Scientists have known for about two decades that some neurons – the fundamental cells in the brain that transmit signals – are generated throughout life. But now a controversial new study from the University of California, San Francisco, casts doubt on whether many neurons are added to the human brain after birth.
As a translational neuroscientist, this work immediately piqued my interest. It has direct implications for the research my lab does: We transplant young neurons into damaged brain areas in mice in an attempt to treat epileptic seizures and the damage they’ve caused. Like many labs, part of our work is based on a foundational belief that the hippocampus is a brain region where new neurons are born throughout life.
If the new study is right, and human brains for the most part don’t add new neurons after infancy, researchers like me need to reconsider the validity of the animal models we use to understand various brain conditions – in my case temporal lobe epilepsy. And I suspect other labs that focus on conditions including drug addiction, depression and post-traumatic stress disorder are thinking about what the UCSF study means for their investigations, too.
In the brain of a baby who died soon after birth, there are many new neurons (green in this image) in the hippocampus.Sorrells et al, CC BY-ND
Neurogenesis – the production of new neurons – was previously thought to only occur during embryonic life, a time of extremely rapid brain growth and expansion, and the rodent findings were met with considerable skepticism. Then researchers discovered that new neurons are also born throughout life in the songbird brain, a species scientists use as a model for studying vocal learning. It started to look like neurogenesis plays a key role in learning and neuroplasticity – at least in some brain regions in a few animal species.
Even so, neuroscientists were skeptical that many nerve cells could be renewed in the adult brain; evidence was scant that dividing cells in mammalian brains produced new neurons, as opposed to other cell types. It wasn’t until researchers extracted neural stem cells from adult mouse brains and grew them in cell culture that scientists showed these precursor cells could divide and differentiate into new neurons. Now it is generally well accepted that neurogenesis takes place in two areas of the adult rodent brain: the olfactory bulbs, which process smell information, and the hippocampus, a region characterized by neuroplasticity that is required for forming new declarative memories.
Adult neural stem cells cluster together in what scientists call niches – hotbeds for cultivating the birth and growth of new neurons, recognizable by their distinctive architecture. Despite the mounting evidence for regional growth of new neurons, these studies underscored the point that the adult brain harbors only a few stem cell niches and their capacity to produce neurons is limited to just a few types of cells.
With this knowledge, and new tools for labeling proliferating cells and identifying maturing neurons, scientists began to look for postnatal neurogenesis in primate and human brains.
What’s happening in adult human brains?
Many neuroscientists believe that by understanding the process of adult neurogenesis we’ll gain insights into the causes of some human neurological disorders. Then the next logical step would be trying to develop new treatments harnessing neurogenesis for conditions such as Alzheimer’s disease or trauma-induced epilepsy. And stimulating resident stem cells in the brain to generate new neurons is an exciting prospect for treating neurodegenerative diseases.
However, obtaining rigorous proof for adult neurogenesis in the human and primate brain has been technically challenging – both due to the limited experimental approaches and the larger sizes of the brains, compared to reptiles, songbirds and rodents.
Researchers injected a compound found in DNA, nicknamed BrdU to identify brand new neurons in human adult hippocampus – but the labeled cells were extremely rare. Other groups demonstrated that adult human brain tissue obtained during neurosurgery contained stem cell niches that housed progenitor cells that could generate new neurons in the lab, showing that these cells had an inborn neurogenic capacity, even in adults.
But even when scientists saw evidence for new neurons in the brain, they tended to be scarce. Some neurogenesis experts were skeptical that evidence based on incorporating BrdU into DNA was a reliable method for proving that new cells were actually being born through cell division, rather than just serving as a marker for other normal cell functions.
Further questions about how long human brains retain the capacity for neurogenesis arose in 2011, with a study that compared numbers of newborn neurons migrating in the olfactory bulbs of infants versus older individuals up to 84 years of age. Strikingly, in the first six months of life, the baby brains contained lots of chains of young neurons migrating into the frontal lobes, regions that guide executive function, long-range planning and social interactions. These areas of the human cortex are hugely increased in size and complexity compared to rodents and other species. But between 6 to 18 months of age, the migrating chains dwindled to a thin stream. Then, a very different pattern emerged: Where the migrating chains of neurons had been in the infant brain, a cell-free gap appeared, suggesting that neural stem cells become depleted during the first six months of life.
Questions still lingered about the human hippocampus and adult neurogenesis as a source for its neuroplasticity. One group came up with a clever approach based on radiocarbon dating. They measured how much atmospheric ¹⁴C – a radioactive isotope derived from nuclear bomb tests – was incorporated into people’s DNA. This method suggested that as many as 700 new cells are added to the adult human hippocampus every day. But these findings were contradicted by a 2016 study that found that the neurogenic cells in the adult hippocampus could only produce non-neuronal brain cells called microglia.
Rethinking neurogenesis research
Now the largest and most comprehensive study conducted to date presents even stronger evidence that robust neurogenesis doesn’t continue throughout adulthood in the human hippocampus – or if it does persist, it is extremely rare. This work is controversial and not universally accepted. Critics have been quick to cast doubt on the results, but the finding isn’t totally out of the blue.
So where does this leave the field of neuroscience? If the UCSF scientists are correct, what does that mean for ongoing research in labs around the world?
Because lots of studies of neurological diseases are done in mice and rats, many scientists are invested in the possibility that adult neurogenesis persists in the human brain, just as it does in rodents. If it doesn’t, how valid is it to think that the mechanisms of learning and neuroplasticity in our model animals are comparable to those in the human brain? How relevant are our models of neurological disorders for understanding how changes in the hippocampus contribute to disorders such as the type of epilepsy I study?
In my lab, we transplant embryonic mouse or human neurons into the adult hippocampus in mice, after damage caused by epileptic seizures. We aim to repair this damage and suppress seizures by seeding the mouse hippocampus with neural stem cells that will mature and form new connections. In temporal lobe epilepsy, studies in adult rodents suggest that naturally occurring hippocampal neurogenesis is problematic. It seems that the newborn hippocampal neurons become highly excitable and contribute to seizures. We’re trying to inhibit these newborn hyperexcitable neurons with the transplants. But if humans don’t generate new hippocampal neurons, then maybe we’re developing a treatment in mice for a problem that has a different mechanism in people.
Perhaps our species has evolved separate mechanisms for neuroplasticity, distinct from those used by species such as rats and mice. One possibility is that there are other sites in the human brain where neurogenesis occurs – its a big structure and more exploration will be necessary. If it turns out to be true that the human brain has a diminished capacity for neurogenesis after birth, the finding will have important implications for how neuroscientists like me think about tackling brain disorders.
Perhaps most importantly, this work underscores how crucial it is to learn how to increase the longevity of the neurons we do have, born early in life, and how we might replace or repair neurons that become damaged.
Epilepsy affects more than 65 million people worldwide. One-third of these patients have seizures that are not controlled by medications. In addition, one-third have brain lesions, the hallmark of the disease, which cannot be located by conventional imaging methods. Researchers at the Perelman School of Medicine at the University of Pennsylvania have piloted a new method using advanced noninvasive neuroimaging to recognize the neurotransmitter glutamate, thought to be the culprit in the most common form of medication-resistant epilepsy. Their work is published today in Science Translational Medicine.
Glutamate is an amino acid which transmits signals from neuron to neuron, telling them when to fire. Glutamate normally docks with the neuron, gives it the signal to fire and is swiftly cleared. In patients with epilepsy, stroke and possibly ALS, the glutamate is not cleared, leaving the neuron overwhelmed with messages and in a toxic state of prolonged excitation.
In localization-related epilepsy, the most common form of medication-resistant epilepsy, seizures are generated in a focused section of the brain; in 65 percent of patients, this occurs in the temporal lobe. Removal of the seizure-generating region of the temporal lobe, guided by preoperative MRI, can offer a cure. However, a third of these patients have no identified abnormality on conventional imaging studies and, therefore, more limited surgical options.
“Identification of the brain region generating seizures in location-related epilepsy is associated with significantly increased chance of seizure freedom after surgery,” said the new study’s lead author, Kathryn Davis, MD, MSTR, an assistant professor of Neurology at Penn. “The aim of the study was to investigate whether a novel imaging method, developed at Penn, could use glutamate to localize and identify the epileptic lesions and map epileptic networks in these most challenging patients.”
“We theorized that if we could develop a technique which allows us to track the path of and make noninvasive measurements of glutamate in the brain, we would be able to better identify the brain lesions and epileptic foci that current methods miss,” said senior author Ravinder Reddy, PhD, a professor of Radiology and director of Penn’s Center for Magnetic Resonance and Optical Imaging.
Reddy’s lab developed the glutamate chemical exchange saturation transfer (GluCEST) imaging method, a very high resolution magnetic resonance imaging contrast method not available before now, to measure how much glutamate was in different regions of the brain including the hippocampi, two structures within the left and right temporal lobes responsible for short- and long-term memory and spatial navigation and the most frequent seizure onset region in adult epilepsy patients.
The study tested four patients with medication-resistant epilepsy and 11 controls. In all four patients, concentrations of glutamate were found to be higher in one of the hippocampi, and confirmatory methods (electroencephalography and magnetic resonance spectra) verified independently that the hippocampus with the elevated glutamate was located in the same hemisphere as the epileptic focus/lesion. Consistent lateralization to one side was not seen in the control group.
While preliminary, this work indicates the ability of GluCEST to detect asymmetrical hippocampal glutamate levels in patients thought to have nonlesional temporal lobe epilepsy. The authors say this approach could reduce the need for invasive intracranial monitoring, which is often associated with complications, morbidity risk, and added expense.
“This demonstration that GluCEST can localize small brain hot spots of high glutamate levels is a promising first step in our research,” Davis said. “By finding the epileptic foci in more patients, this approach could guide clinicians toward the best therapy for these patients, which could translate to a higher rate of successful surgeries and improved outcomes from surgery or other therapies in this difficult disease.”
There have been remarkable advances in understanding the brain, but how do you actually study the neurons inside it? Using gorgeous imagery, neuroscientist and TED Fellow Carl Schoonover shows the tools that let us see inside our brains.
Discovery brings with it possible implications for brain regeneration –
In a cross-domain study directed by professor Peter Carmeliet (VIB – KU Leuven), researchers discovered unexpected cells in the protective membranes that enclose the brain, the so called meninges. These ‘neural progenitors’ (stem cells that differentiate into different kinds of neurons) are produced during embryonic development.
These findings show that the neural progenitors found in the meninges produce new neurons after birth, highlighting the importance of meningeal tissue as well as these cells’ potential in the development of new therapies for brain damage or neurodegeneration. A paper highlighting the results is published in the journal Cell Stem Cell.
Scientists’ understanding of brain plasticity, or the ability of the brain to grow, develop, recover from injuries and adapt to changing conditions throughout our lives, has been greatly broadened in recent years. Before the discoveries of the last few decades, neurologists once thought that the brain became ‘static’ after childhood. This dogma has changed, with researchers finding more and more evidence that the brain is capable of healing and regenerating in adulthood, thanks to the presence of stem cells. However, neuronal stem cells were generally believed to only reside within the brain tissue, not in the membranes surrounding it.
The meninges: unappreciated no more
Believed in the past to serve a mainly protective function to dampen mechanical shocks, the meninges have been historically underappreciated by science as having neurological importance in its own right. The data gathered by the team challenges the current idea that neural precursors—or stem cells that give rise to neurons—can only be found inside actual brain tissue.
Prof. Peter Carmeliet notes: “The neuronal stems cells that we discovered inside the meninges differentiate to full neurons, electrically-active and functionally integrated into the neuronal circuit. To show that the stem cells reside in the meninges, we used the extremely powerful single-cell RNA sequencing technique, a very novel top-notch technique, capable of identifying the [complex gene expression signature] nature of individual cells in a previously unsurpassed manner, a première at VIB.”
Following up on future research avenues
When it comes to future leads for this discovery, the scientists also see possibilities for translation into clinical application, though future work is required.
“An intriguing question is whether these neuronal stem cells in the meninges could lead to better therapies for brain damage or neurodegeneration. However, answering this question would require a better understanding of the molecular mechanisms that regulate the differentiation of these stem cells,” says Carmeliet. “How are these meningeal stem cells activated to become different kinds of neurons? Can we therapeutically ‘hijack’ their regeneration potential to restore dying neurons in, for example, Alzheimer’ Disease, Parkinson’s Disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders? Also, can we isolate these neurogenic progenitors from the meninges at birth and use them for later transplantation? These findings open up very exciting research opportunities for the future.”
Moving into unchartered territory is high risk, and can offer high gain, but securing funding for such type of research is challenging. However, Carmeliet’s discoveries were made possible to a large extent by funding through “Opening the Future: pioneering without boundaries”, a recently created Mecenas Funding Campaign for funding of high risk brain research but with potential for breakthrough discoveries, started up by the KU Leuven in 2013 and unique in Flanders.
“Being able to use such non-conventional funding channels is of utmost importance to break new boundaries in research,” says Carmeliet. “This unique Mecenas funding initiative by the KU Leuven is innovative and boundary-breaking by itself. Our entire team is enormously grateful for the opportunities it has created for our investigations”.
Note: Material may have been edited for length and content. For further information, please contact the cited source.
Columbia University Medical Center (CUMC) researchers have discovered how a new epilepsy drug works, which may lead the way to even more effective and safer medications.
The findings were published today in Neuron.
The most commonly used anti-epilepsy drugs are ineffective for about 30 percent of people with seizure disorders.
A new direction in the treatment of epilepsy is aimed at inhibiting AMPA receptors, which help transmit electrical signals in the brain and play a key role in propagating seizures. Currently, perampanel is the only FDA-approved drug that targets AMPA receptors. But because perampanel is associated with significant side effects, its clinical use has been limited.
“The problem is that AMPA receptors are heavily involved in the central nervous system, so if you inhibit their function, you cause an array of unwanted effects,” said study leader Alexander I. Sobolevsky, PhD, professor of biochemistry and molecular biophysics at CUMC. “If we hope to design better drugs for epilepsy, we need to learn more about the structure and function of these receptors.”
In this study, Dr. Sobolevsky employed a technique called crystallography to determine how perampanel and two other inhibitors interact with the AMPA receptors to stop transmission of electrical signals. The study was conducted using rat AMPA receptors, which are almost identical to human receptors.
In the new study, the researchers were able to pinpoint exactly where the drugs bind to AMPA receptors.
“Our data suggest that the inhibitors wedge themselves into the AMPA receptor, which prevents the opening of a channel within the receptor,” said Dr. Sobolevsky. When that channel is closed, ions cannot pass into the cell to trigger an electrical signal.
According to the researchers, these findings may allow drug makers to develop medications that are highly selective for the AMPA receptors, which could be safer and more effective than currently available anti-epilepsy drugs.
TBI Rehabilitation 