made it feel to you all like this was the time that there could be a lot of progress made on these questions?
Nirao Shah (28:36):
The three of us had been collaborating with each other on separate unrelated projects before we came up with this neuropregnancy initiative. And so we started talking, Tan and I and Katrin. We realized that each of us had converging interests on this, Katrin from the peptide side, Tan from the genome architecture and gene regulation side, and from my perspective, the changes in gene expression in neural circuits during pregnancy that might regulate physiology and [inaudible 00:29:06] with the mother.
(29:07):
The Big Ideas is sort of instrumental in allowing us to explore these ideas that are very ambitious and high risk because we don't know much and we don't have a lot of preliminary data. To go into an NIH grant mechanism, for example, would be pretty challenging. But the whole purpose of the Big Ideas is to foster these interdisciplinary collaborations. Asking a big question in biology broadly defined, that if it works, has a huge payoff in terms of not only basic scientific discoveries, but also advancing understanding of human health and also how it might help people afflicted with various disorders. So we now have that freedom thanks to the Big Ideas initiative.
Nicholas Weiler (29:51):
And how are you all planning on taking that opportunity to tackle some of these big questions? We've talked about the many hormones that we think are involved in pregnancy, the way they interact with the brain, what cells they're interacting with, how those are linked to the behaviors and the experience of pregnancy and potentially some of the risks that are associated with pregnancy. What's the strategy?
Katrin Svensson (30:16):
So I think it helps that we all have complementary expertise. So Nirao, in neuroscience, he would know what circuits would be most relevant to study, which would narrow down some of the more important targets. Tan would be really important for understanding the gene regulation. And from my side, I could help with some of the direct functional testing of these molecules because we don't want to just propose and identify some changes, but actually test which ones are functionally important. And I agree with Nirao, this initiative and this mechanism is really important because it allows us to be more exploratory than a regular NIH grant.
Nicholas Weiler (30:59):
Yeah, one of the things that I find so exciting about this is that there are people who are studying neurological changes, there are people who are studying peptide changes. It seems like this has been a growing movement over the past five or 10 years. But you're not proposing to study either of those in isolation. You're proposing to study the crosstalk. And this is part of this turn that we've been seeing more and more in neuroscience to avoid treating the brain as just a black box on its own up in the skull, but as part of a discourse, a dialogue between the brain and all different parts of the body.
(31:34):
And so the focus on what is the placenta saying to the brain? What is the brain saying to the placenta and the uterus? What behaviors are influenced by that? What circuits are being changed by that? Looking from genes to cells to circuits, and so on. Are there answers that you hope to get from this approach that haven't been possible before? If you imagine doing this for two, three, five years, and let's say the experiments go remarkably well-
Nirao Shah (32:03):
Much longer, I hope-
Nicholas Weiler (32:04):
Well, much longer, I hope. Well, let's say 10 years. Let's say you get these, you're getting all the data that you hope to get, which doesn't always happen in science, but let's say things go well. What kinds of questions are we going to be able to answer in five or 10 years as a field that we currently really wish we knew the answers to?
Nirao Shah (32:22):
So I've been thinking about it as starting off with trying to understand what is the molecular signature of pregnancy in the brain? What does the molecular fingerprint look like in the placenta or the uterus when it's pregnant, when it's hosting an embryo?
(32:36):
So I think that's the bedrock of all the projects that Katrin and Tan and I are planning to do. How does this molecular fingerprint change in the brain during pregnancy? And the other signature we want to look at that is an integral part of the project is what is the phenotypic fingerprint? What are the biomarker fingerprints of pregnancy? What are the things that you and I could objectively measure using very simple tests, like blood tests or simple things that happen to you when you go to the clinic? What's your blood pressure like? What's your weight like? So we call this the pregnancy phenome.
(33:10):
So the molecular fingerprints would give us the peptide hormones that are regulating physiology. And the behavior of the molecular fingerprints would be a jumping off point for Tan to go and ask, "What are the regulatory structure of these changes? Are these the shape of the genome, or the architecture of the genome and the nucleus of a cell changing?" And is that conserved across species, across tissues?
(33:32):
And for my own research group, how are these specific genes that are changing regulating brain function and what are these circuits doing in response to these genes to regulate the physiology and the behavior of the mother? But the unifying theme is these fingerprints of pregnancy.
Nicholas Weiler (33:49):
And I just want to jump in there because what I think you're talking about is to map the time course of pregnancy. Like, what are all the different things that are changing across pregnancy? And hopefully what that could get us is also to know if there's something that is going in an unhealthy direction.
Nirao Shah (34:04):
No, that's exactly right. I mean, we talked about 10 years. That's one of our really would be a dream outcome for all three of us, I think. Jump in and disagree if you think, but to be able to have a phenome not only in the mouse for pregnancy, but ultimately extend that even with our clinical colleagues on campus here in obstetrics, gynecology, and pediatrics who are interested in outcomes of pregnancy to sort of extend this and define this also from the human side, so that as you point out, we can just walk into a prenatal clinic and have biomarkers that are lookup tables for where are you with your pregnancy and what are the predictions of these biomarkers for you and your baby.
Katrin Svensson (34:46):
Yeah, my dream scenario would be to not just identify biomarkers and what has changed and the observations that we have, but to be able to actually use them for ecological purposes. So you can imagine, for example, if you have a pregnancy where it's going to lead to a miscarriage, maybe there's a loss of a certain peptide, and can you replenish that peptide hormone and now restore pregnancy?
(35:14):
Or if you have a pregnancy where you have heavy nausea because you have a peptide that is causing nausea and aversion, could you potentially block that to ameliorate those symptoms? So there are many really fantastic things about working with peptides, and one of them is that it's so easy to imagine how they can be translated into something functional. So that is obviously much more long-term, but I think that that would be the hope from my end.
Nicholas Weiler (35:44):
Well, I'm so excited to see what comes from this project. I'm so glad that the Big Ideas program is building this groundwork for understanding the fundamental biology of what happens during pregnancy, which we've lacked for so long. We've talked about these glimpses we've had that certainly many things are changing during pregnancy, both throughout the body and in the brain, and this seems like such an important place to say, well, let's map out everything that we can see and try to connect those to what a healthy pregnancy, what a risky pregnancy looks like, so that we can really understand this fundamental thing that occurs as part of our life on this planet.
(36:26):
So thank you both so much for coming on From Our Neurons to Yours. I look forward to having you both back to tell us about what you are discovering.
Nirao Shah (36:34):
Thanks for having us for this podcast.
Nicholas Weiler (36:37):
Again, a big thank you to the Wu Tsai Neurosciences Institute for funding our initiative.
Katrin Svensson (36:40):
Thanks for having us.
Nicholas Weiler (36:43):
Thanks again so much to our guests, Nirao Shah and Katrin Svensson. Nirao is a professor of psychiatry and behavioral sciences and of neurobiology, and Katrin is an associate professor of pathology at Stanford Medicine. To read more about their Big Idea project and their other work, check out the links in the show notes.
(37:02):
If you enjoyed this episode, be sure to subscribe for more conversations from the frontiers of brain science. We also love hearing from listeners. If you have thoughts about the show or questions about the brain you'd like to hear us discuss in a future episode, send us an email at neuronspodcast@stanford.edu or leave us a comment on your favorite podcast platform. And while you're at it, please give us a rating and share the show with your friends. It may seem like a small thing, but it's tremendously valuable for us to be able to bring more listeners to the frontiers of brain science. Next time on From Our Neurons to Yours...
Kathleen Poston (37:41):
I am trained as a movement disorders Parkinson's Disease neurologist. The fact is that by the time somebody has the clinical symptoms, the pathological progression is actually rather advanced.
Nicholas Weiler (37:59):
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, and Nathan Collins provided additional editing. Our logo was designed by Amy Garza. I'm Nicholas Weiler. Until next time.
