Introduction/ Introduction
Are there still newborn neurons in the adult brain? This issue has long been controversial. Citing the latest research results, Yang Zhengang, a researcher at the Institute of Brain Science of Fudan University, pointed out that there are no longer newborn neurons in the adult brain. He also shared some of his experiences and experiences in life science research.
When we grow up, are there any newborn neurons in the adult brain? This is a very important issue and one that is hugely controversial. The latest experimental evidence in 2021 gives us a relatively clear answer: there are no newborn neurons in the constellational brain region of the adult brain. Next, I will briefly explain the ins and outs of this problem.
Research background
Will the adult brain constantly produce new neurons? This problem, for most people engaged in brain science research, is generally believed that there will be no new neurons in the adult brain. This is based on the simple logic that if we can constantly produce or replace new neurons in our adult brains (a process commonly called adult neurogenesis), just like our blood system, constantly renew (red blood cells live 120 days, white blood cells live less than 2 weeks, platelets live 10 days), then the neural circuits based on storing our memories will cease to exist or will be very unstable, and human beings will not have a splendid civilization.
However, in 1998, an article published in the journal Nature Medicine (Eriksson et al., 1998) showed that specific brain regions in adult brains, such as hippocampal brain regions and olfactory bulbs, similar to adult mice, can constantly produce new neurons. The authors examined the brains of those who voluntarily donated their bodies after death, and found "signs" of newborn neurons in the hippocampal dental gyrus of 5 different ages (57, 58, 67, 68 and 72).
The article caused a huge sensation and has been cited more than 8,000 times since its publication. One of the reasons for this is that for nearly 30 years, neural stem cells have been a hot topic in brain science research, and research related to neural stem cells is very active; second, there are newborn neurons in the adult brain, which is a completely new concept, enough to subvert traditional ideas. The previous idea was that after we humans are born, the neurons in our brains will accompany us throughout our lives and cannot be changed or replaced. The third reason for the sensation is that the hippocampus itself is a key brain area involved in learning and memory, so whether these new neurons of the hippocampus are involved in adult learning and memory, emotional regulation, and whether nerve regeneration after brain damage, etc., these possible functions make workers engaged in brain science research think about it.
However, after the publication of the article in the journal Nature Medicine, it also caused some people to think and doubt, after all, the article only saw possible "newborn mature neurons" (BrdU/NeuN double positive cells) at that time, but did not see the immature neurons that had just been born. Therefore, the evidence provided by this article is missing a link, because from neural stem cells to neural precursor cells, to immature newborn neurons and mature neurons, it is a complete chain of evidence, indispensable.
Are new neurons produced in the adult brain?
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Interpretation of new evidence
In March 2018, 20 years after the publication of the article in the journal Nature Medicine, the journal Nature published an article that contradicted its conclusions (Sorrells et al., 2018), which showed that neurogenesis exists within the hippocampus of adult macaque monkeys and declines with age, and in the 23-year-old macaque hippocampal brain region, there are very few newborns of truly mature neurons.
Subsequently, the authors studied the hippocampal tissue of people of different ages (from 14-week-old fetuses to 77-year-old human brain tissue, a total of 37 specimens), and found that there were a large number of newborn neurons in the hippocampal brain region of newborns, but then the number of newborn neurons decreased sharply, at about the age of 1, there were only a small number of newborn neurons in the hippocampal brain region, and by about the age of 13, the number of newborn neurons was very small, to about 35 years old. It is generally difficult to detect newborn neurons (DCX and PSA-NCAM double positive cells). Through a series of analytical studies, the authors concluded that there are almost no newborn neurons in the adult brain (or almost difficult to detect).
Of course, realistically speaking, although this article has done its best and made a relatively comprehensive analysis, it also has its own certain defects: the markers of newborn neurons used in the article are limited, basically relying on immunohistochemical staining and electron microscopy. Despite this, this article in the journal Nature also caused a huge sensation after publication, the article has been cited nearly 1,000 times in the past 4 years, but it has also caused a lot of controversy, and there is still no complete consensus in the field.
Figure 1 The upper row of this figure shows the brain slice of the hippocampal dental gyrus of a 7-year-old macaque monkey (low-fold); the lower row shows the newborn neurons of the hippocampal-toothed gyrus in the brain of a macaque monkey (high-magnification). These newborn neurons all express both dcx (green) and PSA-NCAM (red) proteins. This is a very critical indicator of whether there are newborn neurons in the adult brain. Such cells are not found in adult brains (staining results published earlier, which many peers believe are inaccurate).
In 2021, the journal Neuron published two articles on single-cell nuclear RNA sequencing (snRNA-Seq) in the adult hippocampal brain region. The first article (Ayhan et al., 2021) sequenced 130,000 single cells from patients ages 24 to 60 using hippocampal tissue excised after surgery in epilepsy patients, and found no real newborn neurons. The second article (Franjic et al., 2021) sequenced 220,000 single cells from hippocampal tissue in people aged 48 to 79 years old, similarly finding no trace of newborn neurons.
Since scRNA-Seq (or snRNA-Seq) is a powerful tool, 1000-4000 genes can often be detected simultaneously within a single cell. Therefore, in the data of single-cell omics, no new neurons were found, which is very convincing. Originally thought that the conclusion that there are no newborn neurons in the adult brain has been basically clarified in 2021, but according to the feedback of peers, there is still no consensus on this issue. In the same way, magazine editors generally give them an equal opportunity to publish their research papers on both sides of the same coin.
So, do the adult brains still have newborn neurons? Based on these new data, the author also has a new interpretation. That is, it has been proven that the neural stem cells of the hippocampal brain region of adult mice are the neural stem cells of the embryonic mouse hippocampal brain region, and the newborn neurons they produce have strong common characteristics. Thus, the process of adult neurogenesis in mice, from neural stem cells to neural precursor cells to immature newborn neurons and mature neurons, is a complete chain. This phenomenon is the same for the human fetus (and newborn) hippocampal brain region and the newborn macaque (and juvenile macaque). Only in the equestrian region of the adult brain, from nearly 350,000 cells, this group of cells with the molecular characteristics of embryonic or juvenile newborn neurons could not be found. This largely explains that there are no newborn neurons in the adult brain. We have reason to believe that as more and more data on scRNA-Seq appear (more than a million single cells are sequenced), the question of whether there are newborn neurons in the adult brain may soon be completely solved.
- Alexey Kashpersky -
Significance of the study conclusions
The author believes that the so-called adult neurogenesis may be a misleading concept. The real concept is that adult neurogenesis is the continued development of some brain regions after birth. Therefore, adult neurogenesis can be called postnatal development. For example, the granulocytes of the cerebellum continue to develop after birth, but soon the development ends. The development time of the hippocampal tooth phylloscopus is slightly longer after birth, the peak period is only 2-6 months, and the vast majority of mammals are basically all over in about 1 year after birth. Olfactory bulbs develop relatively longer after birth, but there are almost no newborn, truly functional neurons in the olfactory bulbs of the adult brain.
The so-called adult neurogenesis of mammals is not something that begins in adulthood or is acquired, but a process that decreases after birth. This phenomenon is in the same vein as neurodevelopment, and there is no interruption in the middle. On the contrary, for example, young children learn language, learn to walk, learn to think logically, etc., are acquired. Adult neurogenesis is more like fetal development, young child growth, from the embryonic stage to adolescent to adulthood, growth is slower and slower, and finally stop. Again, adult nerve occurrence, in the final analysis, is the continued development after birth, since it is development, there is no reason not to stop. All things have a beginning and an end.
Because modern laboratories often need to spend a lot of effort to apply for funding, which is closely related to the survival of the laboratory, so those who are engaged in adult neurogenesis, even if they are likely to have understood, and they also believe that there are no newborn neurons in the adult hippocampal brain region, this research is actually of little significance, but they choose silence for the sake of funding and survival. Of course, many of these people are now simply not making body nerves.
Therefore, in the face of the question of whether there are newborn neurons in the adult brain, the world actually no longer needs to invest in large-scale research funds. If at this time, there are still people who insist on investing heavily in huge amounts of money and manpower and material resources to continue to study this topic, and even study the relationship between newborn neurons and learning memory in the adult brain, the relationship with emotional disorders, or the relationship with nerve repair and regeneration, then please first carefully read the literature, seriously analyze the existing data and spend a lot of effort to think, and then decide whether to start acting.
Taking a step back, even if only occasionally a very small number of newborn neurons have been found in the adult brain, the function of these newborn neurons may be minimal compared to the 86 billion neurons in the human brain. In addition, the stability of the nerve circuit is crucial to its function, which is different from the regeneration after cutting the skin, the healing of fractures after trauma, or the self-replacement of blood cells.
- Vova Brown -
Some insights
Here, I take this opportunity to give my colleagues engaged in life science research, especially young people, to focus on some of my own experiences, suggestions and feelings over the years of my work, because everyone in the process of exploring the unknown world, there will always be some detours, some lessons, of course, successful experience.
Figure out the relationship between stem cell biology and developmental biology
Stem cell biology, including stem cell research, cell transdifferentiation, inverse differentiation, tissue regeneration, organoid neurogenesis research, etc., all belong to the category of stem cell research, which is essentially a division of developmental biology. Therefore, stem cell research must not be separated from developmental biology and its basic scientific laws. Otherwise, the research of stem cells may be water without a source, wood without roots, a castle in the air, a mirage.
Taking hippocampal neurogenesis as an example, the source of neural stem cells in mouse hippocampal dentate gyrus is now clear. It has been clarified that these neural stem cells do not appear suddenly in the hippocampal brain region of adult mice, nor are they pie in the sky. Instead, they share the same embryonic origin as the group of neural stem cells that are dentate back to development, completely in the same vein, and follow the same developmental laws.
In addition, the results of stem cell research in vitro are best repeated in vivo. Conclusions drawn in vitro studies are often more credible than those drawn in vitro.
Figure out the relationship between dry and wet experiments
The relationship between dry experiments and wet experiments is the relationship between fur and skin. If the skin does not exist, the hair will be attached.
People who do bioinformatics (dry experiments) can never leave the cooperation of their peers who do wet experiments (bottles, cans and reagents every day, basically wet things). It is not recommended to blindly sequence for the sake of sequencing, and to publish articles for the sake of publishing articles. The person who does the raw letter should preferably be born to do wet experiments in itself, and at least need to be a doctoral level. The basic paradigm of cooperation between dry experiments and wet experiments is that important scientific questions are first raised by people who do wet experiments, and then people who do dry experiments provide data, and then analyze them together, and it is best to do some solid wet experiments to verify. Otherwise, pure dry experimental data analysis can be very inaccurate.
Emphasis is placed on the relationship between the biology of individual molecules (genes or proteins) and the biology of systems (organisms).
Again, in the case of neurogenesis, in the hippocampal brain region, the same signaling molecule can be used many times at different times, in different locations (hippocampal headquarters and dentate gyrus), and even play different roles. In the process of development, neural stem cells in the same place have always faced a variety of signaling molecules at the same time, and then at a specific time, they make a corresponding choice (choice) for their own proliferation and differentiation.
For example, the Wnt signaling pathway is important for early hippocampal development, but in the hippocampus of adult mice, β-catenin-mediated Wnt signaling is not important for neural stem cells. Knocking out the β-catenin in the Wnt signaling pathway had little effect on adult neural stem cells, because other signaling pathways dominated during this period. However, it is worth noting that mouse adult neural stem cells still respond to the high concentration of foreign Wnt molecules in the non-physiological state, which is the imprint left by the embryonic development period, and this response also follows the basic laws of the hippocampal development period.
In short, from Mendel's laws of genetics, Darwin's theory of evolution, to James Watson and Francis Crick's model of the structure of the DNA double helix, have been strongly demonstrated that the life sciences, like other natural sciences, have strong logic and laws. Of course, this is also the consensus of our peers.
Therefore, life science research must not be "philatelic". A person's early research results may look similar to "stamp collecting" and do a little bit of superficial bits and pieces of research, but considering the problem from the overall point of view can not change, the long-term goal in their heart can not change.
- Tania Yakunova -
Remember the relationship between scientific inheritance and scientific innovation
Scientific research is first of all the study, accumulation and inheritance of scientific knowledge. Contemporary young scientific researchers have stopped following the old ways, sticking to the rules, and no longer blindly worshipping those who have talent hats. On the contrary, they all have very open minds, and minds that accept new things, and they also have a strong desire to overthrow traditional ideas in a certain field. However, it is very difficult to achieve this goal. The accumulation of scientific knowledge cannot be achieved overnight. Contemporary biology, in particular, has published so many and dizzying articles that every young person needs to make a big splash in the vast literature and remove the false from various data (such as the proposition of the new neurons of the human brain). To reach this level, it is very demanding for everyone's usual training! So, first of all, stand on the shoulders of giants (accumulation of knowledge). Only by having both ability and political integrity can we innovate.
One ambition, two preparations
Young people engaged in and love life science research must be prepared to run a marathon, "the bench must sit ten years cold." At the same time, if there is an opportunity, you must also be ready for the 100-meter sprint at any time.
Compared with other fields (such as sports, music, finance, etc.), in the field of life science research, like James Watson's discovery of the DNA double helix structure model, the world war was sealed, and he became famous at a young age, which is very rare (Watson discovered the DNA double helix structure at the age of 25 and won the Nobel Prize at the age of 34, but, in fact, the discovery of the DNA double helix structure also underwent a process of accumulation, innovation and sprint). On the contrary, like Mendel, after more than 30 years of death, the great laws of genetics discovered by himself, this scientific discovery that flashed the light of human wisdom, were widely recognized internationally, and this situation is also quite common.
Life science research is important to persevere, and it cannot be abandoned halfway. It is not advisable to shoot a gun to change a place, what is hot to do, and to change the research direction frequently. Similarly, if you do one thing for ten years, persevere, and work hard for a long time, then success is not so difficult.
For our ambitious young researchers, then, it is necessary to ask ourselves to do high-level free research from the first day of scientific research, to target the most important problems in the field. We must dare to face the most important topics, resolutely do not do those dispensable research, and do not simply pursue the publication of the number of papers. In the process of pursuing and solving important problems, we have developed a real skill. In this way, you can always listen to the call of the country, have the ability to form a strong team to collectively tackle key problems (teamwork and collaborative research around important scientific problems and national strategic needs in today's world), and even sometimes require a 100-meter sprint (such as COVID-19, vaccine research).
Finally, I would like to conclude this article with a quote from the famous Soviet book "How Steel is Made." "A man's life should be lived in such a way that when he looks back, he does not regret having wasted his years, nor is he ashamed of his inaction. In this way, on the verge of death, he was able to say: 'My whole life and all my energies have been devoted to the most magnificent cause in the world— the struggle for the emancipation of mankind.' I think that this passage will definitely have a positive impact on the young scientific researchers of our time, encourage them to do great things, discover important scientific laws, invent new science and technology, and thus make new and greater contributions to the development and progress of human civilization! This is the unshirkable mission of a scientific researcher with a sense of family and country, such as you and me.
bibliography
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Eriksson, P.S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., and Gage, F.H. (1998). Neurogenesis in the adult human hippocampus. Nat Med 4, 1313-1317.
Franjic, D., Skarica, M., Ma, S., Arellano, J.I., Tebbenkamp, A.T.N., Choi, J., Xu, C., Li, Q., Morozov, Y.M., Andrijevic, D., et al. (2021). Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron.
Sorrells, S.F., Paredes, M.F., Cebrian-Silla, A., Sandoval, K., Qi, D., Kelley, K.W., James, D., Mayer, S., Chang, J., Auguste, K.I., et al. (2018). Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature 555, 377-381.
Author: Yang Zhengang | Cover: Nydia Lilian
Edition Editor: Lucas | Typography: Light and shadow
The original article is reproduced from the public account "Intellectuals":
https://mp.weixin.qq.com/s/tvrGuusgAgoBqIIufv9kPA
This article was first published on January 10 in ID The-Intellectual and reprinted with permission. Sponsored by the Beijing Haidian District Intellectual Frontier Science and Technology Promotion Center, a non-profit public welfare organization, intellectuals are committed to paying attention to science, humanities and ideas with the mission of disseminating scientific knowledge, promoting the spirit of science and promoting science and culture.