Neuroscience

ScienceDaily (Mar. 6, 2012) — Antibodies that block the process of synapse disintegration in Alzheimer’s disease have been identified, raising hopes for a treatment to combat early cognitive decline in the disease.

Amyloid beta (cyan blue) binds to nerve cells of the hippocampus (red) and attacks synapses resulting in the loss of memories in Alzheimer’s disease. New research has led to important insights into the mechanisms that induce synapse loss. The discovery brings hope for the development of new therapies that protect synapses and therefore prevent memory loss in Alzheimer’s disease. (Credit: Silvia Purro/Patricia Salinas/UCL)

Alzheimer’s disease is characterized by abnormal deposits in the brain of the protein Amyloid-ß, which induces the loss of connections between neurons, called synapses.

Now, scientists at UCL have discovered that specific antibodies that block the function of a related protein, called Dkk1, are able to completely suppress the toxic effect of Amyloid-ß on synapses. The findings are published March 6 in the Journal of Neuroscience.

Professor Patricia Salinas (UCL Department of Cell & Developmental Biology) who led the study, said: “These novel findings raise the possibility that targeting this secreted Dkk1 protein could offer an effective treatment to protect synapses against the toxic effect of Amyloid-ß.

"Importantly, these results raise the hope for a treatment and perhaps the prevention of cognitive decline early in Alzheimer’s disease."

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March 6, 2012

Schematic diagrams of a normal brain (left) and an autistic brain (right) highlight the white matter alterations in autism. Credit: Carnegie Mellon University

New research from Carnegie Mellon University’s Marcel Just provides an explanation for some of autism’s mysteries — from social and communication disorders to restricted interests — and gives scientists clear targets for developing intervention and treatment therapies.

Autism has long been a scientific enigma, mainly due to its diverse and seemingly unrelated symptoms until now.

Published in the journal Neuroscience and Biobehavioral Reviews, Just and his team used brain imaging and computer modeling to show how the brain’s white matter tracts — the cabling that connects separated brain areas — are altered in autism and how these alterations can affect brain function and behavior. The deficiencies affect the tracts’ bandwidth — the speed and rate at which information can travel along the pathways.

"White matter is the unsung hero of the human brain," said Just, the D.O. Hebb Professor of Psychology within CMU’s Dietrich College of Humanities and Social Sciences and director of the university’s Center for Cognitive Brain Imaging. "In autistic individuals, we can measure the quality of the white matter, and our computer model can predict how coordinated their brain activity will be. This gives us a precise account of the underlying alterations affecting autistic thought."

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March 6, 2012

Thromboembolic stroke, caused by a blood clot in the brain, results in damage to the parts of the brain starved of oxygen. Breaking up the clot with tissue plasminogen activator (tPA) reduces the amount of damage, however, there is a very short time window when the value of the treatment outweighs the side effects. New research published in BioMed Central’s open access journal Experimental & Translational Stroke Medicine shows that, during the first 24 hours after a stroke, mild hypothermia (34C) can reduce the side effects of tPA and potentially increase the window of opportunity for tPA treatment.

When a blood clot blocks off blood flow in the brain (ischemic stroke) the part starved of oxygen quickly begins to die. In order to prevent significant damage tPA must be given to the patient as early as possible after the onset of symptoms - doctors recommend that it must be administered within the first four and a half hours. Delayed treatment also increases the patient’s risk of intracerebral hemorrhage and brain swelling (edema).

Mild hyperthermia is known to be neuroprotective and to reduce damage caused by the return of blood flow to an area of the brain starved of oxygen by a clot. Researchers from the University of Erlangen, led by Dr Rainer Kollmar, tested whether mild hyperthermia could also prevent damage to the brain due to tPA treatment in rats. After 24 hours they found that, while hypothermia reduced the amount of swelling and damaged tissue in the brain after a stroke, tPA (administered 90 minutes after the onset of stroke) increased it. However, they also discovered that hypothermia therapy was able to offset the damage due to tPA.

This seemed to be true for all the measurements they looked at. Dr Kollmar explained, “Patients often loose brain function such as control over parts of their body, speech or memory after stroke. We looked at ‘neuroscore’, to examine how much control of the body had been affected, and at markers for inflammation (TIMP-1 and sICAM) or evidence of damage to the blood brain barrier. In all cases hypothermia was able to offset the side effects of tPA.”

While these results are still experimental, new techniques which prevent shivering mean that this technique is easier to administer in conscious patients. Preliminary clinical trials are also beginning to show that it is possible to treat patients, who have had a stroke, with tPA plus hypothermia. Our results suggest that hypothermia can offset the side effects of tPA and further studies will show if it is also able to increase the window of opportunity of tPA treatment in patients.

Provided by BioMed Central

Source: medicalxpress.com

March 6, 2012

Getting rid of a protein increases the birth of new nerve cells and shortens the time it takes for antidepressants to take effect, according to an animal study in the March 7 issue of The Journal of Neuroscience. The protein, neurofibromin 1, normally helps prevent uncontrolled cell growth. The findings suggest therapeutic strategies aimed at stimulating new nerve cell birth may help treat depression better than current antidepressants that commonly take several weeks to reach full efficacy.

Throughout life, a section of the hippocampus — the brain’s learning and memory center — produces new nerve cells. This process, called neurogenesis, is made possible by specialized cells called neural progenitor cells (NPCs). While previous studies show adult neurogenesis declines with age and stress, therapies known to alleviate symptoms of depression, such as exercise and antidepressants, increase neurogenesis.

In the new study, a team of scientists directed by Luis Parada, PhD, of the University of Texas Southwestern, examined neurogenesis after deleting the neurofibromin 1 (Nf1) gene from NPCs in adult mice. Removal of Nf1 increased the number and maturation of newborn nerve cells in the adult hippocampus. Nf1 mutant mice showed reductions in depressive- and anxiety-like behaviors following 7 days of antidepressant treatment, whereas mice without the mutation took longer to show improvements.

"Our findings establish an important role for Nf1 in controlling neurogenesis in the hippocampus and demonstrate that activation of adult NPCs is enough to regulate depression- and anxiety-like behaviors," said study co-author Renee McKay, PhD, of the University of Texas Southwestern. "Our work is among the first to demonstrate the feasibility of altering mood via direct manipulation of adult neurogenesis," McKay added.

To determine if deleting Nf1 in adult NPCs leads to long-term behavioral changes in mice, the scientists ran 8-month-old mice through a battery of tests designed to measure anxiety- and depressive-like behaviors. Compared with other mice, the mutant mice showed less signs of anxiety and demonstrated resistance to the effects of chronic mild, unpredictable stress. The finding shows even without antidepressants, the deletion of Nf1 from NPCs in adult mice decreases symptoms of depression and anxiety.

"This study demonstrates that inducing neurogenesis is sufficient to produce antidepressant behavioral actions, and provides novel targets for therapeutic interventions," said Ronald Duman, PhD, a neurogenesis expert from Yale University.

Provided by Society for Neuroscience

Source: medicalxpress.com

ScienceDaily (Mar. 5, 2012) — A new marker of Alzheimer’s disease can predict how rapidly a patient’s memory and other mental abilities will decline after the disorder is diagnosed, researchers at Washington University School of Medicine in St. Louis have found.

In 60 patients with early Alzheimer’s disease, higher levels of the marker, visinin-like protein 1 (VILIP-1), in the spinal fluid were linked to a more rapid mental decline in the years that followed.

Scientists need to confirm the results in larger studies, but the new data suggest that VILIP-1 potentially may be a better predictor of Alzheimer’s progression than other markers.

“VILIP-1 appears to be a strong indicator of ongoing injury to brain cells as a result of Alzheimer’s disease,” says lead author Rawan Tarawneh, MD, now an assistant professor of neurology at the University of Jordan. “That could be very useful in predicting the course of the disease and in evaluating new treatments in clinical trials.”

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March 5, 2012 by Bob Yirka

(Medical Xpress) — A group of Australian neuroscientists have been reviewing the results of many studies done over the years regarding the parts of the brain that are thought to be used in different real world scenarios and have found that many of them appear to be involved when people go into what is called a default network - more commonly known as daydreaming, or running on auto-pilot. Their findings suggest, as they write in their paper published in Nature Reviews Neurology, that the default network is tied very closely with the same areas of the brain generally thought of as those used for social skills.

To find connections, the team looked at studies of elderly people that had fallen victim to two distinct forms of early onset dementia. One involved damage to the frontal lobe, the other to the temporal lobe. Damage to the frontal lobe, they point out, generally results in patients displaying an inability to understand why they should curb their language. They’re impulsive and aren’t able to understand the repercussions of their words or actions as they pertain to other people. Those with damage to the temporal lobe on the other hand, have trouble understanding the subtle cues that go on between people when interacting. They generally run into trouble in trying to read emotion in others and also tend to have difficulty remembering faces or other everyday objects. Both conditions obviously have a very direct and troublesome impact on social interaction.

They also found that when people without dementia are placed in an fMRI machine and who are allowed to daydream, various parts of their brain light up, indicating that the default network is quite complicated and involved. But of specific interest to this group of researchers was the fact that many of those areas that light up when transitioning to the default network, are the same ones that are used for social interaction, memory and imagination.

This means, they say, that the default network is more than just daydreaming because for it to occur, there needs to be memory of events that have transpired, imagination to guess about things that might happen in the future and the consequences of different happenings. Not coincidentally, they add, all these things are necessary for social interaction as well. This, they say, is why it’s time to stop looking at individual brain functions as separate events and instead to start looking at events as multi-brain activities that all together add up to the richness of thought we all experience as thinking human beings.

Source: medicalxpress.com

March 5, 2012

The brain has a remarkable ability to learn new cognitive tasks while maintaining previously acquired knowledge about various functions necessary for everyday life. But exactly how new information is incorporated into brain systems that control cognitive functions has remained a mystery.

A study by researchers at Wake Forest Baptist Medical Center and the McGovern Institute of the Massachusetts Institute of Technology shows how new information is encoded in neurons of the prefrontal cortex, the area of the brain involved in planning, decision making, working memory and learning.

"In this study we were able to isolate activity directly from the brain, allowing us to ‘see’ what was happening in the prefrontal cortex before and after a new task was learned," said Christos Constantinidis, Ph.D., associate professor of neurobiology and anatomy at Wake Forest Baptist and senior author of the study, published in the March 5 online edition of Proceedings of the National Academy of Sciences.

To gain insight into how learning a new task affects the prefrontal cortex, the researchers analyzed the electrical activity of neurons before and after training for the performance in two short-term memory tests. Two monkeys initially looked at a computer screen while various shapes, such as squares and circles, were displayed, and researchers recorded the electrical activity occurring in the brain. The same animals were then trained to recognize the various shapes, and to remember whether two symbols matched each other.

Using computational analysis of the neuronal recordings, the researchers compared data to assess what information was present before training and what new information arose while learning a new task. They found that learning was associated with activation of a small number of neurons that were highly specialized for the new task, while the same neurons maintained the existing information that was present before training.

"In essence, this select group of neurons was able to multitask by learning new information while retaining information they were already specialized for," Constantinidis said. "Our results show that although there was little change in the amount of basic stimulus information that neurons encoded before training, more complex information about whether the symbols matched became incorporated throughout the prefrontal cortex after training."

Overall these findings shed light on how new information is incorporated into the prefrontal cortex activity and how neural activity codes information, which should lead to richer theories of how the prefrontal cortex controls behavior and how information is encoded in neural activity more generally.

"We hope that our findings will help others who work with patients who have short-term memory problems resulting from strokes or traumatic brain injuries," Constantinidis said. "Computerized training to perform cognitive tasks, like those used in our study, has shown promise in cognitive rehabilitation, and for treatment of mental illnesses and conditions, such as schizophrenia and ADHD."

Provided by Wake Forest Baptist Medical Center

Source: medicalxpress.com

When the rings of dynamic patterns are presented to the same eye (left column), the subject is able to consciously perceive the target pattern-the stripes in the center of the ring. When the two are presented to different eyes (right column), the dynamic pattern suppresses perception of the target pattern. Under both conditions, participants were asked to perform a task that focused attention on the target (top row) or on letters presented outside the target area (bottom row). Credit: 2012 Masataka Watanabe

From a purely intuitive point of view, it is easy to believe that our ability to actively pay attention to a target is inextricably connected with our capacity to consciously perceive it. However, this proposition remains the subject of extensive debate in the research community, and surprising new findings from a team of scientists in Japan and Europe promise to fuel the debate.

Resolving how these aspects of perception are managed requires a detailed understanding of how the visual centers in our brain process information. A region known as V1 has been investigated as it represents the first portion of the visual cortex to receive and process signals transmitted from the retina.

Many researchers favor a model in which functions pertaining consciousness are widely spread among the whole visual system, including V1. The classical model, which assumes that the neural mechanism of consciousness is integrated into a narrow subset of brain structures, referred to as a homunculus, or ‘little human’, is almost defunct. However, a modern version of this model is under debate. It proposes that the neural mechanism of consciousness is a privileged set of cortical areas, a subpopulation of neurons, or certain neural dynamics (e.g. oscillations); while there are also visual systems that have nothing to do with conscious vision, explains Masataka Watanabe a researcher investigating brain function at the University of Tokyo, Japan.

Watanabe cites studies proposing that visual attention as processed within V1 may be only minimally impacted by conscious perception; but, the experimental data have been contradictory. For example, studies using a technique called functional magnetic resonance imaging (fMRI) to map brain activity have indicated that V1 contributes to both attention and awareness in humans. However, invasive electrophysiological studies in non-human primates yielded different results. “You would find only 10 to 15% of neurons in V1 that are barely modulated by awareness, and 85% or so that are not modulated at all,” says Watanabe. To resolve this ambiguity, he, Kang Cheng from the RIKEN Brain Science Institute, Wako, and their colleagues designed an experiment that examined both processes independently. Surprisingly, their results may lend support the modern homunculus model. 

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ScienceDaily (Mar. 5, 2012) — Studying tiny bits of genetic material that control protein formation in the brain, Johns Hopkins scientists say they have new clues to how memories are made and how drugs might someday be used to stop disruptions in the process that lead to mental illness and brain wasting diseases.

Neuron (red) accumulates messages (green) when treated with BDNF. (Credit: Image courtesy of Johns Hopkins Medicine)

In a report published in the March 2 issue of Cell, the researchers said certain microRNAs — genetic elements that control which proteins get made in cells — are the key to controlling the actions of so-called brain-derived neurotrophic factor (BDNF), long linked to brain cell survival, normal learning and memory boosting.

During the learning process, cells in the brain’s hippocampus release BDNF, a growth-factor protein that ramps up production of other proteins involved in establishing memories. Yet, by mechanisms that were never understood, BDNF is known to increase production of less than 4 percent of the different proteins in a brain cell.

That led Mollie Meffert, M.D., Ph.D., associate professor of biological chemistry and neuroscience at the Johns Hopkins University School of Medicine to track down how BDNF specifically determines which proteins to turn on, and to uncover the role of regulatory microRNAs.

MicroRNAs are small molecules that bind to and block messages that act as protein blueprints from being translated into proteins. Many microRNAs in a cell shut down protein production, and, conversely, the loss of certain microRNAs can cause higher production of specific proteins.

The researchers measured microRNA levels in brain cells treated with BDNF and compared them to microRNA levels in neurons not treated with BDNF. The researchers noticed that levels of certain microRNAs were lower in brain cells treated with BDNF, suggesting that BDNF controls the levels of these microRNAs and, through this control, also affects protein production. Homing in on those specific microRNAS that disappeared when cells were treated with BDNF, the team found all were of the same type, so-called Let-7 microRNAs, and that all shared a common genetic sequence.

"This short genetic sequence has been shown by other researchers to behave like a bar code that can selectively prevent production of Let-7 microRNAs," says Meffert.

To test if the loss of Let-7 microRNAs lets BDNF increase production of specific proteins, Meffert’s team genetically engineered neurons so they could no longer decrease Let-7 microRNAs. They found that treating these neurons with BDNF no longer resulted in decreased microRNA levels or an increase in learning and memory proteins.

In measuring microRNA levels in cells treated with BDNF, the researchers also found more than 174 microRNAs that increased with BDNF treatment. This suggested to the research team that BNDF treatment also can increase other microRNAs and, thereby, decrease production of certain proteins. Says Meffert, some of these proteins may need to be decreased during learning and memory, whereas others may not contribute to the process at all.

To confirm that BDNF, via microRNA action, halts the production of certain proteins, the researchers monitored living brain cells to find out where messages go in response to BDNF. Messages that aren’t translated into proteins can accumulate inside small formations within cells. Using a microscope, the researchers watched a lab dish containing brain cells that had been marked with a fluorescent molecule that labels these formations as glowing spots. Treating cells with BDNF caused the number and size of the glowing spots to increase. The researchers determined that BDNF uses microRNA to send messages to these spots where they can be exiled away from the translating machinery that turns them into protein.

"Monitoring these fluorescent complexes gave us a window that we needed to understand how BDNF is able to target the production of only certain proteins that help neurons to grow and make learning possible," Meffert says.

Adds Meffert, “Now that we know how BDNF boosts production of learning and memory proteins, we have an opportunity to explore whether therapeutics can be designed to enhance this mechanism for treatment of patients with mental disorders and neurodegenerative diseases like Alzheimer’s disease.”

Source: Science Daily

March 4, 2012 

Brain diagram. Credit: dwp.gov.uk

Opening the door to the development of thought-controlled prosthetic devices to help people with spinal cord injuries, amputations and other impairments, neuroscientists at the University of California, Berkeley, and the Champalimaud Center for the Unknown in Portugal have demonstrated that the brain is more flexible and trainable than previously thought.

Their new study, to be published Sunday, March 4, in the advanced online publication of the journal Nature, shows that through a process called plasticity, parts of the brain can be trained to do something it normally does not do. The same brain circuits employed in the learning of motor skills, such as riding a bike or driving a car, can be used to master purely mental tasks, even arbitrary ones.

Over the past decade, tapping into brain waves to control disembodied objects has moved out of the realm of parlor tricks and parapsychology and into the emerging field of neuroprosthetics. This new study advances work by researchers who have been studying the brain circuits used in natural movement in order to mimic them for the development of prosthetic devices.

"What we hope is that our new insights into the brain’s wiring will lead to a wider range of better prostheses that feel as close to natural as possible," said Jose Carmena, UC Berkeley associate professor of electrical engineering, cognitive science and neuroscience. "They suggest that learning to control a BMI (brain-machine interface), which is inherently unnatural, may feel completely normal to a person, because this learning is using the brain’s existing built-in circuits for natural motor control."

Carmena and co-lead author Aaron Koralek, a UC Berkeley graduate student in Carmena’s lab, collaborated on this study with Rui Costa, co-principal investigator of the study and principal investigator at the Champalimaud Neuroscience Program, and co-lead author Xin Jin, a post-doctoral fellow in Costa’s lab.

Previous studies have failed to rule out the role of physical movement when learning to use a prosthetic device.

"This is key for people who can’t move," said Carmena, who is also co-director of the UC Berkeley-UCSF Center for Neural Engineering and Prostheses. "Most brain-machine interface studies have been done in healthy, able-bodied animals. What our study shows is that neuroprosthetic control is possible, even if physical movement is not involved." 

To clarify these issues, the scientists set up a clever experiment in which rats could only complete an abstract task if overt physical movement was not involved. The researchers decoupled the role of the targeted motor neurons needed for whisker twitching with the action necessary to get a food reward.

The rats were fitted with a brain-machine interface that converted brain waves into auditory tones. To get the food reward – either sugar-water or pellets – the rats had to modulate their thought patterns within a specific brain circuit in order to raise or lower the pitch of the signal.

Auditory feedback was given to the rats so that they learned to associate specific thought patterns with a specific pitch. Over a period of just two weeks, the rats quickly learned that to get food pellets, they would have to create a high-pitched tone, and to get sugar water, they needed to create a low-pitched tone.

If the group of neurons in the task were used for their typical function – whisker twitching – there would be no pitch change to the auditory tone, and no food reward.

"This is something that is not natural for the rats," said Costa. "This tells us that it’s possible to craft a prosthesis in ways that do not have to mimic the anatomy of the natural motor system in order to work."

The study was also set up in a way that demonstrated intentional, as opposed to habitual, behavior. The rats were able to vary the amount of pellets or sugar water received based upon their own level of hunger or thirst.

"The rats were aware; they knew that controlling the pitch of the tone was what gave them the reward, so they controlled how much sugar water or how many pellets to take, when to do it, and how to do it in absence of any physical movement," said Costa.

Researchers hope these findings will lead to a new generation of prosthetic devices that feel natural.

"We don’t want people to have to think too hard to move a robotic arm with their brain," said Carmena.

Provided by University of California - Berkeley 

Source: medicalxpress.com

This undated handout artist rendering provided by the Schneider Lab, University of Pittsburgh shows an experimental type of scan showing damage to the brain’s nerve fibers after a traumatic brain injury. The yellow shows missing fibers on one side of the brain, as compared to the uninjured side in green, in a man left with limited use of his left arm and hand. The soldier on the fringes of an explosion. The survivor of a car wreck. The football player who took yet another skull-rattling hit. Too often, only time can tell when a traumatic brain injury will leave lasting harm _ there’s no good way to diagnose the damage. Now scientists are testing a tool that promises to light up breaks that these injuries leave in the brain’s wiring, much like X-rays show broken bones. (AP Photo/Schneider Lab, University of Pittsburgh)

The soldier on the fringes of an explosion. The survivor of a car wreck. The football player who took yet another skull-rattling hit. Too often, only time can tell when a traumatic brain injury will leave lasting harm - there’s no good way to diagnose the damage.

Now scientists are testing a tool that lights up the breaks these injuries leave deep in the brain’s wiring, much like X-rays show broken bones.

Research is just beginning in civilian and military patients to learn if this new kind of MRI-based test really could pinpoint their injuries and one day guide rehabilitation. It’s an example of the hunt for better brain scans, maybe even a blood test, to finally tell when a blow to the head causes damage that today’s standard testing simply can’t see.

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ScienceDaily (Mar. 2, 2012) — A powerful new imaging technique called High Definition Fiber Tracking (HDFT) will allow doctors to clearly see for the first time neural connections broken by traumatic brain injury (TBI) and other neurological disorders, much like X-rays show a fractured bone, according to researchers from the University of Pittsburgh in a report published online in the Journal of Neurosurgery.

High definition fiber-tracking map of a million brain fibers. (Credit: Walt Schneider Laboratory)

In the report, the researchers describe the case of a 32-year-old man who wasn’t wearing a helmet when his all-terrain vehicle crashed. Initially, his CT scans showed bleeding and swelling on the right side of the brain, which controls left-sided body movement. A week later, while the man was still in a coma, a conventional MRI scan showed brain bruising and swelling in the same area. When he awoke three weeks later, the man couldn’t move his left leg, arm and hand.

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ScienceDaily (Mar. 2, 2012) — Impaired social function is a cardinal symptom of autism spectrum disorders (ASDs). One of the brain circuits that enable us to relate to other people is the “mirror neuron” system. This brain circuit is activated when we watch other people, and allows our brains to represent the actions of others, influencing our ability to learn new tasks and to understand the intentions and experiences of other people.

This mirror neuron system is impaired in individuals with ASD and better understanding the neurobiology of this system could help in the development of new treatments.

In their new study, Dr. Peter Enticott at Monash University and his colleagues used transcranial magnetic stimulation to stimulate the brains of individuals with ASD and healthy individuals while they observed different hand gestures. This allowed the researchers to measure the activity of each individual’s mirror neuron system with millisecond precision in response to each observed action.

They found that the individuals with ASD showed a blunted brain response to stimulation of the motor cortex when viewing a transitive hand gesture. In other words, the mirror neuron system in the ASD individuals became less activated when watching the gestures, compared to the healthy group. In addition, among people with ASD, less mirror neuron activity was associated with greater social impairments. This finding adds to the evidence that deficits in mirror neuron system functioning contribute to the social deficits in ASD.

This finding also directly links a specific type of brain dysfunction in people with autism spectrum disorder to a specific symptom. This is important because “we do not have a substantial understanding of the brain basis of autism spectrum disorder, or a validated biomedical treatment for the disorder,” said Dr. Enticott. “If we can develop a substantial understanding of the biology of specific symptoms, this will allow us to develop treatments targeted specifically to the symptoms.”

"This study is an example of the effort to break down the component problems associated with autism spectrum disorder and to map these problems on to particular brain circuits," commented Dr. John Krystal, editor of Biological Psychiatry.

Enticott added, “We are currently investigating whether non-invasive brain stimulation can be used to improve mirror neuron activity in autism spectrum disorder, which would have substantial potential therapeutic implications.”

Source: Science Daily

ScienceDaily (Mar. 2, 2012) — Millions of people suffer from Parkinson’s disease, a disorder of the nervous system that affects movement and worsens over time. As the world’s population ages, it’s estimated that the number of people with the disease will rise sharply. Yet despite several effective therapies that treat Parkinson’s symptoms, nothing slows its progression.

Artist’s rendering of neurons. (Credit: iStockphoto)

While it’s not known what exactly causes the disease, evidence points to one particular culprit: a protein called α-synuclein. The protein, which has been found to be common to all patients with Parkinson’s, is thought to be a pathway to the disease when it binds together in “clumps,” or aggregates, and becomes toxic, killing the brain’s neurons.

Now, scientists at UCLA have found a way to prevent these clumps from forming, prevent their toxicity and even break up existing aggregates.

UCLA professor of neurology Jeff Bronstein and UCLA associate professor of neurology Gal Bitan, along with their colleagues, report the development of a novel compound known as a “molecular tweezer,” which in a living animal model blocked α-synuclein aggregates from forming, stopped the aggregates’ toxicity and, further, reversed aggregates in the brain that had already formed. And the tweezers accomplished this without interfering with normal brain function.

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(Medical Xpress) — As scientists struggle to find an effective way to prevent Alzheimer’s disease, researchers at the University of Wisconsin School of Medicine and Public health may have found a new approach to interrupting the process that leads to the devastating disease.

The image shows that the enzymes ATase1 and ATase2 are abundantly present in the brains of Alzheimer’s disease patients. The green color labels the ATases while the blue labels the nuclei. Both neurons and glial cells are shown.

Building on their knowledge of two enzymes that control an “uber” enzyme critical to the development of the disease, the scientists found that the two enzymes are present in the brains of Alzheimer’s patients. And by screening some 15,000 compounds, they discovered two that lower activity of the enzymes in test tubes. 

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Article Date: 02 Mar 2012 - 1:00 PST

Scientists from Seattle Children’s Research Institute and the University of Washington, in collaboration with the Genomic Disorders Group Nijmegen in the Netherlands, have identified two new genes that cause Baraitser-Winter syndrome, a rare brain malformation that is characterized by droopy eyelids and intellectual disabilities.

“This new discovery brings the total number of genes identified with this type of brain defect to eight,” said William Dobyns, MD, a geneticist at Seattle Children’s Research Institute. Identification of the additional genes associated with the syndrome make it possible for researchers to learn more about brain development. The study, “De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome,” was published online in Nature Genetics.

The brain defect found in Baraitser-Winter syndrome is a smooth brain malformation or “lissencephaly,” as whole or parts of the surface of the brain appear smooth in scans of patients with the disorder. Previous studies by Dr. Dobyns and other scientists identified six genes that cause the smooth brain malformation, accounting for approximately 80% of affected children. Physicians and researchers worldwide have identified to date approximately 20 individuals with Baraitser-Winter syndrome.

While the condition is rare, Dr. Dobyns said the team’s findings have broad scientific implications. “Actins, or the proteins encoded by the ACTB and ACTG1 genes, are among the most important proteins in the function of individual cells,” he said. “Actins are critical for cell division, cell movement, internal movement of cellular components, cell-to-cell contact, signaling and cell shape,” said Dr. Dobyns, who is also a University of Washington professor of pediatrics. “The defects we found occur in the only two actin genes that are expressed in most cells,” he said. Gene expression is akin to a “menu” for conditions like embryo development or healing from an injury. The correct combination of genes must be expressed at the right time to allow proper development. Abnormal expression of genes can lead to a defect or malformation.

“Birth defects associated with these two genes also seem to be quite severe,” said Dr. Dobyns. “Children and people with these genes have short stature, an atypical facial appearance, birth defects of the eye, and the smooth brain malformation along with moderate mental retardation and epilepsy. Hearing loss occurs and can be progressive,” he said.

Dr. Dobyns is a renowned researcher whose life-long work has been to try to identify the causes of children’s developmental brain disorders such as Baraitser-Winter syndrome. He discovered the first known chromosome abnormality associated with lissencephaly (Miller-Dieker syndrome) while still in training in child neurology at Texas Children’s Hospital in 1983. That research led, 10 years later, to the discovery by Dobyns and others of the first lissencephaly gene known as LIS1.

Source: Medical News Today  

ScienceDaily (Mar. 1, 2012) — The association of the inhaled anesthetic isoflurane with Alzheimer’s-disease-like changes in mammalian brains may by caused by the drug’s effects on mitochondria, the structures in which most cellular energy is produced. In a study that will appear in Annals of Neurology and has received early online release, Massachusetts General Hospital (MGH) researchers report that administration of isoflurane impaired the performance of mice on a standard test of learning and memory — a result not seen when another anesthetic, desflurane, was administered. They also found evidence that the two drugs have significantly different effects on mitochondrial function.

"These are the first results indicating that isoflurane, but not desflurane, may induce neuronal cell death and impair learning and memory by damaging mitochondria," says Yiying (Laura) Zhang, MD, a research fellow in the MGH Department of Anesthesia, Critical Care and Pain Medicine and the study’s lead author. "This work needs to be confirmed in human studies, but it’s looking like desflurane may be a better anesthetic to use for patients susceptible to cognitive dysfunction, such as Alzheimer’s patients."

Previous studies have suggested that undergoing surgery and general anesthesia may increase the risk of Alzheimer’s, and it is well known that a small but significant number of surgical patients experience a transient form of cognitive dysfunction in the postoperative period. In 2008, members of the same MGH research team showed that isoflurane induced Alzheimer’s-like changes — increasing activation of enzymes involved with cell death and generation of the A-beta plaques characteristic of the disease — in the brains of mice. The current study was designed to explore the underlying mechanism and behavioral consequences of isoflurane-induced brain cell death and to compare isoflurane’s effects with those of desflurane, another common anesthetic that has not been associated with neuronal damage.

In a series of experiments, the investigators found that the application of isoflurane to cultured cells and mouse neurons increased the permeability of mitochondrial membranes; interfered with the balance of ions on either side of the mitochondrial membrane; reduced levels of ATP, the enzyme produced by mitochondria that powers most cellular processes; and increased levels of the cell-death enzyme caspase. The results also suggested that the first step toward isoflurane-induced cell death was increased generation of reactive oxygen species — unstable oxygen-containing molecules that can damage cellular components. The performance of mice on a standard behavioral test of learning and memory declined significantly two to seven days after administration of isoflurane, compared with the results of a control group. None of the cellular or behavioral effects of isoflurane were seen when the administered agent was desflurane.

In another study by members of the same research team — appearing in the February issue of Anesthesia and Analgesia and published online in November — about a quarter of surgical patients receiving isoflurane showed some level of cognitive dysfunction a week after surgery, while patients receiving desflurane or spinal anesthesia had no decline in cognitive performance. That study, conducted in collaboration with investigators from Beijing Friendship Hospital in China, enrolled only 45 patients — 15 in each treatment group — so its results need to be confirmed in significantly larger groups.

"Approximately 8.5 million Alzheimer’s disease patients worldwide will need anesthesia and surgical care every year," notes Zhongcong Xie, MD, PhD, corresponding author of both studies and director of the Geriatric Anesthesia Research Unit in the MGH Department of Anesthesia, Critical Care and Pain Medicine. "Developing guidelines for safer anesthesia care for these patients will require collaboration between specialists in anesthesia, neurology, geriatric medicine and other specialties. As the first step, we need to identify anesthetics that are less likely to contribute to Alzheimer’s disease neuropathogenesis and cognitive dysfunction." Xie is an associate professor of Anesthesia at Harvard Medical School (HMS)

Source: Science Daily

ScienceDaily (Mar. 1, 2012) — Down syndrome (DS) is the most common genetic disorder in live born children arising as a consequence of a chromosomal abnormality. It occurs as a result of having three copies of chromosome 21, instead of the usual two. It causes substantial physical and behavioral abnormalities, including life-long cognitive dysfunction that can range from mild to severe but which further deteriorates as individuals with DS age.

It is not currently possible to effectively treat the cognitive impairments associated with DS. However, these deficits are an increasing focus of research. In this issue of Biological Psychiatry, researchers at Stanford University, led by Dr. Ahmad Salehi, have published a review which highlights potential strategies for the treatment of these cognitive deficits.

The authors focus on insights emerging from animal models of Down syndrome and outline the structural abnormalities in the DS brain. They also discuss studies that have linked the over-expression of the amyloid precursor protein gene, called APP, to the degeneration of neurons in mice. These findings have led to the development of therapeutic treatments in mice, which now must be tested in humans.

"For more than a decade, we have been working on identifying a strategy to treat cognitive disabilities in our Down syndrome mouse models," said Dr. Salehi. "Considering the research and results with mouse models as an indication of success of a strategy in humans, we are ever closer to finding ways to at least partially restore cognitive function in children and adults with Down syndrome."

Interestingly, this research is also providing insights into Alzheimer’s disease (AD), the archetypal disorder of late life. All adults with Down syndrome develop AD pathology by age 40, and there are some remarkable similarities in the brain degeneration and cognitive dysfunction of individuals with DS and those with AD.

The leading AD hypothesis posits that it is caused by increasingly elevated levels of amyloid-related proteins, which are toxic to nerve cells in the brain. These same proteins also accumulate in the brains of people with DS because they are made by the APP gene, which is located on chromosome 21. Individuals with AD don’t have the extra chromosome, of course; rather, it is mutations in APP that appear to cause the brain degeneration associated with AD.

Dr. John Krystal, editor of Biological Psychiatry, commented: “The convergence of research on Down syndrome and Alzheimer’s disease highlights a central point that cannot be overstated. When we understand the fundamental biology of the brain, important new conceptual bridges emerge that guide new treatment approaches.”

Salehi added, “In the near future, we may very likely look back with the perspective that Down syndrome represents an example of how families of affected individuals came together and by supporting basic research, changed the course of a disorder that was considered untreatable for more than a century.”

Source: Science Daily

ScienceDaily (Mar. 1, 2012) — Despite the promise associated with the therapeutic use of human stem cells, a complete understanding of the mechanisms that control the fundamental question of whether a stem cell becomes a specific cell type within the body or remains a stem cell has-until now-eluded scientists.

A University of Georgia study published in the March 2 edition of the journal Cell Stem Cell, however, creates the first ever blueprint of how stem cells are wired to respond to the external signaling molecules to which they are constantly exposed. The finding, which reconciles years of conflicting results from labs across the world, gives scientists the ability to precisely control the development, or differentiation, of stem cells into specific cell types.

"We can use the information from this study as an instruction book to control the behavior of stem cells," said lead author Stephen Dalton, Georgia Research Alliance Eminent Scholar of Molecular Biology and professor of cellular biology in the UGA Franklin College of Arts and Sciences. "We’ll be able to allow them to differentiate into therapeutic cell types much more efficiently and in a far more controlled manner."

The previous paradigm held that individual signaling molecules acted alone to set off a linear chain of events that control the fate of cells. Dalton’s study, on the other hand, reveals that a complex interplay of several molecules controls the “switch” that determines whether a stem cell stays in its undifferentiated state or goes on to become a specific cell type, such as a heart, brain or pancreatic cell.

"This work addresses one of the biggest challenges in stem cell research-figuring out how to direct a stem cell toward becoming a specific cell type," said Marion Zatz, who oversees stem cell biology grants at the National Institutes of Health’s National Institute of General Medical Sciences, which partially supported the work.

"In this paper, Dr. Dalton puts together several pieces of the puzzle and offers a model for understanding how multiple signaling pathways coordinate to steer a stem cell toward differentiating into a particular type of cell. This framework ultimately should not only advance a fundamental understanding of embryonic development, but facilitate the use of stem cells in regenerative medicine."

To get a sense of how murky the understanding of stem cell differentiation was, consider that previous studies reached opposite conclusions about the role of a common signaling molecule known as Wnt. About half the published studies found that Wnt kept a molecular switch in an “off” position, which kept the stem cell in its undifferentiated, or pluripotent, state. The other half reached the opposite conclusion.

Could the same Wnt molecule be responsible for both outcomes? As it turns out, the answer is yes. Dalton’s team found that in small amounts, Wnt signaling keeps the stem cell in its pluripotent state. In larger quantities, it does the opposite and encourages the cell to differentiate.

But Wnt doesn’t work alone. Other molecules, such as insulin-like growth factor (Igf), fibroblast growth factor (Fgf2) and Activin A also play a role. To complicate things further, these signaling molecules amplify each other so that a two-fold increase in one can result in a 10-fold increase in another. The timing with which the signals are introduced matters, too.

"One of the things that surprised us was how all of the pathways ‘talk’ to each other," Dalton said. "You can’t do anything to the Igf pathway without affecting the Fgf2 pathway, and you can’t do anything to Fgf2 without affecting Wnt. It’s like a house of cards; everything is totally interconnected."

Dalton and his team spent a painstaking five years creating hypotheses about the how the signaling molecules function, testing those hypotheses, and-when faced with an unexpected result-rebuilding their hypotheses and re-testing. This process continued until the entire system was resolved.

Their finding gives scientists a more complete understanding of the first step that stem cells take as they differentiate, and Dalton is confident that the same approach can be used to understand subsequent developmental steps that occur as the cells in an embryo divide into ever-more specific cell types.

"Hopefully this type of approach will give us a greater understanding of cells and how they can be manipulated so that we can progress much more rapidly toward the routine use of stem cells in therapeutic settings," Dalton said.

The research was funded by the National Institute of Child Health and Human Development and the National Institute of General Medical Sciences.

Source: Science Daily

(Medical Xpress) — Researchers from Western University have utilized their own game-changing technology – previously developed for use with patients in a vegetative state – to assess a more prevalent group of brain-injured patients, those in the minimally conscious state (MCS). Their findings were released today in Neurology, the medical journal of the American Academy of Neurology.

The study, led by Adrian Owen, Canada Excellence Research Chair in Cognitive Neuroscience and Imaging, and Damian Cruse of Western’s Brain and Mind Institute, is a follow-up to the team’s groundbreaking Lancet publication from November 2011 that used electroencephalography (EEG) to show that some vegetative state patients were able to reliably follow commands, even though this ability was entirely undetectable from their external behaviour. 

In the new paper, titled “The relationship between aetiology and covert cognition in the minimally-conscious state,” the MCS patients showed some inconsistent but reproducible external signs of awareness, such as being able to follow their eyes in a mirror.  Cruse says, however, that currently very little is known about their ‘internal’ state of awareness that may be hidden from their external behaviour. 

"Using our EEG approach, we found that 22 per cent of 23 MCS patients were able to complete a complex task which required them to imagine particular types of movement," says Cruse, a Post-Doctoral Fellow at the Brain and Mind Institute and the lead writer of the paper. "This tells us that these patients have a much higher level of cognitive ability than what you could detect from their behaviour."

Cruse adds that the cause of the brain injury was a determining factor in finding these cognitive abilities as 33 per cent of traumatically injured patients (e.g. traffic accident, fall) returned positive EEG results compared to zero per cent of non-traumatically injured patients (e.g. heart attack, stroke).

The research team, in collaboration with Steven Laureys at the University of Liège, Belgium, asked patients approximately 100 times each to imagine moving his or her right-hand and toes. By making recordings of the patients’ EEG, a measure of the electrical activity of the brain, the team showed that 22 per cent of the MCS patients were able to produce patterns of brain activity that were indistinguishable from a healthy individual following the same commands. 

"There are a large number of patients in the MCS worldwide, and our approach highlights the importance of using EEG and other forms of brain imaging when assessing the mental capabilities of patients following brain injury," says Cruse "It reinforces our understanding that the externally observable abilities of a patient are not necessarily a true reflection of their internal state."

Provided by University of Western Ontario

Source: medicalxpress.com

A major downside of the medical use of marijuana is the drug’s ill effects on working memory, the ability to transiently hold and process information for reasoning, comprehension and learning. Researchers reporting in the March 2 print issue of the Cell Press journal Cell provide new insight into the source of those memory lapses. The answer comes as quite a surprise: Marijuana’s major psychoactive ingredient (THC) impairs memory independently of its direct effects on neurons. The side effects stem instead from the drug’s action on astroglia, passive support cells long believed to play second fiddle to active neurons.

The findings offer important new insight into the brain and raise the possibility that marijuana’s benefits for the treatment of pain, seizures and otherailments might some day be attained without hurting memory, the researchers say.

With these experiments in mice, “we have found that the starting point for this phenomenon – the effect of marijuana on working memory – is the astroglialcells,” said Giovanni Marsicano of INSERM in France.

"This is the first direct evidence that astrocytes modulate working memory," added Xia Zhang of the University of Ottawa in Canada.

The new findings aren’t the first to suggest astroglia had been given short shrift. Astroglial cells (also known as astrocytes) have been viewed as cells that support, protect and feed neurons for the last 100 to 150 years, Marsicano explained. Over the last decade, evidence has accumulated that these cells play a more active role in forging the connections from one neuron to another.

The researchers didn’t set out to discover how marijuana causes its cognitive side effects. Rather, they wanted to learn why receptors that respond to both THC and signals naturally produced in the brain are found on astroglial cells. These cannabinoid type-1 (CB1R) receptors are very abundant in the brain, primarily on neurons of various types.

Zhang and Marsicano now show that mice lacking CB1Rs only on astroglial cells of the brain are protected from the impairments to spatial working memory that usually follow a dose of THC. In contrast, animals lacking CB1Rs in neurons still suffer the usual lapses. Given that different cell types express different variants of CB1Rs, there might be a way to therapeutically activate the receptors on neurons while leaving the astroglial cells out, Marsicano said.

"The study shows that one of the most common effects of cannabinoid intoxication is due to activation of astroglial CB1Rs," the researchers wrote.

The findings further suggest that astrocytes might be playing unexpected roles in other forms of memory in addition to spatial working memory, Zhang said.

The researchers hope to explore the activities of endogenous endocannabinoids, which naturally trigger CB1Rs, on astroglial and other cells. The endocannabinoid system is involved in appetite, pain, mood, memory and many other functions. “Just about any physiological function you can think of in the body, it’s likely at some point endocannabinoids are involved,” Marsicano said.

And that means an understanding of how those natural signaling molecules act on astroglial and other cells could have a real impact. For instance, Zhang said, “we may find a way to deal with working memory problems in Alzheimer’s.”

Source: medicalxpress.com

(PhysOrg.com) — Geraldo Barbosa, professor of electrical engineering and computer science at Northwestern University has posed an interesting challenge. He wonders if the human eye and brain together are capable of actually seeing entangled images. This is not a philosophical question, as he has phrased the query as part of a practical experiment that someone with the proper lab could actually carry out. To that end, he’s posted a paper on the preprint server arXiv with the hope that a physics team will take up the challenge.

The whole idea is based on entanglement and the means by which researchers make it come about. What they do is shoot a laser at a non-linear crystal causing the photons in the beam to be converted into lower frequency entangled pairs. Those pairs are then directed to sensors which individually are able to measure a fuzzy or blurred “image”. But when both of the entangled photons are taken together as a single measurement, the image sharpens. These images are of course far too small for the human eye to see, plus they don’t last long enough for them to be seen anyway. To address these issues, researchers have taken to firing lasers that are formed into patterns such as a doughnut shape in a continuous sequence. The result is a steady stream of entangled pairs being created in the shape of a doughnut.

Barbosa wants to know what would happen if instead of forming a doughnut shape, the lasers were made to look like a letter in the alphabet, such as the letter A, and then of course if it were made large enough to be seen by the human eye. Two entangled letter As should be created and seeable albeit in a lower frequency. If that happened, would the human eye when paired with the brain’s abilities, be able to merge the two into a sharp readable image, or would we see just the individual blurred images captured by just one sensor?

Barbosa doesn’t know, and neither does anyone else, thus he suggests someone or some group build an experiment to find out.

The ability to see things differently than we are accustomed to seeing isn’t anything new of course. Some animals can see things in the infrared spectrum for example and evidence has been slowly emerging as described here, here and here, suggesting that some migrating birds are able to “see” the Earth’s magnetic field. So maybe it’s possible that we see entangled images every day, and just don’t know it.

Hopefully someone will take Barbosa up on his challenge, and then we’ll all find out if it’s possible or not.

More information: Can humans see beyond intensity images? by Geraldo A. Barbosa, arXiv:1202.5434v1 [q-bio.NC] http://arxiv.org/abs/1202.5434

Source: PHYSORG.com

Decreased cerebral blood flow (CBF) after psilocybin imaged by fMRI. Regions where there was significantly decreased CBF after psilocybin versus after placebo are shown in blue. No CBF increases in any region were observed. Image Copyright © PNAS, doi:10.1073/pnas.1119598109

(Medical Xpress) — Psychedelic substances have long been used for healing, ceremonial, or mind-altering subjective experiences due to compounds that, when ingested or inhaled, generate hallucinations, perceptual distortions, or altered states of awareness. Of these, the psychedelic substance psilocybin, the prodrug (a precursor of a drug that must in vivo chemical conversion by metabolic processes before becoming an active pharmacological agent) of psilocin (4-hydroxy-dimethyltryptamine) and the key hallucinogen found in so-called magic mushrooms, is widely used not only in healing ceremonies, but, more recently, in psychotherapy as well – but little has been known about its specific activity in the brain.

Recently, however, scientists in the Neuropsychopharmacology Unit at Imperial College London used complementary blood-oxygen level dependent (BOLD) functional MRI, or fMRI, in conjunction with a technique for imaging the transition from normal waking consciousness to the psychedelic state. The study found decreased blood flow and BOLD in the thalamus, anterior and posterior cingulate cortex, and medial prefrontal cortex. The researchers concluded that the surprising results strongly suggest that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain’s key connector hubs, enabling a state of unconstrained cognition.

Lead researcher Dr. Robin L. Carhart-Harris, working in the Neuropsychopharmacology Unit created by Prof. David J. Nutt, recounts the team’s main challenges in establishing an fMRI methodology that would be specific enough to highly correlate neurophysiological activity with the neuronal presence or absence of psilocybin. “There were a number of considerations,” Carhart-Harris tells Medical Xpress. “In terms of experimental design, we had to determine the precise dose and delivery protocol that would be appropriate for obtaining clear fMRI results. “For example,” he explains, “we had to consider temporal dynamics: If the drug was administered orally, the protracted period of time between ingestion, metabolism, and crossing of the blood-brain barrier would fall outside of the short scanning window needed to capture induced brain activity.” They therefore had to rely on intravenous administration.

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ScienceDaily (Feb. 29, 2012) — A repression of gene activity in the brain appears to be an early event affecting people with Alzheimer’s disease, researchers funded by the National Institutes of Health have found. In mouse models of Alzheimer’s disease, this epigenetic blockade and its effects on memory were treatable.

In a mouse model of Alzheimer’s disease (right), HDAC2 levels in the hippocampus are higher than in the normal mouse hippocampus (left). Credit: (Credit: Dr. Li-Huei Tsai, MIT)

"These findings provide a glimpse of the brain shutting down the ability to form new memories gene by gene in Alzheimer’s disease, and offer hope that we may be able to counteract this process," said Roderick Corriveau, Ph.D., a program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research.

The study was led by Li-Huei Tsai, Ph.D., who is director of The Picower Institute for Learning and Memory at the Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute. It was published online February 29 in Nature.

Dr. Tsai and her team found that a protein called histone deacetylase 2 (HDAC2) accumulates in the brain early in the course of Alzheimer’s disease in mouse models and in people with the disease. HDAC2 is known to tighten up spools of DNA, effectively locking down the genes within and reducing their activity, or expression.

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ScienceDaily (Feb. 29, 2012) — In a mouse model of Alzheimer’s disease, memory problems stem from an overactive enzyme that shuts off genes related to neuron communication, a new study says.

When researchers genetically blocked the enzyme, called HDAC2, they ‘reawakened’ some of the neurons and restored the animals’ cognitive function. The results, published February 29, 2012, in the journal Nature, suggest that drugs that inhibit this particular enzyme would make good treatments for some of the most devastating effects of the incurable neurodegenerative disease.

"It’s going to be very important to develop selective chemical inhibitors against HDAC2," says Howard Hughes Medical Institute investigator Li-Huei Tsai, whose team at the Massachusetts Institute of Technology performed the experiments. "If we could delay the cognitive decline by a certain period of time, even six months or a year, that would be very significant."

In every cell, DNA wraps itself around proteins called histones. Chemical groups such as methyl and acetyl can bind to histones and affect DNA expression. HDAC2 is a histone deacetylase, an enzyme that removes acetyl groups from the histone, effectively turning off nearby genes.

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A DRUG which minimises brain damage when given three hours after stroke has proved successful in monkeys and humans.

A lack of oxygen in the brain during a stroke can cause fatal brain damage. There is only one approved treatment - tissue plasminogen activator - but it is most effective when administered within 90 minutes after the onset of stroke. Immediate treatment isn’t always available, however, so drugs that can be given at a later time have been sought.

In a series of experiments, Michael Tymianski and colleagues at Toronto Western Hospital in Ontario, Canada, replicated the effects of stroke in macaques before intravenously administering a PSD-95 inhibitor, or a placebo. PSD-95 inhibitors interfere with the process that triggers cell death when the brain is deprived of oxygen.

To test its effectiveness the team used MRI to measure the volume of damaged brain for 30 days following the treatment, and conducted behavioural tests at various intervals within this time.

Monkeys treated with the PSD-95 inhibitor one hour after stroke had 55 per cent less damaged tissue in the brain after 24 hours and 70 per cent less after 30 days, compared with those that took a placebo. These animals also did better in behavioural tests. Importantly, the drug was also effective three hours after stroke (Nature, DOI: 10.1038/nature10841).

An early stage clinical trial in humans, run by firm NoNO in Ontario has also seen positive results.

Source: New Scientist

ScienceDaily (Feb. 28, 2012) — Slowing or preventing the development of Alzheimer’s disease, a fatal brain condition expected to hit one in 85 people globally by 2050, may be as simple as ensuring a brain protein’s sugar levels are maintained.

Slowing or preventing the development of Alzheimer’s disease, a fatal brain condition expected to hit one in 85 people globally by 2050, may be as simple as ensuring a brain protein’s sugar levels are maintained. (Credit: © ktsdesign / Fotolia)

That’s the conclusion seven researchers, including David Vocadlo, a Simon Fraser University chemistry professor and Canada Research Chair in Chemical Glycobiology, make in the latest issue of Nature Chemical Biology.

The journal has published the researchers’ latest paper “Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation.”

Vocadlo and his colleagues describe how they’ve used an inhibitor they’ve chemically created — Thiamet-G — to stop O-GlcNAcase, a naturally occurring enzyme, from depleting the protein Tau of sugar molecules.

"The general thinking in science," says Vocadlo, "is that Tau stabilizes structures in the brain called microtubules. They are kind of like highways inside cells that allow cells to move things around."

Previous research has shown that the linkage of these sugar molecules to proteins, like Tau, in cells is essential. In fact, says Vocadlo, researchers have tried but failed to rear mice that don’t have these sugar molecules attached to proteins.

Vocadlo, an accomplished chess player in his spare time, is having great success checkmating troublesome enzymes with inhibitors he and his students are creating in the SFU chemistry department’s Laboratory of Chemical Glycobiology.

Research prior to Vocadlo’s has shown that clumps of Tau from an Alzheimer brain have almost none of this sugar attached to them, and O-GlcNAcase is the enzyme that is robbing them.

Such clumping is an early event in the development of Alzheimer’s and the number of clumps correlate with the disease’s severity.

Scott Yuzwa and Xiaoyang Shan, grad students in Vocadlo’s lab, found that Thiamet-G blocks O-GlcNAcase from removing sugars off Tau in mice that drank water with a daily dose of the inhibitor. Yuzwa and Shan are co-first authors on this paper.

The research team found that mice given the inhibitor had fewer clumps of Tau and maintained healthier brains.

"This work shows targeting the enzyme O-GlcNAcase with inhibitors is a new potential approach to treating Alzheimer’s," says Vocadlo. "This is vital since to date there are no treatments to slow its progression.

"A lot of effort is needed to tackle this disease and different approaches should be pursued to maximize the chance of successfully fighting it. In the short term, we need to develop better inhibitors of the enzyme and test them in mice. Once we have better inhibitors, they can be clinically tested.

Source: Science Daily

Yale University researchers have discovered a key cellular mechanism that may help the brain control how much we eat, what we weigh, and how much energy we have.

The findings, published in the Feb. 28 issue of the Journal of Neuroscience, describe the regulation of a family of cells that project throughout the nervous system and originate in an area of the brain call the hypothalamus, which has been long known to control energy balances.

Scientists and pharmaceutical companies are closely investigating the role of melanin-concentrating hormone (MCH) neurons in controlling food intake and energy. Previous studies have shown that MCH makes lab animals eat more, sleep more, and have less energy. In contrast, other hypothalamic neurons use the thyrotropin-releasing hormone (TRH) as a neurotransmitter, and these neurons reduce food intake and body weight, and increase physical activity.

The Yale study of brains of mice shows that the two systems appear to act in direct opposition, to help the organism keep these crucial functions in balance.

Although TRH is normally an excitatory neurotransmitter, the Yale study shows that in mice TRH inhibits MCH cells by increasing inhibitory synaptic input. In contrast, TRH had little effect on other types of neurons also involved in energy regulation.

“That these two types of neurons interact at the synaptic level gives us clues as to how the brain controls the amount of food we eat, and how much we sleep,” said Anthony van den Pol, senior author and professor of neurosurgery at Yale School of Medicine.

Three MCH neurons in the hypothalamus region of a mouse brain are highlighted in green. In animals, these neurons are associated with high calorie intake and lower energy levels. Yale researchers have shown how the effects of these key cells are reversed. Image adapted from Yale press release image.

Source: Neuroscience News

By SUSAN GREENFIELD

Human identity, the idea that defines each and every one of us, could be facing an unprecedented crisis. It is a crisis that would threaten long-held notions of who we are, what we do and how we behave. It goes right to the heart -or the head- of us all. This crisis could reshape how we interact with each other, alter what makes us happy, and modify our capacity for reaching our full potential as individuals. And it’s caused by one simple fact: the human brain, that most sensitive of organs, is under threat from the modern world.

PROFESSOR SUSAN GREENFIELD

Unless we wake up to the damage that the gadget-filled, pharmaceutically-enhanced 21st century is doing to our brains, we could be sleepwalking towards a future in which neuro-chip technology blurs the line between living and non-living machines, and between our bodies and the outside world.

It would be a world where such devices could enhance our muscle power, or our senses, beyond the norm, and where we all take a daily cocktail of drugs to control our moods and performance.

Already an electronic chip is being developed that could allow a paralysed patient to move a robotic limb just by thinking about it. As for drug manipulated moods, they’re already with us - although so far only to a medically prescribed extent.

Increasing numbers of people already take Prozac for depression, Paxil as an antidote for shyness, and give Ritalin to children to improve their concentration. But what if there were still more pills to enhance or “correct” a range of other specific mental functions?

Read more: Daily Mail

Article Date: 27 Feb 2012 - 10:00 PST

In a study, due to appear in the March 30 issue of Cell, researchers at MIT’s Picower Institute for Learning and Memory have discovered, for the first time, that neurons at different stages of their life cycles potentially perform two separate functions, such as forming distinct memories of almost identical situations, and the ability to recall an entire event when prompted by a tiny detail.

The study describes a brain structure that produces new neurons in adults as a possible vital target for developing drugs for the treatment of memory disorders. 


Lead author, Toshiaki Nakashiba at the Picower Institute said that an imbalance between young and old neurons in the brain region, called dentate gyrus can potentially disrupt memory formation, recalling and potentially affect cognitive dysfunctions related to post-traumatic stress disorder (PTSD), as well as aging. In dentate gyrus, only one of the two brain sites continuously generates new neurons throughout adult life.

Co-author Susumu Tonegawa, Picower Professor of Neuroscience at the Picower Institute explained:

"In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging."

The brain detects small differences between similar experiences by pattern separation. Humans are able to recall explicit content of earlier memories with only limited clues related to the original experience when these patterns are complete. For instance, a person who has dinner at the same French restaurant two nights in a row makes similar experiences or observations on both occasions, like the menu, the surroundings, the time of their visit, etc.

The distinct memories that the person’s brains forms for each event are called pattern separation. If a friend, for instance, mentions a liking for onion soup some time later, the person may recall not only the dish they had at the restaurant, but the entire experience of which people were at the restaurant, what they did after the meal, etc. This process is recalled by pattern completion. 


Whilst pattern separation forms a unique new memory based on differences between experiences, pattern completion recalls memories by identifying similarities. People who have suffered severe brain injury or trauma are often unable to recognize their family and friends’ faces that they see on a regular basis, whilst others with PTSD are unable to forget harrowing events.

Tonegawa explains:

"Impaired pattern separation due to loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients."

For a long time, neuroscientists believed that these two opposing and competing processes occur in different neural circuits within the hippocampus, thinking that the dentate gyrus, a structure of significant interest for its plasticity within the nervous system and its impact on conditions ranging from depression and epilepsy to traumatic brain injury, is involved in pattern separation, whilst the CA3 region is involved in pattern completion. However, the MIT researchers discovered that the neurons spawned by the dentate gyrus alone could potentially have distinct roles as they age.

The MIT researchers explored a pattern separation in mice that learned to distinguish between two chambers, of which one was safe and the other gave them an unpleasant shock to their feet. To assess the mice pattern completion abilities, the researchers gave the mice limited cues in finding their way out of a maze they knew how to negotiate earlier. They compared normal mice with mice that lacked young or old neurons, and discovered that the mice exhibited defects in pattern completion or separation, depending on which set of neurons was depleted. Previous research supported the idea that the dentate gyrus or young neurons performed pattern separation when examining pattern separation, by manipulating the entire dentate gyrus or only adult-born young neurons.

Nakashiba concluded:

"By studying mice genetically modified to block neuronal communication from old neurons—or by wiping out their adult-born young neurons—we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it. Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons."

Written by Petra Rattue  

Source: Medical News Today

ScienceDaily (Feb. 27, 2012) — Most of us know what it means when it’s said that someone is depressed. But commonly, true clinical depression brings with it a number of other symptoms. These can include anxiety, poor attention and concentration, memory issues, and sleep disturbances.

Brain hyperactivity. Maps showing the difference in the strength of brain connections between depressed subjects (left) and controls (right). Depressed subjects show much stronger connections, as evidenced by red colors in their maps. (Credit: Image courtesy of University of California - Los Angeles)

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Debora A Rothmond, Cynthia S Weickert and Maree J Webster

BMC Neuroscience 2012, 13:18 doi:10.1186/1471-2202-13-18 Published: 15 February 2012           

Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).

Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p<0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p<0.001) and D2L (p=0.003) isoforms, monoamine oxidase A (p<0.001) and catechol-O-methyltransferase (p=0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32kDa, p=0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p=0.002) and dopamine D1 receptor protein expression increased throughout development (p<0.001) with adults having the highest D1 protein levels (p[less than or equal to]0.01). Monoamine oxidase B mRNA and protein (p<0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r=-0.31, p=0.018) in an expression profile opposite to that of the dopamine D1 receptor.

We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function. 

Source: BMC Neuroscience

February 24, 2012 by Stuart Mason Dambrot

Mechanisms of fluorescent voltage sensing. (A) Electrochromic voltage-sensitive dyes (VDSs) sense voltage when the chromophore interacts directly with the electric field. Changes in the energy levels of the chromophore result in small spectral shifts in the emission of the dye. (B) Fluorescence resonance energy transfer-pair voltage sensors use lipophilic anions (red). Depolarization causes translocation of the anion, which can now quench the fluorescence of an immobilized fluorophore (green). (C) Molecular wire photo-induced electron transfer (PeT) VSDs depend upon the voltage-sensitive electron transfer from an electron-rich donor (orange) through a membrane-spanning molecular wire (black) to a fluorescent reporter (green). Image Copyright © PNAS, doi: 10.1073/pnas.1120694109

(Medical Xpress) — Optically monitoring the brain’s neuronal activity can be accomplished in several ways, including electrochromic dyes, hydrophobic anions, calcium imaging, or voltage-sensitive ion channels. Fluorescence imaging is an attractive method due to its ability to map the electrical activity and communication of multiple spatially resolved neurons. While this complements traditional electrophysiological measurements, historically fluorescent voltage imaging has been limited by the difficulty of developing sensors that give both large and fast responses to voltage changes. Recently, however, scientists in the Department of Pharmacology and other areas in the University of California at San Diego’s Howard Hughes Medical Institute have designed, synthesized, and implemented fluorescent sensors in the form of photo-induced electron transfer (PeT)-based molecular wire probes for voltage imaging in neurons. Moreover, they have used these so-called VoltageFluor sensors to perform single-trial detection of synaptic and action potentials in cultured hippocampal neurons and intact leech ganglia.

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Article Date: 24 Feb 2012 - 8:00 PST

A new study, in this week’s online edition of the Proceedings of the National Academy of Sciences , shows an incredible degree of biological diversity in a surprising location, i.e. in a single neural connection in the body wall of flies. The finding opens up a new spectrum of interesting questions regarding the importance of the nervous system structure and the evolution of neural wiring.

Geneticist Barry Ganetzky, Steenbock Professor of Biological Sciences at the University of Wisconsin-Madison declared:

 ”We know almost nothing about the evolution of the nervous system, although we know it has to happen - behaviors change, complexity changes, there is the addition of new neurons, formation of different synaptic connections.”

The finding proves even more astounding given that Ganetzky and his graduate student Megan Campbell discovered the unexpected diversity in a location very familiar to scientists, i.e. the neuromuscular junction 4 (NMJ4), the location where a single motor neuron contacts a particular muscle in the fly body wall to drive its activity. The synapses where neurons link to their neuronal or muscular targets have a complex structural form, looking like miniature trees decorated with tiny bulbs that are the nerve terminals (synaptic boutons).

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February 23rd, 2012

Researchers at the RIKEN-MIT Center for Neural Circuit Genetics have discovered an answer to the long-standing mystery of how brain cells can both remember new memories while also maintaining older ones.

They found that specific neurons in a brain region called the dentate gyrus serve distinct roles in memory formation depending on whether the neural stem cells that produced them were of old versus young age.

The study will appear in the March 30 issue of Cell and links the cellular basis of memory formation to the birth of new neurons – a finding that could unlock a new class of drug targets to treat memory disorders.

The findings also suggest that an imbalance between young and old neurons in the brain could disrupt normal memory formation during post-traumatic stress disorder (PTSD) and aging. “In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging,” said the study’s senior author Susumu Tonegawa, 1987 Nobel Laureate and Director of the RIKEN-MIT Center.

Other authors include Toshiaki Nakashiba and researchers from the RIKEN-MIT Center and Picower Institute at MIT; the laboratory of Michael S. Fanselow at the University of California at Los Angeles; and the laboratory of Chris J. McBain at the National Institute of Child Health and Human Development.

In the study, the authors tested mice in two types of memory processes. Pattern separation is the process by which the brain distinguishes differences between similar events, like remembering two Madeleine cookies with different tastes. In contrast, pattern completion is used to recall detailed content of memories based on limited clues, like recalling who one was with when remembering the taste of the Madeleine cookies.

Pattern separation forms distinct new memories based on differences between experiences; pattern completion retrieves memories by detecting similarities. Individuals with brain injury or trauma may be unable to recall people they see every day. Others with PTSD are unable to forget terrible events. “Impaired pattern separation due to the loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients,” Tonegawa said.

Neuroscientists have long thought these two opposing and potentially competing processes occur in different neural circuits. The dentate gyrus, a structure with remarkable plasticity within the nervous system and its role in conditions from depression to epilepsy to traumatic brain injury — was thought to be engaged in pattern separation and the CA3 region in pattern completion. Instead, the MIT researchers found that dentate gyrus neurons may perform pattern separation or completion depending on the age of their cells.

The MIT researchers assessed pattern separation in mice who learned to distinguish between two similar but distinct chambers: one safe and the other associated with an unpleasant foot shock. To test their pattern completion abilities, the mice were given limited cues to escape a maze they had previously learned to negotiate. Normal mice were compared with mice lacking either young neurons or old neurons. The mice exhibited defects in pattern completion or separation depending on which set of neurons was removed.

“By studying mice genetically modified to block neuronal communication from old neurons — or by wiping out their adult-born young neurons — we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it,” co-author Toshiaki Nakashiba said. “Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons.”

Source: Neuroscience News

ScienceDaily (Feb. 23, 2012) — After we sense a threat, our brain center responsible for responding goes into gear, setting off a chain of biochemical reactions leading to the release of cortisol from the adrenal glands.

Dr. Gil Levkowitz and his team in the Molecular Cell Biology Department have now revealed a new kind of ON-OFF switch in the brain for regulating the production of a main biochemical signal from the brain that stimulates cortisol release in the body. This finding, which was recently published in Neuron, may be relevant to research into a number of stress-related neurological disorders.

This signal is corticotropin releasing hormone (CRH). CRH is manufactured and stored in special neurons in the hypothalamus. Within this small brain region the danger is sensed, the information processed and the orders to go into stress-response mode are sent out. As soon as the CRH-containing neurons have depleted their supply of the hormone, they are already receiving the directive to produce more.

The research — on zebrafish — was performed in Levkowitz’s lab and spearheaded by Dr. Liat Amir-Zilberstein together with Drs. Janna Blechman, Adriana Reuveny and Natalia Borodovsky and Maayan Tahor. The team found that a protein called Otp is involved in several stages of CRH production. As well as directly activating the genes encoding CRH, it also regulates the production of two different receptors on the neurons’ surface for receiving and relaying CRH production signals — in effect, ON and OFF switches.

The team found that both receptors are encoded in a single gene. To get two receptors for the price of one, Otp regulates a gene-editing process known as alternative splicing, in which some of the elements in the sequence encoded in a gene can be “cut and pasted” to make slightly different “sentences.” In this case, it generates two variants of a receptor called PAC1: The short version produces the ON receptor; the long version, containing an extra sequence, encodes the OFF receptor. The researchers found that as the threat passed and the supply of CRH was replenished, the ratio between the two types of PAC1 receptor on the neurons’ surface gradually changed from more ON to mostly OFF. In collaboration with Drs Laure Bally-Cuif and William Norton of the Institute of Neurobiology Alfred Fessard at the Centre National de la Recherche Scientifique (CNRS) in France, the researchers showed that blocking the production of the long receptor variant causes an anxiety-like behavior in zebrafish.

Together with Drs. Alon Chen and Yehezkel Sztainberg of the Neurobiology Department, Levkowitz’s team found the same alternatively-spliced switch in mice. This conservation of the mechanism through the evolution of fish and mice implies that a similar means of turning CRH production on and off exists in the human brain.

Faulty switching mechanisms may play a role in a number of stress-related disorders. The action of the PAC1 receptor has recently been implicated in post-traumatic stress disorder, as well as in schizophrenia and depression. Malfunctions in alternative splicing have also been associated with epilepsy, mental retardation, bipolar disorder and autism.

Source: Science Daily

ScienceDaily (Feb. 22, 2012) — While RNA is an appealing drug target, small molecules that can actually affect its function have rarely been found. But now scientists from the Florida campus of The Scripps Research Institute have for the first time designed a series of small molecules that act against an RNA defect directly responsible for the most common form of adult-onset muscular dystrophy.

In two related studies published recently in online-before-print editions of Journal of the American Chemical Society and ACS Chemical Biology, the scientists show that these novel compounds significantly improve a number of biological defects associated with myotonic dystrophy type 1 in both cell culture and animal models.

"Our compounds attack the root cause of the disease and they improve defects in animal models," said Scripps Research Associate Professor Matthew Disney, PhD. "This represents a significant advance in rational design of compounds targeting RNA. The work not only opens up potential therapies for this type of muscular dystrophy, but also paves the way for RNA-targeted therapeutics in general."

Myotonic dystrophy type 1 involves a type of RNA defect known as a “triplet repeat,” a series of three nucleotides repeated more times than normal in an individual’s genetic code. In this case, the repetition of the cytosine-uracil-guanine (CUG) in RNA sequence leads to disease by binding to a particular protein, MBNL1, rendering it inactive. This results in a number of protein splicing abnormalities. Symptoms of this variable disease can include wasting of the muscles and other muscle problems, cataracts, heart defects, and hormone changes.

To find compounds that acted against the problematic RNA in the disease, Disney and his colleagues used information contained in an RNA motif-small molecule database that the group has been developing. By querying the database against the secondary structure of the triplet repeat that causes myotonic dystrophy type 1, a lead compound targeting this RNA was quickly identified. The lead compounds were then custom-assembled to target the expanded repeat or further optimized using computational chemistry. In animal models, one of these compounds improved protein-splicing defects by more than 40 percent.

"There are limitless RNA targets involved in disease; the question is how to find small molecules that bind to them," Disney said. "We’ve answered that question by rationally designing these compounds that target this RNA. There’s no reason that other bioactive small molecules targeting other RNAs couldn’t be developed using a similar approach."

Source: Science Daily

February 22nd, 2012

The notion of a pain switch is an alluring idea, but is it realistic? Well, chemists at LMU Munich, in collaboration with colleagues in Berkeley and Bordeaux, have now shown in laboratory experiments that it is possible to inhibit the activity of pain-sensitive neurons using an agent that acts as a photosensitive switch. For the LMU researchers, the method primarily represents a valuable tool for probing the neurobiology of pain. (Nature Methods, 19.02.2012)

The system developed by the LMU team, led by Dirk Trauner, who is Professor of Chemical Biology and Genetics, is a chemical compound they call QAQ. The molecule is made up of two functional parts, each containing a quaternary ammonium, which are connected by a nitrogen double bond (N=N). This bridge forms the switch, as its conformation can be altered by light. Irradiation with light of a specific wavelength causes the molecule to flip from a bent to an extended form; exposure to light of a different color reverses the effect.

One half of QAQ closely resembles one of the active analogs of lidocaine, a well-known local anesthetic used by dentists. Lidocaine blocks the perception of pain by inhibiting the action of receptors found on specific nerve cells in the skin, which respond to painful stimuli and transmit signals to the spinal cord.

Neuroreceptors are proteins that span the outer membrane of nerve cells. They possess deformable pores that open in response to appropriate stimuli, and function as conduits that permit electrically charged ions to pass into or out of the cells. The ion channel targeted by the lidocaine-like end of QAQ responds to heat by allowing positively charged sodium ions to pass into the cells that express it. This alters the electrical potential across the membrane, which ultimately leads to transmission of the nerve impulse.

In their experiments, the researchers exploited the fact that QAQ can percolate through endogenous ion channels to get the molecule into nerve cells. This is a crucial step, because its site of action is located on the inner face of the targeted ion channel.

Furthermore, the lidocaine-like end of QAQ binds to this site only if the molecule is in an extended conformation. When the cells were irradiated with 380-nm light, which bends the bridge, signal transmission was reactivated within a matter of milliseconds. Exposure to light with a wavelength of 500 nm, on the other hand, reverts the molecule to the extended form and restores its inhibitory action. The analgesic effect of the switch was confirmed using an animal model.
Trauner’s team has been working for some considerable time on techniques with which biologically critical molecular machines such as neuroreceptors can be controlled in living animals by means of light impulses. The researchers themselves regard the new method primarily as a tool for neurobiological studies, particularly for pain research. Therapeutic applications of the principle are “a long way off”, says Timm Fehrentz, one of Dirk Trauner’s PhD students and one of the two equal first authors on the new paper. For one thing, the monochromatic light used to isomerize the QAQ molecule cannot penetrate human skin sufficiently to reach the pain-sensitive neurons. The researchers hope to address that problem by looking for alternatives to QAQ that respond to red light of longer wavelength, which more readily passes through the skin. (math/PH)

Source: Neuroscience News

February 21, 2012

There are a number of drugs and experimental conditions that can block cognitive function and impair learning and memory. However, scientists have recently shown that some drugs can actually improve cognitive function, which may have implications for our understanding of cognitive disorders such as Alzheimer’s disease. The new research is reported 21 February in the open-access journal PLoS Biology.

The study, led by Drs. Jose A. Esteban, Shira Knafo and Cesar Venero, is the result of collaboration between researchers from The Centro de Biología Molecular Severo Ochoa and UNED (Spain), the Brain Mind Institute (EPFL, Switzerland) and the Department of Neuroscience and Pharmacology (Faculty of Health Sciences, Denmark).

The human brain contains trillions of neuronal connections, called synapses, whose pattern of activity controls all our cognitive functions. These synaptic connections are dynamic and constantly changing in their strength and properties. This process, known as synaptic plasticity, has been proposed as the cellular basis for learning and memory. Indeed, alterations in synaptic plasticity mechanisms are thought to be responsible for multiple cognitive deficits, such as autism, Alzheimer’s disease and several forms of mental retardation.

The study by Knafo et al. provides new information on the molecular mechanisms of synaptic plasticity, and how this process may be manipulated to improve cognitive performance. They find that synapses can be made more plastic by using a small protein fragment (peptide) derived from a neuronal protein involved in cell-to-cell communication. This peptide (called FGL) initiates a cascade of events inside the neuron that results in the facilitation of synaptic plasticity. Specifically, the authors found that FGL triggers the insertion of new neurotransmitter receptors into synapses in a region of the brain called the hippocampus, which is known to be involved in multiple forms of learning and memory. Importantly, when this peptide was administered to rats, their ability to learn and retain spatial information was enhanced.

Dr. Esteban remarks: “We have known for three decades that synaptic connections are not fixed from birth, but they respond to neuronal activity modifying their strength. Thus, outside stimuli will lead to the potentiation of some synapses and the weakening of others. It is precisely this code of ups and downs what allows the brain to store information and form memories during learning”.

Within this framework, these new findings demonstrate that synaptic plasticity mechanisms mechanisms can be manipulated pharmacologically in adult animals, with the aim of enhancing cognitive ability. Dr. Knafo adds: “These are basic studies on the molecular and cellular processes that control our cognitive function. Nevertheless, they shed light into potential therapeutic avenues for mental disorders where these mechanisms go awry”.

Source: medicalxpress.com

ScienceDaily (Feb. 21, 2012) — The carnage evident in disasters like car wrecks or wartime battles is oftentimes mirrored within the bodies of the people involved. A severe wound can leave blood vessels and nerves severed, bones broken, and cellular wreckage strewn throughout the body — a debris field within the body itself.

Thriving DRG cells. (Credit: Image courtesy of University of Rochester Medical Center)

It’s scenes like this that neurosurgeon Jason Huang, M.D., confronts every day. Severe damage to nerves is one of the most challenging wounds to treat for Huang and colleagues. It’s a type of wound suffered by people who are the victims of gunshots or stabbings, by those who have been involved in car accidents — or by soldiers injured on the battlefield, like those whom Huang treated in Iraq.

Now, back in his university laboratory, Huang and his team have taken a step forward toward the goal of repairing nerves in such patients more effectively. In a paper published in the journal PLoS ONE, Huang and colleagues at the University of Rochester Medical Center report that a surprising set of cells may hold potential for nerve transplants.

In a study in rats, Huang’s group found that dorsal root ganglion neurons, or DRG cells, help create thick, healthy nerves, without provoking unwanted attention from the immune system.

The finding is one step toward better treatment for the more than 350,000 patients each year in the United States who have serious injuries to their peripheral nerves. Huang’s laboratory is one of a handful developing new technologies to treat such wounds.

"These are very serious injuries, and patients really suffer, many for a very long time," said Huang, associate professor of Neurosurgery and chief of Neurosurgery at Highland Hospital, an affiliate of the University of Rochester Medical Center. "There are a variety of options, but none of them is ideal.

"Our long-term goal is to grow living nerves in the laboratory, then transplant them into patients and cut down the amount of time it takes for those nerves to work," added Huang, whose project was funded by the National Institute of Neurological Disorders and Stroke and by the University of Rochester Medical Center.

For a damaged nerve to repair itself, the two disconnected but healthy portions of the nerve must somehow find each other through a maze of tissue and connect together. This happens naturally for a very small wound — much like our skin grows back over a small cut — but for some nerve injuries, the gap is simply too large, and the nerve won’t grow back without intervention.

For surgeons like Huang, the preferred option is to transplant nerve tissue from elsewhere in the patient’s own body — for instance, a section of a nerve in the leg — into the wounded area. The transplanted nerve serves as scaffolding, a guide of sorts for a new nerve to grow and bridge the gap. Since the tissue comes from the patient, the body accepts the new nerve and doesn’t attack it.

But for many patients, this treatment isn’t an option. They might have severe wounds to other parts of the body, so that extra nerve tissue isn’t available. Alternatives can include a nerve transplant from a cadaver or an animal, but those bring other challenges, such as the lifelong need for powerful immunosuppressant drugs, and are rarely used.

One technology used by Huang and other neurosurgeons is the NeuraGen Nerve Guide, a hollow, absorbable collagen tube through which nerve fibers can grow and find each other. The technology is often used to repair nerve damage over short distances less than half an inch long.

In the PLoS One study, Huang’s team compared several methods to try to bridge a nerve gap of about half an inch in rats. The team transplanted nerve cells from a different type of rat into the wound site and compared results when the NeuraGen technology was was used alone or when it was paired with DRG cells or with other cells known as Schwann cells.

After four months, the team found that the tubes equipped with either DRG or Schwann cells helped bring about healthier nerves. In addition, the DRG cells provoked less unwanted attention from the immune system than the Schwann cells, which attracted twice as many macrophages and more of the immune compound interferon gamma.

While both Schwann and DRG cells are known players in nerve regeneration, Schwann cells have been considered more often as potential partners in the nerve transplantation process, even though they pose considerable challenges because of the immune system’s response to them.

"The conventional wisdom has been that Schwann cells play a critical role in the regenerative process," said Huang, who is a scientist in the Center for Neural Development and Disease. "While we know this is true, we have shown that DRG cells can play an important role also. We think DRG cells could be a rich resource for nerve regeneration."

In a related line of research, Huang along with colleagues in the laboratory of Douglas H. Smith, M.D. , at the University of Pennsylvania are creating DRG cells in the laboratory by stretching them, which coaxes them to grow about one inch every three weeks. The idea is to grow nerves several inches long in the laboratory, then transplant them into the patient, instead of waiting months after surgery for the nerve endings to travel that distance within the patient to ultimately hook up.

Source: Science Daily

Article Date: 20 Feb 2012 - 2:00 PST

New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories.

The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new “dendritic spines,” structures that form the connections (synapses) between nerve cells.

“For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory,” said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.

In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo’s lab, analyzed the spatial distribution of the newly formed synapses.

Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.

In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. “We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry,” Zuo said. “The clustering of synapses may serve to magnify the strength of the connections.”

Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.

The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.

“Repetitive activation of the same cortical circuit is really important in learning a new task,” Zuo said. “But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories.”

The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.  

Source: Medical News Today

ScienceDaily (Feb. 19, 2012) — New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories.

Rendering of neural network. New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study. (Credit: © nobeastsofierce / Fotolia)

The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new “dendritic spines,” structures that form the connections (synapses) between nerve cells.

"For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory," said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.

In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo’s lab, analyzed the spatial distribution of the newly formed synapses.

Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.

In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. “We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry,” Zuo said. “The clustering of synapses may serve to magnify the strength of the connections.”

Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.

The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.

"Repetitive activation of the same cortical circuit is really important in learning a new task," Zuo said. "But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories."

The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.

Source: Science Daily