Neuroscience

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."

Researchers at Newcastle University have revealed the mechanism by which neurons, the nerve cells in the brain and other parts of the body, age.

The research, published in Aging Cell, opens up new avenues of understanding for conditions where the ageing of neurons are known to be responsible, such as dementia and Parkinson’s disease.

The ageing process has its roots deep within the cells and molecules that make up our bodies. Experts have previously identified the molecular pathway that react to cell damage and stems the cell’s ability to divide, known as cell senescence.

However, in cells that do not have this ability to divide, such as neurons in the brain and elsewhere, little was understood of the ageing process. Now a team of scientists at Newcastle University, led by Professor Thomas von Zglinicki have shown that these cells follow the same pathway.

This challenges previous assumptions on cell senescence and opens new areas to explore in terms of treatments for conditions such as dementia, motor neuron disease or age-related hearing loss.

Newcastle University’s Professor Thomas von Zglinicki who led the research said: “We want to continue our work looking at the pathways in human brains as this study provides us with a new concept as to how damage can spread from the first affected area to the whole brain.”

Working with the University’s special colony of aged mice, the scientists have discovered that ageing in neurons follows exactly the same rules as in senescing fibroblasts, the cells which divide in the skin to repair wounds.

DNA damage responses essentially re-program senescent fibroblasts to produce and secrete a host of dangerous substances including oxygen free radicals or reactive oxygen species (ROS) and pro-inflammatory signalling molecules. This makes senescent cells the ‘rotten apple in a basket’ that can damage and spoil the intact cells in their neighbourhood.  However, so far it was always thought that ageing in cells that can’t divide - post-mitotic, non-proliferating cells - like neurons would follow a completely different pathway.

Now, this research explains that in fact ageing in neurons follows exactly the same rules as in senescing fibroblasts.

Professor von Zglinicki, professor of Cellular Gerontology at Newcastle University said: “We will now need to find out whether the same mechanisms we detected in mouse brains are also associated with brain ageing and cognitive loss in humans. We might have opened up a short-cut towards understanding brain ageing, should that be the case.”

Dr Diana Jurk, who did most of this work during her PhD in the von Zglinicki group, said: “It was absolutely fascinating to see how ageing processes that we always thought of as completely separate turned out to be identical.  Suddenly so much disparate knowledge came together and made sense.”

Non-smokers who live with or spend time with smokers are damaging their memory, according to new research from Northumbria University. 

The findings, published in the latest online edition of the journal Addiction is the first study to explore the relationship between exposure to other people’s smoke and everyday memory problems.

Dr Tom Heffernan and Dr Terence O’Neil, both researchers at the Collaboration for Drug and Alcohol Research Group at Northumbria University, compared a group of current smokers with two groups of non-smokers – those who were regularly exposed to second-hand smoke and those who were not.

Those exposed to second-hand smoke either lived with smokers or spent time with smokers, for example in a designated “smoking area,” and reported being exposed to second-hand smoke for an average of 25 hours a week for an average of four and a half years.

The three groups were tested on time-based memory (remembering to carry out an activity after some time) and event-based memory (which refers to memory for future intentions and activities).

Researchers found that the non-smokers who had been exposed to second-hand smoke forgot almost 20% more in the memory tests than those non-smokers not exposed. However, both groups out-performed the current smokers who forgot 30% more than those who were not exposed to second-hand smoking.

Dr Heffernan said: “According to recent reports by the World Health Organisation, exposure to second-hand smoke can have serious consequences on the health of people who have never smoked themselves, but who are exposed to other people’s tobacco smoke.

“Our findings suggest that the deficits associated with second-hand smoke exposure extend to everyday cognitive function. We hope our work will stimulate further research in the field in order to gain a better understanding of the links between exposure to second-hand smoke, health problems and everyday cognitive function.”

Researchers from the University of Utah have gained new insight into the regulation of adult nerve cell generation in the hypothalamus, the part of the brain that regulates many aspects of behavior, mood, and metabolism. In the Sept. 10, 2012, issue of Developmental Cell they report that a cell-to-cell communication network known as the Wnt signaling pathway plays an important role in both the production and specialization of nerve cell precursors in the hypothalamus.

The hypothalamus is a highly complex region of the brain that controls hunger, thirst, fatigue, body temperature, and sleep. It also links the central nervous system to the body system that regulates hormone levels. Recent studies have shown that the hypothalamus is one of the parts of the brain in which neurogenesis, the birth of new nerve cells, continues throughout adulthood.

“In our earlier work, we discovered that Wnt signaling was required for neurogenesis in the embryonic zebrafish hypothalamus,” says Richard Dorsky, Ph.D., associate professor of neurobiology and anatomy at the University of Utah School of Medicine and senior author on the study. “We also found that, in zebrafish, both Wnt signaling and hypothalamic neurogenesis continue into adulthood. The goal of this study was to define specific roles for Wnt signaling in neurogenesis.”

The Wnt signaling pathway is a network of proteins that transmits signals from the cell surface to DNA in the cell nucleus to regulate gene expression, and it is known to play a critical role in cell-to-cell communication in both embryos and adults. In this study, Dorsky and his colleagues demonstrated that in zebrafish embryos Wnt signaling is present in progenitor cells that are actively multiplying in the hypothalamus. Progenitor cells have the potential to divide and differentiate into a variety of specialized cell types. Dorsky and his colleagues also found that Wnt signaling continues to be required for hypothalamic neurogenesis throughout life.

Neural progenitor cells arise from neural stem cells, and retain the capacity to develop into more specialized types of nerve cells. After the embryo is formed, some neural stem cells lie dormant in the brain and spinal cord until they are activated to serve as a repair system. When tissue damage or death occurs, chemical substances trigger these neural stem cells to make neural progenitor cells that assist in tissue recovery. Recent research suggests that other neural progenitor cells continue to make new nerve cells in the uninjured brain and contribute to the plasticity of the brain in response to changes in the environment.

“From a functional standpoint, it is not yet clear why the ability to continuously produce hypothalamic nerve cells is important in adult zebrafish,” says Dorsky. “However, in adult mice, hypothalamic neurogenesis seems to be significant in the regulation of feeding behaviors due to environmental changes.”

Dorsky and his colleagues discovered that the role of the Wnt signaling pathway differs between embryos and adults. In zebrafish embryos, activation of Wnt signaling is required for proliferation of progenitor cells contributing to growth of brain structures. However, at later stages of development including adulthood, Wnt signaling must be active for neural progenitor cells to commit to becoming nerve cells, but then must be inhibited for these cells to complete the differentiation process. Significantly, Dorsky and his colleagues also found that mice displayed a similar pattern of Wnt activity.

“Compared to other regions of the brain, the hypothalamus is relatively unstudied as a model of post-embryonic neurogenesis,” says Dorsky. “Our research represents a significant contribution to the field because it establishes the vertebrate hypothalamus as a model of Wnt-regulated neural progenitor differentiation that can be used to shed light on the plasticity of the adult brain.”

A computer is being taught to interpret human emotions based on lip pattern, according to research published in the International Journal of Artificial Intelligence and Soft Computing. The system could improve the way we interact with computers and perhaps allow disabled people to use computer-based communications devices, such as voice synthesizers, more effectively and more efficiently.

Karthigayan Muthukaruppanof Manipal International University in Selangor, Malaysia, and co-workers have developed a system using a genetic algorithm that gets better and better with each iteration to match irregular ellipse fitting equations to the shape of the human mouth displaying different emotions. They have used photos of individuals from South-East Asia and Japan to train a computer to recognize the six commonly accepted human emotions - happiness, sadness, fear, angry, disgust, surprise - and a neutral expression. The upper and lower lip is each analyzed as two separate ellipses by the algorithm.

"In recent years, there has been a growing interest in improving all aspects of interaction between humans and computers especially in the area of human emotion recognition by observing facial expression," the team explains. Earlier researchers have developed an understanding that allows emotion to be recreated by manipulating a representation of the human face on a computer screen. Such research is currently informing the development of more realistic animated actors and even the behavior of robots. However, the inverse process in which a computer recognizes the emotion behind a real human face is still a difficult problem to tackle.

It is well known that many deeper emotions are betrayed by more than movements of the mouth. A genuine smile for instance involves flexing of muscles around the eyes and eyebrow movements are almost universally essential to the subconscious interpretation of a person’s feelings. However, the lips remain a crucial part of the outward expression of emotion. The team’s algorithm can successfully classify the seven emotions and a neutral expression described.

The researchers suggest that initial applications of such an emotion detector might be helping disabled patients lacking speech to interact more effectively with computer-based communication devices, for instance.

Executive function tests key to early detection of Alzheimer’s, Concordia study shows

By the time older adults are diagnosed with Alzheimer’s disease, the brain damage is irreparable. For now, modern medicine is able to slow the progression of the disease but is incapable of reversing it. What if there was a way to detect if someone is on the path to Alzheimer’s before substantial and non-reversible brain damage sets in?

This was the question Erin K. Johns, a doctoral student in Concordia University’s Department of Psychology and member of the Center for Research in Human Development (CRDH), asked when she started her research on older adults with mild cognitive impairment (MCI). These adults show slight impairments in memory, as well as in “executive functions” like attention, planning, and problem solving. While the impairments are mild, adults with MCI have a high risk of developing Alzheimer’s disease.

“We wanted to help provide more reliable tools to identify people who are at increased risk for developing Alzheimer’s so that they can be targeted for preventive strategies that would stop brain damage from progressing,” says Johns.

The new study was published in the Journal of the International Neuropsychological Society and was funded by the Quebec Network for Research on Aging and the Canadian Institutes of Health Research. In it, Johns and her colleagues found that people with MCI are impaired in several aspects of executive functioning, the biggest being inhibitory control. 

This ability is crucial for self-control: everything from resisting buying a candy bar at the checkout aisle to resisting the urge to mention the obvious weight gain in a relative you haven’t seen in a while. Adults with MCI also had trouble with tests that measure the ability to plan and organize.

Johns and her colleagues found that all the adults with MCI they tested were impaired in at least one executive function and almost half performed poorly in all the executive function tests. This is in sharp contrast with standard screening tests and clinical interviews, which detected impairments in only 15 percent of those with MCI.

“The problem is that patients and their families have difficulty reporting executive functioning problems to their physician, because they may not have a good understanding of what these problems look like in their everyday life.” says Johns. “That’s why neuropsychological testing is important.”

Executive function deficits affect a person’s everyday life and their ability to plan and organize their activities. Even something as easy as running errands and figuring out whether to go to the drycleaners or to the supermarket can be difficult for adults with MCI. Detecting these problems early could improve patient care and treatment planning.

“If we miss the deficits, we miss out on an opportunity to intervene with the patient and the family to help them know what to expect and how to cope,” says Johns. She is now conducting a follow-up study funded by the Alzheimer Society of Canada and Canadian Institutes of Health Research, along with her supervisor, Natalie Phillips, associate professor in the Department of Psychology and member of CRDH.

Johns hopes her continued research will lead to a better understanding of why these deficits start at such an early stage of Alzheimer’s and what other tools could be used for earlier detection of the disease.

Washington State University researchers have found a cellular mechanism that contributes to the lack of motivation and negative emotions of a cocaine addict going through withdrawal. Their discovery, published in the latest Proceedings of the National Academy of Sciences, offers a deeper look into the cellular and behavioral implications of addiction.

Bradley Winters, lead author of the PNAS paper and a freshly minted WSU doctor of neuroscience, says he, his major advisor Yan Dong, and colleagues at WSU, the University of Pittsburgh and the European Neuroscience Institute focused on cells that produce a signaling molecule called cannabinoid receptor 1, or CB1. Its main function is regulating the communication between nerve cells related to the functions like memory, motor control, perception, mood and appetite. Those same functions are affected by THC, the cannabinoid in its namesake cannabis, or marijuana.

"These receptors are not here just to make marijuana fun,” says Winters. "Their main function is changes in how nerve cells communicate with each other.”

The researchers studied the CB1 cells by producing a line of mice in which the cells that make CB1 were labeled fluorescently. The researchers could then identify the cells and target them with glass pipettes 1/100th the width of a human hair and record electrical currents they use to communicate with other nerve cells.

The CB1 cells act like brakes, slowing down activity in a brain region called the nucleus accumbens, which governs emotion and motivation.

"Cocaine causes profound cellular changes in the nucleus accumbens, but no one has ever looked at this type of cell, and these cells are important because they help organize the output,” says Winters.

The researchers found that cocaine increases the excitability of the CB1 cells, in effect stepping on the brakes of emotion and motivation. When an addict is high on cocaine, the brakes are struggling to slow things down. The problem is, they stay on even when the cocaine has worn off.

"As you do cocaine, it speeds everything up, pushing you to a highly rewarding emotional state,” says Winters. "It is kind of like going down a steep hill so you have to start riding that brake really hard. But then after the cocaine wears off and the hill levels out, you’re still riding that brake just as hard. Now you’re going down a regular, low-grade hill but you’re going 2 mph because your foot is still jammed on the brake.”

The result is a drag on the emotions and motivation of an addict in withdrawal—a drag that could be linked to sluggish activation of the nucleus accumbens.

"That state is like, ‘I feel terrible and I don’t want to do anything,’” says Winters. "You have the high and the crashing low and this low that you feel is what brings you back to the drug because you want to feel better and the drug is the only thing you feel motivation for.”

Muscles that burn energy without contracting have yielded new clues about how the body retains a constant temperature – and they may provide new targets for combating obesity.

Traditionally, the body’s main thermostat was thought to be brown fat. It raids the body’s white fat stores in cold conditions to burn energy and keep the body warm.

Muscles also play a role in keeping the body warm by contracting and triggering the shiver response – but this is only a short-term fix because prolonged shivering damages muscles. Now it seems that muscles have another way to turn up the heat.

"Our findings demonstrate for the first time that muscle, which accounts for 40 per cent of body weight in humans, can generate heat independent of shivering," says Muthu Periasamy of Ohio State University in Columbus.

Sarcolipin: idle body’s thermostat (Image: David Trood/Stone/Getty)

Surviving the chill

Through experiments on mice that had their usual thermostat – brown fat – surgically removed, Periasamy and his colleagues proved that a protein called sarcolipin helps muscle cells keep the body warm by burning energy, almost like an idling motor car, even if the muscles do not contract.

All of the mice had their brown fat removed, but some of them had been genetically engineered to lack sarcolipin too. These rodents could not survive when held at 4 °C, and died of hypothermia within 10 hours. By contrast, mice that could make sarcolipin were able to survive the chilly temperatures and maintained their core body temperature – despite having no brown fat.

Periasamy also showed that an inability to make sarcolipin made mice 33 per cent heavier than normal when fed a high-fat diet. This suggests that idling muscles might also help combat obesity by burning off excess energy. The search is now on for drugs that perform the same role, triggering idling muscles to burn off excess fat.

"The most interesting finding is that mice unable to make sarcolipin are more susceptible to obesity," says Andy Whittle of the University of Cambridge, who is testing spicy dietary treatments to ramp up the fat-burning activity of brown fat. "The research demonstrates that muscle is an important component even in mice, which have comparatively more brown fat than humans. In humans, burning fat in muscle is likely to be even more important for proper energy balance."