Posts tagged science
Articles and news from the latest research reports.
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
Research links ‘brain waves’ to cognition, attention and diagnosing disorders
February 7, 2012
Professor Jason Mattingley, Foundation Chair in Cognitive Neuroscience at The University of Queensland, released his findings into ‘brain waves’ at the Australian Neuroscience Society’s (ANS) annual conference last week.
'Brain waves' are the oscillations produced by the brain, which are thought to contribute to its remarkable capacity to integrate information about the world.
According to Professor Mattingley’s research, brain oscillations can be linked to sleep, navigation, cognition, attention, and to diagnosing a wide range of disorders including autism, schizophrenia and epilepsy.
To understand how the brain filters information during visual attention and perception, Professor Mattingley and his fellow researchers encouraged subjects to perform tasks involving the use of flickering stimuli on a computer display. This included embedding colour-coded visual information to see how well subjects track a specific target colour from a myriad of distracting information.
“Imagine the brain as a stadium full of sports fans. Each spectator is like an individual neuron in the brain. Now imagine the spectators starting a Mexican wave that sweeps through the crowd from one side of the stadium to the other. Our research shows that neurons in the brain act in much the same way. Distinct waves of neural activity, moving at different speeds and in different directions, help coordinate neurons across widely separated areas of the brain,” Professor Mattingley said.
“We can measure these brain waves as people engage in different tasks, such as focusing their attention on just one colour in multi-coloured display. The measurements we take from the brain are a bit like the ripples from a handful of pebbles thrown into a pond.”
“While interesting in their own right, these studies are also relevant to brain dysfunction, as defects in neural responses to flickering visual stimuli have been found in individuals with autism, schizophrenia, and epilepsy, and such oscillations have been found to be significantly altered in aging, depression, and neurodegenerative disorders. Using these tasks may help to both diagnose and understand the basis for differences in brain function in people with these conditions.”
The Australian Neuroscience Society’s (ANS) annual conference brings together researchers in search of a greater understanding of the human nervous system and its functions.
As part of the program around 100 international speakers and delegates shared their insights into the peripheral senses - touch, sight, hearing and smell – perception, cognition, learning and memory, with a particular focus on neurological and neurodegenerative disease.
Provided by University of Queensland
Source: medicalxpress.com
Brain cells created from patients’ skin cells
Cambridge scientists have, for the first time, created cerebral cortex cells – those that make up the brain’s grey matter – from a small sample of human skin. The researchers’ findings, which were funded by Alzheimer’s Research UK and the Wellcome Trust, were published today inNature Neuroscience.
Source: medicalxpress.com
Warning! Collision imminent! The brain’s quick interceptions help you navigate the world
February 7, 2012
Researchers at The Neuro and the University of Maryland have figured out the mathematical calculations that specific neurons employ in order to inform us of our distance from an object and the 3-D velocities of moving objects and surfaces relative to ourselves.
When you are about to collide into something and manage to swerve away just in the nick of time, what exactly is happening in your brain? A new study from the Montreal Neurological Institute and Hospital – The Neuro, McGill University shows how the brain processes visual information to figure out when something is moving towards you or when you are about to head into a collision. The study, published in the Proceedings of the National Academy of Sciences (PNAS), provides vital insight into our sense of vision and a greater understanding of the brain.
Researchers at The Neuro and the University of Maryland have figured out the mathematical calculations that specific neurons employ in order to inform us of our distance from an object and the 3D velocities of moving objects and surfaces relative to ourselves. Highly specialized neurons located in the brain’s visual cortex, in an area known as MST, respond selectively to motion patterns such as expansion, rotation, and deformation. However, the computations underlying such selectivity were unknown until now.
Using mathematical models and sophisticated recording techniques, researchers have discovered how individual MST neurons function. “Area MST is typical of high-level visual cortex, in that information about important aspects of vision can be seen in the firing patterns of single neurons. A classic example is a neuron that only fires when the subject is looking at the image of a particular face. This type of neuron has to gather information from other neurons that are selective to simpler features, like lines, colors, and textures, and combine these pieces of information in a fairly sophisticated way,” says Dr. Christopher Pack, neuroscientist at The Neuro and senior author. “Similarly, for motion detection, neurons have to combine input from many other neurons earlier in the visual pathway, in order to determine whether something is moving toward you or just drifting past.” The brain’s visual pathway is made up of building blocks. For example, neurons in the retina respond to very simple stimuli, such as small spots of light. Further along the visual pathway, neurons respond to more complex stimulus such as straight lines, by combining inputs from neurons earlier on. Neurons further along respond to even more complex stimulus such as combinations of lines (angles), ultimately leading to neurons that can respond to, or recognize, faces and objects for example.
Source: medicalxpress.com
Study of Live Human Neurons Reveals Parkinson’s Origins
ScienceDaily (Feb. 7, 2012) — Parkinson’s disease researchers at the University at Buffalo have discovered how mutations in the parkin gene cause the disease, which afflicts at least 500,000 Americans and for which there is no cure.
The results are published in the current issue of Nature Communications. The UB findings reveal potential new drug targets for the disease as well as a screening platform for discovering new treatments that might mimic the protective functions of parkin. UB has applied for patent protection on the screening platform.
"This is the first time that human dopamine neurons have ever been generated from Parkinson’s disease patients with parkin mutations," says Jian Feng, PhD, professor of physiology and biophysics in the UB School of Medicine and Biomedical Sciences and the study’s lead author.
As the first study of human neurons affected by parkin, the UB research overcomes a major roadblock in research on Parkinson’s disease and on neurological diseases in general. The problem has been that human neurons live in a complex network in the brain and thus are off-limits to invasive studies, Feng explains.
"Before this, we didn’t even think about being able to study the disease in human neurons," he says. "The brain is so fully integrated. It’s impossible to obtain live human neurons to study."
But studying human neurons is critical in Parkinson’s disease, Feng explains, because animal models that lack the parkin gene do not develop the disease; thus, human neurons are thought to have “unique vulnerabilities.”
"Our large brains may use more dopamine to support the neural computation needed for bipedal movement, compared to quadrupedal movement of almost all other animals," he says. Since in 2007, when Japanese researchers announced they had converted human cells to induced pluripotent stem cells (iPSCs) that could then be converted to nearly any cells in the body, mimicking embryonic stem cells, Feng and his UB colleagues saw their enormous potential. They have been working on it ever since.
"This new technology was a game-changer for Parkinson’s disease and for other neurological diseases," says Feng. "It finally allowed us to obtain the material we needed to study this disease."
The current paper is the fruition of the UB team’s ability to “reverse engineer” human neurons from human skin cells taken from four subjects: two with a rare type of Parkinson’s disease in which the parkin mutation is the cause of their disease and two healthy subjects who served as controls.
"Once parkin is mutated, it can no longer precisely control the action of dopamine, which supports the neural computation required for our movement," says Feng.
The UB team also found that parkin mutations prevent it from tightly controlling the production of monoamine oxidase (MAO), which catalyzes dopamine oxidation.
"Normally, parkin makes sure that MAO, which can be toxic, is expressed at a very low level so that dopamine oxidation is under control," Feng explains. "But we found that when parkin is mutated, that regulation is gone, so MAO is expressed at a much higher level. The nerve cells from our Parkinson’s patients had much higher levels of MAO expression than those from our controls. We suggest in our study that it might be possible to design a new class of drugs that would dial down the expression level of MAO."
He notes that one of the drugs currently used to treat Parkinson’s disease inhibits the enzymatic activity of MAO and has been shown in clinical trials to slow down the progression of the disease.
Parkinson’s disease is caused by the death of dopamine neurons. In the vast majority of cases, the reason for this is unknown, Feng explains. But in 10 percent of Parkinson’s cases, the disease is caused by mutations of genes, such as parkin: the subjects with Parkinson’s in the UB study had this rare form of the disease.
"We found that a key reason for the death of dopamine neurons is oxidative stress due to the overproduction of MAO," explains Feng. "But before the death of the neurons, the precise action of dopamine in supporting neural computation is disrupted by parkin mutations. This paper provides the first clues about what the parkin gene is doing in healthy controls and what it fails to achieve in Parkinson’s patients."
He noted in this study that these defects are reversed by delivering the normal parkin gene into the patients’ neurons, thus offering hope that these neurons may be used as a screening platform for discovering new drug candidates that could mimic the protective functions of parkin and potentially even lead to a cure for Parkinson’s.
While the parkin mutations are only responsible for a small percentage of Parkinson’s cases, Feng notes that understanding how parkin works is relevant to all Parkinson’s patients. His ongoing research on sporadic Parkinson’s disease, in which the cause is unknown, also points to the same direction.
Source: ScienceDaily