Tag Archives: neurogenesis

New neurons are formed in the brain well into old age — but this stops in Alzheimer’s

The magic happens in the hippocampus.

Image credits: Gerry Shaw.

The majority of our neurons are already in place by the time we are born, although some are still produced during childhood. Traditionally, it was thought that no new neurons are produced during adulthood, but researches are still arguing whether this is truly the case.

Neurogenesis, the production of new neurons, has remained a controversial topic. A recent study found that even if new neurons are produced into adulthood, this process happens early in adulthood, and is very limited. Other studies have claimed that neurogenesis doesn’t happen at all, while some teams have reported evidence of new neurons being formed. The situation is still murky, but a new study tries to clear the waters, reporting that neurons are formed well into old age.

According to a paper published in Nature Medicine, new neurons continuously develop in the healthy human brain up to the ninth decade of life — at least in the hippocampus. Maria Llorens-Martin and colleagues from the Universidad Autónoma de Madrid analyzed tissue samples from 58 human participants.

They found that while neurogenesis can decline with old age, it is still present across the lifespan in the hippocampus, particularly in an area called the dentate gyrus, a region associated with the formation of new episodic memories and the spontaneous exploration of novel environments.

They also find that this process decreases sharply in people suffering from Alzheimer’s.

“By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the dentate gyrus of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages. In sharp contrast, the number and maturation of these neurons declined as AD advanced.”

So not only does the study provide new insight on neurogenesis, but it also highlights a mechanism associated with Alzheimer’s.

“The hippocampus is one of the most affected areas in Alzheimer’s disease,” researchers write in the paper. “Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of new neurons throughout life.”

As for the discrepancies between this study and previous results, researchers say it’s owed to methodological differences. Having high-quality samples and processing them properly and quickly is vital, they argue — otherwise, the evidence of neurogenesis can be destroyed. Factors such as tissue fixation techniques or delays in the time between tissue acquisition and processing can alter the results, they explain.

“Our data demonstrate that the prolonged or uncontrolled fixation conditions to which human samples are typically exposed in brain banks worldwide lead to a sharp reduction in the number of [neurons] detected in the adult dentate gyrus,” the paper concludes.

The study “Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease” has been published in Nature Medicine.

 

We can’t grow new neurons in adulthood after all, new study says

Previous research has suggested neurogenesis — the birth of new neurons — was able to take place in the adult human brain, but a new controversial study published in the journal Nature seems to challenge this idea.

a. Toluidine-blue-counterstained semi-thin sections of the human Granule Cell Layer (GCL) from fetal to adult ages. Note that a discrete cellular layer does not form next to the GCL and the small dark cells characteristic of neural precursors are not present.

Scientists have been struggling to settle the matter of human neurogenesis for quite some time. The first study to challenge the old theory that humans did not have the ability to grow new neurons after birth was published in 1998, but scientists had been questioning this entrenched idea since the 60’s when emerging techniques for labeling dividing cells revealed the birth of new neurons in rats. Another neurogenesis study was published in 2013, reinforcing the validity of the results from 1998.

Arturo Alvarez-Buylla, a neuroscientist at the University of California, San Francisco, and his team conducted a study to test the neurogenesis theory using immunohistochemistry — a process that applies various fluorescent antibodies on brain samples. The antibodies signal if young neurons as well as dividing cells are present. Researchers involved in this study were shocked by the findings.

“We went into the hippocampus expecting to see many young neurons,” says senior author Arturo Alvarez-Buylla. “We were surprised when we couldn’t find them.”

In the new study, scientists analyzed brain samples from 59 patients of various ages, ranging from fetal stages to the age of 77. The brain tissue samples came from people who had died or pieces were extracted in an unrelated procedure during brain surgery. Scientists found new neurons forming in prenatal and neonatal samples, but they did not find any sustainable evidence of neurogenesis happening in humans older than 13. The research also indicates the rate of neurogenesis drops 23 times between the ages one and seven.

But some other uninvolved scientists say that the study left much room for error. The way the brain slices were handled, the deceased patients’ psychiatric history, or whether they had brain inflammation could all explain why the researchers failed to confirm earlier findings.

The 1998 study was performed on brains of dead cancer patients who had received injections of a chemical called bromodeoxyuridine while they were still alive. The imaging molecule — which was used as a cancer treatment — became integrated into the DNA of actively dividing cells. Fred Gage, a neuroscientist involved in the 1998 study, says that this new paper does not really measure neurogenesis.

“Neurogenesis is a process, not an event. They just took dead tissue and looked at it at that moment in time,” he adds.

Gage also thinks that the authors used overly restrictive criteria for counting neural progenitor cells, thus lowering the chances of seeing them in adult humans.

But some neuroscientists agree with the findings. “I feel vindicated,” Pasko Rakic, a longtime outspoken skeptic of neurogenesis in human adults, told Scientific American. He believes the lack of new neurons in adult primates and humans helps preserve complex neural circuits. If new neurons would be constantly born throughout adulthood, they could interfere with preexisting precious circuits, causing chaos in the central nervous system.

“This paper not only shows very convincing evidence of a lack of neurogenesis in the adult human hippocampus but also shows that some of the evidence presented by other studies was not conclusive,” he says.

Dividing neural progenitors in the granule cell layer (GCL) are rare at 17 gestational weeks (orthogonal views, inset) but were abundant in the ganglionic eminence at the same age (data not shown). Dividing neural progenitors were absent in the GCL from 22 gestational weeks to 55 years.

Steven Goldman, a neurologist at the University of Rochester Medical Center and the University of Copenhagen, said, “It’s by far the best database that has ever been put together on cell turnover in the adult human hippocampus. The jury is still out about whether there are any new neurons being produced.” He added that if there is neurogenesis, “it’s just not at the levels that have been presumed by many.”

The debate still goes on. No one really seems to know the answer yet, but I think that’s a positive — the controversy will generate a new wave of research on the subject.

Evidence that RMST is necessary for neuronal differentiation: overexpression of RMST led to a 3-fold increase in neuron-specific beta tubulin (bottom) compared to control (top). Scale bars represent 100 microns. (Credit: Shi-Yan Ng et al./Molecular Cell)

Gene key in neuron generation discovered

Scientists have discovered an atypical gene that is thought to be crucial for the generation of new neurons in the brain, a process called neurogenesis. The discovery and further study of the gene might help scientists better understand how neurodegenerative diseases such as Alzheimer’s affect the brain and, in term, how to address them.

Evidence that RMST is necessary for neuronal differentiation: overexpression of RMST led to a 3-fold increase in neuron-specific beta tubulin (bottom) compared to control (top). Scale bars represent 100 microns. (Credit: Shi-Yan Ng et al./Molecular Cell)

Evidence that RMST is necessary for neuronal differentiation: overexpression of RMST led to a 3-fold increase in neuron-specific beta tubulin (bottom) compared to control (top). Scale bars represent 100 microns. (Credit: Shi-Yan Ng et al./Molecular Cell)

New neurons are born through a complex temporal and spatial control of hundreds of genes. The expression of these genes is controlled by regulatory networks, usually involving proteins, indispensable for the well functioning of the central nervous system. When one or some of these genes are inhibited or over expressed,  neurological disorders develop. Understanding the mechanisms that govern neurogenesis becomes thus of the utmost importance when developing treatments for such serious diseases.

A major breakthrough in this respect was recently made by scientists at A*STAR’s Genome Institute of Singapore (GIS), who discovered a key component within a gene regulatory network that controls the birth of new neurons, called RMST. This component isn’t a protein like most people, even the researchers involved in the study, thought. RMST is an atypical, long non-coding RNA, a newly discovered class of RNA whose functions remain largely unknown

In this latest study, one of the components in this new class has been at least demystified. They found that RMST acts directly within a gene regulatory network.

“Stanton and colleagues show how RMST, a human lncRNA, directly regulates SOX2, a key transcription factor protein that is instrumental for directing the birth of new neurons,” said Associate Prof Leonard Lipovich, from the Center for Molecular Medicine and Genetics at the Wayne State University and a member of GENCODE. Even more intriguingly, they highlight that RMST controls SOX2 by directly interacting with the protein.

Their work is important not only because it sheds light on the process of neurogenesis, but also new insight into how lncRNA works together with protein components to regulate the important biological processes of gene expression.

“The paper is therefore an important advance in the still nascent and controversial field of riboregulators, or RNAs that regulate proteins in our cells. DNA-binding proteins that turn genes on and off were traditionally thought to be distinct from RNA-binding proteins. Stanton et al, however, illuminate the cryptic, yet crucial, RNA-binding roles for DNA-binding transcription factors: lncRNAs just might be the definitive regulatory switch that controls these factors’ activity.”

Findings were reported in the journal Molecular Cell.

[via KurzweilAI]