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Do new neurons divide propotionally?

Do new neurons divide propotionally?



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Do new neurons divide propotionally?

  • if i try to improve my reasoning skills,are the new neurons only made for that specific region of the brain that controls reasoning skill?

  • i have heard that one side of the brain controls the other side of the body, if i try to use my non-dominant hand(left hand in my case),are new neurons only made for right side of the brain,does it improve only some of the brain regions?


It seem's you are assuming that your / the adult human brain produces new neurons over time- this is (largely) incorrect: neurons are non-dividing cells and are all formed throughout embryogenesis and very early childhood / infancy (see also this question).

Only very exceptions to this are known as adult neurogenesis (generation of new neurons), the most likely or active region in humans would be the hippocampus, however the extent or importance of the process in humans is still not really known. Additionally the hippocampus is an area of the brain that mostly holds memories and is not really related to reasoning skills or body / motor control.


Not an answer, but a clarification. By "hippothalamus" (a probable typo) above it is probably meant "hippocampus", as is mentioned in wiki link. It is hippocampus which is known "to hold memories", but it is a part of a larger "memory" circuit and is a bit similar to temporary memory responsible for holding only recent memories and integrating recent memories into long-term memory. This overview of neurogenesis can also be useful.


Journal Club: Reversing Parkinson’s with New Neurons

Neurons do not divide or replicate, so how can we replace neurons killed by neurodegenerative diseases like Parkinson’s Disease? On the Bio Eats World Journal Club, UCSD Professor Xiang-Dong Fu and host Lauren Richardson discuss his team’s work generating new neurons in the brain by inducing non-neuronal cells to become neurons. The conversation covers how they programmed this cell type conversion, how they verified that these newly created neurons were functioning correctly, and how they demonstrated that these neurons could replace those destroyed in a mouse model of Parkinson’s Disease, reversing the disease phenotype. This work paves the way for a potential curative treatment for this and other devastating neurodegenerative and neurological diseases.

“Reversing a model of Parkinson’s disease with in situ converted nigral neurons” by Hao Qian, Xinjiang Kang, Jing Hu, Dongyang Zhang, Zhengyu Liang, Fan Meng, Xuan Zhang, Yuanchao Xue1, Roy Maimon, Steven F. Dowdy, Neal K. Devaraj, Zhuan Zhou, William C. Mobley, Don W. Cleveland & Xiang-Dong Fu.


Pivotal Research on Monkeys

Princeton researchers first found cell regeneration in the hippocampus and the subventricular zone of the lateral ventricles in monkeys, which are important structures for memory formation and functions of the central nervous system.

This was significant but not quite as important as the 1999 finding of neurogenesis in the cerebral cortex section of the monkey brain. The cerebral cortex is the most complex part of the brain and scientists were startled to find neuron formation in this high-function brain area. The lobes of the cerebral cortex are responsible for higher-level decision making and learning.

Adult neurogenesis was discovered in three areas of the cerebral cortex:

  • The prefrontal region, which controls decision-making
  • The inferior temporal region, which plays a role in visual recognition
  • The posterior parietal region, which plays a role in 3D representation

Researchers believed that these results called for a fundamental reassessment of the development of the primate brain. Although the cerebral cortex research had been pivotal for advancing scientific research in this area, the finding remains controversial since it has not yet been proved to occur in the human brain.


How cells measure themselves

Ever since scientists discovered cells under the microscope more than 350 years ago, they have noted that each type of cell has a characteristic size. From tiny bacteria to inches-long neurons, size matters for how cells work. The question of how these building blocks of life regulate their own size, however, has remained a mystery.

Now we have an explanation for this long-standing biological question. In a study focusing on the growing tip of plants, researchers show that cells use their DNA content as an internal gauge to assess and adjust their size.

Professor Robert Sablowski, a group leader at the John Innes Centre and corresponding author of the study said: "It has been suggested for a long time that DNA could be used as a scale for cell size, but it was unclear how cells could read the scale and use the information. The key is to use the DNA as a template to accumulate the right amount of a protein, which then needs to be diluted before the cell divides. It's exciting to come across such a simple solution to a long-standing problem."

The average cell size results from a balance between how much cells grow and how often they split in two. It has long been clear that cells grow to a certain size before they divide. But how can a cell know how much it has grown?

A good place to investigate this question is in the shoot meristem, the growing tip of the plant, which supplies new cells to make leaves, flowers and stems. Meristem cells constantly grow and divide. Their divisions are often not equal, producing cells of different sizes. Over time, these differences should build up, but the meristem cells stay within a narrow range of sizes over long periods.

In this study, which appears in Science, John Innes Centre researchers carefully followed the growth and division of meristem cells over time. They found that although cells can start their life with variable sizes, by the time the cells are ready to replicate their DNA (a necessary step before cell division, as each new cell needs its own copy of the DNA), most of the initial variability in cell sizes has been corrected.

They then monitored a protein called KRP4, whose role is to delay the start of DNA replication, and found that, regardless of their initial size, cells were always born with the same amount of KRP4. This means that when a cell is born too small, it receives a higher concentration of KRP4, which delays its progression to DNA replication, allowing time for the cell to catch up to the same size of the other cells. Conversely, if a cell is born too big, KRP4 is diluted so it can move quickly onto the next stage without growing further. Over time this keeps meristem cells within a narrow size range.

But what ensures that cells start off with the same amount of KRP4? It turned out that when cells divide, KRP4 "takes a ride" on the DNA, which is given in identical copies to each newborn cell. In this way, the initial amount of KRP4 becomes proportional to the cell's DNA content. To make sure that KRP4 accumulates in the mother cell in proportion to the DNA content, any excess KRP4 not bound to the DNA is destroyed before cell division by another protein called FBL17. Mathematical models and using gene-edited mutants with varying quantities of these genetic components confirmed the mechanism.

Professor Robert Sablowski, explains this process, "One riddle we had to solve is how a cell can know how much it has grown when most of the components of a cell increase together in number and size so they cannot be used as a fixed ruler to measure size. One exception is DNA which exists in the cell in a discrete amount -- its amount precisely doubles before cell division, but it does not vary with cell growth."

Future experiments will seek to explain exactly how the regulatory protein KRP4 associates, then dissociates from chromosomes during cell division. The researchers also want to understand whether the mechanism is modulated in different cell types to produce different average sizes.

The findings may explain the relation between genome size and cell size -- species with large genomes and, therefore a lot of DNA in their cells, tend to have larger cells. This is particularly important in crop plants, many of which have been selected to contain multiple copies of the genomes present in their wild ancestors, leading to larger cells and often larger fruits and seeds.

Components of the genetic mechanism that includes KRP4 are present in many organisms, and it has been suggested that these components are important to regulate cell size in human cells. Thus the mechanism uncovered in the study may also be relevant across biological Kingdoms, with implications for animal and human cell biology.


Humans produce new brain cells throughout their lives, say researchers

Humans continue to produce new neurons in a part of their brain involved in learning, memory and emotion throughout adulthood, scientists have revealed, countering previous theories that production stopped after adolescence. The findings could help in developing treatments for neurological conditions such as dementia.

Many new neurons are produced in the hippocampus in babies, but it has been a matter of hot debate whether this continues into adulthood – and if so, whether this rate drops with age as seen in mice and nonhuman primates.

Although some research had found new neurons in the hippocampus of older humans, a recent study scotched the idea, claiming that new neurons in the hippocampus were at undetectable levels by our late teens.

Now another group of scientists have published research that pushes back, revealing the new neurons are produced in this brain region in human adults and does not drop off with age. The findings, they say, could help in the hunt for ways to treat conditions ranging from Alzheimer’s to psychiatric problems.

“The exciting part is that the neurons are there throughout a lifetime,” said Dr Maura Boldrini from Columbia University in New York and first author of the new study published in the journal Cell Stem Cell. “It seems that indeed humans are different from mice – where [neuron production] goes down with age really fast – and this could mean that we need these neurons for our complex learning abilities and cognitive behavioural responses to emotions,” she said.

Boldrini and colleagues looked at the hippocampus in 28 men and women aged between 14 and 79, collected just hours after they had died. Importantly, Boldrini notes, all of the individuals were healthy before death, unlike in many previous studies.

Using a number of techniques, the team examined the degree of new blood vessel formation, the volume, and the number of cells of different stages of maturity, in an area known as the dentate gyrus – the region of the hippocampus where new neurons are produced.

“According to mice studies there are these pluripotent stem cells that are a pool of cells that don’t normally do anything, they are quiescent, and then they can undergo division,” said Boldrini, adding that some studies have suggested that we might be born with a finite pool of these ‘mother cells’. “Those daughter cells are the ones that exponentially divide and make many more cells and differentiate towards becoming a neuron.”

The team found levels of these “mother cells” dropped with age in the front and middle region of the dentate gyrus. However, levels of the cells they give rise to did not drop, with the team finding thousands of new, immature neurons in the dentate gyrus at the time of death regardless of age.

“We can still make enough neurons even with fewer left of these ‘mothers’.” said Boldrini.

However, there was a drop in the front of the dentate gyrus in the number of cells producing substances linked to neuroplasticity – the ability for the brain to change or “rewire”.

“Even though we make these new neurons, they might be less plastic, or maybe making fewer connections or migrating less,” said Boldrini.

The authors note that a drop in plasticity might help explain why even healthy people can become more emotionally vulnerable as they age, but that the formation of new cells including neurons might help protect against cognitive or emotional decline.

Boldrini said it was now important to look at what happens in the brains of those with Alzheimer’s and emotional problems, since if there are differences in the formation of new cells in the hippocampus it could offer scientists new targets for treatment.

Dr Mercedes Paredes from the University of California San Francisco, an author of last month’s paper suggesting adults do not develop new neurons, said she was not persuaded. “For now, we do not think this new study challenges what we have concluded from our own recently published observations: if neurogenesis continues in the adult human hippocampus, it is an extremely rare phenomenon,” she said. “It boils down to interpretation of equivocal cells which we took extra steps to characterise extensively and showed not to be new neurons as they first appeared.”

But Dr Niels Haan from Cardiff University said he was convinced new neurons form in the adult human brain, although their function was as yet unclear.

“We know from work in animal models that adult born neurons are required for various learning and memory processes, and there is some evidence suggesting neurogenesis is disrupted in human psychiatric conditions,” he said. “This is a promising area for potential treatments.”


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."


Contents

Developmental neurogenesis Edit

During embryonic development, the mammalian central nervous system (CNS brain and spinal cord) is derived from the neural tube, which contains NSCs that will later generate neurons. [2] However, neurogenesis doesn't begin until a sufficient population of NSCs has been achieved. These early stem cells are called neuroepithelial cells (NEC)s, but soon take on a highly elongated radial morphology and are then known as radial glial cells (RGC)s. [2] RGCs are the primary stem cells of the mammalian CNS, and reside in the embryonic ventricular zone, which lies adjacent to the central fluid-filled cavity (ventricular system) of the neural tube. [3] [4] Following RGC proliferation, neurogenesis involves a final cell division of the parent RGC, which produces one of two possible outcomes. First, this may generate a subclass of neuronal progenitors called intermediate neuronal precursors (INP)s, which will divide one or more times to produce neurons. Alternatively, daughter neurons may be produced directly. Neurons do not immediately form neural circuits through the growth of axons and dendrites. Instead, newborn neurons must first migrate long distances to their final destinations, maturing and finally generating neural circuitry. For example, neurons born in the ventricular zone migrate radially to the cortical plate, which is where neurons accumulate to form the cerebral cortex. [3] [4] Thus, the generation of neurons occurs in a specific tissue compartment or 'neurogenic niche' occupied by their parent stem cells.

The rate of neurogenesis and the type of neuron generated (broadly, excitatory or inhibitory) are principally determined by molecular and genetic factors. These factors notably include the Notch signaling pathway, and many genes have been linked to Notch pathway regulation. [5] [6] The genes and mechanisms involved in regulating neurogenesis are the subject of intensive research in academic, pharmaceutical, and government settings worldwide.

The amount of time required to generate all the neurons of the CNS varies widely across mammals, and brain neurogenesis is not always complete by the time of birth. [2] For example, mice undergo cortical neurogenesis from about embryonic day (post-conceptional day) (E)11 to E17, and are born at about E19.5. [7] Ferrets are born at E42, although their period of cortical neurogenesis does not end until a few days after birth. [8] In contrast, neurogenesis in humans generally begins around gestational week (GW) 10 and ends around GW 25 with birth about GW 38-40. [9]

Epigenetic modification Edit

As embryonic development of the mammalian brain unfolds, neural progenitor and stem cells switch from proliferative divisions to differentiative divisions. This progression leads to the generation of neurons and glia that populate cortical layers. Epigenetic modifications play a key role in regulating gene expression in the cellular differentiation of neural stem cells. Epigenetic modifications include DNA cytosine methylation to form 5-methylcytosine and 5-methylcytosine demethylation. [10] [11] These modifications are critical for cell fate determination in the developing and adult mammalian brain.

DNA cytosine methylation is catalyzed by DNA methyltransferases (DNMTs). Methylcytosine demethylation is catalyzed in several stages by TET enzymes that carry out oxidative reactions (e.g. 5-methylcytosine to 5-hydroxymethylcytosine) and enzymes of the DNA base excision repair (BER) pathway. [10]

Adult neurogenesis Edit

Neurogenesis can be a complex process in some mammals. In rodents for example, neurons in the central nervous system arise from three types of neural stem and progenitor cells: neuroepithelial cells, radial glial cells and basal progenitors, which go through three main divisions: symmetric proliferative division asymmetric neurogenic division and symmetric neurogenic division. Out of all the three cell types, neuroepithelial cells that pass through neurogenic divisions have a much more extended cell cycle than those that go through proliferative divisions, such as the radial glial cells and basal progenitors. [12] In the human, adult neurogenesis has been shown to occur at low levels compared with development, and in only two regions of the brain: the adult subventricular zone (SVZ) of the lateral ventricles, and the dentate gyrus of the hippocampus. [13] [14] [15]

Subventricular zone Edit

In many mammals, including rodents, the olfactory bulb is a brain region containing cells that detect smell, featuring integration of adult-born neurons, which migrate from the SVZ of the striatum to the olfactory bulb through the rostral migratory stream (RMS). [13] [16] The migrating neuroblasts in the olfactory bulb become interneurons that help the brain communicate with these sensory cells. The majority of those interneurons are inhibitory granule cells, but a small number are periglomerular cells. In the adult SVZ, the primary neural stem cells are SVZ astrocytes rather than RGCs. Most of these adult neural stem cells lie dormant in the adult, but in response to certain signals, these dormant cells, or B cells, go through a series of stages, first producing proliferating cells, or C cells. The C cells then produce neuroblasts, or A cells, that will become neurons. [14]

Hippocampus Edit

Significant neurogenesis also occurs during adulthood in the hippocampus of many mammals, from rodents to some primates, although its existence in adult humans is debated. [17] [18] The hippocampus plays a crucial role in the formation of new declarative memories, and it has been theorized that the reason human infants cannot form declarative memories is because they are still undergoing extensive neurogenesis in the hippocampus and their memory-generating circuits are immature. [19] Many environmental factors, such as exercise, stress, and antidepressants have been reported to change the rate of neurogenesis within the hippocampus of rodents. [20] [21] Some evidence indicates postnatal neurogenesis in the human hippocampus decreases sharply in newborns for the first year or two after birth, dropping to "undetectable levels in adults." [17]

Neurogenesis has been best characterized in model organisms such as the fruit fly Drosophila melanogaster. Neurogenesis in these organisms occur in the medulla cortex region of their optic lobes. These organisms can represent a model for the genetic analysis of adult neurogenesis and brain regeneration. There has been research that discuss how the study of “damage-responsive progenitor cells” in Drosophila can help to identify regenerative neurogenesis and how to find new ways to increase brain rebuilding. Recently, a study was made to show how “low-level adult neurogenesis” has been identified in Drosophila, specifically in the medulla cortex region, in which neural precursors could increase the production of new neurons, making neurogenesis occur. [22] [23] [24] In Drosophila, Notch signaling was first described, controlling a cell-to-cell signaling process called lateral inhibition, in which neurons are selectively generated from epithelial cells. [25] [26] In some vertebrates, regenerative neurogenesis has also been shown to occur. [27]

There is evidence that new neurons are produced in the dentate gyrus of the adult mammalian hippocampus, the brain region important for learning, motivation, memory, and emotion. A study reported that newly made cells in the adult mouse hippocampus can display passive membrane properties, action potentials and synaptic inputs similar to the ones found in mature dentate granule cells. These findings suggested that these newly made cells can mature into more practical and useful neurons in the adult mammalian brain. [28]


New neurons for life? Old people can still make fresh brain cells, study finds

One of the thorniest debates in neuroscience is whether people can make new neurons after their brains stop developing in adolescence—a process known as neurogenesis. Now, a new study finds that even people long past middle age can make fresh brain cells, and that past studies that failed to spot these newcomers may have used flawed methods.

The work “provides clear, definitive evidence that neurogenesis persists throughout life,” says Paul Frankland, a neuroscientist at the Hospital for Sick Children in Toronto, Canada. “For me, this puts the issue to bed.”

Researchers have long hoped that neurogenesis could help treat brain disorders like depression and Alzheimer’s disease. But last year, a study in Nature reported that the process peters out by adolescence, contradicting previous work that had found newborn neurons in older people using a variety of methods. The finding was deflating for neuroscientists like Frankland, who studies adult neurogenesis in the rodent hippocampus, a brain region involved in learning and memory. It “raised questions about the relevance of our work,” he says.

But there may have been problems with some of this earlier research. Last year’s Nature study, for example, looked for new neurons in 59 samples of human brain tissue, some of which came from brain banks where samples are often immersed in the fixative paraformaldehyde for months or even years. Over time, paraformaldehyde forms bonds between the components that make up neurons, turning the cells into a gel, says neuroscientist María Llorens-Martín of the Severo Ochoa Molecular Biology Center in Madrid. This makes it difficult for fluorescent antibodies to bind to the doublecortin (DCX) protein, which many scientists consider the “gold standard” marker of immature neurons, she says.

The number of cells that test positive for DCX in brain tissue declines sharply after just 48 hours in a paraformaldehyde bath, Llorens-Martín and her colleagues report today in Nature Medicine . After 6 months, detecting new neurons “is almost impossible,” she says.

When the researchers used a shorter fixation time—24 hours—to preserve donated brain tissue from 13 deceased adults, ranging in age from 43 to 87, they found tens of thousands of DCX-positive cells in the dentate gyrus, a curled sliver of tissue within the hippocampus that encodes memories of events. Under a microscope, the neurons had hallmarks of youth, Llorens-Martín says: smooth and plump, with simple, undeveloped branches.

In the sample from the youngest donor, who died at 43, the team found roughly 42,000 immature neurons per square millimeter of brain tissue. From the youngest to oldest donors, the number of apparent new neurons decreased by 30%—a trend that fits with previous studies in humans showing that adult neurogenesis declines with age. The team also showed that people with Alzheimer’s disease had 30% fewer immature neurons than healthy donors of the same age, and the more advanced the dementia, the fewer such cells.

Some scientists remain skeptical, including the authors of last year’s Nature paper. “While this study contains valuable data, we did not find the evidence for ongoing production of new neurons in the adult human hippocampus convincing,” says Shawn Sorrells, a neuroscientist at the University of Pittsburgh in Pennsylvania who co-authored the 2018 paper. One critique hinges on the DCX stain, which Sorrells says isn’t an adequate measure of young neurons because the DCX protein is also expressed in mature cells. That suggests the “new” neurons the team found were actually present since childhood, he says. The new study also found no evidence of pools of stem cells that could supply fresh neurons, he notes. What’s more, Sorrells says two of the brain samples he and his colleagues looked at were only fixed for 5 hours, yet they still couldn’t find evidence of young neurons in the hippocampus.

Llorens-Martín says her team used multiple other proteins associated with neuronal development to confirm that the DCX-positive cells were actually young, and were “very strict,” in their criteria for identifying young neurons.

Heather Cameron, a neuroscientist at the National Institute of Mental Health in Bethesda, Maryland, remains persuaded by the new work. Based on the “beauty of the data” in the new study, “I think we can all move forward pretty confidently in the knowledge that what we see in animals will be applicable in humans, she says. “Will this settle the debate? I’m not sure. Should it? Yes.”


Concluding Remarks

Recently there has been a remarkable progress in our understanding about the control of adult hippocampal neurogenesis by the CC. However, despite accumulating evidence for multiple and diverse interactions between CC components and fate decisions of NPCs, we are far from drawing a comprehensive picture. Still, several CC proteins await investigation in adult NPCs or are subject to ongoing work. On the other hand, interpretation of existing data is frequently complicated because many G1 regulators, including D-cyclins and CDKs, (i) emerge as pleiotropic molecules regulating multiple cellular functions, often independent from their CC regulatory role and localized to different protein domains, and (ii) display functional redundancy and counter-regulate if the expression of related proteins is experimentally manipulated. Additional detailed analyses of expression patterns in combination with spatiotemporally controlled manipulation of genes, as well as of individual functional domains of CC regulators, may help to answer outstanding questions. We believe that a detailed understanding of the regulatory mechanisms underlying adult neurogenesis may open new avenues for developing therapies of neurodegenerative diseases. The first attempts to exploit this potential have already been made and have produced promising results.


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: Stress, brain plasticity and new neurons - Paul Lucassen (August 2022).