Transcript: Jason Snyder on Neurogenesis – #24

Steve: Thanks for joining us. I’m Steve Hsu.

Corey: And I’m Corey Washington and we’re your hosts for Manifold.

Corey: Our guest today is Dr. Jason Snyder, Assistant Professor of Psychology and member of the Center for Brain Health at the university of British Columbia.

Corey: Jason’s research focuses on neurogenesis and specifically how hippocampal neurogenesis across the lifespan regulates memory, decision making, and stress related behaviors. His research uses transgenic techniques, immunohistochemistry, electrophysiology to quantify neurogenesis, understand the circuit mechanisms by which new neurons regulate behavior. Beyond neurogenesis, Jason’s lab is interested in how neurons throughout the dentate gyrus, hippocampus and related structures interact to guide behavior.

Corey: Today we’ll be speaking with Jason about his article, Recalibrating the Relevance of Adult Neurogenesis that appear in Trends in Neuroscience early this year, some of his other recent papers on the topic.

Corey: Welcome to Manifold, Jason.

Jason: Thank you so much for having me.

Corey: So I think we all grew up with the general idea that you don’t grow new neurons. And we’re all counseled as kids informally, that there are many things you could do to kill your brain cells like drinking and staying up way too late. But there’s nothing you could do to actually grow new neurons. And this dogma became extremely widely held, in fact, I believe it was held for all animals, all mammals, mammalian species when we were growing up.

Corey: It was thought that many parts of our body regularly generate new cells, whether it’s skin or the blood, but there’s something special about brain cells that made this impossible.

Steve: Corey, our guest is much younger than we are, you’ve got to remember, we’re old guys now. So I’m not sure he grew up with that dogma. You and I definitely were fed that dogma, which I never believed.

Corey: It stuck in my head, but I kind of repress our age in this context.

Steve: It’s good for us not to come to grips with how old we are, but let’s ask him whether he was also force fed that dogma when he was a young person.

Jason: I grew up, in the academic sense, in graduate school, just as this dogma was being overturned. So it was kind of an exciting time because there were only a dozen papers saying that the adult brain could produce new cells, and every time something came out you knew about it and you knew the literature.

Jason: And I mean, at this point I feel like that’s an advantage because it’s helped me totally stay on track of the literature. But in my lab, obviously, we were studying this so we believed in it and it wasn’t a dogma to me. But we felt the impact because it was still really hard just to get funding to study this and anxiety about, will we be able to publish our paper because people still don’t believe it. That was still in the air because this was, 2001 I think was my first publication on this topic, and it still wasn’t accepted. So I could definitely appreciate it that this had been a problem.

Jason: And it still was. Maybe in the hippocampus people were starting to appreciate neurogenesis was happening, but at that time there were other studies saying, well maybe it’s happening in other parts of the brain. And that was really opposed strongly. So the dogma was still there.

Corey: What was the change that allowed people to see that neurogenesis was possibly occurring? Were there new techniques developed?

Jason: Yeah, I think many things came together. I mean in the background, there were decades of research just on the brain’s ability to change in general that I think set the stage for this discovery, it’s really the rediscovery of neurogenesis.

Jason: You had the famous patient, HM, who was discovered in the 60s when his hippocampus was removed. He could recall old memories, but he couldn’t form new memories. And so it became clear with that discovery and with subsequent discoveries that connections between neurons strengthen and can change, and that’s happening in the same region that is required for memory. It gave birth to this real idea that this region where neurogenesis is happening, the hippocampus, is capable of changing structurally, functionally, and then that may underlie behavioral change.

Jason: And so that was known and that progressed over decades. So that was 60s, 70s, 80s. And then 90s is when neurogenesis started to become a topic. And so it took a while and there were signs that neurogenesis happened earlier in the sixties, people could see what looked like mitotic cells, but they didn’t have unambiguous verification that these were neurons. They could be glial cells, which at the time nobody cared about it. I listened to some of your earlier podcasts where you talked about this, another dogma that the brain is only composed to one important cell type neurons.

Jason: And so they thought, well, maybe these are just glial cells that are being born. How do we know that they are neurons, even though the shape might suggest so. But in the 90s new microscopes, antibodies that could target neurons and not glia, those sorts of techniques became available to identify a cell unambiguously as a birth dated neuron and maybe forming connections in the brain.

Jason: And so that was happening in this background of knowing that the brain could change structurally. Those kinds of things I think came together to allow it to begin to be accepted.

Corey: Can we go one step even further back, which is that I recall being told with high confidence, like in textbooks and I think even once when I was an undergrad at Caltech by a famous neuroscientist, that it was known that we couldn’t grow new brain cells or new neurons. This was the eighties and I actually questioned this guy pretty aggressively for an under undergrad. I said, well, how do you know that? And I just didn’t quite understand why the field, if there is such a thing, could come to a high confidence belief about this specific question.

Corey: So what’s the pre history for how that happened?

Jason: Yeah, I think people just hadn’t looked close enough. But there was some evidence that, I mean clearly the brain largely forms prenatally and around the time of birth, so early neuro anatomists like [Ramon Y Cajal were 00:06:45] were characterizing the development of the nervous system. They knew that most cells are born when you’re an infant or in the womb. If 99% of them are born then, then they either couldn’t detect the ones that were added later, didn’t think that they were significant enough. And so I think that just led to this view that was perpetuated and like many things certain ideas get perpetuated without really being ever tested.

Jason: And I think the field is still like that. We’ll probably get into it later. There’s whole territories of relevant research related to this that haven’t been addressed. People think it’s a certain way, but I think we still need to do the experiments to test it. So I think it was this early neuro anatomists and then people who characterize the development of the brain, coming to these conclusions that it is born according to a timetable and early development and that’s it. Without really looking hard enough at the adult brain.

Corey: At what age does your brain reach its full size?

Jason: Well most of the neurons are born by the time of birth, but they continue to myelinate and they continue to grow in size for, in humans at least, many years after, until childhood or so. So maybe by the time you’re 10 it’s…

Corey: And a lot of neural development is actually not the growth of cells but the pruning of connections that tends to occur in the first few years of life, and the lack of pruning has been linked to autism. I think there is a complexity in neuroscience that doesn’t exist in other areas of medicine, and that’s that you could open up the human body, and we do for various reasons, and you can see healing in almost every other part of your body. And you just couldn’t do this in the case of humans in their brain.

Corey: So it’s weird. A lack of evidence doesn’t necessarily evidence for the negative that people took it as. In fact, they didn’t seem to see these things, they made the jump saying that’s compelling evidence that it does not occur.

Corey: In fact, probably simply didn’t have the techniques, like some of the techniques were developed in the 90s involved the ability to label mitotic cells, label cells by the stage of development. And as far as I understand, and correct me if I’m wrong Jason, these studies are done, at least in humans the later ones, after death. And often the case in primates. And you’re sort of looking back retrospectively rather than watching cells sort of develop kind of in vivo.

Steve: Yeah, I totally get why it’s a hard question to answer and I’m not complaining. If I had gone to that freshman neuroscience seminar in 1983 or whatever and the guy said, well, we don’t actually know, there doesn’t seem to be a lot of growth, but we’re not sure. I would have been 100% satisfied with the answer.

Steve: But instead I got some kind of categorical answer and I just didn’t believe they knew the answer, and then it led me to question the cognitive ability of people to reason. So I was like, what is the reasoning? You have a strong belief, how did you arrive at that belief? And it really disturbed me.

Jason: Maybe he was teaching a class and now that I’m been teaching a class, I’ve learned that when you reveal the complexities and that you don’t know the answer to something, the students sometimes get confused and then they get upset.

Steve: Yeah, but this is Caltech, the students were much smarter than this professor, let’s just put it that way.

Steve: I mean there’s a tendency I think for human beings to think in a [bivalate 00:10:05] way, things are either true or false. People are not very good at making-

Steve: Professors of advanced science at top universities?

Corey: Yeah, I think so. Look, it’s easier to publish things where you state categorical findings and that kind of gets absorbed into the literature. People talk in that way. Just a natural tendency. You really have to restrict yourself. We were not very good at processing probabilities. It’s very hard for us to categorize them. You can’t put a number on these things.

Steve: I do think as a scientist it’s part of your professional skill to be able to characterize the strength of belief, uncertainties. Because that’s very integral to what we do as scientists.

Corey: But it’s hard. You can’t put a number on the probability that there were new neurons, right? We’d say we met be totally certain that there weren’t any back then, but no one can put a number on it.

Steve: No, we don’t have to have a number, but you could say we’re not sure, but we can put an upper bound on the rate at which it’s happening because we would have detected it if it were happening at that faster rate. That kind of answers what you’re looking for I think. I mean, that’s what a physicist would say.

Corey: Yeah, I think upper bounds are easier to calculate in a field like physics, which are fairly simple systems. But since those findings, right, this is probably what we’re going to talk to Jason about, things have become messy again and they did over the past 20 years. And so once the initial finding was established that there looked like there were new neurons, but now have been some reversals back and forth and the field looks much more complicated than that, we are once wrong about the big new neurons and there are. Now it’s, they seem to appear to be under certain circumstances.

Corey: So, Jason can you talk a little bit about what you reviewed in your article?

Jason: Yeah. So, I think it’s still worth mentioning, before this latest controversy, which is about whether it’s really happening in humans. Sure, in the late nineties finally someone did use the technique used in animals where you can inject an exogenous, a chemical that labels the DNA used to identify a mitotic cell, a cell that was born. This molecule called BrdU was used in cancer patients to label cells, and then in the postmortem tissue they could verify this using techniques used in animals that are tried and true, show that these new neurons were indeed added in humans.

Corey: Was BrdU used in the 1998 paper by Ericsson?

Jason: Yeah, that’s what I’m talking about.

Corey: Can you just take a minute to describe that technique in some detail?

Jason: Yeah. So DNA is composed of four bases. Adenine, thymine, Guanine and Cytosine, ATCG. And when you inject an analog of one of these, the [thymidine analog 00:00:12:43], Bromodeoxyuridine into the bloodstream it gets taken up by cells anywhere in the body. And then they synthesize DNA with BrdU instead of with thymidine.

Jason: And you can go back at a later date and look at the postmortem tissue and use antibodies that specifically target the BrdU, and you attach a fluorescent tag to those antibodies. And then under the microscope you can see, where are those cells that were born when we injected BrdU? And you can look anywhere in the body, see where they migrated to, and you can use other antibodies to say, do they also express proteins that are only found in neurons? And so if you’ve got a cell that has both BrdU in it and a neuronal specific protein, then you could say this was a neuron that was born on that day we injected it, it became a neuron. We can quantify them.

Jason: And this was used to basically stage the progression of the cancer because cancer cells are also dividing and will take up the BrdU. So the byproduct was that we had these extremely valuable, useful brains that could then be used to quantify neurogenesis as well.

Jason: Now that was then validated and extended using other endogenous markers that are present in neurons. There was a study that actually used carbon dating to estimate the number of cells that were added at different stages of life, because during the [bomb 00:14:07] testing there was radioactive carbon that was taken up by dividing cells and as that dissipated later born cells would be taking up less radioactive carbon. So they could kind of differentiate cells that were born in different stages of life. So there were many of these techniques that have been used that really cemented the idea.

Jason: It made me believe yeah, okay, there’s neurogenesis happening in humans. And in the side there were these other controversies about neurogenesis happening in other brain regions. So that’s a whole other ballgame. But it kind of contributed to the general sense of controversy and unease that this field has felt over the years. And so what we all could at least rest assured about was that in the hippocampus, new neurons are added. That’s what everybody believed in. Every species we’ve examined, except maybe bats and I think dolphins or something possibly, it seemed like they’re added to every species, including humans. And so it changed over the course of a decade from something that people didn’t believe in, to something that we’re going full force and investigating.

Jason: And then a study comes out, and it always depends where study is published in terms of how much attention it gets, And it was published in a very high profile journal, Nature, and said that humans don’t have neurogenesis in the hippocampus after childhood.

Corey: This was last year, right?

Jason: This was last year, early 2018 I think, yeah.

Corey: Can you describe that study?

Jason: So this was by [Arturo Alvarez Voya 00:15:44] and his lab at UCSF. They had about 60 different brains from people of all ages, spanning prenatally through to old age. And they didn’t have BrdU to label their cells, which is kind of like the gold standard. But what they used, they used antibodies against proteins that are known to be expressed in newborn neurons in animals. So they did staining for these proteins, histological staining, and they quantified the number of immature cells. Immature cells of unknown exact age but presumably adult born immature cells, or recently born I should say. And they quantified throughout the lifespan and found that they were present embryonically, early postnatal period. But rarely, if ever, found after the age of, I think 13 was their oldest subject.

Jason: And they had a lot of controls. Their staining quality, their pictures were quite good and the lab was very reputable. I mean they do great careful work. Sometimes it’s so careful, like an extremely stringent criteria. Which on one hand of course is good, if they’re detecting you know what’s real. But if they’re not detecting them, are they just failing to capture it?

Jason: But they had some positive controls in that they could see plenty of neurogenesis in the children. And so that was to me a real strength. That they could find it when it was there in some cases, but not others. Now, maybe that is easier to detect in children, like everything is softer and squishier and the antibodies may be able to detect better in the children. So people have the reservations about this study for many reasons, but it really made everybody stop and question the field I think, including me.

Corey: So your paper I think is then kind of analyzing findings across the field of the past 20 years across different animals, trying to sort out what’s going on. Neurogenesis happens.

Jason: Yeah. I was trying to think about what made me start writing this paper. And I think what I end up doing when something like this happens, because they had numbers at least it wasn’t just pictures of neurons, they actually quantified cell proliferation and immature cell numbers. And so I think I realized, well there are other studies that have looked at neurogenesis in humans and they cited a few papers that I hadn’t read. So I thought, Oh, let me look at what they found too. And I found every single paper that looked at cell proliferation in the dentate gyrus, this sub region of the hippocampus. And the cool thing was, all of these studies in humans used essentially the same kinds of methods. They found a marker that’s a protein that’s expressed in mitotic cells and they use antibodies to detect it.

Jason: So they’re looking at proliferation and they had a common method. Proliferation at the time of death essentially. And because it’s humans, you don’t have any control about the age of your subjects, they die and they do or do not donate the brain. So you’ve got a lot of young subjects, you’ve got a lot of children, adolescents, you got a lot of people in old age. And so then this is kind of messy to put it all together. So they’re, okay, well let’s just put it together in time. And we actually have better data on humans I think neurogenesis, than most animal studies. Where everything’s really well controlled we know less about the early development of the structure in terms of the quantitative nature.

Jason: And it all seemed to come together to me. There’s a lot of neurogenesis in development as we should know and expect, and it goes down rapidly. And now we need to compare this to animals. Like we know neurogenesis goes down to animals with age two, but the conflict in everybody’s mind was neurogenesis is not happening in humans, but it is happening in animals. How do we reconcile this? And whereas in humans, people are studying all ages, I knew in animals for lots of practical reasons and financial reasons and whatever, you tend to study young adults. And so when I looked at the data there too, it didn’t look that different from humans. Humans are not that different from animals. By mid age, neurogenesis is very low. Some would say negligible.

Corey: So you looked back and you found the studies were pretty heterogeneous, especially as regards the age of the subjects, right?

Jason: Yeah.

Corey: Studies across humans and animals, but the animal study focused on young animals, and that’s where you’re seeing neurogenesis. And human studies were not adequately taking that into account, you think?

Jason: The reason why it’s so surprising is that everybody is studying animals that are about two months of age and calling them adults. And not animals, I mean rodents. And you know at that point they become sexually mature, but they’re still very young, they’re almost like children or teenagers. They appear mature, but they’re not totally mature.

Jason: So this is where all of our understanding about adult neurogenesis comes from. It’s animals that are barely adults or in some cases, definitely not adults. And so everybody has this impression that it’s happening. And a lot of our understanding from humans of course also comes from whatever subjects you get, which are often depressed patients or older individuals. And so these are adults who are well beyond that window when neurogenesis was still high.

Jason: I think what became apparent is we’re comparing adults at the later stage of their life when neurogenesis is very low, to rodents that are very young. And there appears to be this mismatch and people don’t believe that neurogenesis might in fact be low for much of our adult lives. But it actually makes sense when you compare it to older rodents too.

Steve: So, if I’m understanding correctly, it seems like in the case of rodents, there’s immediate motivation to do, for example, one-year-old rodents. Just go out and immediately run the same experiments on…

Jason: No, they’re too old. That’d be a great idea, but from the perspective of a Masters student that needs to get a thesis, that’s like the-

Steve: I mean you can’t buy… I mean, essentially you’re only interested in whether neurogenesis is happening. Couldn’t you just go down the hall and get somebody else’s mice that happened to be a year old and use them?

Jason: Most people across neuroscience don’t use mice that old. Every electrophysiologist tends to study animals that are two or three weeks old. They maybe just open their eyes. It’s very easy to do these electrical recordings on the young brain because it’s healthier and it’s more robust and viable. But yeah, most of your colleagues-

Steve: How about people who study disease? Surely they’re interested in old mice. There are some people-

Corey: Some people study aging and so they do it, yeah. But if you want to get an old animal, you often have to order a former breeder, just a rodent that was used to produce experimental animals and now it’s done breeding. And of course now it’s an animal that was breeding, so it’s very different than the traditional model, which is a bit abnormal because it’s never bred in his life. They’re more expensive too, of course, when they’re older.

Steve: So the second question I had is, I wasn’t quite clear what you were saying about the actual status of the evidence for adult humans, or humans that are out of childhood. So the new paper claims not to detect any evidence for neurogenesis in humans in adulthood?

Jason: That’s right.

Steve: But of course, being an actual quantitative scientist, there’s no such thing as evidence that is zero it’s just an upper bound on the rate, otherwise they would have detected something.

Corey: The title of paper is undetectable.

Steve: Yes.

Corey: It’s undetectable.

Steve: But then they have to be able to estimate at what rate they would have detected it, had it been there. So then you get a quantitative upper bound. That’s right?

Corey: Yeah. They didn’t detect, they didn’t try to quantify that or state that.

Steve: Ah, okay. But then when you go back and look at the earlier studies, are there-

Steve: … can look at the earlier studies, are there actual detections of rates that are non zero in that population, say adult humans?

Jason: There are. So there’s a mixed bag. Some report kind of like the negative report in nature that maybe they see a cell here or there and they don’t really quantify it. They just note that it’s very low. And maybe some quantify it, one cell in 25,000 or something. And then others do find higher rates. So then it’s a question of methods. So people are basically uncertain about whose methods are right, who’s doing this right. I don’t know. That creates a bit of a tough environment in the field because people are doubting each other’s abilities. And it’s easy. It’s easy to say, “Well, your methods aren’t specific enough or sensitive enough.” But to some extent there has been some positive developments because this negative report I think has kind of reinvigorated interest in this.

Jason: There was one recent study in Nature Medicine showing very nicely that if you histologically treat the tissue and do things to make these proteins that are only in immature cells sort of reveal themselves a bit better, you break down the bonds of the fixative that are preventing the antibodies from reaching their targets. When you get rid of those things, the antibodies are better able to find these new cells and the quality of the pictures in this paper are outstanding. There’s always this sort of stuff to factor in. You get the numbers and then you look at the pictures. And human tissue never looks that good. It sat around for two days before it was preserved and it sat in a preservation agent for several days. So things don’t look … are never going to look as good as they do in animals in controlled studies.

Jason: But this one study found, even with well-preserved tissue, they were able to get it to a state where you could show these new cells in a way that looked much more like what we see in animals. Now I still question whether these are recently born cells or not, but they’re definitely immature cells and the quality is much better than I’ve seen anywhere else. So it’s been back and forth, and methods are a little contributing to the uncertainty, but it has been working itself out I think.

Corey: I’d like to take a step back and underscore something for our listeners. When you stain for these markers of immature cells, you’re not simply staining human tissue, you’re staining preserved human tissue that’s been processed.

Jason: Yeah.

Corey: And that’s going to decrease the efficiency. So can you describe the process that goes through the process of preparation of these tissues and getting a good signal?

Jason: Of course, the brain is extracted. In an ideal situation, the brain is always put into something usually called paraformaldehyde, which is infused into the brain in a liquid form. But it prelimerizes and links together proteins and carbohydrates and makes the brain stiff such that with basically essentially a fine blade you can cut the brain into thin sections that can be analyzed. And it may not get into the paraformaldehyde preservative immediately. In the laboratory of course it would. There’d be no time between death and preservation. And so everything would be kept in the ideal state, the morphology of the cells, the proteins they express.

Jason: But if you wait an hour or two hours, six hours, 24 hours, especially with some of these markers that are only in immature cell, some of these, the cells tend to degrade. The neuron center processes to other parts of the brain to form connections. And these are the first things that retract and begin to fall apart in the dead brain. And the sooner you can get in the preservative, you can retain that structure and be able to look at something that resembles what you look at in animals and know and understand.

Jason: So 24 hours passes. You may get something that you can detect and might be a newborn cell, but it might have … It might look different. Anyway, once it’s preserved and cut into sections, then that’s when you apply these antibodies that have fluorescent tags that then you can use to visualize the cells under a microscope.

Steve: So you mentioned the gold standard method, which is to actually substitute a base for …

Jason: Yeah.

Steve: One that’s already in the DNA. And does that have similar uncertainties to what you’re describing, or is that method sort of qualitatively different?

Jason: It is more robust because it doesn’t degrade. It’s in the nucleus. So the nucleus is probably one of the last regions of the cell to deteriorate. I think it’s easier to detect and more robust. But this negative report study, they did some good controls where they removed … These brains didn’t even have the BrdU, this thymidine analog. And when they did the immunohistochemistry, because the brains weren’t preserved very well and because they’re old brains too, they could get signals that looked kind of like it.

Jason: And so it just pointed out that when you’re dealing with a different beast, when you’re dealing with 60, 70 year old human brains, you can get a false signal that if you’re not careful, might look like a cell, but really it’s not. So the BrdU is a better technique, but it’s not immune to false positives.

Steve: I just happened to know that if you take a cell sample and ship it on just regular ice, the DNA is good for at least a couple of days, if not more, so. So if you sacrificed someone and got their brain out within a day or two, you could definitely probably detect 100% the BrdU substitution.

Jason: Yeah, yeah, yeah.

Steve: Not that, I don’t know how practical that is in reality, but.

Corey: So Jason, I want to ask a question slightly different direction. I want to begin to get at where neurogenesis is occurring, where we have good evidence of occurring, and why it might be occurring there. So can you talk about the places in the brain where you think there’s pretty good evidence of neurogenesis, at least in young animals, and the potential purpose it might be serving?

Jason: Yeah. So there are scattered reports about neurogenesis happening in a number of places. Most people focus … I was thinking of actually quantifying this and starting a paper with the statement, 42% of studies and their introduction of a statement, something like neurogenesis occurs in two places in the mammalian brain, the subventricular zone and the subgranular zone. The subventricular zone in mammals gives rise to neurons that go to many places. But in adults they go to the olfactory bulb.

Jason: And the same group that published the negative report in the hippocampus, published a report a few years ago saying that in humans there is no neurogenesis going to the olfactory bulb. But in most animals, it seems that that’s the case.

Jason: The other reason that’s totally agreed upon is the dentate gyrus subregion of the hippocampus. The lesser agreed upon areas are the neocortex, which is of course highly evolved in humans. And that’s partly why it’s so controversial that you’d add new cells there because it would raise questions about, well, how can representations be stable when you’re adding new cells? This is the seat of higher intelligence and it’s … can’t happen. But there are reports that’s happened there too. But most people have sort of stayed away from that. So really it’s the olfactory bulb and the hippocampus.

Corey: It’s, I think, easy to understand why you might expect to find new neurons in the hippocampus. It’s [inaudible 00:31:56] the seat of at least short-term memory and presumably adding new neurons increases plasticity. It also increases forgetting as it turns out. What do we know in detail about the effect of new neurons on memory in young animals?

Jason: Well, the cells, of course, when they’re born, they don’t have any connections. Over the course of about two months, they’re like children. They just soak up everything around them. They’re like blank slates in a sense. They go from having no connections to acquiring all these connections with incoming fibers. And so they’re very plastic. They’re better able at forming these connections. They’re also more excitable in that they’re, they fire action potentials. The main sort of unit of neural signaling sort of occurs more readily in them.

Jason: So essentially you have all of this sensory information coming in from the cortex, information about places and the things in these places, and they need to be bound together into an experience, into holistic kind of memory. Neurogenesis is happening in this area where these different types of information converge. So if they’re better able to form connections, it seems plausible that they should be better at associating all of these components of memory into a memory. They’re really at this point where everything converges.

Jason: So when you get rid of them, and typically in mice and rats are really the only models where people have looked at this, you see deficits in various types of memory and all the things that memory is important for. So impairments in, maybe in learning about a place in a maze, but maybe also an impairment in once you’ve learned an escape or some goal, when that changes and you have to learn something else, you may have difficulties in extinguishing that old memory and switching to something new, some sort of new goal.

Jason: So learning about places that are safe versus those that are fearful or where something bad happens, especially when there’s some similarity between these two experiences that makes them hard to disambiguate. That’s one of the classic sort of proposed functions of the hippocampus, is this balance between the precision, the extent to which memories are precise or generalized. Because when you have a precise memory, of course you can apply it to a specific situation. But if you at the same time you also need to extract sort of generalities from your memories and learn how to apply something from one situation to something else that is similar.

Jason: And it seems in neurogenesis, one of the main ideas is that it’s important for forming precise memories so that you can distinguish one memory from the next so that you can avoid the sort of memory interference.

Steve: Sorry. I might’ve missed … You might’ve answered this and I just missed it. There’s evidently a technique by which you can inhibit neurogenesis and then these things where memories are not formed as well, et cetera, that you’re describing are consequences of that.

Jason: Yeah. So classically, before really transgenic mice took the stage, we would do this with the radiation. We’d use radiation to stop dividing cells, just like you would kill dividing cancer cells. That remains one of the most effective ways for stopping neurogenesis. Of course, radiation can have side effects. People have used anti mitotic drugs as well. But more recently there are transgenic animals where you can basically allow the brain to develop normally and then at a defined time in adulthood, kill the STEM cells that produce the new neurons.

Jason: You wait some period of time, maybe a month, maybe two months. That’s about the interval when these cells are very plastic and able to form connections. So if you wait a couple of months, you lose two months of cells that would be in this plastic stage when they’re able to learn and see do these animals have difficulties learning or remembering, retrieving memories. That’s typically how we test the function of these cells behaviorally.

Corey: In addition, I guess there are also physiological signals that mark these neurons. They’re young. They’re more plastic. But what does that mean on a molecular level? Is it that they are more susceptible to long-term potentiation? Do they create axonal connections or dendrite connections more easily?

Jason: Yeah. So they, really the first discovery was that they have a lower threshold for long-term potentiation. So this idea that when incoming connections from a neuron, an upstream neuron are active and they’re active to a certain extent, that may be what happens during an important experience, that will strengthen the connection between those cells and the downstream neurons. And with that connection strengthened, it makes it easier to essentially … Well, that’s the basis of forming a memory. The linkage of different … of two neurons that may store different pieces of information essentially. And by linking those neurons, you’re essentially linking the information and creating sort of memory.

Jason: The adult born cells have a lower threshold for that, the physiological sort of plasticity. But they also have plasticity for extending dendrites. So an experience will cause them to extend their processes outwards to form these connections. It will cause them to grow. It will rescue them from cell death. So when the cells are born, they pass through a period of several weeks when some survive and some die. And if the mouse or rat is in an enriched environment or learned something during a precise interval in those first few weeks, some of those cells will no longer die. But there’ll be rescued and suggesting that they’re integrated into the circuit and they’re needed to perhaps store that memory or that information. So yeah, they’re plastic in that they’re better able to structurally form these connections and also functionally process the incoming signals.

Corey: So I think it’s also hypothesized that one of the consequence of neurogenesis is forgetting, and the high levels of neurogenesis in childhood might explain infantile amnesia. So can you explain infantile amnesia and try to describe the evidence from linking early neurogenesis to our inability to recall?

Jason: Yeah. Yeah.

Corey: What happened to us before age three or four?

Jason: Yeah. So that’s really exciting work done by Paul Frankland and Sheena Josselyn, this story of forgetting. And people have known for years, but not really had an idea why, why do we have all these experiences when we’re children and infants that we cannot remember. And it’s striking because if you’ve got kids and you talk to them when they’re three, four, and five, you can have a conversation and they’ll remember something, sometimes from six months earlier, quite a long time ago, but then six months later they have no recollection of it. So it’s not that they can’t remember anything for a long time. They can. But a lot of this gets erased. So why, why is it this amnesia?

Jason: So what was found was that if you stop neurogenesis, actually the memories become more stable and persistent. So the idea was that you’re adding all these new cells into the circuit and you can never really … You can add a new cell and add it into the circuit and maybe it’s able to store new information. But you can’t add a new cell that can then participate in the circuitry without disrupting something else. I mean, every neuron in the brain is connected. Every influence between one set of neurons is influencing other connections and other relationships. So it kind of makes sense that if you’re adding new cells into the circuit, you might be disrupting the presence of existing memories, for example.

Jason: And even when you look at how these neurons integrate, they form synaptic connections with downstream neurons, not at entirely new sites on the post-synaptic on a downstream neuron. They tend to connect with existing connections. So there’s already a connection between the dentate gyrus where the neurogenesis happens in the downstream region, which is called CA3. And there’s already a connection there. And the new neuron comes in, and it almost like maybe hijacks that. You can see that anatomically these new cells come in and they begin to take advantage of this existing connection. They connect to the downstream portion of that existing connection.

Jason: It seems like over time it might be the old one sort of gets kicked off or maybe they butt off and they separate and they’re both still persistent. We don’t know the answer to this. But it certainly at an anatomical level seems plausible that the new neurons are coming in and kind of hijacking the system and maybe taking over to some extent. So that could lead to the turnover of memory. And we actually, because of our interest in looking at neurogenesis throughout the lifespan, we started looking, not just at neurons born in adulthood, which is when most people are looking these days. We became more interested in like what are the neurons born in development also doing because nobody’s studying them as much.

Jason: And we found that these neurons actually die throughout young adult life, not in huge amounts, but about 15% of this large population born when rats were infants. So about 15% of these cells end up dying throughout young adulthood. I don’t know if it’s part of the same forgetting process, but it could be related. It could be that the new neurons are coming in and they’re learning new things and they could be actually kicking out the old ones that have older memories that are maybe less relevant or need to be forgotten. As life circumstances change, we don’t know. But this, the idea of forgetting and turnover of memories is certainly one of the more exciting ones.

Corey: So I think this kind of points the fact that you’ve got plus and minuses to most [inaudible 00:42:15] biological developments. People were very excited about neurogenesis because it suggested the brain might be more resilient, and that as people get old, that there’s still potential for learning and rejuvenation. But, evolution made that process fairly minimal and it seems like it if it did so, it may be because there are negative consequences to significant neurogenesis in adulthood.

Jason: Yeah.

Corey: Has anybody looked at this phenomenon in older mice? Is there a way to actually spark neurogenesis later on and maybe see whether that has a negative effect on older animals?

Jason: It definitely goes down a lot with age. We’ve established that. And people have looked in older animals, not many as I mentioned, because of just mainly practical limitations and cost. That’s when it’s needed the most possibly. I mean it seems, it certainly seems evolutionarily and considering the lifespan of the organism, like most important to have it younger.

Jason: When we’re learning about the world, learning about the world we live in and sort of forming the memories that will guide our future behaviors to survive in our current inner environment, so maybe you need to be more … You acquire habits that do become efficient with age, right? Maybe you don’t need to be as plastic. You’ve got a behavioral repertoire that works, and if you’re a little inflexible but habit like, that may be good to have efficient and effective behavior and adaptive behavior throughout life.

Corey: Is there a way to actually spark neurogenesis in …

Jason: Yeah. So I mean typically it seems like the most robust method approach is exercise. And for decades that’s been shown. Put a mouse on a running wheel and neurogenesis will approximately double. Now in an old animal neurogenesis is so low, that doubling is still low. But I think that day after day after day of adding new cells, you’re adding up something appreciable. A low rate every single day for the latter portion of life certainly adds up to something substantial, so.

Corey: You actually attempt to quantify this in your paper.

Jason: Yeah.

Corey: Do you have the figures at your fingertips?

Jason: Roughly. Yeah. Yeah.

Corey: What kind of numbers you may be looking at given a certain assumed level of data?

Jason: Yeah. The human work suggests that about one point, if I remember, it’s about like 1.5% a year is added. Per day it’s a fraction, a fraction of a percent. And that’s why people think maybe neurogenesis isn’t that important in old age, or that’s the argument that has been put forth. But obviously, think about 1.5% over the course of a decade. You got 15%. People are entering old age and living in a portion of their life when memory, these types of memory functions are in decline or could be not working so well for a few decades. And all of a sudden, three decades times 15% is nearly half of the neurons maybe could be replaced or added.

Jason: So at any one moment it’s not very much, but if you can exercise and add a bit more, then I think it’s obvious that that’s a lot of new cells and a lot of new connections that could promote memory, which enhance behavior, behavior functions, for example.

Corey: The other function of neurogenesis as I recall from my deep involvement with literature about 10 years ago was in treating depression. It was thought that neurogenesis seemed to protect people against depression. Is that still something that’s commonly believed?

Jason: Yeah. It was a difficult sort of question I think back in the day because everybody’s so focused on the role of neurogenesis and hippocampus and memory, and it was people were wondering why could it be evolved also in depression. But I think as people became aware of what the hippocampus is doing more broadly, beyond just memory or how memory can play a role in the depressive phenotype, I think it’s opened up whole … many new doors.

Jason: But essentially we know that these new neurons buffer the stress response. They can help reduce anxiety levels in animals for example. But then depression is also characterized by things like reward deficits as well. And when you look at, for example, the way the hippocampus is involved in not just creating representations of the past memories, but also envisioning, creating representations of the future, it’s sort of like over the years this, the picture of what the hippocampus is doing has broadened. And if it’s needed, not just to represent past experiences but also possible future ones, and neurogenesis is important for creating these types of representations, then all of a sudden neurogenesis can potentially play a role in much more than just stress and anxiety, but also in decision making and reward behaviors that are disruptive in depression.

Jason: We’ve sort of started playing with these things and looking at the role of neurogenesis in decision making that’s disrupted into depression. And we see important, new exciting roles for it there too. So it’s not just for memory. It’s everything that memory is involved in. And that’s a lot of mental health disorders.

Corey: What kind of decision making is impaired in depression?

Jason: We got interested in this idea of episodic future thinking. And this is work that’s not peer reviewed published, but is available in a pre-print on bioRxiv and it’s on our website. And I think …

Jason: Available in a pre-print on bio archive and it’s on our website. And, I think we’re pretty excited about the finding, but essentially people have found that hippocampal [inaudible 00:48:10] can’t imagine the future. If you ask them what they see in a fictitious scene on the beach, it’s just impoverished. They maybe just see blue sky everywhere, they can’t fill it with anything. And it’s also known that when you have hippocampal damage, you’re a little more impulsive and more likely to choose something that might be rewarding immediately rather than something that’s more longterm. But by envisioning the future, you can shift your decision making such that you can prefer that sort of more beneficial longterm outcome and bias your behavior in that way. So we put rats in a task where you pit an immediate small reward against the larger delayed reward.

Jason: These are just sugar pellets. But we found that the… and this is disruptive and in depression, this sort of tendency to be myopic and preserve the sort of prefer the immediate over the reward that’s going to take more time and effort and is going to occur in the future. And our rats, if you give them the choice, they’ll take a single sugar pellet now over a larger one that they have to wait 30 seconds for. So this, we think we’re interpreting this, you know, this traditionally it would be very hard to explain in terms of a memory and what the hippocampus does.

Jason: But now that we know the hippocampus is important for thinking about the future, we think that maybe these rats that don’t have neurogenesis are not able to envision, when I press this lever, that’s going to give me four sugar pellets, I can’t quite picture what’s going to happen in 30 seconds. So I’m just going to take the one now. So we see these sorts of changes in decision making when you disrupt neurogenesis and that that sort of behavior is disrupted in all sorts of disorders. So to me that’s really exciting in terms of thinking about neurogenesis being important for all sorts of mental health disorders.

Steve: I have a question. I hope I’m not derailing Cory’s finely tuned outline for this, but since we’re on the topic of neurogenesis, are you guys familiar with something called the Pits McCullough neural, neuron or neural net? So this guy McCulloch I guess was an early neuroscientist, I guess. And I once watched a video, an old interview in black and white with him probably like, you know, it was on CBS in 1955 or something like this. And he said something very striking to me. I don’t know whether it’s true. I never know whether to believe these characters. But he claimed that by the time you’re an old person, there are gigantic holes, literally holes in your brain where huge regions where the neurons are not working. And there might still be tissue there, but it’s not actually a functional part of your brain. And he said this very authoritatively in the video that I watched, is it true?

Jason: Oh dear. Giant holes. Like, not just like the neuron size holes or like many neuron size…

Steve: I don’t think. I don’t think he gave like really specific dimensions, but he made it sound like, you know, they were macroscopic chunks of brain that were just not functional by the time you got old.


[Clip from 1969 interview with Warren McCulloch]

McCulloch: You got holes in your head. [inaudible 00:51:08] Cells have died in there. There’s literally holes in your head. Sure. Places were there used to be neurons [inaudible 00:51:15] anymore.

Interviewer: How many holes have you got in your head?

McCulloch: Oh, I suppose somewhere between 10 and 20% of the cells that I had in my brain are dead and gone.


Steve: I mean, I don’t know how he knew this. And you know, it’s my usual problem with neuroscience. I don’t know how he knew it. I don’t know why he was saying it so authoritatively. I don’t know why the interviewer didn’t just stop him and say, what are you talking about? But it’s there. It’s on the video.

Jason: It seems plausible to some extent. I mean you, I hear my colleagues talking about micro infarcts, you know, like little, you know your vasculature, it gets so fine grained. And you know, these little things get clogged. You could get like little like lesions everywhere that are hard to detect with a big brain scan. But, you know, it could be there.

Steve: Could he have known that in 1955 or whenever this video…

Jason: No, I don’t think so. But, I don’t look at human tissue that much. You know?

Steve: Yeah. It just seemed like a very, like Corey and I are being old guys are obsessed with you know, decline and aging of our muscles and brains and stuff. And so when I saw this video a few years ago, I was like, Oh my God. So there they’re giant holes in my brain that aren’t working, that used to work. But still I’m able to function barely. Is it true?

Jason: I mean certainly with dementia these sorts of things happen, but in the everyday person, I mean on the other hand we all eventually go that direction and it’s whether we fall off the cliff or not is another question.

Steve: Yeah. He might’ve meant like right near the end, you know, like when you’re 70, 80, 90 or who knows, maybe it’s not true when you’re 50 or something.


[Clip from 1969 interview with Warren McCulloch]

Interviewer: When do you start losing?

McCulloch: At the age of about 16, you can begin to see the holes and the [inaudible] are the easiest to count.

Interviewer: No way to arrest this?

McCulloch: Not that I know of.


Steve: But, that stuck in my, it was such a vivid claim, you know, if you just imagine it in your head, like that’s what’s happening to your brain as you age. I just didn’t know whether it was true, so I thought you guys might be able to tell me.

Corey: I have had a similar thought with this. You’ll hear people say things like, you know, his body had broken down but his mind was sharp as ever and I just think that’s just ridiculous. The idea that your brain is isolated part of your body is going to function like you are when you’re 30 when you’re 70 or 80 and the rest of your body is totally falling apart. I think that’s a fantasy.

Steve: Yeah, I mean, I think the way that’s usually meant, I actually have to say that in my own career in theoretical physics, I’ve watched some of the people who say, when I first knew them, when they were say 40 they were among acknowledged to be, you know, among the smartest people on the planet.

Steve: And then, I got to watch them in seminar rooms for decades de-grappling with really cognitively hard stuff for 20 years and then saw the cognitive decline, like they’re just not as sharp at age 65 or 70 as they were when they were 40 or something like. So I literally have carefully studied this subject, at least in limited population pool. But I think what’s meant by the statement you are referencing is you can’t have a situation where your body is completely ravaged, right? Your hip is messed up and you can’t walk, but your brain is still pretty sharp, right? You can’t do the work Einstein did in 1905 but you are able to process most of what’s going on and you’re able to read a novel and discuss politics and then you die. So it’s you, you can comprehend your own death very clearly at the end. And that I think that’s what people are kind of…

Corey: Well I think people actually being there being a little more Rose colored than that right where they’re actually suggesting the brain just works totally fine. It has been a lot of decline. And I think that may be the impression from the outside. Right. I think people, my mother had a stroke about 10 years ago and you know, and she said to me, even though I kind of seem normal on the outside, from the inside, you know that something’s very different.

Steve: I think you can definitely have, I mean for sure there’s decline and, and the reason I kept, the reason I emphasize this seminar room aspect of it is cause you’re forcing them to try to function at the highest level and you detect that decline. But keep in mind the same people were teaching graduate class in electrodynamics at the same time, you know reasonably well, the students were like not complaining.

Steve: They were able to actually learn the material from this person. So the person was functioning at, many of these people, at well above the normal level, but far below what they were at their peak.

Corey: And this is the functional people called cognitive reserve, right? These guys had, women had such incredibly high functioning brains at one point in time, right? If they lost quite a lot, they’re still doing very well.

Steve: But I thought, so I think you and I maybe we’re referring to slightly different aspects of it. So you’re saying it’s like great that their brain is still awesome even though their body’s messed up. And I was thinking like, isn’t it sad that your system is about to break down, but your brain is functioning well enough to you will for you to really fully understand that that’s what’s happening to you. So I guess I took the half glass full aspect of it.

Corey: Yeah, it is. So you’ve walked right in some Steve and my most intense disagreements here. I’m going to ask you to step right in the middle of a few others. So I think, you know, once you get old, you begin to worry about how to preserve your brain. I’m going to ask you a few questions along the lines of, what is best to maintain basically high function cognitive ability, assuming that neurogenesis might be somehow linked to that phenomenon. So most of the studies in rodents, in fact, I think nearly all are done on running. There are swimming experiments, but many of these claims about neurogenesis are done with the running wheel and the natural assumption without, you know, realizing that the study’s really only done in one modality is that running has some special connection to neurogenesis. And I heard early on that humans, it was the one form exercise is supposed to spark neurogenesis more effectively than others.

Jason: I don’t think people have compared other types enough to say running’s better than other things. And I don’t see why it would be, I mean, as long as I think the key is that you’re engaging in some sort of regular, intense, you know, aerobic exercise is the idea. In rodents it’s very effective. In humans, we don’t know if it’s increasing neurogenesis, but we know that it’s increasing blood flow to the hippocampus and these new neurons are born in a, it’s very indirect measure, but it’s the new neurons are added in a, you know, very vascular rich area.

Jason: And so it’s thought that this, you know, that this increased blood flow is a proxy for, you know, promoting this sort of neurogenic plasticity in humans. And even a little bit of exercise actually can have effects on recruiting the hippocampus and improving memory. So who knows exactly how it’s working. And exercise does so many things in the brain. It’s not specific to neurogenesis by any means. And we’ve done experiments to show that you can get improvements in memory and then wipe out neurogenesis and those memory improvements persist. So they don’t always depend on neurogenesis either, but it’s probably one of the best things you can do to preserve your brain and aging.

Steve: Corey, are you trying to decide whether to allocate more time to weightlifting and more time to distance running to preserve your brain?

Corey: Yeah, of course. Because as you get older, right, you lose muscle mass so you want to spend some time maintaining your muscle mass, but you want to maintain your brain. If running, it’s also a very time efficient activity. Are you familiar with the experiments in mice that were done by the physiologist, Tabata?

Jason: No.

Corey: Because, Tabata, he was the guy who really started this high intensity exercise, I think [inaudible 00:00:58:32], they call it a craze. Steve and I are both wrapped up in and what he found is that if you gave mice very intense bouts of exercise, what he did is he took a little mouse and tied a little weight to it and dropped it in water. These are basically drowning and have to basically swim their butts off to survive. You do this for a 20 seconds, give them 10 seconds off, 20 seconds, eight times, three times a week, that affect the same effect on muscle mass and endurance as having them swim for an hour, normally three times a week. So this high intense exercise has that same effect. And I’m curious as to whether maybe any evidence, again I take it the answer would be no from your previous response, for like this kind of very short term super-intense versus longer term activity as far as memory goes.

Jason: Just curious, did this person also, did they look at brain function at all or is-

Corey: They did not look at brain function, no.

Steve: It’s mainly something in the area of sort of exercise physiology and it’s made its way into like human exercise regimens. But-

Jason: The biggest compound, from my perspective would be that would be very stressful to worry about, to be exercising because you’re worried about drowning and stress is one of the biggest inhibitors of neurogenesis. I mean it can also promote neurogenesis under certain circumstances. But if you give a like Elizabeth Gould showed that if you give socially isolated rats a running wheel, running actually decreases neurogenesis, because it also increases stress hormones. But then if they run long enough, eventually the exercise overcomes the negative effects of stress, or if they’re group housed and they have some sort of social buffering, then they benefit from exercise sooner. So you know, how to tease apart the the terrifying aspects of worrying about drowning from the intense exercise would be hard. But people are looking at this. I don’t pay too much attention to all of these things because everything affects the brain too.

Jason: So you know, all the dietary claims and experiences are true. Then the way these things affect brain structure and function. But the brain is sensitive to everything. So in a sense it’s like, well what’s the longterm benefit of this? Or what does it really do? Like increasing neurogenesis isn’t always sufficient. You know, you want to show that these new cells can be integrated under the circuit and be used in a way. A rat sitting in its cage doing nothing will add new cells, just like in the rat in the wild. At some point they kind of come to some similar like equilibrium and both maybe adding the same numbers of cells, but the one out in the wild is learning so much that they’re actually taking advantage of these and then using them for some, some benefit. So I wouldn’t doubt that this type of exercise would affect neurogenesis in some way. But you know what it exactly means…

Steve: I guess we’re not even sure Corey, that that exercise induced neurogenesis in our brains is better for us in the long run. Right. Is there actually evidence for that? That’s just kind of a convenient leap of…

Corey: You know, exercise looks like it’s good for memory and neurogenesis seems like it may be good for, you know, at least mental health-

Steve: Maybe better than the alternative.

Corey: Exactly. But yeah, the cause link hasn’t been established. That’s right. So you just also signaled maybe your lack of interest or in my next question, so you know the hype is kind of hard to avoid and I think neurogenesis caught the attention of the public partly because it seemed like a way of state of cognitive decline. But one of the things that people often link to brain health and cognitive decline is diet. And so here’s something, I Googled neurogenesis and brain health.

Corey: I got taken to a webpage that made the following claims that included a claim that Steve appears to believe. Now, the claims included a diet high in unhealthy or bad fat slows down neurogenesis, but a diet high in healthier good Omega threes increases neurogenesis to a higher level. Green teas, polyphenols have been shown to increase BDNF, brain derived neurotrophic factor, which appears to be the main signal, turns on neurogenesis. They talked about blueberries being healthy for neurogenesis. Steve eats lots of blueberries every day and curcumin has a strong neurogenic effect. You signal that you actually pay no attention, probably for good reason. But I just want to… Do any of these claims ring true for yours. Anything, you know, might bear on their truth, including-

Jason: I’m not going to make any recommendations for the public district.

Corey: How about Steve’s blueberry habit?

Jason: Sprinkle some cumin on your blueberries and actually there’s another study showing that chewing increases neurogenesis. So you should probably put it in the freezer, eat frozen blueberries that have cumin on them. And then you’ll be like a superhuman.

Steve: The first approximation, we’ve said this before on the podcast because this is a recurring theme to me. To me, nutrition is because of the difficulty in obtaining decisive evidence and also the fact that we’re all genetically different from each other. You know, nutrition is a lot like a religion. You just believe what you believe in and that’s it, it’s faith-based. I’ve been eating blueberries almost every day for over 20 years. And largely because one of my colleagues at the University of Oregon, who’s a theoretical chemist, had studied the literature very carefully for things that aid your brain against cognitive decline. And he had concluded the only two things that he found the studies decisive for were fish oil and blueberries. And I just took his word for it, because I figured it wasn’t going to do any harm and I like blueberries.

Jason: I would say it’s not going to do any harm, but you wouldn’t only eat those two things either.

Steve: Yeah, I eat other things.

Jason: So we’re good. Yeah, my feeling is like just eat what your grandmother would have told you is probably healthy food and don’t worry about it too much. It’d be nice to know if things can boost neurogenesis for when we really need it. When in aging, if there is, you know, in Alzheimer’s, the first region to go down hill is the hippocampus and the area that protects to it. So you know, there might be a case for identifying things that can boost neurogenesis at that point. Like we really need to do all we can. But you know, I feel like now you’re going to do one thing, it’s going to come at the, you’re eating all of one thing, it’s going to come at the expense of something else. And we just don’t know how all these things interact at this point.

Steve: My guests from your comments is that maybe this isn’t a particular area of interest for you, but there are people that I think are intellectually pretty careful who have looked carefully at the literature and say for example, are only impressed by very large scale random control RCTs, randomized controlled trials. And so I haven’t done that work of looking through literature, but I have had people tell me who I think are careful thinkers that there is, you know, a significant amount of evidence in favor of hypothesis X, like, you know, fish oil or something like this. You know, I don’t know, maybe the state of the science is that you just can’t with high confidence to conclude anything about nutrition, but there are definitely people who believe otherwise.

Corey: I’ve read a few systematic reviews that suggest that there is evidence that fish oil is good for cardiovascular health. It seems like one of the strongest. I’d like to hear your views on what are the important questions going and where do you see yourself concentrating your laboratories, precious time and energy?

Jason: So, I mean, I think this negative report in humans, which stemmed this, you know, inspired this like lit review on neurogenesis throughout the lifespan sort of just made me really think about not just focusing all my research on new cells born in the adult, but really trying to understand how this relates to neurons born in development and at all stages of the lifespan. You know, we go through all sorts of experiences from childhood to adolescence through adulthood and all of these stages, you’re going to have new cells added in this region involved in memory that are probably going to be tuned to learn. You know, they’re going to be, they’re going to learn about all these experiences at important stages of life. And you know, for the most part, most neurons do stick around for the lifespan. So what they learn is going to shape a behavior later, you know, years later.

Jason: So I think that’s one of my main interests is seeing how are the neurons born in development different from those born in adulthood and those in aging. And this is, you know, we have some intriguing evidence that this is important because, you know, if neurogenesis declines a lot in all animals, well the question becomes, well maybe it day by day this adds up like we discussed and become something meaningful. But if we’ve never studied them when they become older, beyond this sort of critical period of heightened plasticity, you know, what are they doing when they’re older, they become silent, nonfunctional, are they less relevant?

Jason: And what we found is that even well beyond their supposed critical period, they continue to grow and develop and add plasticity that circuit. And to me this is exciting because it suggests that, well, even if neurogenesis declines earlier in humans, it may suggest that, you know, even neurons born way earlier, you know, even in childhood may still be developing throughout the lifespan and may give a plasticity throughout the life that is akin to the neurogenesis that we may observe, you know, in young rodents or something.

Jason: And maybe doing a similar function. So I think it’s trying to be a little more holistic about understanding how experiences that are early in life or later in life are shaping, you know, behavior. Because the way we behave as adults is the, sum not just of what happened five minutes ago or the day before, you know, learning where did I park my car? But it is also like, you know, was I assaulted when I was 8 and what effect did that have on my global disposition and behavior for the lifespan? I think understanding these experiences at different stages of life will be important for kind of a better big picture look at how memories accumulate.

Steve: Coming back to the very beginning of the episode, how do you think the field will process and react to this prominent paper, UCSF in nature? I mean, will it stimulate more careful studies to try to establish the rate of neurogenesis in adult humans?

Jason: I hope so. I mean, that’s what it’s doing for me. I still believe neurogenesis is really interesting and important. But it really to me focused on the fact that we don’t know what’s happening and development. We don’t know what’s happening at aging and we can’t know who we are if we don’t don’t know about these other aspects of our lives. So, but at the same time it’s a little, I kind of feel like there’s been so much pushback that people are almost ignoring it.

Steve: It didn’t really move people.

Jason: It kind of didn’t move people. And, I don’t think how this could be published and sure they may have missed something a little bit, but it’s not like they’re totally off base. Maybe they failed to detect some neurogenesis. It could be meaningful, but you know, they raised some important points and we’re almost like swaying back. It used to be there’s no neurogenesis. Now it’s like there’s neurogenesis at the cost of everything and you’re wrong if you believe otherwise. And I don’t think this binary, it’s not one or the other. I think there’s some truth to both and sort of for me it’s become more exciting because I think it’s identified areas of research, but I hope it has for others too.

Steve: It seems like in at least say in a mouse model and using sort of the gold plated method, DNA method, you should be able to estimate the rate at which neurogenesis declines with age in that mouse at least. And I’m surprised people don’t know that already.

Jason: They have done that. They just don’t, people just don’t pay much attention to it and think about it in the context of our full lifespan and… Does that sort of answer your question? Yeah.

Steve: Absolutely. Great. Well, thank you very much, Jason. This has really been a pleasure to talk to you.

Jason: Oh my pleasure. It’s been a great time.

Steve: Thanks a lot.