Neuroscience

New research at Rutgers University may help shed light on how and why nervous system changes occur and what causes some people to suffer from life-threatening anxiety disorders while others are better able to cope.

Maureen Barr, a professor in the Department of Genetics, and a team of researchers, found that the architectural structure of the six sensory brain cells in the roundworm, responsible for receiving information, undergo major changes and become much more elaborate when the worm is put into a high stress environment.

Scientists have known for some time that changes in the tree-like dendrite structures that connect neurons in the human brain and enable our thought processes to work properly can occur under extreme stress, alter brain cell development and result in anxiety disorders like depression and Post Traumatic Stress Disorder affecting millions of Americans each year.

What scientists don’t understand for sure, Barr says, is the cause behind these molecular changes in the brain.

“This type of research provides us necessary clues that ultimately could lead to the development of drugs to help those suffering with severe anxiety disorders,” Barr says.

In the study published today in Current Biology, scientists at Rutgers have identified six sensory nerve cells in the tiny, transparent roundworm, known as the C. elegans and an enzyme called KPC-1/furin which triggers a chemical reaction in humans that is needed for essential life functions like blood-clotting. 

While the enzyme also appears to play a role in the growth of tumors and the activation of several types of virus and diseases in humans, in the roundworm the enzyme enables its simple neurons to morph into new elaborately branched shapes when placed under adverse conditions.

Normally, this one-millimeter long worm develops from an embryo through four larval stages before molting into a reproductive adult. Put it under stressful conditions of overcrowding, starvation and high temperature and the worm transforms into an alternative larval stage known as the dauer that becomes so stress-resistant it can survive almost anything – including the Space Shuttle Columbia disaster in 2003 of which they were the only living things to survive.  

“These worms that normally have a short life cycle turn into super worms when they go into the dauer stage and can live for months, although they are no longer able to reproduce,” Barr says.

What is so interesting to Barr is that when a perceived threat is over, these tiny creatures and their IL2 neurons transform back to a normal lifespan and reproductive state like nothing had ever happened. Under a microscope, the complicated looking tree-like connectors that receive information are pruned back and the worm appears as it did before the trauma occurred.

This type of neural reaction differs in humans who can suffer from extreme anxiety months or even years after the traumatic event even though they are no longer in a threatening situation.   

The ultimate goal, Barr says, is to determine how and why the nervous system responds to stress. By identifying molecular pathways that regulate neuronal remodeling, scientists may apply this knowledge to develop future therapeutics.

When something gets in the way of our ability to see, we quickly pick up a new way to look, in much the same way that we would learn to ride a bike, according to a new study published in the Cell Press journal Current Biology on August 15.

Our eyes are constantly on the move, darting this way and that four to five times per second. Now researchers have found that the precise manner of those eye movements can change within a matter of hours. This discovery by researchers from the University of Southern California might suggest a way to help those with macular degeneration better cope with vision loss.

"The system that controls how the eyes move is far more malleable than the literature has suggested," says Bosco Tjan of the University of Southern California. "We showed that people with normal vision can quickly adjust to a temporary occlusion of their foveal vision by adapting a consistent point in their peripheral vision as their new point of gaze."

The fovea refers to the small, center-most portion of the retina, which is responsible for our high-resolution vision. We move our eyes to direct the fovea to different parts of a scene, constructing a picture of the world around us. In those with age-related macular degeneration, progressive loss of foveal vision leads to visual impairment and blindness.

In the new study, MiYoung Kwon, Anirvan Nandy, and Tjan simulated a loss of foveal vision in six normally sighted young adults by blocking part of a visual scene with a gray disc that followed the individuals’ eye gaze. Those individuals were then asked to complete demanding object-following and visual-search tasks. Within three hours of working on those tasks, people showed a remarkably fast and spontaneous adjustment of eye movements. Once developed, that change in their “point of gaze” was retained over a period of weeks and was reengaged whenever their foveal vision was blocked.

Tjan and his team say they were surprised by the rate of this adjustment. They note that patients with macular degeneration frequently do adapt their point of gaze, but in a process that takes months, not days or hours. They suggest that practice with a visible gray disc like the one used in the study might help speed that process of visual rehabilitation along. The discovery also reveals that the oculomotor (eye movement) system prefers control simplicity over optimality.

"Gaze control by the oculomotor system, although highly automatic, is malleable in the same sense that motor control of the limbs is malleable," Tjan says. "This finding is potentially very good news for people who lose their foveal vision due to macular diseases. It may be possible to create the right conditions for the oculomotor system to quickly adjust," Kwon adds.

The active ingredient in an over-the-counter skin cream might do more than prevent wrinkles. Scientists have discovered that the drug, called kinetin, also slows or stops the effects of Parkinson’s disease on brain cells.

Scientists identified the link through biochemical and cellular studies, but the research team is now testing the drug in animal models of Parkinson’s. The research is published in the August 15, 2013 issue of the journal Cell.

“Kinetin is a great molecule to pursue because it’s already sold in drugstores as a topical anti-wrinkle cream,” says HHMI investigator Kevan Shokat of the University of California, San Francisco. “So it’s a drug we know has been in people and is safe.”

Parkinson’s disease is a degenerative disease that causes the death of neurons in the brain. Initially, the disease affects one’s movement and causes tremors, difficulty walking, and slurred speech. Later stages of the disease can cause dementia and broader health problems. In 2004, researchers studying an Italian family with a high prevalence of early-onset Parkinson’s disease discovered mutations in a protein called PINK1 associated with the inherited form of the disease.

Since then, studies have shown that PINK1 normally wedges into the membrane of damaged mitochondria inside cells that causes another protein, Parkin, to be recruited to the mitochondria, which are organelles responsible for energy generation. Neurons require high levels of energy production, therefore when mitochondrial damage occurs, it can lead to neuronal death. However, when Parkin is present on damaged mitochondria, studding the mitochondrial surface, the cell is able to survive the damage. In people who inherit mutations in PINK1, however, Parkin is never recruited to the organelles, leading to more frequent neuronal death than usual.

Shokat and his colleagues wanted to develop a way to turn on or crank up PINK1 activity, therefore preventing an excess of cell death, in those with inherited Parkinson’s disease. But turning on activity of a mutant enzyme is typically more difficult than blocking activity of an overactive version.

“When we started this project, we really thought that there would be no conceivable way to make something that directly turns on the enzyme,” says Shokat. “For any enzyme we know that causes a disease, we have ways to make inhibitors but no real ways to turn up activity.”

His team expected it would have to find a less direct way to mimic the activity of PINK1 and recruit Parkin. In the hopes of more fully understanding how PINK1 works, they began investigating how PINK1 binds to ATP, the energy molecule that normally turns it on. In one test, instead of adding ATP to the enzymes, they added different ATP analogues, versions of ATP with altered chemical groups that slightly change its shape. Scientists typically must engineer new versions of proteins to be able to accept these analogs, since they don’t fit into the typical ATP binding site. But to Shokat’s surprise, one of the analogs—kinetin triphosphate, or KTP—turned on the activity of not only normal PINK1, but also the mutated version, which doesn’t bind ATP.

“This drug does something that chemically we just never thought was possible,” says Shokat. “But it goes to show that if you find the right key for the right lock, you’ll be able to open the door.”

To test whether the binding of KTP to PINK1 led to the same consequences as the usual ATP binding, Shokat’s group measured the activity of PINK1 directly, as well as the downstream consequences of this activity, including the amount of Parkin recruited to the mitochondrial surface, and the levels of cell death. Adding the precursor of KTP, kinetin, to cells—both those with PINK1 mutations and those with normal physiology—amplified the activity of PINK1, increased the level of Parkin on damaged mitochondria, and decreased levels of neuron death, they found.

“What we have here is a case where the molecular target has been shown to be important to Parkinson’s in human genetic studies,” says Shokat. “And now we have a drug that specifically acts on this target and reverses the cellular causes of the disease.”

The similar results in cells with and without PINK1 mutations suggest that kinetin, which is a precursor to KTP, could be used to treat not only Parkinson’s patients with a known PINK1 mutation, but to slow progression of the disease in those without a family history by decreasing cell death.

Shokat is now performing experiments on the effects of kinetin in mice with various forms of Parkinson’s disease. However, the usefulness of animal models in Parkinson’s research has been debated, and therefore the positive results from the cellular data, he says, is as good an indicator as results in animals that this drug has potential to treat Parkinson’s in humans. Initial human studies will likely focus on the small population of patients with PINK1 mutations, and if successful in that group the drug could later be tested in a wider array of Parkinson’s patients.

There is no evidence that impaired blood flow or blockage in the veins of the neck or head is involved in multiple sclerosis, says a McMaster University study.

The research, published online by PLOS ONE Wednesday, found no evidence of abnormalities in the internal jugular or vertebral veins or in the deep cerebral veins of any of 100 patients with multiple sclerosis (MS) compared with 100 people who had no history of any neurological condition.

The study contradicts a controversial theory that says that MS, a chronic, neurodegenerative and inflammatory disease of the central nervous system, is associated with abnormalities in the drainage of venous blood from the brain. In 2008 Italian researcher Paolo Zamboni said that angioplasty, a blockage clearing procedure, would help MS patients with a condition he called chronic cerebrospinal venous insufficiency (CCSVI). This caused a flood of public response in Canada and elsewhere, with many concerned individuals lobbying for support of the ‘Liberation Treatment’ to clear the veins, as advocated by Zamboni.

“This is the first Canadian study to provide compelling evidence against the involvement of CCSVI in MS,” said principal investigator Ian Rodger, a professor emeritus of medicine in the Michael G. DeGroote School of Medicine. “Our findings bring a much needed perspective to the debate surrounding venous angioplasty for MS patients”.

In the study all participants received an ultrasound of deep cerebral veins and neck veins as well as a magnetic resonance imaging (MRI) of the neck veins and brain. Each participant had both examinations performed on the same day. The McMaster research team included a radiologist and two ultrasound technicians who had trained in the Zamboni technique at the Department of Vascular Surgery of the University of Ferrara.

Researchers from King’s College London and the University of Nottingham have identified neuroimaging markers in the brain which could help predict whether people with psychosis respond to antipsychotic medications or not.

In approximately half of young people experiencing their first episode of a psychosis (FEP), the symptoms do not improve considerably with the initial medication prescribed, increasing the risk of subsequent episodes and worse outcome. Identifying individuals at greatest risk of not responding to existing medications could help in the search for improved medications, and may eventually help clinicians personalize treatment plans.

In a study published today in JAMA Psychiatry, researchers used structural Magnetic Resonance Imaging (MRI) to scan the brains of 126 individuals – 80 presenting with FEP, and 46 healthy controls. Participants had an MRI scan shortly after their FEP, and another assessment 12 weeks later, to establish whether symptoms had improved following the first treatment with antipsychotic medications.

The researchers examined a particular feature of the brain called “cortical gyrification” - the extent of folding of the cerebral cortex and a marker of how it has developed. They found that the individuals who did not respond to treatment already had a significant reduction in gyrification across multiple brain regions, compared to patients who did respond and to individuals without psychosis. This reduced gyrification was particularly present in brain areas considered important in psychosis, such as the temporal and frontal lobes. Those who responded to treatment were virtually indistinguishable from the healthy controls.

The researchers also investigated whether the differences could be explained by the type of diagnosis of psychosis (eg. with or without affective symptoms, such as depression or elated mood). They found that reduced gyrification predicted non-response to treatment independently of the diagnosis. 

Dr Paola Dazzan from the Department of Psychosis Studies at King’s College London’s Institute of Psychiatry, and senior author of the paper, says: “Our study provides crucial evidence of a neuroimaging marker that, if validated, could be used early in psychosis to help identify those people less likely to respond to medications. It is possible that the alterations we observed are due to differences in the way the brain has developed early on in people who do not respond to medication compared to those who do.”

She continues:”There have been few advances in developing novel anti-psychotic drugs over the past 50 years and we still face the same problems with a sub-group of people who do not respond to the drugs we currently use. We could envisage using a marker like this one to identify people who are least likely to respond to existing medications and focus our efforts on developing new medication specifically adapted to this group. In the longer term, if we were able to identify poor responders at the outset, we may be able to formulate personalized treatment plans for that individual patient.” 

Dr Lena Palaniyappan from the University of Nottingham adds: “All of us have complex and varying patterns of folding in our brains. For the first time we are showing that the measurement of these variations could potentially guide us in treating psychosis. It is possible that people with specific patterns of brain structure respond better to treatments other than antipsychotics that are currently in use. Clearly, the time is ripe for us to focus on utilising neuroimaging to guide treatment decisions.”

Psychosis is a term used to indicate mental health disorders that present with symptoms like hallucinations (such as hearing voices) or delusions (unshakeable beliefs based on the person’s altered perception of reality, which may not correspond to the way others see the world). Psychotic episodes are present in conditions such as schizophrenia and bipolar disorder.

Approximately 1 in 100 people in England have at least one episode of psychosis throughout their lives. In most cases, psychosis develops during late adolescence (15 or above) or adulthood. Treatment involves a combination of antipsychotic medication, psychological therapies and social support. Many people with psychosis go on to lead ordinary lives and for about 60% of people, the symptoms disappear within 12 months from onset. However, for others, treatment is less straightforward and many do not respond to the initial antipsychotic treatment prescribed by their doctor. Early response to antipsychotic medication is known to be associated with better outcome and fewer subsequent episodes, and intervening early with effective treatments is therefore important.

Researchers at Johns Hopkins have uncovered a protein switch that can either increase or decrease memory-building activity in brain cells, depending on the signals it detects. Its dual role means the protein is key to understanding the complex network of signals that shapes our brain’s circuitry, the researchers say. A description of their discovery appears in the July 31 issue of the Journal of Neuroscience.

“What’s interesting about this protein, AGAP3, is that it is effectively double-sided: One side beefs up synapses in response to brain activity, while the other side helps bring synapse-building back down to the brain’s resting state,” says Richard Huganir, Ph.D., a professor and director of the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine and co-director of the Brain Science Institute at Johns Hopkins. “The fact that it links these two opposing activities indicates AGAP3 may turn out to be central to controlling the strength of synapses.”

Huganir has long studied how connections between brain cells, known as synapses, are strengthened and weakened to form or erase memories. The new discovery came about when he and postdoctoral fellow Yuko Oku, Ph.D., investigated the chain reaction of signals involved in one type of synaptic strengthening.

In a study of the proteins that interact with one of the known proteins from that chain reaction, the previously unknown AGAP3 turned up. It contained not only a site designed to bind another protein involved in the chain reaction that leads from brain stimulation to learning, but also a second site involved in bringing synapse-building activity down to normal levels after a burst of activity.

Although it might seem the two different functions are behaving at cross-purposes, Oku says, it also could be that nature’s bundling of these functions together in a single protein is an elegant way of enabling learning and memory while preventing dangerous overstimulation. More research is needed, Oku says, to figure out whether AGAP3’s two sites coordinate by affecting each other’s activity, or are effectively free agents.

The steady accumulation of a protein in healthy, aging brains may explain seniors’ vulnerability to neurodegenerative disorders, a new study by researchers at the Stanford University School of Medicine reports.

The study’s unexpected findings could fundamentally change the way scientists think about neurodegenerative disease.

The pharmaceutical industry has spent billions of dollars on futile clinical trials directed at treating Alzheimer’s disease by ridding brains of a substance called amyloid plaque. But the new findings have identified another mechanism, involving an entirely different substance, that may lie at the root not only of Alzheimer’s but of many other neurodegenerative disorders — and, perhaps, even the more subtle decline that accompanies normal aging.

The study, published Aug. 14 in the Journal of Neuroscience, reveals that with advancing age, a protein called C1q, well-known as a key initiator of immune response, increasingly lodges at contact points connecting nerve cells in the brain to one another. Elevated C1q concentrations at these contact points, or synapses, may render them prone to catastrophic destruction by brain-dwelling immune cells, triggered when a catalytic event such as brain injury, systemic infection or a series of small strokes unleashes a second set of substances on the synapses.

“No other protein has ever been shown to increase nearly so profoundly with normal brain aging,” said Ben Barres, MD, PhD, professor and chair of neurobiology and senior author of the study. Examinations of mouse and human brain tissue showed as much as a 300-fold age-related buildup of C1q.

The finding was made possible by the diligence and ingenuity of the study’s lead author, Alexander Stephan, PhD, a postdoctoral scholar in Barres’ lab. Stephan screened about 1,000 antibodies before finding one that binds to C1q and nothing else. (Antibodies are proteins, generated by the immune system, that adhere to specific “biochemical shapes,” such as surface features of invading pathogens.)

Comparing brain tissue from mice of varying ages, as well as postmortem samples from a 2-month-old infant and an older person, the researchers showed that these C1q deposits weren’t randomly distributed along nerve cells but, rather, were heavily concentrated at synapses. Analyses of brain slices from mice across a range of ages showed that as the animals age, the deposits spread throughout the brain.

“The first regions of the brain to show a dramatic increase in C1q are places like the hippocampus and substantia nigra, the precise brain regions most vulnerable to neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, respectively,” said Barres. Another region affected early on, the piriform cortex, is associated with the sense of smell, whose loss often heralds the onset of neurodegenerative disease.

Other scientists have observed moderate, age-associated increases (on the order of three- or four-fold) in brain levels of the messenger-RNA molecule responsible for transmitting the genetic instructions for manufacturing C1q to the protein-making machinery in cells. Testing for messenger-RNA levels — typically considered reasonable proxies for how much of a particular protein is being produced — is fast, easy and cheap compared with analyzing proteins.

But in this study, Barres and his colleagues used biochemical measures of the protein itself. “The 300-fold rise in C1q levels we saw in 2-year-old mice — equivalent to 70- or 80-year-old humans — knocked my socks off,” Barres said. “I was not expecting that at all.”

C1q is the first batter on a 20-member team of immune-response-triggering proteins, collectively called the complement system. C1q is capable of clinging to the surface of foreign bodies such as bacteria or to bits of our own dead or dying cells. This initiates a molecular chain reaction known as the complement cascade. One by one, the system’s other proteins glom on, coating the offending cell or piece of debris. This in turn draws the attention of omnivorous immune cells that gobble up the target.

The brain has its own set of immune cells, called microglia, which can secrete C1q. Still other brain cells, called astrocytes, secrete all of C1q’s complement-system “teammates.” The two cell types work analogously to the two tubes of an Epoxy kit, in which one tube contains the resin, the other a catalyst.

Previous work in Barres’ lab has shown that the complement cascade plays a critical role in the developing brain. A young brain generates an excess of synapses, creating a huge range of options for the potential formation of new neural circuits. These synapses strengthen or weaken over time, in response to their heavy use or neglect. The presence of feckless connections contributes noise to the system, so the efficiency of the maturing brain’s architecture is improved if these underused synapses are pruned away.

In a 2007 paper in Cell, Barres’ group reported that the complement system is essential to synaptic pruning in normal, developing brains. Then in 2012, in Neuron, in a collaboration with the lab of Harvard neuroscientist Beth Stevens, PhD, they showed that it is specifically microglia — the brain’s in-house immune cells — that attack and ingest complement-coated synapses.

Barres now believes something similar is happening in the normal, aging brain. C1q, but not the other protein components of the complement system, gradually becomes highly prevalent at synapses. By itself, this C1q buildup doesn’t trigger wholesale synapse loss, the researchers found — although it does seem to impair their performance. Old mice whose capacity to produce C1q had been eliminated performed subtly better on memory and learning tests than normal older mice did.

Still, this leaves the aging brain’s synapses precariously perched on the brink of catastrophe. A subsequent event such as brain trauma, a bad case of pneumonia or perhaps a series of tiny strokes that some older people experience could incite astrocytes — the second tube in the Epoxy kit — to start secreting the other complement-system proteins required for synapse destruction.

Most cells in the body have their own complement-inhibiting agents. This prevents the wholesale loss of healthy tissue during an immune attack on invading pathogens or debris from dead tissue during wound healing. But nerve cells lack their own supply of complement inhibitors. So, when astrocytes get activated, their ensuing release of C1q’s teammates may set off a synapse-destroying rampage that spreads “like a fire burning through the brain,” Barres said.

“Our findings may well explain the long-mysterious vulnerability specifically of the aging brain to neurodegenerative disease,” he said. “Kids don’t get Alzheimer’s or Parkinson’s. Profound activation of the complement cascade, associated with massive synapse loss, is the cardinal feature of Alzheimer’s disease and many other neurodegenerative disorders. People have thought this was because synapse loss triggers inflammation. But our findings here suggest that activation of the complement cascade is driving synapse loss, not the other way around.”

The synapses in the brain act as key communication points between approximately one hundred billion neurons. They form a complex network connecting various centres in the brain through electrical impulses.

New research from Lund University suggests that it is precisely here, in the synapses, that Huntington’s disease might begin.

The researchers looked into the brains of mice with real-time imaging methods, following some of the very first stages of the disease through advanced microscopes. What they discovered was an unprecedented degradation of synaptic activity. Long before the well documented nerve cell death, synapses that are important for communication between brain centres that control memory and learning begin to wither. This process has never been mapped before and could be an important step towards understanding the serious non-motor symptoms that affect Huntington patients long before the movement disorders start to show.
“With the naked eye, we have now been able to follow the step by step events when these synapses start to break down. If we are to halt or reverse this process in the future, it is necessary to understand exactly what happens in the initial phase of the disease. Now we know more”, says Professor Jia-Yi Li, the research group leader.

Huntington’s disease has long been characterized by the involuntary writhing movements faced by patients. But in fact, Huntington’s has a very broad and highly individual symptomatology. Depression, memory loss and sleep disorders are all common early on in the disease.
“Many patients testify that these symptoms affect quality of life significantly more than the involuntary jerky movements. Therefore, it is extremely important that we achieve progress in this field of research. Our goal now is to find new therapies that can increase the lifespan of these synapses and maintain their vital function”, explains postdoc Reena, who lead the imaging experiments.

Johns Hopkins researchers suggest neural stem cells may regenerate after anti-cancer treatment

Scientists have long believed that healthy brain cells, once damaged by radiation designed to kill brain tumors, cannot regenerate. But new Johns Hopkins research in mice suggests that neural stem cells, the body’s source of new brain cells, are resistant to radiation, and can be roused from a hibernation-like state to reproduce and generate new cells able to migrate, replace injured cells and potentially restore lost function.

“Despite being hit hard by radiation, it turns out that neural stem cells are like the special forces, on standby waiting to be activated,” says Alfredo Quiñones-Hinojosa, M.D., a professor of neurosurgery at the Johns Hopkins University School of Medicine and leader of a study described online today in the journal Stem Cells. “Now we might figure out how to unleash the potential of these stem cells to repair human brain damage.”

The findings, Quiñones-Hinojosa adds, may have implications not only for brain cancer patients, but also for people with progressive neurological diseases such as multiple sclerosis (MS) and Parkinson’s disease (PD), in which cognitive functions worsen as the brain suffers permanent damage over time.

In Quiñones-Hinojosa’s laboratory, the researchers examined the impact of radiation on mouse neural stem cells by testing the rodents’ responses to a subsequent brain injury. To do the experiment, the researchers used a device invented and used only at Johns Hopkins that accurately simulates localized radiation used in human cancer therapy. Other techniques, the researchers say, use too much radiation to precisely mimic the clinical experience of brain cancer patients.

In the weeks after radiation, the researchers injected the mice with lysolecithin, a substance that caused brain damage by inducing a demyelinating brain lesion, much like that present in MS. They found that neural stem cells within the irradiated subventricular zone of the brain generated new cells, which rushed to the damaged site to rescue newly injured cells. A month later, the new cells had incorporated into the demyelinated area where new myelin, the protein insulation that protects nerves, was being produced.

“These mice have brain damage, but that doesn’t mean it’s irreparable,” Quiñones-Hinojosa says. “This research is like detective work. We’re putting a lot of different clues together. This is another tiny piece of the puzzle. The brain has some innate capabilities to regenerate and we hope there is a way to take advantage of them. If we can let loose this potential in humans, we may be able to help them recover from radiation therapy, strokes, brain trauma, you name it.”

His findings may not be all good news, however. Neural stem cells have been linked to brain tumor development, Quiñones-Hinojosa cautions. The radiation resistance his experiments uncovered, he says, could explain why glioblastoma, the deadliest and most aggressive form of brain cancer, is so hard to treat with radiation.

In a breakthrough that could have wide-ranging applications in molecular medicine, Stanford University researchers have created a bioengineered peptide that enables imaging of medulloblastomas, among the most devastating of malignant childhood brain tumors, in lab mice.

The researchers altered the amino acid sequence of a cystine knot peptide — or knottin — derived from the seeds of the squirting cucumber, a plant native to Europe, North Africa and parts of Asia. Peptides are short chains of amino acids that are integral to cellular processes; knottin peptides are notable for their stability and resistance to breakdown.

The team used their invention as a “molecular flashlight” to distinguish tumors from surrounding healthy tissue. After injecting their bioengineered knottin into the bloodstreams of mice with medulloblastomas, the researchers found that the peptide stuck tightly to the tumors and could be detected using a high-sensitivity digital camera.

The findings are described in a study published online Aug. 12 in the Proceedings of the National Academy of Sciences.

“Researchers have been interested in this class of peptides for some time,” said Jennifer Cochran, PhD, an associate professor of bioengineering and a senior author of the study. “They’re extremely stable. For example, you can boil some of these peptides or expose them to harsh chemicals, and they’ll remain intact.”

That makes them potentially valuable in molecular medicine. Knottins could be used to deliver drugs to specific sites in the body or, as Cochran and her colleagues have demonstrated, as a means of illuminating tumors.

For treatment purposes, it’s critical to obtain accurate images of medulloblastomas. In conjunction with chemotherapy and radiation therapy, the tumors are often treated by surgical resection, and it can be difficult to remove them while leaving healthy tissue intact because their margins are often indistinct.

“With brain tumors, you really need to get the entire tumor and leave as much unaffected tissue as possible,” Cochran said. “These tumors can come back very aggressively if not completely removed, and their location makes cognitive impairment a possibility if healthy tissue is taken.”

The researchers’ molecular flashlight works by recognizing a biomarker on human tumors. The bioengineered knottin is conjugated to a near-infrared imaging dye. When injected into the bloodstreams of a strain of mice that develop tumors similar to human medullublastomas, the peptide attaches to the brain tumors’ integrin receptors — sticky molecules that aid in adhesion to other cells.

But while the knottins stuck like glue to tumors, they were rapidly expelled from healthy tissue. “So the mouse brain tumors are readily apparent,” Cochran said. “They differentiate beautifully from the surrounding brain tissue.”

The new peptide represents a major advance in tumor-imaging technology, said Melanie Hayden Gephart, MD, neurosurgery chief resident at the Stanford Brain Tumor Center and a lead author of the paper.

"The most common technique to identify brain tumors relies on preoperative, intravenous injection of a contrast agent, enabling most tumors to be visualized on a magnetic resonance imaging scan," Gephart said. These MRI scans are used like in a computer program much like an intraoperative GPS system to locate and resect the tumors.

“But that has limitations,” she added. “When you’re using the contrast in an MRI scan to define the tumor margins, you’re basically working off a preoperative snapshot. The brain can sometimes shift during an operation, so there’s always the possibility you may not be as precise or accurate as you want to be. The great potential advantage of this new approach would be to illuminate the tumor in real time — you could see it directly under your microscope instead of relying on an image that was taken before surgery.”

Though the team’s research focused on medulloblastomas, Gephart said it’s likely the new knottins could prove useful in addressing other cancers.

“We know that integrins exist on many types of tumors,” she said. “The blood vessels that tumors develop to sustain themselves also contain integrins. So this has the potential for providing very detailed, real-time imaging for a wide variety of tumors.”

And imaging may not be the only application for the team’s engineered peptide.

“We’re very interested in related opportunities,” Cochran said. “We envision options we didn’t have before for getting molecules into the brain.” In other words, by substituting drugs for dye, the knottins might allow the delivery of therapeutic compounds directly to cranial tumors — something that has proved extremely difficult to date because of the blood/brain barrier, the mechanism that makes it difficult for pathogens, as well as medicines, to traverse from the bloodstream to the brain.

“We’re looking into it now,” Cochran said.

A little serendipity was involved in the peptide’s development, said Sarah Moore, a recently graduated bioengineering PhD student and another lead author of the study. Indeed, the propinquity of Cochran’s laboratory to co-author Matthew Scott’s lab at Stanford’s James H. Clark Center catalyzed the project. “Our labs are next to each other,” Moore said. “We had the peptide, and Matt had ideal models of pediatric brain tumors  —mice that develop tumors in a similar manner to human medulloblastomas. Our partnership grew out of that.”

Scott, PhD, professor of bioengineering and of developmental biology, credits the design of the Clark Center as a contributor to the project. The building is home to Stanford’s Bioengineering Department, a collaboration between the School of Engineering and the School of Medicine, and Stanford Bio-X, an initiative that encourages communication among researchers in diverse scientific disciplines.

“So in a very real sense, our project wasn’t an accident,” Scott said. “In fact, it’s exactly the kind of work the Clark Center was meant to foster. The lab spaces are wide and open, with very few walls and lots of glass. We have a restaurant that only has large tables — no tables for two, so people have to sit together. Everything is designed to increase the odds that people will meet and talk. It’s a form of social engineering that really works.”

Scott said he is gratified by the collaboration that led to the team’s breakthrough, and observed that the peptide has proved a direct boon to his own work. About 15 percent of Scott’s mice develop the tumors requisite for medulloblastoma research. The problem, he said, is that the cancers are cryptic in their early stages.

“By the time you know the mice have them, many of the things you want to study — the genesis and development of the tumors — are past,” Scott said. “We needed ways to detect these tumors early, and we needed methods for following the steps of tumor genesis.”

Ultimately, Scott concluded, the development of the new peptide can be attributed to Stanford’s long-established traditions of openness and relentless inquiry.

“You find not just a willingness, but an eagerness to exchange ideas and information here,” Scott said. “It transcends any competitive instinct, any impulse toward proprietary thinking. It is what makes Stanford — well, Stanford.”

A team of neuroscientists has identified a modification to a protein in laboratory mice linked to conditions associated with Alzheimer’s Disease. Their findings, which appear in the journal Nature Neuroscience, also point to a potential therapeutic intervention for alleviating memory-related disorders.

The research centered on eukaryotic initiation factor 2 alpha (eIF2alpha) and two enzymes that modify it with a phosphate group; this type of modification is termed phosphorylation. The phosphorylation of eIF2alpha, which decreases protein synthesis, was previously found at elevated levels in both humans diagnosed with Alzheimer’s and in Alzheimer’s Disease (AD) model mice.

"These results implicate the improper regulation of this protein in Alzheimer’s-like afflictions and offer new guidance in developing remedies to address the disease," said Eric Klann, a professor in New York University’s Center for Neural Science and the study’s senior author.

The study’s co-authors also included: Douglas Cavener, a professor of biology at Pennsylvania State University; Clarisse Bourbon, Evelina Gatti, and Philippe Pierre of Université de la Méditerranée in Marseille, France; and NYU researchers Tao Ma, Mimi A. Trinh, and Alyse J. Wexler.

It has been known for decades that triggering new protein synthesis is vital to the formation of long-term memories as well as for long-lasting synaptic plasticity — the ability of the neurons to change the collective strength of their connections with other neurons. Learning and memory are widely believed to result from changes in synaptic strength.

In recent years, researchers have found that both humans with Alzheimer’s Disease and AD model mice have relatively high levels of eIF2alpha phosphorylation. But the relationship between this characteristic and AD-related afflictions was unknown.

Klann and his colleagues hypothesized that abnormally high levels of eIF2alpha phosphorylation could become detrimental because, ultimately, protein synthesis would diminish, thereby undermining the ability to form long-term memories.

To explore this question, the researchers examined the neurological impact of two enzymes that phosphorylate eIF2alpha, kinases termed PERK and GCN2, in different populations of AD model mice — all of which expressed genetic mutations akin to those carried by humans with AD. These were: AD model mice; AD model mice that lacked PERK; and AD model mice that lacked GCN2.

Specifically, they looked at eIF2alpha phosphorylation and the regulation of protein synthesis in the mice’s hippocampus region — the part of the brain responsible for the retrieval of old memories and the encoding of new ones. They then compared these levels with those of postmortem human AD patients.

Here, they found both increased levels of phosphorylated eIF2alpha in the hippocampus of both AD patients and the AD model mice. Moreover, in conjunction with these results, they found decreased protein synthesis, known to be required for long-term potentiation — a form of long-lasting synaptic plasticity—and for long-term memory.

To test potential remedies, the researchers examined phosphorylation of eIF2alpha in mice lacking PERK, hypothesizing that removal of this kinase would return protein synthesis to normal levels. As predicted, mice lacking PERK had levels of phosphorylated eIF2alpha and protein synthesis similar to those of normal mice.

They then conducted spatial memory tests in which the mice needed to navigate a series of mazes. Here, the AD model mice lacking PERK were able to successfully maneuver through the mazes at rates achieved by normal mice. By contrast, the other AD model mice lagged significantly in performing these tasks.

The researchers replicated these procedures on AD model mice lacking GCN2. The results here were consistent with those of the AD model mice lacking PERK, demonstrating that removal of both kinases diminished memory deficits associated with Alzheimer’s Disease.

Bad language could be good for you, a new study shows. For the first time, psychologists have found that swearing may serve an important function in relieving pain.

The study, published in the journal NeuroReport, measured how long college students could keep their hands immersed in cold water. During the chilly exercise, they could repeat an expletive of their choice or chant a neutral word. When swearing, the 67 student volunteers reported less pain and on average endured about 40 seconds longer.

Although cursing is notoriously decried in the public debate, researchers are now beginning to question the idea that the phenomenon is all bad. “Swearing is such a common response to pain that there has to be an underlying reason why we do it,” says psychologist Richard Stephens of Keele University in England, who led the study. And indeed, the findings point to one possible benefit: “I would advise people, if they hurt themselves, to swear,” he adds.

How swearing achieves its physical effects is unclear, but the researchers speculate that brain circuitry linked to emotion is involved. Earlier studies have shown that unlike normal language, which relies on the outer few millimeters in the left hemisphere of the brain, expletives hinge on evolutionarily ancient structures buried deep inside the right half.

One such structure is the amygdala, an almond-shaped group of neurons that can trigger a fight-or-flight response in which our heart rate climbs and we become less sensitive to pain. Indeed, the students’ heart rates rose when they swore, a fact the researchers say suggests that the amygdala was activated.

That explanation is backed by other experts in the field. Psychologist Steven Pinker of Harvard University, whose book The Stuff of Thought (Viking Adult, 2007) includes a detailed analysis of swearing, compared the situation with what happens in the brain of a cat that somebody accidentally sits on. “I suspect that swearing taps into a defensive reflex in which an animal that is suddenly injured or confined erupts in a furious struggle, accompanied by an angry vocalization, to startle and intimidate an attacker,” he says.

But cursing is more than just aggression, explains Timothy Jay, a psychologist at the Massachusetts College of Liberal Arts who has studied our use of profanities for the past 35 years. “It allows us to vent or express anger, joy, surprise, happiness,” he remarks. “It’s like the horn on your car, you can do a lot of things with that, it’s built into you.”

In extreme cases, the hotline to the brain’s emotional system can make swearing harmful, as when road rage escalates into physical violence. But when the hammer slips, some well-chosen swearwords might help dull the pain.

There is a catch, though: The more we swear, the less emotionally potent the words become, Stephens cautions. And without emotion, all that is left of a swearword is the word itself, unlikely to soothe anyone’s pain.

Self-perceived social status predicts hippocampal function and stress hormones

A mother’s perceived social status predicts her child’s brain development and stress indicators, finds a study at Boston Children’s Hospital. While previous studies going back to the 1950s have linked objective socioeconomic factors — such as parental income or education — to child health, achievement and brain function, the new study is the first to link brain function to maternal self-perception.

In the study, children whose mothers saw themselves as having a low social status were more likely to have increased cortisol levels, an indicator of stress, and less activation of their hippocampus, a structure in the brain responsible for long-term memory formation (required for learning) and reducing stress responses.

Findings were published online August 6th by the journal Developmental Science, and will be part of a special issue devoted to the effects of socioeconomic status on brain development.

"We know that there are big disparities among people in income and education," says Margaret Sheridan, PhD, of the Labs of Cognitive Neuroscience at Boston Children’s Hospital, the study’s first author. "Our results indicate that a mother’s perception of her social status ‘lives’ biologically in her children."

Sheridan, senior investigator Charles Nelson, PhD, of Boston Children’s Hospital and colleagues studied 38 children aged 8.3 to 11.8 years. The children gave saliva samples to measure levels of cortisol, and 19 also underwent functional MRI of the brain, focusing on the hippocampus.

Mothers, meanwhile, rated their social standing on a ladder on a scale of 1 to 10, comparing themselves with others in the United States. Findings were as follows:

• After controlling for gender and age, the mother’s self-perceived social status was a significant predictor of cortisol levels in the child. This finding is consistent with studies in animals. “In animal research, your stress response is related to your relative standing in the hierarchy,” Sheridan says.
• Similarly, the mother’s perceived social status significantly predicted the degree of hippocampal activation in their children during a learning task.
• In contrast, actual maternal education or income-to-needs ratio (income relative to family size) did not significantly predict cortisol levels or hippocampal activation.

The findings suggest that while actual socioeconomic status varies, how people perceive and adapt to their situation is an important factor in child development. Some of this may be culturally determined, Sheridan notes. She is currently participating in a much larger international study of childhood poverty, the Young Lives Project, that is looking at objective and subjective measures of social status along with health measures and cognitive function. The study will capture much wider extremes of socioeconomic status than would a U.S.-based study.

What the current study didn’t find was evidence that stress itself alters hippocampal function; no relationship was found between cortisol and hippocampal function, as has been seen in animals, perhaps because of the small number children having brain fMRIs. “This needs further exploration,” says Sheridan. “There may be more than one pathway leading to differences in long-term memory, or there may be an effect of stress on the hippocampus that comes out only in adulthood.”

NIH-funded scientists show new genetically engineered proteins may be important tool for the President’s BRAIN Initiative

Scientists used fruit flies to show for the first time that a new class of genetically engineered proteins can be used to watch electrical activity in individual brain cells in live brains. The results, published in Cell, suggest these proteins may be a promising new tool for mapping brain cell activity in multiple animals and for studying how neurological disorders disrupt normal nerve cell signaling. Understanding brain cell activity is a high priority of the President’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative.

Brain cells use electricity to control thoughts, movements and senses.  Ever since the late nineteenth century, when Dr. Luigi Galvani induced frog legs to move with electric shocks, scientists have been trying to watch nerve cell electricity to understand how it is involved in these actions. Usually they directly monitor electricity with cumbersome electrodes or toxic voltage-sensitive dyes, or indirectly with calcium detectors. This study, led by Michael Nitabach, Ph.D., J.D., and Vincent Pieribone, Ph.D., at the Yale School of Medicine, New Haven, CT, shows that a class of proteins, called genetically encoded fluorescent voltage indicators (GEVIs), may allow researchers to watch nerve cell electricity in a live animal.

Dr. Pieribone and his colleagues helped develop ArcLight, the protein used in this study. ArcLight fluoresces, or glows, as a nerve cell’s voltage changes and enables researchers to watch, in real time, the cell’s electrical activity. In this study, Dr. Nitabach and his colleagues engineered fruit flies to express ArcLight in brain cells that control the fly’s sleeping cycle or sense of smell. Initial experiments in which the researchers simultaneously watched brain cell electricity with a microscope and recorded voltage with electrodes showed that ArcLight can accurately monitor electricity in a living brain. Further experiments showed that ArcLight illuminated electricity in parts of the brain that were previously inaccessible using other techniques. Finally, ArcLight allowed the researchers to watch brain cells spark and fire while the flies were awakening and smelling. These results suggest that in the future neuroscientists may be able to use ArcLight and similar GEVIs in a variety of ways to map brain cell circuit activity during normal and disease states.

An innovative series of experiments could help to unlock the mysteries of how the brain makes sense of the hustle and bustle of human activity we see around us every day.

Very little is known about the psychological processes which enable us to pick out a potential mugger from a busy street or to spot an old friend approaching us across a crowded room. Such judgements of social intention, which we make countless times each day, enable us to respond in appropriate ways to the dynamic and complex world around us.

George Mather, Professor of Vision Science at the University of Lincoln, UK, and one of the world’s foremost experts on human visual perception, will lead a new research project investigating the mechanisms behind this crucial ability to perceive and interpret the intentions of other people from the way they move.

Numerous experiments have explored the way we use visual signals to extract meaning from our environment, but most have been based on static images, such as photos of different facial expressions.

Other studies into the perception of moving images have relied on very simple animated scenes, like moving patterns of regularly-spaced lines or random dots, devoid of the richness and nuances of scenes from the ‘real world’.

There remains limited scientific understanding of how the human visual system makes sense of the flurry of movement we see around us in modern societies: for example, whether a person approaching us is sprinting or strolling, whether that means they are angry or calm, and how we should react in response.

Professor Mather aims to bridge this gap in the academic literature through a series of world-first experiments. He has been awarded a grant of £287,000 by the UK’s Economic & Social Research Council (ESRC) for a three-year study. The aim is to shed new light on the process by which the human visual system identifies and decodes ‘dynamic cues of social intention’.

Professor Mather said: “It’s true that actions speak louder than words. Perception of movement is fundamental to many of our everyday social interactions. But simply judging speed is in itself a very complex task. When you see somebody walking across your field of view, how do you know how fast they are going? That information can be very useful because it might tell you something about their intentions but it’s surprisingly difficult to make an accurate judgement. A basic problem is that the further away a moving object is, the slower it moves in the image received by the eye. We don’t really understand at the moment how the human visual system is able to compensate for different viewing conditions.”

Motion perception has been a consistent theme of Professor Mather’s research career. In previous studies he has shown that the brain can deduce socially meaningful information from very simple depictions of human movement, such as collections of dots denoting the major joints of the body.

The research in this latest project will answer fundamental questions about how the brain combines ‘low-level’ information about image motion with ‘high level’ knowledge of the social world to make meaningful assessments of the speed and nature of human movements.

If you forget where you put your car keys and you can’t seem to remember things as well as you used to, the problem may well be with the GluN2B subunits in your NMDA receptors.

And don’t be surprised if by tomorrow you can’t remember the name of those darned subunits.

They help you remember things, but you’ve been losing them almost since the day you were born, and it’s only going to get worse. An old adult may have only half as many of them as a younger person.

Research on these biochemical processes in the Linus Pauling Institute at Oregon State University is making it clear that cognitive decline with age is a natural part of life, and scientists are tracking the problem down to highly specific components of the brain. Separate from some more serious problems like dementia and Alzheimer’s disease, virtually everyone loses memory-making and cognitive abilities as they age. The process is well under way by the age of 40 and picks up speed after that.

But of considerable interest: It may not have to be that way.

“These are biological processes, and once we fully understand what is going on, we may be able to slow or prevent it,” said Kathy Magnusson, a neuroscientist in the OSU Department of Biomedical Sciences, College of Veterinary Medicine, and professor in the Linus Pauling Institute. “There may be ways to influence it with diet, health habits, continued mental activity or even drugs.”

The processes are complex. In a study just published in the Journal of Neuroscience, researchers found that one protein that stabilizes receptors in a young animal – a good thing conducive to learning and memory – can have just the opposite effect if there’s too much of it in an older animal.

But complexity aside, progress is being made. In recent research, supported by the National Institutes of Health, OSU scientists used a genetic therapy in laboratory mice, in which a virus helped carry complementary DNA into appropriate cells and restored some GluN2B subunits. Tests showed that it helped mice improve their memory and cognitive ability.

The NMDA receptor has been known of for decades, Magnusson said. It plays a role in memory and learning but isn’t active all the time – it takes a fairly strong stimulus of some type to turn it on and allow you to remember something. The routine of getting dressed in the morning is ignored and quickly lost to the fog of time, but the day you had an auto accident earns a permanent etching in your memory.

Within the NMDA receptor are various subunits, and Magnusson said that research keeps pointing back to the GluN2B subunit as one of the most important. Infants and children have lots of them, and as a result are like a sponge in soaking up memories and learning new things. But they gradually dwindle in number with age, and it also appears the ones that are left work less efficiently.

“You can still learn new things and make new memories when you are older, but it’s not as easy,” Magnusson said. “Fewer messages get through, fewer connections get made, and your brain has to work harder.”

Until more specific help is available, she said, some of the best advice for maintaining cognitive function is to keep using your brain. Break old habits, do things different ways. Get physical exercise, maintain a good diet and ensure social interaction. Such activities help keep these “subunits” active and functioning.

Gene therapy such as that already used in mice would probably be a last choice for humans, rather than a first option, Magnusson said. Dietary or drug options would be explored first.

“The one thing that does seem fairly clear is that cognitive decline is not inevitable,” she said. “It’s biological, we’re finding out why it happens, and it appears there are ways we might be able to slow or stop it, perhaps repair the NMDA receptors. If we can determine how to do that without harm, we will.”

Study could help yield new drugs for brain disorders

Johns Hopkins biophysicists have discovered that full activation of a protein ensemble essential for communication between nerve cells in the brain and spinal cord requires a lot of organized back-and-forth motion of some of the ensemble’s segments. Their research, they say, may reveal multiple sites within the protein ensemble that could be used as drug targets to normalize its activity in such neurological disorders as epilepsy, schizophrenia, Parkinson’s and Alzheimer’s disease.

The glutamate-binding segments (blue, yellow) of ionotropic glutamate receptors undergo a “rocking” motion during activation by glutamate (red). (The dotted line provides a point of reference.)

A summary of the results, published online in the journal Neuron on Aug. 7, shows that full activation of so-called ionotropic glutamate receptors is more complex than previously envisioned. In addition to the expected shape changes that occur when the receptor “receives” and clamps down on glutamate messenger molecules, the four segments of the protein ensemble also rock back and forth in relation to each other when fewer than four glutamates are bound.

“We believe that our study is the first to show the molecular architecture and behavior of a prominent neural receptor protein ensemble in a state of partial activation,” says Albert Lau, Ph.D., assistant professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine.

Glutamate receptors reside in the outer envelope of every nerve cell in the brain and spinal cord, Lau notes, and are responsible for changing chemical information — the release of glutamate molecules from a neighboring nerve cell — into electrical information, the flow of charged particles into the receiving nerve cell. There would be sharply reduced communication between nerve cells in our brains if these receptors were disabled, he added, and thought and normal brain function in general would be severely compromised. Malfunctioning receptors, says Lau, have been linked with numerous neurological disorders and are therefore potential targets for drug therapies.

Lau explained that each glutamate receptor is a united group of four protein segments that has a pocket for clamping down on glutamate like a Venus fly trap snaring a bug. Below the glutamate-binding segments are four other segments embedded in the cell’s outer envelope to form a channel for charged particles to flow through. When no glutamates are bound to the receptor, the channel is closed; full activation of the receptor and full opening of the channel occur when four glutamates are bound, each to a difference pocket.

Previously, Lau says, investigators thought that the level of receptor activation simply corresponded to the degree to which each glutamate-binding segment changed shape during the glutamate-binding process. Using a combination of computer modeling, biophysical “imaging” of molecular structure, biochemical analysis and electrical monitoring of individual cells, the researchers teased apart some of the steps in between zero activation and full activation. They were able to show that the four glutamate-binding segments, in addition to clamping down on glutamate, also rock back and forth in pairs when fewer than four glutamates are bound.

“It isn’t clear yet how this rocking motion affects receptor function, but we now know that activation depends on more than how much each glutamate-binding segment clamps down,” says Lau. Previous development of drugs targeting the receptor focused on the four glutamate-binding pockets. “Our discovery of this molecular motion could aid the development of drugs by revealing additional drug-binding sites on the receptor,” he adds.