Posts tagged neuroscience

ScienceDaily (June 24, 2012) — Researchers at Yale School of Medicine have zeroed in on a set of neurons in the part of the brain that controls hunger, and found that these neurons are not only associated with overeating, but also linked to non-food associated behaviors, like novelty-seeking and drug addiction.

A lean animal and a control were both exposed to a novelty item (center). The lean animal spent more time exploring the novelty, as shown by the higher concentration of yellow in the slide. (Credit: Image courtesy of Yale University)

Published in the June 24 online issue of Nature Neuroscience, the study was led by Marcelo O. Dietrich, postdoctoral associate, and Tamas L. Horvath, the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine.

In attempts to develop treatments for metabolic disorders such as obesity and diabetes, researchers have paid increasing attention to the brain’s reward circuits located in the midbrain, with the notion that in these patients, food may become a type of “drug of abuse” similar to cocaine. Dietrich notes, however, that this study flips the common wisdom on its head.

"Using genetic approaches, we found that increased appetite for food can actually be associated with decreased interest in novelty as well as in cocaine, and on the other hand, less interest in food can predict increased interest in cocaine," said Dietrich.

Horvath and his team studied two sets of transgenic mice. In one set, they knocked out a signaling molecule that controls hunger-promoting neurons in the hypothalamus. In the other set, they interfered with the same neurons by eliminating them selectively during development using diphtheria toxin. The mice were given various non-invasive tests that measured how they respond to novelty, and anxiety, and how they react to cocaine.

"We found that animals that have less interest in food are more interested in novelty-seeking behaviors and drugs like cocaine," said Horvath. "This suggests that there may be individuals with increased drive of the reward circuitry, but who are still lean. This is a complex trait that arises from the activity of the basic feeding circuits during development, which then impacts the adult response to drugs and novelty in the environment."

Horvath and his team argue that the hypothalamus, which controls vital functions such as body temperature, hunger, thirst fatigue and sleep, is key to the development of higher brain functions. “These hunger-promoting neurons are critically important during development to establish the set point of higher brain functions, and their impaired function may be the underlying cause for altered motivated and cognitive behaviors,” he said.

"There is this contemporary view that obesity is associated with the increased drive of the reward circuitry," Horvath added. "But here, we provide a contrasting view: that the reward aspect can be very high, but subjects can still be very lean. At the same time, it indicates that a set of people who have no interest in food, might be more prone to drug addiction."

Source: Science Daily

ScienceDaily (June 24, 2012) — Want to nail that tune that you’ve practiced and practiced? Maybe you should take a nap with the same melody playing during your sleep, new provocative Northwestern University research suggests.

Want to nail that tune that you’ve practiced and practiced? Maybe you should take a nap with the same melody playing during your sleep. (Credit: © Anton Maltsev / Fotolia)

The research grows out of exciting existing evidence that suggests that memories can be reactivated during sleep and storage of them can be strengthened in the process.

In the Northwestern study, research participants learned how to play two artificially generated musical tunes with well-timed key presses. Then while the participants took a 90-minute nap, the researchers presented one of the tunes that had been practiced, but not the other.

"Our results extend prior research by showing that external stimulation during sleep can influence a complex skill," said Ken A. Paller, professor of psychology in the Weinberg College of Arts and Sciences at Northwestern and senior author of the study.

By using EEG methods to record the brain’s electrical activity, the researchers ensured that the soft musical “cues” were presented during slow-wave sleep, a stage of sleep previously linked to cementing memories. Participants made fewer errors when pressing the keys to produce the melody that had been presented while they slept, compared to the melody not presented.

"We also found that electrophysiological signals during sleep correlated with the extent to which memory improved," said lead author James Antony of the Interdepartmental Neuroscience Program at Northwestern. "These signals may thus be measuring the brain events that produce memory improvement during sleep."

The age-old myth that you can learn a foreign language while you sleep is sure to come to mind, said Paul J. Reber, associate professor of psychology at Northwestern and a co-author of the study.

"The critical difference is that our research shows that memory is strengthened for something you’ve already learned," Reber said. "Rather than learning something new in your sleep, we’re talking about enhancing an existing memory by re-activating information recently acquired."

The researchers, he said, are now thinking about how their findings could apply to many other types of learning.

"If you were learning how to speak in a foreign language during the day, for example, and then tried to reactivate those memories during sleep, perhaps you might enhance your learning."

Paller said he hopes the study will help them learn more about the basic brain mechanisms that transpire during sleep to help preserve memory storage.

"These same mechanisms may not only allow an abundance of memories to be maintained throughout a lifetime, but they may also allow memory storage to be enriched through the generation of novel connections among memories," he said.

The study opens the door for future studies of sleep-based memory processing for many different types of motor skills, habits and behavioral dispositions, Paller said.

Source: Science Daily

ScienceDaily (June 23, 2012) — The commonly-used epilepsy drug, valproic acid (VPA), can have a highly beneficial effect on some babies born with spinal muscular atrophy (SMA), the number one genetic killer during early infancy. But in about two-thirds of such cases it is either damaging or simply has no effect. Now, for the first time, researchers have found a way to identify which patients are likely to respond well to VPA prior to starting treatment. Their results have major implications, not just for SMA patients, but for other conditions treated with the drug such as migraine and epilepsy, and may even provide the conditions for turning VPA non-responders into responders, the researchers say.

Dr. Lutz Garbes, from the Institute of Human Genetics, University of Cologne, Germany, will tell the annual conference of the European Society of Human Genetics on June 24 that he and his colleagues had analysed blood RNA samples from a small group of SMA patients who had been treated with VPA. They found, as expected, that only about one third of patients responded well. In an attempt to discover whether blood sampling was the most appropriate test method to use, they also looked at VPA response in another tissue — fibroblasts (a type of skin cell). They found that the response in blood and in skin was the same in 60% of cases.

The researchers then generated pluripotent stem cells from fibroblasts of both a VPA responder and a non-responder, and differentiated them into GABAergic neurons (neurons that produce the amino acid GABA, the chief neurotransmitter in the mammalian nervous system). These neurons, when treated with VPA, exhibited a similar response to that previously found in blood and fibroblasts.

"This indicates for the first time that response to VPA is the same among blood and skin and suggests that monitoring blood for VPA therapy is indeed feasible in central nervous system diseases," says Dr. Garbes. "But, even more importantly, by using the SMA patients’ fibroblasts we were able to identify a decisive factor in the suppression of the positive response to VPA treatment. Utilising transcriptome-wide microarray profiling*, we found that high levels of the fatty acid transporter protein CD36 are associated with the lack of positive response to treatment.

"The implications of this discovery are far-reaching. First, we have been able to prove that monitoring blood is a reliable method for doctors to determine response to VPA treatment in many central nervous system diseases, since our findings are not specific to SMA. Second, the identification of CD36 as the crucial factor in suppressing response to treatment provides a simple way of appraising whether a patient will respond to therapy before treatment starts. And third, in the long run we may find a way to target CD36 in order to be able to change a non-VPA responder into a responder."

Knowing that CD36 is a crucial factor here means that the current, potentially dangerous, ‘trial and error’ approach to VPA treatment is now obsolete, the researchers say. Screening of patients for CD36 prior to treatment would mean that only those who would respond positively to VPA would be given it. This is important because, in some cases, VPA can cause life-threatening side-effects such as impairment of liver, blood cell and pancreatic function, especially in those just starting the treatment. “But we still do not understand how CD36 suppresses response to VPA, only that it does so,” says Dr. Garbes. “A greater understanding of its effects could also lead to the detection of even better targets to overcome the problem. “

In the case of SMA, VPA works by inhibiting enzymes called histone deacetylase (HDACs) which are involved in regulating the packaging of DNA. HDACs lead to a denser DNA packaging whereby protein production from genes is reduced. Other enzymes called histone acetyltransferases (HATs) lead to a more relaxed DNA structure, producing more protein. By inhibiting HDACs with VPA, the DNA packaging balance shifts towards the more relaxed structure and thus genes get activated and proteins produced. In SMA, the crucial gene is SMN2, a copy gene of the disease-determining gene SMN1. In healthy individuals, SMN1 is the major source of SMN protein, but SMN2 cannot fully compensate for the loss of SMN1 in SMA patients. By increasing SMN2 activity, it will produce more SMN protein and ameliorate the condition.

"Avoiding needless VPA treatment of non-responders would have a major effect on healthcare costs and improve quality of life for patients," Dr. Garbes will say. "Half of the babies born with SMA will die within two years, but the other half can live to twenty or even longer, so this is an important finding for them. Our findings may also help identify patients who are candidates for VPA treatment in many other diseases of the central nervous system, some of them very common.

"In the EU, approximately 550 SMA babies are born each year, and there are about 311,000 new cases of epilepsy per year. It is estimated that, in Europe, migraine affects up to 28% of people at some time in their lives. We are happy that we may have been able to contribute to the development of personalised medicine for so many people," he will conclude.

*A transcriptome-wide microarray profile provides a way of identifying all the genes that are differentially expressed in distinct cell populations or subtypes, allowing the effects of treatment to be monitored.

Source: Science Daily

ScienceDaily (June 22, 2012) — Some dementia patients show symptoms of a malfunctioning immune system and can receive appropriate treatment.

Scientists at Charité — Universitätsmedizin Berlin have succeeded in recommending a new type of therapeutic approach to dementia. The study published in the journal Neurology shows that immune reactions against the body’s own nerve cells can be the cause of advanced dementia and an appropriate immune suppressive therapy can develop with significant effectiveness.

Dementia burdens society with high costs, and those affected by it and their family members carry a tremendous psychosocial burden. Dementia is increasingly perceived as a sword of Damocles over an aging society due to its often unclear origin, difficult prevention and unsatisfactory therapies.

Together with a workgroup and cooperation partners in Germany and the US, Dr. Harald Prüß, physician at the Klinik für Neurologie of the Charité, was able to prove that dementia is also caused by the immune system. As an accessory symptom of an autoimmune disease, dementia can thus be treated. This approach to diagnostic criteria has been overlooked until now. It was proven that a number of patients in this study who suffered from advanced memory loss had developed an immune defense response with antibodies against an ion channel in the brain, a so-called NMDA-type glutamate channel. Particular proteins in the nerve cell membrane are reduced leading to the characteristic disruption in nerve function and synapsis loss. Those affected exhibit memory problems and abnormalities in mood and emotion. Eliminating these antibodies through hemodialysis improved the symptoms in cerebral metabolism in the hippocampus region — a part of the brain that is relevant for memory performance and particularly affected by dementia.

"Through the study results, a completely new approach to diagnosing dementia can possibly result. At the moment we are working on a follow-up study with larger test groups in order to verify our approach even further," explains Harald Prüß. He adds: "The potential promise of this new approach is that completely new perspectives could result for an entire group of people suffering from dementia for whom no specific therapeutic option exists."

Source: Science Daily

ScienceDaily (June 22, 2012) — A longstanding question in brain research is how information is processed in the brain. Neuroscientists at the Charité — Universitätsmedizin Berlin, Cluster of Excellence NeuroCure and University of Newcastle have made a contribution towards answering this question. In a new study, they have shown that signals are generated not only in the cell body of nerve cells, but also in their output extension, the axon. A specific filter cell regulates signal propagation.

These findings have now been published in the journal Science.

Until now it has been assumed that information flow in nerve cells proceeds along a “one-way street.” Electrical impulses are initiated at the cell body and propagate along the axon to the next neuron, where they are received by extensions, the dendrites, acting as antennae. However, the team around Charité researchers Tengis Gloveli and Tamar Dugladze has demonstrated that this model needs to be revised. They discovered that signals can also be initiated in axons, i.e. outside the cell body. This happens during highly synchronous neuronal activity as, for example, in a state of heightened attention. Moreover, these axonally generated signals flow bidirectionally and represent a new principle of information processing: on the one hand, impulses propagate from their origin towards other nerve cells; on the other hand, the signals also backpropagate towards the cell body, i.e. in the “wrong direction” down the one-way street. A potential problem is that backpropagating signals could lead to excessive cell activation.

However, the researchers found that backpropagating signals do not reach the cell body under normal conditions. The reason for this, the scientists discovered, is a natural filter that prevents these signals from passing. “Axo-axonic cells, an inhibitory cell type, regulate signal propagation and thus occupy an outstanding strategic position,” explains Tamar Dugladze. Through the filter function, these cells allow signals initiated at the cell body to pass, but suppress backpropagating impulses generated in the axon. By this means, excessive activation of the cell body is prevented. In experiments, the scientists could show that when this filter function is deactivated, backpropagating signals are allowed to pass, resulting in higher cell activation.

These filter cells can become damaged in various neurological diseases. The consequent misregulation of signal flow, in turn, has fatal effects on information processing in the brain. “Results of this study shed new light on the central question of how signals are processed in the brain. In addition, these findings could help us better understand the development and progress of neuronal diseases such as epilepsy, which involves excessive hypersynchronous activity of large sets of neurons. This knowledge could open up new therapeutic approaches,” says Tengis Gloveli. The neuroscientists will therefore focus their future research on both basic understanding of the mechanisms of signal flow in the nervous system, and the relevance of these mechanisms in the genesis of epilepsy.

Source: Science Daily

ScienceDaily (June 22, 2012) — The gene p53 is the most commonly mutated gene in cancer. p53 is dubbed the “guardian of the genome” because it blocks cells with damaged DNA from propagating and eventually becoming cancerous. However, new research led by Ute M. Moll, M.D., Professor of Pathology at Stony Brook University School of Medicine, and colleagues, uncovers a novel role for p53 beyond cancer in the development of ischemic stroke. The research team identified an unexpected critical function of p53 in activating necrosis, an irreversible form of tissue death, triggered during oxidative stress and ischemia.

Dr. Ute Moll, Professor of Pathology, has uncovered a novel role for p53 in the development of ischemic stroke. (Credit: Image courtesy of Stony Brook Medicine)

The findings are detailed online in Cell.

Ischemia-associated oxidative damage leads to irreversible necrosis which is a major cause of catastrophic tissue loss. Elucidating its signaling mechanism is of paramount importance. p53 is a central cellular stress sensor that responds to multiple insults including oxidative stress and is known to orchestrate apoptotic and autophagic types of cell death. However, it was previously unknown whether p53 can also activate oxidative stress-induced necrosis, a regulated form of cell death that depends on the mitochondrial permeability transition pore (PTP) pore.

"We identified an unexpected and critical function of p53 in activating necrosis: In response to oxidative stress in normal healthy cells, p53 accumulates in the mitochondrial matrix and triggers the opening of the PTP pore at the inner mitochondrial membrane, leading to collapse of the electrochemical gradient and cell necrosis," explains Dr. Moll. "p53 acts via physical interaction with the critical PTP regulator Cyclophylin D (CypD). This p53 action occurs in cultured cells and in ischemic stroke in mice. "

Of note, they found in their model that when the destructive p53-CypD complex is blocked from forming by using Cyclosporine-A type inhibitors, the brain tissue is strongly protected from necrosis and stroke is prevented.

"The findings fundamentally expand our understanding of p53-mediated cell death networks," says Dr. Moll. "The data also suggest that acute temporary blockade of the destructive p53-CypD complex with clinically well-tolerated Cyclosporine A-type inhibitors may lead to a therapeutic strategy to limit the extent of an ischemic stroke in patients."

"p53 is one of the most important genes in cancer and by far the most studied," says Yusuf A. Hannun, M.D., Director of the Stony Brook University Cancer Center, Vice Dean for Cancer Medicine, and the Joel Kenny Professor of Medicine at Stony Brook. "Therefore, this discovery by Dr. Moll and her colleagues in defining the mechanism of a new p53 function and its importance in necrotic injury and stoke is truly spectacular."

Dr. Moll has studied p53 for 20 years in her Stony Brook laboratory. Her research has led to numerous discoveries about the function of p53 and two related genes. For example, previous to this latest finding regarding p53 and stroke, Dr. Moll identified that p73, a cousin to p53, steps in as a tumor suppressor gene when p53 is lost and can stabilize the genome. She found that p73 plays a major developmental role in maintaining the neural stem cell pool during brain formation and adult learning. Her work also helped to identify that another p53 cousin, called p63, has a critical surveillance function in the male germ line and likely contributed to the evolution of humans and great apes, enabling their long reproductive periods.

Source: Science Daily

ScienceDaily (June 22, 2012) — Scientists have discovered that plant compounds from a South African flower may in time be used to treat diseases originating in the brain — including depression. At the University of Copenhagen, a number of these substances have now been tested in a laboratory model of the blood-brain barrier.

Crinum from South Africa. (Credit: Gary I. Stafford)

Scientists at the University of Copenhagen have previously documented that substances from the South African plant species Crinum and Cyrtanthus — akin to snowdrops and daffodils — have an effect on the mechanisms in the brain that are involved in depression. This research has now yielded further results, since a team based at the Faculty of Health and Medical Sciences has recently shown how several South African daffodils contain plant compounds whose characteristics enable them to negotiate the defensive blood-brain barrier that is a key challenge in all new drug development.

"Several of our plant compounds can probably be smuggled past the brain’s effective barrier proteins. We examined various compounds for their influence on the transporter proteins in the brain. This study was made in a genetically-modified cell model of the blood-brain barrier that contains high levels of the transporter P-glycoprotein. Our results are promising, and several of the chemical compounds studied should therefore be tested further, as candidates for long-term drug development," says Associate Professor Birger Brodin.

"The biggest challenge in medical treatment of diseases of the brain is that the drug cannot pass through the blood-brain barrier. The blood vessels of the brain are impenetrable for most compounds, one reason being the very active transporter proteins. You could say that the proteins pump the drugs out of the cells just as quickly as they are pumped in. So it is of great interest to find compounds that manage to ‘trick’ this line of defence."

The results of the study have been published in the Journal of Pharmacy and Pharmacology.

It will nonetheless be a long time before any possible new drug reaches our pharmacy shelves: “This is the first stage of a lengthy process, so it will take some time before we can determine which of the plant compounds can be used in further drug development,” says Birger Brodin.

Yet this does not curb his enthusiasm for the opportunities from the interdisciplinary cooperation with organic scientists from the Department of Drug Design and Pharmacology and the Natural History Museum of Denmark.

"In my research group, we have had a long-term focus on the body’s barrier tissue — and in recent years particularly the transport of drug compounds across the blood-brain barrier. More than 90 per cent of all potential drugs fail the test by not making it through the barrier, or being pumped out as soon as they do get in. Studies of natural therapies are a valuable source of inspiration, giving us knowledge that can also be used in other contexts," Birger Brodin emphasises.

Source: Science Daily

June 22, 2012 By Virat Markandeya

Listening to a single voice in a crowded cocktail party sometimes seems like picking a needle out of a haystack, but new research shows that people may be better at this than expected.

New research shows that people can comprehend one sound among many.

The results surprised the University of Washington, Seattle, research team, which tested how well people could pick out one sound from a dense collection of noises.

The researchers asked ten subjects to listen to multiple streams of letters. A stream consisted of a repeating letter, for example, Q-Q-Q-Q. If four streams were played, the listener heard four different repeating letters, say, D, C, Q and J. The letters came fast —the time interval between each letter was just one-twelfth of a second.

In front of the listener was a computer screen. Before the start of each trial, the researchers put one of the four letters on the screen to prime the subject to focus on it. If he heard an oddball letter in that stream, such as R instead of Q, he was to press a button.

To make it easier on the listener, each letter stream carried a different pitch and came from a different location in the room. R was chosen as the oddball because it doesn’t rhyme with any other letter.  

"Unlike most experiments where you try to make it difficult for the listener to do the task, we tried to give every advantage we could," said Adrian K.C. Lee, a speech and hearing researcher at the university, who worked closely with Ross Maddox.

As expected, when the number of streams went up, the ability to discern the letter came down. But even with 12 streams the letter was identified correctly around 70 percent of the time.

"We expected that 12 streams would have broken the upper limits of the [subject’s hearing] system," said Lee. "It is surprising that even with twelve things coming at you at the same time you can lock on to one with reasonably high accuracy."

The work was presented last month at the Acoustics 2012 Hong Kong conference.

Down the line, the researchers want to use these experiments to design a way for paralyzed patients to control a wheelchair or a computer using brain signals. Such devices, called brain-computer interfaces, have mostly relied on visual or motor stimuli. Typically, a subject might focus on a visual cue or imagine making a movement. Using a machine that detects brain signals, such as an electroencephalogram, researchers would attempt to characterize the brain responses connected with that task and translate them into commands. Focusing on an auditory signal too produces brain signals that can be characterized. However, the current study did not look at brain signals.

A very practical reason to look at auditory interfaces is that eye-gaze control — on which visually-controlled interfaces are based — is often absent in people in a late stage of a neurodegenerative disease, said Martijn Schreuder, a researcher at the Berlin Institute of Technology.

Schreuder, who has worked on an interface where subjects spelled words by focusing on particular sounds, pointed out that auditory interfaces allow someone who is completely blind to communicate.

Schreuder said Lee’s work provides hints on “whether or not it’s good or bad to have different [audio] streams or whether it is good to have a quicker repetition or not.” To his knowledge, this is the first time researchers have gone up to 12 streams. Previous research included only two streams.

The other part Schreuder found interesting was how quickly the listeners learned how to discriminate between letter streams.

"There is a difference between being able to spell one letter every two minutes or spelling three letters per minute, which is the range [brain-computer interfaces] go," Schreuder said. "So if one selection takes 20 seconds, it’s worse than if it goes 10 seconds."

The University of Washington researchers are planning follow-up experiments to directly investigate how the brain responds to audio streams.

Provided by Inside Science News Service

Source: medicalxpress.com