Neuroscience
Month
Vitamin D treatment acts in the brain to improve weight and blood glucose (sugar) control in obese rats, according to a new study being presented Saturday at the joint meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 in Chicago.
“Vitamin D deficiency occurs often in obese people and in patients with Type 2 diabetes, yet no one understands if it contributes to these diseases,” said Stephanie Sisley, MD, the study’s principal investigator and an assistant professor at Baylor College of Medicine, Houston. “Our results suggest that vitamin D may play a role in the onset of both obesity and Type 2 diabetes by its action in the brain.”
“The brain is the master regulator of weight,” Sisley said. A region of the brain called the hypothalamus controls both weight and glucose, and has vitamin D receptors there.
In this study funded by the National Institutes of Health, Sisley and partners at the University of Cincinnati delivered vitamin D directly to the hypothalamus. The investigators administered the active, potent form of vitamin D—called 1,25-dihydroxyvitamin D3—to obese male rats through a cannula (thin tube) surgically inserted using anesthesia into the brain’s third ventricle. This narrow cavity lies within the hypothalamus. Rats recovered their presurgery body weight, and the researchers verified the correct cannula placement.
The animals received nothing to eat for four hours, so they could have a fasting blood sugar measurement. Afterward, 12 rats received vitamin D dissolved in a solution acting as a vehicle for drug delivery. Another 14 rats, matched in body weight to the first group, received only the vehicle, thus serving as controls. One hour later, all rats had a glucose tolerance test, in which they received an injection of dextrose, a sugar, in their abdomen, followed by measurement of their blood sugar levels again.
Compared with the control rats, animals that received vitamin D had improved glucose tolerance, which is how the body responds to sugar. In a separate experiment, these treated rats also had greatly improved insulin sensitivity, the body’s ability to successfully respond to glucose. When this ability decreases—called insulin resistance—it eventually leads to high blood sugar levels. Two of insulin’s main effects are to clear glucose from the bloodstream and decrease glucose production in the liver. In this study, vitamin D in the brain decreased the glucose created by the liver.
In a separate experiment of long-term vitamin D treatment, the researchers gave three rats vitamin D and four rats vehicle alone for four weeks. They observed a large decrease in food intake and weight in rats receiving vitamin D compared with the group that did not get vitamin D. Over 28 days, the treated group ate nearly three times less food and lost 24 percent of their weight despite not changing the way they burned calories, study data showed. The control group did not lose any weight.
“Vitamin D is never going to be the silver bullet for weight loss, but it may work in combination with strategies we know work, like diet and exercise,” Sisley commented.
She said more research is necessary to determine if obesity alters vitamin D transport into the brain or its action in the brain.
One of the deadliest forms of paediatric brain tumour, Group 3 medulloblastoma, is linked to a variety of large-scale DNA rearrangements which all have the same overall effect on specific genes located on different chromosomes. The finding, by scientists at the European Molecular Biology Laboratory (EMBL), the German Cancer Research Centre (DKFZ), both in Heidelberg, Germany, and Sanford-Burnham Medical Research Institute in San Diego, USA, is published online today in Nature.
To date, the only gene known to play an important role in Group 3 medulloblastoma was a gene called MYC, but that gene alone couldn’t explain some of the unique characteristics of this particular type of medulloblastoma, which has a higher metastasis rate and overall poorer prognosis than other types of this childhood brain tumour. To tackle the question, Jan Korbel’s group at EMBL and collaborators at DKFZ tried to identify new genes involved, taking advantage of the large number of medulloblastoma genome sequences now known.
“We were surprised to see that in addition to MYC there are two other major drivers of Group 3 medulloblastoma – two sister genes called GFI1B and GFI1,” says Korbel. “Our findings could be relevant for research on other cancers, as we discovered that those genes had been activated in a way that cancer researchers don’t usually look for in solid tumours.”
Rather than take the usual approach of looking for changes in individual genes, the team focused on large-scale rearrangements of the stretches of DNA that lie between genes. They found that the DNA of different patients showed evidence of different rearrangements: duplications, deletions, inversions, and even complex alterations involving many ‘DNA-shuffling’ events. This wide array of genetic changes had one effect in common: they placed GFI1B close to highly active enhancers – stretches of DNA that can dramatically increase gene activity. So large-scale DNA changes relocate GFI1B, activating this gene in cells where it would normally be switched off. And that, the researchers surmise, is what drives the tumour to form.
“Nobody has seen such a process in solid cancers before,” says Paul Northcott from DKFZ, “although it shares similarities with a phenomenon implicated in leukaemias, which has been known since the 80s.”
GFI1B wasn’t affected in all cases studied, but in many patients where it wasn’t, a related gene with a similar role, GFI1, was. GFI1B and GFI1 sit on different chromosomes, and interestingly, the DNA rearrangements affecting GFI1 put it next to enhancers sitting on yet other chromosomes. But the overall result was identical: the gene was activated, and appeared to drive tumour formation.
To confirm the role of GFI1B and GFI1 in causing medulloblastoma, the Heidelberg researchers turned to the expertise of Robert Wechsler-Reya’s group at Sanford-Burnham. Wechsler-Reya’s lab genetically modified neural stem cells to have either GFI1B or GFI1 turned on, together with MYC. When they inserted those modified cells into the brains of healthy mice, the rodents developed aggressive, metastasising brain tumours that closely resemble Group 3 medulloblastoma in humans.
These mice are the first to truly mimic the genetics of the human version of Group 3 medulloblastoma, and researchers can now use them to probe further. The mice could, for instance, be used to test potential treatments suggested by these findings. One interesting option to explore, the scientists say, is that highly active enhancers – like the ones they found were involved in this tumour – can be vulnerable to an existing class of drugs called bromodomain inhibitors. And, since neither GFI1B nor GFI1 is normally active in the brain, the study points to possible routes for diagnosing this brain tumour, too.
But the mice also raised another question the scientists are still untangling. For the rodents to develop medulloblastoma-like tumours, activating GFI1 or GFI1B was not enough; MYC also had to be switched on. In human patients, however, scientists have found a statistical link between MYC and GFI1, but not between MYC and GFI1B, so the team is now following up on this partial surprise.
“What we’re learning from this study is that clearly one has to think outside the box when trying to understand cancer genomes,” Korbel concludes.
Covert changes of mind can be discovered by tracking neural activity when subjects make decisions, researchers from New York University and Stanford University have found. Their results, which appear in the journal Current Biology, offer new insights into how we make decisions and point to innovative ways to study this process in the future.
“The methods used in this study allowed us to see the idiosyncratic nature of decision making that was inaccessible before,” explains Roozbeh Kiani, an assistant professor in NYU’s Center for Neural Science and the study’s lead author.
The study’s other authors included Christopher Cueva and John Reppas of Stanford’s Department of Neurobiology and William Newsome, who holds appointments at the university’s Department of Neurobiology and at the Howard Hughes Medical Institute at Stanford’s School of Medicine.
Previous work on the decision-making process—a plan of action based on evidence, prior knowledge, and payoff—has been methodologically limited. In earlier studies, scientists analyzed one neuron at a time, then averaged these results across neurons to develop an understanding of this activity. However, such a measurement offers only snapshots of neurological behavior and misses the fine-scale dynamics that lead up to a decision.
In the Current Biology study, the researchers examined many neurons at once, giving them a more detailed understanding of decision making.
“Now we can look at the nuances of this dynamic and track changes over a specified period,” explains Kiani. “Looking at one neuron at a time is ‘noisy’: results vary from trial to trial so you cannot get a clear picture of this complex activity. By recording multiple neurons at the same time, you can take out this noise and get a more robust picture of the underlying dynamics.”
The researchers studied macaque monkeys, running them through a series of tasks while monitoring the animals’ neuronal workings.
In the experiment, the monkeys viewed a patch of randomly moving dots on a computer screen. Following the stimulus, monkeys received a “Go” signal to report the motion direction by making an eye movement. The scientists sought to predict the monkeys’ choices purely based on the recorded neural responses before the Go signal. Their model achieved highly accurate predictions.
The same model was then used to study potential dynamics of the monkeys’ decision at different times before the Go signal. The scientists confirmed these predictions by stopping the decision-making process at arbitrary times and comparing the model predictions with the monkeys’ actual choices.
Surprisingly, the monkeys’ decisions were not always stable. Occasionally, they vacillated from one choice to another, indicating covert changes of mind during decision-making. These changes of mind closely matched the properties of human changes of mind, which were uncovered in a 2009 study. They were more frequent in uncertain conditions, more likely to correct an initial mistake, and more likely to happen earlier during a decision.
Twist and hold your neck to the left. Now down, and over to the right, until it hurts. Now imagine your neck – or arms or legs – randomly doing that on their own, without you controlling it.
That’s a taste of what children and adults with a neurological condition called dystonia live with every day – uncontrollable twisting and stiffening of neck and limb muscles.
The mystery of why this happens, and what can prevent or treat it, has long puzzled doctors, who have struggled to help their suffering dystonia patients. Now, new research from a University of Michigan Medical School team may finally open the door to answering those questions and developing new options for patients.
In a new paper in the Journal of Clinical Investigation, the researchers describe new strains of mice they’ve developed that almost perfectly mimic a human form of the disease. They also detail new discoveries about the basic biology of dystonia, made from studying the mice.
They’ll soon make the mice available for researchers everywhere to study, to accelerate understanding of all forms of dystonia and the search for better treatments. The lack of such mice has held back research on dystonia for years.
The U-M team’s success in creating a mouse model for the disease came only after 17 years of stubborn, persistent effort – often in the face of setbacks and failure.
Led by U-M neurologist William Dauer, M.D., the team tried to figure out how and why a gene defect leads to an inherited form of dystonia that, intriguingly, doesn’t start until the pre-teen or teen years, after which it progresses for many years but then stops getting worse after the person reaches their mid-20s.
The gene defect responsible, called DYT1, causes brain cells to make a less-active form of a protein called torsinA. But despite more than a decade of effort by Dauer’s team and many others around the world, no one has been able to translate this information into an animal model with dystonia’s characteristic movements.
Using the childhood onset as a clue, Dauer and his team used cutting-edge genetic technology to severely impair torsinA function during early brain development. This novel twist caused the new mice to closely mimic the human disease: they don’t develop dystonia until they reach preteen age in “mouse years,” and their symptoms stop getting worse after a while.
With this powerful tool in hand, Dauer’s team were now able to peer into the brains of these animals to begin to unravel the mysteries of the disease.
In an unexpected development, they found that the lack of torsinA in the brains of dystonic mice led to the death of neurons – a process called neurodegeneration – in just a few highly localized parts of the brain that control movement. Like the dystonic movements, this neurodegeneration began in young mice, progressed for a time, and then became fixed.
“We’ve created a model for understanding why certain parts of the brain are more vulnerable to problems from a certain genetic insult,” says Dauer, an associate professor in the U-M departments of Neurology and Cell & Developmental Biology.
“In this case, we’re showing that in dystonia, the lack of this particular protein during a critical window of time is causing cell death. Every disease is telling us something about biology — one just has to listen carefully.”
(Image caption: The brains of the mice with dystonia (shown in the right column) had much higher levels of neuron death than those without the condition (left column) — and this neurodegeneration was limited to certain areas involved in controlling muscle movements.)
More discoveries to come
Dauer and his team don’t yet know why only one-third of human DYT1 gene mutation carriers develop primary dystonia during their school years, and why those who don’t develop the disease before their early 20s will never go on to develop it.
They believe some critical events during the brain’s development in infancy and childhood may have to do with it - and they’re already working to explore that question in mice.
They also believe their mouse model will help them and other researchers understand how dystonia occurs in people who have Parkinson’s disease, Huntington’s disease, or damage caused by a stroke or brain injury. Some people develop dystonia without either a known gene defect or any of these other diagnoses – a condition called idiopathic dystonia.
In all these cases, as in people with DYT1 mutations, dystonia’s twisting and curling motions likely arise from problems in the area of the brain that controls the body’s motor control system.
In other words, something’s going wrong in the process of sending signals to the nerves that control muscles involved in movement. Studying a “pure” form of dystonia using the mice will allow researchers to understand just what’s going on.
The team’s ultimate goal is to find new treatments for all kinds of dystonia. Currently, children, teens and young adults who develop it can take medications or even opt for a form of neurosurgery called deep brain stimulation. But the drugs carry major side effects and are only partially effective – and brain surgery carries its own risks. Dauer and his team are working to screen drug candidates.
In a report published today in Nature Communications, an Ottawa-led team of researchers describe the role of a specific gene, called Snf2h, in the development of the cerebellum. Snf2h is required for the proper development of a healthy cerebellum, a master control centre in the brain for balance, fine motor control and complex physical movements.
Athletes and artists perform their extraordinary feats relying on the cerebellum. As well, the cerebellum is critical for the everyday tasks and activities that we perform, such as walking, eating and driving a car. By removing Snf2h, researchers found that the cerebellum was smaller than normal, and balance and refined movements were compromised.
Led by Dr. David Picketts, a senior scientist at the Ottawa Hospital Research Institute and professor in the Faculty of Medicine at the University of Ottawa, the team describes the Snf2h gene, which is found in our brain’s neural stem cells and functions as a master regulator. When they removed this gene early on in a mouse’s development, its cerebellum only grew to one-third the normal size. It also had difficulty walking, balancing and coordinating its movements, something called cerebellar ataxia that is a component of many neurodegenerative diseases.
"As these cerebellar stem cells divide, on their journey toward becoming specialized neurons, this master gene is responsible for deciding which genes are turned on and which genes are packed tightly away," said Dr. Picketts. "Without Snf2h there to keep things organized, genes that should be packed away are left turned on, while other genes are not properly activated. This disorganization within the cell’s nucleus results in a neuron that doesn’t perform very well—like a car running on five cylinders instead of six."
The cerebellum contains roughly half the neurons found in the brain. It also develops in response to external stimuli. So, as we practice tasks, certain genes or groups of genes are turned on and off, which strengthens these circuits and helps to stabilize or perfect the task being undertaken. The researchers found that the Snf2h gene orchestrates this complex and ongoing process. These master genes, which adapt to external cues to adjust the genes they turn on and off, are known as epigenetic regulators.
"These epigenetic regulators are known to affect memory, behaviour and learning," said Dr. Picketts. "Without Snf2h, not enough cerebellar neurons are produced, and the ones that are produced do not respond and adapt as well to external signals. They also show a progressively disorganized gene expression profile that results in cerebellar ataxia and the premature death of the animal."
There are no studies showing a direct link between Snf2h mutations and diseases with cerebellar ataxia, but Dr. Picketts added that it “is certainly possible and an interesting avenue to explore.”
In 2012, Developmental Cell published a paper by Dr. Picketts’ team showing that mice lacking the sister gene Snf2l were completely normal, but had larger brains, more cells in all areas of the brain and more actively dividing brain stem cells. The balance between Snf2l and Snf2h gene activity is necessary for controlling brain size and for establishing the proper gene expression profiles that underlie the function of neurons in different regions, including the cerebellum.
The hormone progesterone could become part of therapy against the most aggressive form of brain cancer. High concentrations of progesterone kill glioblastoma cells and inhibit tumor growth when the tumors are implanted in mice, researchers have found.
The results were recently published in the Journal of Steroid Biochemistry and Molecular Biology.
Glioblastoma is the most common and the most aggressive form of brain cancer in adults, with average survival after diagnosis of around 15 months. Surgery, radiation and chemotherapy do prolong survival by several months, but targeted therapies, which have been effective with other forms of cancer, have not lengthened survival in patients fighting glioblastoma.
The lead author of the current paper is Fahim Atif, PhD, Assistant Professor of Emergency Medicine at Emory University. The findings with glioblastoma came out of Emory researchers’ work on progesterone as therapy for traumatic brain injury and more recently, stroke. Atif, Donald Stein and their colleagues have been studying progesterone for the treatment of traumatic brain injury for more than two decades, prompted by Stein’s initial observation that females recover from brain injury more readily than males. There is a similar tilt in glioblastoma as well: primary glioblastoma develops three times more frequently in males compared to females.
These results could pave the way for the use of progesterone against glioblastoma in a human clinical trial, perhaps in combination with standard-of-care therapeutic agents such as temozolomide. However, Stein says that more experiments are necessary with grafts of human tumor cells into animal brains first. His team identified a factor that may be important for clinical trial design: progesterone was not toxic to all glioblastoma cell lines, and its toxicity may depend on whether the tumor suppressor gene p53 is mutated.
Atif, Stein, and colleague Seema Yousuf found that low, physiological doses of progesterone stimulate the growth of glioblastoma tumor cells, but higher doses kill the tumor cells while remaining nontoxic for healthy cells. Similar effects have been seen with the progesterone antagonist RU486, but the authors cite evidence that progesterone is less toxic to healthy cells. Progesterone has also been found to inhibit growth of neuroblastoma cells (neuroblastoma is the most common cancer in infants), as well as breast, ovarian and colon cancers in cell culture and animal models.
For the first time, researchers have found that the ‘ERK pathway’ must be constantly active for salamander cells to be reprogrammed, and hence able to contribute to the regeneration of different body parts.
The team identified a key difference between the activity of this pathway in salamanders and mammals, which helps us to understand why humans can’t regrow limbs and sheds light on how regeneration of human cells can be improved.
The study published in Stem Cell Reports, demonstrates that the ERK pathway is not fully active in mammalian cells, but when forced to be constantly active, gives the cells more potential for reprogramming and regeneration. This could help researchers better understand diseases and design new therapies.
Lead researcher on the study, Dr Max Yun (UCL Institute of Structural & Molecular Biology) said: “While humans have limited regenerative abilities, other organisms, such as the salamander, are able to regenerate an impressive repertoire of complex structures including parts of their hearts, eyes, spinal cord, tails, and they are the only adult vertebrates able to regenerate full limbs.
We’re thrilled to have found a critical molecular pathway, the ERK pathway, that determines whether an adult cell is able to be reprogrammed and help the regeneration processes. Manipulating this mechanism could contribute to therapies directed at enhancing regenerative potential of human cells.”
The ERK pathway is a way for proteins to communicate a signal from the surface of a cell to the nucleus which contains the cell’s genetic material. Further research will focus on understanding how this important pathway is regulated during limb regeneration, and which other molecules are involved in the process.
A team of Stanford University investigators has linked a particular brain circuit to mammals’ tendency to interact socially. Stimulating this circuit — one among millions in the brain — instantly increases a mouse’s appetite for getting to know a strange mouse, while inhibiting it shuts down its drive to socialize with the stranger.
The new findings, published June 19 in Cell, may throw light on psychiatric disorders marked by impaired social interaction such as autism, social anxiety, schizophrenia and depression, said the study’s senior author, Karl Deisseroth, MD, PhD, a professor of bioengineering and of psychiatry and behavioral sciences. The findings are also significant in that they highlight not merely the role of one or another brain chemical, as pharmacological studies tend to do, but rather the specific components of brain circuits involved in a complex behavior. A combination of cutting-edge techniques developed in Deisseroth’s laboratory permitted unprecedented analysis of how brain activity controls behavior.
Deisseroth, the D.H. Chen Professor and a member of the interdisciplinary Stanford Bio-X institute, is a practicing psychiatrist who sees patients with severe social deficits. “People with autism, for example, often have an outright aversion to social interaction,” he said. They can find socializing — even mere eye contact — painful.
Deisseroth pioneered a brain-exploration technique, optogenetics, that involves selectively introducing light-receptor molecules to the surfaces of particular nerve cells in a living animal’s brain and then carefully positioning, near the circuit in question, the tip of a lengthy, ultra-thin optical fiber (connected to a laser diode at the other end) so that the photosensitive cells and the circuits they compose can be remotely stimulated or inhibited at the turn of a light switch while the animal remains free to move around in its cage.
Monitoring activity in real time
Using optogenetics and other methods he and his associates have invented, Deisseroth and his associates were able to both manipulate and monitor activity in specific nerve-cell clusters, and the fiber tracts connecting them, in mice’s brains in real time while the animals were exposed to either murine newcomers or inanimate objects in various laboratory environments. The mice’s behavioral responses were captured by video and compared with simultaneously recorded brain-circuit activity.
In some cases, the researchers observed activity in various brain centers and nerve-fiber tracts connecting them as the mice variously examined or ignored one another. Other experiments involved stimulating or inhibiting impulses within those circuits to see how these manipulations affected the mice’s social behavior.
To avoid confusing simple social interactions with mating- and aggression-related behaviors, the researchers restricted their experiments to female mouse pairs.
The scientists first examined the relationship between the mice’s social interactions and a region in the brain stem called the ventral tegmental area. The VTA is a key node in the brain’s reward circuitry, which produces sensations of pleasure in response to success in such survival-improving activities as eating, mating or finding a warm shelter in a cold environment.
The VTA transmits signals to other centers throughout the brain via tracts of fibers that secrete chemicals, including one called dopamine, at contact points abutting nerve cells within these faraway centers. When dopamine lands on receptors on those nerve cells, it can set off signaling activity within them.
Abnormal activity in the VTA has been linked to drug abuse and depression, for example. But much less is known about this brain center’s role in social behavior, and it had not previously been possible to observe or control activity along its connections during social behavior.
Deisseroth and his colleagues used mice whose dopamine-secreting, or dopaminergic, VTA nerve cells had been bioengineered to express optogenetic control proteins that could set off or inhibit signaling in the cells in response to light. They observed that enhancing activity in these cells increased a mouse’s penchant for social interaction. When a newcomer was introduced into its cage, it came, it saw, it sniffed. Inhibiting the dopaminergic VTA cells had the opposite effect: The host lost much of its interest in the guest.
Only social interaction affected
On the other hand, such manipulations of the VTA’s dopaminergic cells had no effect on the mice’s penchant for exploring novel objects (a golf ball, for example) placed in their cages. Nor did it change their overall propensity to move around. The effect appeared to be specific for social interaction.
Finding out exactly which dopaminergic projections from the VTA, traveling to which remote brain structures, were carrying the signals that generate exploratory social behavior required designing a new monitoring methodology. The signals traveling along such projections are extremely weak and confounded by background noise, especially when located deep within the brains of ambulatory animals. Deisseroth’s group overcame this by developing a highly sensitive technology capable of plucking these tiny signals out of the surrounding noise. The new technique, called fiber photometry, is a sophisticated way of measuring calcium flux, which invariably accompanies signaling activity along the fibers projecting from nerve cells.
Using a combination of optogenetics and fiber photometry, the investigators were able to demonstrate that a particular tract projecting from the VTA to a mid-brain structure called the nucleus accumbens (also strongly implicated in the reward system) was the relevant conduit carrying the impetus to social interaction in the mice.
A third technological trick helped determine which recipient nerve cells within the nucleus accumbens were involved in the social-behavior circuitry. That structure’s two types of dopamine-responsive cells are differentiated by the types of dopamine receptors, referred to as D1 and D2, on their surfaces. The team performed experiments in animals bioengineered so that the normally D1-containing cells instead expressed a modified, light-inducible version of that receptor. These experiments, along with complementary experiments blocking the D1 receptors with specific drug antagonists, showed that the D1 nucleus-accumbens nerve cells were mediating the changes in social behavior. Tripping off those receptors, either by optogenetically inducing incoming tracts to deliver dopamine to these receptors, or by directly stimulating light-activated forms of these receptors on the target cells, enhanced mice’s social exploration.
Helping to see how social behavior can go wrong
“Every behavior presumably arises from a pattern of activity in the brain, and every behavioral malfunction arises from malfunctioning circuitry,” said Deisseroth, who is also co-director of Stanford’s Cracking the Neural Code Program. “The ability, for the first time, to pinpoint a particular nerve-cell projection involved in the social behavior of a living, moving animal will greatly enhance our ability to understand how social behavior operates, and how it can go wrong.”
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shed light on how a specific kind of genetic mutation can cause damage during early brain development that results in lifelong learning and behavioral disabilities. The work suggests new possibilities for therapeutic intervention.
The study, which focuses on the role of a gene known as Syngap1, was published June 18, 2014, online ahead of print by the journal Neuron. In humans, mutations in Syngap1 are known to cause devastating forms of intellectual disability and epilepsy.
“We found a sensitive cell type that is both necessary and sufficient to account for the bulk of the behavioral problems resulting from this mutation,” said TSRI Associate Professor Gavin Rumbaugh, who led the study. “Because we found the root biological cause of this genetic brain disorder, we can now shift our research toward developing tailor-made therapies for people affected by Syngap1 mutations.”
In the study, Rumbaugh and his colleagues used a mouse model to show that mutations in Syngap1 damage the development of a kind of neuron known as glutamatergic neurons in the young forebrain, leading to intellectual disability. Higher cognitive processes, such as language, reasoning and memory arise in children as the forebrain develops.
Repairing damaging Syngap1 mutations in these specific neurons during development prevented cognitive abnormalities, while repairing the gene in other kinds of neurons and in other locations had no effect.
Rumbaugh noted prenatal diagnosis of some infant genetic disorders is on the horizon. Technological advances in genetic sequencing allow for individual genomes to be scanned for damaging mutations; it is possible to scan the entire genome of a child still in the womb. “Our research suggests that if Syngap1 function can be fixed very early in development, this should protect the brain from damage and permanently improve cognitive function,” said TSRI Research Associate Emin Ozkan, a first author of the study, along with TSRI Research Associate Thomas Creson. “In theory, patients then wouldn’t have to be subjected to a lifetime of therapies and worry that the drugs might stop working or have side effects from chronic use.”
Mutations to Syngap1 are a leading cause of “sporadic intellectual disability,” resulting from new, random mutations arising spontaneously in genes, rather than faulty genes inherited from parents. Intellectual disability affects approximately one to three percent of the population worldwide.
Rumbaugh and his colleagues are continuing to investigate. “Our findings have also identified exciting potential biomarkers in the brain of cognitive failure, allowing us to test new therapeutic strategies in our Syngap1 animal model,” said Creson.
Young adult men who watched more violence on television showed indications of less mature brain development and poorer executive functioning, according to the results of an Indiana University School of Medicine study published online in the journal Brain and Cognition.
The researchers used psychological testing and MRI scans to measure mental abilities and volume of brain regions in 65 healthy males with normal IQ between the age of 18 and 29, specifically chosen because they were not frequent video game players.
Lead author Tom A. Hummer, Ph.D., assistant research professor in the IU Department of Psychiatry, said the young men provided estimates of their television viewing over the past year and then kept a detailed diary of their TV viewing for a week. Participants also completed a series of psychological tests measuring inhibitory control, attention and memory. At the conclusion, MRI scans were used to measure brain structure.
Executive function is the broad ability to formulate plans, make decisions, reason and problem-solve, regulate attention, and inhibit behavior in order to achieve goals.
"We found that the more violent TV viewing a participant reported, the worse they performed on tasks of attention and cognitive control," Dr. Hummer said. "On the other hand, the overall amount of TV watched was not related to performance on any executive function tests."
Dr. Hummer noted that these executive functioning abilities can be important for controlling impulsive behaviors, including aggression. “The worry is that more impulsivity does not mix well with the behaviors modeled in violent programming.”
Tests that measured working memory, another subtype of executive functioning, were not found to be related to overall or violent TV viewing.
Comparing TV habits to brain images also produced results that Dr. Hummer and colleagues believe are significant.
"When we looked at the brain scans of young men with higher violent television exposure, there was less volume of white matter connecting the frontal and parietal lobes, which can be a sign of less maturity in brain development," he said.
White matter is tissue in the brain that insulates nerve fibers connecting different brain regions, making functioning more efficient. In typical development, the amount or volume of white matter increases as the brain makes more connections until about age 30, improving communication between regions of the brain. Connections between the frontal and parietal lobes are thought to be especially important for executive functioning.
"The take-home message from this study is the finding of a relationship between how much violent television we watch and important aspects of brain functioning like controlled attention and inhibition," Dr. Hummer said.
Dr. Hummer cautions that more research is needed to better understand the study findings.
"With this study we could not isolate whether people with poor executive function are drawn to programs with more violence or if the content of the TV viewing is responsible for affecting the brain’s development over a period of time," Dr. Hummer said. "Additional longitudinal work is necessary to resolve whether individuals with poor executive function and slower white matter growth are more drawn to violent programming or if exposure to media violence modifies development of cognitive control," Dr. Hummer said.
A neuroscientist from Trinity College Dublin has proposed a new, ground-breaking explanation for the fundamental process of ‘habituation’, which has never been completely understood by neuroscientists.
Typically, our response to a stimulus is reduced over time if we are repeatedly exposed to it. This process of habituation enables organisms to identify and selectively ignore irrelevant, familiar objects and events that they encounter again and again. Habituation therefore allows the brain to selectively engage with new stimuli, or those that it ‘knows’ to be relevant. For example, the unusual sensation created by a spider walking over our skin should elicit an appropriate evasive response, but the touch of a shirt or blouse on the same skin should be functionally ignored by the nervous system. If habituation does not occur, then such unimportant stimuli become distracting, which means that complex environments can become overwhelming.
The new perspective on the way habituation occurs has implications for our understanding of neuropsychiatric conditions, because normal habituation, emotional responses and attentional abilities are altered in several of these conditions. In particular, hypersensitivity to complex environments is common in individuals on the autism spectrum.
Habituation has long been recognised as the most fundamental form of learning, but it has never been satisfactorily explained. In a Perspective article just published in the leading international journal Neuron (embargoed copy), Professor of Neurogenetics in the School of Genetics & Microbiology at Trinity, Mani Ramaswami, explains habituation through what he terms the ‘negative-image model’. The model proposes and explains how a repeated activation of any group of neurons that respond to a given stimulus results in the build-up of ‘negative activation’, which inhibits responses from this same group of cells.
For example, the first view of an unfamiliar and scary face can trigger a fearful response. However after multiple exposures, the group of neurons activated by the face is less effective at activating fear centres because of increased inhibition on this same group of neurons. Significantly, a strong response to new faces persists for much longer in people on the autism spectrum. This matched increase in inhibition (the ‘negative image’), proposed to underlie habituation, is not normally consciously perceived but it can be revealed under particular conditions (see accompanying video for a visual example here).
Professor Ramaswami said: “This Perspective outlines scalable circuit mechanisms that can account for habituation to stimuli encoded by very small or very large assemblies of neurons. Its strength is its simplicity, its basis in experimental data, and its ability to explain many features of habituation. However, more high-quality studies of habituation mechanisms will be required to establish its generality.”
Professor of Experimental Brain Research at Trinity, and Director of the Trinity College Institute for Neuroscience, Shane O’Mara, said: “The arguments and ideas expressed by Professor Ramaswami should lead to additions and changes to our current text-book sections on habituation, which is a process of great relevance to cognition, attention and psychiatric disease. It is possible that highlighting the process of negative image formation as crucial for habituation will prove useful to clinical genetic studies of autism, by helping to place diverse autism susceptibility genes in a common biological pathway.”
When a woman experiences a stressful event early in pregnancy, the risk of her child developing autism spectrum disorders or schizophrenia increases. Yet how maternal stress is transmitted to the brain of the developing fetus, leading to these problems in neurodevelopment, is poorly understood.
New findings by University of Pennsylvania School of Veterinary Medicine scientists suggest that an enzyme found in the placenta is likely playing an important role. This enzyme, O-linked-N-acetylglucosamine transferase, or OGT, translates maternal stress into a reprogramming signal for the brain before birth.
(Image caption: Mice with reduced OGT in their placenta were shorter and leaner than their normal counterparts.)
“By manipulating this one gene, we were able to recapitulate many aspects of early prenatal stress,” said Tracy L. Bale, senior author on the paper and a professor in the Department of Animal Biology at Penn Vet. “OGT seems to be serving a role as the ‘canary in the coal mine,’ offering a readout of mom’s stress to change the baby’s developing brain.”
Bale also holds an appointment in the Department of Psychiatry in Penn’s Perelman School of Medicine. Her co-author is postdoctoral researcher Christopher L. Howerton. The paper was published online in PNAS this week.
OGT is known to play a role in gene expression through chromatin remodeling, a process that makes some genes more or less available to be converted into proteins. In a study published last year in PNAS, Bale’s lab found that placentas from male mice pups had lower levels of OGT than those from female pups, and placentas from mothers that had been exposed to stress early in gestation had lower overall levels of OGT than placentas from the mothers’ unstressed counterparts.
“People think that the placenta only serves to promote blood flow between a mom and her baby, but that’s really not all it’s doing,” Bale said. “It’s a very dynamic endocrine tissue and it’s sex-specific, and we’ve shown that tampering with it can dramatically affect a baby’s developing brain.”
To elucidate how reduced levels of OGT might be transmitting signals through the placenta to a fetus, Bale and Howerton bred mice that partially or fully lacked OGT in the placenta. They then compared these transgenic mice to animals that had been subjected to mild stressors during early gestation, such as predator odor, unfamiliar objects or unusual noises, during the first week of their pregnancies.
The researchers performed a genome-wide search for genes that were affected by the altered levels of OGT and were also affected by exposure to early prenatal stress using a specific activational histone mark and found a broad swath of common gene expression patterns.
They chose to focus on one particular differentially regulated gene called Hsd17b3, which encodes an enzyme that converts androstenedione, a steroid hormone, to testosterone. The researchers found this gene to be particularly interesting in part because neurodevelopmental disorders such as autism and schizophrenia have strong gender biases, where they either predominantly affect males or present earlier in males.
Placentas associated with male mice pups born to stressed mothers had reduced levels of the enzyme Hsd17b3, and, as a result, had higher levels of androstenedione and lower levels of testosterone than normal mice.
“This could mean that, with early prenatal stress, males have less masculinization,” Bale said. “This is important because autism tends to be thought of as the brain in a hypermasculinized state, and schizophrenia is thought of as a hypomasculinized state. It makes sense that there is something about this process of testosterone synthesis that is being disrupted.”
Furthermore, the mice born to mothers with disrupted OGT looked like the offspring of stressed mothers in other ways. Although they were born at a normal weight, their growth slowed at weaning. Their body weight as adults was 10-20 percent lower than control mice.
Because of the key role that that the hypothalamus plays in controlling growth and many other critical survival functions, the Penn Vet researchers then screened the mouse genome for genes with differential expression in the hypothalamus, comparing normal mice, mice with reduced OGT and mice born to stressed mothers.
They identified several gene sets related to the structure and function of mitochrondria, the powerhouses of cells that are responsible for producing energy. And indeed, when compared by an enzymatic assay that examines mitochondria biogenesis, both the mice born to stressed mothers and mice born to mothers with reduced OGT had dramatically reduced mitochondrial function in their hypothalamus compared to normal mice. These studies were done in collaboration with Narayan Avadhani’s lab at Penn Vet.
Such reduced function could explain why the growth patterns of mice appeared similar until weaning, at which point energy demands go up.
“If you have a really bad furnace you might be okay if temperatures are mild,” Bale said. “But, if it’s very cold, it can’t meet demand. It could be the same for these mice. If you’re in a litter close to your siblings and mom, you don’t need to produce a lot of heat, but once you wean you have an extra demand for producing heat. They’re just not keeping up.”
Bale points out that mitochondrial dysfunction in the brain has been reported in both schizophrenia and autism patients.
In future work, Bale hopes to identify a suite of maternal plasma stress biomarkers that could signal an increased risk of neurodevelopmental disease for the baby.
“With that kind of a signature, we’d have a way to detect at-risk pregnancies and think about ways to intervene much earlier than waiting to look at the term placenta,” she said.
UT Arlington researchers have successfully used a portable brain-mapping device to show limited prefrontal cortex activity among student veterans with Post Traumatic Stress Disorder when they were asked to recall information from simple memorization tasks.
The study by bioengineering professor Hanli Liu and Alexa Smith-Osborne, an associate professor of social work, and two other collaborators was published in the May 2014 edition of NeuroImage: Clinical. The team used functional near infrared spectroscopy to map brain activity responses during cognitive activities related to digit learning and memory retrial.
Smith-Osborne has used the findings to guide treatment recommendations for some veterans through her work as principal investigator for UT Arlington’s Student Veteran Project, which offers free services to veterans who are undergraduates or who are considering returning to college.
“When we retest those student veterans after we’ve provided therapy and interventions, they’ve shown marked improvement,” Smith-Osborne said. “The fNIRS data have shown improvement in brain functions and responses after the student veterans have undergone treatment.”
Liu said this type of brain imaging allows us to “see” which brain region or regions fail to memorize or recall learned knowledge in student veterans with PTSD.
“It also shows how PTSD can affect the way we learn and our ability to recall information, so this new way of brain imaging advances our understanding of PTSD.” Liu said.
This study is multi-disciplinary, associating objective brain imaging with neurological disorders and social work.
While UT Arlington bioengineering faculty associate Fenghua Tian is the primary author assisted by bioengineering graduate research assistant Amarnath Yennu, collaborators of the study include UT Austin psychology professor Francisco Gonzalez-Lima and psychology professor Carol North with UT Southwestern Medical Center and the Veterans Administration North Texas Health Care System.
Khosrow Behbehani, dean of the UT Arlington College of Engineering, said this collaborative research is “allowing the researchers to objectively measure the changes in the level of oxygen in the brain and relate them to some of the brain functions that may have been adversely affected by trauma or stress.”
Numerous neuropsychological studies have linked learning dysfunctions – such as memory loss, attention deficits and learning disabilities – with PTSD.
The new study involved 16 combat veterans previously diagnosed with PTSD who were experiencing distress and functional impairment affecting cognitive and related academic performance. The veterans were directed to perform a series of number-ordering tasks on a computer while researchers monitored their brain activity through near infrared spectroscopy, a noninvasive neuroimaging technology.
The research found that participants with PTSD experienced significant difficulty recalling the given digits compared with a control group. This deficiency is closely associated with dysfunction of a portion in the right frontal cortex. The team also determined that near infrared spectroscopy was an effective tool for measuring cognitive dysfunction associated with PTSD.
With that information, Smith-Osborne said mental healthcare providers could customize a treatment plan best suited for that individual.
“It’s not a one-size-fits-all treatment plan but a concentrated effort to tailor the treatment based on where that person is on the learning scale,” Smith-Osborne said.
Smith-Osborne and Liu hope that their research results lead to better and more comprehensive care for veterans and a better college education.
Researchers from Emory’s Rollins School of Public Health discovered that an increase in the protein that helps store dopamine, a critical brain chemical, led to enhanced dopamine neurotransmission and protection from a Parkinson’s disease-related neurotoxin in mice.
Dopamine and related neurotransmitters are stored in small storage packages called vesicles by the vesicular monoamine transporter (VMAT2). When released from these packages dopamine can help regulate movement, pleasure and emotional response. Low dopamine levels are associated with neurodegenerative diseases such as Parkinson’s disease and recent research has shown that VMAT2 function is impaired in people with the disease.
Lead researcher Gary W. Miller, PhD professor and associate dean for research at the Rollins School of Public Health and his team generated transgenic mice with increased levels of VMAT2 and found it led to an increase in dopamine release. In addition, the group found improved outcomes on anxiety and depressive behaviors, increased movement, and protection from MPTP, the chemical that can cause Parkinson’s disease-related damage in the brain.
The complete study is available in the June 17, 2014 edition of Proceedings of the National Academy of Sciences (PNAS).
According to Miller, “This work suggests that enhanced vesicular filling can be sustained over time and may be a viable therapeutic approach for a variety of central nervous system disorders that involve the storage and release of dopamine, serotonin or norepinephrine.”
From animated ads on Main Street to downtown intersections packed with pedestrians, the eyes of urban drivers have much to see.
But while city streets have become increasingly crowded with distractions, our ability to process visual information has remained unchanged for millions of years. Can modern eyes keep up?
Encouragingly, a new study suggests that even as we’re processing a million things at once, we are still sensitive to certain kinds of changes in our visual environment — even while performing a difficult task.
In a paper published in Visual Cognition, researchers from Concordia University, Kansas State University, the University of Findlay, the University of Central Florida and the University of Illinois prove that we can automatically detect changes in blur across our field of view.
To investigate, the research team focused on the common problem of blurred sight, which can be caused by factors like changes in distance between objects, as well as vision disorders like near-sightedness, far-sightedness and astigmatism.
“Blur is normally compensated for by adjusting the lens of the eye to bring the image back into focus,” says study co-author Aaron Johnson, a professor in the Department of Psychology at Concordia.
“We wanted to know if the detection of this blur by the brain happens automatically, because previous research had resulted in two conflicting views.”
Those views suggest:
“If blur is detected automatically and doesn’t require attention, then performing another cognitive task — driving, say — at the same time shouldn’t change our ability to detect the blur,” Johnson says.
To determine which of these two theories was correct, he and his colleagues used a new technique that presented different amounts of blur to various regions of the eye.
The researchers showed study participants (individuals with normal, or corrected-to-normal, vision) 1,296 distinct images — pictures of things ranging from forests to building interiors — and used a window that moved based on the their eye movements to give the pictures two levels of resolution.
As they changed the resolution from blurry to sharp, the researchers gave participants mental tasks of varying degree of difficulty. Regardless of the difficulty levels, though, the subjects’ ability to detect blur in these pictures was unchanged.
“Our study proves that, much like other simple visual features such as colour and size, blur in an image doesn’t seem to require mental effort to detect,” Johnson says.
“The process may be what we call ‘pre-attentive’ — that is, little or no attention is required to detect it. As such, this research provides insight into a key task, compensating for blur, that the visual system must perform on a daily basis. In the future, I hope to study how blur detection changes with age.”
An international team of researchers has discovered a significant genetic component of Idiopathic Generalized Epilepsy (IGE), the most common form of epilepsy. Epilepsy is a neurological disorder characterized by sudden, uncontrolled electrical discharges in the brain expressed as a seizure. The new research, published in this week’s issue of EMBO Reports, implicates a mutation in the gene for a protein, known as cotransporter KCC2.
KCC2 maintains the correct levels of chloride ions in neurons, playing a major part in regulating excitation and inhibition of neurons. The results indicate that a genetic mutation of KCC2 might be a risk factor for developing IGE.
“We found a clear statistical association between two variants of KCC2 and severe IGE in a large French-Canadian patient sample,” said Dr. Guy Rouleau, Director of the Montreal Neurological Institute and Hospital (The Neuro) at McGill University and the McGill University Health Centre, and senior author of the study. “Our data not only corroborate recent findings by other groups but vastly extend them from genetic, physiological and biochemical standpoints.” The first authors on the paper are Dr. Kristopher Kahle, chief neurosurgery resident at Massachusetts General Hospital and post-doctoral fellow at Harvard University, and Dr. Nancy Merner, a former post-doctoral fellow in Dr. Rouleau’s laboratory and now a professor at Auburn University.
The study examined 380 French Canadians with IGE living in Montreal and Quebec City. Results were compared to data from a control group of more than 1,200 people. “KCC2 is a hot topic in neuroscience given its important role in neuronal signaling and in its potential role in neurological diseases such as epilepsy, neuropathic pain, and other diseases,” said Dr. Rouleau.
Each day in Canada, an average of 42 people learn that they have epilepsy. In 50 – 60% of cases, the cause of epilepsy is unknown. The major form of treatment is long-term drug therapy. Drugs are not a cure and can have numerous, sometimes severe, side effects. Brain surgery is recommended only when medication fails and when the seizures are confined to one area of the brain where brain tissue can be safely removed without damaging personality or function.
The hippocampus is a small structure in the brains of mammals that plays a crucial role in processing input from our senses and allows perceptions to be stored as memories. Nerve cells that inhibit the activity of other cells have now been shown to play a much larger and more complex role in these processes than previously assumed. Teams led by Prof. Dr. Marlene Bartos from the Cluster of Excellence BrainLinks-BrainTools at the University of Freiburg and Prof. Dr. Imre Vida from the Cluster of Excellence NeuroCure at the hospital Charité in Berlin report these findings in the current issue of the Journal of Neuroscience.
(Image caption: Three different cell types in the hippocampus (BC, HCP, and HIPP) were previously known to have different morphologies (top). New research shows that they respond to electrical stimulation (black traces) by inhibiting other nerve cells in very different patterns (bottom), allowing for more powerful information processing. Credit: BrainLinks-BrainTools)
In their study, the scientists investigated how special types of so-called interneurons build connections with each other within the hippocampus and how their function influences the network of nerve cells as a whole. Interneurons do not prompt other nerve cells to become active but, on the contrary, inhibit them. This kind of suppression plays an important role in brain activity in general. Information processing would not be possible otherwise, because a brain in which all nerve cells are active at the same time is effectively put out of order.
The hippocampus is home to a variety of different inhibitory cells, which were known so far to differ greatly in their form and function. But up to now it has been generally assumed that their actual influence on the activity of the brain structure they belong to is rather small. By combining several different experimental methods, Bartos, Vida, and their teams succeeded in showing that these cells are actually able to strongly interfere with the activity and the timing of activity patterns within the hippocampus. Moreover, the various possible combinations of connections between these different cell types show markedly different characteristics in their function. This makes the inhibition within the hippocampus much more flexible and versatile than previously assumed. The team of scientists suspects that this also makes the capability to process information within the hippocampus much bigger. The results published in this study are from experiments conducted in acute slice preparations of the hippocampus. Up next for the researchers will be the task of verifying these results within the actual brain.