April 22, 2012

A key protein, which may be activated to protect nerve cells from damage during heart failure or epileptic seizure, has been found to regulate the transfer of information between nerve cells in the brain. The discovery, made by neuroscientists at the University of Bristol and published in Nature Neuroscience and PNAS, could lead to novel new therapies for stroke and epilepsy.

The research team, led by Professor Jeremy Henley and Dr Jack Mellor from Bristol’s Medical School, has identified a protein, known as SUMO, responsible for controlling the chemical processes which reduce or enhance protection mechanisms for nerve cells in the brain.

These key SUMO proteins produce subtle responses to the brain’s activity levels to regulate the amount of information transmitted by kainate receptors - responsible for communication between nerve cells and whose activation can lead to epileptic seizures and nerve cell death.

Protein function is controlled by altering their structure in processes that can be independent or inter-related including phosphorylation, ubiquitination and SUMOylation. In the present work it is shown that phosphorylation of kainate receptors on its own promotes their activity. However, phosphorylation also facilitates SUMOylation of kainate receptors that reduces their activity. Thus there is a dynamic and delicate interplay between phosphorylation and SUMOylation that regulates kainate receptor function.

This fine balance between phosphorylation and SUMOylation is dependent on brain activity levels where damaging activity that occurs during stroke or epilepsy will enhance SUMOylation and therefore reduce kainate receptor function to protect nerve cells.

Dr Mellor, Senior Lecturer from the University’s School of Physiology and Pharmacology, said: “Kainate receptors are a somewhat mysterious but clearly very important group of proteins that are known to be involved in a number of diseases including epilepsy. However, we currently know little about what makes kainate receptors so important. Likewise, we also know that SUMO proteins play an important role in neuroprotection. These findings provide a link between SUMO and kainate receptors that increases our understanding of the processes that nerve cells use to protect themselves from excessive and abnormal activity.”

Professor Henley added: “This work is important because it gives a new perspective and a deeper understanding of how the flow of information between cells in the brain is regulated. The team has found that by increasing the amount of SUMO attached to kainate receptors – which would reduce communication between the cells – could be a way to treat epilepsy by preventing over-excitation of the brain’s nerve cells.”

The research follows on from previous findings published in Nature(447, 321-325) that discovered SUMO proteins target the brain’s kainate receptors altering their cellular location.

Provided by University of Bristol

Source: medicalxpress.com

April 22, 2012

New research from Mount Sinai Medical Center in New York reveals that repeated exposure to cocaine decreases the activity of a protein necessary for normal functioning of the brain’s reward system, thus enhancing the reward for cocaine use, which leads to addiction. Investigators were also able to block the ability of repeated cocaine exposure, to induce addiction. The findings, published online April 22 in the journal Nature Neuroscience, provide the first evidence of how cocaine changes the shape and size of neuron rewards in a mouse model.

Repeated exposure to cocaine decreases the expression of a protein necessary for normal functioning of the brain’s reward system, thus enhancing the reward for cocaine use and stimulating addiction. Using the protein’s light-activated form in real time, in a technique known as optogenetics, investigators were also able to block repeated cocaine exposure from enhancing the brain’s reward center from cocaine. Even though the results are very early and many steps will be important in moving from mice to humans, the researchers say that the finding opens the door to a new direction for treatment for cocaine addiction.

"There are virtually no medication regimens for cocaine addiction, only psychotherapy, and some early work with vaccines," said the study’s senior investigator, Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience, Chairman of the Neuroscience and Director of the Friedman Brain Institute at Mount Sinai School of Medicine. The protein, Rac1, is found in many cells in mice, rats, monkeys, and humans, and it is known to be involved in controlling the growth of nerve cells.

Investigators “knocked out,” or deleted, the gene responsible for Rac1 production, or injected a virus to enhance expression of Rac1.

"The research gives us new information on how cocaine affects the brain’s reward center and how it could potentially be repaired," said Dr. Nestler. "This is the first case in the brain in vivo where it’s been possible to control the activity of a protein, inside nerve cells in real time. Our findings reveal new pathways and target — a proof of principle study really — for treatment of cocaine addiction."

Provided by The Mount Sinai Hospital / Mount Sinai School of Medicine

Source: medicalxpress.com

ScienceDaily (Apr. 22, 2012) — A key protein, which may be activated to protect nerve cells from damage during heart failure or epileptic seizure, has been found to regulate the transfer of information between nerve cells in the brain. The discovery, made by neuroscientists at the University of Bristol and published in Nature Neuroscience and PNAS, could lead to novel new therapies for stroke and epilepsy.

An image of a hippocampal neuron. (Credit: Inma Gonzalez-Gonzalez)

The research team, led by Professor Jeremy Henley and Dr Jack Mellor from Bristol’s Medical School, has identified a protein, known as SUMO, responsible for controlling the chemical processes which reduce or enhance protection mechanisms for nerve cells in the brain.

These key proteins produce subtle responses to the brain’s activity levels to regulate the amount of information transmitted by kainate receptors — responsible for communication between nerve cells and whose activation can lead to epileptic seizures and nerve cell death.

Protein function is controlled by altering their structure in processes that can be independent or inter-related including phosphorylation, ubiquitination and SUMOylation. In the present work it is shown that phosphorylation of kainate receptors on its own promotes their activity. However, phosphorylation also facilitates SUMOylation of kainate receptors that reduces their activity. Thus there is a dynamic and delicate interplay between phosphorylation and SUMOylation that regulates kainate receptor function.

This fine balance between phosphorylation and SUMOylation is dependent on brain activity levels where damaging activity that occurs during stroke or epilepsy will enhance SUMOylation and therefore reduce kainate receptor function to protect nerve cells.

Dr Mellor, Senior Lecturer from the University’s School of Physiology and Pharmacology, said: “Kainate receptors are a somewhat mysterious but clearly very important group of proteins that are known to be involved in a number of diseases including epilepsy. However, we currently know little about what makes kainate receptors so important. Likewise, we also know that SUMO proteins play an important role in neuroprotection. These findings provide a link between SUMO and kainate receptors that increases our understanding of the processes that nerve cells use to protect themselves from excessive and abnormal activity.”

Professor Henley added: “This work is important because it gives a new perspective and a deeper understanding of how the flow of information between cells in the brain is regulated. The team has found that by increasing the amount of SUMO attached to kainate receptors — which would reduce communication between the cells — could be a way to treat epilepsy by preventing over-excitation of the brain’s nerve cells.”

The research follows on from previous findings published in Nature that discovered SUMO proteins target the brain’s kainate receptors altering their cellular location.

Source: Science Daily

ScienceDaily (Apr. 22, 2012) — Engineers at the University of Sheffield have developed a method of assisting nerves damaged by traumatic accidents to repair naturally, which could improve the chances of restoring sensation and movement in injured limbs.

Scanning electron microscopy images of the structures fabricated by (left) 2PP and (right) microreplication techniques. (Credit: Image courtesy of University of Sheffield)

In a collaborative study with Laser Zentrum Hannover (Germany) published April 23, 2012 in the journal Biofabrication, the team describes a new method for making medical devices called nerve guidance conduits or NGCs.

The method is based on laser direct writing, which enables the fabrication of complex structures from computer files via the use of CAD/CAM (computer aided design/manufacturing), and has allowed the research team to manufacture NGCs with designs that are far more advanced than previously possible.

Currently patients with severe traumatic nerve damage suffer a devastating loss of sensation and/or movement in the affected limb. The traditional course of action, where possible, is to surgically suture or graft the nerve endings together. However, reconstructive surgery often does not result in complete recovery.

"When nerves in the arms or legs are injured they have the ability to re-grow, unlike in the spinal cord; however, they need assistance to do this," said University of Sheffield Professor of Bioengineering, John Haycock. "We are designing scaffold implants that can bridge an injury site and provide a range of physical and chemical cues for stimulating this regrowth."

The new conduit is made from a biodegradable synthetic polymer material based on polylactic acid and has been designed to guide damaged nerves to re-grow through a number of small channels.

"Nerves aren’t just like one long cable, they’re made up of lots of small cables, similar to how an electrical wire is constructed," said lead author Dr Frederik Claeyssens, of the University’s Department of Materials Science and Engineering. "Using our new technique we can make a conduit with individual strands so the nerve fibres can form a similar structure to an undamaged nerve."

Once the nerve is fully regrown, the conduit biodegrades naturally. The team hopes that this approach will significantly increase recovery for a wide range of peripheral nerve injuries.

In laboratory experiments, nerve cells added to the polymer conduit grew naturally within its channelled structure and the research team is now working towards clinical trials.

"If successful we anticipate these scaffolds will not just be applicable to peripheral nerve injury, but could also be developed for other types of nerve damage too. The technique of laser direct writing may ultimately allow production of scaffolds that could help in the treatment of spinal cord injury" said Dr Claeyssens.

"What’s exciting about this work is that not only have we designed a new method for making nerve guide scaffolds which support nerve growth, we´ve also developed a method of easily reproducing them through micromolding.

"This technology could make a huge difference to patients suffering severe nerve damage," he added.

Source: Science Daily

ScienceDaily (Apr. 22, 2012) — Researchers at Columbia University Medical Center (CUMC) have identified a molecular pathway that controls the retention and release of the brain’s stem cells. The discovery offers new insights into normal and abnormal neurologic development and could eventually lead to regenerative therapies for neurologic disease and injury. The findings, from a collaborative effort of the laboratories of Drs. Anna Lasorella and Antonio Iavarone, were published April 22in the online edition of Nature Cell Biology.

Neural stem cells detaching from the vascular niche. (Credit: Anna Lasorella, CUMC /Nature Cell Biology)

The research builds on recent studies, which showed that stem cells reside in specialized niches, or microenvironments, that support and maintain them.

"From this research, we knew that when stem cells detach from their niche, they lose their identity as stem cells and begin to differentiate into specific cell types," said co-senior author Antonio Iavarone, MD, professor of Pathology and Neurology at CUMC.

"However, the pathways that regulate the interaction of stem cells with their niche were obscure," said co-senior author Anna Lasorella, MD, associate professor of Pathology and Pediatrics at CUMC and a member of the Columbia Stem Cell Initiative.

In the brain, the stem cell niche is located in an area adjacent to the ventricles, the fluid-filled spaces within the brain. Neural stem cells (NSCs) within the niche are carefully regulated, so that enough cells are released to populate specific brain areas, while a sufficient supply is kept in reserve.

In previous studies, Drs. Iavarone and Lasorella focused on molecules called Id (inhibitor of differentiation) proteins, which regulate various stem cell properties. They undertook the present study to determine how Id proteins maintain stem cell identity.

The team developed a genetically altered strain of mice in which Id proteins were silenced, or knocked down, in NSCs. In the absence of Id proteins, mice died within 24 hours of birth. Their brains showed markedly lowered NSC proliferative capacity, and their stem cell populations were reduced.

Studies of NSCs from this strain of mice revealed that Id proteins directly regulate the production of a protein called Rap1GAP, which in turn controls Rap1, one of the master regulators of cell adhesion. The researchers found that the Id-Rap1GAP-Rap1 pathway is critical for the adhesion of NSCs to their niche and for NSC maintenance. “There may be other pathways involved, but we believe this is the key pathway,” said Dr. Iavarone. “There is good reason to believe that it operates in other kinds of stem cells, and our labs are investigating this question now.”

"This is a new idea," added Dr. Lasorella. "Before this study, the prevailing wisdom was that NSCs are regulated by the niche components, conceivably through the release of chemical attractants such as cytokines. However, our findings suggest that stem cell identity relies on this mechanism."

More research needs to be done before the findings can be applied therapeutically, Dr. Iavarone said. “Multiple studies show that NSCs respond to insults such as ischemic stroke or neurodegenerative diseases. If we can understand how to manipulate the pathways that determine stem cell fate, in the future we may be able to control NSC properties for therapeutic purposes.”

"Another aspect," added Dr. Lasorella, "is to determine whether Id proteins also maintain stem cell properties in cancer stem cells in the brain. In fact, normal stem cells and cancer stem cells share properties and functions. Since cancer stem cells are difficult to treat, identifying these pathways may lead to more effective therapies for malignant brain tumors."

Stephen G. Emerson, MD, PhD, director of the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, added that, “Understanding the pathway that allows stem cells to develop into mature cells could eventually lead to more effective, less toxic cancer treatments. This beautiful study opens up a wholly unanticipated way to think about treating brain tumors.”

Source: Science Daily

April 20th, 2012

Multiple disease-related changes progress in parallel through distinct stages.

This schematic illustration shows the experimental arrangement for in vivo two-photon calcium imaging of stimulation-evoked neuronal activity in anesthetized mice. At left, in vivo two-photon image of the visual cortex. The neurons are stained with the calcium indicator dye Oregon Green BAPTA-1 (green, OGB-1) and the astrocytes with Sulforhodamine 101 (yellow, SR101). Right, visual stimuli were projected on a screen placed in front of the eye of the mouse. Image adapted from image credited to Konnerth lab, TU Muenchen.

Studying a mouse model of Alzheimer’s disease, neuroscientists at the Technische Universitaet Muenchen have observed correlations between increases in both soluble and plaque-forming beta-amyloid – a protein implicated in the disease process – and dysfunctional developments on several levels: individual cortical neurons, neuronal circuits, sensory cognition, and behavior. Their results, published in Nature Communications, show that these changes progress in parallel and that, together, they reveal distinct stages in Alzheimer’s disease with a specific order in time.

In addition to its well known, devastating effects on memory and learning, Alzheimer’s disease can also impair a person’s sense of smell or vision. Typically these changes in sensory cognition only show themselves behaviorally when the disease is more advanced. A new study sheds light on what is happening in the brain throughout the disease process, specifically with respect to the part of the cerebral cortex responsible for integrating visual information. A team led by Prof. Arthur Konnerth, a Carl von Linde Senior Fellow of the TUM Institute for Advanced Study, has observed Alzheimer’s-related changes in the visual cortex at the single-cell level.

Using a technique called two-photon calcium imaging, the researchers recorded both spontaneous and stimulated signaling activity in cortical neurons of living mice: transgenic mice carrying mutations that cause Alzheimer’s disease in humans, and wild-type mice as a control group. By observing how neuronal signaling responded to a special kind of vision test – in which a simple grating pattern of light and dark bars moves in front of the mouse’s eye – the scientists could characterize the visual circuit as being more or less “tuned” to specific orientations and directions of movement.

Konnerth explains, “Like many Alzheimer’s patients, the diseased mice have impairments in their ability to discriminate visual objects. Our results provide important new insights on the cause that may underlie the impaired behavior, by identifying in the visual cortex a fraction of neurons with a strongly disturbed function.” And within this group, the researchers discovered, there are two subsets of neurons – both dysfunctional, but in completely different ways. One subset, thought to be the first neurons to degenerate, showed no activity at all; the other showed a pathologically high level of activity, rendering these neurons incapable of properly sensing objects in the mouse’s environment. “While around half of the neurons in the visual cortex were disturbed in one way or the other, roughly half responded normally,” notes Christine Grienberger, a doctoral candidate in Konnerth’s institute and first author of this paper. “That could have significant implications for future research in the field of Alzheimer’s disease, as our findings raise the question of whether future work only needs to target this population of neurons that are disturbed in their function.”

The in vivo single-neuron experiments were carried out for three age groups, corresponding to different stages of this progressive, degenerative disease. The results were correlated with other measurements, including soluble beta-amyloid levels and the density of beta-amyloid plaques in the brain tissue. The researchers’ findings show for the first time a progressive decline of function in cortical circuits. “An important conclusion from this study,” Konnerth says, “is that the Alzheimer’s disease-related changes on all levels – including behavior, cortical circuit dysfunction, and the density of amyloid plaques in diseased brains – progress in parallel in a distinct temporal order. In the future, the identification of such stages in patients may help researchers pinpoint stage-specific and effective therapies, with reduced levels of side effects.”

Source: Neuroscience News

April 20th, 2012

A miniature atom-based magnetic sensor developed by the National Institute of Standards and Technology (NIST) has passed an important research milestone by successfully measuring human brain activity.

NIST’s atom-based magnetic sensor, about the size of a sugar cube, can measure human brain activity. Inside the sensor head is a container of 100 billion rubidium atoms (not seen), packaged with micro-optics (a prism and a lens are visible in the center cutout). The light from a low-power infrared laser interacts with the atoms and is transmitted through the grey fiber-optic cable to register the magnetic field strength. The black and white wires are electrical connections. Image adapted from image by Knappe/NIST.

Experiments reported this week in Biomedical Optics Express verify the sensor’s potential for biomedical applications such as studying mental processes and advancing the understanding of neurological diseases.

NIST and German scientists used the NIST sensor to measure alpha waves in the brain associated with a person opening and closing their eyes as well as signals resulting from stimulation of the hand. The measurements were verified by comparing them with signals recorded by a SQUID (superconducting quantum interference device). SQUIDs are the world’s most sensitive commercially available magnetometers and are considered the “gold standard” for such experiments. The NIST mini-sensor is slightly less sensitive now but has the potential for comparable performance while offering potential advantages in size, portability and cost.

The study results indicate the NIST mini-sensor may be useful in magnetoencephalography (MEG), a noninvasive procedure that measures the magnetic fields produced by electrical activity in the brain. MEG is used for basic research on perceptual and cognitive processes in healthy subjects as well as screening of visual perception in newborns and mapping brain activity prior to surgery to remove tumors or treat epilepsy. MEG also might be useful in brain-computer interfaces.

MEG currently relies on SQUID arrays mounted in heavy helmet-shaped flasks containing cryogenic coolants because SQUIDs work best at 4 degrees above absolute zero, or minus 269 degrees Celsius. The chip-scale NIST sensor is about the size of a sugar cube and operates at room temperature, so it might enable lightweight and flexible MEG helmets. It also would be less expensive to mass produce than typical atomic magnetometers, which are larger and more difficult to fabricate and assemble.

“We’re focusing on making the sensors small, getting them close to the signal source, and making them manufacturable and ultimately low in cost,” says NIST co-author Svenja Knappe. “By making an inexpensive system you could have one in every hospital to test for traumatic brain injuries and one for every football team.”

The mini-sensor consists of a container of about 100 billion rubidium atoms in a gas, a low-power infrared laser and fiber optics for detecting the light signals that register magnetic field strength—the atoms absorb more light as the magnetic field increases. The sensor has been improved since it was used to measure human heart activity in 2010. NIST scientists redesigned the heaters that vaporize the atoms and switched to a different type of optical fiber to enhance signal clarity.

The brain experiments were carried out in a magnetically shielded facility at the Physikalisch Technische Bundesanstalt (PTB) in Berlin, Germany, which has an ongoing program in biomagnetic imaging using human subjects. The NIST sensor measured magnetic signals of about 1 picotesla (trillionths of a tesla). For comparison, the Earth’s magnetic field is 50 million times stronger (at 50 millionths of a tesla). NIST scientists expect to boost the mini-sensor’s performance about tenfold by increasing the amount of light detected. Calculations suggest an enhanced sensor could match the sensitivity of SQUIDS. NIST scientists are also working on a preliminary multi-sensor magnetic imaging system in a prelude to testing clinically relevant applications.

Source: Neuroscience News

April 20, 2012 by Bob Yirka 

(Medical Xpress) — Researchers from the University of Groningen Medical Centre in the Netherlands have found that for women at least, watching pornographic videos tends to quiet the part of the brain most heavily involved in looking at and processing things in the immediate environment, suggesting that the brain finds arousal more important during that time than is processing what is actually being seen. The team has published a paper in The Journal of Sexual Medicine describing their findings.

To find out if the primary visual cortex is essentially deactivated during sexual arousal in women, the team enlisted 12 volunteers; all women between the ages of 18 and 47, who had not yet reached menopause. Also each was on oral birth control pills which tend to flatten menstrual cycles and smooth out sexual desire and/or anxiety. Each was shown three videos, one with no sexual connotation, another with mild sexual content, and a third that was full on hard-core porn. While they were watching the videos, the women were also having their brain activity watched via PET scans, which work by measuring blood flow to the various brain regions. It is thought that more blood flow indicates that more brainwork is occurring, which implies that when the brain delegates tasks to different regions, by sending more blood, it is demonstrating that it finds certain activities more important than others.

The team found virtually no difference in brain activity in all of the women when watching the first two videos. When watching the third however, they found that blood flow to the visual cortex was reduced in all of the volunteers indicating that the brain had decided that focusing on arousal was more important than fixating on exactly what was occurring on the screen in front of them (or that women just don’t want to really see what is going on with sex). This is in direct contrast to most other visual activities which tend to cause more blood to flow to the visual cortex to process all of the information that is coming in.

The researchers also suggest their findings help explain why women who exhibit symptoms of anxiety often report sexual problems, as high anxiety is often correlated with increased blood flow to the visual cortex due to the person reacting on a nearly constant basis to visual stimuli. They point out that for people in general, the brain cannot be both anxious and aroused, it generally has to be one or the other, or neither.

Source: medicalxpress.com

April 19th, 2012

Scientists have discovered proof that the evolution of intelligence and larger brain sizes can be driven by cooperation and teamwork, shedding new light on the origins of what it means to be human.

Scientists have discovered proof that the evolution of intelligence and larger brain sizes can be driven by cooperation and teamwork, shedding new light on the origins of what it means to be human. Image adapted from Trinity College Dublin image.

The study appears online in the journal Proceedings of the Royal Society B and was led by scientists at Trinity College Dublin: PhD student, Luke McNally and Assistant Professor Dr Andrew Jackson at the School of Natural Sciences in collaboration with Dr Sam Brown of the University of Edinburgh.

The researchers constructed computer models of artificial organisms, endowed with artificial brains, which played each other in classic games, such as the ‘Prisoner’s Dilemma’, that encapsulate human social interaction.  They used 50 simple brains, each with up to 10 internal processing and 10 associated memory nodes. The brains were pitted against each other in these classic games.

The game was treated as a competition, and just as real life favours successful individuals, so the best of these digital organisms which was defined as how high they scored in the games, less a penalty for the size of their brains were allowed to reproduce and populate the next generation of organisms.

By allowing the brains of these digital organisms to evolve freely in their model the researchers were able to show that  the transition to cooperative society  leads to the strongest selection for bigger brains. Bigger brains essentially did better as cooperation increased.

The social strategies that emerge spontaneously in these bigger, more intelligent brains show complex memory and decision making. Behaviours like forgiveness, patience, deceit and Machiavellian trickery all evolve within the game as individuals try to adapt to their social environment.

“The strongest selection for larger, more intelligent brains, occurred when the social groups were first beginning to start cooperating, which then kicked off an evolutionary Machiavellian arms race of one individual trying to outsmart the other by investing in a larger brain. Our digital organisms typically start to evolve more complex ‘brains’ when their societies first begin to develop cooperation.” explained Dr Andrew Jackson.

The idea that social interactions underlie the evolution of intelligence has been around since the mid-70s, but support for this hypothesis has come largely from correlative studies where large brains were observed in more social animals.  The authors of the current research provide the first evidence that mechanistically links decision making in social interactions with the evolution of intelligence. This study highlights the utility of evolutionary models of artificial intelligence in answering fundamental biological questions about our own origins.

“Our model differs in that we exploit the use of theoretical experimental evolution combined with artificial neural networks to actually prove that yes, there is an actual cause-and-effect link between needing a large brain to compete against and cooperate with your social group mates.”

“Our extraordinary level of intelligence defines mankind and sets us apart from the rest of the animal kingdom. It has given us the arts, science and language, and above all else the ability to question our very existence and ponder the origins of what makes us unique both as individuals and as a species,” concluded PhD student and lead author Luke McNally.

Source: Neuroscience News