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Why can't neurons undergo cell division?

Why can't neurons undergo cell division?


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Many cells in the human body can divide and reproduce, making healing possible. Neurons, however, cannot reproduce, which makes diseases affecting the brain particularly crippling. Why can't neurons divide - that is, what makes them different from "normal" cells? Are there any ways to artificially stimulate neuron cell division?


Neurons do not divide due to the reasons mentioned in Cornelius's answer. However, some new neurons can be generated in adults (Ref: Neuroscience, 2nd edition).

Generation of new neurons in adults was first demonstrated in birds, where labeled DNA precursors could be found in differentiated neurons. Experiments in mammals and humans demonstrated later that new neurons are created in the central nervous system (CNS) in adults, although it seems to be restricted to some particular regions: granule cell layer of the olfactory bulb and dentate gyrus of the hippocampus. These new neurons seem to be local circuit neurons and interneurons (i.e. no long distance neurons).

How are the new neurons produced if neurons cannot divide? They come from neural stem cells (NSCs) that were preserved in the sub-ventricular zone during development. NSCs are presumed to play a part in brain plasticity in the adult brain. However, they have therapeutic potential. Check the brief information in wikipedia), or this perspective in Nature neuroscience that may contain further details.

References:

  1. Neuroscience, 2nd edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.
  2. Gene therapy: can neural stem cells deliver? Müller FJ, Snyder EY, Loring JF. Nat Rev Neurosci. 2006 Jan;7(1):75-84. Review. Erratum in: Nat Rev Neurosci. 2006 Feb;7(2):167. PMID: 16371952 [PubMed - indexed for MEDLINE]

Morphological point of view

Neurons cannot divide because they lack centrioles.

Because centrioles function in cell division, the fact that neurons lack these organelles is consistent with the amitotic nature of the cell [1].

Functional point of view

New cells in the nervous system wouldn't do any good. The whole nervous system is based on interneuronal connections, so adding an extra neuron would mess up these connections and alter both the functionality and the "stored" information.

Each nerve cell has a specific place in our nervous system. Its job is all about taking a signal from one specific place to another one. Adding new nerve cells would mess up these very specific connections in a very complex system [2].


References:

  1. SEER Training. NERVE TISSUE. Available from http://training.seer.cancer.gov/anatomy/nervous/tissue.html
  2. UCSB Science Line. Available from http://scienceline.ucsb.edu/getkey.php?key=1710

I would like to propose an "answer" from a personal belief (no sources) based on an evolutionary approach to this question.

If neurons were readily capable of division, that is, healing, they would require a different form, thus mandating a different function; ultimately, they would be less efficient at what it is they are supposed to do (transfer electricity)--thus, not advantageous for the organism (during the evolutionary period); thus, did not occur.

Think of this for a moment: in physical space, what would happen to the other neurons if one were to divide? It would push into them, possibly 'disconnecting' a pathway, or impairing it's ability to fire (possibly below the activation threshold)--a whole new host of diseases could emerge.

Perhaps plausible, there was at one point something similar to what I've described above (a mitosing nervous system). The question is, though, would it be more efficient than a non-dividing nervous system? Would it have fewer diseases?


This colourful picture (Figure 8.3.1) could be an abstract work of modern art. You might imagine it hanging in an art museum or art gallery. In fact, the picture illustrates real life — not artistic creation. It is a micrograph of human nervous tissue . The neon green structures in the picture are neurons . The neuron is one of two basic types of cells in the nervous system. The other type is the neuroglial cell.

Neurons — also called nerve cells — are electrically excitable cells that are the main functional units of the nervous system . Their function is to transmit nerve impulses , and they are the only type of human cells that can carry out this function.


Scientists discover how epithelial cells maintain constant cell numbers

Research published in Nature from scientists at Huntsman Cancer Institute (HCI) at the University of Utah shows how epithelial cells naturally turn over, maintaining constant numbers between cell division and cell death.

Epithelial cells comprise the skin and skin-like linings that coat internal organs, giving organs a protective barrier so they can function properly. Cells turn over very quickly in epithelia. To maintain healthy cell densities, an equal number of cells must divide and die. If that balance gets thrown off, inflammatory diseases or cancers can arise.

The study leader, Jody Rosenblatt, PhD, investigator at HCI and associate professor of oncological sciences at the University of Utah, says, "If too many epithelial cells die, you can lose the organ barrier function and inflammatory diseases like asthma and colitis can result. On the other hand, if too many cells divide compared to the number dying, this can cause an overabundance of cells, which can lead to tumor formation. So imbalance on either side is problematic."

Around ninety percent of cancers arise in the simple epithelia that coat the organs. Understanding what normally controls cell division and death, and how these processes are linked, is essential to understanding how these events become misregulated to drive cancer formation. While scientists had previously studied cell division and death in response to experimental triggers, how these processes naturally occur was less clear.

The HCI team discovered an answer to this puzzle. They learned that opposing mechanical tensions control both cell division and cell death. Specifically, they found that stretching epithelial cells causes them to divide, and crowding epithelial cells causes them to expel and die.

"We knew there had to be some kind of regulation to tie the death and division processes together," says Rosenblatt. "What we found boils down to really simple principles. It's all mechanical tension. If the cells get too crowded -- 1.6-fold more crowded -- then they pop some cells out that later die. The extrusion of cells enables the cell sheets to return to densities they like."

On the flip side, researchers noticed that cells divided in sparser areas. They realized those sparse regions were creating a tension on the cells to stretch.

"If the cells become too sparse, then they activate cells to divide -- and that signal to divide comes from mechanical stretch," explains Rosenblatt. "To test this, we stretched cells and found that stretch could trigger cells to divide within only one hour! The process also showed us that stretch is a normal trigger for cell division."

Rosenblatt's team analyzed human colon cells, zebrafish cells, and dog cell cultures. The places where the cells divided were always more stretched out -- 1.6-fold more stretched out, just like the ratio for cell death.

The next question was figuring out what caused these processes to happen. Rosenblatt's team discovered both cell division and death were controlled by the same protein, Piezo1.

"Basically this same protein is sensing both crowding and stretch -- but the outcome is very different, depending on what state the cells are in," says Rosenblatt. "Piezo1 is sort of like a thermostat, regulating two different sides. Just like a thermostat regulates both heat and cold, it makes sense to have one sensor measuring crowding and stretch. If there were two separate regulators, things could get out of hand fairly quickly if one sensor breaks."

In addition to understanding how Piezo1 is involved in regulation, Rosenblatt's team also identified a stage in the cell cycle where cells sit paused for repair.

"We had always assumed that once cells start a division cycle, they just power through. We didn't know that they take breaks throughout the cell cycle," explains Rosenblatt. "But we found a point where the cells were just stalled, waiting to divide. A lot of things need to happen for cells to divide. The DNA needs to replicate so it can divide in half, providing each new cell with the same DNA as the parent. These cells have everything ready to do that, but they still pause there at a step that we did not expect to be regulated. Cells could be paused waiting to reach a certain size. Once they reach this size, stretch triggers them to divide."

With the insight into how cells normally divide on their own, Rosenblatt believes scientists will have better insight into how epithelial cells divide when they shouldn't, like in cancer.

"By understanding how cell death and division are normally regulated," she explains, "we are discovering new ways that these processes go wrong -- especially in diseases we don't currently have treatments for, things like asthma and metastatic cancers."


Does your brain produce new cells?

Here's the original draft of a feature article I wrote for New Scientist, about adult neurogenesis in the human brain. You'll need to register in order to read the magazine version, but registration is free and only takes a minute.

Neurogenesis refers to the production of new nerve cells. Everyone wants to believe the human brain continues to produce new cells throughout life, but as you'll see from the article, the evidence for this is thin on the ground, and several prominent researchers are very sceptical about it.

I'm sitting at a long lab bench in the MRC Centre for Developmental Neurobiology, peering down a microscope at the hindbrain of a three-day-old chicken embryo. Earlier, the egg had been injected with bromodeoxyuridine (BrdU), a compound whose structure resembles that of thymidine, one of the four main components of DNA, and which is incorporated into newly-synthesized DNA.

The embryo was then removed, the hindbrain dissected and treated with an antibody that binds BrdU. Now, split along the top and splayed onto a glass slide, it appears subdivided into eight compartments, each revealing its newborn cells with their DNA stained dark brown.

Andrew Lumsden, the centre's director, explains that each segment expresses a unique combination of patterning genes and that the segment boundaries restrict the movements of immature cells. Neurons in each segment acquire a unique identity – those born in the front segment coalesce to form the nucleus of the fifth cranial nerve, while those further back form other cranial nerves.

At this developmental stage, the nervous system is a hollow tube running along the embryo's back. Its walls contain wedge-shaped cells that divide near the inner surface to produce neurons that migrate outwards. This occurs at different rates along the tube, producing three bulges at one end, which eventually form the brain. Successive waves of migrating cells populate the developing brain to give the cortex its characteristic layered appearance. Upon arrival at their destination, they differentiate into the brain's three main cell types – neurons, astrocytes and oligodendrocytes – then sprout connecting branches to form functional tissue.

Fountain of eternal youth?

For much of the past century, it was thought that the production of new neurons – neurogenesis – was restricted to embryonic development. "Once development was ended," wrote Santiago Ramón y Cajal, the father of modern neuroscience, "the founts of growth… dried up irrevocably. In the adult, the nerve paths are… immutable. Everything may die, nothing may be regenerated."

This became the central dogma of neuroscience, but the view began to change in the 1980s, when Fernando Nottebohm of Rockefeller University published the first clear evidence of adult neurogenesis in the vertebrate brain. Nottebohm showed that the adult canary brain undergoes seasonal changes in size. Males sing to serenade females, but the song-producing brain regions decrease dramatically in size after breeding season. The following spring, they are regenerated by neurogenesis so the male can learn new songs.

In fact, Joseph Altman of the Massachusetts Institute of Technology had reported evidence of adult neurogenesis in the 1960s, in the hippocampus of adult rats and guinea pigs and cortex of cats, but his work was ignored and then ridiculed. "Altman started the idea of adult neurogenesis, but his data weren't convincing," says Nottebohm. "Our results showed, beyond reasonable doubt, that neurons are born in adulthood and incorporated into existing circuits. They brought to an end most resistance against the idea."

Evidence of adult neurogenesis in mammals quickly followed. In 1992, Samuel Weiss and Brent Reynolds of the University of Calgary isolated neural stem cells from the brains of adult mice and showed that they can generate neurons and astrocytes when grown in a Petri dish. This was confirmed by Fred Gage of the Salk Institute. In collaboration with various colleagues, Gage also showed that exercise and environmental enrichment increase the rate of adult neurogenesis, and that the number of new cells produced declines with age. Thousands of studies have now been published, and it is widely accepted that the adult mouse brain continues to produce new neurons.

In all mammalian embryos, neurogenesis occurs along the entire length of the neural tube. In adults, the tube's hollow cavity has transformed into the brain ventricles, which are filled with cerebrospinal fluid, and neurogenesis is restricted to two brain regions, each containing a niche of different types of stem cells.

The larger niche, in the walls of the C-shaped lateral ventricles, produces immature neurons that migrate in chains within the rostral migratory stream (RMS) to the olfactory bulb. Some differentiate into mature neurons that integrate into local circuits and participate in the processing of smell information. The other produces cells that integrate into the dentate gyrus of the hippocampus and play important roles in learning and memory. Exactly how new cells participate in information processing remains unclear. They may replace dying cells, or could be added to existing circuits to provide additional information processing capabilities.

Other regions of the lateral ventricles contain dormant stem cells, which can be activated following brain injury to produce new cells that migrate to the injury site.

From mice to monkeys and men

In the late 1990s, Elizabeth Gould of Princeton University reported evidence of adult neurogenesis in the monkey hippocampus, and showed that stress decreases stem cell division in the dentate gyrus. The monkey brain is much bigger than that of rodents, however, and the process is protracted. Fewer cells are produced, they migrate larger distances and take longer to mature. According to one recent study by researchers from the University of Illinois, new cells in the macaque dentate gyrus take at least six months to mature fully.

Adult neurogenesis is implicated in depression and Alzheimer's disease, both of which involve hippocampal shrinkage. The anti-depressants Prozac and imipramine stimulate hippocampal neurogenesis in adult mice and some of their effects depend on the new cells. They also make immature hippocampal cells derived from human embryos divide in the Petri dish.

It is now taken for granted that adult neurogenesis occurs in humans, and the idea has revolutionized the way we think about the brain. It is widely believed that physical and mental exercise can stimulate hippocampal neurogenesis that offsets age-related cognitive decline and may protect against depression and Alzheimer's. "Everyone wants to believe that functional neurogenesis happens in adult humans," says Lumsden. "Everyone wants to believe that we can repair damaged brains, but there's precious little evidence for it."

The biggest sceptic is Pasko Rakic, who revealed how newborn cells migrate in the developing brain in a series of classic experiments performed in the early 1970s. Rakic injected macaque monkey fetuses with radioactive thymidine and sliced their brains into hundreds of ultra-thin sections. He identified migrating neurons by their newly-synthesized, radioactive DNA and painstakingly reconstructed the sections, to show that the cells climb onto elongated cells called radial glia, which span the thickness of the tube to contact its inner and outer surfaces and they then crawl, amoeba-like, along the radial glial fibres to the outer surface. His hand-drawn diagrams depicting the process appear in textbooks to this day.

Now chairman of Yale's neurobiology department and director of the Kavli Institute for Neuroscience, Rakic casts a long shadow, and has been extremely critical of some of the adult neurogenesis research. He points out that BrdU can induce cell division, and also labels dying cells, which synthesize DNA just before they die, so cannot give accurate counts of newborn cells in adult brain tissue. This can be overcome by double staining with other antibodies, to verify that BrdU-labelled cells are indeed dividing.

Rakic has published evidence both for and against adult neurogenesis in macaques. He estimates that neurons added to the adult human hippocampus take a year to mature, and argues that anti-depressants cannot work by stimulating neurogenesis because their effects take about a month to kick in.

"Rakic was reasonable in demanding higher levels of proof," says Nottebohm, "but he railed against adult neurogenesis so aggressively that to many it struck as a defence of the old dogma. As a participant in the battles, I found him too negative and not particularly perceptive. His own work used animals housed under conditions that inhibit the formation and survival of new neurons."

Nottebohm and others say that Rakic has held back adult neurogenesis research, but according to Gage, he has been "an important driver for making the field more rigorous. He challenges the weakness in their work and it's up to researchers in the field to address them." But Gage notes that immature neurons derived from mouse stem cells are more active than their mature counterparts, so an extended maturation period may actually be beneficial. "I'm not surprised that maturation would take longer in humans, but the other way to look at it is that newborn cells have an extended period of plasticity."

Rakic's scepticism is, however, supported by the scientific evidence – or rather, lack of it.

In 1998, Gage and the late Peter Eriksson examined the brains of five cancer patients who had been injected with BrdU for diagnostic purposes. They treated the hippocampal tissue with antibodies against BrdU and proteins synthesized by immature neurons, and found some staining in the dentate gyrus. This was the first evidence that the adult human brain contains newborn neurons, but the researchers emphasized that it did not show that the cells are functional.

Others have isolated stem cells from various regions of the adult human brain. These cells have a limited capacity for self-renewal when grown in the lab, but can generate mature astrocytes, oligodendrocytes and neurons with normal electrical properties.

In 2006, Jonas Frisén of the Karolinska Institute and colleagues examined the cortex in autopsied brains of seven adults. They looked for radioactive carbon from Cold War nuclear bomb tests, which accumulates in newly-synthesized DNA, but detected only atmospheric levels, and concluded that neurogenesis does not occur in the cortex.

More recently, Gerd Kempermann of the Center for Regenerative Therapies in Dresden and colleagues examined brains from 54 individuals aged up to 100, using antibodies for multiple proteins, and found small numbers of newborn hippocampal cells in all of them. "It appears to be the same as in rodents," says Kempermann. "There's very steep decline in early life but you end up with a very low level that is maintained. We saw small numbers of cells, but we saw them up to very old age."

But Arturo Alvarez-Buylla, a professor in the Department of Neurological Surgery at the University of California, San Francisco, isn't entirely convinced. "Gage and Erikkson provided evidence that some proliferation occurs in the adult hippocampus," he says, "but this has to be treated with caution, because some of the labelled cells might have been dying."

Alvarez-Buylla obtained his Ph.D. working on songbirds with Nottebohm before turning his attention to rodents, where he showed that newborn neurons migrate long distances to the olfactory bulb. He has since published several studies suggesting that this migration probably does not occur in adult humans. Working with Nader Sanai, director the Barrow Brain Tumor Research Center in Phoenix, Arizona, he has examined the brains of approximately 100 people of all ages, and a similar number of tissue samples removed during neurosurgery.

They identified a 'ribbon' of astrocytes in the walls of the lateral ventricles which produce immature neurons, astrocytes and oligodendrocytes and which has not been seen in other species. They also identified the RMS in infants, and found that it contains small numbers of migrating cells, as well as a previously unidentified migratory pathway, which branches off from the RMS to enter the prefrontal cortex.

According to their data, migration occurs in both streams postnatally, but declines steeply by 18 months of age and has almost completely disappeared by early adulthood. "We concluded that if migration occurs then it is very scarce," says Alvarez-Buylla, "and that cells are not forming large bundles that migrate to the olfactory bulb." The data conflict with those of a 2007 study by Erikkson and Maurice Curtis, who saw a robust RMS containing large numbers of migrating cells, but were confirmed last year by Chinese researchers, who found small numbers of migrating neurons in the adult RMS, but no new cells in the olfactory bulb itself.

"How much neurogenesis occurs in older people, and how much it contributes to local plasticity, are still open questions," says Alvarez-Buylla. "There is controversy over how much cell renewal there is in the hippocampus and how persistent the stem cells are throughout life. If they decline with age they're not really self-renewing."

Overall, the few available studies suggest that the fountain of youth is reduced to a mere trickle in adults. There is no evidence whatsoever for adult neurogenesis in the human cortex the existence of the RMS in adults is still disputed, and evidence for hippocampal neurogenesis is very thin on the ground. If the hippocampus does produce new cells, are there enough to be any significance?

Kempermann believes there are: "The network requires very few cells to be added and still be functionally relevant," he says. Other adult neurogenesis researchers also believe that small numbers of cells could be relevant to the function of the hippocampus. But this question remains unanswered, and the possibility that the number of cells produced is not large enough to be functionally significant has serious implications for popular claims, such as that exercise can improve memory, and also for the new view of the brain that has been adopted so quickly.

"One side-effect of having a large and complex brain is that you wouldn't want naïve newcomers barging in," says Lumsden. "How would new neurons usefully integrate into complex neural networks? If anything, evolution would have made damn sure that mechanisms exist to eliminate these party-crashers. Lack of neurogenesis after the connectional plan of the brain is complete would be a selective advantage."

The brain may, therefore, favour stability over plasticity. Human adult neurogenesis may be an evolutionary relic, and one that comes at a very high cost, as stem cells in the adult human brain likely contribute to brain tumour formation.

There's still hope

"Rakic was mostly correct," says Nottebohm. "Until now, the overwhelming evidence is that most neurons are formed early in development, including a short while after birth." But even if functional adult neurogenesis does not occur in the human brain, or if the numbers of cells produced are too small to be of any significance, there is still hope that neural stem cells could be of therapeutic value.

"Rakic missed what was central about the argument," Nottebohm continues. "There is a rich collection of neural stem cells that continue to generate new neurons in adulthood. This is of the greatest importance. It shows, in principle, that this reservoir might be exploited for purposes of brain repair."

To this end, researchers are exploring two approaches to develop neural stem cell-based therapies for neurological conditions, although any such treatments are still a long way off. One approach is to coax the brain's stem cells to generate neurons that migrate to injured or diseased sites. The other is to transplant lab-grown neurons of specified types directly into the brain. Indeed, neurons derived from human neural stem cells can differentiate into fully functional neurons when transplanted into foetal rat brain, and can now be tracked in live animals using magnetic resonance imaging.

"We found the first evidence for replaceable neurons," says Nottebohm, "and I have no doubt that a whole new field will emerge around this concept. I'm sure this will have a profound effect sooner or later. This is just the beginning."


Why nerve cells can’t reproduce/ regenerate?

Neuron is the main cell of the Nervous System. It is an excitable cell with electric potential which is responsible for the transmission of the nerve impulse to other neurons. With this transmission, they process and transmit information in the brain and spinal cord.

A human brain has around 100.000 millions of neurons.

The other type of cell is glia, which protects the neurons.

Neurons do not reproduce like many others type of cells (they are amitotic, they do not have mitosis). Their DNA copying is blocked. Thus, they usually don’t regenerate (except for aferent and eferent neurons) and have to be protected from damage by the glial cells. The regeneration is done via Schwann cells (glia).

The brain has an architecture which is what’s called post- mitotic. There are only a few restricted areas in the brain and central nervous system where there are new nerve cells being born. For the most part, you rely on the compliment of nerve cells you are born with and which continue to divide for a very short window after you were born and then stopped. We used to think that people never got new nerve cells, but it turns out that we get a small number of them around the teen years. This does seem to make life a bit more complicated for young people whose brains have to adjust to the new nerve cells.

But why? Why don’t nerve cells reproduce? The process of reproducing is division of one cell into two using a process called Mitosis. As you might imagine, nerve cells are very specialized – they do a very specific, complicated job in the body. As a result, their structures are very specialized – they have a small “cell body” and then long processes that branch off the to connect with other neurons or other types of cells such as muscles. As they become specialized, the cells devote energy and structures to their “new” jobs as neuronal cells and they give up the ability to do other things, such as division.

Morphological point of view

Neurons cannot divide because they lack centrioles.

Because centrioles function in cell division, the fact that neurons lack these organelles is consistent with the amitotic nature of the cell.

Functional point of view

New cells in the nervous system wouldn’t do any good. The whole nervous system is based on interneuronal connections, so adding an extra neuron would mess up these connections and alter both the functionality and the “stored” information.

Each nerve cell has a specific place in our nervous system. Its job is all about taking a signal from one specific place to another one. Adding new nerve cells would mess up these very specific connections in a very complex system.

Always remember though – the brain can rewire itself without making new neurons. This is the charisma of the brain – that it can repair without cells themselves repair or regenerate. This is why this is the most adaptive organ of all – because of its ability to make alternative pathways for one and the same process.

However, some new neurons can be generated in adults.

Generation of new neurons in adults was first demonstrated in birds, where labeled DNA precursors could be found in differentiated neurons. Experiments in mammals and humans demonstrated later that new neurons are created in the central nervous system (CNS) in adults, although it seems to be restricted to some particular regions: granule cell layer of the olfactory bulb and dentate gyrus of the hippocampus. These new neurons seem to be local circuit neurons and interneurons (i.e. no long distance neurons).

How are the new neurons produced if neurons cannot divide? They come from neural stem cells (NSCs) that were preserved in the sub-ventricular zone during development. NSCs are presumed to play a part in brain plasticity in the adult brain. However, they have therapeutic potential.


Neuroscience. 2nd edition.

It has long been known that mature, differentiated neurons do not divide (see Chapter 22). It does not follow, however, that all the neurons that make up the adult brain are produced during embryonic development, even though this interpretation has generally been assumed. The merits of this assumption were questioned in the 1980s, when Fernando Nottebohm and colleagues at Rockefeller University demonstrated the production of new neurons in the brains of adult songbirds. They showed that labeled DNA precursors injected into adult birds could be found subsequently in fully differentiated neurons, indicating that the neurons had undergone their final round of cell division after the labeled precursor was injected. Moreover, the new neurons were able to extend dendrites and project long axons to establish appropriate connections with other brain nuclei. Production of new neurons was apparent in many parts of the birds' brains, but was especially prominent in areas involved in song production (see Box B in Chapter 24). These observations showed that the adult brain can generate at least some new nerve cells and incorporate them into neural circuits (see also Chapter 15).

The production of new neurons in the adult brain has now been examined in mice, rats, monkeys and, finally, humans. In all cases, however, the new nerve cells in the mammalian CNS have been restricted to just two regions of the brain: (1) The granule cell layer of the olfactory bulb and (2) the dentate gyrus of the hippocampus. Furthermore, the new nerve cells are primarily local circuit neurons or interneurons. New neurons with long distance projections have not been seen. Each of these populations in the olfactory bulb and hippocampus is apparently generated from nearby sites near the surface of the lateral ventricle. As in bird brains, the newborn nerve cells extend axons and dendrites and become integrated into functional synaptic circuits. Evidently, a limited production of new neurons occurs continually in a few specific loci.

If neurons cannot divide (see Chapter 22), how does the adult brain generate these nerve cells? The answer emerged with the discovery that the sub-ventricular zone that produces neurons during development retains some neural stem cells in the adult. The term “stem cells” refers to a population of cells that are self-renewing�h cell can divide symmetrically to give rise to more cells like itself, but also can divide asymmetrically, giving rise to a new stem cell plus one or more differentiated cells. Over the past decade, several research groups have isolated stem cells from the adult brain that can reproduce in large numbers in cell culture. Such cells can then be induced to differentiate into neurons and glial cells, when exposed to appropriate signals. Many of these same signals mediate neuronal differentiation in normal development. Adult stem cells can be isolated not only from the anterior subventricular zone (near the olfactory bulb) and dentate gyrus, but from many other parts of the forebrain, cerebellum, midbrain, and spinal cord, although they do not apparently produce any new neurons in these sites. Inhibitory signals in these regions may prevent stem cells from generating neurons.

Why the generation of neurons is so limited in the adult brain is not known. This peculiar limitation is presumably related to the reasons discussed in Box D. Nevertheless, the fact that new neurons can be generated in a few regions of the adult brain suggests that this phenomenon can occur throughout the adult CNS. The ability of newly generated neurons to integrate into at least some synaptic circuits adds to the mechanisms available for plasticity in the adult brain. Thus, many investigators have begun to explore the potential applications of stem cell technology for the repair of circuits damaged by traumatic injury or degenerative disease.

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Scientists used to think that nerve cells were incapable of regeneration if they were damaged. This means that when you are born, you would have all the neurons that you would ever have in your life — take care of them because if they die they don't come back.

More recently, biologists have discovered that nerve cells probably can regenerate. They just don't do it very much or very fast. This has been a problem for people who injure their nerves or nervous system. Damage to the nervous system can often cause a person to be paralyzed. These broken nerves can't regenerate their neurons to fix themselves. Without these neurons, it becomes difficult or impossible to move arms or legs or even to breathe.


Glial Cell Types

Glial cell types all stem from two major categories – the macroglia and microglia. While macroglia are involved in regulating and optimizing nerve cell function, microglia make the immediate environment safer. Macroglia and macroglia (or their sub-types) are found in both the CNS and PNS and present with specific but often overlapping or collaborative roles.

Macroglia are found in seven different forms spread throughout the entire nervous system. These are oligodendrocytes, astrocytes, ependymal cells, radial glia, Schwann cells, satellite cells, and enteric glia. We will look at these in more detail further on. Microglia were, until very recently, thought to be limited to the central nervous system. They were then seen to cross into the peripheral nervous system in zebrafish, where they would pick up cellular debris from places of nerve fiber injury. The microglia would then return to the brain still holding this debris but the cells would become altered in the process. As altered microglial cells are found in large quantities in human neurodegenerative disease, this migration and return probably occurs in higher species, too.

Macroglia in the CNS

Macroglia in the CNS are grouped into subcategories of ependymal cells, oligodendrocytes, radial glia, and astrocytes.

Oligodendrocytes are best known for their ability to manufacture, repair, and arrange myelin sheaths around neuron axons. Myelin sheaths insulate nerve cell axons to prevent electrical impulses from leaking and enabling longer-distance communication. Oligodendrocytes also support the metabolic needs of the nerve cell axon.

Astrocytes are divided into star-like fibrous astrocytes and protoplasmic astrocytes, both of which connect signal-producing tissues (neurons) to cells that do not have this mode of communication, like blood vessels. Astrocytes also help to maintain the permeability of the blood-brain barrier where they sense glucose and ion levels inside the brain and regulate their flow into or out of it.

Radial glia are only found in specific areas of the CNS. This subgroup includes the Bergmann and Müller cells of the cerebellum and retina respectively. Radial cells modulate neurotransmission and optimize how information is processed. By forming a framework or scaffold on which other neurons can travel, radial glial cells are highly communicative. They also play roles in ion homeostasis, increased synapse stability, and improved brain plasticity and neuroprotection. This is done by regulating the surrounding extracellular fluid.

Müller cells act as optical fibers that guide incoming light through the retina to minimize scattering this makes for a clearer image. At the same time, they surround neurons and stabilize and protect the nervous tissue of the back of the eye. And, like all radial glia, they simultaneously regulate ions and glucose in the extracellular space.

Ependymal cells (ependymocytes) line the brain ventricles and spinal cord canal in a continuous sheet of epithelium known as the ependyma. These cells primarily produce cerebrospinal fluid (CSF). Depending on where they are located, ependymal cells also help to distribute neurotransmitters and hormones associated with the central nervous system. Furthermore, the microvilli of ependymal cells can absorb CSF and influence its flow and let certain substances in and out of the brain. Like the majority of glial cells, the ependyma also contributes to osmotic control within the brain via glucose and ion regulation.

Macroglia in the PNS

Macroglia contained in the peripheral nervous system are satellite glial cells, Schwann cells, and enteric glia.

Schwann cells (neurolemma) of the PNS mirror the role of oligodendrocytes in the central nervous system they myelinate the axons of neurons and modulate extracellular fluid. However, while a single oligodendrocyte will provide insulation for multiple neurons in the CNS, the opposite is true in the PNS – a single axon hosts multiple Schwann cells, each of which myelinates its own section. The picture shows the tree-ring form of the myelin layers that surround the central axon of the nerve cell.

Satellite glial cells or SGCs surround the sensory and autonomic ganglia. Ganglia are relay stations where one nerve enters and another exits. In autonomic (involuntary) nervous system pathways, SGCs respond to chemical messengers (neurotransmitters) and optimize them so that vital responses such as heart rate and vasoconstriction go as smoothly as possible. In the sensory nervous system, satellite cells regulate potassium levels and the neurons’ response to evoked potentials without the presence of neurotransmitters. Charcot-Marie-Tooth disease (CMT) describes a group of inherited conditions that cause damage to the peripheral nerves, often specifically to SGCs. Symptoms include impaired sensory and motor activity of the limbs that causes mild to severe loss of sensation and muscle weakness. Satellite glial cells are also associated with chronic and acute pain responses.

Enteric glia are found in the lining of the intestines. They assist with gut motility (peristalsis) and enable contact between different cells of the intestinal wall. The enteric nervous system or ENS is secondary in cell population only to the central nervous system. Enteric glial cells seem to feature characteristics of other nervous tissue cells such as astrocytes and oligodendrocytes. Recent topics such as the gut-brain axis will undoubtedly throw more light on the importance of enteric glia. The fact that these cells are more broadly differentiated than any other type of glial cells makes them interesting subjects. What is already known is that enteric glial cells change in function and form according to their location, the age of the host, and even that person’s gender.

Microglia in the CNS

Microglia in the CNS are not totally limited to the central nervous system – they like to take short trips into peripheral nerve tissue. Researchers have found that they temporarily migrate into the peripheral nervous syste in rodents and zebrafish, and the presence of slightly changed microglia in human brain degeneration tells us that this occurs in humans, too. Microglia seem to change after they have traveled into the peripheral nervous system – imagine coming home with a sun tan or tummy bag after a trip away from home.

Microglia play important roles in nervous tissue immunity and inflammatory responses, working much like macrophages and clearing away cellular debris and toxins. Other roles include optimizing different brain circuits to enable cognitive development – microglia cells eliminate previously-formed synapses that are no longer useful. These cells can modulate the mechanisms of memory and learning, and their degeneration has been associated with Alzheimer’s disease.


Contents

Three G0 states exist and can be categorized as either reversible (quiescent) or irreversible (senescent and differentiated). Each of these three states can be entered from the G1 phase before the cell commits to the next round of the cell cycle. Quiescence refers to a reversible G0 state where subpopulations of cells reside in a 'quiescent' state before entering the cell cycle after activation in response to extrinsic signals. Quiescent cells are often identified by low RNA content, lack of cell proliferation markers, and increased label retention indicating low cell turnover. [5] [6] Senescence is distinct from quiescence because senescence is an irreversible state that cells enter in response to DNA damage or degradation that would make a cell's progeny nonviable. Such DNA damage can occur from telomere shortening over many cell divisions as well as reactive oxygen species (ROS) exposure, oncogene activation, and cell-cell fusion. While senescent cells can no longer replicate, they remain able to perform many normal cellular functions. [7] [8] [9] [10] Senescence is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis. In contrast to cellular senescence, quiescence is not a reactive event but part of the core programming of several different cell types. Finally, differentiated cells are stem cells that have progressed through a differentiation program to reach a mature – terminally differentiated – state. Differentiated cells continue to stay in G0 and perform their main functions indefinitely.

Transcriptomes Edit

The transcriptomes of several types of quiescent stem cells, such as hematopoietic, muscle, and hair follicle, have been characterized through high-throughput techniques, such as microarray and RNA sequencing. Although variations exist in their individual transcriptomes, most quiescent tissue stem cells share a common pattern of gene expression that involves downregulation of cell cycle progression genes, such as cyclin A2, cyclin B1, cyclin E2, and survivin, and upregulation of genes involved in the regulation of transcription and stem cell fate, such as FOXO3 and EZH1. Downregulation of mitochondrial cytochrome C also reflects the low metabolic state of quiescent stem cells. [11]

Epigenetic Edit

Many quiescent stem cells, particularly adult stem cells, also share similar epigenetic patterns. For example, H3K4me3 and H3K27me3, are two major histone methylation patterns that form a bivalent domain and are located near transcription initiation sites. These epigenetic markers have been found to regulate lineage decisions in embryonic stem cells as well as control quiescence in hair follicle and muscle stem cells via chromatin modification. [11]

Cell cycle regulators Edit

Functional tumor suppressor genes, particularly p53 and Rb gene, are required to maintain stem cell quiescence and prevent exhaustion of the progenitor cell pool through excessive divisions. For example, deletion of all three components of the Rb family of proteins has been shown to halt quiescence in hematopoietic stem cells. Lack of p53 has been shown to prevent differentiation of these stem cells due to the cells’ inability to exit the cell cycle into the G0 phase. In addition to p53 and Rb, cyclin dependent kinase inhibitors (CKIs), such as p21, p27, and p57, are also important for maintaining quiescence. In mouse hematopoietic stem cells, knockout of p57 and p27 leads to G0 exit through nuclear import of cyclin D1 and subsequent phosphorylation of Rb. Finally, the Notch signaling pathway has been shown to play an important role in maintenance of quiescence. [11]

Post-transcriptional regulation Edit

Post-transcriptional regulation of gene expression via miRNA synthesis has been shown to play an equally important role in the maintenance of stem cell quiescence. miRNA strands bind to the 3’ untranslated region (3’ UTR) of target mRNA’s, preventing their translation into functional proteins. The length of the 3’ UTR of a gene determines its ability to bind to miRNA strands, thereby allowing regulation of quiescence. Some examples of miRNA's in stem cells include miR-126, which controls the PI3K/AKT/mTOR pathway in hematopoietic stem cells, miR-489, which suppresses the DEK oncogene in muscle stem cells, and miR-31, which regulates Myf5 in muscle stem cells. miRNA sequestration of mRNA within ribonucleoprotein complexes allows quiescent cells to store the mRNA necessary for quick entry into the G1 phase. [11]

Response to stress Edit

Stem cells that have been quiescent for a long time often face various environmental stressors, such as oxidative stress. However, several mechanisms allow these cells to respond to such stressors. For example, the FOXO transcription factors respond to the presence of reactive oxygen species (ROS) while HIF1A and LKB1 respond to hypoxic conditions. In hematopoietic stem cells, autophagy is induced to respond to metabolic stress. [11]

Tissue stem cells Edit

Stem cells are cells with the unique ability to produce differentiated daughter cells and to preserve their stem cell identity through self-renewal. [12] In mammals, most adult tissues contain tissue-specific stem cells that reside in the tissue and proliferate to maintain homeostasis for the lifespan of the organism. These cells can undergo immense proliferation in response to tissue damage before differentiating and engaging in regeneration. Some tissue stem cells exist in a reversible, quiescent state indefinitely until being activated by external stimuli. Many different types of tissue stem cells exist, including muscle stem cells (MuSCs), neural stem cells (NSCs), intestinal stem cells (ISCs), and many others.

Stem cell quiescence has been recently suggested to be composed of two distinct functional phases, G0 and an ‘alert’ phase termed GAlert. [13] Stem cells are believed to actively and reversibly transition between these phases to respond to injury stimuli and seem to gain enhanced tissue regenerative function in GAlert. Thus, transition into GAlert has been proposed as an adaptive response that enables stem cells to rapidly respond to injury or stress by priming them for cell cycle entry. In muscle stem cells, mTORC1 activity has been identified to control the transition from G0 into GAlert along with signaling through the HGF receptor cMet. [13]

Mature hepatocytes Edit

While a reversible quiescent state is perhaps most important for tissue stem cells to respond quickly to stimuli and maintain proper homeostasis and regeneration, reversible G0 phases can be found in non-stem cells such as mature hepatocytes. [14] Hepatocytes are typically quiescent in normal livers but undergo limited replication (less than 2 cell divisions) during liver regeneration after partial hepatectomy. However, in certain cases, hepatocytes can experience immense proliferation (more than 70 cell divisions) indicating that their proliferation capacity is not hampered by existing in a reversible quiescent state. [14]

Senescent cells Edit

Often associated with aging and age-related diseases in vivo, senescent cells can be found in many renewable tissues, including the stroma, vasculature, hematopoietic system, and many epithelial organs. Resulting from accumulation over many cell divisions, senescence is often seen in age-associated degenerative phenotypes. Senescent fibroblasts in models of breast epithelial cell function have been found to disrupt milk protein production due to secretion of matrix metalloproteinases. [15] Similarly, senescent pulmonary artery smooth muscle cells caused nearby smooth muscle cells to proliferate and migrate, perhaps contributing to hypertrophy of pulmonary arteries and eventually pulmonary hypertension. [16]

Differentiated muscle Edit

During skeletal myogenesis, cycling progenitor cells known as myoblasts differentiate and fuse together into non-cycling muscle cells called myocytes that remain in a terminal G0 phase. [17] As a result, the fibers that make up skeletal muscle (myofibers) are cells with multiple nuclei, referred to as myonuclei, since each myonucleus originated from a single myoblast. Skeletal muscle cells continue indefinitely to provide contractile force through simultaneous contractions of cellular structures called sarcomeres. Importantly, these cells are kept in a terminal G0 phase since disruption of muscle fiber structure after myofiber formation would prevent proper transmission of force through the length of the muscle. Muscle growth can be stimulated by growth or injury and involves the recruitment of muscle stem cells – also known as satellite cells – out of a reversible quiescent state. These stem cells differentiate and fuse to generate new muscle fibers both in parallel and in series to increase force generation capacity.

Cardiac muscle is also formed through myogenesis but instead of recruiting stem cells to fuse and form new cells, heart muscle cells – known as cardiomyocytes – simply increase in size as the heart grows larger. Similarly to skeletal muscle, if cardiomyocytes had to continue dividing to add muscle tissue the contractile structures necessary for heart function would be disrupted.

Differentiated bone Edit

Of the four major types of bone cells, osteocytes are the most common and also exist in a terminal G0 phase. Osteocytes arise from osteoblasts that are trapped within a self-secreted matrix. While osteocytes also have reduced synthetic activity, they still serve bone functions besides generating structure. Osteocytes work through various mechanosensory mechanisms to assist in the routine turnover over bony matrix.

Differentiated nerve Edit

Outside of a few neurogenic niches in the brain, most neurons are fully differentiated and reside in a terminal G0 phase. These fully differentiated neurons form synapses where electrical signals are transmitted by axons to the dendrites of nearby neurons. In this G0 state, neurons continue functioning until senescence or apoptosis. Numerous studies have reported accumulation of DNA damage with age, particularly oxidative damage, in the mammalian brain. [18]

Role of Rim15 Edit

Rim15 was first discovered to play a critical role in initiating meiosis in diploid yeast cells. Under conditions of low glucose and nitrogen, which are key nutrients for the survival of yeast, diploid yeast cells initiate meiosis through the activation of early meiotic-specific genes (EMGs). The expression of EMGs is regulated by Ume6. Ume6 recruits the histone deacetylases, Rpd3 and Sin3, to repress EMG expression when glucose and nitrogen levels are high, and it recruits the EMG transcription factor Ime1 when glucose and nitrogen levels are low. Rim15, named for its role in the regulation of an EMG called IME2, displaces Rpd3 and Sin3, thereby allowing Ume6 to bring Ime1 to the promoters of EMGs for meiosis initiation. [19]

In addition to playing a role in meiosis initiation, Rim15 has also been shown to be a critical effector for yeast cell entry into G0 in the presence of stress. Signals from several different nutrient signaling pathways converge on Rim15, which activates the transcription factors, Gis1, Msn2, and Msn4. Gis1 binds to and activates promoters containing post-diauxic growth shift (PDS) elements while Msn2 and Msn4 bind to and activate promoters containing stress-response elements (STREs). Although it is not clear how Rim15 activates Gis1 and Msn2/4, there is some speculation that it may directly phosphorylate them or be involved in chromatin remodeling. Rim15 has also been found to contain a PAS domain at its N terminal, making it a newly discovered member of the PAS kinase family. The PAS domain is a regulatory unit of the Rim15 protein that may play a role in sensing oxidative stress in yeast. [19]

Nutrient signaling pathways Edit

Glucose Edit

Yeast grows exponentially through fermentation of glucose. When glucose levels drop, yeast shift from fermentation to cellular respiration, metabolizing the fermentative products from their exponential growth phase. This shift is known as the diauxic shift after which yeast enter G0. When glucose levels in the surroundings are high, the production of cAMP through the RAS-cAMP-PKA pathway (a cAMP-dependent pathway) is elevated, causing protein kinase A (PKA) to inhibit its downstream target Rim15 and allow cell proliferation. When glucose levels drop, cAMP production declines, lifting PKA's inhibition of Rim15 and allowing the yeast cell to enter G0. [19]

Nitrogen Edit

In addition to glucose, the presence of nitrogen is crucial for yeast proliferation. Under low nitrogen conditions, Rim15 is activated to promote cell cycle arrest through inactivation of the protein kinases TORC1 and Sch9. While TORC1 and Sch9 belong to two separate pathways, namely the TOR and Fermentable Growth Medium induced pathways respectively, both protein kinases act to promote cytoplasmic retention of Rim15. Under normal conditions, Rim15 is anchored to the cytoplasmic 14-3-3 protein, Bmh2, via phosphorylation of its Thr1075. TORC1 inactivates certain phosphatases in the cytoplasm, keeping Rim15 anchored to Bmh2, while it is thought that Sch9 promotes Rim15 cytoplasmic retention through phosphorylation of another 14-3-3 binding site close to Thr1075. When extracellular nitrogen is low, TORC1 and Sch9 are inactivated, allowing dephosphorylation of Rim15 and its subsequent transport to the nucleus, where it can activate transcription factors involved in promoting cell entry into G0. It has also been found that Rim15 promotes its own export from the nucleus through autophosphorylation. [19]

Phosphate Edit

Yeast cells respond to low extracellular phosphate levels by activating genes that are involved in the production and upregulation of inorganic phosphate. The PHO pathway is involved in the regulation of phosphate levels. Under normal conditions, the yeast cyclin-dependent kinase complex, Pho80-Pho85, inactivates the Pho4 transcription factor through phosphorylation. However, when phosphate levels drop, Pho81 inhibits Pho80-Pho85, allowing Pho4 to be active. When phosphate is abundant, Pho80-Pho85 also inhibits the nuclear pool of Rim 15 by promoting phosphorylation of its Thr1075 Bmh2 binding site. Thus, Pho80-Pho85 acts in concert with Sch9 and TORC1 to promote cytoplasmic retention of Rim15 under normal conditions. [19]

Cyclin C/Cdk3 and Rb Edit

The transition from G1 to S phase is promoted by the inactivation of Rb through its progressive hyperphosphorylation by the Cyclin D/Cdk4 and Cyclin E/Cdk2 complexes in late G1. An early observation that loss of Rb promoted cell cycle re-entry in G0 cells suggested that Rb is also essential in regulating the G0 to G1 transition in quiescent cells. [20] Further observations revealed that levels of cyclin C mRNA are highest when human cells exit G0, suggesting that cyclin C may be involved in Rb phosphorylation to promote cell cycle re-entry of G0 arrested cells. Immunoprecipitation kinase assays revealed that cyclin C has Rb kinase activity. Furthermore, unlike cyclins D and E, cyclin C's Rb kinase activity is highest during early G1 and lowest during late G1 and S phases, suggesting that it may be involved in the G0 to G1 transition. The use of fluorescence-activated cell sorting to identify G0 cells, which are characterized by a high DNA to RNA ratio relative to G1 cells, confirmed the suspicion that cyclin C promotes G0 exit as repression of endogenous cyclin C by RNAi in mammalian cells increased the proportion of cells arrested in G0. Further experiments involving mutation of Rb at specific phosphorylation sites showed that cyclin C phosphorylation of Rb at S807/811 is necessary for G0 exit. It remains unclear, however, whether this phosphorylation pattern is sufficient for G0 exit. Finally, co-immunoprecipitation assays revealed that cyclin-dependent kinase 3 (cdk3) promotes G0 exit by forming a complex with cyclin C to phosphorylate Rb at S807/811. Interestingly, S807/811 are also targets of cyclin D/cdk4 phosphorylation during the G1 to S transition. This might suggest a possible compensation of cdk3 activity by cdk4, especially in light of the observation that G0 exit is only delayed, and not permanently inhibited, in cells lacking cdk3 but functional in cdk4. Despite the overlap of phosphorylation targets, it seems that cdk3 is still necessary for the most effective transition from G0 to G1. [21]

Rb and G0 exit Edit

Studies suggest that Rb repression of the E2F family of transcription factors regulates the G0 to G1 transition just as it does the G1 to S transition. Activating E2F complexes are associated with the recruitment of histone acetyltransferases, which activate gene expression necessary for G1 entry, while E2F4 complexes recruit histone deacetylases, which repress gene expression. Phosphorylation of Rb by Cdk complexes allows its dissociation from E2F transcription factors and the subsequent expression of genes necessary for G0 exit. Other members of the Rb pocket protein family, such as p107 and p130, have also been found to be involved in G0 arrest. p130 levels are elevated in G0 and have been found to associate with E2F-4 complexes to repress transcription of E2F target genes. Meanwhile, p107 has been found to rescue the cell arrest phenotype after loss of Rb even though p107 is expressed at comparatively low levels in G0 cells. Taken together, these findings suggest that Rb repression of E2F transcription factors promotes cell arrest while phosphorylation of Rb leads to G0 exit via derepression of E2F target genes. [20] In addition to its regulation of E2F, Rb has also been shown to suppress RNA polymerase I and RNA polymerase III, which are involved in rRNA synthesis. Thus, phosphorylation of Rb also allows activation of rRNA synthesis, which is crucial for protein synthesis upon entry into G1. [21]


Transitions from proliferative to neurogenic mode

Evidence indicates that the cell-intrinsic and extrinsic cues coordinately regulate proliferation vs. neurogenic balances of the fate of aRGs (Miyata et al., 2010 Okano and Temple, 2009). In vivo clonal analysis demonstrated that mouse NEs/aRGs change their division mode from proliferative (symmetric) to neurogenic (asymmetric) around E11–E12 (Gao et al., 2014). Importantly, this proliferative-to-neurogenic (symmetric-to-asymmetric) transition occurs once and is irreversible in individual


Well, the answer is that the brain's neurones have an architecture that's what's called post-mitotic: there are only a few restricted areas in the brain and central nervous system where there are new nerve cells being born in an adult brain.

This means that, for the most part, you must rely on the complement of nerve cells that you are born with - and which continue to divide for a very short window after you were born - meaning that what you're born with is what you have to make last a lifetime.

There's a reason for this, because if brain cells were dividing all over the place - and remember that brain cells have long connections that they make from one cell to the other, and those connections are crucial to you being able to do the right thing, say the right thing, have memories and for your brain to be able to work properly - if those cells were dividing all over the place and making aberrant connections, then it will be very, very difficult to preserve that architecture. So there's kind of method in the madness.

The problem is that, as that is a fixed structure, it's very hard to repair it by getting the cells to re-divide because basically, if you have an injury that's bad enough to destroy a part of your brain or your nervous system, evolutionarily speaking the chances are you'd be dead anyway. So, we haven't really evolved the ability to repair the brain and spinal cord.

In some animals though, that can happen and things like gold fish, lampreys, and also even salamanders can restore whole limbs, and bits of their nervous systems. If you take the eye out of a frog, turn it around and put it back in again, it will rewire itself back into the brain, only, because the eyes now are upside down, the animals see upside down and it does the wrong thing. If you hold a fly in front of it, instead of jumping forward at the fly, it jumps backwards and takes a bite out of the deck.

That won a Nobel Prize for Roger Sperry a few years ago and proves that some animals can regenerate their nervous system, but certainly, not us unfortunately.


Watch the video: Cells of the Nervous System Neurons and Glia (May 2022).