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Rusty Gage 5:50
Left us, um, ya know, I'm, my name is Rusty Gage, I'm at the Salk Institute and in the laboratory of genetics. For the last five years, I've also been present in the sock, but that is coming to an end on April 21 of this year. So go back full time to the lab. Work on neurobiologists, so I'm interested in generally, sort of lifespan of neurons, and how they interact with their environment, and what what influences their, their development from a stem cell through to a full, fully functioning neuron. More recently, as a result of this sort of focusing of my attention, I've been concentrating on the general concept of of aging. And we use a variety of model systems to study this. We will 10,000 years ago, we started working with induced pluripotent cells. But the problem with that is you race the epigenetic profile of the of the cells, so they go back into an infant state. So trying to study aging with IPS cells is a struggle. So we use a technology where we can directly program fibroblasts into neurons. And when you do that, you retain the epigenetic profile of the person from whom the fibroblast retain. So the fate of the cells is actually changed from fibroblast to neuron. But the developmental state of the cell, or its age, its chronological age is, is consistent and remains the same. And that's afforded us a lot of opportunities to look at that and focus a lot of attention on on Alzheimer's disease, but not regular aging, but also Alzheimer's disease, and, and other neurodegenerative diseases like Parkinson's disease. But aging is sort of the major, major thrust, we do do. Most of that in a monolayer setting. But we do mix layers of mix and matching cells together, but also use organoids. And have a variety of methods that you can drill down on, if you wish about how we approach the organoid. You're going to need technology to sort of encourage its generalizability. All is there and let you jump in.
Nick Jikomes 8:41
Yeah, why don't we just start with you know, when we think about aging, and, and cell fate, and things at the cellular level for the nervous system? You know, one of the things that's fairly unique about neurons compared to many and many other cell types in our body is they have to essentially last almost a lifetime, right? So most neurons in the brain don't divide. And so can you speak a little bit about, you know, why that is at a very basic level? And then then we'll kind of get into some of the questions around neurogenesis.
Rusty Gage 9:11
Yeah, um, well, wiser often hard, you fall back on evolution when you talk about why things are selected for because of their survival value. And so it's not so much why as a consequence of the environment that you found yourself, and that's a very general statement to avoid. The why, question, but so what's crucial for neurons, of course, is circuitry and connectivity and every neuron or many neurons have as many as 1000 or 5000 connections to them. And so if neurons were undergoing cell division, this would be a breakage of the connections between in them. So one could argue that the nervous system has evolved to a non dividing state. So that circuits could be maintained. And memories in particular, can be sustained for long periods of time. A good question is, you know, what are the molecular mechanisms surrounding that trenches transition that occurs between a, a neural progenitor cell, which has the potential for self renewal, and generation of progeny. And in Iran, and we're, we are particularly interested in that transition point. And sort of a very exciting area of research that's emerged out of this recently, we're starting to catch on a little bit is that when cells are undergoing cell division, they are in a state where they use the same sort of energy source that cancer cells use in many other dividing cells, they use glycolysis. And we should be nine years ago that, in iPS cells, when they transition from dividing neural progenitor cells using lots of glycolysis, I can go into why that would be the shift into oxidative phosphorylation over a week period of time when they stopped dividing. The advantage of oxidative phosphorylation is that you have you generate a lot more ATP. And for neurons, we think that's sort of the key to their unique function is that they have so many synapses have so much, so many activities that they can do in a static state, that they need a lot of ready ATP to do all those things. The advantage of glycolysis, though, is that, like horses can, has other shunting pathways where they don't make as much ATP, but they can make nucleotides, amino acids, lipids, so they're, they're involved in generating the bulk that would be necessary for a dividing cell. So that's a Molech. That molecular distinction in pathways is an area we're spending a lot of time in right now.
Nick Jikomes 12:31
I see. So so as, as you go from a stem cell to mature neuron, in this case, the sort of energetic and metabolic requirements of the cell change when I see. And that's presumably because you know, when a cell is dividing, you know, it's almost analogous to a baby versus an adult, right? When a baby's growing, it just has different energy, nutritional requirements, because it's, it's growing. And then eventually, it stops growing. And it needs to sort of sit in that state, so to speak, and do what it does,
Rusty Gage 12:59
yeah, and generate ATP to do lots of things that it wants to do. You know, the other analogy we use is, is this, this energy state of the stem cell, or the neural progenitor cell is very much like cancer. So a cancer cell is in the same state where it needs lots of bulk, to renew itself to divide to make more more constituents. So there, we make that analogy quite a bit. I don't know if we're gonna go in this direction or not. But I can riff off of that for a bit.
Nick Jikomes 13:33
Yeah. Before we circle back to that, why don't we just talk about neurogenesis, you know, very broadly speaking. So just define for people what neurogenesis is and how the rate of neurogenesis changes from prenatal the postnatal development to maturity in general.
Rusty Gage 13:47
Yeah, I think you're talking about adult neurogenesis, not not in vitro. neurogenesis. Yeah.
Nick Jikomes 13:54
Yeah. Like in an organism,
Rusty Gage 13:56
right? An organism. neurogenesis, as I like to encourage people is not an event. It's a process where cells and in the central nervous system, there are two locations where this occurs, Nomad and mammals. One is in hippocampus, and one is in the subventricular zone. The there are these niches that are in very specific locations, and they're quite near blood vessels. And they get in there in the dividing state, they get a lot of nourishment from the vasculature too. We've called this the vascular niche, where stem cells and they're in these niches that exist in other body areas too, as well. So they can either be in a proliferative state where they're making copies of themselves and as a stem cell. They can either self renew that means give rise to a copy of themselves. They're still pluripotent or multi potent at that stage. Ah they can go into a quiescent state or where they are silent for a period of time. And the progeny of a stem cell can also give rise to specific lineages, so that you can become a glial progenitor cell or neural progenitor cell. And these cells then can divide as a committed lineage restricted cell and give rise to themselves. And then from then they they generally give rise to one additional cell that will differentiate into a fully mature cell. And then the progeny can either continue to divide it as they'll or again go quiet and for a period of time, what's crucial about this phase where the cell is linearly committed to becoming mature neuron is there's this many interesting things going on while they're maturing, as what happens when the cell is fully mature. And so a lot is known about this in the hippocampus, where these cells are in a region of the campus called the dentate gyrus. And they have a period of time during their commitment to becoming neuron, where they're what's called hyper excitable. They, they fire action potentials at lower thresholds than mature cells. And this is in part because all the inhibition has not come, all the inhibitory contacts haven't come to the cell yet. So they have this, they're adding a sort of a new dimension or an additional dimension to the cells by virtue of the fact that they respond in a hyper excitable state, they actually can retain firing for a longer period of time. Again, we think in part because of this lack of inhibition that's coming in, they have generally four or five different inhibitory neurons that make contact with them. But ultimately, but that it takes some time for that to come in. So there's even an earlier phase where this is amazing. Where the cells will respond to GABA, which is an inhibitory transmitter as an excitatory transmitter, so it gets depolarize to GABA. So you have this cell on its way to becoming a neuron. And it's, it's responding to an inhibition by being more excited. And this obviously contributes to their hyper excitability, because even the GABA that's supposed to be silencing is causing excitability. And then they mature further, they begin responding, inhibitory Aliy, to GABA, but there's, there's not enough GABA there. So you have this extended period of time, or they're hyper excitable. In rodents, this period is three to four weeks, so from the time they're left division to they're fully mature, is about eight weeks in the rodent brain. But in primates and humans, this period is extended dramatically. So it's, I think the last paper last year in nature, suggested it was more than six months, but it had been published in primates that they're out to six months or so. But in humans, it may be even longer. So that means that this period of time, where they're they're contributing, they're hyper excitability to the to the circuitry is extended, once they become mature neurons, then they're really not different from the rest of their peers, other than the fact that they have now acquired new information during their maturation, that they can contribute to the circuit. So they'll have sort of interesting studies that have shown that if you put an animal into a novel environment, let's say and then label the cells that are born during that period of time with some deliberative die, and then you take them out, let them mature fully, and then bring them back either to the same environment or a different environment and put them the same environment, then those cells are born during that time are more likely to respond by expressing an early early MIDI gene like arc or Foss, then would be other cells. So it's as if they're time stamped with some information in them about what happened during that critical period of maturation. I don't know if that's too complicated, but it's a fun fact.
Nick Jikomes 19:48
Yeah. So so a new neuron is born, it starts to integrate into pre existing circuitry that's already in the brain. But if an animal is in a novel environment, while that's happening, the new neurons seem to be He specifically related to the novelty there, the newness of that environment.
Rusty Gage 20:04
That's right. That's that's what the evidence supports. Yeah.
Nick Jikomes 20:08
And you mentioned that this is only happening in a couple of spots in the brain, which spots? Are those again? And is this because? Do we think that there might be other spots where it's happening? Or do they require a very specific kind of nourishment from blood vessels, and there really only are a couple spots in the brain that can really harbor the stem cells. You know, there
Rusty Gage 20:26
there plenty of look back on it. There are lots of places that could be sites of neurogenesis. There is evidence that there's neurogenesis in the hypothalamus. There's some evidence that in humans, the so the second place where it occurs is in ventricles or lateral ventricles, and they migrate out to the olfactory bulb in lower animals, which have large olfactory bulbs, there's a contribution in there, they go through the same sort of period where they're hyper excitable there, and they contribute to a factory memories, that sort of thing. But there is evidence that there's some sort of neurogenesis occurring around the fourth ventricle in the hypothalamus. And then there was this surprising study where there was neurogenesis being reported in the in the striatum itself. And I think that they're migrating from the ventricle instead of the olfactory bulb, they go to the striatum. But yeah, there is also in the cerebellum postnatally up for the first couple of weeks in mice, you see that there's neurogenesis going there. But that pretty much stops in the cerebellum.
Nick Jikomes 21:46
But is the main spot for adult neurogenesis, that's the hippocampus.
Rusty Gage 21:50
Yeah. And in a particular region of hippocampus called the dentate gyrus. So that's the first site. So if you think of a circuitry where the hippocampus is receiving inputs from the cortex, so it's being alerted or brought information in from the cortex, the first place that it goes is to the branches of the dentate granule neurons, and they're just in the inner base of those is a highly vascularized area. And that's where the neural progenitor cells and stem cells of the dentate gyrus occur. And that's that sort of formation is pretty is unique to the nervous system. Despite the fact there have been observations of occurring. I think there's actually some evidence for neurogenesis in the Piriform cortex, but they never fully mature, I think they get to the state of an immature neuron, but then they I guess, they die. I haven't studied, I haven't studied that I'm just recalling to some published literature.
Nick Jikomes 22:51
And so you know, the sort of biology 101 view of the hippocampus is that it's very important for memory, generally speaking, do stem cells, do these stem cells that turn into neurons even into adulthood? Are they mostly involved in memory formation? And that type of thing? Or? Or what are the sort of main functions they tend to take on?
Rusty Gage 23:13
Yeah, the current way of describing this is that they are involved in what's called pattern separation. And what I mean by that it's a terminology used in computer logic, but you have in information coming into the hippocampus and dentate gyrus from the cortex, the dentate, is very, very densely layered. It's very packed in and what the role of the young cells in their hyper excitable state is they send their processes out to the inhibitory neurons and highlights an activated inhibition. And because they're so excitable, they inhibit a lot of the cells in the dentate and s, non random way. But at the same time, they're sending out a process that goes to this second relay station, the hippocampus called the CA three. Now, what the data show for many people have have shown us is that by a blading, or getting rid of these young neurons at critical times, if you present and this is done by Craig Stark in humans actually was he's both computational and human imaging persons. And what he has shown is that if you put people in an FMRI machine, and then present them with images, okay, so you've flashing a lot of them You know, a, let's say, an automobile, a flower, car and different objects, okay? Then those are the those are the first phase, you're just looking at it, then he presents to you another object that is either exactly the same as the one that you saw, or slightly different. And what would happens with age and disease settings that he's looked at is that you lose the ability to make the distinction between closely related objects. So.
So if if somebody says, they bring you this flower, it's the same colors of flowers. But it's sort of twisted in some way angled in some way. If you have good neurogenesis, you'd be able to see that is the same flower, but it's just oriented in different way. Whereas in then you can do these things to the mouse, where you have a touchscreen, and you'll show two images, and ask whether or not they are in the same location or the same shape. And the closer they are to one another, the more difficult it is for the animal to distinguish between them. But but they can make these distinctions between highly similar objects. But then, with, if you delete neurogenesis, you lose that ability to do the finer points and things are very different from each other, they can see the difference very easily. But it's really working on on this fine distinction. And people have done this not with visual objects, not only with digital objects, but with spatial relate spatial locations, with emotions. So if emotional things are highly charged, or have a have a big experience, or have a big impact, they're easily distinguished from each other. But if you don't have nerve Genesis, you have a harder time making the distinction. You know, it's people for the for, for from the clinical side, people have thought about PTSD, where you have somebody who's had a very bad experience, and is associated with some traumatic event, maybe a gunshot or something like that. People that have this PTSD will hear a sound or hear a something that sounds like that other one, but they can't distinguish it well. They will react as if they're experiencing again.
Nick Jikomes 28:09
So be like, if you hear a firework go off, you have traumatic experience from war, you don't distinguish the the thud from the fireworks from the battlefield that used to be exactly
Rusty Gage 28:19
and so people, physicians abused this. So the donor Genesis has been linked to depression. And that's where this whole hypothesis about serotonin reuptake inhibitors were being good for that because serotonin inhibitors increase neurogenesis over time through a particular serotonin receptor. So that's, that's one practical application of it. But it's also true that it's linked to, say, a aging and Alzheimer's disease when your your inability to recognize faces as being folks that you actually know, you know, and it gets progressively worse. You're, you've lost the ability, let's say to retain a, if you get distracted, you lose the context in which you were having an interaction previously. So you start over again, as if it was a novel event. So it has it has implications. But the general idea of people the way generally people talk about is this idea of pattern separation, being able to district and distinguish between closely related objects, emotions, spaces.
Nick Jikomes 29:44
Yeah, so you, you show an animal, you know, a blue car and a red flower. Those are very different. They're gonna have very distinct patterns. It's very easy to do that. You don't sort of need new neurons to do that. But when you show them a blue car, and then a blue car again, that's just sort of turned in different way. Those two patterns are more similar and harder to separate. And so a lot of these newly born neurons in the adult help that sort of fine scale pattern separation.
Rusty Gage 30:07
That's That is exactly right. Well said. And, and so there's a lot of work right now is, is on that circuitry, how that can be translated most of its electrophysiology and behavior. But now people are doing single cell sequencing to try to understand the molecular mechanisms that may underlie what, what are those cells actually doing? What is the event? And it's so it's a very exciting time, actually, right now, because the tools are there to do this. And, yeah, I'm glad you got that.
Nick Jikomes 30:43
Yeah. So, I mean, this is fascinating. So new neurons are coming in to these specific parts of the brain. In particular, the hippocampus, the dentate gyrus of the hippocampus is an important area where this happens. Are these newly born neurons in the adults? Are they replacing neurons that have died? Or does the brain keep sort of packing in more and more neurons throughout the lifespan?
Rusty Gage 31:06
Yeah, you got to do they keep adding new neurons. But on the other hand, it's not, it's maybe one to 2% of the cells are proliferating it in any one time. So as much as we can determine in the rodent, there is an A growing, so if you look at an early developing Rodin, for example, of a very thin layer, of dentate gyrus, so you can see it expanding over the first three months where there's lots and lots of proliferation occurring, that's still building up new memories, building up new experiences, about your environment, then as you mature, you're not going to see as many novel things in your life anymore. So the need for vast amounts of neurogenesis is, is sort of left however, what is quite remarkable is that if you expose an animal to multiple complex environments, you turn and turn into new environments, every day, for months, their hippocampal will grow even further, after an adult you can actually measure the volumetric and the number of neurons growing. So it's a process. And then the other feature of what what's manipulative, so it's as if So normally, what would happen, if somebody were in a pet, an animal isolation cage, it very little neurogenesis almost stops, if you put the animals in a cage with no new experiences. But if you move them into enriched experience, then they start dividing again. And so you can actually manipulate this back and forth by the amount of exposure that they have in their in their environment. And people are working and have published on the underlying molecular mechanisms that gets that going. And it's circulating, peptides are important, as well as neuronal activity. The other big feature that affects neurogenesis is physical exercise. So just movement alone, independently of the environment with movement comes in from an ecological perspective or evolutionary perspective, you could argue that movement is indicative of in of coming in contact with new things. So, that will stimulate proliferation and the mechanisms underlying that blood derived IGF one stimulation is has been worked out by a variety of people, but also turns out that serotonin input to the hippocampus is also you know, involved in that activity dependent increase in neurogenesis. So, so you have the flip side, you got, you know, lack of activity restrictions, you know, anesthesia, you know, just no movement, and a lack of, of visual exposure to novelty, are two of the biggest influences on neurogenesis both positively and negatively. So, lack of exercise versus exercise, environmental enrichment versus the lack of environmental enrichment. People are doing all kinds of things to like, trying different sensory stimuli. Is it just visual stimulus important? Or can you have an impact? One would argue it should be true for olfactory stimuli to because you're making distinctions between these things, but that might be for animals that might be going on in the, in the, in the olfactory bulb. But as animals became bipedal, their dependence on olfaction became has become less. So I mean, it's almost lethal to ablate olfactory bulbs and rodents and I mean, think of horses and dogs and how dependent they Aren't olfaction we are dependent. It's nice, but it's not a absolute criteria.
Nick Jikomes 35:07
Yeah, so the amount of neurogenesis into parts of the brain probably varies from animal to animal, depending on its, you know, its biology. And so it sounds like, you know, you said, so in terms of thinking about, like the things that trigger neurogenesis, it sounds like some of it comes from just patterns of activity in the brain itself, the way that neurons are firing in the hippocampus and elsewhere. Some of it comes from things that are circulating in the bloodstream. And those things change as a function of, you know, novel environments and movement and exercise and things. What are some of the key what are some examples of the sort of key molecular triggers that promote the differentiation of the stem cells into mature neurons?
Rusty Gage 35:49
Yeah, no, actually, it goes back to the my original discussion that we were having. So we do know, I'll take it this way. We do know, for example, that the serotonin activation from serotonin is the serotonin neurons of the RAF, a fire when the animals are an active setting that synapse onto the neural progenitor cells, and they activate through serotonin receptors, the activation of genes involved in proliferation, you know, CDKs, and things of that nature. So there is a biological part of it. There's also, as I said, IGF one can get through the blood brain barrier to stimulate neural progenitor cells that are near the blood vessels, essentially, their location is, is key to a large extent, because they're, they're getting access to the vasculature during those times. And what is also happening is that there's an increase in angiogenesis. So there's actually increasing of blood vessels, small, small auxiliary vessels are branching out. In these cases where you have a proliferation, or when you have running experiences going on increased, there isn't as much. I think on the environment enrichment is I know, I'm trying to recall whether or not people have shown increasing vascularization with enrichment, I guess it depends on the size, Richmond, how much move, I think it's really a movement dependent phenomenon. There, I think. So we asked her component, angiogenic component, direct stimulation from increases in cytokines and growth factors in the blood that are released as a function of movement, that there's also central mediated pathways like serotonin, that mediate it. So it's not a single event.
Nick Jikomes 38:03
And so Exercise and Movement can be a stimulus that promotes neurogenesis. You know, if there's also stuff circulating through the blood, what about just dietary components? If you just change the the composition of an animal's diet, Does that have an effect on neurogenesis independent of movement and other things?
Rusty Gage 38:23
Yeah, there's actually been a fair amount of work on that. The trouble a little bit with that, is that mechanistically, it's less well known. What is causing that, but one thing that has been repeated is this dietary fasting, intermittent fasting also increases neurogenesis. I'm not sure what that is about. But it might play a role in the this discussion we had earlier about metabolic shifts. So from glycolysis, like a living activity, and dependency on glucose for generating lactate, during the glycolytic pathway, versus sort of generating pyruvate. So it can go into the TCA cycle. So these, these metabolic elements can be affected by diet and might influence whether or not it shifts. And that's a that's a speculation on my part, but what I might I'm interested in, in following up on,
Nick Jikomes 39:31
ya know, the metabolic side of this is interesting, it makes sense that as a cell is, you know, changing what it is going from one phase of its lifecycle to another, it's naturally going to have different kinds of energetic requirements. And so there's going to have to be metabolic shifts there. So you mentioned when the cells are proliferating, they sort of use energy in the way that cancer cells do. And after all, cancer cells are really just, you know, very fast dividing cells. And so that that piece makes sense. Um, it sounds you know, when people talk about neurogenesis, we tend to talk about, you know it helping with pattern separation memory and these things. Is it always a good thing? Are there times when neurogenesis can be a bad thing? Can some of those proliferate, proliferating cells become cancer cells?
Rusty Gage 40:17
No, there's not. We looked at the while you're seeing whether we could do that generate by overexpressing cancer genes in the cells, and you can force them to do it. But spontaneously, there's not a lot of evidence for that. And even even the gliomas that people study. I'm not convinced that the evidence supports the fact that they're derived from from the dentate. area, it's more likely derived from proliferating glial cell that then has the capacity to turn rather than really a committed neural progenitor. So, but it is very interesting that, that there are no neural cancers. So once a cell is committed to a neuron, you don't see neuromas coming from that they're always coming from if anything very early development, where the neurons are still in a proliferative state. So it is conceivable, but there's not a lot in my my read of the literature, there's not a lot of evidence supporting the fact that that's a site where neuroblastomas are coming from.
Nick Jikomes 41:28
And so when the cells are sort of coming out of the, the niche where the stem cells can be nourished, they have to differentiate into neurons or other cell types. And then they have to physically get somewhere, right? Like, how are they physically moving from one spot to another? And how far do they actually travel? Is it fairly local? Or can they travel long distances?
Rusty Gage 41:51
Very, pretty local. So think of it so you had a blood vessel, trying to give you an analogy here, and the stem cells would be sitting right in the cupboard, they're getting all their nutrients, maintaining, and also, their oxygen levels are dependent upon their proximity to blood vessels. As they move away, they are less lucrative. So that's when their polyphony of naturally occurs with these nutrients and their oxygen content when they move away. So they can, you know, there's there's sort of morphological evidence suggesting that along these layers, you can you, you'll have glial cells on the base, and then you have neurons that are focusing up into what's called the molecular layer, where the dendrites all receiving inputs from the cortex. And these cells can migrate along the surface of some of these cells. But the distance that they're traveling is really not very far, it's a little lateral from the, from the vasculature, and they move up, you know, 15 microns, to 30 microns up into the ground layer. What happens, interestingly, during development, when there's such a thin layer of cranial neurons, initially, is that they're born in the base, and they, the ones that are worn earliest, they move up, and the other ones just move into the lace place below them. So it's there, they're not migrating up the top, they're coming up from the bottom. And that's been demonstrated in a variety of different ways to show that they're not really moving very far. And they're, they're laced all along the inner called the intergranular zone, which is where they they're born. But the toad listen travels, not much of their dendrites, of course, when they're maturing, their processes have to extend out over long distances, but that's a and, and the directionality of those. Dendrites, if you will, is really very important. The molecular mechanisms controlling that is well studied. And it's, there's wind signaling, which is really important for that noncanonical wind signaling. So the canonical wind signaling, the beta continued, and etc, as is evolved in the Blueford estate, but then it shifts over to the noncanonical. And that controls the directionality of the dendrites as they migrate up into the molecule layer.
Nick Jikomes 44:24
I see. So you've got this population of stem cells that live in your blood vessels, and they're sort of essentially standing in line waiting to get right up next to the blood vessel. And the ones that are right there, get all of the signals circulating the blood that might tell them to start dividing and becoming a neuron, and then the cell body the neuron does physically move but not an incredible distance. But once it gets to where it's going, the branches of the neuron do do grow outwards and upwards and a different directions to make all the connections that it needs to make.
Rusty Gage 44:57
Yeah, just one refinement is that When they're next to the blood vessels, they are in either requested or proliferative state, they're not becoming neurons, they have to move away from the blood vessel. I see. And they shift from using wind signaling went through a and those kinds of deliberative signals into the non canonical form of went where you went seven and went five, which uses for it stops the proliferative kinds of signaling at that point,
Nick Jikomes 45:27
I see. So that they really are distinct phases are different, ever deliberate. And then you turn into,
Rusty Gage 45:33
like, away from the basket, sure, we're getting all these proliferation signals, I see move into the parenchyma, where you're, you're involved more in this differentiation process. And that's where this metabolic shift is happening as well.
Nick Jikomes 45:46
Interesting. And so. So we've mentioned that the things that can stimulate neurogenesis, just novelty in general movement, probably different aspects of diet, just, you know, being exposed to new sensory information that you haven't seen before learning new skills. And it sounds like, you know, it sounds like there can be a significant amount of neurogenesis in the sense that you could see it macroscopically. So you mentioned that you can just see that, you know, the hippocampus can grow. So this be like, I know, there's a famous example of like the London taxi cab drivers have to memorize every road and fuel image their brains as they do that their hippocampus literally is physically bigger, in in the imaging pictures that you see. And so there's enough neurogenesis that it can lead to that level of macroscopic change?
Rusty Gage 46:34
Well, the concern about that study is true as it is, is that are people that are good at memorizing things and already have a big hippocampus? Are they more likely to pass the test for taxi drivers, or even choose that application, you need to do the study where you have a pre measure their hippocampus prior to even thinking about wanting to become a taxi driver, and then all that experience leading up to it. I'm not saying it's not causing that it's just that particular experiment doesn't, you know, count out the possibility there was a selecting for that kind of behavior, because you had that capacity.
Nick Jikomes 47:20
But it sounds like neurogenesis is happening. You know, it's not necessarily an ultra ultra rare event, depending on the type of experience in animals having. So like, just to give,
Rusty Gage 47:33
give you one example. Yeah, um, so postdoc in my lab, called Henrietta, Prague was the one that discovered that running could increase neurogenesis. And what you do is you inject the animal with a, with a false nucleotide called bromodeoxyuridine Yearning. And it's incorporated into the DNA of cells that are undergoing cell division. And you can stain it turns black. And so she injected the animals and ran them in a running wheel, and then looked at their brains later. And she didn't have to look under the microscope, you could see the black lining inside and, and she was showing it to everybody in the lab, that it was and it was, you know, you can you can quadruple the number of dividing cells by the some of the experiences or the the running and running, we'll just running it wasn't doing anything extraordinary, just allowing it to run was enforcing them to run. It was just allowing them to run. So that that gets to your point that it you know, it's not the whole hippocampus. It's not it's not the whole dentate. But it's adequate enough to actually see it visually.
Nick Jikomes 48:44
And does this ever go away? So if you'd if you took elderly animals to this neurogenesis ever turn off or Loli
Rusty Gage 48:51
Absolutely, and it can turn off experimentally. So if you are I mean, in your life, if you are under severe stress, it definitely shuts down neurogenesis. So there's a cortisol link there to the proliferative event. There, if you do physical restraint, if you put animals into a physical restraint, which they can't move around at all, for a period of time, that will dampen neurogenesis dramatically. So there are ways you can do this. By doing the opposite of increasing exploration or increasing activity, you can do it down that way. Some people have claimed that even depression and anxiety, those kinds of things, but that's also linked to the lack of movement, oftentimes, where people are not moving around, they're sedentary, not eating right. And so it's, it's harder to link activity of neurogenesis to a cognitive state than it is to the primary readout which would be movement or or exploration. Now, to your point it in rodents, it clearly decreases with age to the point where, so rodents have a, let's say, mice have a lifespan roughly, in captivity in captivity, you know, the way we breed them, about two years, 24 months. And neurogenesis peak would be around six months, maybe a little bit younger, combined nine months, you're definitely declining. And by, you know, 18 months is very, very little going on. However,
Nick Jikomes 50:44
what would that correspond to, and a human is six months, sort of like an adolescent and 18 is like a middle aged person.
Rusty Gage 50:51
Um, so hard to make that extrapolation. But yes, we think of two months, as a teenager, think of four month four to five months as a mature adult, and nine months. So so this is the real trick. And that is that in the wild, the half life of a mouse is nine months. Yeah. So what we're doing, we're keeping these animals alive for a much longer time.
Nick Jikomes 51:23
So six months is a fully mature adult, young adult mouse. Oh, absolutely.
Rusty Gage 51:27
Absolutely. I mean, for some people, you know, yes, that's fully mature, but then it drops dramatically over time, however, even at 12 months, 15 months, you can take them out of their isolated cage, put them into a running wheel, and increase neurogenesis again. So they're remain stem cells, many of them are quiescent at this point. And partly because they're living in these locations, you will not experience a whole lot of new things. And the need for neurogenesis. Is is not in this way. The interpretation of that would be just like when people are on when people older people, they're more sedentary, they may be bedridden, you know, they're not seeing a lot of not traveling and not seeing a lot of new things. The question that faces us is, is there a real biological clock? Where it decreases like many things? Or is this just a function of activity, and you can maintain high levels of neurogenesis if you kept experiencing new things kept physically active? And so that, you know that it's to two ways of thinking about it, but experimentally testable.
Nick Jikomes 52:51
And you mentioned before the importance of serotonin as a signal involved in the process of neurogenesis generally. So when we think about serotonin, well, what are some of the drugs that tend to promote neurogenesis? You mentioned SSRIs do other serotonin serotonergic drugs do this do other completely different types of drugs promote neurogenesis.
Rusty Gage 53:12
Um, so just just to clarify, when we say neurogenesis, you need to break it up into its its process. So if some drugs that have an impact on proliferation, so you're increasing the pool of cells, then they're drugs or mechanisms that drive the cell from a proliferative state into a differentiation state. So that's how it's best to think about it rather than saying, just a drug affects neurogenesis. It really, is it affecting the proliferative state? Or is it affecting differentiation state? And yes, so there are like I said, serotonin receptors on the neural progenitor cells that's involved in their proliferative state. And, you know, there are a variety of drugs that can be used to induce differentiation, the concern that you have there is, are you taking them out of cell cycle and driving the pool of dividing cells all into different shades of state, and you lose the pool that you're drawing from under a more natural setting? So when thinking about using pharmacology, to induce or potentiate, quote, neurogenesis, they like to encourage people to think about what is it that you really want to do you know, is it do you want to increase the pool? Do you want to increase the available cells that can go into the circuit that can contribute to an ongoing event over the next few weeks? Or are you trying to retain the pool for later later in life? You know, it's a or actually the third piece, we think even more so in humans and primates is that their fair number of quiescent cells? And so the question is, how do we reactivate those quiescent cells to bring them back into cycle, or, I'm sorry to make this even more complicated. But it's, it's not just differentiating the cells. But do you want to make sure that the cells differentiate at the right pace, because there is this concept of new yakni, where the maturation of an organ of an individual of anything is, is timed. So that you can have the appropriate amount of experience during that maturation period. Think of it in terms of your your kids, when they're born, you want to make sure that they have that adolescence and that childhood experience those childhood experiences, you want to rush them all the way through to become mature adults with all the responsibilities mature adult, when you're 11 years old, you want to make sure that they have that opportunity to mature. And it's the same with cells. And same certainly same with neurons, you want to make sure that they have that full ability to make all the appropriate synapses to make all that their dendrites get as long as they can, before they become contributing members to the to the network. And
Nick Jikomes 56:16
so you wouldn't necessarily want to pharmacologically induce proliferation or differentiation, if it wasn't also in the right context, meaning in a novel environment or in the context of learning something new.
Rusty Gage 56:30
I think that's I mean, this supposition, and but based on the accumulated data and the knowledge that that would be my approach is to think of it now in a in a in a in aging state, I think it makes a lot of sense to pull cells out of quiescence to activate the clients themselves into a proliferating state. And then, in the context of experience, you would have them naturally mature because you've increased the pool, then by giving them more experiences, they're being integrated by virtue of the experiences that they have. So it it to me, it likely strikes me that in cases where neurogenesis is stopped, due to disease, aging, anxiety, whatever the the onset is, getting the class and pool, back in cycle, and then getting the individual to have enriching experiences, makes a lot of sense. I remember talking to a clinician who dealt with PTSD and, and depression. And their view of it was that they felt that the SSRIs work best if you can link them to physical exercise, say at home clinic was making sure. And so one of the interesting things about that, and again, I'm not a clinician, but just from my, in their books and papers written about this. So it's not, I'm not making this up from porque. La, is that one type of therapy for one for after therapy is going well is in PTSD, if you if you we expose them in an in a safe environment, to that stimulus that was evoking a traumatic like event. And you expose them you give that stimulus and they react, but it's now in a very safe environment, you have multiple times, they'll they'll begin to dissociate that stimulus from the initial event and link it more to the new events that are where it's happening. That makes sense.
Nick Jikomes 59:01
Yes, yes.
Rusty Gage 59:02
It made sense to me. Yeah.
Nick Jikomes 59:04
So it's yeah, it's allowing someone to allowing that traumatic association to disintegrate and effectively be replaced by a new association associated
Rusty Gage 59:15
with a new experience, which is non threatening. Yeah. Interesting or non non harmful?
Nick Jikomes 59:23
What are some of the Are there particular serotonin receptors that are important with respect to our
Rusty Gage 59:30
AI? And it's five H team? I think it's one A, maybe one B, but you know, I would have looked it up. But I, yeah, there are very specific receptors that people have been targeting.
Nick Jikomes 59:44
Yeah. And I know that there's been some discussion, you know, there's been quite a lot of research excitement going on with respect to psilocybin and other tryptamine psychedelics, and I believe there's some evidence out there that they promote neurogenesis in animals, but I'm not quite sure is that is that true?
Rusty Gage 59:59
I Not enough of an expert in that, my understanding, and is that most of the research that's been done at a sort of morphological level shows that there's increase in plasticity of the synapse, so they can somehow open up plastic window. I'm not sure how mechanistically that has been really evaluated. I'll bet you somebody has done you know, psychedelics in a rodent? With the new labeling to see whether or not it increases neurogenesis. I just embarrassed to say, I don't know the literature on that.
Nick Jikomes 1:00:41
Okay, yeah, no worries. What are what would you say some of the latest discoveries and surprises are in in the field of adult neurogenesis, broadly speaking, what are some of the things that we've learned recently that we didn't know? I don't know. 510 years ago?
Rusty Gage 1:00:56
Yeah, I think one of the the I think people speculated that this was true, but a group in Spain has now they have this amazing, fast autopsy
situation where they can get brains from people at all different ages and different disease states. And they were the first to really show that there was a decrease in Lt. neurogenesis and Alzheimer disease that is greater than much greater than decrease of natural aging. And then that was replicated by two other groups, one in Chicago and another one in Colombia. So I think we had the idea was, well, that aging even in rodents, that that it specifically elevate or decrease more in AD. And they've gone on to have a link to microglia. So that I think is a there's one also, I think, interesting set of experience. And we didn't know, I don't know how long this is published. There's a group in Canada that believes that increase in your reports, strong evidence that we're that increases in neurogenesis, like with running or something like that can increase the rate of forgetting. And so, and they talked about the importance of forgetting, you don't want to remember everything. And but the other way of doing of saying that, and what other people interpreted me is that it's not so much they're forgetting it is they are generalizing about one event is similar to, but it's exactly not the same. So it gives you a broader focus or broader range of things, to categorize them, rather than just a very specific memory. I mean, I think for it to intuit that a little bit, think of you know, you have Yeah, here's a good example. But I don't have a good example is my best one, I can come up at the moment. So this is a clear plastic spoon, right? What's this?
Nick Jikomes 1:03:29
That is a looks like a metal spoon. Okay?
Rusty Gage 1:03:34
If you didn't have neurogenesis, one would argue that you could, you would say they're different. But really, the truth of the matter is, they're also quite similar. Functionally, they're quite similar. And one way of interpreting the importance of neurogenesis, if not only can distinguish between things, but also helps to determine the relationship between things. And that is, this pattern separation is followed by what's called pattern completion. And that occurs, we believe in the CA three, that next layer, so you're, you're separate, but they have a relationship between them. They're Linga way,
Nick Jikomes 1:04:16
I was gonna say it, it reminds me of what you were saying earlier about pattern separation. So on the one hand, in order to form a general concept, say of spoons and what spirits do, you have to be able to identify different, slightly different individual cases of spoons. And if you can do that, well, which neurogenesis you said was important for that then should also aid in the forming of just the concept or the category of
Rusty Gage 1:04:38
spoons, right? That's right. That's right.
Nick Jikomes 1:04:42
What are some of the big unanswered questions? What are some of the things that your lab has
Rusty Gage 1:04:46
talked about? So another one, I'll tell you another new observation, I think, in the human field, is that
That embryonic stem cells in the brain are have a signature. That's very much like the adult cells. So human, but those signatures are very different in other species. So there's something unique about that, then it turns out that, and this is I mentioned this too, before this concept of neon, any word? You know, it's important to go through a time period to get lots of experience before you mature. Well, an area big area of investigation right now is the fact that it differs dramatically in different species. And humans, it's much, much longer, so it takes much longer for, and this is something I've worked on many neural systems, both in vitro and in vivo, is human cells take a very long time to differentiate into fully functional cells,
Nick Jikomes 1:06:04
like weeks, months,
Rusty Gage 1:06:06
months, months. Yeah. And versus weeks in rodents. And, you know, you can go ahead and ask your question about why was that important. But I would only speculate that, that period of time, when they are maturing, they are playing a role, a special role in the function of the dentate gyrus, because they're adding this hyper excitable state in there. They're, they're doing other things. And we're particularly interested in understanding what information are they actually contributing, I'll tell you this, we just have a paper coming out where we
we went into it thinking, well, these young cells, and they're hyper excitable me, maybe they're there, if you looked at them transcriptionally. At the single cells, you're measuring single cell transcriptome for all the young cells versus the mature cells, you might guess that these young cells were expressing more genes, and a unique set of genes because they're contributing something more. But it turns out, shows that there's their transcriptionally, less active, the mature cells, which is paradoxical in my mind, but then they're also pretty young, you know, so they're, they haven't developed a full repertoire. So that transcriptional profile is reflecting something different from the mature cells. But it's given us a hook, say they are different to now we're, we're we're into this, now trying to find out what is the molecular, these pathways that are important for understanding the cells. And the paradigm is that you, you take an animal out of a home cage, individual house, okay, put them into a very rich environment where they're seeing all sorts of things for the first time. And then you shortly take single cells from the hippocampus, and you sequence all the cells. But you first sort them for the cells that responded by expressing a gene called Foss, the immediate early gene, or others that you can use, we sort those cells out and compare them to the cells in the mature dentate, that responded to the same set of same animal. And that's where you're seeing the cells did respond. But the impact of the environment on the young cells is much less despite the fact that they're excitable, whereas the mature cells have a lot more genes being expressed. Interestingly, and this is a broader issue is if you look in the CA one C three, which are other areas in hippocampus, they're their expression levels really low. They're not, they're not making much of this, a lot of the inflammation, the biggest impact is on these granule neurons, even though only a few of them are firing, the ones that are firing are are responding or responding with massive numbers of genes. So we're very excited to try to dig into this understand what that molecular information is. That is is going on. I'm not sure how we got down that road. But
Nick Jikomes 1:09:42
ya know, I was just asking about exciting new stuff that's going on more general questions. So the dentate gyrus of the hippocampus, this very important region where a lot of these new neurons go, what happens if that region is just damaged generally speaking to an animal or to a human what what kinds of problems do they tend to have? Have
Rusty Gage 1:10:02
Yeah, and actually prior to the involvement of neurogenesis, so, you know, in behavior, which really started happening in the 80s 90s, but in the 70s, and earlier, people would do selective damage to the dentate gyrus, and you do see, you know, profound profound differences, I'm trying to think of any test that was used in those days, I think was a
lot of they read a lot of maze type type of tests, let's just say that they're clearly have selected damage. It's hard, though, because this is a very complex structure, think of the hippocampus is in your brain is comes like this, and it goes up here, it's about the size of my finger. And in the middle of it is a is a band of cells that form a you that go all the way through like this. So trying to kill or destroy that curve, C shaped structure, as it winds its way through there selectively has always been sort of a,
Nick Jikomes 1:11:18
a, you can't, you can't cleanly and specifically, it's
Rusty Gage 1:11:21
very hard to cleanly do that. And the other part is that the, the rostral, and the caudal part of the structure are doing different things. The current thinking is that I mentioned that there was both an affective and a cognitive component, or emotional component and sort of learning memory. And the more rostral portion is thought to be involved mostly in the cognitive components, and the ventral, which is closer to the amygdala is thought to be more involved in the affective components. So it's different even along its route, even though it's playing the same role. Separation, one is thought to be more than the other. But I would I would
Nick Jikomes 1:12:01
imagine, in general, if you get some damage somewhere along that structure, they're going to have some kind of learning and memory or navigate. Yeah,
Rusty Gage 1:12:07
this is this is I'm sorry, yeah, this is the classic case of, you know, hippocampal losses where people think of, there was a very famous case in Canada, called Hm. Individual it had damage to one temporal lobe in hippocampus, and then had seizures and remove the other hippocampus. And the person had a very difficult time acquiring new information, it was sort of a very classic text, that's what the textbook description is, of hippocampal damage is this inability to, to integrate new information into your you have some past memories that you can recall, acquiring new memories is particularly disadvantaged in the absence of hippocampus
Nick Jikomes 1:12:58
bilaterally. Yeah, I think I remember that example from from my school days. So like this person would, after the procedure, they would meet someone new, and then you know, meet them again the next day, and they wouldn't remember that they met them the previous day.
Rusty Gage 1:13:11
That's, that's exactly right. So, but that's where the whole hippocampus were, let's say major ports and hippocampus. What's interesting as you can, oftentimes, we've been reports or there have been reports of individuals with unilateral damage, they can compensate with a single single side, which is an interesting, I don't know whether or not the clinicians have dug in deeper to that where they can actually tease out some differences between them or not, but But it's much less with a unilateral damage compared to a bilateral damage.
Nick Jikomes 1:13:43
And you mentioned earlier, I think that that you, in experimental animals, like rodents, you can just inhibit neurogenesis. In general, when you do that, what what kinds of deficits Do you see?
Rusty Gage 1:13:55
Yeah, this is where I was getting into this discussion of pattern separation where you can they can make distinctions between so let's one one of the classics is a fear conditioning test where the animals are given a slight shock in a in a chamber with certain features about it as has very distinctive features. And if you put the animal back into that, after 24 hours, they will freeze, anticipating they're gonna get shocked, right, a normal animal will breeze because they, they, when they see the first time they're wandering around sniffing, smelling, but if they put back in 24 hours in that same environment, they freeze. And if you eliminate neurogenesis, you put them back into the bathroom four hours later, and they walk around the box this they've never seen it before. So it's a they they they don't see this environment is something that they have previously seen. So it's a but interestingly, You can put them into a chamber that is slightly like this one but different. And a healthy animal will still freeze a bit. Because they're they're seeing the similarity between it. But a, a, an animal with out neurogenesis will doesn't recognize it even further without. And then if you take a put them into a chamber that is completely different. Even the animal without neurogenesis can configure that out. So it's really only looking at those events and locations and emotions. That's making a slightly different clip slightly different. Yeah, that's the sort of the nuances of life.
Nick Jikomes 1:15:48
Yeah, yeah. So again, I mean, it's this idea of pattern separation, being connected to generalization, your ability to make fine scale distinctions also impacts your ability to generalize and determine when things are part of the same category or context and when they're not.
Rusty Gage 1:16:03
Absolutely, that's exactly the way I see it. So,
Nick Jikomes 1:16:07
you know, based on everything, you've told us everything, you know, you know, everyone's always getting older, obviously, I'm sort of, I guess, early middle age, as I go through the rest of my life, what are the what are the major elements of a person's lifestyle that they can easily control that will help preserve neurogenesis and maintain it at healthy levels throughout the second half of their life.
Rusty Gage 1:16:32
For things, get plenty of healthy exercise, expose yourself to novel experiences, learn new things travel, you know, just learn things, you know, you know, acquire new information. clearly have a healthy diet. And by that this means, you know, all the things that people talking about in terms of processed food, because we know the glucose glycogen metabolic activities are key to this whole process. So metabolics is big, and you can impact metabolics, by diet, by by not dieting, necessarily, but by eating appropriate foods. And the first is to live in a social and low stress, try to keep your anxiety levels down and try to keep your stress levels down. Avoid places make you tremendously stressful, on the other hand, do a good amount of, you know, excitement and, and challenges are important, but not to the point where it's causing a release of critical restroom and cortisol levels rise in your blood. You want to keep away from those kinds of things.
Nick Jikomes 1:17:47
I would imagine, I almost see an analogy with like you said intermittent fasting can help on the diet side, it's almost like novelty, in some sense, is almost like, intermittent as opposed to chronic stress.
Rusty Gage 1:17:59
Yeah, you know, there's good stress and bad stress. Stress is a continuum too. So that's what I was trying to say exactly. Right. Is it this low level excitatory activity novelties, you know, learning a new thing, frustration of no learning a new language in the early stages or are tough but staying with it and acquiring it and builds up? And then there's sort of growing evidence that socialization is a key feature as well. So social isolation is, has been evidenced to show decreased neurogenesis as well. So highly social low stress environments are part of it. So that may be five if I separate out sort of anxiety from the social environment, but I sometimes linked those sort of things together.
Nick Jikomes 1:18:49
Interesting. Well, Professor, Rusty Gage, this is fascinating stuff. Thank you for taking the time. Is there anything else you want to say? Or maybe reiterate based on anything that we discussed today?
Rusty Gage 1:19:02
Or anything? I think not think that was was good. I hope, I hope it was understandable and recognize that many of the things that I said were my opinions or my interpretations of the data, and and there's lots more to discover. So it's, it's a great area for young people to, to get into, because it's thought provoking. And yet there's really good underlying molecular mechanisms and circuitry questions for the for neuroscientists. It's a rich, rich area in an area of importance for cognitive decline as well.
Nick Jikomes 1:19:43
All right, Professor Rusty Gage, thank you for your time.
Rusty Gage 1:19:46
Great, thank you very much. Have a great day.
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