How to grow new neurons, raise yourself and your children

Hello, my name is Vasilisa Zhukova. Welcome to my channel about brain research. Today we will talk about neurogenesis. Neurogenesis is the process of growth and maturation of neuronal cells in the nervous system. And of course this process is very active during early stages of the brain development, but also it continues afterwards and for a long time researchers considered neuronal cells as the cells that cannot grow in the adult brain. But nowadays we understand that it is not true. It is a myth. And today we have a guest on our channel, a neuroscientist from Australia, from the Brain Institute of Queensland, Dr. Tanisha Jhavari. She was one of the first people who could disprove the myth about neurons and neurogenesis in the adult brain. Hello, Tanisha. Hello, Vasilisa. Thank you so much for the kind invitation. Oh, thank you. Thank you for coming. I actually asked people in my social media what they think about neurogenesis, like the appearance of new neurons in the adult brain. And still a lot of people think that neurons cannot grow in the adult brain. And today we will explain that they actually can, but it is not always good, but sometimes it is very good. So, first of all, when I prepared to this episode, I found that the first marks of neurogenesis were discovered already in the 60s. But then this event, this phenomenon was rediscovered in the 90s. Could you please explain why it took almost 30 years to rediscover neurogenesis in the adult brain? Yes. So I think you're absolutely right. I think some of the first evidence were published by Joseph Altman and his colleagues, Gopal Das, actually. And they were working at MIT in those days. And what they did, it's almost like they challenged the dogma that was prevailing at that time. And the dogma, as you correctly said, was that no new neurons can be generated in the adult brain. And this perhaps was based on some of the initial work of, you know, the father of our modern neuroscience, Ramon y Cajal. And in his doctrine, he had basically emphasized that these nerve parts are something immutable. Everything may die, but nothing can be regenerated. And I think that view really prevailed and dominated in the neuroscience community till the time Joseph Altman challenged it. And what he did was very interesting. So at that time, a radio labelled thymidine, one of the analogs of, you know, the base pairs. So actually, the base pair itself, the radio labelled thymidine, the technique was developed where that can be administered in animals and through radio, through radiography, one can see which cells are taking up. And as you know, it's only during cell division that, you know, thymidine will be incorporated into DNA. So he provided some of the first evidence and he published a series of papers, I think, in 1960, starting from 62 to 63, 65, where especially in rodent brain, he showed that in the hippocampus, a region which is involved in learning and memory, he could see really nice cells which were positive or radiographically positive, suggesting that they were newly generated. But one of the issues of those times were that he was not able to definitively prove that these were neurons. So the thinking in the field for some time was perhaps they could be glial cells or other support cells. So there was no definitive evidence during that time. And in fact, some of those studies were replicated later on, about 15 years later. So not in 1990s, but more in 1970s by another researcher, Michael Kaplan. And he was another brilliant researcher who also showed in a series of work which backed actually Joseph Altman's data. But again, his work was dismissed. And this is very interesting keeping in mind, really, the history of science and history of especially neurogenesis, how when one tried to go against the prevailing dogma. Yes, people were not. Yeah, people were not taken seriously. And perhaps there was also sort of a dominant figure and a dominant voice in the field. He was considered one of the at the forefront of primate development. And he opposed this idea or that he could not really replicate some of the studies that Joseph Altman and Kaplan did. So I think that's where the field went almost silenced and flat. It's almost like no other people really took up that. But again, in 1990s, as you said, there was a resurgence in this field. So it was almost like the field was rediscovered. And that was perhaps because I think there were a lot of advances in the technology that were made. I mean, sometimes I feel science advances along with the technological advancement. Indeed. And in this. Yeah. And in this case, I think it was probably three major development that really reestablished the concept of adult neurogenesis in the field. The first was where there were new techniques that allowed labeling of specific cell types, in this case, distinguishing between neurons and glial. So there were definitive markers like MAP2, NEON antibodies. Those were developed. And along with that, a major other development was using the analog of thymidine, you know, BRD, the bromodeoxyridine. So that could be administered to animals. And the incorporation into the dividing cells could be read out using simple immunohistochemistry. It didn't require all the autoradiography, which can be quite tedious. I want to just explain a bit for the broad audience that in the brain, we have neuronal progenitor cells. These cells are quite similar to stem cells. It means that in a specific environment or under specific conditions, these cells can turn into neuronal cells or into astrocytes, for example. And each of these cells during different stages of their development, they express specific proteins. And researchers apply some techniques, for example, fluorescent labeling or immunohistochemistry, trying to identify cells during their development. This is how researchers can prove that this is a neuron, this is a newly generated neuron, or this is an astrocyte, for example. So they are looking for these specific proteins. Absolutely. The expression of specific proteins, which defines a particular cell type, whether it is a neuron or whether it's a glia. So as I was saying, it's the really advancement in this technology where one could use simpler methods to label dividing cells and actually read out what those cells are. That allowed researchers to actually show again, mainly in the hippocampus, initially in the dentate virus, a region of the hippocampus that these neurons are generated in the adult life. Along with that, there were also other assays that were developed in 1990s. Now that you mentioned stem cells, in fact, some of the earlier assays, which are now really famously called as neurosphere assays, were developed where you could actually take a stem cell. You know, if you take a stem cell, which, as you described, has the potential to proliferate and generate many of its cells, like of its progeny. This potential was captured in a dish where you can harvest a stem cell and provide certain factors which allow their proliferation. And if these stem cells were present, you would then start getting a cell forming two cells and four cells and eight cells and forming like a sphere or a ball. And by counting how many of these, how many spheres you get, you could actually estimate or quantify how many stem cells were present. So this cell culture assay also provided additional evidence or maybe more definitive evidence that there were resident population of stem cells in these adult brains. So this was all related to sort of, I would say, technological advancement. But at the same time, really, there was another very interesting line of research which was pursued at the Rockefeller University by Professor Fernando Nottebohm. He was very famous for studying avian song biology and how in the songbirds, the zebra finches, during the mating season where they produce song, he noticed that certain brain regions actually expand. And he then showed that that was because there was additional neurogenesis or work of new neurons happening during this learning period of the song. So this provided another angle that not only in rodents, but in other species as well, this process is happening. And I think finally, in 1990s, there were then several labs working quite intensely on understanding that if this process is indeed happening in the adult brain, is it some way regulated? You know, is it just happen at some basal level or can it can we actually enhance the production of new neurons? Can we increase it? And that's where they found that there were factors that could influence to both increase neurogenesis, but also decrease neurogenesis. So factors like exercise could increase and stress could decrease. So I think these three lines of evidence in a way solidified and the position of adult neurogenesis primarily still though are coming from laboratory animals. I have a question about technological aspects. You mentioned that it's possible to grow this organoid, so these spheres which are composed of neuronal cells. But is it possible in the petri dish to grow a brain? I'm pretty sure that many, many people can ask you this question. And I think this is this is actually where I think neuroscience in the current century is going. I wouldn't say it's possible to grow the entire brain, but I think I'm sure some of you may have heard about something called mini brains. So I think there are technologies where the cells during from the embryonic brain, like when the developing brain can be seeded and they form these organoids and these organoids actually start self assembling and they they can actually look like a little mini brain. They are not fully mature or adult brain, but they have certainly interesting characteristics which resemble early developments. And and that technology has actually been quite useful for understanding some of the disease progression, especially if they are genetic linkage to those disease progression with respect to neurodevelopmental disorders like autism. And also have become a very valuable platform to screen drug candidates. Yes, to minimize the experiments with animals. Yes. And to test it on organoids. Danish, I have a question specifically about your career. What did motivate you to go into this field? Yes, I think that's been a very interesting journey for me. So my background. So I would say a bit about where I come from. So I actually come from India. I was born and brought up in India, in Mumbai or as previously known as Bombay. That's where I did my schooling. I did my bachelor's of science, which with majoring in life sciences and biochemistry, and then did masters in zoology. And that's where I got really interested in the the developmental biology as a as a as a subject. I was really fascinated to learn about really how a single. Egg and sperm, once they fuse, how that carries the genetic information to develop the entire organism, how different parts are specified, body plan is laid, what makes the head versus what makes the, you know, the head. Yeah. So that's where I got really interested in developmental biology. And I joined the PhD program at the Tata Institute of Fundamental Research, which is one of the premier research institutes in India. And I joined the lab, which was looking at the development of the olfactory system, of the the system in the brain, which allows us to smell, you know, at this very one location. Yes. So in this lab, interestingly, I actually worked. I used the model organism fruit fly. In other words, they're called Drosophila melanogaster to study how from their larval to pupils transition and from pupil to when they become adult, how that olfactory neurons from the antenna, how they connect and wire up in the brain, you know, and how that whole what we now known as the ototopic map gets laid. So I was looking at the cellular mechanism, which means which are the different cell types involved with this and what are the molecular mechanism in terms of which are the different genes involved in laying down this plan. And this was my five years of PhD, where we made really interesting discoveries in understanding the mechanisms of how this olfactory lobe and how how the olfactory system develops. And that really led me to the interesting question from the perspective of that. I have studied the mechanisms of neurodevelopment, but I wanted to understand the mechanisms of neuroplasticity. But once this development plan is completed, what are the different elements that can influence? You know, you already connected and wired up. Yes. What makes you connected and wired up brain? Yeah. And that's where I was read about this whole process of neurogenesis. And I think it intrigued me because I was also not aware. And I thought for many years that, you know, adult in adult brain, you cannot have any new neurons. And I was surprised to read a number of papers that showed that, in fact, this is not true and you can actually generate new neurons. And that really got me into the field because I felt like this is really a form of cellular plasticity. So as to say it's and I feel it one of the extreme form of plasticity where you have to make space and accommodate new cells into a circuit which is already formed. And to think that this could be beneficial for the brain was a very captivating concept for me. And then I decided that I really want to understand how this process is regulated and more importantly, how this process can contribute to our cognition and mood regulation. Is it possible to define brain regions where neurogenesis is most active and not so active? I mean, in the adult brain. Sure. Sure. So, yeah, we know now that it's not like all the brain regions actually cannot support the birth of new neurons. OK. And what has been very well established is that the region which I referred earlier, the hippocampus, which is in in the temporal lobe, that is one of the major regions which actually support this process of generating new neurons. And this has been shown across different animals and even in humans. There is evidence supporting that. The other major region that has been shown where neurogenesis does occur is it's along the ventricle lining. So it's a region called the subventricular zone. And in rodents, at least there are stem cells which are lining that are along the subventricular zone, which can then divide and differentiate into neurons. And this is a very interesting region because these neurons don't stay there, but in fact, migrate into the olfactory bulb. Yeah. So this is like a little station of. So there is a depot of where the generation happens. But then these neurons have to migrate along what is known as the rostral migratory stream to enter into the olfactory bulb. And once they are in the olfactory bulb, a number of studies have shown that they can contribute to olfactory learning, olfactory discrimination between different smells. But they do play a very interesting role in supporting some of the basic functions of the olfactory bulb. So these are the two major regions which have been shown to be active with respect to neurogenesis. But in addition to that, there are some other regions which have also gained some attention over the years. One of them is amygdala, the center for, you know, fear learning and memory. And probably an emotional learning also. And emotional fear and learning. And in fact, we were one of the first to show quite definitively that in the rodent amygdala, there are resident population of stem cells which can generate new neurons. And we could show using modern neuroscience tools that these neurons were active so they could actually fire action potential that their basic function of the neuron. So amygdala is one of the other regions. But the level of neurogenesis or the number of neurons produced there are relatively much smaller than what's been produced in the hippocampus or in the subventricular zone. And there have been some reports that even in the hypothalamus, the center which is involved with feeding, hunger, aggression type of behavior. Hormonal regulation also. Yes. And hormone. So even they support, to a certain extent, a level of neurogenesis. So hypothalamic neurogenesis has also been shown. So I think I would say these are the major areas. There were earlier reports of neurogenesis in the cortex, you know, one of our major brain regions. But those have been quite heavily contested. And perhaps it happens only in the disease conditions a lot more than in the basal conditions, in the normal healthy situation. Can we say, since these newly generated neurons can migrate to different regions, can we say that actually in any brain regions, the new neurons can appear? Again, I think there has been a lot of controversy regarding that, because I think there are certain regions where this migration capacity is limited. But again, upon, yeah, upon injury, what could happen is some of the neurons which are already mature and differentiated can go back in time. They can de-differentiate what is known as, you know, de-differentiation. I didn't know that. Yeah. And that perhaps sometimes is mistaken as generation of new neurons, but it could be de-differentiation of neurons, especially in conditions of stroke, I would say. So I think I don't think so. There is strong evidence to support that neurons from any region can migrate into any other region, like extensive migration, I would say. Yeah, I think it's still a very restricted, very restricted migration. So I have a question about... I have a different question. Just forget it. I read that actually the average number of neurons in the brain is almost the same during the adult lifespan. And does it mean that if we have the active neurogeneration, we also have the active neuronal death? Yes and no. This is a quite complicated and a complex issue, which hasn't been, I would say, fully resolved in the literature. If you talk about just the newborn neurons, I think what has been well established is there are many more that are produced, but more than half of them die within a very short window, in rodents, within the first week. So you can produce 100 neurons and 50 of them will be already gone within the first week. So not everything survives. OK? OK. But whether the ones that survive and mature and then integrate into the circuit, if they integrate into the circuit, does it mean that equivalent numbers of other mature neurons should die or will die? And I don't think so. There is evidence supporting that. So I think the whole question about whether these new neurons actually lead to some sort of a growth over a period of time to the hippocampus, there is some evidence supporting that with some quantitative measurements. So there is an increase in cell number in the dentate gyrus, especially in animals. But at the same time, there is also a complementary or an opposite view. That suggests that these neurons, new neurons only persist. They are like a transient population. They persist for a while and then they die off. So I think I think all these theories are perhaps true to a certain extent, because I think all of this are happening simultaneously, that some of them integrate, but some of them die. So, yeah, the field is still open to provide definitive evidence in this instance. Thank you very much. I have two questions, but they are very related to each other. Are the newly generated neurons different from the neurons that were generated in during embryonic development, for example? And how do these new neurons integrate into the existing neuronal circuits? In the brain, we have like a system of neurons that work together to establish some functions. It's like a team in the work, for example. And a new neuron, like a new person that needs to integrate into the existing team. Absolutely. Yeah. It's like a little social party going on there where, you know, there are newcomers, new friends, and that they have to integrate into the existing social circle. Exactly right. So I think to answer the first question with respect to whether we think that the newly generated neurons in the adult brain are similar to their counterpart that are generated in the embryonic brain. I think we have some evidence. I think the evidence from the rodent studies, especially from mice and rats, suggests that they are highly similar, but there could be subtle differences in terms of, you know, as we know, the neurons have what I call like a tree like structure. So they have their branches, you know, the dendrites and the roots, which are like the axons connecting to the other cell. So there could be subtle differences in their branching pattern. The adult neurons may be slightly different than the ones that are generated in the embryo. But this is all really from the rodent studies. I don't think so there has been any systematic study. And I imagine that would be extremely challenging perhaps to do is to compare in the human and within the same individual, you know, whether they're in. Yeah. Whether they're neurons which were born during development. Would be very similar in the adult, unless unless there are very clear ways to isolate them or to mark them. So I feel I think what's important here to remember, though, is in a way adult neurogenesis or generating the new neurons in the adult brain is actually a continuation of a developmental program. It's a developmental program that is continuing in the adult brain in certain restricted regions. So in a way, one can think about this as this is a lifelong developmental process. This is this is a very optimistic, actually, because when I was a pupil at school and, you know, I had biology to invest in my time in our biology books, it was said that your neurodevelopment stops at the age of 24, approximately, and then neurons only die. And it was very pessimistic. But actually, it's not true. And I also found that neurogenesis declines during aging. But again, in the normal brain, it doesn't stop immediately. And is it true, Dinesha, that the learning of a principle and new things can trigger these neurogenetic processes? Oh, yes. I think there have been a number of studies in rodents using especially some sort of spatial learning paradigm or even olfactory learning. And that can enhance the production or increase this process of neurogenesis. So that's absolutely true. And that's why, you know, the correlation of the the the take home after that for humans is, yeah, make sure that you engage in new learning activities, learn new languages, solve some puzzles, you know, play games and musical instruments or musical instruments. And all these things actually help and assist our brain to maintain that plasticity process, you know, to make to make a brain really to enhance this neuroplasticity in the brain. And that includes the production of sort of new neurons. Just a beauty secret. If you want to stay young, learn new things. Absolutely. And be in the social circle. I think that is very important. We sometimes forget that we as humans are social animals. And one of the one of the factors that affect the ongoing plasticity in the brain and brain health is actually loneliness. Yeah, social social isolation. So I think ever so in this connect in this modern world where we actually like to, in a way, connect through the social media. I think it's also important to have one on one and personal connection with people to to remain active, to share stories and laugh. I think for me, I feel laughter is the best medicine that keeps you young. This is absolutely great words. And I wanted to add that it was already proved in patients with neurodegenerative diseases that if these patients were exposed to social engagement, communication, listening to music, communication with the children, especially it helped to retard neurodegeneration. Neurodegeneration, I'm sorry. So this is very important. And it is very important to understand how to help elderly population, because if we leave people alone, we almost leave people without this social engagement, which triggers neuronal death. Absolutely. I think, yeah, that is. Yeah, it's for the brain health. I feel there are a number of things that are important. Yes, social engagement is very important. Good nutrition is very important. So in terms of having healthy diet and a healthy lifestyle, like with exercise, as I said, exercise is one of the biggest, I would say, regulator, one of the largest regulator of neurogenesis. It's one of the major regulator of neurogenesis. So it really helps to exercise, helps to enhance neuronal production and their survival. So exercise is important. Diet is important. Social engagement is important. And so is stress management. I think we are increasingly, we are living in a world which has increasing levels of human stress, I would say. Absolutely. I think the stress that we see in all sorts of forms, from financial stress to social stress to even, you know, geopolitical stress that we are all experiencing at the moment with number of conflicts that are happening in the world. And this has a huge impact, huge impact on, you know, the development and the maintenance of a healthy brain. So I think one has to be mindful in terms of having ways to reduce and manage that stress level. In fact, stress has been shown to be a major negative regulator of neurogenesis. Stress can be very different. Stress can be acute. So, for example, if you have a cup of coffee and coffee is a biological stressor, you expose your body to a small portion of stress. And as a result of this stress, you have a release of cortisol. This is a stress hormone that helps to activate all your body to cope with stress or with a stressful situation. In general, this is actually a good mechanism. And to stop this loop, you need again to have some cortisol. But if we have a situation of chronic stress, for example, as you mentioned, long, very tough geopolitical conflicts that affect us all or some social social problems or lack of money or I don't know, a shitty boss. Everything can be yes. This this leads to chronic release of cortisol. It leads that your body lives in the state of permanent alarm. And as a result, your body doesn't have enough amount of cortisol to stop this loop. And it triggers actually a sequence of very tough events for your health, including the decline of neurogenesis. Could you please explain how is it possible to manage if it's possible to and how it is linked with the depression? Yeah, you're absolutely right. I think when you think about a stress response and stress circuit in the brain, it's actually a circuit which is evolutionary conserved over millions of years across different organisms. OK, and it's a it's a stress response. The the the axis, which we call the hypothalamic pituitary adrenal gland axis, which regulates our stress response and recovery is underpinning basically survival of an organism. If this axis is not functioning properly, survival of an organism is is is put in the question mark, you know. So you're right that this axis really mobilizes energy stores and it allows an organism to respond to a threat because in a threatening situation like whether you come across, you know, a snake or you have to present at a major event, these are all the acute stresses, as you say, that can trigger the release of cortisol. But again, what was a very interesting discovery in 1950s and 60s by another brilliant neuroscientist, Bruce McQueen, was that he found that there are the receptors that bind to the stress hormone in the brain. And the concentration of these receptor is highest. One of the high regions that expresses these receptors is the hippocampus. So hippocampus is actually quite a major region which is involved in regulation of stress response and recovery. And so it is by no coincidence that, you know, neurogenesis in a way and stress impacting neurogenesis and that playing a role in the consequence of the behavioral effects of stress is no coincidence. So excessive stress, as we know, can lead to neuropsychiatric conditions like anxiety, like depression. And I think what the research has shown, especially in the neurogenesis field, is this could happen by multiple different ways. One is where this chronic stress can lead to a reduction in the production of new neurons. Although the mechanism by which this occurs is not entirely clear, but we know and we have some evidence and others have published this as well to show that these stem cells actually express these stress hormone receptors. And even the newborn neurons, yeah, at certain stages during their development actually have expression of these stress hormone receptors. So stress hormone can actually directly regulate the process of maturation. And that's what we are finding. So this is a new evidence besides the evidence which is already existing in the field where they have shown it reduces neurogenesis. What we are finding is what stress does is actually alters the maturation pattern of these newborn neurons. And that actually leads to miswiring of these newborn neurons. And disturbance of neuronal circuits. And that's why that leads to disturbance of neuronal circuits. And in fact, what we have been able to show is if we eliminate these dysfunctional neurons from the circuit in mice using very selective targeted techniques, we can actually almost ameliorate the anxiety related behavior that otherwise is seen in these rodents. Is it possible to apply somehow in humans for anxiety treatment, for example? Yeah, so I think obviously translating these into humans to find pharmaceutical ways or other ways, neuromodulation ways to target this process is still, I would say, a while away. I don't think so we are there yet. But I would say there are other ways that that we can adopt to reduce stress reduction. And that is, I feel, by engaging in positive and sort of activities that bring you pleasure, whether that is engaging with music, engaging with friends, reading books or, you know, even being out in nature. I think nature helps a lot to reduce the levels of cortisol, the stress hormone in the body to regulate that. I'm pretty sure that we became very sensitive to different stressful situations. So also because we started to spend more time in the city and to spend less time in nature. So I think the natural environment certainly helps. And I think one of the other biggest regulator of our stress response is, I think, our breathing itself. I think breathing is one of the modalities which allows our connection of external world to the internal world. And I think paying attention to breath work, you know, and that's why they suggest that when you are stressed, take some long, deep breaths. You know, yes, there is a reason. Yeah. And this is why Pranayama helps. Yeah. And it helps, you know, take a deep breath and it helps. So the question is whether one can actually do this in a systematic fashion in an everyday life such that we can actually increase our resilience to stress. So rather than just managing stress, we become more resilient to stress. And I think I think the future research should really focus on understanding the neurobiological mechanisms of resilience, not just recovery from stress. And not just avoiding, because not just avoiding. About some modern methods of educating children, for example. Sometimes I think it is it is it's it can be very dangerous when you try to make absolutely ideal stress free environment for children, because we are made biologically in a way to cope with stress. We have actually resources and we it is essential to learn children how to cope, how to understand that you have resources to deal with some situations or problems in your life. Absolutely. A bang on target. And I completely believe in this, that, you know, we shouldn't be putting our kids into cotton wool and protecting them all the time. I think they have to experience stress because I think they have to get a sense, as you say, that you are equipped to deal with all the challenges. I think the modern way sometimes I feel is forgets that we can help ourselves. I think sometimes we feel the way the society works. I feel we are always trained to ask for help and we forget that we can actually help ourselves. We don't have to ask for help all the time. Yes, you ask for help when it is, you know, absolutely required. But when you understand that you don't have enough resources to cope with a problem. Yeah, that's it. But if you are equipped with that to to learn and and sort of practice that systematically in your everyday life, you are, you know, with with mindfulness, with breathing practices, spending, as I said, time in nature and and and challenging yourself with things where you require to think of strategies to cope and not only as an adult, but as a child as well. So challenging children with interesting problems where they do feel a bit of stress, but then where they can find solution and say that, look, you know, this is stress that I can manage. I can cope again with something. Yes. Yeah. So giving that in in low doses rather than not giving it at all would be a good strategy. I would like to continue with this topic about education. I found that in rodents, researchers saw that the animals who were exposed to physical activity and social engagement, as you mentioned in there when they were pups. These animals had much more developed hippocampus and then later could perform better. So it means that they learned faster than animals that didn't have didn't have this training. So can we say that if we educate children in a way that we provide them with a lot of different activities and things to learn, it makes that we create a substantial basement for their success in the future. I think there's no doubt and there's enough research supporting that enriched environment is one of the major factors regulating the brain plasticity, including neurogenesis. So if you are put in an enriched environment and that may include new learnings or new toys or new social interaction, all these things count as an enriched environment. And on the opposite side, in fact, deprivation, like, for example, in animals, I think there have been models that they have been developed to study stress, maternal stress especially. So they actually separate the pups from the mother for some time every day, just for two hours every day. And that leads to lifelong issues in those pups with respect to their emotional well-being, their affective behavior with respect to anxiety and depression. So I think enriched environment, new languages are absolutely very good for growing children and perhaps throughout life. Yes, exactly. It means that even even this, I cannot say short term experience, but still this experience leads to a long term development in the brain. And I think this is absolutely fascinating. I think I look at brain as one of the hardwares that is supporting a lot of the software, right? So I think and I think the more malleable you keep this hardware, it can support more functions. We mentioned cortisol as a hormone that has a strong impact on neurogenesis. But I also found that women during pregnancy, they had the growth of gray matter in the hippocampus and that afterwards the same woman was studied. And also they established a higher level of neurons in the hippocampus. I can't remember how it was checked. I'm sorry. But is it true that the pregnancy itself can be a very good neuroprotective and neurogenic event? Yeah, so I think I'm not I'm not sure in terms of any human studies, but I do remember a couple of years ago, there was a study that was published in Science, actually, from a lab of Fiona Deutsch. She's quite a well-known figure in the field of adult neurogenesis from University of Basel, where they studied rodents. So again, I think mice and showed that during pregnancy, there was a stimulation of a very subset, a subset of a population of these neural stem cells in the subventricular zone. Actually, the one that gives neurons sends neurons to the olfactory bulb. And this process was limited during this pregnancy and postpartum period. So it was considered a very transient increase in neurogenesis. As soon as the pups were weaned, the neurogenesis levels in the mother were back to the baseline level. So, in fact, the study showed that this production of new neurons during and after pregnancy played a very important role in pup recognition, some maternal and pup recognition behavior, because if they perturbed this process, that behavior was impacted. Of course, you have a new creature in your life. You need to have at least some like the bonding to remember and communicate with the creature. I know to bond, to bond with and especially as you can imagine with rodents. I mean, they they they produce a litter. So there are usually, you know, multiple, multiple babies that are born. And it could be in nature that, you know, there are multiple mothers who are living in a in a small dwelling. So how do they know that this pup belongs to me and not to the other? So I think perhaps this bonding requires and that's where neurogenesis certainly plays an important role in this bonding process. Now, whether something similar has been done in in humans, I'm not 100 percent sure. But yeah, I think and it was also very interesting to see that only subset of neural stem cells respond. And it's something that we have also proposed a number of years ago in the hippocampus that not all the neural stem cells in hippocampus are not all the same. There is a huge heterogeneity and differences. So depending on which part of hippocampus they reside, they can respond to different stimuli. For example, some can respond to antidepressants, whereas some can respond to hormone cortisol. How do antidepressants interact with these progenitor cells? So this has been a very fascinating area of research, something which is very close to my heart and something that we do in our lab as well. And it dates back to some of the pioneering studies that Ron Newman at Yale University did. I think it was in 2000, he published the first paper showing that the clinical antidepressants such as Prozac, fluoxetine, could enhance neurogenesis. And what subsequent studies, including ours, have shown that different classes of antidepressants can act in slightly different fashion, but they do influence both the stem cell activity. So they can actually activate stem cells, which are otherwise, you know, lying dormant or quiescent. So they can lead to their activation and these stem cells can then proliferate and generate more cells. It can also influence how these newborn neurons survive. So it has a positive influence overall in the process of neurogenesis, and some of our work has shown that depending on which class of antidepressant, some classes have a direct effect on stem cells, whereas the other classes act via mechanisms which are yet to be well understood. Is it possible that antidepressants also leads to the decline in the level of cortisol? And now like this high, this this cortisol actually doesn't intervene into natural neurogenetic events and we have recovery. Absolutely. Absolutely. In fact, almost all antidepressants have been shown to impact the hypothalamic pituitary adrenal axis, the main axis regulating the levels of cortisol. And yes, you're right that it actually does regulate that. So as I said, there are multiple mechanisms by which these antidepressants act in the brain, some of them more direct and some of them via indirect mechanisms. You told that new neurons can replace the injured neurons. But is it known which neurons, neuronal types are more susceptible to injuries and more susceptible to the death, for example, induced by the stress? OK, I think I yeah, I'm not too sure whether there are certain population of neurons which are more vulnerable, but certainly the excitatory neurons are certainly being shown to be affected. I don't know whether the inhibitory neurons which are there in the brain are also affected by stress to the same extent. They are certainly affected. But then whether there is a differential response in terms of the stress causing death. And I don't think the stress really causes death. I think what it does is it changes the the structural maturity, the structure of the neurons. So sometimes these neurons what undergo something, what we call atrophy. So their dendrites shrink. So, you know, the branching shrinks. Branches die. Yeah. Yeah. They shrink. And that leads to the changes in their physiology in terms of how these neurons would respond. So because in the end, each neuron is having some sort of an electrical activity. Right. So their function is defined by their electrical activity. And if you have shorter branches, it means that you will have less contact. They will have less contact with other neurons. And also the timing of their activity will be disturbed because in the brain, it's all about the timing as well. Timing plays a very important role in terms of when the signal arrives, when the neurons fire, and if they don't fire in certain patterns, that can be problematic as well. Thank you very much, Danisha. So we need to conclude our, I think, wonderful discussion. Could you please name three things that help you to to develop in science and to that help you just in your life? Three things. Three things. Wow. This is This is it. They can go on. For me, I think science is all about having patience and perseverance. It's a slow process. Discovery process is a slow process. It doesn't happen overnight. And I think if one wants to make real contributions in scientific field, one has to be patient, but one has to persevere. I think the second thing which has helped me a lot is you just have to work hard. I don't think so there is any easy way out in science. But I think the most important thing for me is having that determination, having that vision. You know, vision to be one of the best vision to make a contribute something new to the field and have that taste for original contribution is something that, you know, I have aspired and I have strived for. So I would say, yeah, patience and perseverance, hard work and determination are the elements that I feel really help the making of a scientist and the scientific career. Thank you very much. I think I totally agree with it. And we started our episode with talking about people who had to go against dogma. And yes, science always means to be to be a very strong person. Yes. Yeah. Be strong. Yeah. And at the same time, be ready to accept that you could be wrong. I think that is also very important. This is a very important form of strength. Yes, it is. You propose a hypothesis, then if you disprove it or you study and you have some evidence, but later on, you basically say that this was probably not true, because now we have further evidence to suggest that this is the way. I think to be open about the fact that you could be wrong, I think is another great characteristic of being a scientist. Thank you very much, Dinesh.