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.

(Source: the-scientist.com)

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.

(Source: newsdesk.umd.edu)

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."

(Source: news.wisc.edu)

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."

(Source: news.wisc.edu)