Posts tagged neuroscience
Articles and news from the latest research reports.
Brain picks out salient sounds from background noise by tracking frequency and time
New research reveals how our brains are able to pick out important sounds from the noisy world around us. The findings, published online today in the journal ‘eLife’, could lead to new diagnostic tests for hearing disorders.
Our ears can effortlessly pick out the sounds we need to hear from a noisy environment - hearing our mobile phone ringtone in the middle of the Notting Hill Carnival, for example - but how our brains process this information (the so-called ‘cocktail party problem’) has been a longstanding research question in hearing science.
Researchers have previously investigated this using simple sounds such as two tones of different pitches, but now researchers at UCL and Newcastle University have used complicated sounds that are more representative of those we hear in real life. The team used ‘machine-like beeps’ that overlap in both frequency and time to recreate a busy sound environment and obtain new insights into how the brain solves this problem.
In the study, groups of volunteers were asked to identify target sounds from within this noisy background in a series of experiments.
Sundeep Teki, a PhD student from the Wellcome Trust Centre for Neuroimaging at UCL and joint first author of the study, said: “Participants were able to detect complex target sounds from the background noise, even when the target sounds were delivered at a faster rate or there was a loud disruptive noise between them.”
Dr Maria Chait, a senior lecturer at UCL Ear Institute and joint first author on the study, adds: “Previous models based on simple tones suggest that people differentiate sounds based on differences in frequency, or pitch. Our findings show that time is also an important factor, with sounds grouped as belonging to one object by virtue of being correlated in time.”
Professor Tim Griffiths, Professor of Cognitive Neurology at Newcastle University and lead researcher on the study, said: “Many hearing disorders are characterised by the loss of ability to detect speech in noisy environments. Disorders like this that are caused by problems with how the brain interprets sound information, rather than physical damage to the ear and hearing machinery, remain poorly understood.
"These findings inform us about a fundamental brain mechanism for detecting sound patterns and identifies a process that can go wrong in hearing disorders. We now have an opportunity to create better tests for these types of hearing problems."
No Link Between Mercury Exposure and Autism-like Behaviors
The potential impact of exposure to low levels of mercury on the developing brain – specifically by women consuming fish during pregnancy – has long been the source of concern and some have argued that the chemical may be responsible for behavioral disorders such as autism. However, a new study that draws upon more than 30 years of research in the Republic of Seychelles reports that there is no association between pre-natal mercury exposure and autism-like behaviors.
“This study shows no evidence of a correlation between low level mercury exposure and autism spectrum-like behaviors among children whose mothers ate, on average, up to 12 meals of fish each week during pregnancy,” said Edwin van Wijngaarden, Ph.D., an associate professor in the University of Rochester Medical Center’s (URMC) Department of Public Health Sciences and lead author of the study which appears online today in the journal Epidemiology. “These findings contribute to the growing body of literature that suggest that exposure to the chemical does not play an important role in the onset of these behaviors.”
The debate over fish consumption has long created a dilemma for expecting mothers and physicians. Fish are high in beneficial nutrients such as, selenium, vitamin E, lean protein, and omega-3 fatty acids; the latter are essential to brain development. At the same time, exposure to high levels of mercury has been shown to lead to developmental problems, leading to the claim that mothers are exposing their unborn children to serious neurological impairment by eating fish during pregnancy. Despite the fact that the developmental consequences of low level exposure remain unknown, some organizations, including the U.S. Food and Drug Administration, have recommended that pregnant women limit their consumption of fish.
The presence of mercury in the environment is widespread and originates from both natural sources such as volcanoes and as a byproduct of coal-fired plants that emit the chemical. Much of this mercury ends up being deposited in the world’s oceans where it makes its way into the food chain and eventually into fish. While the levels of mercury found in individual fish are generally low, concerns have been raised about the cumulative effects of a frequent diet of fish.
The Republic of Seychelles has proven to be the ideal location to examine the potential health impact of persistent low level mercury exposure. With a population of 87,000 people spread across an archipelago of islands in the Indian Ocean, fishing is a both an important industry and a primary source of nutrition – the nation’s residents consume fish at a rate 10 times greater than the populations of the U.S. and Europe.
The Seychelles Child Development Study – a partnership between URMC, the Seychelles Ministries of Health and Education, and the University of Ulster in Ireland – was created in the mid-1980s to specifically study the impact of fish consumption and mercury exposure on childhood development. The program is one of the largest ongoing epidemiologic studies of its kind.
“The Seychelles study was designed to follow a population over a very long period of time and focus on relevant mercury exposure,” said Philip Davidson, Ph.D., principal investigator of the Seychelles Child Development Study and professor emeritus in Pediatrics at URMC. “While the amount of fish consumed in the Seychelles is significantly higher than other countries in the industrialized world, it is still considered low level exposure.”
The autism study involved 1,784 children, adolescents, and young adults and their mothers. The researchers were first able to determine the level of prenatal mercury exposure by analyzing hair samples that had been collected from the mothers around the time of birth, a test which can approximate mercury levels found in the rest of the body including the growing fetus.
The researchers then used two questionnaires to determine whether or not the study participants were exhibiting autism spectrum-like behaviors. The Social Communication Questionnaire was completed by the children’s parents and the Social Responsiveness Scale was completed by their teachers. These tests – which include questions on language skills, social communication, and repetitive behaviors – do not provide a definitive diagnosis, but they are widely used in the U.S. as an initial screening tool and may suggest the need for additional evaluation.
The mercury levels of the mothers were then matched with the test scores of their children and the researchers found that there was no correlation between prenatal exposure and evidence of autism-spectrum-like behaviors. This is similar to the result of previous studies of the nation’s children which have measured language skills and intelligence, amongst other outcomes, and have not observed any adverse developmental effects.
The study lends further evidence to an emerging belief that the “good” may outweigh the possible “bad” when it comes to fish consumption during pregnancy. Specifically, if mercury does adversely influence child development at these levels of exposure then the benefits of the nutrients found in the fish may counteract or perhaps even supersede the potential negative effects of the mercury.
“This study shows no consistent association in children with mothers with mercury levels that were six to ten times higher than those found in the U.S. and Europe,” said Davidson. “This is a sentinel population and if it does not exist here than it probably does not exist.”
“NIEHS has been a major supporter of research looking into the human health risks associated with mercury exposure,” said Cindy Lawler, Ph.D., acting branch chief at the National Institute of Environmental Health Sciences, part of National Institutes of Health. “The studies conducted in the Seychelles Islands have provided a unique opportunity to better understand the relationship between environmental factors, such as mercury, and the role they may play in the development of diseases like autism. Although more research is needed, this study does present some good news for parents.”
Researchers develop new approach for studying deadly brain cancer
Human glioblastoma multiforme, one of the most common, aggressive and deadly forms of brain cancer, is notoriously difficult to study. Scientists have traditionally studied cancer cells in petri dishes, which have none of the properties of the brain tissues in which these cancers grow, or in expensive animal models.
Now a team of engineers has developed a three-dimensional hydrogel that more closely mimics conditions in the brain. In a paper in the journal Biomaterials, the researchers describe the new material and their approach, which allows them to selectively tune up or down the malignancy of the cancer cells they study.
The new hydrogel is more versatile than other 3-D gels used for growing glioma (brain cancer) cells in part because it allows researchers to change individual parameters – the gel’s stiffness, for example, or the presence of molecular signals that can influence cancer growth – while minimally altering its other characteristics, such as porosity.
Being able to adjust these traits individually will help researchers tease out important features associated with the initial growth of a tumor as well as its response to clinical therapies, said University of Illinois chemical and biomolecular engineering professor Brendan Harley, who led the study with postdoctoral researcher Sara Pedron and undergraduate student Eftalda Becka. Harley is an affiliate of the Institute for Genomic Biology at Illinois.
The researchers found that they could increase or decrease the malignancy of glioma cells in their hydrogel simply by adding hyaluronic acid, a naturally occurring carbohydrate found in many tissues, especially the brain.
Hyaluronic acid (HA) is a key component of the extracellular matrix that provides structural and chemical support to cells throughout the body. HA contributes to cell proliferation and cell migration, and local changes in HA levels have been implicated in tumor growth.
“Hyaluronic acid is one of the major building blocks in the brain,” Harley said. “The structure of a newly forming brain tumor has some of this HA within it, but there’s also a lot of the HA in the brain surrounding the tumor.”
Previous studies have used hydrogels made out of nothing but hyaluronic acid to study gliomas, Harley said. “The problem there is that HA is structurally not very strong.” It also is difficult to adjust the amount of HA that the glioma cells are exposed to if their environment is 100 percent HA, he said.
In the new study, Pedron observed how glioma cells behaved in two different hydrogels – one based on methacrylated gelatin (GelMA) and the other using a more conventional polyethylene glycol (PEG) biomaterial. These two materials vary in one important trait: GelMA is a naturally derived material that contains adhesive sites that allow cells to latch onto it; synthetic PEG does not.
“The purpose of having these two systems was to isolate the effect of HA on glioma cells,” Pedron said. If changing HA levels produced different effects in different gels, that would indicate that the gels were contributing to those effects, she said.
Instead, Harley and Pedron found that additions of HA to glioma cells had “very similar” effects in both materials. Adding too little or too much HA led to reduced malignancy, while incorporating just enough HA led to significantly enhanced malignancy. This held true for multiple types of glioblastoma multiforme cells. This suggests that “it’s the HA itself that is likely the cause for this malignant change,” Harley said.
“If you have a material that allows you to selectively tune up or down malignancy, that will allow you to ask lots of questions about treatment methods for more malignant or less malignant forms of glioma. It also will allow scientists to try to get a response that’s closer to what you see in the body,” he said.
“If you talk to pathologists, they’ll say a biomaterial will never allow you to grow a full brain tumor, which is probably true,” Harley said. “But it’s realistic to think that a well-designed biomaterial will allow you to study aspects of glioma growth and treatment in a way that’s much richer than simply looking in a petri dish and much more accessible than trying to study tumor development within the brain itself.”
Controlling genes with light
New technique can rapidly turn genes on and off, helping scientists better understand their function.
Although human cells have an estimated 20,000 genes, only a fraction of those are turned on at any given time, depending on the cell’s needs — which can change by the minute or hour. To find out what those genes are doing, researchers need tools that can manipulate their status on similarly short timescales.
That is now possible, thanks to a new technology developed at MIT and the Broad Institute that can rapidly start or halt the expression of any gene of interest simply by shining light on the cells.
The work is based on a technique known as optogenetics, which uses proteins that change their function in response to light. In this case, the researchers adapted the light-sensitive proteins to either stimulate or suppress the expression of a specific target gene almost immediately after the light comes on.
“Cells have very dynamic gene expression happening on a fairly short timescale, but so far the methods that are used to perturb gene expression don’t even get close to those dynamics. To understand the functional impact of those gene-expression changes better, we have to be able to match the naturally occurring dynamics as closely as possible,” says Silvana Konermann, an MIT graduate student in brain and cognitive sciences.
The ability to precisely control the timing and duration of gene expression should make it much easier to figure out the roles of particular genes, especially those involved in learning and memory. The new system can also be used to study epigenetic modifications — chemical alterations of the proteins that surround DNA — which are also believed to play an important role in learning and memory.
Konermann and Mark Brigham, a graduate student at Harvard University, are the lead authors of a paper describing the technique in the July 22 online edition of Nature. The paper’s senior author is Feng Zhang, the W.M. Keck Assistant Professor in Biomedical Engineering at MIT and a core member of the Broad Institute and MIT’s McGovern Institute for Brain Research.
Shining light on genes
The new system consists of several components that interact with each other to control the copying of DNA into messenger RNA (mRNA), which carries genetic instructions to the rest of the cell. The first is a DNA-binding protein known as a transcription activator-like effector (TALE). TALEs are modular proteins that can be strung together in a customized way to bind any DNA sequence.
Fused to the TALE protein is a light-sensitive protein called CRY2 that is naturally found in Arabidopsis thaliana, a small flowering plant. When light hits CRY2, it changes shape and binds to its natural partner protein, known as CIB1. To take advantage of this, the researchers engineered a form of CIB1 that is fused to another protein that can either activate or suppress gene copying.
After the genes for these components are delivered to a cell, the TALE protein finds its target DNA and wraps around it. When light shines on the cells, the CRY2 protein binds to CIB1, which is floating in the cell. CIB1 brings along a gene activator, which initiates transcription, or the copying of DNA into mRNA. Alternatively, CIB1 could carry a repressor, which shuts off the process.
A single pulse of light is enough to stimulate the protein binding and initiate DNA copying. The researchers found that pulses of light delivered every minute or so are the most effective way to achieve continuous transcription for the desired period of time. Within 30 minutes of light delivery, the researchers detected an uptick in the amount of mRNA being produced from the target gene. Once the pulses stop, the mRNA starts to degrade within about 30 minutes.
In this study, the researchers tried targeting nearly 30 different genes, both in neurons grown in the lab and in living animals. Depending on the gene targeted and how much it is normally expressed, the researchers were able to boost transcription by a factor of two to 200.
Karl Deisseroth, a professor of bioengineering at Stanford University and one of the inventors of optogenetics, says the most important innovation of the technique is that it allows control of genes that naturally occur in the cell, as opposed to engineered genes delivered by scientists.
“You could control, at precise times, a particular genetic locus and see how everything responds to that, with high temporal precision,” says Deisseroth, who was not part of the research team.
Epigenetic modifications
Another important element of gene-expression control is epigenetic modification. One major class of epigenetic effectors is chemical modification of the proteins, known as histones, that anchor chromosomal DNA and control access to the underlying genes. The researchers showed that they can also alter these epigenetic modifications by fusing TALE proteins with histone modifiers.
Epigenetic modifications are thought to play a key role in learning and forming memories, but this has not been very well explored because there are no good ways to disrupt the modifications, short of blocking histone modification of the entire genome. The new technique offers a much more precise way to interfere with modifications of individual genes.
“We want to allow people to prove the causal role of specific epigenetic modifications in the genome,” Zhang says.
So far, the researchers have demonstrated that some of the histone effector domains can be tethered to light-sensitive proteins; they are now trying to expand the types of histone modifiers they can incorporate into the system.
“It would be really useful to expand the number of epigenetic marks that we can control. At the moment we have a successful set of histone modifications, but there are a good deal more of them that we and others are going to want to be able to use this technology for,” Brigham says.
(Source: web.mit.edu)
UC Davis stem cell study uncovers the brain-protective powers of astrocytes
One of regenerative medicine’s greatest goals is to develop new treatments for stroke. So far, stem cell research for the disease has focused on developing therapeutic neurons — the primary movers of electrical impulses in the brain — to repair tissue damaged when oxygen to the brain is limited by a blood clot or break in a vessel. New UC Davis research, however, shows that other cells may be better suited for the task.
Published today in the journal Nature Communications, the large, collaborative study found that astrocytes — neural cells that transport key nutrients and form the blood-brain barrier — can protect brain tissue and reduce disability due to stroke and other ischemic brain disorders.
“Astrocytes are often considered just ‘housekeeping’ cells because of their supportive roles to neurons, but they’re actually much more sophisticated,” said Wenbin Deng, associate professor of biochemistry and molecular medicine at UC Davis and senior author of the study. “They are critical to several brain functions and are believed to protect neurons from injury and death. They are not excitable cells like neurons and are easier to harness. We wanted to explore their potential in treating neurological disorders, beginning with stroke.”
Deng added that the therapeutic potential of astrocytes has not been investigated in this context, since making them at the purity levels necessary for stem cell therapies is challenging. In addition, the specific types of astrocytes linked with protecting and repairing brain injuries were not well understood.
The team began by using a transcription factor (a protein that turns on genes) known as Olig2 to differentiate human embryonic stem cells into astrocytes. This approach generated a previously undiscovered type of astrocyte called Olig2PC-Astros. More importantly, it produced those astrocytes at almost 100 percent purity.
The researchers then compared the effects of Olig2PC-Astros, another type of astrocyte called NPC-Astros and no treatment whatsoever on three groups of rats with ischemic brain injuries. The rats transplanted with Olig2PC-Astros experienced superior neuroprotection together with higher levels of brain-derived neurotrophic factor (BDNF), a protein associated with nerve growth and survival. The rats transplanted with NPC-Astros or that received no treatment showed much higher levels of neuronal loss.
To determine whether the astrocytes impacted behavior, the researchers used a water maze to measure the rats’ learning and memory. In the maze, the rats were required to use memory rather than vision to reach a destination. When tested 14 days after transplantation, the rats receiving Olig2PC-Astros navigated the maze in significantly less time than the rats that received NPC-Astros or no treatment.
The investigators used cell culture experiments to determine whether the astrocytes could protect neurons from oxidative stress, which plays a significant role in brain injury following stroke. They exposed neurons co-cultured with both types of astrocytes to hydrogen peroxide to replicate oxidative stress. They found that, while both types of astrocytes provided protection, the Olig2PC-Astros had greater antioxidant effects. Further investigation showed that the Olig2PC-Astros had higher levels of the protein Nrf2, which increased antioxidant activity in the mouse neurons.
“We were surprised and delighted to find that the Olig2PC-Astros protected neurons from oxidative stress in addition to rebuilding the neural circuits that improved learning and memory,” said Deng.
The investigators also investigated the genetic qualities of the newly identified astrocytes. Global microarray studies showed they were genetically similar to the standard NPC-Astros. The Olig2PC-Astros, however, expressed more genes (such as BDNF and vasoactive endothelial growth factor, or VEGF) associated with neuroprotection. Many of these genes help regulate the formation and function of synapses, which carry signals between neurons.
Additional experiments showed that both the Olig2PC-Astros and NPC-Astros accelerated synapse development in mouse neurons. The Olig2PC-Astros, however, had significantly greater protective effects over the NPC-Astros.
In addition to being therapeutically helpful, the Olig2PC-Astros showed no tumor formation, remained in brain areas where they were transplanted and did not differentiate into other cell types, such as neurons.
“Dr. Deng’s team has shown that this new method for deriving astrocytes from embryonic stem cells creates a cell population that is more pure and functionally superior to the standard method for astrocyte derivation,” said Jan Nolta, director of the UC Davis Institute for Regenerative Cures. “The functional improvement seen in the brain injury models is impressive, as are the higher levels of BDNF. I will be excited to see this work extended to other brain disease models such as Huntington’s disease and others, where it is known that BDNF has a positive effect.”
Deng added that the results could lead to stem cell treatments for many neurodegenerative diseases.
“By creating a highly purified population of astrocytes and showing both their therapeutic benefits and safety, we open up the possibility of using these cells to restore brain function for conditions such as Alzheimer’s disease, epilepsy, traumatic brain disorder, cerebral palsy and spinal cord injury,” said Deng.
New clues illuminate Alzheimer’s roots
Scientists at Rice University and the University of Miami have figured out how synthetic molecules designed at Rice latch onto the amyloid peptide fibrils thought to be responsible for Alzheimer’s disease. Their discovery could point the way toward therapies to halt or even reverse the insidious disease.
The metallic dipyridophenazine ruthenium molecules strongly bind to pockets created when fibrils form from misfolded proteins that cells fail to destroy. When excited under a spectroscope, the molecules luminesce, which indicates the presence of the fibrils. That much was known by Rice researchers, but until now the process was a mystery.
By combining their talents in biophysics (at Rice) and computer simulation (at Miami), researchers pinpointed four such pockets along the fibril where the hydrophobic (water-averse) molecules can bind. They believe their work will help chemists design molecules to keep the fibrils from forming the plaques found in Alzheimer’s patients.
The teams led by Rice chemist Angel Martí and Miami chemist Rajeev Prabhakar reported their results in the Journal of the American Chemical Society this month.
Two years ago, Martí and Nathan Cook, a graduate student in his lab and lead author of the new paper, combined ruthenium complexes with solutions containing the spaghetti-like amyloid fibrils. The complexes don’t luminesce by themselves, but when they link to an amyloid fibril, they can be triggered by light at one wavelength to glow at another; this helps the researchers “see” the fibrils.
This ability to track amyloids was a great step forward, but left open the question of why the complexes latched onto the fibrils at all, Cook said.
“We had no way to figure it out because our experimental techniques can’t identify binding sites,” he said. “The standard (used to analyze proteins) is to crystallize your material and use X-rays to determine where everything is positioned. The problem with amyloid beta is the fibrils are not uniform, and you can’t crystallize them. All you would get is an amorphous lump.”
But a door opened when Prabhakar, a theoretical and computational chemist who specializes in amyloids, contacted Martí and suggested a collaboration. “We both knew the other was working with amyloid betas,” Martí said. “We were able to figure out how many amyloid beta monomers (molecules that can bind with each other) had to come together to form fibrils, while he modeled the interactions. When we brought all the data together, we had a perfect match.”
“Basically, we learned from the model that we need two monomers to form a binding site,” Marti said. “The cleft where the ruthenium complex binds is completely hydrophobic, the same as the complex. Neither wants to be exposed to water, so when they find each other, they don’t have a choice but to come together. It turns out that’s exactly what needs to happen to turn on the photoluminescent response of the compound.”
Martí said testing various concentrations of monomers with ruthenium complexes helped them determine that a little more than two monomers, on average, was sufficient to get the “light switch” effect. Prabhakar’s analysis found four specific locations along the aggregating monomers where the ruthenium complexes could bind: two at the ends where the monomers tend to bind to each other, and two in the middle.
“It was a complicated system to model and we tried hard, using a variety of computational techniques,” Prabhakar said. “In the end, we were amazed to find our results in perfect agreement with the experiments performed in the Martí lab.”
The researchers called the end locations “A and B,” and the middle clefts “C and D.” The hydrophobic A and B sites exist only at the edges of the fibrils, which limits their exposure to the complexes, Martí said. “But there are lots of C and D sites,” he said. “That explains why the ruthenium complexes don’t inhibit the aggregation of fibrils. It seems the system prefers to bind another monomer, rather than a ruthenium complex, at the ends.
“But now that we understand the mechanism, we can design more hydrophobic complexes that could bind strongly to the ends and prevent further elongation of the fibril,” he said.
“There’s a whole variety of ways to tweak this that could potentially disrupt a binding pocket,” Cook said.
More challenges lie beyond the new discovery, he said. New research indicates toxic oligomers may be catalyzed by the formation of amyloid fibrils. “We might be able to prevent the formation of these oligomeric species by binding ruthenium complexes to the surface, which would completely change the surface chemistry of the fibrils,” Martí said. “These are the things we are really interested in doing right now.”
Chips that mimic the brain
Novel microchips imitate the brain’s information processing in real time. Neuroinformatics researchers from the University of Zurich and ETH Zurich together with colleagues from the EU and US demonstrate how complex cognitive abilities can be incorporated into electronic systems made with so-called neuromorphic chips: They show how to assemble and configure these electronic systems to function in a way similar to an actual brain.
No computer works as efficiently as the human brain – so much so that building an artificial brain is the goal of many scientists. Neuroinformatics researchers from the University of Zurich and ETH Zurich have now made a breakthrough in this direction by understanding how to configure so-called neuromorphic chips to imitate the brain’s information processing abilities in real-time. They demonstrated this by building an artificial sensory processing system that exhibits cognitive abilities.
New approach: simulating biological neurons
Most approaches in neuroinformatics are limited to the development of neural network models on conventional computers or aim to simulate complex nerve networks on supercomputers. Few pursue the Zurich researchers’ approach to develop electronic circuits that are comparable to a real brain in terms of size, speed, and energy consumption. “Our goal is to emulate the properties of biological neurons and synapses directly on microchips,” explains Giacomo Indiveri, a professor at the Institute of Neuroinformatics (INI), of the University of Zurich and ETH Zurich.
The major challenge was to configure networks made of artificial, i.e. neuromorphic, neurons in such a way that they can perform particular tasks, which the researchers have now succeeded in doing: They developed a neuromorphic system that can carry out complex sensorimotor tasks in real time. They demonstrate a task that requires a short-term memory and context-dependent decision-making – typical traits that are necessary for cognitive tests. In doing so, the INI team combined neuromorphic neurons into networks that implemented neural processing modules equivalent to so-called “finite-state machines” – a mathematical concept to describe logical processes or computer programs. Behavior can be formulated as a “finite-state machine” and thus transferred to the neuromorphic hardware in an automated manner. “The network connectivity patterns closely resemble structures that are also found in mammalian brains,” says Indiveri.
Chips can be configured for any behavior modes
The scientists thus demonstrate for the first time how a real-time hardware neural-processing system where the user dictates the behavior can be constructed. “Thanks to our method, neuromorphic chips can be configured for a large class of behavior modes. Our results are pivotal for the development of new brain-inspired technologies,” Indiveri sums up. One application, for instance, might be to combine the chips with sensory neuromorphic components, such as an artificial cochlea or retina, to create complex cognitive systems that interact with their surroundings in real time.
Literature:
E. Neftci, J. Binas, U. Rutishauser, E. Chicca, G. Indiveri, R. J. Douglas. Synthesizing cognition in neuromorphic electronic systems. PNAS. July 22, 2013.
(Source: mediadesk.uzh.ch)
Novel ‘top-down’ mechanism repatterns developing brain regions
Dennis O’Leary of the Salk Institute was the first scientist to show that the basic functional architecture of the cortex, the largest part of the human brain, was genetically determined during development. But as it so often does in science, answering one question opened up many others. O’Leary wondered what if the layout of the cortex wasn’t fixed? What would happen if it were changed?
In the August issue of Nature Neuroscience, O’Leary, holder of the Vincent J. Coates Chair of Molecular Neurobiology at Salk, and Andreas Zembrzycki, a postdoctoral researcher in his lab, demonstrate that altering the cortical layout is possible, and that this alteration produces significant changes in parts of the brain that connect with the cortex and define its functional properties. These mechanisms may lay at the heart of neural developmental problems, such as autism spectrum disorders (ASD).
The human cortex is involved in higher functions such as sensory perception, spatial reasoning, conscious thought and language. All mammals have areas in the cortex that process the senses, but they have them in different proportions. Mice, the favorite laboratory animal, are nocturnal, so they have a large somatosensory area (S1) in the cortex, responsible for somatosensation, or feelings of the body that include touch, pain, temperature and proprioception.
"The area layout of the cortex directly relates to the lifestyle of an animal," says Zembrzycki. "Areas are bigger or smaller according to the functional needs of the animal, not the physical size of the body parts from which they receive input."
Even with relative sizes to other species set in place, areas in the cortex of humans may differ greatly across individuals. Such variations may underlie why some people appear to be naturally better at certain perceptual tasks, such as hitting a baseball or detecting the details of visual illusions. In patients with neurological disorders, there is an even wider range of differences.
The neurons in S1 are arranged in functional groups called body maps according to the density of nerve endings in the skin; thus, there’s a larger group of neurons dedicated to the skin on the face, than the skin on the legs. Neurosurgeon Wilder Penfield famously illustrated this idea as a “sensory homunculus,” a cartoon of disproportionately sized body parts arching over the cortex. Mice have a similar “mouseunculus” in their cortex in which the body map of the facial whiskers is highly enlarged.
These perceptual maps are not set for life. For example, if innervation of a body part is diminished early in life during a critical period, its map may shrink, while other parts of the body map may grow in compensation. This is a version of “bottom-up plasticity,” in which external experience affects body maps in the brain.
In order to study cortical layout, O’Leary’s team altered a regulatory gene, Pax6, in the cortex in mice. In response, S1 became much smaller, demonstrating that Pax6 regulates its development. They found that the shrinkage in S1 subsequently affected other regions of the brain that feed sensory information into the cortex, but more interestingly, it also altered the body maps in these subcortical brain regions, overturning the idea that once established, these brain regions could only be changed by external experience. They dubbed this previously unknown phenomenon “top down plasticity.”
"Top-down plasticity complements in a reverse fashion the well-known bottom-up plasticity induced by sensory deprivation," says O’Leary.
Normally, the body map in S1 cortex mirrors similar body maps in the thalamus, the main switching station for sensory information, which transmits somatosensation from the body periphery to the S1 cortex through outgoing neural “wires” known as axons. In the newly discovered top-down plasticity, when S1 was made smaller, the sensory thalamus that feeds into it is also subsequently reduced in size.
But the story has a more intriguing twist. “According to our present knowledge about the development of sensory circuits, we anticipated that all body representations in S1 would be equally affected when S1 was made smaller,” says O’Leary. “It was a surprise to us that not only was the body map smaller, but some parts of it were completely missing. The specific deletion of parts of the body map is controlled by exaggerated competition for cortical resources dictated by S1 size and played out between the connections from thalamic neurons that form these maps in the cortex.”
"To put it in lay terms, ‘If you snooze, you lose,’" adds Zembrzycki. "Axons that differentiate later are preferentially excluded from the smaller S1 leading to the specific deletion of the body parts that they represent."
"The essential point about top-down plasticity is that altering the size and patterning of sensory cortex results in matching alterations in sensory thalamus through the selective death of thalamic neurons that normally would represent body parts absent from S1," Zembrzycki adds. "Therefore, a downstream part of the brain is repatterned to match the architecture in S1, resulting in aberrant wiring of the brain that has important implications for sensory perception and function. For example, autistics have very robust abnormalities in touching and other features of somatosensation."
O’Leary and Zembrzycki believe that this process provides significant insights into the development of autism and other neural disorders. “One of the hallmarks of the autistic brain early in development is the area profile seems to be abnormal, with for example, the frontal cortex being enlarged, while the overall cortex keeps its normal size,” says O’Leary. “It is implicit then that other cortical areas positioned behind the frontal areas, such as S1, would be reduced in size, and thalamus would exhibit defects that match those in sensory cortex, as has been shown to be the case in autistic patients.”
Breastfeeding Could Prevent ADHD
TAU research finds that breastfed children are less likely to develop ADHD later in life
We know that breastfeeding has a positive impact on child development and health — including protection against illness. Now researchers from Tel Aviv University have shown that breastfeeding could also help protect against Attention Deficit/Hyperactivity Disorder (ADHD), the most commonly diagnosed neurobehavioral disorder in children and adolescents.
Seeking to determine if the development of ADHD was associated with lower rates of breastfeeding, Dr. Aviva Mimouni-Bloch, of Tel Aviv University’s Sackler Faculty of Medicine and Head of the Child Neurodevelopmental Center in Loewenstein Hospital, and her fellow researchers completed a retrospective study on the breastfeeding habits of parents of three groups of children: a group that had been diagnosed with ADHD; siblings of those diagnosed with ADHD; and a control group of children without ADHD and lacking any genetic ties to the disorder.
The researchers found a clear link between rates of breastfeeding and the likelihood of developing ADHD, even when typical risk factors were taken into consideration. Children who were bottle-fed at three months of age were found to be three times more likely to have ADHD than those who were breastfed during the same period. These results have been published in Breastfeeding Medicine.
Understanding genetics and environment
In their study, the researchers compared breastfeeding histories of children from six to 12 years of age at Schneider’s Children Medical Center in Israel. The ADHD group was comprised of children that had been diagnosed at the hospital, the second group included the siblings of the ADHD patients, and the control group included children without neurobehavioral issues who had been treated at the clinics for unrelated complaints.
In addition to describing their breastfeeding habits during the first year of their child’s life, parents answered a detailed questionnaire on medical and demographic data that might also have an impact on the development of ADHD, including marital status and education of the parents, problems during pregnancy such as hypertension or diabetes, birth weight of the child, and genetic links to ADHD.
Taking all risk factors into account, researchers found that children with ADHD were far less likely to be breastfed in their first year of life than the children in the other groups. At three months, only 43 percent of children in the ADHD group were breastfed compared to 69 percent of the sibling group and 73 percent of the control group. At six months, 29 percent of the ADHD group was breastfed, compared to 50 percent of the sibling group and 57 percent of the control group.
One of the unique elements of the study was the inclusion of the sibling group, says Dr. Mimouni-Bloch. Although a mother will often make the same breastfeeding choices for all her children, this is not always the case. Some children’s temperaments might be more difficult than their siblings’, making it hard for the mother to breastfeed, she suggests.
Added protection
While researchers do not yet know why breastfeeding has an impact on the future development of ADHD — it could be due to the breast milk itself, or the special bond formed between mother and baby during breastfeeding, for example — they believe this research shows that breastfeeding can have a protective effect against the development of the disorder, and can be counted as an additional biological advantage for breastfeeding.
Dr. Mimouni-Bloch hopes to conduct a further study on breastfeeding and ADHD, examining children who are at high risk for ADHD from birth and following up in six-month intervals until six years of age, to obtain more data on the phenomenon.
(Source: aftau.org)
The Love Hormone is Two-Faced
Finding shows oxytocin strengthens bad memories and can increase fear and anxiety
It turns out the love hormone oxytocin is two-faced. Oxytocin has long been known as the warm, fuzzy hormone that promotes feelings of love, social bonding and well-being. It’s even being tested as an anti-anxiety drug. But new Northwestern Medicine® research shows oxytocin also can cause emotional pain, an entirely new, darker identity for the hormone.
Oxytocin appears to be the reason stressful social situations, perhaps being bullied at school or tormented by a boss, reverberate long past the event and can trigger fear and anxiety in the future.
That’s because the hormone actually strengthens social memory in one specific region of the brain, Northwestern scientists discovered.
If a social experience is negative or stressful, the hormone activates a part of the brain that intensifies the memory. Oxytocin also increases the susceptibility to feeling fearful and anxious during stressful events going forward.
(Presumably, oxytocin also intensifies positive social memories and, thereby, increases feelings of well being, but that research is ongoing.)
The findings are important because chronic social stress is one of the leading causes of anxiety and depression, while positive social interactions enhance emotional health. The research, which was done in mice, is particularly relevant because oxytocin currently is being tested as an anti-anxiety drug in several clinical trials.
“By understanding the oxytocin system’s dual role in triggering or reducing anxiety, depending on the social context, we can optimize oxytocin treatments that improve well-being instead of triggering negative reactions,” said Jelena Radulovic, the senior author of the study and the Dunbar Professsor of Bipolar Disease at Northwestern University Feinberg School of Medicine. The paper was published July 21 in Nature Neuroscience.
This is the first study to link oxytocin to social stress and its ability to increase anxiety and fear in response to future stress. Northwestern scientists also discovered the brain region responsible for these effects — the lateral septum – and the pathway or route oxytocin uses in this area to amplify fear and anxiety.
The scientists discovered that oxytocin strengthens negative social memory and future anxiety by triggering an important signaling molecule — ERK (extracellular signal regulated kinases) — that becomes activated for six hours after a negative social experience. ERK causes enhanced fear, Radulovic believes, by stimulating the brain’s fear pathways, many of which pass through the lateral septum. The region is involved in emotional and stress responses.
The findings surprised the researchers, who were expecting oxytocin to modulate positive emotions in memory, based on its long association with love and social bonding.
“Oxytocin is usually considered a stress-reducing agent based on decades of research,” said Yomayra Guzman, a doctoral student in Radulovic’s lab and the study’s lead author. “With this novel animal model, we showed how it enhances fear rather than reducing it and where the molecular changes are occurring in our central nervous system.’
The new research follows three recent human studies with oxytocin, all of which are beginning to offer a more complicated view of the hormone’s role in emotions.
All the new experiments were done in the lateral septum. This region has the highest oxytocin levels in the brain and has high levels of oxytocin receptors across all species from mice to humans.
“This is important because the variability of oxytocin receptors in different species is huge,” Radulovic said. “We wanted the research to be relevant for humans, too.”
Experiments with mice in the study established that 1) oxytocin is essential for strengthening the memory of negative social interactions and 2) oxytocin increases fear and anxiety in future stressful situations.
Experiment 1: Oxytocin Strengthens Bad Memories
Three groups of mice were individually placed in cages with aggressive mice and experienced social defeat, a stressful experience for them. One group was missing its oxytocin receptors, essentially the plug by which the hormone accesses brain cells. The lack of receptors means oxytocin couldn’t enter the mice’s brain cells. The second group had an increased number of receptors so their brain cells were flooded with the hormone. The third control group had a normal number of receptors.
Six hours later, the mice were returned to cages with the aggressive mice. The mice that were missing their oxytocin receptors didn’t appear to remember the aggressive mice and show any fear. Conversely, when mice with increased numbers of oxytocin receptors were reintroduced to the aggressive mice, they showed an intense fear reaction and avoided the aggressive mice.
Experiment 2: Oxytocin Increases Fear and Anxiety in Future Stress
Again, the three groups of mice were exposed to the stressful experience of social defeat in the cages of other more aggressive mice. This time, six hours after the social stress, the mice were put in a box in which they received a brief electric shock, which startles them but is not painful. Then 24 hours later, the mice were returned to the same box but did not receive a shock.
The mice missing their oxytocin receptors did not show any enhanced fear when they re-entered the box in which they received the shock. The second group, which had extra oxytocin receptors showed much greater fear in the box. The third control group exhibited an average fear response.
“This experiment shows that after a negative social experience the oxytocin triggers anxiety and fear in a new stressful situation,” Radulovic said.
(Source: northwestern.edu)