Study findings have potential to prevent, reverse serious disabilities affecting children born prematurely

Physician-scientists at Oregon Health & Science University Doernbecher Children’s Hospital are challenging the way pediatric neurologists think about brain injury in the pre-term infant. In a study published online in the Jan. 16 issue of Science Translational Medicine, the OHSU Doernbecher researchers report for the first time that low blood and oxygen flow to the developing brain does not, as previously thought, cause an irreversible loss of brain cells, but rather disrupts the cells’ ability to fully mature. This discovery opens up new avenues for potential therapies to promote regeneration and repair of the premature brain.

“As neurologists, we thought ischemia killed the neurons and that they were irreversibly lost from the brain. But this new data challenges that notion by showing that ischemia, or low blood flow to the brain, can alter the maturation of the neurons without causing the death of these cells. As a result, we can focus greater attention on developing the right interventions, at the right time early in development, to promote neurons to more fully mature and reduce the often serious impact of preterm birth. We now have a much more hopeful scenario,” said Stephen Back, M.D., Ph.D., lead investigator and professor of pediatrics and neurology in the Papé Family Pediatric Research Institute at OHSU Doernbecher Children’s Hospital.

Researchers at OHSU Doernbecher have conducted a number of studies in preterm fetal sheep to define how disturbances in brain blood flow lead to injury in the developing brain. Their findings have led to important advances in the care of critically ill newborn infants.

For this study, Back and colleagues used pioneering new MRI studies that allow injury to the developing brain to be identified much earlier than previously feasible. They looked at the cerebral cortex, or “thinking” part of the brain, which controls the complex tasks involved with learning, attention and social behaviors that are frequently impaired in children who survive preterm birth. Specifically, they observed how brain injury in the cerebral cortex of fetal sheep evolved over one month and found no evidence that cells were dying or being lost. They did notice, however, that more brain cells were packed into a smaller volume of brain tissue, which led to, upon further examination, the discovery that the brain cells weren’t fully mature.

In a related study published in the same online issue of Science Translational Medicine, investigators at The Hospital for Sick Children and the University of Toronto studied 95 premature infants using MRI and found that impaired growth of the infants was the strongest predictor of the MRI abnormalities, suggesting that interventions to improve infant nutrition and growth may lead to improved cortical development.

“I believe these studies provide hope for the future for preterm babies with brain injury, because our findings suggest that neurons are not being permanently lost from the human cerebral cortex due to ischemia. This raises the possibility that neurodevelopmental enrichment — or perhaps improved early infant nutrition — as suggested by the companion paper, might make a difference in terms of improved cognitive outcome,” Back said.

“Together, these studies challenge the conventional wisdom that preterm birth is associated with a loss of cortical neurons. This finding may change the way neurologists think about diagnosing and treating children born prematurely,” said Jill Morris, Ph.D., a program director at the National Institute’s of Health’s National Institute Neurological Disorders and Stroke.

Possible role for Huntington’s gene discovered

About 20 years ago, scientists discovered the gene that causes Huntington’s disease, a fatal neurodegenerative disorder that affects about 30,000 Americans. The mutant form of the gene has many extra DNA repeats in the middle of the gene, but scientists have yet to determine how that extra length produces Huntington’s symptoms.

In a new step toward answering that question, MIT biological engineers have found that the protein encoded by this mutant gene alters patterns of chemical modifications of DNA. This type of modification, known as methylation, controls whether genes are turned on or off at any given time.

The mutant form of this protein, dubbed “huntingtin,” appears to specifically target genes involved in brain cell function. Disruptions in the expression of these genes could account for the neurodegenerative symptoms seen in Huntington’s disease, including early changes in cognition, says Ernest Fraenkel, an associate professor of biological engineering at MIT.

Fraenkel’s lab is now investigating the details of how methylation might drive those symptoms, with an eye toward developing potential new treatments. “One could imagine that if we can figure out, in more mechanistic detail, what’s causing these changes in methylation, we might be able to block this process and restore normal levels of transcription early on in the patients,” says Fraenkel, senior author of a paper describing the findings in this week’s issue of the Proceedings of the National Academy of Sciences.

Lead author of the paper is Christopher Ng, an MIT graduate student in biological engineering. Other authors are MIT postdoc Ferah Yildirim; recent graduates Yoon Sing Yap, Patricio Velez and Adam Labadorf; technical assistants Simona Dalin and Bryan Matthews; and David Housman, the Virginia and D.K. Ludwig Professor of Biology.

Study: Model for Brain Signaling Flawed

A new study out today in the journal Science turns two decades of understanding about how brain cells communicate on its head. The study demonstrates that the tripartite synapse – a model long accepted by the scientific community and one in which multiple cells collaborate to move signals in the central nervous system – does not exist in the adult brain. 

“Our findings demonstrate that the tripartite synaptic model is incorrect,” said Maiken Nedergaard, M.D., D.M.Sc., lead author of the study and co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine. “This concept does not represent the process for transmitting signals between neurons in the brain beyond the developmental stage.”

The central nervous system is home to many different cells. While neurons tend to garner the most attention, it is only recently that the function of the brain’s other cells have been fully appreciated. Glial cells known as astrocytes, for example, had long been considered mainly the “glue” that helps hold all the other cells in the central nervous system in place. Scientists now understand that that these cells are essential to maintaining a healthy environment in the brain by helping carry out functions such as removing waste.

“Neurons are like a racing car,” said Nedergaard. “While the driver gets all the credit, there are often 20 people behind the scenes that are optimizing his or her success.”

However, when it comes to moving signals between neurons in the brain it turns out that the scientists may have vastly exaggerated the role of the astrocyte.   

Neurons are connected to each other via axons or “arms” that extend from the cell’s main body. Communication between neighboring neurons takes place where axons meet other nerve cells – called a synaptic juncture – when an electrical charge causes chemicals called neurotransmitters or glutamate to be released by one cell and “read” by receptors on the surface of the opposite. The two cells do not actually touch, so the chemicals messages must pass through a gap in the synaptic juncture. The space around this gap is insulated by astrocytes.   

Under the tripartite synapse model, both astrocytes and neurons were believed to play a role in the “conversation” between cells. This understanding was largely based on animal models which showed active receptors and neurotransmission between not only the nerve cells but also the nearby astrocytes.  

Specifically, a key neurotransmission receptor called metabotropic glutamate receptor 5 (mGluR5) was observed to be present and active in astrocytes at the synaptic juncture. It was also observed that when the mGluR5 receptor was activated, the astrocytes would release chemical transmitters that were in turn read by the nerve cells. These findings led to the conclusion that astrocytes must in some manner modulate the signaling process between brain cells. 

While this model has held sway for decades, scientists have long been frustrated by their inability to influence this process by targeting it with drugs.

“If this concept was correct, it should have given rise to a clinical trial by now,” said Nedergaard. “It has not, which tells us that with so many labs work on this for 20 years that there must be something wrong.”

One of the barriers to understanding precise mechanics of passing signals from one neuron to another has been the inability to observe this process in the adult brain. The tripartite synapse model was based – in part – by examining the activity in the brains of very young rodents. Adult rodents could not be similarly studied because the synapses in the brain would die before they could be fully analyzed. This ultimately led to the presumption that the signaling process that was witnessed in the young brain carried over to adulthood. 

Collaborating with researchers at the University of Rochester’s Institute of Optics, Nedergaard and her team developed a new 2-photon microscope that enables researchers to observe glia activity in the living brain. Using both this method and by analyzing the gene and protein expression in the brain the researchers discovered that the mGluR5 largely disappear in the glial cells of adult mice meaning that these cells do not directly respond to synaptic neuronal signalling, thus calling into question the concepts that drive most of ongoing research in the field.

“The process of neuron-glial transmission as conceived by the tripartite synapse model appears to just be a simplistic signaling pathway that ‘teaches’ the synapse how to behave,” said Nedergaard. “Once the brain matures, it goes away.”

Study Refutes Accepted Model of Memory Formation

A study by Johns Hopkins researchers has shown that a widely accepted model of long-term memory formation — that it hinges on a single enzyme in the brain — is flawed. The new study, published in the Jan. 2 issue of Nature, found that mice lacking the enzyme that purportedly builds memory were in fact still able to form long-term memories as well as normal mice could.

“The prevailing theory is that when you learn something, you strengthen connections between your brain cells called synapses,” explains Richard Huganir, Ph.D., a professor and director of the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience. “The question is, how exactly does this strengthening happen?”

A research group at SUNY Downstate, led by Todd Sacktor, Ph.D., has suggested that key to the process is an enzyme they discovered, known as PKM-zeta. In 2006, Sacktor’s group made waves when it created a molecule that seemed to block the action of PKM-zeta — and only PKM-zeta. When the molecule, dubbed ZIP, was given to mice, it erased existing long-term memories. The molecule caught the attention of reporters and bloggers, who mused on the social and ethical implications of memory erasure.

But for researchers, ZIP was exciting primarily as a means for studying PKM-zeta. “Since 2006, many papers have been published on PKM-zeta and ZIP, but no one knew what PKM-zeta was acting on,” says Lenora Volk, Ph.D., a member of Huganir’s team. “We thought that learning the enzyme’s target could tell us a lot about how memories are stored and maintained.”

For the current study, Volk and fellow team member Julia Bachman made mice that lacked working PKM-zeta, so-called genetic “knockouts.” The goal was to compare the synapses of the modified mice with those of normal mice, and find clues about how the enzyme works.

But, says Volk, “what we got was not at all what we expected. We thought the strengthening capacity of the synapses would be impaired, but it wasn’t.” The brains of the mice without PKM-zeta were indistinguishable from those of other mice, she says. Additionally, the synapses of the PKM-zeta-less mice responded to the memory-erasing ZIP molecule just as the synapses of normal mice do.

The team then considered whether, in the absence of PKM-zeta, the mouse brains had honed a substitute synapse-building pathway, much in the way that a blind person learns to glean more information from her other senses. So the researchers made mice whose PKM-zeta genes functioned normally until they were given a drug that would suddenly shut the gene down. This allowed them to study PKM-zeta-less adult mice that had had no opportunity to develop a way around the loss of the gene. Still, the synapses of the so-called conditional knockout mice responded to stimuli just as synapses in normal mice did.

What this means, the researchers say, is that PKM-zeta is not the key long-term memory molecule previous studies had suggested, although it may have some role in memory. “We don’t know what this ZIP peptide is really acting on,” says Volk. “Finding out what its target is will be quite important, because then we can begin to understand at the molecular level how synapses strengthen and how memories form in response to stimuli.”

Definitive proof for receptor’s role in synapse development

Jackson Laboratory researchers led by Associate Professor Zhong-wei Zhang, Ph.D., have provided direct evidence that a specific neurotransmitter receptor is vital to the process of pruning synapses in the brains of newborn mammals.

Faulty pruning at this early developmental stage is implicated in autism-spectrum disorders and schizophrenia. The definitive evidence for N-methyl-D-aspartate receptor (NMDAR) in pruning has eluded researchers until now, but in research published in the Proceedings of the National Academy of Sciences, Zhang’s lab had serendipitous help in the form of a mouse model containing brain cells lacking NMDAR side-by-side with cells containing the receptor.

Soon after birth, mammals’ brains undergo significant development and change. Initially, large numbers of synapses form between neurons. Then, in response to stimuli, the synaptic connections are refined—some synapses are strengthened and others eliminated, or pruned.

In most synapses, glutamate serves as the neurotransmitter, and NMDAR, a major type of post-synaptic glutamate receptor, was previously known to play an important role in neural circuit development. Previous research has implicated the importance of NMDARs in pruning, but it remained unclear whether they played a direct or indirect role.

Zhang and colleagues focused on the thalamus, a brain region where synapse pruning and strengthening can be monitored and quantified with relative ease. They got unexpected help when they realized the mouse model they were using had thalamus cells lacking NMDARs right next to cells with normal NMDAR levels.

The researchers showed that the refinement process was disrupted in the absence of NMDARs. At the same time, neighboring neurons with the receptors proceeded through normal synaptic strengthening and pruning, clearly establishing the necessity of NMDARs in postsynaptic neurons for synaptic refinement.

"Whenever I give a talk or meet colleagues," Zhang says, "the first question that comes up is whether the NMDA receptor is important. It’s good that this is now settled definitively."

There has been extensive research into synaptic strengthening, and most of these studies indicate that the presence of NMDARs may support the recruitment of larger numbers of another kind of glutamate receptor to strengthen the synaptic connections. How NMDARs regulate the pruning process remains largely unknown, however.

Carbon nanotubes could one day enhance your brain

Swiss Federal Institute of Technology scientists found that carbon nanotubes offer the potential to establish functional links between neurons that could fight disease and enhance our brains.

The human brain contains about 10 billion neurons, each connecting to other nerve cells through 10,000 or more synapses. Neurons process signals from these connections, then produce output commands that stimulate biological functions, everything from breathing to thinking to kissing.

Many scientists consider our brain similar to a massive parallel processing system, a supercomputer. However, when that computer breaks down we can lose memory or worse, develop sicknesses such as Parkinson’s, Alzheimer’s or other forms of dementia.

Unfortunately, we can’t take our brain down to Wall Mart or Fry’s for an upgrade; however, what if we could put something in our brain that would enhance the signal processing capabilities of individual neurons. Swiss scientists say they’ve done just that with carbon nanotubes.

The forward-thinking research team; led by Michel Giugliano, now a professor at the University of Antwerp, created carbon nanotube scaffolds, which serve as electrical bypass circuitry, to not only repair faulty neural networks, but also enhance performance of healthy cells.

Although there are still some engineering hurdles to overcome, the scientists see huge potential for strengthening neural networks with carbon nanotubes. This procedure could allow brain-machine interfaces for neuroprosthetics that process sight, sound, smell and motion.

Such circuits might be used, for instance, to veto epileptic attacks before they occur, perform spinal bypasses around injuries, and repair or enhance normal cognitive functions. In the not-too-distant future, non-biological nano-neurons could enable our brains to process information much faster than today’s biological brains can.

Removing protein ‘garbage’ in nerve cells may help control 2 neurodegenerative diseases

Neuroscientists at Georgetown University Medical Center say they have new evidence that challenges scientific dogma involving two fatal neurodegenerative diseases — amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) — and, in the process, have uncovered a possible therapeutic target as a novel strategy to treat both disorders.

The study, posted online in the Journal of Biological Chemistry, found that the issue in both diseases is the inability of the cell’s protein garbage disposal system to “pull out” and destroy TDP-43, a powerful, sometimes mutated gene that produces excess amounts of protein inside the nucleus of a nerve cell, or neuron.

"This finding suggests that if we’re able to ‘rev up’ that clearance machinery and help the cell get rid of the bad actors, it could possibly reduce or slow the development of ALS and FTD," says the study’s lead investigator, neuroscientist Charbel E-H Moussa, MB, PhD. "The potential of such an advance is very exciting." He cautions, though, that determining if this strategy is possible in humans could take many years and will involve teams of researchers.

The way to rev up protein disposal is to add parkin — the cell’s natural disposal units — to brain cells. In this study, Moussa and his colleagues demonstrated in two animal experiments that delivering parkin genes to neurons slowed down ALS pathologies linked to TDP-43.”

Moussa says that his study further demonstrates that clumps known as “inclusions” of TDP-43 protein found inside neuron bodies in both disorders do not promote these diseases, as some researchers have argued.

What happens in both diseases is that this protein, which is a potent regulator of thousands of genes, leaves the nucleus and collects inside the gel-like cytoplasm of the neuron. In ALS, also known as Lou Gehrig’s disease, this occurs in motor neurons, affecting movement; in FTD, it occurs in the frontal lobe of the brain, leading to dementia.

"In both diseases, TDP-43 is over-expressed or mutated, and the scientific debate has been whether loss of TDP-43 in the nucleus or gain of TDP-43 in the cytoplasm is the problem," Moussa says.

"Our study suggests TDP-43 in the cell cytoplasm is deposited there in order to eventually be destroyed — without contributing to disease — and that TDP-43 in the nucleus is causing the damage," he says. "Because so much protein is being produced, the cell can’t keep up with removing these toxic particles in the nucleus and the dumping of them in the cytoplasm. There may be a way to fix this problem."

Moussa has long studied parkin, a molecule best known, when mutated and inactive, for its role in a familial form of Parkinson’s disease. He has studied it in Alzheimer’s disease and other forms of dementia. His hypothesis, which he has demonstrated in several recently published studies, is that parkin could help remove the toxic fragments of amyloid beta protein that builds up in the brains of Alzheimer’s disease patients.

What’s more, he developed a method to clear this amyloid beta when it begins to build up in neurons — a gene therapy strategy he has shown works in rodents. Work continues on this potential therapy.

In this study, Moussa found that parkin “tags” TDP-43 protein in the nucleus with a molecule that takes it from the nucleus and into the cytoplasm of the cell. “This is good. If TDP-43 is in the cytoplasm, it will prevent further nuclear damage and deregulation of genetic materials that determine protein identity,” he says.

"This discovery challenges the dogma that accumulation of TDP-43 in the cytoplasm is," Moussa says. "We think parkin is tagging proteins in the nucleus for destruction, but there just isn’t enough parkin around — compared with over-production of TDP-43 — to do the job."

Moussa says his next research steps will be to inject a drug that activates parkin to see whether that can prolong the lifespan and reduce motor defects in mice with ALS.

(Image: iStock)

Dragonflies have human-like ‘selective attention’

In a discovery that may prove important for cognitive science, our understanding of nature and applications for robot vision, researchers at the University of Adelaide have found evidence that the dragonfly is capable of higher-level thought processes when hunting its prey.

The discovery, published online in the journal Current Biology, is the first evidence that an invertebrate animal has brain cells for selective attention, which has so far only been demonstrated in primates.

Dr Steven Wiederman and Associate Professor David O’Carroll from the University of Adelaide’s Centre for Neuroscience Research have been studying insect vision for many years.

Using a tiny glass probe with a tip that is only 60 nanometres wide - 1500 times smaller than the width of a human hair - the researchers have discovered neuron activity in the dragonfly’s brain that enables this selective attention.

They found that when presented with more than one visual target, the dragonfly brain cell ‘locks on’ to one target and behaves as if the other targets don’t exist.

"Selective attention is fundamental to humans’ ability to select and respond to one sensory stimulus in the presence of distractions," Dr Wiederman says.

Associate Professor O’Carroll says this brain activity makes the dragonfly a more efficient and effective predator.

"Recent studies reveal similar mechanisms at work in the primate brain, but you might expect it there. We weren’t expecting to find something so sophisticated in lowly insects from a group that’s been around for 325 million years, Associate Professor O’Carroll says.

"We believe our work will appeal to neuroscientists and engineers alike. For example, it could be used as a model system for robotic vision. Because the insect brain is simple and accessible, future work may allow us to fully understand the underlying network of neurons and copy it into intelligent robots," he says.