Neuroscience

Researchers from the Centre for Addiction and Mental Health (CAMH) have identified a new role of a chemical involved in controlling the genes underlying memory and learning.

"The brain is a plastic tissue, and we know that learning and memory require various genes to be expressed,” says CAMH Senior Scientist Dr. Art Petronis, who is a senior author on the new study. “Our research has identified how the chemical 5-hmC may be involved in the epigenetic processes allowing this plasticity.” Dr. Petronis is head of the Krembil Family Epigenetics Laboratory in CAMH’s Campbell Family Mental Health Research Institute.

5-hmC is an epigenetic modification of DNA, and was discovered in humans and mice in 2009. DNA modifications are chemical changes to DNA. They flag genes to be turned “on” - signalling the genome to make a protein - or turned “off.” As the overwhelming majority of cells in an individual contain the same genetic code, this pattern of flags is what allows a neuron to use the same genome as a blood or liver cell, but create a completely different and specialized cellular environment.

The research, published online in Nature Structural & Molecular Biology, sheds light on the role of 5-hmC. Intriguingly, it is more abundant in the brain than in other tissues in the body, for reasons not clear to date.

The CAMH team of scientists examined DNA from a variety of tissues, including the mouse and human brain, and looked at where 5-hmC was found in the genome. They detected that 5-hmC had a unique distribution in the brain: it was highly enriched in genes related to the synapse, the dynamic tips of brain cells. Growth and change in the synapse allow different brain cells to “wire” together, which allows learning and memory.

"This enrichment of 5-hmC in synapse-related genes suggests a role for this epigenetic modification in learning and memory," says Dr. Petronis.

The team further showed that 5-hmC had a special distribution even within the gene. The code for one gene can be edited and “spliced” to create several different proteins. Dr. Petronis found that 5-hmC is located at “splice junctions,” the points where the gene is cut before splicing.

"5-hmC may signal the cell’s splicing machinery to generate the diverse proteins that, in turn, give rise to the unprecedented complexity of the brain," he says.

The research team is continuing to investigate the role of 5-hmC in more detail, and to determine whether 5-hmC function is different in people with bipolar disorder and schizophrenia compared to people without these diagnoses.

This research was funded by the U.S National Institutes of Health, the Canadian Institutes of Health Research, and the Tapscott Chair in Schizophrenia Studies at the University of Toronto.

The Centre for Addiction and Mental Health (CAMH) is Canada’s largest mental health and addiction teaching hospital, as well as one of the world’s leading research centres in the area of addiction and mental health. CAMH combines clinical care, research, education, policy development and health promotion to help transform the lives of people affected by mental health and addiction issues.

An enzyme that could represent a powerful new tool for combating Alzheimer’s disease has been discovered by researchers at Mayo Clinic in Florida. The enzyme — known as BACE2 — destroys beta-amyloid, a toxic protein fragment that litters the brains of patients who have the disease. The findings were published online Sept. 17 in the science journal Molecular Neurodegeneration.

Alzheimer’s disease is the most common memory disorder. It affects more that 5.5 million people in the United States. Despite the disorder’s enormous financial and personal toll, effective treatments have not yet been found.

The Mayo research team, led by Malcolm A. Leissring, Ph.D., a neuroscientist at Mayo Clinic in Florida, made the discovery by testing hundreds of enzymes for the ability to lower beta-amyloid levels. BACE2 was found to lower beta-amyloid more effectively than all other enzymes tested. The discovery is interesting because BACE2 is closely related to another enzyme, known as BACE1, involved in producing beta-amyloid.

“Despite their close similarity, the two enzymes have completely opposite effects on beta-amyloid — BACE1 giveth, while BACE2 taketh away,” Dr. Leissring says.

Beta-amyloid is a fragment of a larger protein, known as APP, and is produced by enzymes that cut APP at two places. BACE1 is the enzyme responsible for making the first cut that generates beta-amyloid. The research showed that BACE2 cuts beta-amyloid into smaller pieces, thereby destroying it, instead. Although other enzymes are known to break down beta-amyloid, BACE2 is particularly efficient at this function, the study found.

Previous work had shown that BACE2 can also lower beta-amyloid levels by a second mechanism: by cutting APP at a different spot from BACE1. BACE2 cuts in the middle of the beta-amyloid portion, which prevents beta-amyloid production.

“The fact that BACE2 can lower beta-amyloid by two distinct mechanisms makes this enzyme an especially attractive candidate for gene therapy to treat Alzheimer’s disease,” says first author Samer Abdul-Hay, Ph.D., a neuroscientist at Mayo Clinic in Florida.

The discovery suggests that impairments in BACE2 might increase the risk of Alzheimer’s disease. This is important because certain drugs in clinical use — for example, antiviral drugs used to treat human immunodeficiency virus (HIV) — work by inhibiting enzymes similar to BACE2.

Although BACE2 can lower beta-amyloid by two distinct mechanisms, only the newly discovered mechanism — beta-amyloid destruction — is likely relevant to the disease, the researchers note. This is because the second mechanism, which involves BACE2 cutting APP, does not occur in the brain. The researchers have obtained a grant from the National Institutes of Health to study whether blocking beta-amyloid destruction by BACE2 can increase the risk for Alzheimer’s disease in a mouse model of the disease.

One small change to the DNA sequence can cause more weighty changes to the human body, according to a new study released today. The discovery comes thanks to a worldwide consortium of researchers that includes Professor and Chair of Quantitative Genetics at The University of Queensland (UQ), Peter Visscher, from the Queensland Brain Institute (QBI) and Diamantina Institute (DI) at UQ.

He and his team have found a single change in genetic sequence at the gene FTO had a significant effect on the variability of body mass index (BMI). BMI is a commonly used measure of obesity. It measures someone’s weight adjusted for his or her height.

Professor Visscher said that the genetic change, called a single nucleotide polymorphism (SNP), was the replacement of one nucleotide – the units that make up our DNA – with another. “They are the most abundant type of variation in the human genome,” he said. “SNPs occur normally throughout our DNA and most have no effect on our health, however, we’ve found one that does have a small but significant effect on variation in BMI.”

After analysing data from almost 170,000 people, he and his team established that those with a sequence variant in the FTO gene not only weighed more on average, but the measured weights varied more than in the group without the variant. The variability of BMI within the group with two copies of the variant was, in fact, 7 per cent larger than the group without the variant.

Professor Visscher said this equated to around half a kilogram difference in the standard deviation of weight. “So as a group, people with two copies of the weight increasing variant are a few kilograms heavier and vary more,” he said. Genetic differences in variability of specific traits have been seen in many plant and animal species but specific genes or mechanisms to explain the phenomenon had not been identified.

Professor Visscher’s study is the first to look systematically at genetic effects on variation of a complex trait in humans using a very large sample size. “The study is important because it demonstrates that genes can be found that affect trait variability. “This is a first step towards understanding how genes control variation,” Professor Visscher said.

This study is also the first to offer researchers an indirect method to measure genotype by environment interactions without having a measure of specific environmental factors. “If a gene interacts with specific environmental factors then this can be observed with our method,” Professor Visscher said.

“For example, if the effect of a gene on weight is smaller in people who physically exercise than in people who do not, then this will lead to less variation among people with two copies of the weight decreasing variant.

“In our study we did not measure specific environmental effects such as physical exercise so we can’t say for sure whether our results are due to a genotype-environment interaction.”

This is the second study Professor Visscher has published in the prestigious journal Nature this year. Earlier this year he identified that genetic differences also affect how intelligence changes across a lifetime. The work also suggested these changes in intelligence were largely influenced by environmental factors.

The rare disorder Wolfram syndrome is caused by mutations in a single gene, but its effects on the body are far reaching. The disease leads to diabetes, hearing and vision loss, nerve cell damage that causes motor difficulties, and early death.

Now, researchers at Washington University School of Medicine in St. Louis, the Joslin Diabetes Center in Boston and the Novartis Institutes for BioMedical Research report that they have identified a mechanism related to mutations in the WFS1 gene that affects insulin-secreting beta cells. The finding will aid in the understanding of Wolfram syndrome and also may be important in the treatment of milder forms of diabetes and other disorders.

The study is published online in the journal Nature Cell Biology

“We found something we didn’t expect,” says researcher Fumihiko Urano, MD, PhD, associate professor of medicine in Washington University’s Division of Endocrinology, Metabolism and Lipid Research. “The study showed that the WFS1 gene is crucial to producing a key molecule involved in controlling the metabolic activities of individual cells.” That molecule is called cyclic AMP (cyclic adenosine monophosphate).

Insulin-secreting beta cells in the pancreas (above) cannot make enough cyclic AMP in patients with Wolfram syndrome. As a result, the pancreas produces and secretes less insulin, and the cells eventually die.

In insulin-secreting beta cells in the pancreas, for example, cyclic AMP rises in response to high blood sugar, causing those cells to produce and secrete insulin.

“I would compare cyclic AMP to money,” Urano says. “You can’t just take something you make to the store and use it to buy food. First, you have to convert it into money. Then, you use the money to buy food. In the body, external signals stimulate a cell to make cyclic AMP, and then the cyclic AMP, like money, can ‘buy’ insulin or whatever else may be needed.”

The reason patients with Wolfram syndrome experience so many problems, he says, is because mutations in the WFS1 gene interfere with cyclic AMP production in beta cells in the pancreas.

“In patients with Wolfram syndrome, there is no available WFS1 protein, and that protein is key in cyclic AMP production,” he explains. “Then, because levels of cyclic AMP are low in insulin-secreting beta cells, those cells produce and secrete less insulin. And in nerve cells, less cyclic AMP can lead to nerve cell dysfunction and death.”

By finding that cyclic AMP production is affected by mutations in the WFS1 gene, researchers now have a potential target for understanding and treating Wolfram syndrome.

“I don’t know whether we can find a way to control cyclic AMP production in specific tissues,” he says. “But if that’s possible, it could help a great deal.”

Meanwhile, although Wolfram syndrome is rare, affecting about 1 in 500,000 people, Urano says the findings also may be important to more common disorders.

“It’s likely this mechanism is related to diseases such as type 2 diabetes,” he says. “If a complete absence of the WFS1 protein causes Wolfram syndrome, perhaps a partial impairment leads to something milder, like diabetes.”

Hear the word “party” and memories of your 8th birthday sleepover or the big bash you attended last New Year’s may come rushing to mind. But it’s exactly these kinds of memories, embedded in a specific place and time, that people with depression have difficulty recalling.

Research has shown that people who suffer from, or are at risk of, depression have difficulty tapping into specific memories from their own past, an impairment that affects their ability to solve problems and leads them to focus on feelings of distress.

In a study forthcoming in Clinical Psychological Science, a new journal of the Association for Psychological Science, psychological scientists Hamid Neshat-Doost of the University of Isfahan, Iran, Laura Jobson of the University of East Anglia, Tim Dalgleish of the Cognition and Brain Sciences Unit, Medical Research Council, Cambridge and colleagues investigated whether a particular training program, Memory Specificity Training, might improve people’s memory for past events and ameliorate their symptoms of depression.

In Iran, the researchers recruited 23 adolescent Afghani refugees who had lost their fathers in the war in Afghanistan and who showed symptoms of depression. Twelve of the adolescents were randomly assigned to participate in the memory training program and 11 were randomly assigned to a control group that received no training.

All of the adolescents completed a memory test in which they saw 18 positive, neutral, and negative words in Persian and were asked to recall a specific memory related to each word. Their responses were categorized as either a specific or a non-specific type of memory. They also completed questionnaires design to measure symptoms of depression and anxiety symptoms.

For five weeks, the adolescents assigned to the training attended a weekly 80-minute group session, in which they learned about different types of memory and memory recall, and practiced recalling specific memories after being given positive, neutral, and negative keywords.

At the end of the five weeks, both the training group and the control group were given the same memory test that they were given at the beginning of the study. And they took the memory test again as part of a follow-up visit two months later.

The adolescents who participated in the training were able to provide more specific memories after the training than those who did not receive intervention. They also showed fewer symptoms of depression than the control group at the two month follow-up. The researchers found that the relationship between participant group (training or control) and their symptoms of depression at follow-up could be accounted for by changes in specific memory recall over time.

These findings are promising because they suggest that a standalone training program that focuses on specific memory recall can actually improve depression symptoms.

Based on the results of this study, Jobson, Dalgleish, and colleagues conclude that, for individuals suffering from depression, “including a brief training component that targets memory recall as an adjunct to cognitive behavioral therapy or prior therapy may have beneficial effects on memory recall and mood.”

What makes a person altruistic? Philosophers throughout the ages often pondered the question but failed to get concrete answers. New research from the University of Zurich in Switzerland shows that the answer may lie in our brains, or more accurately, that the volume of a small brain region can influences one’s predisposition for altruistic behaviour. The results, presented in the journal Neuron, indicate that individuals who behave more altruistically than others have more grey matter at the junction between the parietal and temporal lobe. This shows for the very first time that there is a connection between brain anatomy, brain activity and altruistic behaviour.

Contary to past studies that showed that social categories like gender, income or education cannot fully explain differences in altruistic behaviour, recent research in the area of neuroscience have demonstrated that differences in brain structure might be linked to differences in personality traits and abilities. Now, for the first time, a team of researchers from the University of Zurich, headed by Ernst Fehr, the director of the Department of Economics, demonstrates that there is a connection between brain anatomy and altruistic behaviour.

For their study, the researchers asked volunteers to divide money between themselves and someone else who was anonymous. The participants always had the option of sacrificing a certain portion of the money for the benefit of the other person. The monetary sacrifice was considered to be altruistic because it helped someone else at one’s own expense. The researchers found major differences in this respect: some participants were almost never willing to sacrifice money to benefit others while others behaved very altruistically.

Previous studies showed that the place where the parietal and temporal lobes meet is linked to the ability to put oneself in someone else’s shoes in order to understand their thoughts and feelings, an ability the researchers considered closely related to altruism.

So the team hypothesised that individual differences in this part of the brain might be linked to differences in altruistic behaviour. And, according to Yosuke Morishima, a postdoctoral researcher at the Department of Economics at the University of Zurich, they were right: ‘People who behaved more altruistically also had a higher proportion of grey matter at the junction between the parietal and temporal lobes.’

The researchers also discovered that the subjects displayed marked differences in brain activity while they were deciding how to split up the money. In the case of selfish people, the small brain region behind the ear is already active when the cost of altruistic behaviour is very low. In altruistic people, however, this brain region only becomes more active when the cost is very high. The brain region is activated especially strongly when people reach the limits of their willingness to behave altruistically. The reason, the researchers suspect, is that this is when there is the greatest need to overcome man’s natural self-centeredness by activating this brain region.

Said Dr Fehr: ‘These are exciting results for us. However, one should not jump to the conclusion that altruistic behaviour is determined by biological factors alone.’

It appears that the volume of grey matter can also be influenced by social processes. According to Dr Fehr, the findings therefore raise the question as to whether it is possible to promote the development of brain regions that are important for altruistic behaviour through training or social norms.

People who bear the genetic mutation for Huntington’s disease learn faster than healthy people. The more pronounced the mutation was, the more quickly they learned. This is reported by researchers from the Ruhr-Universität Bochum and from Dortmund in the journal Current Biology. The team has thus demonstrated for the first time that neurodegenerative diseases can go hand in hand with increased learning efficiency. “It is possible that the same mechanisms that lead to the degenerative changes in the central nervous system also cause the considerably better learning efficiency” says Dr. Christian Beste, head of the Emmy Noether Junior Research Group “Neuronal Mechanisms of Action Control” at the RUB.

Passive learning through repeated stimulus presentation

In a previous study, the Bochum psychologists reported that the human sense of vision can be changed in the long term by repeatedly exposing subjects to certain visual stimuli for short periods (we reported in May 2011). The task of the participants was to detect changes in the brightness of stimuli. They performed better if they had viewed the stimuli passively for a while first. In the current study, the researchers presented the same task to 29 subjects with the genetic mutation for Huntington’s disease, who, however, did not yet show any symptoms. They also tested 45 control subjects without such mutations in the genome. In both groups, the learning efficiency was better after passive stimulus presentation than without the passive training. Subjects with the Huntington’s mutation, however, increased their performance twice as fast as those without the mutation.

Glutamate may have paradoxical effect

Degenerative diseases of the nervous system are based on complex changes. A key mechanism is an increased release of the neurotransmitter glutamate. However, since glutamate is also important for learning, in some cases it could lead to the paradoxical effect: better learning efficiency despite degeneration of the nerve cells.

Detecting differences in brightness under aggravated conditions

In each experimental run, the subjects saw two consecutive small bars on a computer screen that either had the same or different brightness. Sometimes, however, not only the brightness changed from bar one to bar two, but also the orientation of the bar (vertical or horizontal). “Normally, the distraction stimulus, i.e. the change in orientation, draws all the attention” Christian Beste explains. “But after the passive training with the visual stimuli, the distraction stimulus has no effect at all.” The shift of attention from the non-relevant to the relevant properties of the stimulus was also visible in the electroencephalogram (EEG) in brain areas for early visual processing.

Better performance with stronger mutation

In Huntington’s disease, a short segment of a gene is repeated. The number of repetitions determines when the disease breaks out. In the present study, a greater number of repetitions was, however, also associated with higher learning efficiency. “This shows that neurodegenerative changes can cause paradoxical effects” says Christian Beste. “The everyday view that neurodegenerative changes fundamentally entail deterioration of various functions can no longer be maintained in this dogmatic form.”

A drug designed for diabetes sufferers could have the potential to treat neurodegenerative diseases like Alzheimer’s, a study by scientists at the University of Ulster has revealed.

Type II diabetes is a known risk factor for Alzheimer’s and it is thought that impaired insulin signalling in the brain could damage nerve cells and contribute to the disease.

Scientists believe that drugs designed to tackle Type II diabetes could also have benefits for keeping our brain cells healthy.

To investigate this, Prof Christian Hölscher and his team at the Biomedical Sciences Research Institute on the Coleraine campus used an experimental drug called (Val8)GLP-1.

This drug simulates the activity of a protein called GLP-1, which can help the body control its response to blood sugar. The scientists treated healthy mice with the drug and studied its effects in the brain.

Although it is often difficult for drugs to cross from the blood into the brain, the team found that (Val8)GLP-1 entered the brain and appeared to have no side-effects at the doses tested.

The drug promoted new brain cells to grow in the hippocampus, an area of the brain known to be involved in memory. This finding suggests that as well as its role in insulin signalling, GLP-1 may also be important for the production of new nerve cells in the mouse brain.

The team found that blocking the effect of GLP-1 in the brain made mice perform more poorly on learning and memory task, while boosting it with the drug seemed to have no effect on behaviour.

The new findings, published this week in the journal Brain Research, are part of ongoing research funded by Alzheimer’s Research UK, the leading dementia research charity.

Prof Hölscher, said: “Here at the Biomedical Sciences Research Institute, we are really interested in the potential of diabetes drugs for protecting brain cells from damage and even promoting new brain cells to grow. This could have huge implications for diseases like Alzheimer’s or Parkinson’s, where brain cells are lost.

“It is very encouraging that the experimental drug we tested, (Val8)GLP-1, entered the brain and our work suggests that GLP-1 could be a really important target for boosting memory. While we didn’t see benefits on learning and memory in these healthy mice, we are keen to test the drugs in mice with signs of Alzheimer’s disease, where we could see real improvements.”

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, said: “We are pleased to have supported this early stage research, suggesting that this experimental diabetes drug could also promote the growth of new brain cells. While we know losing brain cells is a key feature of Alzheimer’s, there is a long way to go before we would know whether this drug could benefit people with the disease.

"This research will help us understand the factors that keep nerve cells healthy, knowledge that could hold vital clues to tackling Alzheimer’s. With over half a million people in the UK living with the disease, learning more about how to keep our brain cells healthy is of vital importance. Funding for dementia research lags far behind that of other common diseases, but is essential if we are to realise the true potential of research like this.”

Signs of autism—such as impaired social skills and repetitive, ritualistic movements—usually begin to appear when a child is about 18 months old. Autism is thought to result from miswired connections in the developing brain, and many experts believe that therapies must begin during a “critical window,” before the faulty circuits become fixed in place. But a new study online today in Science shows that at least one malfunctioning circuit can be repaired after that window closes, holding out hope that in some forms of autism, abnormal circuits in the brain can be corrected even after their development is complete.

Faulty wiring. Shutting off the Nlgn3 gene in mice (right panel) results in miswired synaptic connections, which may be fixable. Credit: S. J. Baudouin et al., Science

According to developmental neurobiologist Peter Scheiffele of the University of Basel in Switzerland, autism doesn’t result from a handful of “culprit” genes that point to a treatable flaw. Instead, patients appear to carry mutations in one out of dozens, even hundreds of risk genes. “This genetic complexity is a huge issue with respect to developing treatments [for autism],” Scheiffele says. To complicate the picture further, autism is not always an isolated disorder; it’s often a common feature in syndromes that otherwise differ drastically. For example, in fragile X syndrome, a form of mental retardation, about 25% of patients are also autistic.

Scheiffele and colleagues were studying a gene called neuroligin-3 (Nlgn3), involved in building the contact points, called synapses, between neurons. Many researchers believe that autism begins at the synapse, and mutations in Nlgn3 have appeared in some forms of the disorder. Sheiffele’s team was focusing on synapses in the cerebellum, a part of the brain that controls movement, but, according to recent research, may also be involved in social behavior. Abnormalities in this region may contribute to both the unusual movements and the social problems seen in autistic patients.

To get a better handle on the role of Nlgn3, the scientists studied mice whose Nlgn3 genes were engineered with an on-off switch, called a promoter region, that is controlled by the antibiotic doxycycline. The animals were raised with the drug in their drinking water, which kept the switch in the off position. With the Nlgn3 gene disabled in the mice, neurons in their cerebellum made the abnormal connections seen in the autistic brain.

Specifically, and much to the researchers’ surprise, the lack of Nlgn3 led to the overactivation of a receptor abbreviated as mGluR1α. This receptor is a component of a pathway that is also disrupted in fragile X syndrome, though it results from mutations in an entirely different gene. In the mice, the overabundance of these receptors led the neurons to make synaptic connections in the wrong places.

To see if turning Nlgn3 gene back on would correct these problems, the researchers withdrew the doxycycline. It worked: With Nlgn3 functioning once more, levels of the extraneous receptor receded back to normal, and the misplaced synapses began to disappear.

"Our finding demonstrates that there is still flexibility after the ‘critical window’ of brain development,” Scheiffele says. “It raises the question: To what extent can a miswired brain be corrected?” The next step, he says, is to see whether motor abnormalities, such as ladder-climbing difficulties, and social interactions can be corrected with similar treatment in the engineered mice. His team is also studying whether drugs that block the mGluR1α receptor can have the same effect as genetically controlling the Nlgn3 gene, which isn’t a treatment option for humans.

"This study holds out hope for children and even adults with developmental disorders. Maybe their conditions aren’t set in stone and can be treated," says neuroscientist Kimberly Huber of the University of Texas Southwestern Medical Center in Dallas. Huber adds that drugs that block a similar receptor, mGluR5, are in clinical trials to treat fragile X syndrome.

In diabetic mice, the cells of the pancreas don’t die, but rather revert to an earlier state incapable of producing the insulin the body needs.

(Image credit: Wikipedia, Chistin Süß, Jakob Suckale, Michele Solimena)

As cases of type 2 diabetes progress, people get increasingly worse at making their own insulin, a hormone that controls levels of sugar in the blood. The usual explanation is that the insulin-producing beta cells of the pancreas are dying.  But according to a study published today (September 13) in Cell, the beta cells of several breeds of diabetic mice don’t die at all. Instead, they de-differentiate into a less specialized cell type.

If a similar mechanism is occurring in humans, it might be possible to ease the progression of diabetes by finding new ways of preventing dedifferentiation, the authors suggest.

“This piece of work is not only thorough and methodologically superb but highly original and relevant,” said Ele Ferrannini, a diabetes biologist from the CNR (National Research Council) in Pisa, Italy. “The implications are that beta cell dysfunction is potentially reversible, to an extent that probably is still underappreciated.”

For Domenico Accili of Columbia University in New York, the prevailing idea about dying beta cells never quite fit all the available data. First, while traditional methods of counting beta cells indicates that these cells are indeed disappearing as diabetes progresses, the loss of cells and the severity of the symptoms are not always correlated, and some healthy people have fewer beta cells than those with diabetes. “There was always a healthy amount of scepticism,” said Accili.

To understand what was really going on, Accili and his colleague Chutima Talchai from Columbia University turned to FoxO1, a gene that produces a transcription factor in beta cells. In healthy cells, the protein is abundant in the cytoplasm but inactive. If the cells are swamped by glucose or fats—such as via a high-sugar and high-fat diet—the protein is activated, at which point it travels to the nucleus to regulate gene expression. Eventually, it disappears altogether.

To find out how FoxO1’s activation and subsequent disappearance might be related to the simultaneous disappearance of beta cells, Talchai engineered a breed of FoxO1 knockout mice. The mice seemed normal, but when they went through bouts of bodily stress, such as aging or pregnancy, their beta cell populations fell by 30 percent, their blood sugar rose, and their insulin levels fell, “reproduc[ing] perfectly the course of diabetes in humans,” said Accili.

But the beta cells did not die. By tagging both the cells themselves and the insulin they produced with fluorescent molecules, the researchers showed that the cells had merely reverted to an undifferentiated state in which they no longer produced insulin.  About 25 percent of the beta cells changed in this way, accounting for nearly all of the vanished population.

The results suggest that beta cells require FoxO1 to maintain their identity in the face of long-term stress. Without this protein, they dedifferentiate into a “pre-beta” state.

Accili thinks that this phenomenon could explain the observance of “empty” beta cells in diabetic mice and humans, which look like beta cells, but make no insulin. “These are, in fact, former beta cells that have dedifferentiated,” Accili hypothesized. Once dedifferentiated, the pre-beta cells can then give rise to other types of hormone-producing pancreatic cells, including those that make glucagon, which has the opposite effect of insulin on blood sugar levels. Indeed, the diabetic pancreas is often characterised by a rise in glucagon as well as a fall in insulin.

Accili thinks that beta cells dedifferentiate as an act of self-preservation, allowing them to escape the pressure of extreme insulin production when exposed to unusually high glucose levels. “The cells perceive high blood sugar as a temporary storm, and batten down the hatches waiting for better times,” he says. This would also explain why beta cells disappear slowly as diabetes progresses and blood sugar levels get more and more unruly.

Currently, there are no drugs that can either prevent the dedifferentiation or to reverse it, but two lines of evidence suggest that such treatments are possible. First, pre-beta cells can become other cells types, and “there’s no reason to think that they can’t become beta cells again,” said Accili. Second, “we have known since the 1970s that treating patients with insulin early in the course of the disease can temporarily restore beta-cell function,” he added. This idea is known as “beta-cell rest” and it might work by easing the pressure on the beta cells to produce insulin, and possibly giving the dedifferentiated population a chance to regain their previous identity.

But Peter Butler, a diabetes specialist at the University of California, Los Angeles, advises caution. Although he praises Accili’s study, he notes that other groups have found evidence of dying beta cells in other breeds of mice. Furthermore, many diabetes discoveries in mouse models do not translate to humans, he added.  The next step, he said, is to show that the undifferentiated cells are more common in the pancreas of people with type 2 diabetes than in healthy individuals.

Ferrannini added that we do not know what type of metabolic stress would trigger beta cell dedifferentiation in humans, or how genetics would affect the process.

Moderate exercise may help people cope with anxiety and stress for an extended period of time post-workout, according to a study by kinesiology researchers in the University of Maryland School of Public Health published in the journal Medicine and Science in Sports and Exercise.

"While it is well-known that exercise improves mood, among other benefits, not as much is known about the potency of exercise’s impact on emotional state and whether these positive effects endure when we’re faced with everyday stressors once we leave the gym," explains J. Carson Smith, assistant professor in the Department of Kinesiology. "We found that exercise helps to buffer the effects of emotional exposure. If you exercise, you’ll not only reduce your anxiety, but you’ll be better able to maintain that reduced anxiety when confronted with emotional events."

Smith, whose research explores how exercise and physical activity affect brain function, aging and mental health, compared how moderate intensity cycling versus a period of quiet rest (both for 30 minutes) affected anxiety levels in a group of healthy college students. He assessed their anxiety state before the period of activity (or rest), shortly afterward (15 minutes after) and finally after exposing them to a variety of highly arousing pleasant and unpleasant photographs, as well as neutral images. At each point, study participants answered 20 questions from the State-Trait Anxiety inventory, which is designed to assess different symptoms of anxiety. All participants were put through both the exercise and the rest states (on different days) and tested for anxiety levels pre-exercise, post-exercise, and post-picture viewing.

Smith found that exercise and quiet rest were equally effective at reducing anxiety levels initially. However, once they were emotionally stimulated (by being shown 90 photographs from the International Affective Picture System, a database of photographs used in emotion research) for ~20 minutes, the anxiety levels of those who had simply rested went back up to their initial levels, whereas those who had exercised maintained their reduced anxiety levels.

"The set of photographic stimuli we used from the IAPS database was designed to simulate the range of emotional events you might experience in daily life," Smith explains. "They represent pleasant emotional events, neutral events and unpleasant events or stimuli. These vary from pictures of babies, families, puppies and appetizing food items, to very neutral things like plates, cups, furniture and city landscapes, to very unpleasant images of violence, mutilations and other gruesome things."

The study findings suggest that exercise may play an important role in helping people to better endure life’s daily anxieties and stressors.

Smith plans to explore if exercise could have the same persistent beneficial effect in patients who regularly experience anxiety and depression symptoms. In collaboration with the new Maryland Neuroimaging Center, he is also exploring the addition of functional magnetic resonance imaging, or fMRI, to measure brain activity during the period of exposure to emotionally stimulating images to see how exercise may alter the brain’s emotion-related neural networks.

Smith also investigates the role of exercise in preventing cognitive decline in older adults. His research has shown that physical activity promotes changes in the brain that may protect those at high risk for Alzheimer’s disease.

Stress has long been pegged as the enemy of attention, disrupting focus and doing substantial damage to working memory — the short-term juggling of information that allows us to do all the little things that make us productive.

By watching individual neurons at work, a group of psychologists at the University of Wisconsin-Madison has revealed just how stress can addle the mind, as well as how neurons in the brain’s prefrontal cortex help “remember” information in the first place.

Working memory is short-term and flexible, allowing the brain to hold a large amount of information close at hand to perform complex tasks. Without it, you would have forgotten the first half of this sentence while reading the second half. The prefrontal cortex is vital to working memory.

"In many respects, you’d look pretty normal without a prefrontal cortex," said Craig Berridge, UW-Madison psychology professor. "You don’t need that part of the brain to hear or talk, to keep long-term memories, or to remember what you did as a child or what you read in the newspaper three days ago."

But without your prefrontal cortex you’d be unable to stay on task or modulate your emotions well.

"People without a prefrontal cortex are very distractible," Berridge said. "They’re very impulsive. They can be very argumentative."

The neurons of the prefrontal cortex help store information for short periods. Like a chalkboard, these neurons can be written with information, erased when that information is no longer needed, and rewritten with something new.

It’s how the neurons maintain access to that short-term information that leaves them vulnerable to stress. David Devilbiss, a scientist working with Berridge and lead author on a study published today in the journal PLOS Computational Biology, applied a new statistical modeling approach to show that rat prefrontal neurons were firing and re-firing to keep recently stored information fresh.

"Even though these neurons communicate on a scale of every thousandth of a second, they know what they did one second to one-and-a-half seconds ago," Devilbiss said. "But if the neuron doesn’t stimulate itself again within a little more than a second, it’s lost that information."

Apply some stress — in the researchers’ case, a loud blast of white noise in the presence of rats working on a maze designed to test working memory — and many neurons are distracted from reminding themselves of … what was it we were doing again?

"We’re simultaneously watching dozens of individual neurons firing in the rats’ brains, and under stress those neurons get even more active," said Devilbiss, whose work was supported by the National Science Foundation and National Institutes of Health. "But what they’re doing is not retaining information important to completing the maze. They’re reacting to other things, less useful things."

Without the roar of white noise, which has been shown to impair rats in the same way it does monkeys and humans, the maze-runners were reaching their goal about 90 percent of the time. Under stress, the animals completed the test at a 65 percent clip, with many struggling enough to fall to blind chance.

Recordings of the electrical activity of prefrontal cortex neurons in the maze-running rats showed these neurons were unable to hold information key to finding the next chocolate chip reward. Instead, the neurons were frenetic, reacting to distractions such as noises and smells in the room.

The effects of stress-related distraction are well-known and dangerous.

"The literature tells us that stress plays a role in more than half of all workplace accidents, and a lot of people have to work under what we would consider a great deal of stress," Devilbiss said. "Air traffic controllers need to concentrate and focus with a lot riding on their actions. People in the military have to carry out these thought processes in conditions that would be very distracting, and now we know that this distraction is happening at the level of individual cells in the brain."

The researchers’ work may suggest new directions for treatment of prefrontal cortex dysfunction.

"Based on drug studies, it had been believed stress simply suppressed prefrontal cortex activity," Berridge said. "These studies demonstrate that rather than suppressing activity, stress modifies the nature of that activity. Treatments that keep neurons on their self-stimulating task while shutting out distractions may help protect working memory."

Looking at a tangled mass of network cables plugged into a crowded router doesn’t yield much insight into the network traffic that runs through the hardware.

Similarly, Lynn H. Matthias Professor of Electrical and Computer Engineering Barry Van Veen says that looking at the three pounds of interwoven neurons that make up the hardware of the human brain doesn’t give the complete picture of the brain activity that supports human cognition and consciousness.

Working with multiple collaborators, Van Veen has applied signal analysis techniques to the electric or magnetic fields measured noninvasively at the scalp through electroencephalography (EEG) or magnetoencephalography (MEG) to develop methods for identifying network models of brain function — essentially, traffic patterns of neural activity present in the human brain.

"It’s analogous to coming up with a new microscope," says Van Veen.

Having a reliable traffic map of normal brain function provides a baseline for comparison for understanding how different disorders, substances and devices affect the brain. “Now that we’ve got the tool ready, the opportunities to try it out on scientifically interesting questions are really blossoming,” says Van Veen.

For instance, network models may provide a better blueprint for how medical devices can interface with the brain. Van Veen recently began working with biomedical engineering Associate Professor Justin Williams to apply his work toward making better brain-machine interfaces.

But the implications of network models go beyond engineering questions. The effect of alcohol on the brain just begs for network analysis, according to Van Veen. The network model could allow researchers to see precisely which parts of the brain are altered by alcohol consumption. It could provide insight into how short-term memory works, help explain the effects of schizophrenia and monitor treatment, help measure the depth and effectiveness of different types of anesthesia, and even help give insight into the brain activity that precedes — or prevents — a miraculous recovery from a coma.

"We’re developing this tool as a significant improvement over what people have had access to before," says Van Veen. "The possibilities for using it to study different aspects of brain function are nearly unlimited."