Neuroscience

ScienceDaily (June 18, 2012) — The legal system needs to take greater account of new discoveries in neuroscience that show how a difficult childhood can affect the development of a young person’s brain which can increase the risk adolescent crimes, according to researchers.

The research will be presented as part of an Economic and Social Research Council seminar series in conjunction with the Parliamentary Office of Science and Technology.

Neuroscientists have recently shown that early adversity — such as a very chaotic and frightening home life — can result in a young child becoming hyper vigilant to potential threats in their environment. This appears to influence the development of brain connectivity and functions.

Such children may come to adolescence with brain systems that are set differently, and this may increase their likelihood of taking impulsive risks. For many young offenders such early adversity is a common experience, and it may increase both their vulnerability to mental health problems and also their risk of problem behaviours.

These insights, from a team led by Dr Eamon McCrory, University College London, are part of a wave of neuroscientific research questions that have potential implications for the legal system.

Other research by Dr Seena Fazel of Oxford University has shown that while social disadvantage is a major risk factor for offending, a Traumatic Brain Injury (TBI) — from an accident or assault — significantly increases the risk of involvement in violent crime. Professor Huw Williams, at University of Exeter, has similarly shown that around 45 per cent of young offenders have TBI histories, and more injuries are associated with greater violence.

Professor Williams said: “The latest message from neuroscience is that young people who suffer troubled childhoods may experience a kind of ‘triple whammy’. A difficult social background may put them at greater risk of offending and influence their brain development early on in childhood in a way that increases risky behaviour. This can then increase their chances of experiencing an injury to their brains that would compromise their ability to stay in school or contribute to society still further.”

Professor Williams wants to see better communication between neuroscientists, clinicians and lawyers so that research findings like these lead to changes in the legal system. “There is a big gap between research conducted by neuroscientists and the realities of the day to day work of the justice system,” he said. “Although criminal behaviour results from a complex interplay of a host of factors, neuroscientists and clinicians are identifying key risk factors that — if addressed — could reduce crime. Investment in earlier, focussed interventions may offset the costs of years of custody and social violence.”

Dr Eileen Vizard, a prominent adolescent forensic psychiatrist, will talk at the event Neuroscience, Children and the Law, about how the criminal justice system needs to be changed to age appropriate sentencing for children as young as ten years old, whilst also providing for the welfare needs of these deprived children. Laura Hoyano — a leading expert on vulnerable people in criminal courts — will discuss the problems children face when testifying in criminal courts.

Source: Science Daily

ScienceDaily (June 18, 2012) — UC Santa Barbara scientists turned to the simple sponge to find clues about the evolution of the complex nervous system and found that, but for a mechanism that coordinates the expression of genes that lead to the formation of neural synapses, sponges and the rest of the animal world may not be so distant after all. Their findings, titled “Functionalization of a protosynaptic gene expression network,” are published in the Proceedings of the National Academy of Sciences.

The genes of Amphimedon queenslandica, a marine sponge native to the Great Barrier Reef, Australia, have been fully sequenced, allowing the researchers to monitor gene expression for signs of neural development. (Credit: UCSB)

"If you’re interested in finding the truly ancient origins of the nervous system itself, we know where to look," said Kenneth Kosik, Harriman Professor of Neuroscience Research in the Department of Molecular, Cellular & Developmental Biology, and co-director of UCSB’s Neuroscience Research Institute.

That place, said Kosik, is the evolutionary period of time when virtually the rest of the animal kingdom branched off from a common ancestor it shared with sponges, the oldest known animal group with living representatives. Something must have happened to spur the evolution of the nervous system, a characteristic shared by creatures as simple as jellyfish and hydra to complex humans, according to Kosik.

A previous sequencing of the genome of the Amphimedon queenslandica — a sponge that lives in Australia’s Great Barrier Reef — showed that it contained the same genes that lead to the formation of synapses, the highly specialized characteristic component of the nervous system that sends chemical and electrical signals between cells. Synapses are like microprocessors, said Kosik explaining that they carry out many sophisticated functions: They send and receive signals, and they also change behaviors with interaction — a property called “plasticity.”

"Specifically, we were hoping to understand why the marine sponge, despite having almost all the genes necessary to build a neuronal synapse, does not have any neurons at all," said the paper’s first author, UCSB postdoctoral researcher Cecilia Conaco, from the UCSB Department of Molecular, Cellular, and Developmental Biology (MCDB) and Neuroscience Research Institute (NRI). "In the bigger scheme of things, we were hoping to gain an understanding of the various factors that contribute to the evolution of these complex cellular machines."

This time the scientists, including Danielle Bassett, from the Department of Physics and the Sage Center for the Study of the Mind, and Hongjun Zhou and Mary Luz Arcila, from NRI and MCDB, examined the sponge’s RNA (ribonucleic acid), a macromolecule that controls gene expression. They followed the activity of the genes that encode for the proteins in a synapse throughout the different stages of the sponge’s development.

"We found a lot of them turning on and off, as if they were doing something," said Kosik. However, compared to the same genes in other animals, which are expressed in unison, suggesting a coordinated effort to make a synapse, the ones in sponges were not coordinated.

"It was as if the synapse gene network was not wired together yet," said Kosik. The critical step in the evolution of the nervous system as we know it, he said, was not the invention of a gene that created the synapse, but the regulation of preexisting genes that were somehow coordinated to express simultaneously, a mechanism that took hold in the rest of the animal kingdom.

The work isn’t over, said Kosik. Plans for future research include a deeper look at some of the steps that lead to the formation of the synapse; and a study of the changes in nervous systems after they began to evolve.

"Is the human brain just a lot more of the same stuff, or has it changed in a qualitative way?" he asked.

Source: Science Daily

June 18, 2012

Among well-functioning older adults without dementia, diabetes mellitus (DM) and poor glucose control among those with DM are associated with worse cognitive function and greater cognitive decline, according to a report published Online First by Archives of Neurology, a JAMA Network publication.

Findings from previous studies have suggested an association between diabetes mellitus and an increased risk of cognitive impairment and dementia, including Alzheimer disease, but this association continues to be debated and less is known regarding incident DM in late life and cognitive function over time, the authors write as background in the study.

Kristine Yaffe, M.D., of the University of California, San Francisco and the San Francisco VA Medical Center, and colleagues evaluated 3,069 patients (mean age, 74.2 years; 42 percent black; 52 percent female) who completed the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and selected intervals over 10 years.

At study baseline, 717 patients (23.4 percent) had prevalent DM and 2,352 (76.6 percent) were without DM, 159 of whom developed DM during follow-up. Patients who had prevalent DM at baseline had lower 3MS and DSST test scores than patients without DM, and results from analysis show similar patterns for 9-year decline with participants with prevalent DM showing significant decline on both the 3MS and DSST compared with those without DM.

Also, among participants with prevalent DM at baseline, higher levels of hemoglobin A1c (HbA1c) were associated with lower 3MS and DSST scores. However, after adjusting for age, sex, race and education, scores remained significantly lower for those with mid (7 percent to 8 percent) and high (greater than or equal to 8 percent) HbA1c levels on the 3MS but were no longer significant for the DSST.

"This study supports the hypothesis that older adults with DM have reduced cognitive function and that poor glycemic control may contribute to this association,” the authors conclude. “Future studies should determine if early diagnosis and treatment of DM lessen the risk of developing cognitive impairment and if maintaining optimal glucose control helps mitigate the effect of DM on cognition.”

Provided by JAMA and Archives Journals

Source: medicalxpress.com

June 18, 2012

A new study proposes a communication routing strategy for the brain that mimics the American highway system, with the bulk of the traffic leaving the local and feeder neural pathways to spend as much time as possible on the longer, higher-capacity passages through an influential network of hubs, the so-called rich club.

The study, published this week online in the Early Edition of the Proceedings of the National Academy of Sciences, involves researchers from Indiana University and the University Medical Center Utrecht in the Netherlands and advances their earlier findings that showed how select hubs in the brain not only are powerful in their own right but have numerous and strong connections between each other.

The current study characterizes the influential network within the rich club as the “backbone” for global brain communication. A costly network in terms of the energy and space consumed, said Olaf Sporns, professor in the Department of Psychological and Brain Sciences at IU Bloomington, but one with a big pay-off: providing quick and effective communication between billions and billions of brain cells.

"Until now, no one knew how central the brain’s rich club really was," Sporns said. "It turns out the rich club is always right in the middle when it comes to how brain regions talk to each other. It absorbs, transforms and disseminates information. This underscores its importance for brain communication.”

In earlier work, using diffusion imaging, the researchers found a group of 12 strongly interconnected bihemispheric hub regions, comprising the precuneus, superior frontal and superior parietal cortex, as well as the subcortical hippocampus, putamen and thalamus. Together, these regions form the brain’s “rich club.” Most of these areas are engaged in a wide range of complex behavioral and cognitive tasks, rather than more specialized processing such as vision and motor control.

For the current study, Martijn van den Heuvel, a professor at the Rudolf Magnus Institute of Neuroscience at University Medical Center Utrecht, used diffusion tensor imaging data for two sets of 40 healthy subjects to map the large-scale connectivity structure of the brain. The cortical sheet was divided into 1,170 regions, and then pathways between the regions were reconstructed and measured. As in the previous study, the rich club nodes were widely distributed and had up to 40 percent more connectivity compared to other areas.

The connections measured — almost 700,000 in total — were classified in one of three ways: as rich club connections if they connected nodes within the rich club; as feeder connections if they connected a non-rich club node to a rich club node; and as local connections if they connected non-rich club nodes. Rich club connections made up the majority of all long-distance neural pathways. The study also found that connections classified as rich club connections were used more heavily for communication than other feeder and local connections. A path analysis showed that when a minimally short path is traced from one area of the brain to another, it travels through the rich club network 69 percent of the time, even though the network accounts for only 10 percent of the brain.

A common pattern in communication paths spanning long distances, Sporns said, was that such paths involved sequences of steps leading across local, feeder, rich club, feeder and back to local connections. In other words, he said, many communication paths first traveled toward the rich club before reaching their destinations.

"It is as if the rich club acts as an attractor for signal traffic in the brain," Sporns said. "It soaks up information which is then integrated and sent back out to the rest of the brain."

Van den Heuvel agreed.

"It’s like a big ‘neuronal magnet’ for communication and information integration in our brains," he said. "Seeking out the rich club may offer a strategy for neurons and brain regions to find short communication paths across the brain, and might provide insight into how our brain manages to be so highly efficient."

From an evolutionary standpoint, it was important for the brain to minimize energy consumption and wiring volume, but if these were the only factors, there would be no rich club because of the extra resources it requires, Sporns said. The rich club is expensive, at least in terms of wiring volume, and perhaps also in terms of metabolic cost. The trade-off for higher cost, Sporns said, is higher performance — the integration of diverse signals and the ability to select short paths across the network.

“Brain neurons don’t have maps; how do they find paths to get in touch? Perhaps the rich club helps with this, offering the brain’s neurons and regions a way to communicate efficiently based on a routing strategy that involves the rich club.”

People use related strategies to navigate social networks.

"Strangely, neurons may solve their communication problems just like the people to which they belong," Sporns said.

Provided by Indiana University

Source: medicalxpress.com

June 18, 2012

A new study shows that the compound Coenzyme Q10 (CoQ) reduces oxidative damage, a key finding that hints at its potential to slow the progression of Huntington disease. The discovery, which appears in the inaugural issue of the Journal of Huntington’s Disease, also points to a new biomarker that could be used to screen experimental treatments for this and other neurological disorders.

"This study supports the hypothesis that CoQ exerts antioxidant effects in patients with Huntington’s disease and therefore is a treatment that warrants further study," says University of Rochester Medical Center neurologist Kevin M. Biglan, M.D., M.P.H., lead author of the study. “As importantly, it has provided us with a new method to evaluate the efficacy of potential new treatments.”

Huntington’s disease (HD) is a genetic, progressive neurodegenerative disorder that impacts movement, behavior, cognition, and generally results in death within 20 years of the disease’s onset. While the precise causes and mechanism of the disease are not completely understood, scientists believe that one of the important triggers of the disease is a genetic “stutter" which produces abnormal protein deposits in brain cells. It is believed that these deposits – through a chain of molecular events – inhibit the cell’s ability to meet its energy demands resulting in oxidative stress and, ultimately, cellular death.

Scientists had previously identified the correlation between a specific fragment of genetic code, called 8-hydroxy-2’-deoxyguanosine (80HdG) and the presence of oxidative stress in brain cells. 80HdG can be detected in a person’s blood, meaning that it could serve as a convenient and accessible biomarker for the disease. Researchers have also been evaluating the compound Coenzyme Q10 as a possible treatment for HD because of its ability to support the function of mitochondria – the tiny power plants the provide cells with energy – and counter oxidative stress.

The study’s authors evaluated a series of blood samples of 20 individuals with HD who had previously undergone treatment with CoQ in clinical trial titled Pre-2Care. While these studies showed that CoQ alleviated some symptoms of the disease, it was not known what impact – if any – the treatment had at the molecular level in the brain. Upon analysis, the authors found that 80HdG levels dropped by 20 percent in individuals who had been treated with CoQ.

CoQ is currently being evaluated in a Phase 3 clinical trial, which is the largest therapeutic clinical study to date for HD. The trial – called 2Care – is being run by the Huntington Study Group, an international networks or investigators.

"Identifying treatments that slow the progression or delay the onset of Huntington’s disease is a major focus of the medical community," said Biglan. "This study demonstrates that 80HdG could be an ideal marker to identify the presence oxidative injury and whether or not treatment is having an impact."

Provided by University of Rochester Medical Center

Source: medicalxpress.com

June 18, 2012

Studies suggest that neurotrophic factors, which play a role in the development and survival of neurons, have significant therapeutic and restorative potential for neurologic diseases such as Huntington’s disease. However, clinical applications are limited because these proteins cannot easily cross the blood brain barrier, have a short half-life, and cause serious side effects. Now, a group of scientists has successfully treated neurological symptoms in laboratory rats by implanting a device to deliver a genetically engineered neurotrophic factor directly to the brain. They report on their results in the latest issue of Restorative Neurology and Neuroscience.

The tip of the EC biodelivery system, a straw-like device that is implanted in the brain of patients, contains living cells which are genetically modified to produce a therapeutic factor. The membrane enclosing the cells allows the factor to flow out of the device and into the patient’s brain tissue. This way, areas deep within the brain affected by Huntington’s disease can be treated to delay or prevent the disease. Credit: Jens Tornøe, NsGene A/S, Ballerup, Denmark

Researchers used Encapsulated Cell (EC) biodelivery, a platform which can be applied using conventional minimally invasive neurosurgical procedures to target deep brain structures with therapeutic proteins. “Our study adds to the continually increasing body of preclinical and clinical data positioning EC biodelivery as a promising therapeutic delivery method for larger biomolecules. It combines the therapeutic advantages of gene therapy with the well-established safety of a retrievable implant,” says lead investigator Jens Tornøe, NsGene A/S, Ballerup, Denmark.

Investigators made a catheter-like device consisting of a hollow fiber membrane encapsulating a polymeric “scaffold,” which provides a surface area to which neurotrophic factor-producing cells can attach. When implanted in the brain, the membrane allows the neurotrophic factor to flow out of the device, as well as allowing nutrients in. Dr. Tornøe and his colleagues used the neurotrophic factor Meteorin, which plays a role in the development of striatal projection neurons, whose degeneration is a hallmark of Huntington’s disease. The scientists engineered ARPE-19 cells to produce Meteorin and used those that produced high levels of Meteorin in their experiment.

The EC biodelivery devices were implanted in the brains of rats followed by injection with quinolinic acid (QA), a potent neurotoxin that causes excitotoxicity, a component of Huntington’s disease. They tested three different implant types: devices filled with the high-producing ARPE-19 cells (EC-Meteorin), devices with unmodified ARPE-19 cells (ARPE-19), and devices without cells. Motor dysfunction was tested immediately prior to injection with QA and at two and four weeks after injection.

The research team found that the EC-Meteorin devices significantly protected against QA-induced toxicity. Rats with EC-Meteorin devices manifested near normal neurological performance and significantly reduced loss of brain cells from the QA injection compared to controls. Analysis of the Meteorin-treated brains showed a markedly reduced striatal lesion size. The EC biodelivery devices were found to produce stable or even increasing levels of Meteorin throughout the study. Meteorin diffused readily from the biodelivery device to the striatal tissue.

"Huntington’s disease can be diagnosed with high accuracy by genetic testing. Pre-symptomatic administration of a safe therapeutic treatment providing sustained delay or prevention of disease would be of great benefit to patients," says Dr. Tornøe. "With additional functional and safety data, tests in animals larger than the rat to study distribution, and more accurate disease models to evaluate the therapeutic potential of Meteorin, we anticipate that EC biodelivery can be developed as a platform technology for targeted therapy in patients with Huntington’s disease."

Provided by IOS Press

Source: medicalxpress.com

June 18, 2012

New pictures from the University of Iowa show what it looks like when a person runs out of patience and loses self-control.

This image shows brain activity when people exert self-control. Credit: University of Iowa

A study by University of Iowa neuroscientist and neuro-marketing expert William Hedgcock confirms previous studies that show self-control is a finite commodity that is depleted by use. Once the pool has dried up, we’re less likely to keep our cool the next time we’re faced with a situation that requires self-control.

But Hedgcock’s study is the first to actually show it happening in the brain using fMRI images that scan people as they perform self-control tasks. The images show the anterior cingulate cortex (ACC)—the part of the brain that recognizes a situation in which self-control is needed and says, “Heads up, there are multiple responses to this situation and some might not be good”—fires with equal intensity throughout the task.

However, the dorsolateral prefrontal cortex (DLPFC)—the part of the brain that manages self-control and says, “I really want to do the dumb thing, but I should overcome that impulse and do the smart thing”—fires with less intensity after prior exertion of self-control.

This image shows brain activity after people have been engaged in self-control tasks long enough that self-control resources have been depleted. Credit: University of Iowa

He said that loss of activity in the DLPFC might be the person’s self-control draining away. The stable activity in the ACC suggests people have no problem recognizing a temptation. Although they keep fighting, they have a harder and harder time not giving in.

Which would explain why someone who works very hard not to take seconds of lasagna at dinner winds up taking two pieces of cake at desert. The study could also modify previous thinking that considered self-control to be like a muscle. Hedgcock says his images seem to suggest that it’s like a pool that can be drained by use then replenished through time in a lower conflict environment, away from temptations that require its use.

The researchers gathered their images by placing subjects in an MRI scanner and then had them perform two self-control tasks—the first involved ignoring words that flashed on a computer screen, while the second involved choosing preferred options. The study found the subjects had a harder time exerting self-control on the second task, a phenomenon called “regulatory depletion.” Hedgcock says that the subjects’ DLPFCs were less active during the second self-control task, suggesting it was harder for the subjects to overcome their initial response.

Hedgcock says the study is an important step in trying to determine a clearer definition of self-control and to figure out why people do things they know aren’t good for them. One possible implication is crafting better programs to help people who are trying to break addictions to things like food, shopping, drugs, or alcohol. Some therapies now help people break addictions by focusing at the conflict recognition stage and encouraging the person to avoid situations where that conflict arises. For instance, an alcoholic should stay away from places where alcohol is served.

But Hedgcock says his study suggests new therapies might be designed by focusing on the implementation stage instead. For instance, he says dieters sometimes offer to pay a friend if they fail to implement control by eating too much food, or the wrong kind of food. That penalty adds a real consequence to their failure to implement control and increases their odds of choosing a healthier alternative.

The study might also help people who suffer from a loss of self-control due to birth defect or brain injury.

"If we know why people are losing self-control, it helps us design better interventions to help them maintain control," says Hedgcock, an assistant professor in the Tippie College of Business marketing department and the UI Graduate College’s Interdisciplinary Graduate Program in Neuroscience.

Provided by University of Iowa

Source: medicalxpress.com

June 18, 2012

Fear conditioning using sound and taste aversion, as applied to mice, have revealed interesting information on the basis of memory allocation.

Credit: Thinkstock

European ‘Cellular mechanisms underlying formation of the fear memory trace in the mouse amygdala’ (FEAR Memory TRACE) project is investigating memory allocation and the recruitment of certain neurons to encode a memory. By studying conditioned fear memory in response to an auditory stimulus, the researchers have delved into pathological emotional states and neural mechanisms involved in memory allocation, retrieval and extinction.

Prior research has revealed that the conditioned fear response in mice is located in a specific bundle of neurons in the amygdala. Memory allocation modulation is due to expression of the transcription factor, cyclic adenosine 3’, 5’-monophosphate response element binding protein (CREB) and possibly neuronal excitability.

FEAR Memory TRACE focused on the electrophysiological properties of neurons encoding the same memory. The project also aimed to ascertain the biophysical mechanisms in the plasticity changes recorded in the specific set of neurons in the fear memory trace.

Recording information on auditory fear conditioning and conditioned taste aversion, the scientists used intra-amygdala surgery using viral vectors and electrophysiological experiments to detect neuronal excitability.

Transfected by virus, CREB tagged with green fluorescent protein together with the gene for channelrhodopsin2 were used in neural control experiments. Combined, these two elements caused neuron firing in specific nerve cells. Molecular techniques included western blot for protein detection, genotyping and viral DNA preparation.

Behavioural tests on long- and short-term memory of mice involving fear conditioning and taste aversion showed increased memory performance at the three-hour point rather than the five-hour point. The intrinsic excitability of the mice receiving both shock and the tone was increased at three hours, not five, compared to mice that only received the tone.

As the project continues to its close in two years, the aim is to identify biophysical mechanisms involved in recruiting neurons that compete with each other for a specific memory. FEAR Memory TRACE will also develop computational models to assess the role of these mechanisms in memory performance.

Information on biochemical processes in neural mechanisms has wide application in many clinical situations including patients suffering memory loss, such as stroke victims. Fear response manipulation can be applied in treatment of neuroses and phobias.

Provided by CORDIS

Source: medicalxpress.com

June 17, 2012

A collaborative research team led by Professor Tadashi ISA from The National Institute for Physiological Sciences, The National Institutes of Natural Sciences and Fukushima Medical University and Kyoto University, developed a “double viral vector transfection technique” which can deliver genes to a specific neural circuit by combining two new kinds of gene transfer vectors. With this method, they found that “indirect pathways”, which were suspected to have been left behind when the direct connection from the brain to motor neurons (which control muscles) was established in the course of evolution, actually plays an important role in the highly developed dexterous hand movements. This study was supported by the Strategic Research Program for Brain Sciences by the MEXT of Japan. This research result will be published in Nature (June 17th, advance online publication).

It is said that the higher primates including human beings accomplished explosive evolution by having acquired the ability to move hands skillfully. It has been thought that this ability to move individual fingers is a result of the evolution of the direct connection from the cerebrocortical motor area to motor neurons of the spinal cord which control the muscles. On the other hand, in lower animals with clumsy hands, such as cats or rats, the cortical motor area is connected to the motor neurons, only through interneurons of the spinal cord. Such “indirect pathway”remains in us, primates, without us fully understanding its functions. Is this “phylogenetically old circuit” still in operation? Or maybe suppressed since it is obstructive? The conclusion was not attached to this argument.

The collaborative research team led by Professor Tadashi ISA, Project Assistant Professor Masaharu KINOSHITA from The National Institute for Physiological Sciences, The National Institutes of Natural Sciences and Fukushima Medical University and Kyoto University developed “the double viral vector transfection technique”which can deliver genes to a specific neural circuit by combining two new kinds of gene transfer vectors.

With this method, they succeeded in the selective and reversible suppression of the propriospinal neurons (spinal interneurons mediating the indirect connection from cortical motor area to spinal motor neurons)

The results revealed that “indirect pathways” play an important role in dexterous hand movements and finally a longtime debate has come to a close.

The key component of this discovery was”the double viral vector transfection technique”in which one vector is retrogradely transported from the terminal zone back to the neuronal cell bodies and the other is transfected at the location of their cell bodies. The expression of the target gene is regulated only in the cells with double transfection by the two vectors. Using this technique, they succeeded in the suppression of the propriospinal neuron selectively and reversibly.

Such an operation was possible in mice in which the inheritable genetic manipulation of germline cells were possible, but impossible in primates until now.

Using this method, further development of gene therapy targeted to a specific neural circuit can be expected.

Professor Tadashi ISA says “this newly developed double viral vector transfection technique can be applied to the gene therapy of the human central nervous system, as we are the same higher primates.

And this is the discovery which reverses the general idea that the spinal cord is only a reflex pathway, but also plays a pivotal role in integrating the complex neural signals which enable dexterous movements.”

Provided by National Institute for Physiological Sciences

Source: medicalxpress.com

ScienceDaily (June 16, 2012) — A link between unconscious conflicts and conscious anxiety disorder symptoms have been shown, lending empirical support to psychoanalysis.

Data from the experiment showing that subliminal exposure to words related to a person’s unconscious conflict, followed by supraliminal exposure to words related to their anxiety symptoms, led to different alpha wave patterns compared with other scenarios. (Credit: Image courtesy of University of Michigan Health System)

An experiment that Sigmund Freud could never have imagined 100 years ago may help lend scientific support for one of his key theories, and help connect it with current neuroscience.

June 16 at the 101st Annual Meeting of the American Psychoanalytic Association, a University of Michigan professor who has spent decades applying scientific methods to the study of psychoanalysis will present new data supporting a causal link between the psychoanalytic concept known as unconscious conflict, and the conscious symptoms experienced by people with anxiety disorders such as phobias.

Howard Shevrin, Ph.D., emeritus professor of psychology in the U-M Medical School’s Department of Psychiatry, will present data from experiments performed in U-M’s Ormond and Hazel Hunt Laboratory.

The research involved 11 people with anxiety disorders who each received a series of psychoanalytically oriented diagnostic sessions conducted by a psychoanalyst.

From these interviews the psychoanalysts inferred what underlying unconscious conflict might be causing the person’s anxiety disorder. Words capturing the nature of the unconscious conflict were then selected from the interviews and used as stimuli in the laboratory. They also selected words related to each patient’s experience of anxiety disorder symptoms. Although these words differed from patient to patient, results showed that they functioned in the same way.

These verbal stimuli were presented subliminally at one thousandth of a second, and supraliminally at 30 milliseconds. A control category of stimuli was added that had no relationship to the unconscious conflict or anxiety symptom. While the stimuli were presented to the patients, scalp electrodes record the brain responses to them.

In a previous experiment Shevrin had demonstrated that time-frequency features, a type of brain activity, showed that patients grouped the unconscious conflict stimuli together only when they were presented subliminally. But the conscious symptom-related stimuli showed the reverse pattern — brain activity was better grouped together when patients viewed those words supraliminally.

"Only when the unconscious conflict words were presented unconsciously could the brain see them as connected," Shevrin notes. "What the analysts put together from the interview session made sense to the brain only unconsciously."

However, the experimental design in this first experiment did not allow for directly comparing the effect of the unconscious conflict stimuli on the conscious symptom stimuli.

To obtain evidence for that next level, the unconscious conflict stimuli were presented immediately prior to the conscious symptom stimuli and a new measurement was made, of the brain’s own alpha wave frequency, at 8-13 cycles per second, that had been shown to inhibit various cognitive functions.

Highly significant correlations, suggesting an inhibitory effect, were obtained when the amount of alpha generated by the unconscious conflict stimuli were correlated with the amount of alpha associated with the conscious symptom alpha — but only when the unconscious conflict stimuli were presented subliminally. No results were obtained when control stimuli replaced the symptom words. The fact that these findings are a function of inhibition suggests that from a psychoanalytic standpoint that repression might be involved.

"These results create a compelling case that unconscious conflicts cause or contribute to the anxiety symptoms the patient is experiencing," says Shevrin, who also holds an emeritus position in the Department of Psychology in U-M’s College of Literature, Science and the Arts. "These findings and the interdisciplinary methods used — which draw on psychoanalysis, cognitive psychology, and neuroscience — demonstrate that it is possible to develop an interdisciplinary science drawing upon psychoanalytic theory."

He notes that a prominent critic of psychoanalysis and Freudian theory, Adolf Grunbaum, Ph.D., professor of the philosophy of science at the University of Pittsburgh, has expressed satisfaction that the new results, when added to previous evidence, show that fundamental psychoanalytic concepts can indeed be tested in empirical ways.

For more than 40 years, Shevrin has led a team that has pushed at the boundaries between the disciplines of neuroscience, cognitive psychology, and psychoanalysis, looking for evidence that Freudian concepts such as the unconscious and repression could be documented through physical measures of brain activity. His work has explored the territory where neurobiology, thoughts, emotions and behavior meet.

In 1968 he published the first report of brain responses to unconscious visual stimuli in Science, thus providing strong objective evidence for the existence of the unconscious at a time when most scientists were skeptical of Freud’s ideas. In that same study, he showed that unconscious perceptions are processed in different ways from conscious perceptions, a finding consistent with Freud’s views on how the unconscious works.

In recent years, exchanges between Grunbaum and Shevrin explored the nature of the evidence for the existence and impact of unconscious conflicts. In a 1992 publication, the first study referred to, Grunbaum agreed that Shevrin had obtained objective brain based evidence for the existence of unconscious conflict, but Grunbaum noted that he had not shown that these conflicts caused psychiatric symptoms. His response to being informed of the new findings was an email stating: “I am satisfied.”

Source: Science Daily

Adrian Owen has found a way to use brain scans to communicate with people previously written off as unreachable. Now, he is fighting to take his methods to the clinic.

Adrian Owen still gets animated when he talks about patient 23. The patient was only 24 years old when his life was devastated by a car accident. Alive but unresponsive, he had been languishing in what neurologists refer to as a vegetative state for five years, when Owen, a neuro-scientist then at the University of Cambridge, UK, and his colleagues at the University of Liège in Belgium, put him into a functional magnetic resonance imaging (fMRI) machine and started asking him questions.

Incredibly, he provided answers. A change in blood flow to certain parts of the man’s injured brain convinced Owen that patient 23 was conscious and able to communicate. It was the first time that anyone had exchanged information with someone in a vegetative state.

Patients in these states have emerged from a coma and seem awake. Some parts of their brains function, and they may be able to grind their teeth, grimace or make random eye movements. They also have sleep–wake cycles. But they show no awareness of their surroundings, and doctors have assumed that the parts of the brain needed for cognition, perception, memory and intention are fundamentally damaged. They are usually written off as lost.

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ScienceDaily (June 15, 2012) — People make complex judgements about a person from looking at their face that are based on a range of factors beyond simply their race and gender, according to findings of new research funded by the Economic and Social Research Council (ESRC).

The findings question a long-held belief that people immediately put a person they meet into a limited number of social categories such as: female or male; Asian, Black, Latino or White; and young or old.

Dr Kimberly Quinn at the University of Birmingham found that people ‘see’ faces in a multiple of ways. This could have wider importance in understanding stereotyping and discrimination because it has implications on whether and how people categorise others.

Categorisation is not done purely on the physical features of the face in front of us, but depends on other information as well, including whether the person is already known and whether the person is believed to share other important identities with us.

"How we perceive faces is not just a reflection of what’s in those faces," Dr Quinn said. "We are not objective; we bring our current goals and past knowledge to every new encounter. And this happens really quickly — within a couple of hundred milliseconds of seeing the face."

Dr Quinn and her colleagues explored social categories such as sex, race and age; physical attributes such as attractiveness; personality traits such as trustworthiness; and emotional states such as anger, sadness and happiness.

She found that although social categories are used to gather information on faces, these can be easily undermined. This research found that we reject simple stereotypes when something about the situation alerts us to the fact the stereotype does not tell the whole story. If we take, for example, a racial group and the corresponding stereotype of members of that group as unintelligent, seeing a person in that group playing an intellectual game such as chess would tell us to cancel out the stereotype.

In order to investigate the causes, mechanisms, and results of social categorisation, Dr Quinn used techniques from cognitive psychology and neuroscience to investigate how people process faces. The research was designed to provide insight into when and why people categorise others according to social group membership.

Their findings differ from previous research that adopted a ‘dual process’ approach and assumed people initially categorised faces based on factors such as gender, race or age before determining whether to stereotype them or to see them as unique individuals.

Dr Quinn’s findings were more consistent with a single process that initially focuses on ‘coarse’ information that is easy to detect, and then immediately starts to include more fine-grained processing as time elapses. This model allows for either categorisation or more individuated processing to emerge, and does not assume that categorisation always comes before recognising unique identities — thereby allowing for more diverse outcomes than previously thought.

Further information: http://www.esrc.ac.uk/my-esrc/grants/RES-061-23-0130/read

Source: Science Daily

ScienceDaily (June 15, 2012) — Researchers at The University of Nottingham have identified three sets of genetic markers that could potentially pave the way for new diagnostic tools for a deadly type of brain tumour that mainly targets children.

The study, published in the latest edition of the journal Lancet Oncology, was led by Professor Richard Grundy at the University’s Children’s Brain Tumour Research Centre and Dr Suzanne Miller, a post doctoral research fellow in the Centre.

It focuses on a rare and aggressive cancer called Central Nervous System primitive neuro-ectodermal brain tumours. Patients with CNS PNET have a very poor prognosis and current treatments, including high dose chemotherapy and cranio-spinal radiotherapy are relatively unsuccessful and have severe lifelong side-effects. This is particularly the case in very young children.

Despite the need for new and more effective treatments, little research has been done to examine the underlying causes of CNS PNET, partly due to their rarity. The Nottingham study aimed to identify molecular markers as a first step to improving the treatments and therapies available to fight the cancer.

The Nottingham team collaborated with researchers at the Hospital for Sick Kids in Toronto, Canada, to perform an International study collecting 142 CNS PNET samples from 20 institutions in nine countries.

Professor Richard Grundy said: “Following our earlier research we realised that an international effort was needed to bring sufficient numbers of cases together to make the breakthrough we needed to better understand this disease or indeed diseases identified in our study. The next step is to translate this knowledge into improving treatments.”

By studying the genetics of the tumours, they discovered that instead of one cancer, the tumours have three sub-types featuring distinct genetic abnormalities and leading to different outcomes for patients.

They found that each group had its own genetic signature through subtle differences in the way they expressed two genetic markers, LIN28 and OLIG2.

When compared with clinical factors including age, survival and metastases (the spread of the tumours through the body), they discovered that group 1 tumours (primitive neural) were found most often in the youngest patients and had the poorest survival rates. Patients with group 3 tumours had the highest incidence of metastases at diagnosis.

Ultimately, the research has identified the two genetic markers LIN28 and OLIG2 as a promising basis for more effective tools for diagnosing and predicting outcomes for young patients with these types of brain tumours.

The research was funded by the Canadian Institute of Health Research, the Brainchild/Sick Kids Foundation and the Samantha Dickson Brain Tumour Trust.

Chief Executive of Samantha Dickson Brain Tumour Trust, Sarah Lindsell, said: “As the UK’s leading brain tumour charity, and the largest dedicated funder of brain tumour research, we are delighted that our investment has led to such significant success. It is great to see that understanding of these tumours is improving — this is desperately needed given the poor outcomes for children with this tumour. Samantha Dickson Brain Tumour Trust is proud to have been instrumental in this work.”

Source: Science Daily

ScienceDaily (June 15, 2012) — A study recently published in the Endocrine Society’s Journal of Clinical Endocrinology and Metabolism (JCEM) suggests that vitamin D — when taken with calcium — can reduce the rate of mortality in seniors, therefore providing a possible means of increasing life expectancy.

During the last decade, there has been increasing recognition of the potential health effects of vitamin D. It is well known that calcium with vitamin D supplements reduces the risk of fractures. The present study assessed mortality among patients randomized to either vitamin D alone or vitamin D with calcium. The findings from the study found that the reduced mortality was not due to a lower number of fractures, but represents a beneficial effect beyond the reduced fracture risk.

"This is the largest study ever performed on effects of calcium and vitamin D on mortality," said Lars Rejnmark, PhD, of Aarhus University Hospital in Denmark and lead author of the study. "Our results showed reduced mortality in elderly patients using vitamin D supplements in combination with calcium, but these results were not found in patients on vitamin D alone."

In this study, researchers used pooled data from eight randomized controlled trials with more than 1,000 participants each. The patient data set was composed of nearly 90 percent women, with a median age of 70 years. During the three-year study, death was reduced by 9 percent in those treated with vitamin D with calcium.

"Some studies have suggested calcium (with or without vitamin D) supplements can have adverse effects on cardiovascular health," said Rejnmark. "Although our study does not rule out such effects, we found that calcium with vitamin D supplementation to elderly participants is overall not harmful to survival, and may have beneficial effects on general health."

Source: Science Daily

ScienceDaily (June 15, 2012) — Exposure to low doses of Bisphenol A (BPA) during gestation had immediate and long-lasting, trans-generational effects on the brain and social behaviors in mice, according to a recent study accepted for publication in the journal Endocrinology, a publication of The Endocrine Society.

BPA is a human-made chemical present in a variety of products including food containers, receipt paper and dental sealants and is now widely detected in human urine and blood. Public health concerns have been fueled by findings that BPA exposure can influence brain development. In mice, prenatal exposure to BPA is associated with increased anxiety, aggression and cognitive impairments.

"We have demonstrated for the first time to our knowledge that BPA has trans-generational actions on social behavior and neural expression," said Emilie Rissman, PhD, of the University of Virginia School of Medicine and lead author of the study. "Since exposure to BPA changes social interactions in mice at a dose within the reported human levels, it is possible that this compound has trans-generational actions on human behavior. If we banned BPA tomorrow, pulled all products with BPA in them, and cleaned up all landfills tomorrow it is possible, if the mice data generalize to humans, that we will still have effects of this compound for many generations."

In this study, female mice received chow with or without BPA before mating and throughout gestation. Plasma levels of BPA in supplemented female mice were in a range similar to those measured in humans. Juveniles in the first generation exposed to BPA in utero displayed fewer social interactions as compared with control mice. The changes in genes were most dramatic in the first generation (the offspring of the mice that were exposed to BPA in utero), but some of these gene changes persisted into the fourth generation.

"BPA is a ubiquitous chemical, it is in the air, water, our food, and our bodies," said Rissman. "It is a man-made chemical, and is not naturally occurring in any plant or animal. The fact that it can change gene expression in mice, and that these changes are heritable, is cause for us to be concerned about what this may mean for human health."

Source: Science Daily

June 15, 2012

The research led by Newcastle University’s Dr Mark Cunningham and Professor Miles Whittington and supported by the Dr Hadwen Trust for Humane Research, indicates a novel electrical bio-marker in humans.

The brain produces electrical rhythms and using EEG - electrodes on the scalp - researchers were able to monitor the brain patterns in patients with epilepsy. Both in patients and in brain tissue samples the team were able to witness an abnormal brain wave noticeable due to its rapidly increasing frequency over time.

Comparing these to a musical ‘glissando’, an upwards glide from one pitch to another, the team found that this brain rhythm is unique to humans and they believe it could be related to epilepsy.

Dr Cunningham, senior lecturer in Neuronal Dynamics at Newcastle University said: “We were able to examine EEG collected from patients with drug resistant epilepsy who were continually monitored over a two week period. During that time we noticed patterns of electrical activity with rapidly increasing frequency, just like glissandi, emerging in the lead-up to an epileptic seizure.”

"We are in the early days of the work and we want to investigate this in a larger group of patients but it may offer a promising insight into when a seizure is going to start."

Professor Whittington added: “Classical composers such as Gustav Mahler are famous for using notes of rapidly increasing pitch – called glissando - to convey intense expressions of anticipation. Similarly we identified glissando-like patterns of brain electrical activity generated in anticipation of seizures in patients with epilepsy.”

The team recorded electrical activity taken from patients in Newcastle and Glasgow with the help of collaborators Dr Roderick Duncan and Dr Aline Russell and worked in collaboration with the Epilepsy Surgery Group at Newcastle General Hospital part of the Newcastle Hospitals NHS Foundation Trust.

Having received permission from patients to use brain tissue removed during an operation to cure their seizures, the team were able to observe and study in great detail glissando discharges in slices of this human epileptic tissue maintained in the lab.

Publishing in Epilepsia online, the team discovered that glissandi are highly indicative of pathology associated with human epilepsy and, unlike other forms of epileptic activity studied previously, are extremely difficult to reproduce in normal, non-epileptic brain tissue. The team worked with Professor Roger Traub at the IBM Watson Research Centre in New York to provide predictions using highly detailed computational models. By manipulating the chemical conditions surrounding human epileptic brain tissue according to these predictions, they discovered that glissandi did not require any of the conventional chemical connections between nerve cells thought to underlie most brain functions. Instead, glissandi were generated by a combination of large changes in the pH of the tissue, specific electrical properties of certain types of nerve cell and, most importantly, direct electrical connections between these nerve cells.

"This work also suggests that given the lengths one has to go to reproduce this experimentally in rodents that the glissandi may be a unique feature of the human epileptic brain," explains Dr Cunningham.

Dr Kailah Eglington, Chief Executive of the Dr Hadwen Trust, said: “Of all human brain disorders, epilepsy research ranks as one that currently employs substantial numbers of laboratory animals worldwide.

"Dr Cunningham’s work at Newcastle University aims to address the shortcomings of existing animal-based research by removing animals from the equation and addressing the issue directly in humans."

Provided by Newcastle University

Source: medicalxpress.com

June 15, 2012

The first large non-commercial study to investigate whether the main active constituent of cannabis (tetrahydrocannabinol or THC) is effective in slowing the course of progressive multiple sclerosis (MS) shows that there is no evidence to suggest this; although benefits were noted for those at the lower end of the disability scale.

The CUPID (Cannabinoid Use in Progressive Inflammatory brain Disease) study was carried out by researchers from the Peninsula College of Medicine and Dentistry (PCMD), Plymouth University. The study was funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership, the Multiple Sclerosis Society and the Multiple Sclerosis Trust.

The preliminary results of CUPID are to be presented by lead researcher Professor John Zajicek at the Association of British Neurologists’ Annual Meeting in Brighton on Tuesday 29th May.

CUPID enrolled nearly 500 people with MS from 27 centres around the UK, and has taken eight years to complete. People with progressive MS were randomised to receive either THC capsules or identical placebo capsules for three years, and were carefully followed to see how their MS changed over this period. The two main outcomes of the trial were a disability scale administered by neurologists (the Expanded Disability Status Scale), and a patient report scale of the impact of MS on people with the condition (the Multiple Sclerosis Impact Scale 29).

Overall the study found no evidence to support an effect of THC on MS progression in either of the main outcomes. However, there was some evidence to suggest a beneficial effect in participants who were at the lower end of the disability scale at the time of enrolment but, as the benefit was only found in a small group of people rather than the whole population, further studies will be needed to assess the robustness of this finding. One of the other findings of the trial was that MS in the study population as a whole progressed slowly, more slowly than expected. This makes it more challenging to find a treatment effect when the aim of the treatment is that of slow progression.

As well as evaluating the potential neuroprotective effects and safety of THC over the long-term, one of the aims of the CUPID study was to improve the way that clinical trial research is done by exploring newer methods of measuring MS and using the latest statistical methods to make the most of every piece of information collected. This analysis will continue for several months. The CUPID study will therefore provide important information about conducting further large scale clinical trials in MS.

Professor John Zajicek, Professor of Clinical Neuroscience at PCMD, Plymouth University, said: “To put this study into context: current treatments for MS are limited, either being targeted at the immune system in the early stages of the disease or aimed at easing specific symptoms such as muscle spasms, fatigue or bladder problems. At present there is no treatment available to slow MS when it becomes progressive. Progression of MS is thought to be due to death of nerve cells, and researchers around the world are desperately searching for treatments that may be ‘neuroprotective’. Laboratory experiments have suggested that certain cannabis derivatives may be neuroprotective.”

He added: “Overall our research has not supported laboratory based findings and shown that, although there is a suggestion of benefit to those at the lower end of the disability scale when they joined CUPID, there is little evidence to suggest that THC has a long term impact on the slowing of progressive MS.”

Dr Doug Brown, Head of Biomedical Research at the MS Society, said: “There are currently no treatments for people with progressive MS to slow or stop the worsening of disability. The MS Society is committed to supporting research in this area and this was an important study for us to fund. While this study sadly suggests THC is ineffective at slowing the course of progressive MS, we will not stop our search for effective treatments. We are encouraged by the possibility shown by this study that THC may have potential benefits for some people with MS and we welcome further investigation in this area.”

Provided by The Peninsula College of Medicine and Dentistry

Source: medicalxpress.com

June 15, 2012 By Angela Herring

Object manip­u­la­tion or tool use is almost a uniquely human trait, said Dagmar Sternad, director of Northeastern’s Action Lab, a research group inter­ested in move­ment coor­di­na­tion. “Not only does it require cer­tain cog­ni­tive abil­i­ties but also dis­tinct motor abilities.”

Professor Dagmar Sternad and postdoctoral researcher C.J. Hasson show that we subconsciously adjust our “safety margin” when we move a dynamic object like a cup of coffee based on the amount of variability in the situation. Credit: John Guillemin

Simply moving one’s own body, for instance by directing a hand toward a coffee cup, requires the orga­ni­za­tion of var­ious phys­i­o­log­ical sys­tems including the cen­tral and periph­eral ner­vous sys­tems and the mus­cu­loskeletal system.

Once the hand grasps and picks up the cup, the ques­tions become even more com­pli­cated. What if the cup is filled with liquid? At this point, the com­plexity of the con­trol problem bal­loons — the pres­ence of the liquid intro­duces non­linear fluid dynamics with the risk of a spill because of the inherent vari­ability in one’s movement.

Sternad, a pro­fessor of , biology, elec­trical and com­puter engi­neering and physics and post­doc­toral researcher C.J. Hasson are inter­ested in how we adapt our move­ment strate­gies when inter­acting with dynamic objects in the environment.

In a recent paper pub­lished in the Journal of Neu­ro­phys­i­ology, Hasson and Sternad explored the ques­tion by looking at the everyday task of manip­u­lating a cup of coffee. They show that how we adapt our move­ment strate­gies is directly related to the amount of vari­ability and reli­a­bility in our sur­round­ings and ourselves.

“Because we’re humans and not machines, we’re noisy and vari­able,” said Hasson. “We can’t expect that a move­ment will unfold exactly as we planned it.”

For the study, 18 healthy par­tic­i­pants vis­ited the Action Lab to play a video game, wherein they attempted to move a vir­tual cup filled with vir­tual liquid across a large video screen. Instead of a normal video-game con­troller, sub­jects moved the vir­tual cup by grasping a manip­u­landum — a large robotic arm. Sim­ilar to the real-life sce­nario, the robot sim­u­lated the forces one would feel from the weight of the object and the sloshing of the liquid in the cup.

They asked par­tic­i­pants to move the cup across the screen within a com­fort­able time of two sec­onds, a task for which there is an infi­nite number of pos­si­bil­i­ties. You could move fast for one second and slow for one second, slow for a half second and then fast for one and a half sec­onds. The team hypoth­e­sized that par­tic­i­pants would nat­u­rally adapt a safe move­ment strategy with prac­tice — and they did.

But the most intriguing result, said Hasson, was that the size of each participant’s safety margin —or how close they let the liquid get to the edge of the cup — could be pre­dicted by how vari­able they were in their move­ments. Those with more vari­ability tended to adapt a “safer” strategy with a larger safety margin.

“If you have a large safety margin and I move with a small margin, the ques­tion is, ‘Why am I more risky than you?’” Hasson said. “Well, you may find that I am much more con­sis­tent in my move­ments, so I don’t need a big safety margin. If you’re more vari­able, you need a larger safety margin.”

The results have impli­ca­tions in assessing elderly patients and patients of motor dis­or­ders such as cere­bral palsy. “If vari­ability deter­mines the move­ments that you do, maybe that’s an inter­ven­tion point,” said Sternad.

Provided by Northeastern University

Source: medicalxpress.com

June 15, 2012

Researchers from the Peninsula College of Medicine and Dentistry, University of Exeter, in collaboration with colleagues from Rutgers University, Newark and University College London, have furthered understanding of the mechanism by which the cells that insulate the nerve cells in the peripheral nervous system, Schwann cells, protect and repair damage caused by trauma and disease.

The findings of the study, published on-line by the Journal of Neuroscience and supported by the Wellcome Trust, are exciting in that they point to future therapies for the repair and improvement of damage to the peripheral nervous system.

The peripheral nervous system is the part of the nervous system outside the brain and the spinal cord. It regulates almost every aspect of our bodily function, carrying sensory information that allows us to feel the sun on our face and motor information, that allows us to move. It also controls the functions of all the organs of the body.

Damage can occur through trauma: it can occur in diabetic neuropathy (suffered by almost half of those with diabetes) and patients with common inherited conditions such as Charcot-Marie-Tooth (CMT) disease. There can be a wide range of symptoms, from loss of sensation in the hands and feet to problems with digestion, blood pressure regulation, sexual function and bladder control.

Schwann cells provide the insulation, or myelin sheath, for the nerve cells that carry electrical impulses to and from the spinal cord. Schwann cells, because of their plasticity, are able to revert back to an immature ‘repair’ cell to repair damage to the peripheral nervous system. The level of repair is remarkably good but incomplete repair, perhaps after the severance of a nerve, may lead to long-term loss of function and pain.

The ability of Schwann cells to demyelinate can make them susceptible to the disease process seen in conditions such as CMT. CMT affects one in 2500people, so is a comparatively common inherited disease of the nervous system. Mutations in the many different genes in CMT can cause cycles of repair and re-insulation (re-myelination) which lead to long-term damage and the death of both Schwann and nerve cells. There is currently no therapy for CMT and patients experience increased sensory and motor problems which may lead to permanent disability.

The research team believes that its work to understand the ability of Schwann cells to revert back to an immature state and stimulate repair will lead to therapies to improve damage from severe trauma and break the cycle of damage caused by CMT. They also believe that there may also be potential to improve repair in cases of diabetic neuropathy.

They have identified a DNA binding protein, cJun, as a key player in the plasticity that allows a Schwann cell to revert back to the active repair state. cJun may be activated by a number of pathways that convey signals from the surface of the Schwann cell to the nucleus. One such pathway, the p38 Mitogen Activated Protein Kinase Pathway, appears to play a vital role: it is activated after PNS damage and may promote the process of repair; conversely it may be abnormally activated in demyelinating diseases such as CMT.

Professor David Parkinson, Associate Professor in Neuroscience, Peninsula College of Medicine and Dentistry, University of Exeter, said: “The findings of our research are exciting because we have pinpointed and are understanding the mechanism by which our bodies can repair damage to the peripheral nervous system. With further investigation, this could well lead to therapies to repair nerve damage from trauma and mitigate the damage which relates to common illnesses, such as CMT.”

Provided by The Peninsula College of Medicine and Dentistry

Source: medicalxpress.com

June 15, 2012

Whether or not a neuron transmits an electrical impulse is a function of many factors. European research is using a heady mixture of techniques – molecular, microscopy and electrophysiological – to identify the necessary input for nerve transmission in the cortex.

Credit: Thinkstock

In the central nervous system (CNS), a nerve cell or neuron has a ‘forest’ of elaborate dendritic trees arising from the cell body. These literally receive many thousands of synapses (junctions that allow transmission of a signal) at positions around the tree. These inputs then are able to generate an impulse, or ‘spike’, known as an action potential at the initial part of the axon.

Previous research has confirmed that an activated synapse will generate an electric signal as a result of neurotransmitters released from pre-synaptic axons. Electrical recordings from the neocortex have confirmed that, in line with the cable theory prediction, that modulation of potential at the dendrite is highly distance-dependent from the cell body or soma.

The ‘Information processing in distal dendrites of neocortical layer 5 pyramidal neurons’ (Channelrhodopsin) project aimed to shed more light on how more distal sites in the ‘tree’ influence the action potential of the post-synaptic neuron. Furthermore, they investigated exactly how dendritic spikes can be generated, another issue about which there is little information so far.

Recent research has highlighted the importance of activation of N-methyl-D-aspartate (NMDA) receptors to bring about the production of a signal that will proceed to the soma and then result in a spike. There is also indirect evidence that interneurons targeting dendrites can control level of dendrite excitability.

Channelrhodopsin scientists simultaneously recorded the pre- and post-synaptic electrical recordings of identified interneurons and a special type of neuron, pyramidal cells that are primary excitation units in the mammalian cortex.

The project team first characterised the different types of inhibitory neuron deep in the cortex in layer 5 at apical tuft dendrites. The researchers then showed that a special type of inhibitory interneuron in the outer layer of the neocortex can suppress dendritic spiking in layer 5.

Project results show that a superficial inhibitory neuron can impact information processing in a specific pyramidal neuron. The research will have massive implications for neuroscience and help to unravel the integrative operations of CNS neurons.

Provided by CORDIS

Source: medicalxpress.com

ScienceDaily (June 14, 2012) — Rockville, Md. — Scientists have found new evidence that people spot a face in the crowd more quickly when teeth are visible — whether smiling or grimacing — than a face with a particular facial expression. The new findings, published in the Journal of Vision, counters the long held “face-in -the-crowd” effect that suggests only angry looking faces are detected more readily in a crowd.

Examples of stimuli — closed mouth and open mouth with visible teeth — presented in the experiment. (Credit: ARVO)

"The research concerned with the face-in-the-crowd effect essentially deals with the question of how we detect social signals of friendly or unfriendly intent in the human face," said author Gernot Horstmann, PhD, of the Center for Interdisciplinary Research and Department of Psychology at Bielefeld University, Germany. "Our results indicate that, contrary to previous assertions, detection of smiles or frowns is relatively slow in crowds of neutral faces, whereas toothy grins and snarls are quite easily detected."

In two studies, the researchers asked subjects to search for a happy or an angry face within a crowd of neutral faces, and measured the search speed. While the search was relatively slow when emotion was signaled with a closed mouth face, the speed search doubled when emotion was signaled with an open mouth and visible teeth. This was the case for both happy and angry faces, and happy faces were found even somewhat faster than angry faces.

Horstmann and his colleagues conducted these experiments as a result of discrepancies in previous studies that investigated visual search for emotional faces. According to the research team, the inconsistent results with respect to which of the two expressions are found faster — the happy face or the angry face — suggested that the emotional expression category could not be the only important factor determining the face-in- the-crowd effect.

The scientists believe this new study may explain the discrepancies. “This will probably inspire researchers to clarify whether emotion and, in particular, threat plays an additional, unique role in face detection,” said Horstmann.

Source: Science Daily

ScienceDaily (June 14, 2012) — An international team of researchers’ study of the spatial patterns of the spread of obesity suggests America’s bulging waistlines may have more to do with collective behavior than genetics or individual choices. The team, led by City College of New York physicist Hernán Makse, found correlations between the epidemic’s geography and food marketing and distribution patterns.

Supermarket. Physicists found correlations between the obesity epidemic’s geography and food marketing and distribution patterns. (Credit: © flashpics / Fotolia)

"We found there is a relationship between the prevalence of obesity and the growth of the supermarket economy," Professor Makse said. "While we can’t claim causality because we don’t know whether obesity is driven by market forces or vice versa, the obesity epidemic can’t be solved by focus on individual behavior."

The teams findings, published online this week in Scientific Reports, come as a policymakers are starting to address the role of environmental factors in obesity. For example, in New York Mayor Michael Bloomberg wants to limit serving sizes of soda sweetened with sugar to 16 ounces as a way to combat obesity.

The World Health Organization considers obesity a global epidemic similar to cancer or diabetes. It is a non-communicable disease for which no prevention strategy has been able to contain the spread.

Because obesity is related to increased calorie intake and physical inactivity, prevention has focused on changing individuals’ behaviors. However, prevalence of non-communicable diseases shows spatial clustering, and the spread of obesity has shown “high susceptibility to social pressure and global economic drivers.”

Professor Makse and his colleagues hypothesized that these earlier findings suggest collective behavior plays a more significant role in the spread of the epidemic than individual factors such as genetics and lifestyle choices. To study collective behavior’s role, they implemented a statistical clustering analysis based on the physics on the critical phenomena.

Using county-level microdata provided by the U.S. Centers for Disease Control Behavior Risk Factor Surveillance Systems for 2004 through 2008, they investigated spatial correlations for specific years. Over that time span, the pattern of the spreading of the epidemic, which has Greene County, Ala., as its epicenter, has shown that two clusters spanning distances of 1,000 kilometers have emerged; one along the Appalachian Mountains, the second in the lower Mississippi River valley.

The spatial map of obesity prevalence in the United States shows that neighboring areas tend to have similar percentages of their populations considered obese, i.e. have a body mass index greater than or equal to 30. Such areas are considered obesity clusters, and their spread can be seen in the maps from 2004 to 2008.

To assess the properties of these spatial arrangements, the researchers calculated an equal-time, two-point correlation function that measured the influence of a set of characteristics in one county on another county at a given distance. The characteristics studied were population density, prevalence of adult obesity and diabetes, cancer mortality rates and economic activity.

The researchers said the form of the correlations in obesity were reminiscent of those in physical systems at a critical point of second-order phase transition. Such systems are uncorrelated and characterized by short-range vanishing fluctuations when they are not at a critical stage.

However, at critical points long-range correlations appear, and these may signal the emergence of strong critical fluctuations in the spreading of obesity and diabetes. Consequently, they concluded the clustering patterns found in obesity were the result of “collective behavior, which may not merely be the consequence of fluctuations in individual habits.”

Professor Makse and his colleagues believe the correlations of fluctuations in the prevalence of obesity may be linked to demographic and economic variables. To test this hypothesis, they compared the spatial characteristics of industries associated with food production and sales, e.g. supermarkets, food and beverage stores, restaurants and bars, to other sectors of the economy.

Their analysis of spatial fluctuations in food economic activity gave rise to the same anomalous values as obesity and diabetes. Areas with above-average concentrations of food-related businesses had high-than-normal prevalence of obesity and diabetes.

In future studies, Professor Makse plans to apply physics concepts to measure the spread of cancer and diabetes. “The basic idea is that if a non-communicable disease is spreading like a virus, then environmental factors have to be at work,” he said. “If only genetics determined obesity, we wouldn’t have seen the correlations.”

Source: Science Daily

ScienceDaily (June 14, 2012) — The first U.S. population prevalence study of mutations in the gene that causes fragile X syndrome, the most common inherited form of intellectual disability, suggests the mutation in the gene — and its associated health risks — may be more common than previously believed.

Writing this month (June 2012) in the American Journal of Medical Genetics, a team of Wisconsin researchers reports that the cascade of genetic amino acid repeats, which accumulate over generations and culminate in the mutation of a single gene causing fragile X, is occurring with more frequency among Americans than previously believed. The study also shows that as the genetic basis for the condition is passed from generation to generation and amplified, risks to neurological and reproductive health emerge in many carriers.

"The premutation of this condition is much more prevalent than we previously thought and there are some clinical risks associated with that," explains Marsha Mailick Seltzer, director of the University of Wisconsin-Madison Waisman Center, who led the new study.

Fragile X is caused by the unexplained runaway expansion of a set of amino acid repeats in a single X chromosome gene known as FMR1. When fully mutated, the gene fails to express and produce a protein that’s required for healthy brain development. The syndrome, which is more common in boys, results in a spectrum of intellectual disability.

However, before the gene fully mutates, carriers of the faulty gene exhibit a smaller number of elevated repeats, which expand as the gene is passed from generation to generation. Normal FMR1 genes exhibit anywhere from five to 40 repeats. Carriers with a premutation may have anywhere from 55 to 200. Those with between 45 and 54 repeats are characterized as falling into a “gray zone.” Carriers of gray zone expansions often pass the mutation on to their children who themselves are at greater risk of having the premutation, and in subsequent generations the risk of a full mutation causing fragile X syndrome is high.

The goal of the new study was to calculate the prevalence in a U.S. population of the premutation and the gray zone. The research was based on data from the Wisconsin Longitudinal Study (WLS), also known as the “Happy Days study,” which for more than 50 years has tracked the careers, family life, health and education of more than 10,000 graduates of Wisconsin’s high school class of 1957.

Using genetic samples from 6,747 WLS participants, the team led by Seltzer, an expert on developmental disability and family life, found that 1 in 151 females and 1 in 468 males carry the fragile X premutation while 1 in 35 females and 1 of every 42 males fall into the gray zone.

"The prevalence is high, the second highest reported in the world literature," says Seltzer, noting that the incidence of fragile X varies by population and is higher in some places such as Israel, and lower in others like Asia.

The expansion of the FMR1 gene is known to vary across ethnic groups. The sample in the WLS study is primarily white and of northern European descent.

People with the premutation are more likely to have a child with disability; to have neurological symptoms such as numbness, dizziness and faintness; and, for women, to experience early menopause. Although these symptoms have been recognized previously in clinical studies, the WLS data represent an unbiased sample and supports those observations.

"This study confirms that there are health risks associated with the premutation," says Seltzer. "People with the premutation have a higher probability of neurological and reproductive problems. There is a significant public health burden."

Source: Science Daily

ScienceDaily (June 14, 2012) — No effective treatments are currently available for the prevention or cure of Alzheimer’s disease (AD), the most frequent form of dementia in the elderly. The most recognized risk factors, advancing age and having the apolipoprotein E Ɛ4 gene, cannot be modified or treated. Increasingly, scientists are looking toward other risk factors to identify preventive and therapeutic strategies. Much attention recently has focused on the metabolic syndrome (MetS), with a strong and growing body of research suggesting that metabolic disorders and obesity may play a role in the development of dementia.

A new supplement to the Journal of Alzheimer’s Disease provides a state-of-the-art assessment of research into the link between metabolic syndrome and cognitive disorders. The supplement is guest edited by Vincenza Frisardi, of the Department of Neurological and Psychiatric Sciences, University of Bari, and the Geriatric Unit and Gerontology-Geriatrics Research Laboratory, IRCCS, Foggia, Italy, and Bruno P. Imbimbo, Research and Development Department, Chiesi Farmaceutici, Parma, Italy.

The prevalence of MetS and obesity has increased over the past several decades. MetS is a cluster of vascular and metabolic risk factors including obesity, hypertension, an abnormal cholesterol profile, and impaired blood glucose regulation. “Although molecular mechanisms underlying the relationship between MetS and neurological disorders are not fully understood, it is becoming increasingly clear that cellular and biochemical alterations observed in MetS may represent a pathological bridge between MetS and various neurological disorders,” explains Dr. Frisardi.

Type 2 diabetes (T2D) has been linked with cognitive impairment in a number of studies. The risk for developing both T2D and AD increases proportionately with age, and evidence shows that individuals with T2D have a nearly twofold higher risk of AD than nondiabetic individuals.

Paula I. Moreira, Faculty of Medicine and Center for Neuroscience and Cell Biology, University of Coimbra, Portugal, outlines some of the likely mechanisms. Both AD and T2D present similar abnormalities in the mitochondria, which play a pivotal role in cellular processes that impair their ability to regulate oxidation in the cell. Human amylin, a peptide that forms deposits in the pancreatic cells of T2D patients, shares several properties with amyloid-ß plaques in the Alzheimer’s brain. Insulin resistance is another feature shared by both disorders. Impairment of insulin signalling is directly involved in the development of tau tangles and amyloid ß (Aß) plaques. “Understanding the key mechanisms underlying this deleterious interaction may provide opportunities for the design of effective therapeutic strategies,” Dr. Moreira notes.

In another article, author, José A. Luchsinger of the Division of General Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, notes that while there seems to be little dispute that T2D can cause cerebrovascular disease and vascular cognitive impairment, whether T2D can cause late onset AD remains to be determined. “Although the idea is highly speculative, the association between T2D and cognitive impairment may not be causal. Several lines of evidence provide some support to the idea that late onset Alzheimer’s disease could cause T2D, or that both could share causal pathways,” he notes. He reviews epidemiological, imaging, and pathological studies and clinical trials to provide insight. “Given the epidemic of T2D in the world, it’s important to determine whether the association between T2D and cognitive impairment, particularly late onset AD, is causal and if so, what are the mechanisms underlying it.”

Dr. Frisardi notes that most efforts by the pharmaceutical industry have been directed against the production and accumulation of amyloid-ß. “Unfortunately, these efforts have not produced effective therapies yet, since the exact mechanisms of AD are largely unknown. Given that the onset of AD most likely results from the interaction of genetic and environmental factors, the research agenda should consider new platforms of study, going beyond the monolithic outlook of AD, by synthesizing epidemiological, experimental, and biological data under a unique pathophysiological model as a point of reference for further advances in the field.”

Source: Science Daily

June 14, 2012

Visual and auditory stimuli that elicit high levels of engagement and emotional response can be linked to reliable patterns of brain activity, a team of researchers from The City College of New York and Columbia University reports. Their findings could lead to new ways for producers of films, television programs and commercials to predict what kinds of scenes their audiences will respond to.

"Peak correlations of neural activity across viewings can occur in remarkable correspondence with arousing moments of the film,” the researchers said in an article published in the journal Frontiers in Human Neuroscience. “Moreover, a significant reduction in neural correlation occurs upon a second viewing of the film or when the narrative is disrupted by presenting its scenes scrambled in time.”

The researchers used EEG (electroencephalography), which measures electrical activity across the scalp, to collect data on brainwaves of 20 human subjects, who were shown scenes from three films with repeat viewings. Two films, Alfred Hitchcock’s “Bang! You’re Dead” and Sergio Leone’s “The Good, the Bad and the Ugly,” contained moments of high drama expected to trigger responses. The third, an amateur film of people walking on a college campus, was used as a control.

"We found moments of high correlation (between brainwave activity during separate viewings) and moments when this did not occur," said Dr. Lucas C. Parra, Herbert G. Kayser Professor of Biomedical Engineering in CCNY’s Grove School of Engineering, and a corresponding author. "By looking at patterns of oscillation we could tell at which moments a person was particularly engaged. Additionally, we could see whether the correlation occurred across subjects and repeated viewings."

[Video: Reading the Brain during Film Viewing]
Video of EEG readings during scenes from “Bang, You’re Dead”

Measurements along the EEG alpha activity scale show the degree of attentiveness in a person, he explained. When the oscillations are strong, a person is relaxed, i.e. not engaged. When a person is very attentive, alpha activity is low.

Peaks in engagement were correlated to three kinds of scenes, said Dr. Jasek Dmochowski, a post-doctoral fellow in the Grove School and a corresponding author. They included moments with powerful visual cues, such as a close-up on the gun in “Bang! You’re Dead,” scenes with ominous music in which the visual component was not significant, and meaningful scene changes.

The researchers found significantly less neural correlation on participants’ second viewings and when scenes were scrambled and shown out of sequence. “Following a narrative is complex and involves a lot of distributed processing. When a person doesn’t have a sense of the narrative there is much less correlation (across views of the same or another subject),” Dr. Dmochowski said.

Having demonstrated the correlations between intense stimuli and brainwave reliability, the research team now wants to locate where in the brain the response occurs, Professor Parra said. He wants to deploy a combination of EEG and magnetic resonance imaging to “get the best of both worlds:” the fine temporal resolution of EEG and the detailed imagery of MRI.

The team sees several potential applications for the ability to quantify levels of engagement, including neuro-marketing, quantitative assessment of entertainment, measuring the impact of narrative discourse and the study of attention deficit disorders. “Advertisers would love to know where and when an ad is engaging,” he noted.

"The potential to measure engagement is huge since this provides an objective way to collect data," added Dr. Dmochowski, who currently is investigating whether there is a correlation between social media usage and brain activity in young people while watching “The Walking Dead,” a drama series on the American Movie Classics cable network.

"We are mining Twitter to measure the depth of watching," he continued. "We think there will be many correlations between scenes that elicit social media responses and neural signatures, and we can look at both positive and negative responses."

Provided by City College of New York

Source: medicalxpress.com

ScienceDaily (June 13, 2012) — Ever wonder why Jimi Hendrix’s rendition of “The Star-Spangled Banner” moved so many people in 1969 or why the music in the shower scene of “Psycho” still sends chills down your spine?

Jimi Hendrix (Credit: Public domain image, courtesy of UCLA)

A UCLA-based team of researchers has isolated some of the ways in which distorted and jarring music is so evocative, and they believe that the mechanisms are closely related to distress calls in animals.

They report their findings in the latest issue of the peer-reviewed scientific journal Biology Letters, which publishes online June 12.

"Music that shares aural characteristics with the vocalizations of distressed animals captures human attention and is uniquely arousing," said Daniel Blumstein, one of the study’s authors and chair of the UCLA Department of Ecology and Evolutionary Biology.

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ScienceDaily (June 13, 2012) — Children who are skilled in understanding how shapes fit together to make recognizable objects also have an advantage when it comes to learning the number line and solving math problems, research at the University of Chicago shows.

The work is further evidence of the value of providing young children with early opportunities in spatial learning, which contributes to their ability to mentally manipulate objects and understand spatial relationships, which are important in a wide range of tasks, including reading maps and graphs and understanding diagrams showing how to put things together. Those skills also have been shown to be important in Science Technology, Engineering and Math (STEM) fields.

Scholars at UChicago have shown, for instance, that working with puzzles and learning to identify shapes are connected to improved spatial understanding and better achievement, particularly in geometry. A new paper, however, is the first to connect robust spatial learning with better comprehension of other aspects of mathematics, such as arithmetic.

"We found that children’s spatial skills at the beginning of first and second grades predicted improvements in linear number line knowledge over the course of the school year," said Elizabeth Gunderson, a UChicago postdoctoral scholar who is lead author of the paper, "The Relation Between Spatial Skill and Early Number Knowledge: The Role of the Linear Number Line," published in the current issue of the journal Development Psychology.

In addition to finding the importance of spatial learning to improving understanding of the number line, the team also showed that better understanding of the number line boosted mathematics performance on a calculation task.

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ScienceDaily (June 13, 2012) — Wake up, America, and lose some weight — it’s keeping you tired and prone to accidents. Three studies being presented June 13 at sleep 2012 conclude that obesity and depression are the two main culprits making us excessively sleepy while awake.

Researchers at Penn State examined a random population sample of 1,741 adults and determined that obesity and emotional stress are the main causes of the current “epidemic” of sleepiness and fatigue plaguing the country. Insufficient sleep and obstructive sleep apnea also play a role; both have been linked to high blood pressure, heart disease, stroke, depression, diabetes, obesity and accidents.

"The ‘epidemic’ of sleepiness parallels an ‘epidemic’ of obesity and psychosocial stress," said Alexandros Vgontzas, MD, the principal investigator for the three studies. "Weight loss, depression and sleep disorders should be our priorities in terms of preventing the medical complications and public safety hazards associated with this excessive sleepiness."

In the Penn State cohort study, 222 adults reporting excessive daytime sleepiness (EDS) were followed up 7½ years later. For those whose EDS persisted, weight gain was the strongest predicting factor. “In fact, our results showed that in individuals who lost weight, excessive sleepiness improved,” Vgontzas said.

Adults from that same cohort who developed EDS within the 7½-year span also were studied. The results show for the first time that depression and obesity are the strongest risk factors for new-onset excessive sleepiness. The third study, of a group of 103 research volunteers, determined once again that depression and obesity were the best predictors for EDS.

"The primary finding connecting our three studies are that depression and obesity are the main risk factors for both new-onset and persistent excessive sleepiness," Vgontzas said.

In the Penn State cohort study, the rate of new-onset excessive sleepiness was 8 percent, and the rate of persistent daytime sleepiness was 38 percent. Like insufficient sleep and obstructive sleep apnea, EDS also is associated with significant health risks and on-the-job accidents.

Source: Science Daily

ScienceDaily (June 13, 2012) — Research into alcohol’s effect on juvenile rats shows they have an ability to build up a physical, but not cognitive, tolerance over the short term — a finding that could have implications for adolescent humans, according to Baylor University psychologists.

The research findings are significant because they indicate that blood alcohol concentration levels alone may not fully account for impaired orientation and navigation ability, said Jim Diaz-Granados, Ph.D., professor and chair of psychology and neuroscience at Baylor. He co-authored the study, published in the journal Brain Research.  “There’s been a lot of supposition about the reaction to blood alcohol levels,” Diaz-Granados said. “We use the blood alcohol level to decide if someone is going to get arrested, because we think that a high level means impairment. But here we see a model where we can separate that out. You may have a tolerance in metabolism, but just because your blood alcohol concentration is less than the legal limit doesn’t mean your behavior isn’t impaired.”

"More research is needed to fully understand how adolescents react to alcohol, but this contributes a piece to the puzzle," said study co-author Douglas Matthews, Ph.D., a research scientist at Baylor and an associate professor in Psychology at Nanyang Technological University in Singapore.

The study was conducted in the Baylor Addiction Research Center of Baylor’s Department of Psychology and Neuroscience in Baylor’s College of Arts & Sciences.

More than half of under-age alcohol use is due to binge drinking, according to the Substance Abuse and Mental Health Services Administration, and “when initial alcohol use occurs during adolescence, it increases the chance of developing alcoholism later in life,” said lead study author Candice E. Van Skike, a doctoral candidate in psychology at Baylor. Researchers have long been interested in whether adolescents react differently to alcohol than adults and how alcohol use affects their brains when they reach adulthood, but Baylor researchers also wanted to test the short-term effect of alcohol on adolescents’ brains in terms of memory about space and dimension.

In the study, 96 rats were trained to navigate a water maze to an escape platform. Half were exposed to alcohol vapor in chambers for 16 hours a day over four days (a method to approximate binge-like alcohol intake), while others were exposed only to air. After a 28-hour break, some were injected with alcohol, then both groups tested again in the maze. A comparison found that those who had undergone the chronic intermittent ethanol exposure built up a metabolic tolerance. They were better able to eliminate alcohol from their systems than ones who had been exposed only to air, based on a comparison of the blood ethanol concentrations of the two groups after they had been injected with alcohol later. While the alcohol-injected rats swam as hard and as fast as the others, their ability to find the escape platform was impaired.

Previous research at Baylor led by Matthews showed that adolescents are less sensitive than adults to motor impairment during alcohol intake because a particular neuron fires more slowly in adults who are drinking. The lack of sensitivity may be part of the reason adolescents do not realize they have had too much to drink.

"It’s difficult to compare metabolic and cognitive tolerance in adults with those of juveniles, because many studies that have looked at the cognitive aspect of chronic ethanol exposure didn’t measure blood alcohol concentration levels," Van Skike said. "It would be an interesting comparison to make, and it is an avenue for future research."

Other research has shown that high levels of alcohol consumption during human adolescence are mirrored in animals. Adolescent rats consume two to three times more ethanol than adults relative to body weight, suggesting that adolescents are who drink are pre-disposed to do so in binges.

Source: Science Daily

ScienceDaily (June 13, 2012) — Normally, male California mice are surprisingly doting fathers, but new research published in the journal Physiological and Biochemical Zoology suggests that high anxiety can turn these good dads bad.

Unlike most rodents, male and female California mice pair up for life with males providing extensive parental care, helping deliver the pups, lick them clean, and keep them warm during their first few weeks of life. Experienced fathers are so paternal that they’ll even take care of pups that aren’t theirs. “If we place a male California mouse in a test cage and present it with an unknown pup, experienced fathers will quickly start to lick and huddle with it,” said Trynke de Jong, a post-doctoral researcher at University of California, Riverside.

Inexperienced males, on the other hand, aren’t always so loving. “Virgin males show more variability,” de Jong explained. “They may behave paternally, or they may ignore the pup, or even attack it. We want to understand what triggers these three behavioral responses in virgin males.”

De Jong and her colleagues thought this variability might have something to do with social status. In other species — including another rodent, Mongolian gerbils — dominant virgin males are more likely than subordinate ones to kill pups. Perhaps social status influences parenting in California mice as well.

To test this, de Jong and her colleagues paired up 12 virgin males in six enclosures, and performed several tests to see which was dominant. First was a food competition. “If a cornflake is dropped in the cage, the more dominant male will manage to eat most of it,” de Jong said. The researchers also observed each mouse’s urine marking. “Dominant males will make more, smaller, and more widespread marks than subordinate males,” said de Jong

After determining the mightier mouse in each pair, the team tested parental behavior by introducing a pup. Contrary to the hypothesis, scores on the dominance tests did not predict whether a male licked or huddled up to the pup. However, the research did turn up signs that anxiety, not status, plays a role in paternal behavior.

Males who shied away from urinating the middle of a new enclosure — a behavioral signal that a mouse is anxious — were slower to approach a pup. Further tests showed that less paternal males had higher levels of the vasopressin in their brains. Vasopressin is a hormone that is strongly associated with stress and anxiety.

"Our findings support the theory that vasopressin may alter the expression of paternal behavior depending on the emotional state of the animal," de Jong said. She believes these results could shed light on the role of stress in paternal care in other mammals — including humans.

Source: Science Daily

ScienceDaily (June 13, 2012) — Human-derived stem cells can spontaneously form the tissue that develops into the part of the eye that allows us to see, according to a study published by Cell Press in the 5th anniversary issue of the journal Cell Stem Cell. Transplantation of this 3D tissue in the future could help patients with visual impairments see clearly.

This is a human ES cell-derived optic cup generated in our self-organization culture (culture day 26). Bright green, neural retina; off green, pigment epithelium; blue, nuclei; red, active myosin (strong in the inner surface of pigment epithelium). (Credit: Nakano et al. Cell Stem Cell Volume 10 Issue 6)

"This is an important milestone for a new generation of regenerative medicine," says senior study author Yoshiki Sasai of the RIKEN Center for Developmental Biology. "Our approach opens a new avenue to the use of human stem cell-derived complex tissues for therapy, as well as for other medical studies related to pathogenesis and drug discovery."

During development, light-sensitive tissue lining the back of the eye, called the retina, forms from a structure known as the optic cup. In the new study, this structure spontaneously emerged from human embryonic stem cells (hESCs) — cells derived from human embryos that are capable of developing into a variety of tissues — thanks to the cell culture methods optimized by Sasai and his team.

The hESC-derived cells formed the correct 3D shape and the two layers of the optic cup, including a layer containing a large number of light-responsive cells called photoreceptors. Because retinal degeneration primarily results from damage to these cells, the hESC-derived tissue could be ideal transplantation material.

Beyond the clinical implications, the study will likely accelerate the acquisition of knowledge in the field of developmental biology. For instance, the hESC-derived optic cup is much larger than the optic cup that Sasai and collaborators previously derived from mouse embryonic stem cells, suggesting that these cells contain innate species-specific instructions for building this eye structure. “This study opens the door to understanding human-specific aspects of eye development that researchers were not able to investigate before,” Sasai says.

Source: Science Daily

ScienceDaily (June 13, 2012) — With their potential to treat a wide range of diseases and uncover fundamental processes that lead to those diseases, embryonic stem (ES) cells hold great promise for biomedical science. A number of hurdles, both scientific and non-scientific, however, have precluded scientists from reaching the holy grail of using these special cells to treat heart disease, diabetes, Alzheimer’s and other diseases.

The Salk researchers found that embryonic stem cells cycle in and out of a state from which they can develop into any kind of tissue. Here, red fluorescent “reporter” molecules indicate that these early embryonic cells are exhibiting genetic activity indicative of this flexible state. (Credit: Courtesy of the Salk Institute for Biological Studies)

In a paper published June 13 in Nature, scientists at the Salk Institute for Biological Studies report discovering that ES cells cycle in and out of a “magical state” in the early stages of embryo development, during which a battery of genes essential for cell potency (the ability of a generic cell to differentiate, or develop, into a cell with specialized functions) is activated. This unique condition, called totipotency, gives ES cells their unique ability to turn into any cell type in the body, thus making them attractive therapeutic targets.

"These findings," says senior author Samuel L. Pfaff, a professor in Salk’s Gene Expression Laboratory, "give new insight into the network of genes important to the developmental potential of cells. We’ve identified a mechanism that resets embryonic stem cells to a more youthful state, where they are more plastic and therefore potentially more useful in therapeutics against disease, injury and aging."

ES cells are like silly putty that can be induced, under the right circumstances, to become specialized cells-for example, skin cells or pancreatic cells-in the body. In the initial stages of development, when an embryo contains as few as five to eight cells, the stem cells are totipotent and can develop into any cell type. After three to five days, the embryo develops into a ball of cells called a blastocyst. At this stage, the stem cells are pluripotent, meaning they can develop into almost any cell type. In order for cells to differentiate, specific genes within the cells must be turned on.

Pfaff and his colleagues performed RNA sequencing (a new technology derived from genome-sequencing to monitor what genes are active) on immature mouse egg cells, called oocytes, and two-cell-stage embryos to identify genes that are turned on just prior to and immediately following fertilization. Pfaff’s team discovered a sequence of genes tied to this privileged state of totipotency and noticed that the genes were activated by retroviruses adjacent to the stem cells.

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June 13, 2012

Researchers from Boston University School of Medicine (BUSM) have identified a novel group of proteins that accumulate in the brains of patients with Alzheimer’s disease. These findings, which appear online in the Journal of Neuroscience, may open up novel approaches to diagnose and stage the progression likelihood of the disease in Alzheimer patients.

Alzheimer’s disease is presumed to be caused by the accumulation of β-amyloid, which then induces aggregation of a neuronal protein, called tau, and neurodegeneration ensues. The diagnosis of Alzheimer’s disease focuses on β-amyloid and tau protein, with much attention focusing on radiolabeled markers that bind to β-amyloid (such as the compound PiB). However, imaging β-amyloid is problematic because many cognitively normal elderly have large amounts of β-amyloid in their brain, and appear as “positives” in the imaging tests.

Therapeutic approaches for Alzheimer’s disease generally have focused on β-amyloid because the process of producing a neurofibrillary tangle composed on tau protein has been poorly understood. Hence, few tau therapies have been developed. According to the researchers, this study makes important advances on both of these fronts.

The BUSM researchers identified a new group of proteins, termed RNA-binding proteins, which accumulate in the brains of patients with Alzheimer’s disease, and are present at much lower levels in subjects who are cognitively intact. The group found two different proteins, both of which show striking patterns of accumulation. “Proteins such as TIA-1 and TTP, accumulate in neurons that accumulate tau protein, and co-localize with neurofibrillary tangles. These proteins also bind to tau, and so might participate in the disease process,” explained senior author Benjamin Wolozin, MD, PhD, a professor in the departments of pharmacology and neurology at BUSM. “A different RNA binding protein, G3BP, accumulates primarily in neurons that do not accumulate pathological tau protein. This observation is striking because it shows that neurons lacking tau aggregates (and neurofibrillary tangles) are also affected by the disease process,” he added.

The researchers believe this work opens up novel approaches to diagnose and stage the likelihood of progression by quantifying the levels of these RNA-binding protein biomarkers that accumulate in the brains of Alzheimer patients.

Wolozin’s group also pursued the observation that some of the RNA binding proteins bind to tau protein, and tested whether one of these proteins, TIA-1, might contribute to the disease process. Previously, scientists have demonstrated that TIA-1 spontaneously aggregates in response to stress as a normal part of the stress response. Wolozin and his colleagues hypothesize that since TIA-1 binds tau, it might stimulate tau aggregation during the stress response. They introduced TIA-1 into neurons with tau protein, and subjected the neurons to stress. Consistent with their hypothesis, tau spontaneously aggregated in the presence of TIA-1, but not in the absence. Thus, the group has potentially identified an entirely novel mechanism to induce tau aggregates de novo. In future work, the group hopes to use this novel finding to understand how neurofibrillary tangles for in Alzheimer’s disease and to screen for novel compounds that might inhibit the progression of Alzheimer’s disease.

Provided by Boston University Medical Center

Source: medicalxpress.com

June 13, 2012

(Medical Xpress) — Consciousness is a selective process that allows only a part of the sensory input to reach awareness. But up to today it has yet to be clarified which areas of the brain are responsible for the content of conscious perception. Theofanis Panagiotaropoulos and his colleagues - researchers at the Max Planck Institute for Biological Cybernetics in Tübingen and University Pompeu Fabra in Barcelona - have now discovered that the content of consciousness is not localized in a unique cortical area, but is most likely an emergent property of global networks of neuronal populations.

Neurons in the lateral prefrontal cortex represent the content of consciousness. The red trace depicts neural activity (neuronal discharges) in the lateral prefrontal cortex when a stimulus is consciously perceived for 1 second while the green trace depicts neural activity when the same stimulus is suppressed from awareness. Credit: MPI for Biological Cybernetics

The question which parts of the brain are responsible for the things that reach our awareness is one of the main puzzles in neurobiology today. Previous research on the brains of primates has shown that neurons in primary and secondary cortices provide poor representation of visual consciousness. In contrast, the neurons in the temporal lobe seem to reliably reflect the actual conscious perception of a visual stimulus. These findings indicated that not all parts of the brain are responsible for the content of conscious awareness. Nevertheless, the question whether only one of the brain’s areas is responsible for the content of perception or whether more regions are involved in the process has so far remained unanswered.

The Max Planck scientists in Tübingen led by Nikos Logothetis have now addressed this issue using electrophysiological methods to monitor the neural activity in the lateral prefrontal cortex of macaque monkeys during ambiguous visual stimulation. The visual stimuli used allow for multiple perceptual interpretations, even though the actual input remained the same. In doing so, Panagiotaropoulos and his team were able to show that the electrical activity monitored in the lateral prefrontal cortex correlates with what the macaque monkeys actually perceive.

They thus concluded that visual awareness is not only reliably reflected in the temporal lobe, but also in the lateral prefrontal cortex of primates. The results depict that the neuronal correlates of consciousness are embedded in this area, which has a direct connection to premotor and motor areas of the brain, and is therefore able to directly affect motor output. These findings support the “frontal lobe hypothesis” of conscious visual perception established in 1995 by the researchers Crick (the co-discoverer of the structure of the DNA molecule) and Koch that awareness is related to neural activity with direct access to the planning stages of the brain.

The results support this theory in so far as they show that the lateral prefrontal cortex is involved in the process of visual awareness. However, the fact that neural activity in two different cortical areas reflects conscious perception shows that the decision which sensory input reaches our awareness is most likely not made in a unique cortical area but, rather, that a global network of neurons from different areas of the brain is responsible for it. “Our results therefore broaden the hypothesis and create new questions regarding the cortical mechanisms of visual awareness”, Panagiotaropoulos explains. In the near future the group is going to record the electrical activity in both regions simultaneously.

By this they will try to find out which of the two areas is activated first and draw conclusions on how the two areas interact with each other during conscious perception. This may lead to a better understanding of why only certain things reach our awareness and others remain suppressed.

Provided by Max Planck Society

Source: medicalxpress.com

June 13, 2012

(HealthDay) — Women with multiple sclerosis (MS) who undergo in vitro fertilization (IVF) are at greater risk of relapse after treatment, particularly if they receive gonadotrophin releasing hormone (GnRH) agonists or if IVF fails, according to a study published online June 11 in the Journal of Neurology, Neurosurgery & Psychiatry.

Women with multiple sclerosis who undergo in vitro fertilization (IVF) are at greater risk of relapse after treatment, particularly if they receive gonadotrophin releasing hormone agonists or if IVF fails, according to a study published online June 11 in the Journal of Neurology, Neurosurgery & Psychiatry.

Noting that pregnancy and treatment with sex steroids can affect the relapse rate in patients with MS, Laure Michel, M.D., from Hôpital Laennec in Nantes, France, and colleagues analyzed data from 32 women with MS who had undergone 70 IVF treatments during an 11-year study period: 48 with GnRH agonists and 19 with GnRH antagonists.

The researchers found that there were significantly more relapses in the three months after IVF (annualized relapse rate [ARR], 1.60), compared with one year before (ARR, 0.68) or three months before (ARR, 0.80). The increase in relapses was significantly associated with GnRH agonist use (P = 0.025) and failed IVF (P = 0.019).

"MS patients should be aware of a possible increased risk of MS relapse after IVF, particularly if the procedure does not result in a pregnancy," Michel and colleagues conclude. "Furthermore, because there is a reasonable doubt that GnRH agonists may make patients more prone to such an increase in relapse rate, GnRH antagonists might be preferred for IVF protocols.”

Source: medicalxpress.com

ScienceDaily (June 12, 2012) — As science rushes to develop safe weight loss drugs, a new research report approaches this problem from an entirely new angle: What if there were a pill that would make you want to exercise harder? It may sound strange, but a new research report appearing online in The FASEB Journal suggests that it might be possible. That’s because a team of Swiss researchers found that when a hormone in the brain, erythropoietin (Epo), was elevated in mice, they were more motivated to exercise.

In addition, the form of erythropoietin used in these experiments did not elevate red blood cell counts. Such a treatment has obvious benefits for a wide range of health problems ranging from Alzheimer’s to obesity, including mental health disorders for which increased physical activity is known to improve symptoms.

"Here we show that Epo increases the motivation to exercise," said Max Gassmann, D.V.M., a researcher involved in the work from the Institute of Veterinary Physiology, Vetsuisse-Faculty and Zurich Center for Integrative Human Physiology at the University of Zurich in Switzerland. "Most probably, Epo has a general effect on a person’s mood and might be used in patients suffering from depression and related diseases."

To make this discovery, Gassmann and colleagues used three types of mice: those that received no treatment, those that were injected with human Epo, and those that were genetically modified to produce human Epo in the brain. Compared to the mice that did not have any increase in Epo, both mouse groups harboring human Epo in the brain showed significantly higher running performance without increases in red blood cells.

"If you can’t put exercise in a pill, then maybe you can put the motivation to exercise in a pill instead," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “As more and more people become overweight and obese, we must attack the problem from all angles. Maybe the day will come when gyms are as easily found as fast food restaurants.”

Source: Science Daily

ScienceDaily (June 12, 2012) — Researchers in France and Sweden have discovered how one of the body’s own proteins is involved in generating chronic pain in rats. The results, which also suggest therapeutic interventions to alleviate long-lasting pain, are reported in The EMBO Journal.

Chronic pain is persistent and often difficult to treat. It is due, at least in part, to changes in molecular signalling events that take place in neurons, alterations that can ultimately disrupt the transmission of nerve signals from the spinal cord to the brain.

"We are fortunate to have a wide range of technologies that allow us to look more precisely at the molecular events that lead to the onset of chronic pain in animals," said Marc Landry, lead author of the study and Professor at the University of Bordeaux.

"Our results show that the levels of the naturally occurring protein 14-3-3 zeta are higher in the spinal cord of rats that have chronic pain. Moreover, we have been able to demonstrate how 14-3-3 zeta triggers changes in the signalling pathway that leads to the symptoms of chronic pain."

The 14-3-3 zeta protein disrupts the interaction between the two subunits of the GABA_B receptor, a protein complex found on the surface of nerve cells. GABA_B receptors are G-protein coupled receptors, a family of receptors that regulate many physiological processes and which are frequently targeted for drug development.

The researchers used antibody labelling and microscopy techniques to investigate the molecular interactions of the signalling proteins. In cells and living animals, they were able to show that the 14-3-3 zeta protein interacts directly with the B1 subunit of the GABA_B receptor. This interaction impairs the effective signalling of the receptor and limits the pain-relieving effects of the GABA_B receptor under conditions of chronic pain.

The researchers also showed that the treatment of rats with a specific small interfering RNA (siRNA) or a competing peptide, molecules that interfere with the action of the 14-3-3 zeta protein, inhibited chronic pain.

"The impairment of the GABA_B receptor by 14-3-3 zeta is a novel mechanism for the modulation of chronic pain,” said Landry. “We see potential in combining the use of inhibitors that interfere with the action of 14-3-3 zeta together with existing drug treatments like Baclofen for chronic pain. Targeting the GABA_B dissociation process may be of therapeutic interest since it may allow classical pain killers to be more effective.”

Source: Science Daily

ScienceDaily (June 12, 2012) — A team led by investigators at the Stanford University School of Medicine has found that the most common genetic risk factor for Alzheimer’s disease disrupts brain function in healthy, older women but has little impact on brain function in healthy, older men. Women harboring the gene variant, known to be a potent risk factor for Alzheimer’s disease, show brain changes characteristic of the neurodegenerative disorder that can be observed before any outward symptoms manifest.

Both men and women who inherit two copies (one from each parent) of this gene variant, known as ApoE4, are at extremely high risk for Alzheimer’s. But the double-barreled ApoE4 combination is uncommon, affecting only about 2 percent of the population, whereas about 15 percent of people carry a single copy of this version of the gene.

The Stanford researchers demonstrated for the first time the existence of a gender distinction among outwardly healthy, older people who carry the ApoE4 variant. In this group, women but not men exhibit two telltale characteristics that have been linked to Alzheimer’s disease: a signature change in their brain activity, and elevated levels of a protein called tau in their cerebrospinal fluid.

One implication of the study, published June 13 in the Journal of Neuroscience, is that men revealed by genetic tests to carry a single copy of ApoE4 shouldn’t be assumed to be at elevated risk for Alzheimer’s, a syndrome afflicting about 5 million people in the United States and nearly 30 million worldwide. The new findings also may help explain why more women than men develop this disease, said Michael Greicius, MD, assistant professor of neurology and neurological sciences and medical director of the Stanford Center for Memory Disorders. Most critically, identifying the prominent interaction between ApoE4 and gender opens a host of new experimental avenues that will allow Greicius’ team and the field generally to better understandhow ApoE4 increases risk for Alzheimer’s disease.

For every three women with Alzheimer’s disease, only about two men have the neurodegenerative disorder, said Greicius, the study’s senior author. (The first author is Jessica Damoiseaux, PhD, a postdoctoral scholar in Greicius’ laboratory. They collaborated with colleagues at the University of California-San Francisco and UCLA.) True, women live longer than men do, on average, and old age is by far the greatest risk factor for Alzheimer’s, Greicius said. “But the disparity in Alzheimer’s risk persists even if you correct for the difference in longevity,” he said. “This disparate impact of ApoE4 status on women versus men might account for a big part of the skewed gender ratio.”

Besides age, another well-studied major risk factor is genetic: possession of a particular version of the gene known as ApoE. This gene is a recipe for a protein involved in transporting cholesterol into cells — an important job, as cholesterol is a crucial constituent of all cell membranes including those of nerve cells. And nerve cells are constantly responding to experience by developing or enhancing small, bulblike electrochemical contacts to other nerve cells, or diminishing or abolishing them. For all these processes, efficient cholesterol transport is critical.

The ApoE protein comes in three versions, each the product of a slightly differing version of the ApoE gene: E2, E3 or E4. Most people have two copies of the E3 version of ApoE. A small percentage carries one copy of E3 and one of E2, and even fewer two copies of E2. The protein specified by the E4 gene version seems to be somewhat defective in comparison to the one encoded by either E2 or the much more common E3. Thus, while only about 10-15 percent of the population carries one copy of E4 (or, much less commonly, two), more than 50 percent of people who develop Alzheimer’s are E4 carriers.

But, as it turns out, the heightened risk E4 imposes may be largely restricted to women.

To demonstrate this, the scientists first obtained functional MRI scans of 131 healthy people, with a median age of 70, to examine connections in the brain’s memory network. They used sophisticated brain-imaging analysis to show that in older women carrying the E4 variant, this network of interconnected brain regions, which normally share a synchronized pattern of activity, exhibit a loss of that synchrony — a pattern typically seen in Alzheimer’s patients. In healthy, older women (but not men) with at least one E4 allele, activity in a brain area called the precuneus appeared be out of synch with other regions whose firing patterns generally are closely coordinated.

The brain-imaging technique Greicius and his colleagues used is known as functional-connectivity magnetic resonance imaging, or fcMRI. Performed on “resting” subjects, who remain in the scanner awake but not focusing on any particular task, fcMRI can discern on the order of 20 different brain networks, each consisting of a set of dispersed brain regions that are physically connected by nerve tracts and whose pulses of activity are synchronized, or in phase. Greicius, Damoiseaux and their associates have previously shown that the synchronous firing pattern of one network in particular, critical to memory function and known as the “default mode network,” is specifically targeted by Alzheimer’s and deteriorates as the disease progresses.

To independently confirm their imaging-based observations, the scientists assessed records from a large public database compiled from the Alzheimer’s Disease Neuroimaging Initiative, a multi-site study of healthy aging and Alzheimer’s disease. The Stanford study focused on the healthy 55- to 90-year-old volunteers who had agreed to undergo a spinal tap and have their cerebrospinal fluid analyzed.

From this database the Greicius team extracted the records of 91 subjects, with an average age of 75, and divided them into four groups representing women with or without a copy of the E4 variant, and men with or without a copy. For each group, they checked recorded concentrations of a protein named tau in these subjects’ cerebrospinal fluid. Elevated tau levels in cerebrospinal fluid are a key biomarker of Alzheimer’s disease. The results — the CSF of women, but not men, who carried at least one E4 allele was substantially enriched in tau — confirmed the brain-imaging findings.

The tau findings constitute another first. “It was only possible to see these differences in tau levels when we separated the patients by gender,” Greicius said.

Notably, all the men and women participating in the Journal of Neuroscience study were screened for cognitive status. Only those whose ability to think and remember appeared normal for their age were admitted. Thus, the observed changes in brain activity and CSF composition were occurring well before the onset of classic Alzheimer’s symptoms such as memory loss, disorientation and dementia. It may someday be practical to substitute fcMRI, which is noninvasive, for a spinal tap as a diagnostic tool, Greicius said.

Source: Science Daily

June 12, 2012

One of the brain’s jobs is to help us figure out what’s important enough to be remembered. Scientists at Yerkes National Primate Research Center, Emory University have achieved some insight into how fleeting experiences become memories in the brain.

Their experimental system could be a way to test or refine treatments aimed at enhancing learning and memory, or interfering with troubling memories. The results were published recently in the Journal of Neuroscience.

The researchers set up a system where rats were exposed to a light followed by a mild shock. A single light-shock event isn’t enough to make the rat afraid of the light, but a repeat of the pairing of the light and shock is, even a few days later.

"I describe this effect as ‘priming’," says the first author of the paper, postdoctoral fellow Ryan Parsons. "The animal experiences all sorts of things, and has to sort out what’s important. If something happens just once, it doesn’t register. But twice, and the animal remembers."

Parsons was working with Michael Davis, PhD, Robert W. Woodruff professor of psychiatry and behavioral sciences at Emory University School of Medicine, who has been studying the molecular basis for fear memory for several years.

Even though a robust fear memory was not formed after the first priming event, at that point Parsons could already detect chemical changes in the amygdala, part of the brain critical for fear responses. Long term memory formation could be blocked by infusing a drug into the amygdala. The drug inhibits protein kinase A, which is involved in the chemical changes Parsons observed.

It is possible to train rats to become afraid of something like a sound or a smell after one event, Parsons says. However, rats are less sensitive to light compared with sounds or smells, and a relatively mild shock was used.

Fear memories only formed when shocks were paired with light, instead of noise or nothing at all, for both the priming and the confirmation event. Parsons measured how afraid the rats were by gauging their “acoustic startle response” (how jittery they were in response to a loud noise) in the presence of the light, compared to before training began.

Scientists have been able to study the chemical changes connected with the priming process extensively in neurons in culture dishes, but not as much in live animals. The process is referred to as “metaplasticity,” or how the history of the brain’s experiences affects its readiness to change and learn.

"This could be a good model for dissecting the mechanisms involved in learning and memory,” Parsons says. “We’re going to be able to look at what’s going on in that first priming event, as well as when the long-term memory is triggered.”

"We believe our findings might help explain how events are selected out for long-term storage from what is essentially a torrent of information encountered during conscious experience," Parsons and Davis write in their paper.

Provided by Emory University

Source: medicalxpress.com

ScienceDaily (June 12, 2012) — UCC scientists have shown that brain levels of serotonin, the ‘happy hormone’ are regulated by the amount of bacteria in the gut during early life. Their research is being published June 12 in the international psychiatry journal, Molecular Psychiatry.

Happy children. UCC scientists have shown that brain levels of serotonin, the ‘happy hormone’ are regulated by the amount of bacteria in the gut during early life. (Credit: © Marzanna Syncerz / Fotolia)

This research shows that normal adult brain function depends on the presence of gut microbes during development. Serotonin, the major chemical involved in the regulation of mood and emotion, is altered in times of stress, anxiety and depression and most clinically effective antidepressant drugs work by targeting this neurochemical.

Scientists at the Alimentary Pharmabiotic Centre in UCC used a germ-free mouse model to show that the absence of bacteria during early life significantly affected serotonin concentrations in the brain in adulthood. The research also highlighted that the influence is sex dependent, with more marked effects in male compared with female animals. Finally, when the scientists colonized the animals with bacteria prior to adulthood, they found that many of the central nervous system changes, especially those related to serotonin, could not be reversed indicating a permanent imprinting of the effects of absence of gut flora on brain function.

This builds on earlier work, from the Cork group and others, showing that a microbiome-gut-brain axis exists that is essential for maintaining normal health which can affect brain and behavior. The research was carried out by Dr Gerard Clarke, Professor Fergus Shanahan, Professor Ted Dinan and Professor John F Cryan and colleagues at the Alimentary Pharmabiotic Centre in UCC.

"As a neuroscientist these findings are fascinating as they highlight the important role that gut bacteria play in the bidirectional communication between the gut and the brain, and opens up the intriguing opportunity of developing unique microbial-based strategies for treatment for brain disorders," said Professor John F Cryan, senior author on the publication and Head of the Department of Anatomy & Neuroscience at UCC.

This research has multiple health implications as it shows that manipulations of the microbiota (e.g. by antibiotics, diet, or infection) can have profound knock-on effects on brain function. “We’re really excited by these findings” said lead author Dr Gerard Clarke. “Although we always believed that the microbiota was essential for our general health, our results also highlight how important our tiny friends are for our mental wellbeing.”

Source: Science Daily

ScienceDaily (June 12, 2012) — In a study published June 12 in the journal Molecular Psychiatry, researchers from the Twins Early Development Study at King’s College London’s Institute of Psychiatry studied data from more than 6700 families relating to 45 childhood characteristics, from IQ and hyperactivity to height and weight. They found that genetic and environmental contributions to these characteristics vary geographically in the UK and have published their results online as a series of nature-nurture maps.

Newborn twins. (Credit: © pojoslaw / Fotolia)

Our development, health and behaviour are determined by complex interactions between our genetic make-up and the environment in which we live. For example, we may carry genes that increase our risk of developing type 2 diabetes, but if we eat a healthy diet and get sufficient exercise, we may not develop the disease. Similarly, someone may carry genes that reduce his or her risk of developing lung cancer, but heavy smoking may still lead to the disease.

The UK-based Twins Early Development Study follows more than 13,000 pairs of twins, both identical and non-identical, born between 1994 and 1996. When the twins were age 12, the researchers carried out a broad survey to assess a wide range of cognitive abilities, behavioural (and other) traits, environments and academic achievement in 6759 twin pairs. The researchers then designed an analysis that reveals the UK’s genetic and environmental hotspots, something which had never been done before.

"These days we’re used to the idea that it’s not a question of nature or nurture; everything, including our behaviour, is a little of both," explains Dr Oliver Davis, a Sir Henry Wellcome Postdoctoral Fellow at King’s College London’s Institute of Psychiatry. "But when we saw the maps, the first thing that struck us was how much the balance of genes and environments can vary from region to region."

"Take a trait like classroom behaviour problems. From our maps we can tell that in most of the UK around 60 per cent of the difference between people is explained by genes. However, in the South East genes aren’t as important: they explain less than half of the variation. For classroom behaviour, London is an ‘environmental hotspot’."

The maps give the researchers a global overview of how the environment interacts with our genomes, without homing in on particular genes or environments. However, the patterns have given them important clues about which environments to explore in more detail.

"The nature-nurture maps help us to spot patterns in the complex data and to try to work out what’s causing these patterns," says Dr Davis. "For our classroom behaviour example, we realised that one thing that varies more in London is household income. When we compare maps of income inequality to our nature-nurture map for classroom behaviour, we find income inequality may account for some of the pattern.

"Of course, this is just one example. There are any number of environments that vary geographically in the UK, from social environments like healthcare or education provision to physical environments like altitude, the weather or pollution. Our approach is all about tracking down those environments that you wouldn’t necessarily think of at first."

It may be relatively easy to explain environmental hotspots, but what about the genetic hotspots that appear on the maps: do people’s genomes vary more in those regions? The researchers believe this is not the case; rather, genetic hotspots are areas where the environment exposes the effects of genetic variation.

For example, researchers searching for gene variants that increase the risk of hay fever may study populations from two regions. In the first region people live among fields of wind-pollinated crops, whereas the second region is miles away from those fields. In this second region, where no one is exposed to pollen, no one develops hay fever; hence any genetic differences between people living in this region would be invisible.

By contrast, in the first region, where people live among the fields of crops, they will all be exposed to pollen and differences between the people with a genetic susceptibility to hay fever and the people without will stand out. That would make the region a genetic hotspot for hay fever.

"The message that these maps really drive home is that your genes aren’t your destiny. There are plenty of things that can affect how your particular human genome expresses itself, and one of those things is where you grow up," says Dr Davis.

Source: Science Daily

June 12, 2012

Financial loss can lead to irrational behavior. Now, research by Weizmann Institute scientists reveals that the effects of loss go even deeper: Loss can compromise our early perception and interfere with our grasp of the true situation. The findings, which recently appeared in the Journal of Neuroscience, may also have implications for our understanding of the neurological mechanisms underlying post-traumatic stress disorder.

The experiment was conducted by Dr. Rony Paz and research student Offir Laufer of the Neurobiology Department. Subjects underwent a learning process based on classic conditioning and involving money. They were asked to listen to a series of tones composed of three different notes. After hearing one note, they were told they had earned a certain sum; after a second note, they were informed that they had lost some of their money; and a third note was followed by the message that their bankroll would remain the same. According to the findings, when a note was tied to gain, or at least to no loss, the subjects improved over time in a learned task – distinguishing that note from other, similar notes. But when they heard the “lose money” note, they actually got worse at telling one from the other.

Functional MRI (fMRI) scans of the brain areas involved in the learning process revealed an emotional aspect: The amygdala, which is tied to emotions and reward, was strongly involved. The researchers also noted activity in another area in the front of the brain, which functions to moderate the emotional response. Subjects who exhibited stronger activity in this area showed less of a drop in their abilities to distinguish between tones.

Paz: “The evolutionary origins of that blurring of our ability to discriminate are positive: If the best response to the growl of a lion is to run quickly, it would be counterproductive to distinguish between different pitches of growl. Any similar sound should make us flee without thinking. Unfortunately, that same blurring mechanism can be activated today in stress-inducing situations that are not life-threatening – like losing money – and this can harm us.”

That harm may even be quite serious: For instance, it may be involved in post-traumatic stress disorder. If sufferers are unable to distinguish between a stimulus that should cause a panic response and similar, but non-threatening, stimuli, they may experience strong emotional reactions in inappropriate situations.

This perceptional blurring may even expand over time to encompass a larger range of stimuli. Paz intends to investigate this possibility in future research.

Provided by Weizmann Institute of Science

Source: medicalxpress.com

June 12, 2012

You pick up your cell phone and dial the new number of a friend. Ten numbers. One. Number. At. A. Time. Because you haven’t actually typed the number before, your brain handles each button press separately, as a sequence of distinct movements.

This image shows identified brain regions linked to the parsing (left) and concatenation (right) processes involved in motor chunking. Trials with greater parsing showed increased activation of the left prefrontal and parietal cortex and trials with greater concatenation showed increased activation of the putamen. Credit: Photo by Nicholas Wymbs

After dialing the number a few more times, you find yourself typing it out as a series of three successive bursts of movement: the area code, the first three numbers, the last four numbers. Those three separate chunks allow you to type the number faster, and with greater precision. Eventually, dialed often enough, the number is stored in your brain as one chunk. Who needs speed dial?

"You can think about a chunk as a rhythm," said Nicholas Wymbs, a postdoctoral researcher in UC Santa Barbara’s Department of Psychological and Brain Sciences, and the lead author of a new study on motor chunking in the journal Neuron, published by Cell Press. “We highlight the two-part process that seems to occur when we are chunking. This is demonstrated by the rhythm we use when typing the phone number: rapid bursts of finger movements that are interspersed by pauses.”

The rhythm is the human brain taking information and processing it in an efficient way, according to Wymbs. “On one level, the brain is going to try to divide up, or parse, long sequences of movement,” he said. “This parsing process functions to group or cluster movements in the most efficient way possible.”

But it is also in our brain’s best interest to assemble single or short strings of movements into longer, integrated sequences so that a complex behavior can be made with as little effort as possible. “The motor system in the brain wants to output movement in the most computational, low-cost way as possible,” Wymbs said. “With this integrative process, it’s going to try to bind as many individual motor movements into a fluid, uniform movement as it possibly can.”

This diagram illustrates how the subjects in the experiment used their left hands to respond to the “notes” on a button box. Credit: Illustration by Nicholas Wymbs

The two processes are at odds with each other, and it’s how the brain reconciles this struggle during motor learning that intrigues Wymbs and the study’s other authors, including Scott Grafton, professor of psychology and director of the UCSB Brain Imaging Center. “What we are interested in is functional plasticity of the brain –– how the brain changes when we learn actions, or motor sequences as we refer to them in this paper,” Wymbs said.

The study was conducted using human subjects in the Magnetic Resonance Imaging (MRI) scanner in the Brain Imaging Center. The experiment involved three days of training with people performing and practicing three separate motor sequences for up to 200 trials each during the collection of functional MRI data. The subjects were all right-handed but they were asked to learn the sequences using the four fingers of their left hands. Participants practiced the sequences during the operation of the MRI scanner by tapping out responses with a button box that looked like a set of piano keys, with long, rectangular buttons.

"People would see a static image shown on a video screen that detailed the sequence to be typed out," Wymbs said. "They’re lying down inside the scanner and they see this image above their eyes. Interestingly, some people reported that the images looked like something out of (the video game) Guitar Hero, and, indeed, it does look a bit like guitar tablature. They would have to type out the ‘notes’ from left to right, as you normally would when reading music.

"After practicing a sequence for 200 trials, they would get pretty good at it," Wymbs added. "After awhile, the note patterns become familiar. At the start of the training, it would take someone about four and a half seconds to complete each sequence of 12 button presses. By the end of the experiment, the average participant could produce the same sequence in under three seconds."

The researchers’ goal was to look at which areas of the brain support the two-part process of chunking. “We feel that the motor process, or the concatenation process as we refer to it in the paper, tends to take over as you continue to practice and continue to learn the sequences,” Wymbs said. “That’s the one that’s tied to the motor output system –– the thing that’s actually accomplishing what we set out to do.”

With the experience of repeating a motor sequence, such as typing out a phone number, speaking, typing on a computer, or even texting, it becomes more automatic. “With automaticity comes the recruitment of core motor output regions,” Wymbs said.

The scientists discovered that the putamen –– a brain region that is critically important to movement –– supports the concatenation process of motor chunking, with robust connectivity to parts of the brain that are intimately tied to the output of skilled motor behavior. On the other hand, they found that cortical regions in the left hemisphere respond more during the parsing process of motor chunking. “These regions have been linked to the manipulation of motor information, which is something that we probably do more of when we just begin to learn the sequences as chunks,” Wymbs said.

"Initially, when you’re doing one of these 12-element sequences, you want to pause,” Wymbs added. “That would evoke more of the parsing mechanism. But then, over time, as you learn a sequence so that it becomes more automatic, and the concatenation process takes over and it wants to put all of these individual elements into a single fluid behavior.”

According to Wymbs, the findings could have implications for the study and diagnosis of Parkinson’s and other diseases of the motor system that involve action. “We show here that there are two potentially competing systems that lead to the isolation of different systems that both work to allow us to process things efficiently when we’re learning,” Wymbs said.

Provided by University of California - Santa Barbara

Source: medicalxpress.com

ScienceDaily (June 12, 2012) — Studying how nerve cells send and receive messages, Johns Hopkins scientists have discovered new ways that genetic mutations can disrupt functions in neurons and lead to neurodegenerative disease, including amyotrophic lateral sclerosis (ALS).

Neurons are shown in green. A normal neuron is on the left and p150glued mutant neuron is on the right. The red cargo accumulates in the mutant but not in the normal neuron. Areas with the highest cargo accumulation are yellow at the tip of the neuron. (Credit: Image courtesy of Johns Hopkins Medicine)

In a report published April 26 in Neuron, the research team says it has discovered that a mutation responsible for a rare, hereditary motor neuron disease called hereditary motor neuropathy 7B (HMN7B) disrupts the link between molecular motors and the nerve cell tip where they reside. This mutation results in the production of a faulty protein that prevents material from being transported from the cell’s edge, which is located at the muscle and extends back toward its “body” in the central nervous system. In pinpointing how and where this cargo transport is disrupted, the scientists are now closer to understanding mechanisms underlying this condition and ALS.

"An important question we need to answer is how defects in proteins that normally perform important cellular functions for neurons lead to disease," says Alex Kolodkin, Ph.D., a Howard Hughes Medical Institute Investigator and professor of neuroscience at the Johns Hopkins University School of Medicine. "A major issue in understanding neurodegenerative diseases is determining how certain proteins that are expressed in all types of neurons, or even in all cells in the body, can lead to devastating effects in one, or a few, subsets of neurons." Kolodkin notes that many neurodegenerative diseases involve proteins that serve general functions required in nearly every type of cell in the body, including the transport of material between different parts of a cell, yet certain alterations in these proteins can result in specific neurological disorders.

One particular protein, p150glued, is known to play a role in at least two of these disorders, HMN7B, which is similar to ALS, and Perry syndrome, which leads to symptoms similar to Parkinson’s disease. p150glued is part of a larger complex of proteins that forms a molecular “motor” capable of transporting various molecules and other “cargo” from the nerve end toward the cell body. To better understand how mutations in p150glued lead to HMN7B and Perry syndrome, the researchers turned to fruit flies, which are easy to genetically manipulate and where the same protein has been well studied.

They engineered the fruit fly p150glued protein to contain the same mutations as those implicated in the two diseases and used microscopy techniques that enable them to follow in live cells the movement of fluorescently tagged cargo along motor neurons.

They found, surprisingly, that the movement of cargo along the length of the cell was normal. However, at the far end of the cell, they found that the HMN7B-associated mutation caused an unusually large accumulation of cargo. “This was an unexpected finding,” says Thomas Lloyd, M.D., Ph.D., an assistant professor in neurology and neuroscience at the Johns Hopkins School of Medicine. “We need to better understand how this is causing disease.”

Using flies engineered to contain mutations in other motor proteins, and again watching cargo transport in live cells, the team found that p150glued works in concert with another motor to control cargo transport. Their results suggest that when p150glued is compromised, this control is lost and cargo accumulates at the nerve end, leading to disease.

"It’s still unclear how these two different mutations in different regions of the same protein cause very distinct neurodegenerative diseases," Lloyd says. Encouraged by their results, the team plans to continue using fruit flies to unravel the molecular mechanisms underlying these diseases.

Source: Science Daily

ScienceDaily (June 11, 2012) — The world needs new antibiotics to overcome the ever increasing resistance of disease-causing bacteria — but it doesn’t need the side effect that comes with some of the most powerful ones now available: hearing loss. Today, researchers report they have developed a new approach to designing antibiotics that kill even “superbugs” but spare the delicate sensory cells of the inner ear.

These delicate hair cells from the inner ear of mice were tested to see the effects of powerful antibiotics on structures that are crucial to hearing. At left, cells that were exposed to the antibiotic gentamycin showed signs of high levels of damaging free radicals (seen in green). But cells treated with the veterinary drug apramycin. shown at right, didn’t show these effects — adding to evidence that this drug could be used to treat humans without damaging hearing. (Credit: University of Michigan, Schacht laboratory)

Surprisingly, they have found that apramycin, an antibiotic already used in veterinary medicine, fits this bill — setting the stage for testing in humans.

In a paper published online in the Proceedings of the National Academy of Sciences, a team from Switzerland, England and the University of Michigan show apramycin’s high efficacy against bacteria, and low potential for causing hearing loss, through a broad range of tests in animals. That testing platform is now being used to evaluate other potential antibiotics that could tackle infections such as multidrug-resistant tuberculosis.

The research aims to overcome a serious limitation of aminoglycoside antibiotics, a class of drugs which includes the widely used kanamycin, gentamicin and amikacin.

While great at stopping bacterial infections, these drugs also cause permanent partial hearing loss in 20 percent of people who take them for a short course, and up to 100 percent of people who take them over months or years, for example to treat tuberculosis or lung infections in cystic fibrosis.

U-M researcher Jochen Schacht, Ph.D., a professor of biological chemistry and otolaryngology and director of the Kresge Hearing Research Institute at the U-M Medical School, has spent decades studying why these drugs cause this “ototoxicity” — a side effect that makes doctors hesitant to prescribe them. Hearing damage has also caused patients to discontinue treatment before their antibiotic prescription is over, potentially allowing drug-resistant strains of bacteria to flourish.

Schacht has found that the drugs produce damaging free radicals inside the hair cells of the inner ear. Hair cells, named for the tiny sound-sensing hairs on their surface, are the linchpin of hearing — and once destroyed, cannot be regrown.

In the new paper, Schacht and his research group joined teams led by University of Zurich microbiologist Erik Böttger, and structural biologist and Nobel Prize winner Venkatraman Ramakrishnan of England’s Medical Research Council Laboratory of Molecular Biology, as well as scientists from ETH Zurich. Each team brought its particular expertise to the issue, and after four years of work they developed and tested this new approach to designing antibiotics.

"Aminoglycosides are some of the most valuable broad-spectrum antibiotics and indispensable drugs today, but we need new options to combat drug-resistant bacteria. Importantly, we must find ways to overcome their ototoxicity," Schacht says. "Instead of the trial-and-error approach of the past, this new hypothesis-driven tactic allows us to design drugs with simultaneous attention toward both antibacterial action and impact on hair cells."

According to the World Health Organization, about 440,000 new cases of multidrug-resistant tuberculosis emerge annually, causing at least 150,000 deaths worldwide. Aminoglycoside antibiotics, while carefully controlled in the U.S., Europe, and other developed countries are available over the counter in many developing nations, leading to overuse that makes it even easier for drug-resistant strains of many kinds of bacteria to emerge and spread.

The new paper outlines a rational approach to designing drugs to combat this threat without ototoxicity, based on a theoretical framework that emerged from the work of the three laboratories and centers around the role of ribosomes, the structures inside the cell that “read” DNA and translate the genetic message into proteins. Böttger’s lab, at the Institut für Medizinische Mikrobiologie which he directs, studies aminoglycoside effects on mitochondrial ribosomes and antibacterial activity with an eye toward designing new ones. Ramakrishnan’s lab studies ribosomes, and partners from ETH Zurich also collaborated.

Aminoglycosides bind to the ribosomes inside bacterial cells, preventing the ability to produce proteins. But while the drugs spare most human ribosomes, they can attach to ribosomes in the mitochondria of cells, which are similar to bacterial ribosomes.

Consistent with U-M-generated theories about ototoxicity, the drugs then cause the production of free radicals in such quantities that they overwhelm the hair cells’ defense mechanisms — destroying the cells and causing hearing loss.

The team’s approach is to design drugs that more specifically target bacterial ribosomes over mitochondrial ribosomes, simultaneously testing the impact on hair cells as well as the ability to kill bacteria. In this way, the researchers try to avoid creating antibiotics that harm hearing.

They are already using the platform employed for this study — which involves cells from mouse ears, and tests of hearing and hair cell damage in guinea pigs — to test other promising novel drugs synthesized based on the theoretical framework that was driving the current research.

Meanwhile, the team hopes to launch a clinical trial of apramycin, an antibiotic that could prove immediately useful because multidrug-resistant TB and lung-infecting bacteria have not shown resistance to the drug yet.

The research also lends more evidence to support the use of antioxidants to protect the hearing of patients taking current aminoglycoside antibiotics. Schacht has already led a clinical trial in China that showed a major reduction in hearing loss if aspirin was given at the same time as aminoglycoside antibiotics. “This kind of protection is important, while we search for the long-term answer to drug resistance without ototoxicity,” he says.

Source: Science Daily

June 11, 2012

Researchers at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital have identified a portion of the brain responsible for determining how far away a sound originates, a process that does not rely solely on how loud the sound is. The investigators’ report, which will appear in the early edition of Proceeding of the National Academy of Sciences, is receiving early online release this week.

This is an image of human cerebral cortex, digitally “inflated” to smooth out normal folds and ridges, showing in red the portion of auditory cortex that responds to the distance from which sounds arrive. Credit: Jyrki Ahveninen, Ph.D., Martinos Center for Biomedical Imaging, Massachusetts General Hospital

"Although sounds get louder when the source approaches us, humans are able to discriminate between loud sounds that come from far away and softer sound from a closer source, suggesting that our brains use distance cues independent of loudness," says Jyrki Ahveninen, PhD, of the Martinos Center, senior author of the PNAS report. "Using functional MRI we found a group of neurons in the auditory cortex sensitive to the distance of sound sources and different from those that process changes in loudness. In addition to providing basic scientific information, our results could help future studies of hearing disorders.”

The human brain has distinct areas for processing sensory information – signals responsible for vision, hearing, taste etc. Studies of the visual cortex, located at the back of the brain, have produced detailed maps of areas handling particular portions of the visual field. But understanding of the auditory cortex, located on the side of the head above and behind the ear, is quite limited. While it is known that the portion of the auditory cortex extending toward the back of the head determines where a sound comes from, exactly how the brain translates complex auditory signals to determine both the location and distance from which a sound originates is not yet known.

In their search for auditory neurons that process sound distance, the research team faced some particular challenges. In research laboratories that study hearing, sounds must be delivered to study participants through headphones, which means the acoustical “space” in which a sound is generated must be simulated. This must be done with exquisite accuracy, since environmental aspects causing sound to reverberate probably contribute to distance perception. Since the MRI equipment itself generates a loud noise, the researchers scanned participants’ brains once every 12 seconds to measure responses to sounds presented during intervening quiet periods.

In the first experiment, study participants – 12 adults with normal hearing – listened to a series of paired sounds of varying degrees of loudness and at simulated distances ranging from 15 to 100 cm and were asked to indicate whether the second sound was closer or farther away than the first. Although the differences in loudness varied randomly, participants were quite accurate in distinguishing the simulated distances of the sounds. Acoustical analysis of the particular sound cues presented indicated that the reverberations produced by a sound, which are more pronounced in a closed environment and for sounds traveling farther, may be more important distance cues than are the differences between sounds perceived by a participant’s two ears.

After the first experiment confirmed the accuracy of the simulated acoustical environment, functional MR images taken while participants listened to another series of paired sounds recorded how activity in the auditory cortex changed in response to sounds of varying loudness and direction as well as during sound of constant levels and silence. The images produced identified a small area that appears to be sensitive to cues indicating distance but not loudness. As far as the investigators know, this is the first time neurons sensitive to sound-source distances have been discovered.

"The identified area is located near other auditory cortical areas that process spatial information," says corresponding author Norbert Kopco, PhD. "This is consistent with a general model of perceptual processing in the brain, suggesting that in hearing, as in vision and other senses, spatial information is processed separately from information about the object’s identity or characteristics such as the musical pitch of sound. Our study also illustrates how important it is to combine expertise from different fields – in our case imaging/physiology, psychology, and computational neuroscience – to advance our understanding of such a complex system as the human brain.”

Provided by Massachusetts General Hospital

Source: medicalxpress.com

ScienceDaily (June 11, 2012) — In a pair of related studies, scientists from the Florida campus of The Scripps Research Institute have identified several proteins that help regulate cells’ response to light — and the development of night blindness, a rare disease that abolishes the ability to see in dim light.

In the new studies, published recently in the journals Proceedings of the National Academy of Sciences (PNAS) and The Journal of Cell Biology, Scripps Florida scientists were able to show that a family of proteins known as Regulator of G protein Signaling (RGS) proteins plays an essential role in vision in a dim-light environment.

"We were looking at the fundamental mechanisms that shape our light sensation," said Kirill Martemyanov, a Scripps Research associate professor who led the studies. "In the process, we discovered a pair of molecules that are indispensible for our vision and possibly play critical roles in the brain."

In the PNAS study, Martemyanov and his colleagues identified a pair of regulator proteins known as RGS7 and RGS11 that are present specifically in the main relay neurons of the retina called the ON-bipolar cells. “The ON-bipolar cells provide an essential link between the retinal light detectors — photoreceptors and the neurons that send visual information to the brain,” explained Martemyanov. “Stimulation with light excites these neurons by opening the channel that is normally kept shut by the G proteins in the dark. RGS7 and RGS11 facilitate the G protein inactivation, thus promoting the opening of the channel and allowing the ON-bipolar cells to transmit the light signal. It really takes a combined effort of two RGS proteins to help the light overcome the barrier for propagating the excitation that makes our dim vision possible.”

In the Journal of Cell Biology study, Martemyanov and his colleagues unraveled another key aspect of the RGS7/RGS11 regulatory response — they identified a previously unknown pair of orphan G protein-coupled receptors (GPCRs) that interact with these RGS proteins and dictate their biological function.

GPCRs are a large family of more than 700 proteins, which sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters, and light. After binding these molecules, GPCRs trigger the appropriate response inside the cell. However, for many GPCRs the activating molecules have not yet been identified and these are called “orphan” receptors.

The Martemyanov group has found that two orphan GPCRs — GPR158 and GPR179 — recruit RGS proteins and thus help serve as brakes for the conventional GPCR signaling rather than play an active signaling role.

In the case of retinal ON-bipolar cells, GPR179 is required for the correct localization of RGS7 and RGS11. Their mistargeting in animal models lacking GPR179 or human patients with mutations in the GPR179 gene may account for their night blindness, according to the new study. Intriguingly, in the brain GPR158 appears to play a similar role in localizing RGS proteins, but instead of contributing to vision, it helps RGS proteins regulate the m-opioid receptor, a GPCRs that mediates pleasurable and pain-killing effects of opioids.

"We are really in the very beginning of unraveling this new biology and understanding the role of discovered orphan GPR158/179 in regulation of neurotransmitter signaling in the brain and retina," Martemyanov said. "The hope is that better understanding of these new molecules will lead to the design of better treatments for addictive disorders, pain, and blindness."

Source: Science Daily