Posts tagged brain
Articles and news from the latest research reports.
Researchers Develop Gene Therapy to Boost Brain Repair for Demyelinating Diseases
February 10th, 2012
Our bodies are full of tiny superheroes—antibodies that fight foreign invaders, cells that regenerate, and structures that ensure our systems run smoothly. One such structure is myelin—a material that forms a protective, insulating cape around the axons of our nerve cells so that they can send signals quickly and efficiently. But myelin, and the specialized cells called oligodendrocytes that make it, become damaged in demyelinating diseases like multiple sclerosis (MS), leaving neurons without their myelin sheaths. As a consequence, the affected neurons can no longer communicate correctly and are prone to damage. Researchers from the California Institute of Technology (Caltech) now believe they have found a way to help the brain replace damaged oligodendrocytes and myelin.
The therapy, which has been successful in promoting remyelination in a mouse model of MS, is outlined in a paper published February 8 in The Journal of Neuroscience.
“We’ve developed a gene therapy to stimulate production of new oligodendrocytes from stem and progenitor cells—both of which can become more specialized cell types—that are resident in the adult central nervous system,” says Benjamin Deverman, a postdoctoral fellow in biology at Caltech and lead author of the paper. “In other words, we’re using the brain’s own progenitor cells as a way to boost repair.”
The therapy uses leukemia inhibitory factor (LIF), a naturally occurring protein that was known to promote the self-renewal of neural stem cells and to reduce immune-cell attacks to myelin in other MS mouse models.
“What hadn’t been done before our study was to use gene therapy in the brain to stimulate these cells to remyelinate,” says Paul Patterson, the Biaggini Professor of Biological Sciences at Caltech and senior author of the study.
According to the researchers, LIF enables remyelination by stimulating oligodendrocyte progenitor cells to proliferate and make new oligodendrocytes. The brain has the capacity to produce oligodendrocytes, but often fails to prompt a high enough repair response after demyelination.
“Researchers had been skeptical that a single factor could lead to remyelination of damaged cells,” says Deverman. “It was thought that you could use factors to stimulate the division and expansion of the progenitor population, and then add additional factors to direct those progenitors to turn into the mature myelin-forming cells. But in our mouse model, when we give our LIF therapy, it both stimulates the proliferation of the progenitor cells and allows them to differentiate into mature oligodendrocytes.”
In other words, once the researchers stimulated the proliferation of the progenitor cells, it appeared that the progenitors knew just what was needed—the team did not have to instruct the cells at each stage of development. And they found that LIF elicited such a strong response that the treated brain’s levels of myelin-producing oligodendrocytes were restored to those found in healthy populations.
The researchers note, too, that by placing LIF directly in the brain, one avoids potential side effects of the treatment that may arise when the therapy is infused into the bloodstream.
“This new application of LIF is an avenue of therapy that has not been explored in human patients with MS,” says Deverman, who points out that LIF’s benefits might also be good for spinal-cord injury patients since the demyelination of spared neurons may contribute to disability in that disorder.
To move the research closer to human clinical trials, the team will work to build better viral vectors for the delivery of LIF. “The way this gene therapy works is to use a virus that can deliver the genetic material—LIF—into cells,” explains Patterson. “This kind of delivery has been used before in humans, but the worry is that you can’t control the virus. You can’t necessarily target the right place, and you can’t control how much of the protein is being made.”
Which is why he and Deverman are developing viruses that can target LIF production to specific cell types and can turn it on and off externally, providing a means to regulate LIF levels. They also plan to test the therapy in additional MS mouse models.
“For MS, the current therapies all work by modulating or suppressing the immune system, because it’s thought to be a disease in which inflammation leads to immune-associated loss of oligodendrocytes and damage to the neurons,” says Deverman. “Those therapies can reduce the relapse rate in patients, but they haven’t shown much of an effect on the long-term progression of the disease. What are needed are therapies that promote repair. We hope this may one day be such a therapy.”
Source: Neuroscience News
A research team in Taiwan has succeeded in isolating two nerve cells in fruit fly brains that are believed to be the major players in allowing for the formation of long term memories. Furthermore, they’ve also found the genes that appear to be essential in creating related proteins that allow such memories to be saved.
Source: medicalxpress.com
Flipping a Light Switch in the Cell: Quantum Dots Used for Targeted Neural Activation
February 9th, 2012
New technique holds promise for better understanding of brain disorders.
Quantum dot film. Optically excited quantum dots in close proximity to a cell control the opening of ion channels. Credit: Lugo et al., University of Washington.
Source: Neuroscience News
FDA-approved drug rapidly clears amyloid from the brain, reverses Alzheimer’s symptoms in mice
February 9, 2012
Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer’s disease. The researchers’ findings, published in the journal Science, show that use of a drug in mice appears to quickly reverse the pathological, cognitive and memory deficits caused by the onset of Alzheimer’s. The results point to the significant potential that the medication, bexarotene, has to help the roughly 5.4 million Americans suffering from the progressive brain disease.
Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer’s disease, and the results were more than promising.
Alzheimer’s disease arises in large part from the body’s inability to clear naturally-occurring amyloid beta from the brain. In 2008 Case Western Reserve researcher Gary Landreth, PhD, professor of neurosciences, discovered that the main cholesterol carrier in the brain, Apolipoprotein E (ApoE), facilitated the clearance of the amyloid beta proteins. Landreth, a professor of neurosciences in the university’s medical school, is the senior author of this study as well.
Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced.
In particular, the researchers were struck by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of Alzheimer’s disease. The present view of the scientific community is that small soluble forms of amyloid beta cause the memory impairments seen in animal models and humans with the disease. Within six hours of administering bexarotene, however, soluble amyloid levels fell by 25 percent; even more impressive, the effect lasted as long as three days. Finally, this shift was correlated with rapid improvement in a broad range of behaviors in three different mouse models of Alzheimer’s.
One example of the improved behaviors involved the typical nesting instinct of the mice. When Alzheimer’s-diseased mice encountered material suited for nesting – in this case, tissue paper – they did nothing to create a space to nest. This reaction demonstrated that they had lost the ability to associate the tissue paper with the opportunity to nest. Just 72 hours after the bexarotene treatment, however, the mice began to use the paper to make nests. Administration of the drug also improved the ability of the mice to sense and respond to odors.
Bexarotene treatment also worked quickly to stimulate the removal of amyloid plaques from the brain. The plaques are compacted aggregates of amyloid that form in the brain and are the pathological hallmark of Alzheimer’s disease. Researchers found that more than half of the plaques had been cleared within 72 hours. Ultimately, the reduction totaled 75 percent. It appears that the bexarotene reprogrammed the brain’s immune cells to “eat” or phagocytose the amyloid deposits. This observation demonstrated that the drug addresses the amount of both soluble and deposited forms of amyloid beta within the brain and reverses the pathological features of the disease in mice.
This study identifies a link between the primary genetic risk factor for Alzheimer’s disease and a potential therapy to address it. Humans have three forms of ApoE: ApoE2, ApoE3, and ApoE4. Possession of the ApoE4 gene greatly increases the likelihood of developing Alzheimer’s disease. Previously, the Landreth laboratory had shown that this form of ApoE was impaired in its ability of clear amyloid. The new work suggests that elevation of ApoE levels in the brain may be an effective therapeutic strategy to clear the forms of amyloid associated with impaired memory and cognition.
"This is an unprecedented finding," says Paige Cramer, PhD candidate at Case Western Reserve School of Medicine and first author of the study. "Previously, the best existing treatment for Alzheimer’s disease in mice required several months to reduce plaque in the brain."
Added Professor Landreth: “This is a particularly exciting and rewarding study because of the new science we have discovered and the potential promise of a therapy for Alzheimer’s disease. We need to be clear; the drug works quite well in mouse models of the disease. Our next objective is to ascertain if it acts similarly in humans. We are at an early stage in translating this basic science discovery into a treatment.”
Daniel Wesson, PhD, assistant professor of neurosciences at Case Western Reserve School of Medicine and co-author of the study agreed.
"Many often think of Alzheimer’s as a problem of remembering and learning, but the prevalent reality is this disease spreads throughout the brain, resulting in serious insults to numerous functions," he said. "The results of this study, showing the preservation of behaviors across a wide spectrum, and accompanying brain function, are tremendously exciting and suggest great promise in the utility of this approach in treatment of Alzheimer’s disease."
Bexarotene has a good safety and side-effect profile. The Case Western Reserve researchers hope these attributes will help speed the transition to clinical trials of the drug.
Professor Landreth said modest resources funded this self-described “far-fetched idea.” Crucial support came from the Blanchette Hooker Rockefeller Foundation, the Thome Foundation, and the National Institutes of Health.
Provided by Case Western Reserve University
Source: medicalxpress.com
Gene Therapy for Inherited Blindness Succeeds in Patients’ Other Eye
After gene therapy for congenital blindness, areas in the part of the brain responsible for vision show a response after a visual stimulus (Credit: The Children’s Hospital of Philadelphia)
Source: Science Daily
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)
Source: medicalxpress.com
'Explorers,' who embrace the uncertainty of choices, use specific part of cortex
February 8, 2012
"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 theprefrontal 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
Source: medicalxpress.com
Scientists delve into the brain roots of hunger and eating
February 8, 2012
Synaptic plasticity – the ability of the synaptic connections between the brain’s neurons to change and modify over time — has been shown to be a key to memory formation and the acquisition of new learning behaviors. Now research led by a scientific team at Beth Israel Deaconess Medical Center (BIDMC) reveals that the neural circuits controlling hunger and eating behaviors are also controlled by plasticity.
Described in the February 9, 2012 issue of the journal Neuron, the findings show that during fasting, the AgRP neurons that drive feeding behaviors actually undergo anatomical changes that cause them to become more active, which results in their “learning” to be more responsive to hunger-promoting neural stimuli.
"The role of plasticity has generally not been evaluated in neuronal circuits that control feeding behavior and with this new discovery we can start to unravel the basic mechanisms underpinning hunger and gain a greater understanding of the factors that influence weight gain and obesity," explains senior author Bradford Lowell, MD, PhD, an investigator in BIDMC’s Division of Endocrinology, Diabetes and Metabolism and Professor of Medicine at Harvard Medical School (HMS).
Adds BIDMC Chairman of Neurology Clifford Saper, MD, PhD, “For most animals, finding enough food to survive is their biggest daily challenge, and so the brain’s increase in feeding drive may be adaptive. But, for humans who are overweight, reducing this drive to the AgRP neurons may prove to be a path to future weight loss therapies.”
The roots of hunger, eating, and weight are based in the brain’s complex and rapid-fire neurocircuitry. Over the years, nerve cells containing agouti-related peptide (AgRP) protein and pro-opiomelanocortin (POMC) protein have emerged as critical players in feeding behaviors. Located in the hypothalamus, the brain area that controls automatic body functions, AgRP neurons have been shown to drive eating and weight gain while POMC neurons inhibit feeding behaviors, causing satiety and weight loss.
Previous work by the Lowell lab and others had demonstrated that when AgRP neurons in mice are artificially switched on, the animals eat voraciously, consuming four times more than control animals. “The ‘switched-on’ animals search in an unrelenting fashion for food, and when given a task to obtain pellets, will work five times harder to get them,” Lowell explains.
Given the important role played by AgRP neurons, the scientists had a great interest in understanding the factors that regulate their activity. While much focus had centered on hormones, including leptin, insulin and ghrelin, as the possible mechanisms directly affecting neuronal activity, the Lowell team hypothesized that other nerve cells might be behind the regulation.
Neurons communicate with one another via neurotransmitters, chemical messengers that traverse synapses, the specialized junctions between upstream and downstream neurons. Glutamate is one such excitatory neurotransmitter.
"Studies in other regions of the brain [for example those controlling learning and reward and addiction behaviors] have demonstrated that glutamate synapses are highly plastic, changing in their strength and sometimes even in their number," explains Lowell. Shown to exert powerful control over behavior, synaptic plasticity is brought about when glutamate binds to NMDA receptors on downstream neurons.
"NMDA receptors are unusual and really interesting," he adds. "When glutamate gets released by upstream neurons and binds to NMDA receptors, calcium enters the downstream neuron. This, in turn, engages signal transduction pathways that cause synaptic plasticity. In other parts of the brain, such as the hippocampus, NMDA receptors drive plasticity which serves to encode memories."
Led by co-first authors Tiemin Liu, PhD, Dong Kong, PhD, Bhavik P. Shah, PhD, and Chianping Ye, PhD, the investigators created and studied mice genetically engineered to lack glutamate-binding NMDA receptors on the AgRP neurons. For the sake of comparison, they also created mice genetically engineered to lack NMDA receptors on POMC neurons.
They found that while mice lacking NMDA receptors on POMC neurons showed no change in feeding behavior, the situation was dramatically different in the mice lacking NMDA receptors on AgRP neurons.
"These mice ate a lot less and were much skinnier than a group of control mice," explains Lowell. Furthermore, the scientists found that a 24-hour period of fasting – which causes intense hunger in the control mice – was associated with a 67 percent increase in the number of dendritic spines on the AgRP neurons.
"Dendritic spines are tiny structures attached to the neuron’s dendrites, the tree-like branches that receive incoming signals from upstream neurons," explains Lowell. "These structures are the physical site, the subcellular communication hub, where synaptic input from upstream glutamate-releasing neurons is received, typically one synaptic input per spine."
"I’ve been studying spines for a long time and I’ve never before seen a manipulation that triggered such rapid and robust changes in spine number," says coauthor Bernardo Sabatini, MD, PhD, a Howard Hughes Medical Institute investigator in the Department of Neurobiology at Harvard Medical School. "Clearly, feeding is plugging in to the most basic mechanisms that control synapse and spine number in these cells. This may be a great system to understand not only feeding behavior, but also to understand the cell biology behind dynamic synapse formation and retraction."
When the control mice were refed – and their hunger alleviated – the number of spines dropped back to normal. (In contrast, fasting had no effect on spine number in the mutant mice lacking NMDA receptors on AgRP neurons.) These dramatic changes in spine number and their tight association with states of hunger and satiety in control mice – and the absence of changes in spine number in mice lacking NMDA receptors on the downstream AgRP neurons– strongly suggests that structural plasticity of excitatory glutamate synapses on AgRP neurons is an important regulator of feeding behavior, says Lowell.
"Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, and certain types of cancer," he adds. "By understanding the neurobiological mechanisms underlying feeding behaviors, we can work on treatments for a problem that has now become a global epidemic. These findings move us closer to a mechanistic understanding of how various factors controlling hunger might work."
Provided by Beth Israel Deaconess Medical Center
Source: medicalxpress.com
Neuroscientists link brain-wave pattern to energy consumption
February 8, 2012 by Anne Trafton
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 PNASpaper. “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
Source: medicalxpress.com
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 | February 8, 2012
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