Posts tagged science
Articles and news from the latest research reports.
Cell-saving drugs could reduce brain damage after stroke
Long-term brain damage caused by stroke could be reduced by saving cells called pericytes that control blood flow in capillaries, suggest researchers from Oxford University, UCL and the University of Copenhagen.
Until now, many scientists believed that blood flow within the brain was solely controlled by changes in the diameter of arterioles, blood vessels that branch out from arteries into smaller capillaries.
In this new study, the UK and Danish researchers reveal that the brain’s blood supply is in fact chiefly controlled by the narrowing or widening of capillaries as pericytes tighten or loosen around them.
Their study, published this week in the journal Nature, shows not only that pericytes are the main regulator of blood flow to the brain, but also that they tighten and die around capillaries after stroke. This significantly impairs blood flow in the long term, causing lasting damage to brain cells.
The scientists showed that certain chemicals can halve pericyte death from simulated stroke in the lab, and they hope to develop these into drugs to treat stroke victims.
'This discovery offers radically new treatment approaches for stroke,' says study co-author Professor Alastair Buchan, Dean of Medicine and Head of the Medical Sciences Division at Oxford University. 'Importantly, we should now be able to identify drugs that target these cells. If we are able to prevent pericytes from dying, it should help restore blood flow in the brain to normal and prevent the ongoing slow damage we see after a stroke which causes so much neurological disability in our patients.'
Professor David Attwell of UCL, who led the study, explains: ‘At present, clinicians can remove clots blocking blood flow to the brain if stroke patients reach hospital early enough. However, the capillary constriction produced by pericytes may, by restricting the blood supply for a long time, cause further damage to nerve cells even after the clot is removed. Our latest research suggests that devising drugs to prevent capillary constriction may offer new therapies for reducing the disability caused by stroke.’
The new research also gives insight into the mechanisms underlying the use of functional magnetic resonance imaging to detect blood flow changes in the brain.
'Functional imaging allows us to see the activity of nerve cells within the human brain but until now we didn't quite know what we were looking at,' says Professor Martin Lauritzen of the University of Copenhagen. 'We have shown that pericytes initiate the increase in blood flow seen when nerve cells become active. So we now know that functional imaging signals are caused by a pericyte-mediated increase of capillary diameter. Knowing exactly what functional imaging shows will help us to better understand and interpret what we see.'
(Source: ox.ac.uk)
Brain Degeneration In Huntington’s Disease Caused By Amino Acid Deficiency
Working with genetically engineered mice, Johns Hopkins neuroscientists report they have identified what they believe is the cause of the vast disintegration of a part of the brain called the corpus striatum in rodents and people with Huntington’s disease: loss of the ability to make the amino acid cysteine. They also found that disease progression slowed in mice that were fed a diet rich in cysteine, which is found in foods such as wheat germ and whey protein.
Their results suggest further investigation into cysteine supplementation as a candidate therapeutic in people with the disease.
Up to 90 percent of the human corpus striatum, a brain structure that moderates mood, movement and cognition, degenerates in people with Huntington’s disease, a condition marked by widespread motor and intellectual disability. And while the genetic mutation underlying Huntington’s disease has long been known, the precise cause of that degeneration has remained a mystery.
In a report on their discovery in the advanced online publication of Nature on March 26, the Johns Hopkins researchers, led by Solomon Snyder, M.D., tracked the degenerative process to the absence of an enzyme, cystathionine gamma lyase, or CSE.
"Usually it’s very hard, if not impossible, to develop straightforward mechanisms that explain what’s going on in a disease. What’s even harder is even if you can find a mechanism that causes a tissue to rot, usually there’s nothing you can do about it,” says Snyder, a professor of neuroscience at the Johns Hopkins University School of Medicine. “In this case, there is."
Huntington’s disease, an inherited disorder, does its damage because of abnormal DNA coding for the amino acid glutamine. Healthy individuals have some 15 to 20 DNA “repeats” in that part of their genetic code, while Huntington’s disease gene carriers have more than 36 — and often upward of 100. Children born to a parent carrier have a 50/50 chance of inheriting the disorder, and the greater the number of repeats, the earlier the age of onset of the incurable disorder.
Bindu Diana Paul, Ph.D., a molecular neuroscientist and faculty instructor in Snyder’s laboratory, was studying mice lacking CSE, which helps make the amino acid cysteine and hydrogen sulfide that moderate blood pressure and heart function. Paul, who had previous research experience with Huntington’s disease, says she was startled to observe that her mutant mice also behaved a lot like those with the disease.
When a normal mouse is dangled upside down from its tail, it will twist and turn and try to bite the offending hand, she explains. But her CSE-knockout mice stayed relatively still and clasped their paws together — the same behavior she’d observed in mice with the rodent equivalent of Huntington’s disease. “It looked like there was a neurological deficit,” Paul says. “But nobody had looked at CSE in the brain.”
Paul and Snyder began monitoring CSE in mouse and human brain tissues and found considerably less CSE in all diseased tissues. All people carry some normal huntingtin protein made by the Huntington’s disease gene, although the protein’s function remains elusive. But people with Huntington’s disease also carry mutant huntingtin proteins. Snyder and his team saw that the mutant proteins were attaching themselves to a crucial protein responsible for turning the CSE gene on or off, which ultimately led the diseased rodent and human brain tissues to be deprived of cysteine.
To see if loss of cysteine was directly responsible for the symptoms associated with Huntington’s disease, the Johns Hopkins team turned to readily available sources of the substance in everyday foods and fed mice a cysteine-rich diet.
The results, Paul says, were striking. When those mice were dangled from their tails, they resumed struggling, although with a bit less vigor than their healthy peers. They were able to grip an object with greater strength, and they took longer to fall off a balancing apparatus than CSE-knockout mice. Their life expectancies increased one to two weeks.
Snyder and Paul say they are cautiously optimistic about the results, noting that although they suggest a possible treatment for Huntington’s disease, it’s clear that a high cysteine diet merely slows rather than halts the progression of the disease. Moreover, the results in live mice may not occur in humans.
(Source: hopkinsmedicine.org)
New clue to autism found inside brain cells
The problems people with autism have with memory formation, higher-level thinking and social interactions may be partially attributable to the activity of receptors inside brain cells, researchers at Washington University School of Medicine in St. Louis have learned.
(Image caption: Learning, social interactions and higher-level thinking in people with autism may be adversely affected by receptors inside brain cells, scientists at Washington University School of Medicine have learned. The type of receptor they studied glows green on the surface of this cell. Inside the cell, the receptor covers a membrane stained red. Credit: Yuh-Jiin I. Jong)
Scientists were already aware that the type of receptor in question was a potential contributor to these problems – when located on the surfaces of brain cells. Until now, though, the role of the same type of receptor located inside the cell had gone unrecognized. Such receptors inside cells significantly outnumber the same type of receptors on the surface of cells.
The receptor under study, known as the mGlu5 receptor, becomes activated when it binds to the neurotransmitter glutamate, which is associated with learning and memory. This leads to chain reactions that convert the glutamate’s signal into messages traveling inside the cell.
In the new study, scientists working with cells in a dish linked mGlu5 receptors inside cells to processes that turn down the volume at which brain cells talk to each other. These volume changes, essential for learning and memory, may become exaggerated in people with autism.
Pharmaceutical companies have developed therapeutic compounds to decrease signaling associated with the mGlu5 receptor, moderating its effects on brain cells’ volume knobs. But the compounds were designed to target mGlu5 surface receptors. In light of the new findings, the scientists question if those drugs will reach the receptors inside cells.
“Our results suggest that to have the greatest therapeutic benefit, we may need to make sure we’re blocking all of this type of receptor, both inside and on the surface of the cell,” said senior investigator Karen O’Malley, PhD, professor of neurobiology.
The findings, published March 25 in The Journal of Neuroscience, also add a significant new dimension to basic brain cell function. Scientists have long assumed that brain cell receptors are only active on the surface of cells. The new study shows that receptors can be active inside cells, and their effects can be considerably different from the same receptors located on the cell surface.
“The traditional wisdom was that receptors inside the cell were either waiting to go to work on the surface or had just finished working there,” said O’Malley. “But when we compared how much of the mGlu5 receptor was on the surface of cells to how much was inside it, we were seeing so much more receptor inside the cell – at least 50 percent, and in some cases as much as 90 percent – that we wondered if the interior receptors had separate functions.”
In earlier studies, O’Malley and her collaborators showed that mGlu5 receptors on the cell surface sent completely different messages than the same receptors inside the cell.
The scientists knew that most autism studies were conducted with compounds that blocked mGlu5 receptors but could not get into the cell. To determine whether blocking inside receptors would have different effects, O’Malley collaborated with Yukitoshi Izumi, MD, PhD, research professor of psychiatry, and Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry, who study cell-based models of learning and memory.
When the scientists examined these model systems using compounds that allowed them to activate only mGlu5 receptors within cells, they found that these receptors played a bigger role in turning down the volume of brain cell communications than did the cell surface receptors.
In the last few years, scientists have found that 20 or more types of brain cell receptors located on cell surfaces also are present at high levels inside cells, O’Malley noted.
“This should be a factor we consider when we design drugs to target brain cell receptors,” she said. “Do we want to reach cell surface receptors, receptors inside the cell or both?”
(Source: news.wustl.edu)
First comprehensive atlas of human gene activity released
A large international consortium of researchers has produced the first comprehensive, detailed map of the way genes work across the major cells and tissues of the human body. The findings describe the complex networks that govern gene activity, and the new information could play a crucial role in identifying the genes involved with disease.
“Now, for the first time, we are able to pinpoint the regions of the genome that can be active in a disease and in normal activity, whether it’s in a brain cell, the skin, in blood stem cells or in hair follicles,” said Winston Hide, associate professor of bioinformatics and computational biology at Harvard School of Public Health (HSPH) and one of the core authors of the main paper in Nature. “This is a major advance that will greatly increase our ability to understand the causes of disease across the body.”
The research is outlined in a series of papers published March 27, 2014, two in the journal Nature and 16 in other scholarly journals. The work is the result of years of concerted effort among 250 experts from more than 20 countries as part of FANTOM 5 (Functional Annotation of the Mammalian Genome). The FANTOM project, led by the Japanese institution RIKEN, is aimed at building a complete library of human genes.
Researchers studied human and mouse cells using a new technology called Cap Analysis of Gene Expression (CAGE), developed at RIKEN, to discover how 95% of all human genes are switched on and off. These “switches”—called “promoters” and “enhancers”—are the regions of DNA that manage gene activity. The researchers mapped the activity of 180,000 promoters and 44,000 enhancers across a wide range of human cell types and tissues and, in most cases, found they were linked with specific cell types.
“We now have the ability to narrow down the genes involved in particular diseases based on the tissue cell or organ in which they work,” said Hide. “This new atlas points us to the exact locations to look for the key genetic variants that might map to a disease.”
High-fat diet in pregnancy linked to Alzheimer’s brain changes in offspring
A new study from scientists in Southampton has suggested that diet during pregnancy may affect an offspring’s risk of brain changes linked to Alzheimer’s disease. The research, which was funded by Alzheimer’s Research UK, studied adult mice whose mothers were fed either a normal or a high-fat diet during pregnancy and lactation. The study is due to be presented at Alzheimer’s Research UK Conference 2014 in Oxford this week.
Led by Dr Cheryl Hawkes at the University of Southampton, the team set out to investigate the links between obesity and Alzheimer’s. Obesity has been linked to a higher risk of the disease, and previous research has suggested that a mother’s diet during pregnancy may affect a child’s risk of obesity and conditions such as heart disease and diabetes in adulthood.
The researchers studied mice which were fed either a standard diet or a high-fat diet, and whose mothers were also fed either a high fat or standard diet during pregnancy and lactation. They then looked at markers of cholesterol and problems with blood vessels in the brain, both of which have been linked to Alzheimer’s.
They found that mice whose mothers ate a high-fat diet during pregnancy were more likely to have vascular changes in their brains later in life. Furthermore, when the offspring of mothers with a high-fat diet were also fed a high-fat diet, their brains’ blood vessels became less efficient at clearing the protein amyloid – a hallmark feature of the disease.
Dr Hawkes, an Alzheimer’s Research UK Senior Research Fellow at the University of Southampton, said: “Our preliminary findings suggest that mothers’ diets during pregnancy may have long-term effects on their children’s brains and vascular health. We still need to do more work to understand how our findings translate to humans, but we have known for some time that protecting mothers’ health during pregnancy can help lower the risk of health problems for their children. Our next step will be to investigate how our findings could relate to Alzheimer’s disease in people. We hope these results could provide a new lead for research to understand how to prevent the disease.”
Alzheimer’s Research UK is the UK’s leading dementia research charity, funding more than £20m of pioneering research into the condition across the UK. The charity’s annual conference on 25 and 26 March is the largest of its kind in the UK, and will see leading dementia scientists share their progress in the drive to defeat dementia.
Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said: “It’s important to remember that this research is in mice, but these results add to existing evidence suggesting that the risk of Alzheimer’s disease in later life is affected by our health earlier in life. This study goes one step further by suggesting that what happens in the womb may also be important. We’re pleased to have funded this research, which has shed new light on the complex picture of Alzheimer’s risk.
“Alzheimer’s is a complicated disease and it’s likely that our risk is affected by a number of different genetic and environmental factors. Research to understand these factors can help equip us to take steps to prevent the disease, but in the meantime, evidence suggests we can lower our risk by eating a healthy, balanced diet, doing regular exercise, not smoking and keeping our blood pressure and weight in check.”
Sensing Gravity with Acid: Scientists Discover a Role for Protons in Neurotransmission
While probing how organisms sense gravity and acceleration, scientists at the Marine Biological Laboratory (MBL) and the University of Utah uncovered evidence that acid (proton concentration) plays a key role in communication between neurons. The surprising discovery is reported this week in Proceedings of the National Academy of Sciences.
The team, led by the late MBL senior scientist Stephen M. Highstein, discovered that sensory cells in the inner ear continuously transmit information on orientation of the head relative to gravity and low-frequency motion to the brain using protons as the key synaptic signaling molecule. (The synapse is the structure that allows one neuron to communicate with another by passing a chemical or electrical signal between them.)
“This addresses how we sense gravity and other low-frequency inertial stimuli, like acceleration of an automobile or roll of an airplane,” says co-author Richard Rabbitt, a professor at University of Utah and adjunct faculty member in the MBL’s Program in Sensory Physiology and Behavior. “These are very long-lasting signals requiring a a synapse that does not fatigue or lose sensitivity over time. Use of protons to acidify the space between cells and transmit information from one cell to another could explain how the inner ear is able to sense tonic signals, such as gravity, in a robust and energy efficient way.”
The team found that this novel mode of neurotransmission between the sensory cells (type 1 vestibular hair cells) and their target afferent neurons (calyx nerve terminals), which send signals to the brain, is continuous or nonquantal. This nonquantal transmission is unusual and, for low-frequency stimuli like gravity, is more energy efficient than traditional synapses in which chemical neurotransmitters are packaged in vesicles and released quantally.
The calyx nerve terminal has a ball-in-socket shape that envelopes the sensory hair cell and helps to capture protons exiting the cell. “The inner-ear vestibular system is the only place where this particular type of synapse is present,” Rabbitt says. “But the fact that protons are playing a key role here suggests they are likely to act as important signaling molecules in other synapses as well.”
Previously, Erik Jorgensen of University of Utah (who recently received a Lillie Research Innovation Award from the MBL and the University of Chicago) and colleagues discovered that protons act as signaling molecules between muscle cells in the worm C. elegans and play an important role in muscle contraction. The present paper is the first to demonstrate that protons also act directly as a nonquantal chemical neurotransmitter in concert with classical neurotransmission mechanisms. The discovery suggests that similar intercellular proton signaling mechanisms might be at play in the central nervous system.
Brain scans show what makes us drink water and what makes us stop drinking
Drinking water when you’re thirsty is a pleasurable experience. Continuing to drink when you’re not, however, can be very unpleasant. To understand why your reaction to water drinking changes as your thirst level changes, Pascal Saker of the University of Melbourne and his colleagues performed fMRI scans on people as they drank water. They found that regions of the brain associated with positive feelings became active when the subjects were thirsty, while regions associated with negative feelings and with controlling and coordinating movement became active after the subjects were satiated. The research appears in the Proceedings of the National Academy of Sciences.
Blood-brain barrier repair after stroke may prevent chronic brain deficits
Following ischemic stroke, the integrity of the blood-brain barrier (BBB), which prevents harmful substances such as inflammatory molecules from entering the brain, can be impaired in cerebral areas distant from initial ischemic insult. This disruptive condition, known as diaschisis, can lead to chronic post-stroke deficits, University of South Florida researchers report.
(Image credit: Mosby’s Medical Dictionary, 8th edition. © 2009, Elsevier)
In experiments using laboratory rats modeling ischemic stroke, USF investigators studied the consequences of the compromised BBB at the chronic post-stroke stage. Their findings appear in a recent issue of the Journal of Comparative Neurology.
“Following ischemic stroke, the pathological changes in remote areas of the brain likely contribute to chronic deficits,” said neuroscientist and study lead author Svitlana Garbuzova-Davis, PhD, associate professor in the USF Health Department of Neurosurgery and Brain Repair. “These changes are often related to the loss of integrity of the BBB, a condition that should be considered in the development of strategies for treating stroke and its long-term effects.”
Edward Haller of the USF Department of Integrative Biology, the coauthor who performed electron microscopy and contributed to image analysis, emphasized that “major BBB damage was found in endothelial and pericyte cells, leading to capillary leakage in both brain hemispheres.” These findings were essential in demonstrating persistence of microvascular alterations in chronic ischemic stroke.
While acute stroke is life-threatening, the authors point out that survivors often suffer insufficient blood flow to many parts of the brain that can contribute to persistent damage and disability. Their previous investigation of subacute ischemic stroke showed far-reaching microvascular damage even in areas of the brain opposite from the initial stroke injury. While most studies of stroke and the BBB explore the acute phase of stroke and its effect on the blood-brain barrier, the present study revealed the longer-term effects in various parts of the brain.
The pathologic processes of stroke-induced vascular injury tend to occur in a “time-dependent manner,” and can be separated into acute (minutes to hours), subacute (hours to days), and chronic (days to months). BBB incompetence during post-stroke changes is well-documented, with some studies showing the BBB opening can last up to four to five days after stroke. This suggests that harmful substances entering the brain during this prolonged BBB leakage might increase post-ischemic brain injury.
In this study, the researchers used laboratory rats modeling ischemic stroke and observed injury not only in the primary area of the stroke, but also in remote areas, where persistent BBB damage could cause chronic loss of competence.
“Our results showed that the compromised BBB integrity detected in post-ischemic rat cerebral hemisphere capillaries — both ipsilateral and contralateral to initial stroke insult — might indicate chronic diaschisis,” Garbuzova-Davis said. “Widespread microvascular damage caused by endothelial cell impairment could aggravate neuronal deterioration. For this reason, chronic diaschisis poses as a therapeutic target for stroke.”
The primary focus for therapy development could be restoring endothelial and/or astrocytic integrity towards BBB repair, which may be “beneficial for many chronic stroke patients,” senior authors Cesar V. Borlongan and Paul R. Sanberg suggest. The researchers also recommend that cell therapy might be used to replace damaged endothelial cells.
“A combination of cell therapy and the inhibition of inflammatory factors crossing the blood-brain barrier may be a beneficial treatment for stroke,” Garbuzova-Davis said.
(Source: research.usf.edu)
Yale researchers reconstruct facial images locked in a viewer’s mind
Using only data from an fMRI scan, researchers led by a Yale University undergraduate have accurately reconstructed images of human faces as viewed by other people.
“It is a form of mind reading,” said Marvin Chun, professor of psychology, cognitive science and neurobiology and an author of the paper in the journal Neuroimage.
The increased level of sophistication of fMRI scans has already enabled scientists to use data from brain scans taken as individuals view scenes and predict whether a subject was, for instance, viewing a beach or city scene, an animal or a building.
“But they can only tell you they are viewing an animal or a building, not what animal or building,” Chun said. “This is a different level of sophistication.”
One of Chun’s students, Alan S. Cowen, then a Yale junior now pursing an advanced degree at the University of California at Berkeley, wanted to know whether it would be possible to reconstruct a human face from patterns of brain activity. The task was daunting, because faces are more similar to each other than buildings. Also large areas of the brain are recruited in the processing of human faces, a testament to its importance in survival.
“We perceive faces in a much greater level of detail than we perceive other things,” Cowen said.
Working with funding from the Yale Provost’s office, Cowen and post doctoral researcher Brice Kuhl, now an assistant professor at New York University, showed six subjects 300 different “training” faces while undergoing fMRI scans. They used the data to create a sort of statistical library of how those brains responded to individual faces. They then showed the six subjects new sets of faces while they were undergoing scans. Taking that fMRI data alone, researchers used their statistical library to reconstruct the faces their subjects were viewing.
Cowen said the accuracy of these facial reconstructions will increase with time and he envisions they can be used as a research tool, for instance in studying how autistic children respond to faces.
Chun said the study shows the value of funding research ambitions of Yale undergraduates.
“I would never have received external funding for this, it was too novel,” Chun said.
![EEG study: Brain infers structure, rules of tasks
A new study documents the brain activity underlying our strong tendency to infer a structure of context and rules when learning new tasks (even when a structure isn’t valid). The findings, which revealed individual differences, shows how we try to apply task knowledge to similar situations and could inform future research on learning disabilities.
In life, many tasks have a context that dictates the right actions, so when people learn to do something new, they’ll often infer cues of context and rules. In a new study, Brown University brain scientists took advantage of that tendency to track the emergence of such rule structures in the frontal cortex — even when such structure was not necessary or even helpful to learn — and to predict from EEG readings how people would apply them to learn new tasks speedily.
Context and rule structures are everywhere. They allow an iPhone user who switches to an Android phone, for example, to reason that dimming the screen would involve finding a “settings” icon that will probably lead to a slider control for “brightness.” But when the context changes, inflexible generalization can lead a person temporarily astray — like a small-town tourist who greets strangers on the streets of New York City. In some developmental learning disabilities, the whole process of inferring abstract structures may be impaired.
“The world tends to be organized, and so we probably develop prior [notions] over time that there is going to be a structure,” said Anne Collins, a postdoctoral scholar in the Department of Cognitive, Linguistic, and Psychological Sciences at Brown and lead author of the study published March 25 in the Journal of Neuroscience. “When the world is organized, you just reduce the size of what you have to learn about by being able to generalize across situations in which the same things usually happen together. It is efficient to generalize if there is structure, and there usually is structure.”
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EEG study: Brain infers structure, rules of tasks
A new study documents the brain activity underlying our strong tendency to infer a structure of context and rules when learning new tasks (even when a structure isn’t valid). The findings, which revealed individual differences, shows how we try to apply task knowledge to similar situations and could inform future research on learning disabilities.
In life, many tasks have a context that dictates the right actions, so when people learn to do something new, they’ll often infer cues of context and rules. In a new study, Brown University brain scientists took advantage of that tendency to track the emergence of such rule structures in the frontal cortex — even when such structure was not necessary or even helpful to learn — and to predict from EEG readings how people would apply them to learn new tasks speedily.
Context and rule structures are everywhere. They allow an iPhone user who switches to an Android phone, for example, to reason that dimming the screen would involve finding a “settings” icon that will probably lead to a slider control for “brightness.” But when the context changes, inflexible generalization can lead a person temporarily astray — like a small-town tourist who greets strangers on the streets of New York City. In some developmental learning disabilities, the whole process of inferring abstract structures may be impaired.
“The world tends to be organized, and so we probably develop prior [notions] over time that there is going to be a structure,” said Anne Collins, a postdoctoral scholar in the Department of Cognitive, Linguistic, and Psychological Sciences at Brown and lead author of the study published March 25 in the Journal of Neuroscience. “When the world is organized, you just reduce the size of what you have to learn about by being able to generalize across situations in which the same things usually happen together. It is efficient to generalize if there is structure, and there usually is structure.”