Flipping a light switch in the cell: Quantum dots used for targeted neural activation

Optically excited quantum dots in close proximity to a cell control the opening of ion channels. Credit: Lugo et al., University of Washington

By harnessing quantum dots—tiny light-emitting semiconductor particles a few billionths of a meter across—researchers at the University of Washington (UW) have developed a new and vastly more targeted way to stimulate neurons in the brain. Being able to switch neurons on and off and monitor how they communicate with one another is crucial for understanding—and, ultimately, treating—a host of brain disorders, including Parkinson's disease, Alzheimer's, and even psychiatric disorders such as severe depression. The research was published today in the Optical Society's (OSA) open-access journalBiomedical Optics Express.

Doctors and researchers today commonly use electrodes—on the scalp or implanted within the brain—to deliver zaps of electricity to stimulate cells. Unfortunately, these electrodes activate huge swaths of neural territory, made up of thousands or even millions of cells, of many different types. That makes it impossible to tease out the behavior of any given cell, or even of particular cell types, to understand cellular communication and how it contributes to the disease process.

Ideally, nerve cells would be activated in a non-invasive way that is also highly targeted. A promising method for doing this is photostimulation—essentially, controlling cells with light. Recently, for example, a team of Stanford University researchers altered mammalian nerve cells to carry light-sensitive proteins from single-celled algae, allowing the scientists to rapidly flip the cells on and off, just with flashes of light. The problem with this process, however, is that the light-controlled cells must be genetically altered to perform their parlor trick.

Optically excited quantum dots in close proximity to a cell control the opening of ion channels. Credit: Image adapted fromJiang et al., Chem. Mater., 2006, 18 (20), pp 4845-4854.

An alternative, says the UW team, led by electrical engineer Lih Y. Lin and biophysicist Fred Rieke, is to use quantum dots—tiny semiconductor particles, just a few billionths of a meter across, that confine electrons within three spatial dimensions. When these otherwise trapped electrons are excited by electricity, they emit light, but at very precise wavelengths, determined both by the size of the quantum dot and the material from which it is made. Because of this specificity, quantum dots are being explored for a variety of applications, including in lasers, optical displays, solar cells, light-emitting diodes, and even medical imaging devices.

In the paper published today, Lin, Rieke and colleagues have extended the use of quantum dots to the targeted activation of cells. In laboratory experiments, the researchers cultured cells on quantum dot films, so that the cell membranes were in close proximity to the quantum-dot coated surfaces. The electrical behavior of individual cells was then measured as the cells were exposed to flashes of light of various wavelengths; the light excited electrons within the quantum dots, generating electrical fields that triggered spiking in the cells.

"We tried prostate cancer cells first because a colleague happened to have the cell line and experience with them, and they are resilient, which is an advantage for culturing on the quantum dot films," Lin says. "But eventually we want to use this technology to study the behavior of neurons, so we switched to cortical neurons after the initial success with the cancer cells."

The experiments, says Lin, show that "it is possible to excite neurons and other cells and control their activities remotely using light. This non-invasive method can provide flexibility in probing and controlling cells at different locations while minimizing undesirable effects."

"Many brain disorders are caused by imbalanced neural activity," Rieke adds, and so "techniques that allow manipulation of the activity of specific types of neurons could permit restoration of normal—balanced—activity levels"—including the restoration of function in retinas that have been compromised by various diseases. "The technique we describe provides an alternative tool for exciting neurons in a spatially and temporally controllable manner. This could aid both in understanding the normal activity patterns in neural circuits, by introducing perturbations and monitoring their effect, and how such manipulations could restore normal circuit activity."

So far, the technique has only been applied to cells cultured outside the body; to gain insight into disease processes and be clinically useful, it would need to be performed within living tissue. To do so, Lin says, "we need to modify the surface of the quantum dots so that they can target specific cells when injected into live animals." The dots also need to be non-toxic, unlike those used in the Biomedical Optics Express report, which often had detrimental effects on the cells to which they were attached. "One solution would be developing non-toxic quantum dots using silicon," Lin says.

More information: "Remote switching of cellular activity and cell signaling using light in conjunction with quantum dots (http://www.opticsi … =boe-3-3-447

 

)," Biomedical Optics Express, Vol. 3, Issue 3, pp. 447-454 (2012).

Provided by Optical Society of America

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Brain Proteins May Be Key to Aging

Deterioration of long-lived proteins on the surface of neuronal nuclei in the brain could lead to age-related defects in nervous function.

By Bob Grant | 

Wikimedia Commons, PLoS Biology

Scientists have found that aptly named extremely long-lived proteins (ELLPs) in the brains of rats can persist for more than one year—a result that suggests the proteins, also found in human brains, last an entire lifetime. Most proteins only last a day or two before being recycled. The researchers reported their findings last week in Science

 

.

A team at the Salk Institute for Biological Studies made the discovery while studying ELLPs that are part of the nuclear pore complex (NPC), which is a transport channel that regulates the flow of molecules into or out of the nucleus in neurons. Because the persistent ELLPs are more likely to accumulate molecular damage, NPC function may eventually become compromised, allowing more toxins into the nucleus. This could result in alterations to DNA, subsequent changes in gene activity, and signs of cellular aging. “Most cells, but not neurons, combat functional deterioration of their protein components through the process of protein turnover, in which the potentially impaired parts of the proteins are replaced with new functional copies,” said senior author Martin Hetzer, of Salk’s Molecular and Cell Biology Laboratory, in a statement

 

. “Our results also suggest that nuclear pore deterioration might be a general aging mechanism leading to age-related defects in nuclear function, such as the loss of youthful gene expression programs.”

In addition to aging, the results may provide key clues to the development of neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases.

Source: TheScientist
http://the-scientist.com/2012/02/08/brain-proteins-may-be-key-to-aging/

 

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Physical activity yields feelings of excitement, enthusiasm

(Medical Xpress) -- People who are more physically active report greater levels of excitement and enthusiasm than people who are less physically active, according to Penn State researchers. People also are more likely to report feelings of excitement and enthusiasm on days when they are more physically active than usual.

"You don't have to be the fittest person who is exercising every day to receive the feel-good benefits of exercise," said David Conroy, professor of kinesiology. "It's a matter of taking it one day at a time, of trying to get your activity in, and then there's this feel-good reward afterwards."

Conroy added that it often is hard for people to commit to an exercise program because they tend to set long-term rather than short-term goals.

"When people set New Year's resolutions, they set them up to include the entire upcoming year, but that can be really overwhelming," he said. "Taking it one day at a time and savoring that feel-good effect at the end of the day might be one step to break it down and get those daily rewards for activity. Doing this could help people be a little more encouraged to stay active and keep up the program they started."

The researchers asked 190 university students to keep daily diaries of their lived experiences, including free-time physical activity and sleep quantity and quality, as well as their mental states, including perceived stress and feeling states. Participants were instructed to record only those episodes of physical activity that occurred for at least 15 minutes and to note whether the physical activity was mild, moderate or vigorous. Participants returned their diaries to the researchers at the end of each day for a total of eight days. The researchers published their results in the current issue of the Journal of Sport & Exercise Psychology.

According to Amanda Hyde, kinesiology graduate student, the team separated the participants' feeling states into four categories: pleasant-activated feelings exemplified by excitement and enthusiasm, pleasant-deactivated feelings exemplified by satisfaction and relaxation, unpleasant-activated feelings exemplified by anxiety and anger, and unpleasant-deactivated feelings exemplified by depression and sadness.

"We found that people who are more physically active have more pleasant-activated feelings than people who are less active, and we also found that people have more pleasant-activatedfeelings on days when they are more physically active than usual," said Hyde, who noted that the team was able to rule out alternative explanations for the pleasant-activated feelings, such as quality of sleep.

"Our results suggest that not only are there chronic benefits of physical activity, but there are discrete benefits as well. Doing more exercise than you typically do can give you a burst of pleasant-activated feelings. So today, if you want a boost, go do some moderate-to-vigorous intensity exercise."

Conroy added that most previous studies have looked only at pleasant or unpleasant feelings and paid less attention to the notion of activation.

"Knowing that moderate and vigorous physical activity generates a pleasant-activated feeling, rather than just a pleasant feeling, might help to explain why physical activity is so much more effective for treating depression rather than anxiety," he said. "People dealing with anxious symptoms don't need an increase in activation. If anything, they might want to bring it down some. In the future, we plan to look more closely at the effects of physical activity on mental health symptoms."

Other authors on the paper include Aaron Pincus, professor of psychology, and Nilam Ram, assistant professor of human development and family studies and of psychology.

National Institute on Aging and the Penn State Social Science Research Institute funded this research.

Provided by Pennsylvania State University

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Stimulant treatment for ADHD not associated with increased risk of cardiac events in youth

Attention-deficit/hyperactivity disorder (ADHD) affects 5-9% of youth and is frequently treated with stimulant medications, such as methylphenidate and amphetamine products. A recent safety communication from the US Food and Drug Administration advised that all patients undergoing ADHD treatment be monitored for changes in heart rate or blood pressure.

Amidst growing concern over the risks of stimulant use in youth, a study by Dr. Mark Olfson of the New York State Psychiatric Institute and Columbia University, and his colleagues, published in the February 2012 issue of the Journal of the American Academy of Child and Adolescent Psychiatry,assessed the risk of adverse cardiovascular events in children and adolescents without known heart conditions treated with stimulants for ADHD. It is one of the largest studies to date focusing primarily on youth while controlling for pre-existing cardiovascular risk factors.

As reported in the study, Olfson and colleagues examined claims records from a large privately insured population for associations between cardiovascular events in youth with ADHD and stimulant treatment. In total 171,126 privately insured youth aged 6-21 years without known pre-existing heart-related risk factors were followed throughout the study.

The study included patients who have previously received stimulant treatment, patients currently receiving stimulant treatment, and patients who began or ceased stimulant treatments during the study period. Olfson and colleagues assessed the various groups for incidents of severe cardiovascular events such as acute myocardial infarction, less severe cardiovascular events such as cardiac dysrhythmias, and cardiovascular symptoms such as tachycardia and palpitations. Analysis showed that cardiovascular events and symptoms were rare in this cohort and not associated with stimulant use.

This finding helps to allay concerns of adverse events in otherwise healthy young people receiving treatment for ADHD. Olfson and colleagues said of the results, "It is reassuring that in these young people, short-term stimulant treatment did not substantially increase the risk of cardiovascular events or symptoms."

More information: The article, "Stimulants and Cardiovascular Events in Youth With Attention-Deficit/Hyperactivity Disorder" by Mark Olfson, Cecilia Huang, Tobias Gerhard, Almut G. Winterstein, Stephen Crystal, Paul D. Allison, Steven C. Marcus (doi:10.1016/j.jaac.2011.11.008

 

) appears in Journal of the American Academy of Child and Adolescent Psychiatry, Volume 51, Issue 2 (February 2012)

Provided by Elsevier

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Growing up on a farm directly affects regulation of the immune system

Immunological diseases, such as eczema and asthma, are on the increase in westernised society and represent a major challenge for 21st century medicine. A new study has shown, for the first time, that growing up on a farm directly affects the regulation of the immune system and causes a reduction in the immunological responses to food proteins.

The research, led by the University of Bristol's School of Veterinary Sciences, found that spending early life in a complex farm environment increased the number of regulatory T-lymphocytes, the cells that damp down the immune system and limit immune responses.

Dr Marie Lewis, Research Associate in Infection and Immunity at the School of Veterinary Sciences, who led the research, said: "Many large-scale epidemiological studies have suggested that growing up on a farm is linked to a reduced likelihood of developing allergic disease. However, until now, it has not been possible to demonstrate direct cause and effect: does the farm environment actively protect against allergies, or are allergy-prone families unlikely to live on farms?"

In the study, piglets were nursed by their mothers on a farm while their siblings spent their early life (from one day onwards) in an isolator unit under very hygienic conditions and were fed formula milk, therefore, reflecting the extremes of environment human babies are raised in.

The work was carried out in piglets as they are valuable translational models for humans since they share many aspects of physiology, metabolism, genetics and immunity.

The researchers demonstrated that compared to their brothers and sisters in the isolator, the farm-reared piglets had reduced overall numbers of T-lymphocytes, the immune cells which drive immune responses, in their intestinal tissues. Importantly, these dirty piglets also had significantly increased numbers of a subset of these cells, the regulatory T-lymphocytes, which pacify immune responses and limit inflammation.

This shift in the ratio of stimulatory and regulatory cells appeared to have functional effects since the farm-reared piglets also exhibited decreased antibody responses to novel food proteins when they were weaned.

Regulatory T-cells have been identified in many mammalian species, including humans, and appear to be universal regulators of immune systems and a reduction in their numbers is often associated with the development of allergies, autoimmune and inflammatory diseases.

Dr Marie Lewis explained: "At this point it is not clear exactly what caused the increased capacity for immune regulation in our farm-reared piglets. Our previous work suggests that intestinal bacteria play a pivotal role in the development of a competent immune system and these bacteria are obtained from the environment during early life."

The researchers suggest additional work is required to determine the extent to which other farm-associated factors, such as social and maternal interactions, aerial contaminants, antigens from bedding and early nutrition, contributed to the impact of the environment on increased local and systemic immune regulation.

Further clarification of the mechanisms underlying these interactions could lead to methods of intervention during infancy to prevent the development of immune diseases in later life.

More information: Direct experimental evidence that early-life farm environment influences regulation of immune responses, Marie C. Lewis, Charlotte F. Inman, Dilip Patel, Bettina Schmidt, Imke Mulder, Bevis Miller, Bhupinder P. Gill, John Pluske, Denise Kelly, Christopher R. Stokes & Michael Bailey, Pediatric Allergy and Immunology, published online ahead of print 03 February 2012.

Provided by University of Bristol

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Smartphone training helps people with memory impairment regain independence

The treatment for moderate-to-severe memory impairment could one day include a prescription for a smartphone.

Baycrest has published the strongest evidence yet that a smartphone training program, theory-driven and specifically designed for individuals with memory impairment, can result in "robust" improvements in day-to-day functioning, and boost independence and confidence levels.

The promising results appear online this week, ahead of print publication, in the international journal Neuropsychological Rehabilitation.

"The goal of our study was to demonstrate the generalizability of our training protocol to a larger number of individuals with moderate-to-severe memory impairment," said Dr. Eva Svoboda, a clinical neuropsychologist in the Neuropsychology and Cognitive Health Program at Baycrest, and lead author of the study.

"Our findings demonstrate that it is possible to harness powerful emerging technologies with brain science in an innovative way to give people with a range of memory deficits some of their independence back."

Memory impairment, particularly when it is severe, can impact virtually all aspects of everyday life. Individuals are unable to readily acquire new information making it difficult or impossible to keep appointments and stay on top of changing personal, social and occupational responsibilities.

Two decades ago, Baycrest pioneered a theory-driven training program that tapped into preserved implicit memory systems in people with amnesia to teach them to use assistive memory devices. Implicit or procedural memory is a type of memory that supports learning but does not require conscious executive control. Common examples of this type of memory include riding a bicycle or brushing one's teeth which doesn't require conscious remembering of where the procedure was learned in order to perform it.

Commercial technologies such as smartphones and other mobile electronic devices have immense potential for individuals with memory impairment as they offer high storage capacity, auditory and vibration alerts, rich multimedia capability and high user acceptability.

The Baycrest study involved 10 outpatients, 18 to 55 years of age, who had moderate-to-severe memory impairment, the result of non-neurodegenerative conditions including ruptured aneurysm, stroke, tumor, epilepsy, closed-head injury, or anoxia (insufficient oxygen to the brain) after a heart attack.

Participants completed two phases of training on either a smartphone or another personal digital assistant (PDA) device. Prior to the training, all participants reported difficulty in day-to-day functioning. Some required ongoing supervision and regular assistance from family members due to their forgetting to pay bills, take medications or attend appointments.

In the first phase, instructors from Baycrest's Memory Link program taught participants the basic functions of their device, using an errorless fading of cues training method that tapped into their preserved implicit /procedural memory. Each participant received several one-hour training sessions to learn calendaring skills such as inputting appointments and reminders.

In the second phase, participants took the device home to apply their newly-acquired calendaring skills in real-life situations. This included setting alarm reminders to take medications and attend future appointments, charging the device, and remembering to keep the device with them at all times. They also learned how to use other software functions, such as phone, contacts, and camera.

As part of the outcome measures, participants were given a schedule of 10 phone calls to complete over a two-week period at different times of the day – to closely approximate real life commitments. Family members who lived with participants kept a behavioural memory log of whether real-life tasks were successfully completed or not by their relative. Participants and family members completed a "memory mistakes" questionnaire which involved rating a list of common memory mistakes on a frequency-of-occurrence scale, ranging from "never" to "all the time".

Participants and family also completed two additional questionnaires. One measured confidence in the participant when dealing with various memory-demanding scenarios (e.g. dentist calls to change appointment dates). The other examined the participant's use of the device to support traveling back in time (e.g. searching activities and events from preceding days, weeks and months), traveling forward in time (e.g. planning ahead, entering future events and appointments), and technical ease of use of the device.

All 10 individuals showed "robust increases" in day-to-day memory functioning after taking the training, based on results from the functional and questionnaire-based measures. Participants continued to report benefit from smartphone and PDA use in short-term follow-up three to eight months later.

Provided by Baycrest Centre for Geriatric Care

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Neuroscientists link brain-wave pattern to energy consumption

Emery Brown, an MIT professor of brain and cognitive sciences and health sciences and technology, left, and ShiNung Ching, a postdoc in Brown’s lab. Photo: M. Scott Brauer

Different brain states produce different waves of electrical activity, with the alert brain, relaxed brain and sleeping brain producing easily distinguishable electroencephalogram (EEG) patterns. These patterns change even more dramatically when the brain goes into certain deeply quiescent states during general anesthesia or a coma. 

MIT and Harvard University researchers have now figured out how one such quiescent state, known as burst suppression, arises. The finding, reported in the online edition of the Proceedings of the National Academy of Sciences the week of Feb. 6, could help researchers better monitor other states in which burst suppression occurs. For example, it is also seen in the brains of heart attack victims who are cooled to prevent brain damage due to oxygen deprivation, and in the brains of patients deliberately placed into a medical coma to treat a traumatic brain injury or intractable seizures.

During burst suppression, the brain is quiet for up to several seconds at a time, punctuated by short bursts of activity. Emery Brown, an MIT professor of brain and cognitive sciences and health sciences and technology and an anesthesiologist at Massachusetts General Hospital, set out to study burst suppression in the anesthetized brain and other brain states in hopes of discovering a fundamental mechanism for how the pattern arises. Such knowledge could help scientists figure out how much burst suppression is needed for optimal brain protection during induced hypothermia, when this state is created deliberately. 

“You might be able to develop a much more principled way to guide therapy for using burst suppression in cases of medical coma,” says Brown, senior author of the PNAS paper. “The question is, how do you know that patients are sufficiently brain-protected? Should they have one burst every second? Or one every five seconds?”

Modeling electrical activity

ShiNung Ching, a postdoc in Brown’s lab and lead author of the PNAS paper, developed a model to describe how burst suppression arises, based on the behavior of neurons in the brain. Neuron firing is controlled by the activity of channels that allow ions such as potassium and sodium to flow in and out of the cell, altering its voltage.

For each neuron, “we’re able to mathematically model the flow of ions into and out of the cell body, through the membrane,” Ching says. In this study, the team combined many neurons to create a model of a large brain network. By showing how both cooling and certain anesthetic drugs reduce the brain’s use of ATP (the cell’s energy currency), the researchers were able to generate burst-suppression patterns consistent with those actually seen in human patients. 

This is the first time that reductions in metabolic activity at the neuron level have been linked to burst suppression, and suggests that the brain likely uses burst suppression to conserve vital energy during times of trauma.

“What’s really exciting about this is the idea that the metabolic regulation of cell energy stores plays a role in the observed dynamics of EEG. That’s a different way to think about the determinants of EEG,” says Nicholas Schiff, a professor of neurology and neuroscience at Weill Cornell Medical College who was not involved in this research. 

The developing brain

Burst suppression is also seen in babies born prematurely. As these babies get older, their brain patterns move into the normal continuous pattern. Brown speculates that in premature infants, the brain may be protecting itself by conserving energy.

“When you’re looking at these kids develop, we can easily start to suggest ways of tracking their improvement quantitatively. So the same algorithms we use to track burst suppression in the operating room could be used to track the disappearance of burst suppression in these kids,” Brown says.

Such tracking could help doctors determine whether premature infants are moving toward normal development or have an underlying brain disorder that might otherwise go undiagnosed, Ching says. 

In future studies, the researchers plan to study premature infants as well as patients whose brains are cooled and those in induced comas. Such studies could reveal just how much burst suppression is enough to protect the brain in those vulnerable situations.

Provided by Massachusetts Institute of Technology

This story is republished courtesy of MIT News (http://web.mit.edu/newsoffice/

 

), a popular site that covers news about MIT research, innovation and teaching.

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'Explorers,' who embrace the uncertainty of choices, use specific part of cortex

"Explorers," whose decision-making style embraces the possibilities of uncertainty, use specific parts (red) of the right rostrolateral prefrontal cortex to make calculations based on relative uncertainty. Credit: Badre-Frank Lab/Brown University

Life shrouds most choices in mystery. Some people inch toward a comfortable enough spot and stick close to that rewarding status quo. Out to dinner, they order the usual. Others consider their options systematically or randomly. But many choose to grapple with the uncertainty head on. "Explorers" order the special because they aren't sure they'll like it. It's a strategy of maximizing rewards by discovering whether as yet unexplored options might yield better returns. In a new study, Brown University researchers show that such explorers use a specific part of their brain to calculate the relative uncertainty of their choices, while non-explorers do not.

The study, published in the journal Neuron, newly exposes an aspect of the brain's architecture for producing decisions and learning, said co-author David Badre, assistant professor of cognitive, linguistic, and psychological sciences at Brown. There was no consensus that a precise area of the prefrontal cortex, in this case the right rostrolateral prefrontal cortex, would be so clearly associated with a specific operation, such as performing the requisite uncertainty comparison for supporting a decision-making strategy.

"There has long been a debate about the functional organization of the frontal cortex," Badre said. "There has been a notion that the frontal lobe lacks specialization when exercising cognitive control, that it's undifferentiated. This study provides evidence that there is a kind of organization. This is an example of how higher-order functions such as decision-making may relate to the frontal lobe's more general functional architecture."

Stop the clock

To spot explorer behavior among their 15 participants, Badre and Michael Frank, associate professor of cognitive, linguistic, and psychological sciences, slid them into an MRI scanner and presented them with a game to play. Participants had to stop the sweeping hand of a virtual clock to win points in different rounds. They were told that they could maximize their rewards by responding quickly in some rounds, and slowly in others. The trick is they did not know round-to-round which response prevailed, and the number of points they could win was highly variable. They therefore had to employ a strategy to discover how to maximize their rewards among uncertain options, keeping track of the current expected value of fast and slow responses in each round.

While the MRI scanner tracked the blood flow in the brains of the subjects — a proxy for neural activity — the game's software tracked their response times in each round. The computer then fed the game's data into mathematical models devised to determine whether participants adapted their response times by taking relative uncertainty into account or adapted in another manner.

Over dozens of rounds a clear pattern emerged. Regardless of which version of the model they used, the researchers found that about half the subjects were engaging in exploratory behavior based on uncertainty: Their choices of response times correlated strongly with the choices that had the greatest outcome uncertainty.

Badre, Frank, and their team then looked at the MRI scans, reasoning that if decision-making is based on relative uncertainty, then the subjects' brains must somehow represent this uncertainty. Sure enough, as relative uncertainty between choice options increased, so did activation in the right rostrolateral prefrontal cortex. This effect was substantially stronger in the explorers than the nonexplorers.

The result is the first to show that this region of the brain keeps track of relative uncertainty to guide exploration, but is consistent with previous studies that have shown an association between the right rostrolateral prefrontal cortex and relative comparisons. It also provides a potential explanation for Frank's previous findings that explorers were more likely to have a variation in a gene called COMT that affects dopamine levels in the prefrontal cortex.

From cortex to choice

Frank said researchers still don't know why some people employ the explorer strategy while others do not, but they might not be so different. According to one hypothesis, they all have an aversion to uncertainty and ambiguity.

"The difference could be that some people are averse to ambiguity in the time point where they make a single decision and other people are averse to ambiguity about their strategy over the long run," Frank said.

In other words, explorers may seek to reduce uncertainty by confronting it, rather than avoiding it.

Badre said that while the study has no direct clinical implications, the findings may still inform efforts to understand a broad set of disorders that affect frontal lobe function.

"There are a lot of diseases and disorders that affect the frontal lobes," Badre said. "They affect the ability to live independently, to carry out the day and make good decisions that get you where you want to go. The more we know about the specificity of these systems, the better that you can diagnose and suggest treatments."

Provided by Brown University

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Unusual alliances enable movement

 

Some unusual alliances are necessary for you to wiggle your fingers, researchers report. Understanding those relationships should enable better treatment of neuromuscular diseases, such as myasthenia gravis, which prevent muscles from taking orders from your brain, said Dr. Lin Mei, director of the Institute of Molecular Medicine and Genetics at Georgia Health Sciences University. Credit: Phil Jones, GHSU Photographer

Some unusual alliances are necessary for you to wiggle your fingers, researchers report.

Understanding those relationships should enable better treatment of neuromuscular diseases, such as myasthenia gravis, which prevent muscles from taking orders from your brain, said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics at Georgia Health Sciences University.

During development, neurons in the spinal cord reach out to muscle fibers to form a direct line of communication called the neuromuscular junction. Once complete, motor neurons send chemical messengers, called acetylcholine, via that junction so you can text, walk or breathe.

As a first step in laying down the junction, motor neurons release the protein agrin, which reaches out to LRP4, a protein on the muscle cell surface. This activates MuSK, an enzyme that supports the clustering of receptors on the muscle cell surface that will enable communication between the brain and muscle. The precise alignment between the neuron and muscle cell that occurs during development ensures there is no confusion about what the brain is telling the muscle to do.

A missing piece was how agrin and LRP4 get together.

A study published in the journal Genes & Development shows that in the space between the neuron and its muscle cell, agrin and LRP4 first form two diverse work teams: each team has one agrin and one LRP4. The two teams then merge to form a four-molecule complex essential to MuSK activation and to the clustering of receptors that will receive the chemical messenger acetylcholine on the muscle cell.

It was expected that the two agrins would get together first then prompt the LRP4s to merge. "This is very novel," said Mei, and an important finding in efforts to intervene in diseases that attack the neuromuscular junction.

Mei and Dr. Rongsheng Jin, neuroscientist and structural biologist in the Del E. Webb Neuroscience, Aging and Stem Cell Research Center at Sanford-Burnham Medical Research Institute in La Jolla, Calif., are co-corresponding authors of the study.

Myasthenia gravis, which paralyzes previously healthy individuals, targets these protein workers. The condition, which can run in families, likely results from a process called mimicry in which the immune system starts making antibodies to the workers, which it confuses with a previous viral or bacterial infection. The majority of patients have antibodies to acetylcholine receptors and a smaller percentage have antibodies to MuSK. Most recently, GHSU researchers also helped identify LRP4 as an antibody target.

The scientists already are looking at the impact of the antibodies on the LRP4 complex. Understanding its unique structure is essential to designing drugs that could one day block such attacks. "Prior to this we had no idea how they interacted," Mei said.

In addition to providing new information on muscle diseases, this study might also have a far-reaching ripple effect in the field of neuroscience.

"This is just the beginning," says Jin. "Now that we know more about how signals are transferred during the formation of neuromuscular junctions, we can start looking at how a similar system might work in brain synapses and how it malfunctions in neurodegenerative conditions like Alzheimer's and Parkinson's diseases. If we can figure out how to trigger the formation of new brain synapses, maintain old synapses, or simply slow their disappearance, we'd be much better equipped to prevent or treat these diseases."

To reveal the novel mechanism, researchers used a technique known as X-ray crystallography, which produces 3-D "pictures" of protein at the atomic level using powerful X-ray beams.

Provided by Georgia Health Sciences University

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Shirdi Songs - Nee Kanule - Krishna - Manasa

Scientists strengthen memory by stimulating key site in brain

 

This undated image provided by the Fried Lab/UCLA shows a brain MRI with an arrow showing where researchers applied deep-brain stimulation during tests on learning. A painless bit of electrical current applied to the brain helped some people play a video game, and someday it might help Alzheimer's disease patients remember what they've learned, a small study suggests. The game-players had to learn where particular stores were in a virtual city. They recalled the locations better if they'd learned them while current was supplied by tiny electrodes buried in their brains. That strategy may someday help people with early Alzheimer's hang on to many kinds of memory, suggested Dr. Itzhak Fried, a neurosurgeon at the University of California, Los Angeles. But "this is obviously a preliminary result,'' he cautioned. (UCLA, Fried Lab)

Ever gone to the movies and forgotten where you parked the car? New UCLA research may one day help you improve your memory.

UCLA neuroscientists have demonstrated that they can strengthen memory in human patients by stimulating a critical junction in the brain. Published in the Feb. 9 edition of the New England Journal of Medicine, the finding could lead to a new method for boosting memory in patients with early Alzheimer's disease.

The UCLA team focused on a brain site called the entorhinal cortex. Considered the doorway to the hippocampus, which helps form and store memories, the entorhinal cortex plays a crucial role in transforming daily experience into lasting memories.

"The entorhinal cortex is the golden gate to the brain's memory mainframe," explained senior author Dr. Itzhak Fried, professor of neurosurgery at the David Geffen School of Medicine at UCLA. "Every visual and sensory experience that we eventually commit to memory funnels through that doorway to the hippocampus. Our brain cells must send signals through this hub in order to form memories that we can later consciously recall."

Fried and his colleagues followed seven epilepsy patients who already had electrodes implanted in their brains to pinpoint the origin of their seizures. The researchers monitored the electrodes to record neuron activity as memories were being formed.

Using a video game featuring a taxi cab, virtual passengers and a cyber city, the researchers tested whether deep-brain stimulation of the entorhinal cortex or the hippocampus altered recall. Patients played the role of cab drivers who picked up passengers and traveled across town to deliver them to one of six requested shops.

"When we stimulated the nerve fibers in the patients' entorhinal cortex during learning, they later recognized landmarks and navigated the routes more quickly," said Fried. "They even learned to take shortcuts, reflecting improved spatial memory.

"Critically, it was the stimulation at the gateway into the hippocampus – and not the hippocampus itself – that proved effective," he added.

The use of stimulation only during the learning phase suggests that patients need not undergo continuous stimulation to boost their memory, but only when they are trying to learn important information, Fried noted. This may lead the way to neuro-prosthetic devices that can switch on during specific stages of information processing or daily tasks.

Six million Americans and 30 million people worldwide are newly diagnosed with Alzheimer's disease each year. The progressive disorder is the sixth leading cause of death in the United States and the fifth leading cause of death for those aged 65 and older.

"Losing our ability to remember recent events and form new memories is one of the most dreaded afflictions of the human condition," said Fried. "Our preliminary results provide evidence supporting a possible mechanism for enhancing memory, particularly as people age or suffer from early dementia. At the same time, we studied a small sample of patients, so our results should be interpreted with caution."

Future studies will determine whether deep-brain stimulation can enhance other types of recall, such as verbal and autobiographical memories. No adverse effects of the stimulation were reported by the seven patients.

Fried's coauthors included first author Nanthia Suthana, as well as Dr. Zulfi Haneef, Dr. John Stern, Roy Mukamel, Eric Behnke and Barbara Knowlton, all of UCLA. The research was supported by grants from the National Institute of Neurological Disorders and Stroke and the Dana Foundation.

Provided by University of California - Los Angeles

"Scientists strengthen memory by stimulating key site in brain." February 8th, 2012. http://medicalxpress.com/news/2012-02-scientists-memory-key-site-brain.html

 

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Robert Karl Stonjek