Posts Tagged Neurogenesis

[VIDEO] Stem Cell Therapy for Stroke – YouTube

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[WEB SITE] The Brain Can Give Birth To New Cells Throughout Life, Study Finds

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Researchers used to think that after adolescence, people were pretty well stuck with the brain cells they’d already formed. No so anymore. Discoveries in recent years have shown that neurogenesis—the formation of new neurons—can occur much later than this, well into adulthood. And now, a new study from the University of Illinois at Chicago finds that brain cells can form into one’s nineties, even if one has cognitive decline and Alzheimer’s disease (though at a much decelerated rate). The question is how the late-in-life growth of new neurons fits into what’s already known about degenerative diseases.

The study was published last week in the journal Cell Stem Cell.

The researchers looked at the postmortem brains of people aged 79-99, some of whom had had cognitive decline or Alzheimer’s disease. They targeted markers for two kinds of burgeoning cells—neuroblasts (stem cells that would one day give rise to neurons), and immature neurons—in the hippocampus, the brain area that’s most affected in Alzheimer’s disease.

People who had died without cognitive problems had proliferation of both kinds of cells in their brains. People with cognitive decline and Alzheimer’s also had evidence of the cells, but in much lower numbers.

Lazarov, neurogenesis study

COURTESY, ORLY LAZAROV, ET AL.

“We found that there was active neurogenesis in the hippocampus of older adults well into their 90s,” said study author Orly Lazarov in a statement. “The interesting thing is that we also saw some new neurons in the brains of people with Alzheimer’s disease and cognitive impairment.”

What was interesting was the finding that people who had scored higher on tests of cognition during their later lives had more neuroblasts in their hippocampi, compared to those who’d scored lower—and this was independent of the level of degeneration that was visible in the brain.

“In brains from people with no cognitive decline who scored well on tests of cognitive function, these people tended to have higher levels of new neural development at the time of their death, regardless of their level of pathology,” Lazarov said. “The mix of the effects of pathology and neurogenesis is complex and we don’t understand exactly how the two interconnect, but there is clearly a lot of variation from individual to individual.”

The finding is intriguing since it’s long been known that a person’s level of brain “gunk” (the plaques and tangles associated with Alzheimer’s disease) doesn’t always correlate with their cognitive and behavioral symptoms. So it’s possible that these new findings helps explain why this disconnect exists—perhaps the level of neurogenesis matters as much or more than the amount of plaques and tangles that develop. If that’s true, then the big question would be how to harness this for therapeutic purposes.

“The fact that we found that neural stem cells and new neurons are present in the hippocampus of older adults means that if we can find a way to enhance neurogenesis, through a small molecule, for example, we may be able to slow or prevent cognitive decline in older adults, especially when it starts, which is when interventions can be most effective,” said Lazarov.

More research will obviously be needed to understand all of this, but preventing cognitive decline and dementia is probably the way to go, especially since medications to treat Alzheimer’s after the fact have fallen flat in recent years. In the meantime, the study is encouraging on another level: Certain lifestyle habits—most notably exercise—have consistently been shown to boost neurogenesis. The findings suggest we’d do well to pick up exercise, and other brain-healthy habits, and engage in them for as much of our lives as we can, as regularly as we’re able.

 

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[WEB SITE] The Adult Brain Does Grow New Neurons After All, Study Says

Study points toward lifelong neuron formation in the human brain’s hippocampus, with implications for memory and disease

The Adult Brain Does Grow New Neurons After All, Study Says

Cerebral cortical neuron. Credit: Getty Images

If the memory center of the human brain can grow new cells, it might help people recover from depression and post-traumatic stress disorder (PTSD), delay the onset of Alzheimer’s, deepen our understanding of epilepsy and offer new insights into memory and learning. If not, well then, it’s just one other way people are different from rodents and birds.

For decades, scientists have debated whether the birth of new neurons—called neurogenesis—was possible in an area of the brain that is responsible for learning, memory and mood regulation. A growing body of research suggested they could, but then a Nature paper last year raised doubts.

Now, a new study published today in another of the Nature family of journals—Nature Medicine—tips the balance back toward “yes.” In light of the new study, “I would say that there is an overwhelming case for the neurogenesis throughout life in humans,” Jonas Frisén, a professor at the Karolinska Institute in Sweden, said in an e-mail. Frisén, who was not involved in the new research, wrote a News and Views about the study in the current issue of Nature Medicine.

Not everyone was convinced. Arturo Alvarez-Buylla was the senior author on last year’s Nature paper, which questioned the existence of neurogenesis. Alvarez-Buylla, a professor of neurological surgery at the University of California, San Francisco, says he still doubts that new neurons develop in the brain’s hippocampus after toddlerhood.

“I don’t think this at all settles things out,” he says. “I’ve been studying adult neurogenesis all my life. I wish I could find a place [in humans] where it does happen convincingly.”

For decades, some researchers have thought that the brain circuits of primates—including humans—would be too disrupted by the growth of substantial numbers of new neurons. Alvarez-Buylla says he thinks the scientific debate over the existence of neurogenesis should continue. “Basic knowledge is fundamental. Just knowing whether adult neurons get replaced is a fascinating basic problem,” he said.

New technologies that can locate cells in the living brain and measure the cells’ individual activity, none of which were used in the Nature Medicinestudy, may eventually put to rest any lingering questions.

A number of researchers praised the new study as thoughtful and carefully conducted. It’s a “technical tour de force,” and addresses the concerns raised by last year’s paper, says Michael Bonaguidi, an assistant professor at the University of Southern California Keck School of Medicine.

The researchers, from Spain, tested a variety of methods of preserving brain tissue from 58 newly deceased people. They found that different methods of preservation led to different conclusions about whether new neurons could develop in the adult and aging brain.

Brain tissue has to be preserved within a few hours after death, and specific chemicals used to preserve the tissue, or the proteins that identify newly developing cells will be destroyed, said Maria Llorens-Martin, the paper’s senior author. Other researchers have missed the presence of these cells, because their brain tissue was not as precisely preserved, says Llorens-Martin, a neuroscientist at the Autonomous University of Madrid in Spain.

Jenny Hsieh, a professor at the University of Texas San Antonio who was not involved in the new research, said the study provides a lesson for all scientists who rely on the generosity of brain donations. “If and when we go and look at something in human postmortem, we have to be very cautious about these technical issues.”

Llorens-Martin said she began carefully collecting and preserving brain samples in 2010, when she realized that many brains stored in brain banks were not adequately preserved for this kind of research. In their study, she and her colleagues examined the brains of people who died with their memories intact, and those who died at different stages of Alzheimer’s disease. She found that the brains of people with Alzheimer’s showed few if any signs of new neurons in the hippocampus—with less signal the further along the people were in the course of the disease. This suggests that the loss of new neurons—if it could be detected in the living brain—would be an early indicator of the onset of Alzheimer’s, and that promoting new neuronal growth could delay or prevent the disease that now affects more than 5.5 million Americans.

Rusty Gage, president of the Salk Institute for Biological Studies and a neuroscientist and professor there, says he was impressed by the researchers’ attention to detail. “Methodologically, it sets the bar for future studies,” says Gage, who was not involved in the new research but was the senior author in 1998 of a paper that found the first evidence for neurogenesis. Gage says this new study addresses the concerns raised by Alvarez-Buylla’s research. “From my view, this puts to rest that one blip that occurred,” he says. “This paper in a very nice way… systematically evaluates all the issues that we all feel are very important.”

Neurogenesis in the hippocampus matters, Gage says, because evidence in animals shows that it is essential for pattern separation, “allowing an animal to distinguish between two events that are closely associated with each other.” In people, Gage says, the inability to distinguish between two similar events could explain why patients with PTSD keep reliving the same experiences, even though their circumstances have changed. Also, many deficits seen in the early stages of cognitive decline are similar to those seen in animals whose neurogenesis has been halted, he says.

In healthy animals, neurogenesis promotes resilience in stressful situations, Gage says. Mood disorders, including depression, have also been linked to neurogenesis.

Hsieh says her research on epilepsy has found that newborn neurons get miswired, disrupting brain circuits and causing seizures and potential memory loss. In rodents with epilepsy, if researchers prevent the abnormal growth of new neurons, they prevent seizures, Hsieh says, giving her hope that something similar could someday help human patients. Epilepsy increases someone’s risk of Alzheimer’s as well as depression and anxiety, she says. “So, it’s all connected somehow. We believe that the new neurons play a vital role connecting all of these pieces,” Hsieh says.

In mice and rats, researchers can stimulate the growth of new neurons by getting the rodents to exercise more or by providing them with environments that are more cognitively or socially stimulating, Llorens-Martin says. “This could not be applied to advanced stages of Alzheimer’s disease. But if we could act at earlier stages where mobility is not yet compromised,” she says, “who knows, maybe we could slow down or prevent some of the loss of plasticity [in the brain].”


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The Adult Brain Does Grow New Neurons After All, Study Says – Scientific American

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[ARTICLE] Impact of Traumatic Brain Injury on Neurogenesis – Full Text

New neurons are generated in the hippocampal dentate gyrus from early development through adulthood. Progenitor cells and immature granule cells in the subgranular zone are responsive to changes in their environment; and indeed, a large body of research indicates that neuronal interactions and the dentate gyrus milieu regulates granule cell proliferation, maturation, and integration. Following traumatic brain injury (TBI), these interactions are dramatically altered. In addition to cell losses from injury and neurotransmitter dysfunction, patients often show electroencephalographic evidence of cortical spreading depolarizations and seizure activity after TBI. Furthermore, treatment for TBI often involves interventions that alter hippocampal function such as sedative medications, neuromodulating agents, and anti-epileptic drugs. Here, we review hippocampal changes after TBI and how they impact the coordinated process of granule cell adult neurogenesis. We also discuss clinical TBI treatments that have the potential to alter neurogenesis. A thorough understanding of the impact that TBI has on neurogenesis will ultimately be needed to begin to design novel therapeutics to promote recovery.

Introduction

Adult neurogenesis in the hippocampal dentate gyrus is widespread in mammals. Generation of dentate granule cells occurs late in embryonic development, continues after birth, and persists into old age in most mammals examined (Amrein et al., 2011Amrein, 2015Ngwenya et al., 2015). Studies in rodents indicate that adult generated granule cells play a role in hippocampal dependent learning (Nakashiba et al., 2012Danielson et al., 2016Johnston et al., 2016). Whether neurogenesis continues into old age in humans remains controversial (Danzer, 2018a), with studies finding evidence for (Eriksson et al., 1998Spalding et al., 2013Boldrini et al., 2018) and against ongoing neurogenesis (Sorrells et al., 2018). Yet there is general agreement that dentate neurogenesis occurs in childhood and continues throughout young adulthood in humans, and that newly-generated neurons are poised to contribute to hippocampal function. At a minimum, therefore, traumatic brain injuries (TBIs) occurring during adolescence have the potential to disrupt this important process.

The generation, maturation, and integration of new neurons is critical for hippocampal function. This tightly regulated process, however, is easily disrupted by pathological events, such as TBI. In this review, we discuss the coordinated process of adult neurogenesis in the hippocampal subgranular zone (SGZ) and the impact that TBI and TBI treatments have on this process. An understanding of the regulation and dysregulation of neurogenesis is important for determining whether and how therapeutic interventions targeted at adult neurogenesis are useful for TBI treatment.

Neurogenesis Is a Complex, Tightly-Regulated Process

Adult neurogenesis is characterized by multiple “control” points. The number of daughter cells produced by neural stem cells (NSC) located in the SGZ of the dentate gyrus can be modulated by the rate of cell proliferation and survival, while factors regulating fate specification control whether and how the new cells become neurons and integrate into the hippocampal circuitry (see recent review by Song et al., 2016). These control points can be regulated by signals released into the extracellular milieu by both neuronal and non-neuronal cells (Alenina and Klempin, 2015Egeland et al., 2015), neurotrophic and transcription factors (Faigle and Song, 2013Goncalves et al., 2016), neuroinflammatory mediators (Belarbi and Rosi, 2013), metabolic and hormonal changes (Cavallucci et al., 2016Larson, 2018), and direct synaptic input from both glutamatergic and GABAergic neurons (Chancey et al., 2014Alvarez et al., 2016Song et al., 2016Yeh et al., 2018). For additional information, the readers are referred to the excellent reviews cited for each mechanism, and the schematic in Figure 1. Critically, all of these factors can be disrupted by TBI, creating an environment in which immature granule cells and granule cell progenitors no longer receive the proper cues to guide their development.

Figure 1. Generation and integration of adult-born granule cells is a coordinated process that is impacted by TBI. At each stage of adult neurogenesis, the normal process (blue) has potential to be altered by TBI (orange). (1) Quiescent radial neural stem cells (NSCs) in the subgranular zone (SGZ) can be depleted by frequent activation early in life, such as by TBI-induced seizures, leading to deficiencies with age. (2) TBI and its effects, including spreading depolarizations and seizures, cause an increase in proliferation of progenitor cells. (3) Newly-generated neurons migrate from the SGZ to the granule cell layer (GCL), and after TBI abnormal hilar migration is apparent. (4) Parvalbumin interneurons and (5) mossy hilar neurons are susceptible to cell death after TBI. Reduction in their numbers results in decreased GABAergic and glutamatergic (respectively) input to the newly-generated neurons. Newly-generated neurons show additional signs of aberrant neurogenesis such as abnormal connectivity (6), hyperexcitability (7) and inappropriate integration and dendritic maturity (8) which can be caused by changes in the environmental milieu.

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Continue —>  Frontiers | Impact of Traumatic Brain Injury on Neurogenesis | Neuroscience

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[WEB SITE] Neuroplasticity and Stroke Recovery

Neuroplasticity

You can ask many different experts, and neuroplasticity will be explained in many different ways. The purpose of this website is not to get into technical jargon that overwhelms the stroke patient but rather to educate persons about stroke rehabilitation in simple laymen terms. In stroke recovery, neuroplasticity basically refers to the ability of the brain to rewire or reorganize itself after injury. Various studies over the past decade have shown that the adult brain can “rewire” itself when damaged. Studies have also shown that the adult brain can create new neurons, a phenomenon called neurogenesis. These new neurons require support from neighboring cells, blood supply, and connection with other neurons to survive. Certain requirements must be met during rehabilitation for neurogenesis and plasticity to actually change the brain. Rehabilitation involving neuroplasticity principles requires repetition of task and task specific practice to be effective. What this means for the stroke patient is that going to see your therapist for a one hour visit (or even a 3 hour visit) is not enough to lead to neuroplastic changes in the brain. Patients need to think of physical, occupational, and speech therapy as an adjunct to stroke recovery. It’s up to the patient to make the most of recovery by continuously using the injured parts of the body and mind outside of therapy sessions in everyday life.

A good comparison would be how one learns multiplication. A teacher doesn’t just show a multiplication table a couple of times to her students for the concept to be mastered. Instead, students have to practice over and over to learn and master multiplication. A child doesn’t learn how to walk overnight. It requires much practice. A baseball player doesn’t become elite just by playing a few games of baseball. You must take control of your stroke recovery process and be willing to invest a lot of time and energy if you want to see change especially with moderate to severe stroke. It’s also important to keep using a skill once you have mastered it – use it or lose it as you often hear in rehab.

Please note that plasticity doesn’t mean that one can practice every task over and over and accomplish them all. Stroke is much more complicated than that. Different parts of the brain control different body functions and the brain adapts better to some areas of damage more than others. Scientists have identified certain areas of the brain that yield neurogenesis but have not identified it in all areas of the brain. If you want to learn more about your specific stroke, ask your neurologist specifically what areas of your brain were affected. The neurologist will also be able to tell you what problems you can expect because of that damage (e.g. speech deficits, vision deficits, dizziness, difficulties with balance, etc.) You can further improve your rehabilitation by specifically targeting the weaknesses caused by your stroke.

In my opinion, neuroplasticity doesn’t necessarily change exercise and therapeutic activities done in stroke rehabilitation but rather emphasizes that more repetition and task specific practice is needed. Probably the most commonly used therapy that is based on neuroplasticity is constraint induced therapy. Constraint induced therapy involves limiting the movement of the non-affected or stronger arm and instead using the affected or weaker arm more frequently and intensely. There has been some positive research results with constraint induced therapy, however, it requires much effort and patience from the stroke patient. Some other treatments that may help with brain reorganization include interactive metronome, brain retraining software and websites, mirror box therapy, and robotic and gait devices that assist with movement repetition.

Research is still needed in the area of brain plasticity and stroke rehabilitation. Scientists have demonstrated that brain reorganization can occur, but only limited rehab treatments have been developed that address neuroplasticity. The stroke patient, however, armed with the knowledge that brain rewiring occurs with repetition, can improve their rehabilitation outcomes by application of this concept in their daily lives. Remember, therapy is an adjunct to recovery. You cannot go to therapy sessions and expect positive outcomes without applying what you have learned on a consistent daily basis.

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[WEB SITE] Human brains make new nerve cells — and lots of them — well into old age.

Previous studies have suggested neurogenesis tapers off or stops altogether

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LAUREL HAMERS, APRIL 5, 2018
nerve cells in hippocampi

NEURON NURSERY  Roughly the same number of new nerve cells (dots) exist in the hippocampus of people in their 20s (three hippocampi shown, top row) as in people in their 70s (bottom). Blue marks the dentate gyrus, where new nerve cells are born.
M. BOLDRINI/COLUMBIA UNIV.

Your brain might make new nerve cells well into old age.

Healthy people in their 70s have just as many young nerve cells, or neurons, in a memory-related part of the brain as do teenagers and young adults, researchers report in the April 5 Cell Stem Cell. The discovery suggests that the hippocampus keeps generating new neurons throughout a person’s life.

The finding contradicts a study published in March, which suggested that neurogenesis in the hippocampus stops in childhood (SN Online: 3/8/18). But the new research fits with a larger pile of evidence showing that adult human brains can, to some extent, make new neurons. While those studies indicate that the process tapers off over time, the new study proposes almost no decline at all.

Understanding how healthy brains change over time is important for researchers untangling the ways that conditions like depression, stress and memory loss affect older brains.

When it comes to studying neurogenesis in humans, “the devil is in the details,” says Jonas Frisén, a neuroscientist at the Karolinska Institute in Stockholm who was not involved in the new research. Small differences in methodology — such as the way brains are preserved or how neurons are counted — can have a big impact on the results, which could explain the conflicting findings. The new paper “is the most rigorous study yet,” he says.

Researchers studied hippocampi from the autopsied brains of 17 men and 11 women ranging in age from 14 to 79. In contrast to past studies that have often relied on donations from patients without a detailed medical history, the researchers knew that none of the donors had a history of psychiatric illness or chronic illness. And none of the brains tested positive for drugs or alcohol, says Maura Boldrini, a psychiatrist at Columbia University. Boldrini and her colleagues also had access to whole hippocampi, rather than just a few slices, allowing the team to make more accurate estimates of the number of neurons, she says.

To look for signs of neurogenesis, the researchers hunted for specific proteins produced by neurons at particular stages of development. Proteins such as GFAP and SOX2, for example, are made in abundance by stem cells that eventually turn into neurons, while newborn neurons make more of proteins such as Ki-67. In all of the brains, the researchers found evidence of newborn neurons in the dentate gyrus, the part of the hippocampus where neurons are born.

Although the number of neural stem cells was a bit lower in people in their 70s compared with people in their 20s, the older brains still had thousands of these cells. The number of young neurons in intermediate to advanced stages of development was the same across people of all ages.

Still, the healthy older brains did show some signs of decline. Researchers found less evidence for the formation of new blood vessels and fewer protein markers that signal neuroplasticity, or the brain’s ability to make new connections between neurons. But it’s too soon to say what these findings mean for brain function, Boldrini says. Studies on autopsied brains can look at structure but not activity.

Not all neuroscientists are convinced by the findings. “We don’t think that what they are identifying as young neurons actually are,” says Arturo Alvarez-Buylla of the University of California, San Francisco, who coauthored the recent paper that found no signs of neurogenesis in adult brains. In his study, some of the cells his team initially flagged as young neurons turned out to be mature cells upon further investigation.

But others say the new findings are sound. “They use very sophisticated methodology,” Frisén says, and control for factors that Alvarez-Buylla’s study didn’t, such as the type of preservative used on the brains.

via Human brains make new nerve cells — and lots of them — well into old age | Science News

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[WEB SITE] Newborn Neurons in the Adult Brain: Real Deal, or Glial Imposters? – Full Text Article

Deep in the hippocampus, are new neurons born throughout life? Just when scientists were about to reach some consensus that the answer was yes, two recent studies disagree. In the April 5 Cell Stem Cell, Maura Boldrini and colleagues at Columbia University, New York, report that adult neurogenesis not only exists, but remains steady into old age. The researchers counted newborn neurons in samples from people aged 14–79 years, and came up with similar numbers. In the March 7 Nature, researchers led by Arturo Alvarez-Buylla at the University of California, San Francisco, reported that while neural progenitors abounded in postmortem hippocampi from prenatal or early childhood brains, they fell off the map by age 7. What gives? In older people, some of the cells that expressed markers of budding neurons turned out to be glia, the authors claim.

  • Neural progenitor cells proliferate in human hippocampus throughout adulthood, says a new study.
  • It blames waning angiogenesis, not faulty neurogenesis, for lost neuroplasticity in old age.
  • In contrast, another paper claims brain neurogenesis fizzles during childhood.
  • It claims some cells bearing neural progenitor markers are actually glia.

Who is right? Researchers who spoke with Alzforum stood squarely behind Boldrini because she used stereology, a gold standard quantitation method, to estimate numbers of neural progenitors throughout the entire dentate gyrus of postmortem brain. Alvarez-Buylla’s team estimated cell numbers using only three to five slices from each postmortem sample. “It would be very difficult to rule out neurogenesis by this method,” said Orly Lazarov of the University of Illinois in Chicago, who pointed out that because the study relied on small numbers of individuals per age group, the data could be misleading.

Others, including Jonas Frisén of the Karolinska Institute in Stockholm, pointed to a long list of previous papers supporting the existence of neurogenesis in the adult human brain. “An analogy is that 10 people go into the woods to search for blueberries,” he wrote, “Nine come back with blueberries and one does not. Are there blueberries in that forest?”

Tracking Neurogenesis.
Scientists used a combination of cell-surface markers to count neural progenitors along the development spectrum in the dentate gyrus. While neurogenesis held steady, angiogenesis and neuroplasticity declined with age. [Courtesy of Boldrini et al., Cell Stem Cell, 2018.]

Still, others acknowledged that some of those “blueberries” might have been glia. “To me, it boils down to a single question: are these proliferating cells truly neural progenitors, or not?” asked Costantino Iadecola of Weill Cornell Medical College in New York.

Numerous studies in rodents support the idea that neural progenitors in the mammalian brain continue to trickle out fresh neurons into adulthood, though factors such as aging and disease dampen the flow (Altman and Das, 1965Sep 2001 newsFeb 2002 newsKempermann et al., 2003Mar 2010 news). Tracking neurogenesis in humans has been trickier, but a seminal study two decades ago set the stage: Five terminal cancer patients received an injection of bromodeoxyuridine (BrdU), a dye that incorporates into DNA during cell division. Postmortem analyses revealed evidence of dividing neurons in the dentate gyri of all of the patients (Eriksson et al., 1998). Since then, carbon-14 tracing and immunohistochemistry studies have supported the idea that new neurons arise in the adult human brain (Knoth et al., 2010Jun 2013 newsFeb 2014 news).

Boldrini and colleagues set out to determine if age affects adult neurogenesis. They acquired hippocampal samples from 11 women and 17 men, aged 14–79, who were cognitively normal, had suffered no brain trauma, had had no microvascular pathology in the brain, and had clean toxicology reports at the time of death. The researchers collected 50-micron thick sections every 2 mm along the entirety of the hippocampus, and used both immunofluorescence and immunocytochemistry to label various cell-surface markers associated with five different stages of neural development (see image below). Finally, they estimated cell numbers throughout the dentate gyrus using stereology, whereby a computer algorithm calculates total cell numbers in a region by combining data from multiple sections. They reported the number of neural progenitors in the anterior, mid-, and posterior dentate gyrus.

The earliest neural progenitors known, called quiescent radial-like type I neural progenitors (QNPs), express GFAP, a marker shared with astrocytes; nestin, an intermediate filament protein that marks neural stem cells; and the transcription factor Sox2, which is required for the maintenance of multipotent stem cells. The researchers found that numbers of these cells decreased with age in the anterior-mid dentate gyrus. This is in keeping with the prevailing view that people are born with a finite number of these QNPs, Boldrini said.

QNPs give rise to type II intermediate neural progenitors. INPs are proliferating cells that express Ki67, a marker of actively dividing cells. Neuroblasts, or type III INPs, also proliferate, but lose expression of GFAP and Sox2. Based on expression of Ki67, nestin, and Sox2, the researchers determined that numbers of type II and III INPs remained steady, on the order of thousands of cells, in all three regions of the dentate gyrus throughout life. These neural progenitors were found in the subgranular zone (SGZ), which is proposed to be the predominant neurogenic niche in the region, as well as the granule cell layer (GCL, see image below). The findings pointed to a stable supply of neural progenitors in the dentate gyrus throughout adult life.

The researchers next asked whether those progenitors would fulfill their destiny and give rise to immature neurons and, ultimately, bona fide granule neurons. On the way to becoming fully fledged neurons, type III INPs start to express doublecortin (DCX), a microtubule-associated protein involved in neural migration. They also produce polysialylated neural cell adhesion molecule (PSA-NCAM), a glycoprotein they need for plasticity. Together, DCX and PSA-NCAM mark young neurons, which continue to express both proteins until they differentiate into mature neurons, whereupon they suppress DCX. The researchers found that the tissue donors had similar numbers of cells co-expressing DCX and PSA-NCAM, regardless of their age, suggesting neurogenesis continued unabated throughout life. Numbers of NeuN+ mature neurons also held steady, indicating that neuronal loss in the dentate gyrus is not a characteristic of healthy aging, either.

The researchers calculated that each dentate gyrus had between 10,000 and 15,000 young neurons (i.e., type III INPs and immature neurons). While the functional significance of these cell numbers is unclear, Boldrini speculated that this ongoing level of neurogenesis influences neural circuitry and cognition. For this reason, boosting neurogenesis could be a therapeutic strategy for neurodegenerative disease, she said.

A New Neuron?
An immature neuron (red arrow) co-expressing PSA-NCAM and DCX lingers between the subgranular zone (SGZ) and the granule cell layer (GCL) in the dentate gyrus. Two other PSA-NCAM+ cells do not express DCX (yellow arrows).[Courtesy of Boldrini et al., Cell Stem Cell, 2018.]

However, while older adults appear to generate as many new neurons as younger people, those new cells may be less plastic, judging by a decline in PSA-NCAM+/DCX– cells in the anterior dentate gyrus. Curiously, using endothelial markers and stereology to measure the numbers, length, bifurcations, and total volume of capillaries, the scientists also found an age-dependent decline in angiogenesis in the same regions. The researchers proposed that a decline in angiogenesis may trigger loss of neuroplasticity without necessarily affecting neurogenesis, for example by starving new neurons of essential growth factors or nutrients.

Others were not convinced, noting that reliance on a single marker—PSA-NCAM—made the plasticity results no more than an interesting correlation. Still, Lazarov and Iadecola said the connection between age-related decline in angiogenesis and neuroplasticity was plausible. Iadecola was surprised that loss of angiogenesis did not appear to affect neurogenesis, but he noted that the donors had no obvious vascular pathology in their brains. Perhaps in people with more severe vascular problems, neurogenesis would be affected, he said.

In Grown-Up Brain, Nary a Newborn Neuron
In the Nature paper, first author Shawn Sorrells and colleagues used many of the same markers—Sox2, GFAP, DCX, and PSA-NCAM—to assess neurogenesis in postmortem samples across the lifespan. This included 11 samples from prenatal donors, the youngest of whom was only at 14 weeks gestation. They also analyzed seven samples from infants who died during their first year of life, one from a 7-year-old, one from a 13-year-old, and 17 samples from adults up to 77 years of age at the time of death. The samples came from multiple sources, and were not limited to healthy donors, or all postmortem. They included hippocampal tissue from surgical resection in 22 people with epilepsy, who ranged from three months to 64 years old.

For the postmortem samples, the researchers used three to five coronal sections to assess cell numbers. Rather than using stereology to estimate the total number of cells in the dentate gyrus, the researchers counted cells in individual sections. Three researchers independently counted each section while blinded to the age of the donor. They identified key structural landmarks, most notably the cell-dense GCL, to infer the relative locations of the cells.

In prenatal samples, the scientists found abundant proliferating Ki67+ cells that expressed the progenitor markers Sox1 and Sox2. Numbers of these cells plummeted during the first year of life, and were near zero in samples from people 7 or older. Notably, these proliferating cells never coalesced beneath the GCL to form a distinctive layer in the SGZ, a structural niche that supports neurogenesis in rodent models. The researchers confirmed the absence of this layer by electron microscopy on a subset of their samples, ranging in age from 22 gestational weeks to 48 years of age.

Neurogenesis Decline. Sections of dentate gyrus reveal a sharp decline in young neurons (yellow) from birth to 77 years of age. Granule cell layer traced in blue. [Courtesy of Sorrells et al., Nature, 2018.]

 

DCX+/PSA-NCAM+ cells, representing intermediate neural progenitors and immature neurons, clustered throughout the GCL at birth to a density of about 1,600 cells per mm2. In prenatal and infant samples, these cells had a smooth, elongated morphology characteristic of young neurons. By 13 years of age, sections only contained around two young neurons per mm2, or roughly one or two cells per section. Likewise, the investigators found no evidence of young neurons in samples from epilepsy patients older than 11. As for adults, none of the surgical or postmortem samples contained DCX+/PSA-NCAM+ cells, however the researchers did find cells that expressed PSA-NCAM without DCX. Unlike the elongated young neurons in infant samples, these cells had a more mature neuronal morphology with distinct axons and dendrites, and expressed NeuN, suggesting they were highly plastic neurons. The researchers also identified DCX+ cells in some older childhood and adult samples, but these cells co-expressed glial markers, and under the gaze of electron microscopy, had glial morphology.

The researchers also looked for evidence of neurogenesis in rhesus macaques. By staining with similar neuronal markers, they found that unlike in the human brain, proliferating neural progenitors did gather in the SGZ before birth. However, the number of these young neurons decreased eightfold between birth and 1.5 years of age, and were sparse in 7-year-old animals. Similarly, labeling dividing cells with BrdU revealed a steep drop-off in dividing neurons between 1.5 and 7 years of age.

Glial Impostor?
DCX+ (green) cells co-expressing the oligodendrocyte marker Olig2 (red). [Courtesy of Sorrells et al., Nature, 2018.]

The researchers concluded that neurogenesis is robust only in the earliest stages of development, and that DCX+ cells in late childhood and adult samples were actually glia. In an email to Alzforum, Sorrells and Alvarez-Buylla speculated that the cells identified as young neurons in the Boldrini study were also likely non-neuronal. “Identifying new neurons is technically challenging—in our own recent study we made similar observations to what Boldrini et al. report, but after extensive additional analysis of the shape and appearance of the cells in question, including electron microscopy and gene expression, we determined that these cells were not in fact young neurons or neural progenitors but different types of cells altogether,” they wrote.

However, Boldrini asserted that in her study, the cells stained for both DCX and PSA-NCAM did not co-localize with cells that appeared to be glia based on the pattern of Nissl staining, and were present in the thousands. Boldrini added that the immature neurons took on a pyramidal shape, characteristic of neurons, not glia.

Sorrells and Alvarez-Buylla further drew attention to the lack of a defined layer of proliferating cells in the SGZ in their study, adding that Boldrini’s samples also appeared to lack a distinct layer of cells there. In rodents, neural progenitors gather and proliferate in the SGZ. On this issue, Boldrini thinks that perhaps in humans neurogenesis occurs in a more scattered fashion. She said that for this reason, taking stock of cells throughout the entire dentate gyrus is crucial to capture these sparse cells.—Jessica Shugart

via Newborn Neurons in the Adult Brain: Real Deal, or Glial Imposters? | ALZFORUM

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[ARTICLE] Neurogenesis: Study Sparks Controversy Over Whether Humans Continue to Make New Neurons Throughout Life

ARTICLE IN BRIEF

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A new study offers new data challenging the prevailing view that neurogenesis occurs beyond childhood into adulthood.

For two decades, humans have been comforted by scientific discoveries showing that specific regions of the human brain, primarily the hippocampus, continue to grow neurons throughout life, a finding that suggests more is better (for learning and memory that are governed by the hippocampus) and that there may be backup plans in case our old neurons die.

But scientists at the University of California, San Francisco (UCSF) have looked at dozens of tissue samples from autopsied brains and epilepsy patients undergoing resection and found that the birth of new neurons is robust in fetal life and during the first year of life but then decreases rapidly in childhood. In adults, it was not possible (with current technology used) to identify populations of new neurons. The oldest samples with evidence of neurogenesis came from seven-year-old and a thirteen-year-old, the researchers reported in the March 15 issue of Nature.

Until the late 1990s, it had long been thought that primates, including humans, are born with the complete set of neurons for a lifetime. Through development and beyond, humans lose neuronal cells, but never gain new ones. First came rodent and bird studies, then monkeys, refuting these age-old beliefs, and then evidence from humans as well.

In an editorial in the same issue of Nature, neuroscientist Jason Snyder, a doctoral candidate and assistant professor in the psychology department at the University of British Columbia, wrote that the findings “are in stark contrast to the prevailing view” and “certain to stir up controversy.”

The study was led by Arturo Alvarez-Buylla, PhD, the Heather and Melanie Muss professor of neurological surgery at the University of California, San Francisco. Dr. Alvarez-Buylla was at Rockefeller University in the 1980s working with his mentor, Fernando Nottebohm, PhD, who first reported the birth of new neurons in the brains of adult canaries and its possible link to learning their annual mating songs. Dr. Alvarez-Buylla has spent his career studying the mechanism of adult neurogenesis and began looking at human samples more than a decade ago.

“We find that neurogenesis in the adult hippocampus in humans, if it occurs at all, is an extremely rare phenomenon, raising questions about its contribution to brain repair or normal brain function,” said the neuroscientist. “We have just looked at one region of the brain. There is a lot more work to do. Clearly the fascinating process of making a new neuron continues in young children. We should continue to study how neurons are made and whether it is possible to induce new neurons to grow in the adult brain to treat brain diseases.”

STUDY METHODS, FINDINGS

Dr. Alvarez-Buylla and his colleagues studied 59 samples of human hippocampal tissue from UCSF and collaborating centers around the world. Thirty-seven came from postmortem brain samples and the rest were from fresh tissue excised from patients undergoing treatment for epilepsy. The samples came from fetuses, newborns, children, adolescents and adults. The oldest sample came from a 77-year-old.

The investigators used several techniques to tag neural stem cells and young neurons (the markers include doublecortin and PSA NCAM) to search for evidence of newborn and mature brain cells. They also used high resolution electron microscopy to examine the cell’s shape and structure to make sure they were looking at neurons and not glial cells.

Dr. Alvarez-Buylla and his colleagues found evidence of new neurons in the dentate gyrus of the hippocampus in the fetal brain tissue and in the samples from newborns and infants. They counted an average of 1,618 young neurons per square millimeter of brain tissue at birth. The older the infant, the fewer the new neurons. The tissue from one-year olds have five-fold fewer new neurons; there was a 23-fold decline by age seven, and new neurons were hard to find by adolescence. The teen brain had about 2.4 new cells per square millimeter of dentate gyrus tissue.

The investigators did find an occasional young neuron in a few adult post-mortem brain samples in the walls of the brain ventricles, as previously reported, but when looking at the hippocampus of samples from people over 18 years old, the group could not find the young neurons or much evidence of proliferation next to the dentate gyrus, said Dr. Alvarez-Buylla.

The group also looked for neural progenitor stem cells that give rise to neurons. Again, it was not surprising that the fetal brain was filled with these progenitors, particularly in regions were the dentate is growing, but these cells were gone by early childhood, he explained.

Dr. Alvarez-Buylla said that the idea for this study was sparked by a visit to the laboratory Zhengang Yang, PhD, at Fudan University in China and co-author on the current paper.

Dr. Yang showed him some beautifully stained samples of hippocampal tissue from a 35-year-old. The tissue was collected within hours of his death. “We could find some new neurons close to the walls of the ventricle, but not in the hippocampus,” said Dr. Alvarez-Buylla. That was four years ago.

Dr. Alvarez Buylla returned to California and started looking at more hippocampal tissue in samples collected at UCSF. Then, he and his colleagues looked at more tissue samples from Jose Manuel Garcia-Verdugo, PhD, of University of Valencia in Spain and from Gary W. Mathern, MD, from the University of California, Los Angeles, also study collaborators.

“We are simply reporting what we observed, and to correct the record that there is no significant neurogenesis in the adult human hippocampus,” Dr. Alvarez-Buylla said.

“The process of making a new neuron in the adult brain remains a fundamental problem that we need to understand,” added Dr. Alvarez-Buylla, who is co-founder of Neurona Therapeutics, and serves on its scientific advisory board. “What’s next is to do more research.”

He thinks that the replacement of neurons in the complex human brain could potentially change brain circuits in detrimental ways. “Neurons have the potential to live for very long periods of time. There may be important reasons why we may need to keep the neurons we develop in fetal and early postnatal development.

There could be other reasons, he explained: “Making a new neuron in large brains, like ours, may be complicated by the changes in development. We have speculated that the early specification of stem cells (that is linked to location) could make it very difficult to seed stem cells within niches that continually expand to incredibly large sizes. It could also be associated to longevity; stem cells may not be able to self-renew infinitively and in species that live as long as we do, these key progenitors may get used up in early life. We, simply, do not know why some species retain significant neurogenesis in adulthood, while others, like us don’t.”

He also stressed that this study focused only in the hippocampus and in the search for the new neurons in the dentate. “There is a lot of human brain yet to be explored.”

“I think that we need to step back and ask what that means,” added UCSF neuroscientist Shawn F. Sorrells, PhD, the first author of the Nature paper. “If neurogenesis is so rare that we can’t detect it, can it really be playing a major role in plasticity or learning and memory in the hippocampus?”

EXPERT COMMENTARY

No one refutes the science that rodents continue to grow neurons throughout adulthood and that these neurons migrate to specialized regions like the dentate gyrus and the olfactory bulb. Elizabeth Gould, PhD, a neuroscientist at Princeton University, described neurogenesis in the dentate gyrus of adult rats in 1992. Fred H. Gage, PhD, a neurobiologist in the laboratory of genetics at The Salk Institute for Biological Sciences, published a series of studies suggesting that enriched environments and exercise could enhance adult neurogenesis in rats. Others showed that stress could diminish it.

Dr. Gage and his colleagues reported the first evidence of adult human neurogenesis in tissue samples from five cancer patients in 1997. Cancer doctors had used an imaging stain called bomodeoxyuridine (BrdU) in their patients to track tumor growth, and the scientists received permission to obtain brain slices right after the patients died. BrdU gets into the DNA of dividing cells, and the Salk scientists found staining in the dentate, which suggested that these were new neurons.

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The science of adult neurogenesis continued to be debated as researchers questioned how robust the cellular growth is, where it is, and, most importantly, what is the purpose of this proliferation.

This new study may fuel this controversy. “This paper is the most thorough and rigorous study to date addressing human hippocampal neurogenesis,” said David R. Kornack, PhD, associate professor in the department of neuroscience at the University of Rochester. “It is such an important issue whether we continue to make new neurons in our brains as adults that the evidence has to be incontrovertible.”

Dr. Kornack has been studying neurogenesis for decades and was working with Pasko Rakic, MD, PhD, at Yale University School of Medicine, in the late 1990s when they identified evidence of adult neurogenesis in macaque monkeys — in a confocal microscope, they saw what they believed to be a small population of new neurons in the dentate gyrus of the hippocampus.

They published the study in 1999 in the Proceedings of the National Academy of Sciences, and Dr. Rakic continued to raise his concerns about adult neurogenesis in humans.

“For me, this new study closes the chapter about the prevalence of hippocampal neurogenesis in human adults,” added Dr. Kornack. “We are learning the powers and limitations of the technology and defining what a new neuron is. The strength of the finding is that they did see new neurons in younger tissue and not in older tissue. It confirms that hippocampal neurogenesis declines with age, which was already shown in monkeys and rodents. We are a long-lived species that rely on stored memories and behavior for our survival and stability. It may be a disadvantage to replace old neurons.”

His mentor agrees. “I feel vindicated,” said Pasko Rakic, MD, PhD, the Dorys McConnell Duberg professor of neuroscience and professor of neurology at Yale University School of Medicine. “I wanted to discover adult human neurogenesis, but I just couldn’t find it.”

Dr. Rakic said that adult neurogenesis is a limited event in the human brain, where even fewer new neurons were found than in the macaques. Additionally, he said adult rats had 10 to 14 times more new neurons in the hippocampus than the macaques had. The decreases in the number of these cells from rats to primates suggests, he said, “it must be more important not to have new neurons.”

Dr. Rakic added: “In evolution, our advantage is to preserve learned behavior. For memory, it isn’t productive to have new neurons but to preserve our old ones. We need stability of our neurons. If we added new neurons, they would not hold the memories of our past experiences. I use the same neurons I did as a child when I think of my mother. We need to invest in understanding how to keep our old neurons healthy. People think this is a negative finding. I think it is positive. It shows the value of keeping old cells in our brain, cells that have accumulated a lifetime of knowledge.”

Dr. Gage, PhD, of the Salk Institute for Biological Sciences, said that this latest study doesn’t disprove adult neurogenesis. Their conclusion is based “on the absence of morphological features and the lack of expression of two marker proteins, DCX and PSA-NCAM,” he said. “Both markers are very sensitive to methodological factors inherent to human brain tissue. One is the postmortem delay, the time between the death of a person and the moment the brain is removed and fixed. DCX is rapidly broken down after death and its staining disappears within a few hours of postmortem delay.”

He continued: “In this paper, many subjects had very long postmortem delays of ‘less than 48 hrs.’ As there is no mention of matching between subjects, or other optimization done in terms of the markers used, this influence of postmortem delay and on DCX integrity, which will also differ strongly between subjects, would question their conclusion about neurogenesis, as no control for DCX degradation was included.”

He added that adult mouse and adult human neurogenesis may use different proteins and they did not quantify or measure adult neurogenesis but rather proteins expressed in mice and immature cells.

LINK UP FOR MORE INFORMATION:

•. Sorrells SF, Paredes MR, Cebrian-Silla A, et al Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults https://www.nature.com/articles/nature25975Nature 2018; 555(7696): 377–381.

•. Snyder JS. Questioning human neurogenesis https://www.nature.com/articles/d41586-018-02629-3Nature 2018; 555(7696):315–316.

•. Kornack DR, Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey http://www.pnas.org/content/96/10/5768Proc Natl Acad Sci USA 1999; 96(10):5768–5773.

© 2018 American Academy of Neurology

 

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[WEB SITE] New brain cells are added in elderly adult brains too

According to a new study from the Columbia University however, brain cells are continuously added to our brains even when we reach our 70s. This is a process called neurogenesis. Their work is published in a study that appeared in the latest issue of the journal Cell Stem Cell this week.

Neuron detailed anatomy illustrations. Neuron types, myelin sheath formation, organelles of the neuron body and synapse. Image Credit: Tefi / Shutterstock

Lead author Dr. Maura Boldrini, a research scientist at the department of psychiatry, Columbia University and her colleagues investigated the brains of 28 dead people aged between 14 and 79 years. They were studying the effects of aging on the brain’s neuron production. The team examined the brains that were donated by the families of the deceased at the time of death. The brains were frozen immediately at minus-112 degrees Fahrenheit before they could be examined. This preserved the tissues.

Neurogenesis has been shown to decline with age in lab mice and rats as well as in experimental primates. The team wanted to explore if same rates of decline are seen in human brains as well. So they checked the brains samples for developing neurons. These developmental stages included stem cells, intermediate progenitor cells, immature neuronal cells and finally new mature neurons. They focused on the hippocampus region of the brain that deals with memory and emotional control and behavior.

The results revealed that for all age groups, the hippocampus shows new developing neurons. The researchers concluded that even during old age, the hippocampus continues to make new neurons. The differences that they noted with age include reduction in the development of new blood vessels as people got older. The proteins that help the neurons to make new connections are reduced with age. This was a finding that differentiated ageing brains from younger ones, they explained. Boldrini said the new neurons are there in older brains but they make fewer connections than younger brains. This explains the memory losses and decrease in emotional resiliency in older adults she said.

An earlier study last month came from another set of researchers led by University of California San Francisco researcher Arturo Alvarez-Buylla. The study titled, “Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults,” was published first week of March this year in the journal Nature.

The team found that after adolescence there is little or no neurogenesis in the brain. They examined the brains of 17 deceased individuals and 12 patients with epilepsy part of whose brains had been surgically resected. The debate between the two teams continues. Boldrini explained that Buylla’s team had examined different types of samples that were not preserved as her samples had been.

Further the other team examined three to five sections of the hippocampus and not the whole of it she explained. More studies on this needed to make concrete conclusions regarding neurogenesis in the elderly say experts.

References

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[WEB SITE] Brain tissue samples suggest we stop adding neurons in our early teens

By Deborah Netburn – Los Angeles Times, Posted: 12:00 a.m. Saturday, March 17, 2018

New research suggests that the human brain does not add more neurons to its circuitry once it has reached maturity.

The work, published in Nature, contradicts a smattering of earlier studies that found that humans did indeed have the ability to add to their neural networks even after they reached adulthood.

Amar Sahay, a professor at the Harvard Stem Cell Institute who was not involved in the research, said the new findings are sure to make a splash.

“But that’s science,” he said. “It’s not always a straight line from point A to point B. Sometimes it’s a winding road.”

Researchers have known for decades that many animals — including mice, canaries and monkeys — have the ability to produce new neurons over the course of their lives in the process known as neurogenesis.

A small number of papers had indicated that adult humans also possessed this capability, specifically in an interior region of the brain known as the hippocampus that is associated with memory.

However, after examining brain tissue samples collected from 59 human subjects ranging in age from a 14-week-old fetus to a 77-year-old man, the authors found that neurogenesis drops off considerably in humans after one year of life. After adolescence, it appears to stop completely.

The findings came as a bit of a shock to the research team from the University of California, San Francisco

“We went into this work thinking we were going to find evidence of neurogenesis because other groups did,” said Mercedes Paredes, an assistant professor of neurology at UCSF and one of the leaders of the study. “So we were actually surprised when we didn’t see any evidence of it in our adult samples.”

Neurons are the oddly shaped cells that process and transmit information in our brain. Arturo Alvarez-Buylla, the principal investigator of the study, described them as the semiconductors of the brain.

The vast majority of neurons are generated during fetal development, but scientists have shown that in some regions of the brain, new neurons can continue to be made in adult animals.

“It is really a feat of biology,” said Alvarez-Buylla. “The cell has to be born, then migrate and integrate into the tissue, make new extensions to connect with other cells, and then it has to contribute to the brain function.”

Although this process has been well studied in mice, rats and canaries among other animals, only a handful of studies have sought to discover if neurogenesis also occurs in people after childhood.

“It’s tricky,” Paredes said. “It’s hard to study human brain tissue, not only to get the samples, but to know how to analyze them and have confidence in the result.”

The samples used in this work were collected from hospitals in China, Spain, Los Angeles and San Francisco. Most of the brain tissue came from people who had just died, but 22 samples came from brain operations that were performed on living people as a treatment for epilepsy.

“In those cases we were able to get the tissue very quickly, preserve them in the best way possible and then analyze them with less concern for degradation,” Paredes said.

Instead of looking for new neurons themselves, the authors analyzed their tissue samples for combinations of proteins that are associated both with young neurons and with the stem cells that would make new neurons.

To make sure there was no mistake with their detection method, the authors looked to see if they could find evidence of new neuron growth in the brain tissue of fetuses, where they were certain that new neurons were developing. And indeed, when they looked at the fetal hippocampus, they were able to see that it was filled with young neurons.

Next they wondered if perhaps their methods were only capable of detecting neurogenesis in young brains, and not in the brains of adults. To see if that was the case they analyzed two post-mortem autopsy samples and looked for evidence of young neurons in another region of the brain that is known to produce new neurons into childhood. There, the authors did find rare examples of young neurons, but very few.

After they were convinced that there was nothing wrong with their detection technique, the authors set about making sense of their data.

Their research had shown that there are significantly fewer immature neurons in the 1-year-old brain, compared to earlier stages of life. In addition, the oldest sample where they still saw evidence of young neurons came from a 13-year-old.

via Brain tissue samples suggest we stop adding neurons in our early teens

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