New gene for bipolar disorder discovered

Team of researchers searched for the foundations of manic-depressive disorder in about 24,000 people

First on top of the world and then in the depths of despair – this is what the extreme mood changes for people with bipolar disorder are like. Under the direction of scientists from the University of Bonn Hospital, the Central Institute of Mental Health of Mannheim and the University of Basel Hospital, an international collaboration of researchers discovered two new gene regions which are connected with the prevalent disease. In addition, they were able to confirm three additional suspect genes. In this unparalleled worldwide study, the scientists are utilizing unprecedented numbers of patients. The results are now being published in the renowned journal “Nature Communications”.

Throughout the course of their lives, about one percent of the population suffers from bipolar disorder, also known as manic-depressive disorder. The patients undergo a veritable rollercoaster of emotions: During extreme shifts, they experience manic phases with delusions of grandeur, increased drive and a decreased need for sleep as well as depressive episodes with a severely depressed mood to the point of suicidal thoughts. The causes of the disease are not yet fully understood, however in addition to psychosocial triggers, genetic factors play a large role. “There is no one gene that has a significant effect on the development of bipolar disorder,” says Prof. Dr. Markus M. Nöthen, Director of the Institute of Human Genetics of the University of Bonn Hospital. “Many different genes are evidently involved and these genes work together with environmental factors in a complex way.”

Scale of the investigation is unparalleled worldwide

In recent years, scientists at the Institute of Human Genetics were already involved in decoding several genes associated with bipolar disorder. The researchers working with Prof. Dr. Marcella Rietschel from the Central Institute of Mental Health of Mannheim, Prof. Dr. Markus M. Nöthen from the University of Bonn Hospital and Prof. Dr. Sven Cichon from the University of Basel Hospital are now using unprecedented numbers of patients in an international research collaboration: New genetic data from 2266 patients with manic-depressive disorder and 5028 control persons were obtained, merged with existing data sets and analyzed together. In total, data on the genetic material of 9747 patients were compared with data from 14,278 healthy persons. “The investigation of the genetic foundations of bipolar disorder on this scale is unique worldwide to date,” says Prof. Rietschel from the Central Institute of Mental Health of Mannheim.

The search for genes involved in manic-depressive disorder is like looking for a needle in a haystack. “The contributions of individual genes are so minor that they normally cannot be identified in the ‘background noise’ of genetic differences,” explains Prof. Cichon from the University of Basel Hospital. Only when the DNA from very large numbers of patients with bipolar disorder are compared to the genetic material from an equally large number of healthy persons can differences be confirmed statistically. Such suspect regions which indicate a disease are known by scientists as candidate genes.

Two new gene regions discovered and three known gene regions confirmed

Using automated analysis methods, the researchers recorded about 2.3 million different regions in the genetic material of patients and comparators, respectively. The subsequent evaluation using biostatistical methods revealed a total of five risk regions on the DNA associated with bipolar disorder. Two of these regions were newly discovered: The gene “ADCY2” on chromosome five and the so-called “MIR2113-POU3F2” region on chromosome six. The risk regions “ANK3”, “ODZ4” and “TRANK1” have already been described in prior studies. “These gene regions were, however, statistically better confirmed in our current investigation - the connection with bipolar disorder has now become even clearer,” says Prof. Nöthen.

The researchers are particularly interested in the newly discovered gene region “ADCY2”. It codes an enzyme which is involved in the conduction of signals into nerve cells. “This fits very well with observations that the signal transfer in certain regions of the brain is impaired in patients with bipolar disorder,” explains the human geneticist of the University of Bonn Hospital. With their search for genetic regions, the scientists are gradually clarifying the causes of manic-depressive disorder. “Only when we know the biological foundations of this disease can be also identify starting points for new therapies,” says Prof. Nöthen.

(Image caption: Illustration of the mirror neuron system in the human brain. Credit: Jan Brascamp)

Brain mapping confirms patients with schizophrenia have impaired ability to imitate

According to George Bernard Shaw, “Imitation is not just the sincerest form of flattery – it’s the sincerest form of learning.” According to psychologists, imitation is something that we all do whenever we learn a new skill, whether it is dancing or how to behave in specific social situations.

Now, the results of a brain-mapping experiment conducted by a team of neuroscientists at Vanderbilt University strengthen the theory that an impaired ability to imitate may underlie the profound and enduring difficulty with social interactions that characterize schizophrenia. In a paper published online on Mar. 14 by the American Journal of Psychiatry, the researchers report that when patients with schizophrenia were asked to imitate simple hand movements, their brains exhibited abnormal brain activity in areas associated with the ability to imitate.

“The fact that patients with schizophrenia show abnormal brain activity when they imitate simple hand gestures is important because action imitation is a primary building block of social abilities,” said first author Katharine Thakkar, who conducted much of the research while completing her doctoral program at Vanderbilt and is now a post-doctoral fellow at the University Medical Center in Utrecht. “The ability to imitate is present early in life and is crucial for learning how to navigate the social world. According to current theory, covert imitation is also the most fundamental way that we understand the intentions and feelings of other people.”

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Contagious Yawning May Not Be Linked to Empathy; Still Largely Unexplained

While previous studies have suggested a connection between contagious yawning and empathy, new research from the Duke Center for Human Genome Variation finds that contagious yawning may decrease with age and is not strongly related to variables like empathy, tiredness and energy levels.

The study, published March 14 in the journal PLOS ONE, is the most comprehensive look at factors influencing contagious yawning to date.

The researchers said a better understanding of the biology involved in contagious yawning could ultimately shed light on illnesses such as schizophrenia or autism.

“The lack of association in our study between contagious yawning and empathy suggests that contagious yawning is not simply a product of one’s capacity for empathy,” said study author Elizabeth Cirulli, Ph.D., assistant professor of medicine at the Center for Human Genome Variation at Duke University School of Medicine.

Contagious yawning is a well-documented phenomenon that occurs only in humans and chimpanzees in response to hearing, seeing or thinking about yawning. It differs from spontaneous yawning, which occurs when someone is bored or tired. Spontaneous yawning is first observed in the womb, while contagious yawning does not begin until early childhood.

Why certain individuals are more susceptible to contagious yawning remains poorly understood. Previous research, including neuroimaging studies, has shown a relationship between contagious yawning and empathy, or the ability to recognize or understand another’s emotions. Other studies have shown correlations between contagious yawning and intelligence or time of day.

Interestingly, people with autism or schizophrenia, both of which involve impaired social skills, demonstrate less contagious yawning despite still yawning spontaneously. A deeper understanding of contagious yawning could lead to insights on these diseases and the general biological functioning of humans.

The current study aimed to better define how certain factors affect someone’s susceptibility to contagious yawning. The researchers recruited 328 healthy volunteers, who completed cognitive testing, a demographic survey, and a comprehensive questionnaire that included measures of empathy, energy levels and sleepiness.

The participants then watched a three-minute video of people yawning, and recorded the number of times they yawned while watching the video.

The researchers found that certain individuals were less susceptible to contagious yawns than others, with participants yawning between zero and 15 times during the video. Of the 328 people studied, 222 contagiously yawned at least once. When verified across multiple testing sessions, the number of yawns was consistent, demonstrating that contagious yawning is a very stable trait.

In contrast to previous studies, the researchers did not find a strong connection between contagious yawning and empathy, intelligence or time of day. The only independent factor that significantly influenced contagious yawning was age: as age increased, participants were less likely to yawn. However, age was only able to explain 8 percent of the variability in the contagious yawn response.

“Age was the most important predictor of contagious yawning, and even age was not that important. The vast majority of variation in the contagious yawning response was just not explained,” Cirulli said.

Because most variability in contagious yawning remains unexplained, the researchers are now looking to see whether there are genetic influences that contribute to contagious yawning. Their long-term goal in characterizing variability in contagious yawning is to better understand human diseases like schizophrenia and autism, as well as general human functioning, by identifying the genetic basis of this trait.

“It is possible that if we find a genetic variant that makes people less likely to have contagious yawns, we might see that variant or variants of the same gene also associated with schizophrenia or autism,” Cirulli said. “Even if no association with a disease is found, a better understanding of the biology behind contagious yawning can inform us about the pathways involved in these conditions.”

Critical role of one gene to our brain development

New research from the University of Adelaide has confirmed that a gene linked to intellectual disability is critical to the earliest stages of the development of human brains.

Known as USP9X, the gene has been investigated by Adelaide researchers for more than a decade, but in recent years scientists have begun to understand its particular importance to brain development.

In a new paper published online in the American Journal of Human Genetics, an international research team led by the University of Adelaide’s Robinson Research Institute explains how mutations in USP9X are associated with intellectual disability. These mutations, which can be inherited from one generation to the next, have been shown to cause disruptions to normal brain cell functioning.

Speaking during Brain Awareness Week, senior co-author Dr Lachlan Jolly from the University of Adelaide’s Neurogenetics Research Program says the USP9X gene has shed new light on the mysteries of brain development and disability.

Dr Jolly says the base framework for the brain’s complex network of cells begins to form at the embryo stage.

"Not surprisingly, disorders that cause changes to this network of cells, such as intellectual disabilities, epilepsy and autism, are hard to understand, and treat," Dr Jolly says.

"By looking at patients with severe learning and memory problems, we discovered a gene - called USP9X - that is involved in creating this base network of nerve cells. USP9X controls both the initial generation of the nerve cells from stem cells, and also their ability to connect with one another and form the proper networks,” he says.

"This work is critical to understanding how the brain develops, and how it is altered in individuals with brain disorders.

"We hope that by learning more about genes such as USP9X, we will create new opportunities to understand brain disorders at a much deeper level than currently known, which could lead to future treatment opportunities.”

How a small worm may help the fight against Alzheimer’s

Scientists at the Max Planck Institute for Biology of Ageing in Cologne have found that a naturally occurring molecule has the ability to enhance defense mechanisms against neurodegenerative diseases. Feeding this particular metabolite to the small round worm Caenorhabditis elegans, helps clear toxic protein aggregates in the body and extends life span.

During ageing, proteins in the human body tend to aggregate. At a certain point, protein aggregation becomes toxic, overloads the cell, and thus prevents it from maintaining normal function. Damage can occur, particularly in neurons, and may result in neurodegenerative diseases like Alzheimer’s, Parkinson’s or Huntington’s disease. By studying model organisms like Caenorhabditis elegans, scientists have begun to uncover the mechanisms underlying neurodegeneration, and thus define possible targets for both therapy and prevention of those diseases. “Although we cannot measure dementia in worms“, explains Martin Denzel of the Max Planck Institute for Biology of Ageing, “we can observe proteins that we also know from human diseases like Alzheimer’s to be toxic by measuring effects on neuromuscular function. This gives us insight into how Alzheimer actually progresses on the molecular level“.

Now, the scientists Martin Denzel, Nadia Storm, and Max Planck Director Adam Antebi have discovered that a substance called N-acetylglucosamine apparently stimulates the body’s own defense mechanism against such toxicity. This metabolite occurs naturally in the organism. If it is additionally fed to the worm, “we can achieve very dramatic benefits“, says Denzel. “It is a broad-spectrum effect that alleviates protein toxicity in Alzheimer’s, Parkinson’s and Huntington’s disease models in the worm, and it even extends their life span.“

This molecule apparently plays a crucial role in quality control mechanisms that keep the body healthy. It helps the organism to clear toxic levels of protein aggregation, both preventing aggregates from forming and clearing already existing ones. As a result, onset of paralysis is delayed in models of neurodegeneration - How exactly the molecule achieves this effect is yet to be uncovered. “And we still don’t know whether it also works in higher animals and humans“, says Antebi. “But as we also have these metabolites in our cells, this gives good reason to suspect that similar mechanisms might work in humans.”

Forgetting Is Actively Regulated

In order to function properly, the human brain requires the ability not only to store but also to forget: Through memory loss, unnecessary information is deleted and the nervous system retains its plasticity. A disruption of this process can lead to serious mental disorders. Basel scientists have now discovered a molecular mechanism that actively regulates the process of forgetting. The renowned scientific journal “Cell” has published their results.

The human brain is build in such a way, that only necessary information is stored permanently - the rest is forgotten over time. However, so far it was not clear if this process was active or passive. Scientists from the transfaculty research platform Molecular and Cognitive Neurosciences (MCN) at the University of Basel have now found a molecule that actively regulates memory loss. The so-called musashi protein is responsible for the structure and function of the synaptic connections of the brain, the place where information is communicated from one neuron to the next.

Using olfactory conditioning, the researchers Attila Stetak and Nils Hadziselimovic first studied the learning abilities of genetically modified ringworms (C. elegans) that were lacking the musashi protein. The experiments showed that the worms exhibited the same learning skills as unmodified animals. However, with extended duration of the experiment, the scientists discovered that the mutants were able to remember the new information much better. In other words: The genetically modified worms lacking the musashi protein were less forgetful.

Forgetting is no coincidence
Further experiments showed that the protein inhibits the synthesis of molecules responsible for the stabilization of synaptic connections. This stabilization seems to play an important role in the process of learning and forgetting. The researchers identified two parallel mechanisms: One the one hand, the protein adducin stimulates the growth of synapses and therefore also helps to retain memory; on the other hand, the musashi protein actively inhibits the stabilization of these synapses and thus facilitates memory loss. Therefore, it is the balance between these two proteins that is crucial for the retention of memories.

Forgetting is thus not a passive but rather an active process and a disruption of this process may result in serious mental disorders. The musashi protein also has interesting implications for the development of drugs trying to prevent abnormal memory loss that occurs in diseases such as Alzheimer’s. Further studies on the therapeutic possibilities of this discovery will be done.

These Boosts Are Made For Walkin’: Study Reveals that Movement Kicks Visual System into Higher Gear

Whether you’re a Major League outfielder chasing down a hard-hit ball or a lesser mortal navigating a busy city sidewalk, it pays to keep a close watch on your surroundings when walking or running. Now, new research by UC San Francisco neuroscientists suggests that the body may get help in these fast-changing situations from a specialized brain circuit that causes visual system neurons to fire more strongly during locomotion.

There has been a great deal of research on changes among different brain states during sleep, but the new findings, reported in the March 13 issue of Cell, provide a compelling example of a change in state in the awake brain.

It has long been known that nerve cells in the visual system fire more strongly when we pay close attention to objects than when we view scenes more passively. But the new research, led by Yu Fu, PhD, a postdoctoral fellow in the UCSF lab of senior author Michael P. Stryker, PhD, the W.F. Ganong Professor of Physiology, breaks new ground, mapping out a visual system amplifier that is directly activated by walking or running.

Though this circuit has not yet been shown to exist in humans, Stryker is designing experiments to find out if it does. He said he would be surprised if his group did not identify a similar mechanism in people, since such systems have been found in fruit flies, and the mouse visual system has so far proved to be a good model of many aspects of human vision.

“The sense of touch only tells you about objects that are close, and the auditory system is generally not as sensitive as the visual system to the exact position of objects,” he said. “It seems that it would be generally useful to have vision – the sensory modality that tells you the most about things that are far away – work better as you’re moving through the world.”

Stryker said that the neural system identified in the new work may have evolved to conserve energy, by allowing the brain to operate at less than peak efficiency in less demanding behavioral situations. “When you don’t need your visual system to be in a high-gain state, your brain may use a lot less energy in responding,” said Stryker. “A change in gain when you’re moving is ideally what you’d like to see – the neuron is doing the same thing that it’s always doing, but it’s talking louder to the rest of the brain.”

In the new research, mice were allowed to walk or run freely on a Styrofoam ball suspended on an air cushion while the scientists used a technique known as two-photon imaging to monitor the activation of cells in the primary visual area of the brain, known as V1.

The researchers found that a subset of V1 neurons, those that contain a substance called vasoactive intestinal peptide (VIP), were robustly activated in a time-locked fashion purely by locomotion, even in darkness, while other V1 neurons remained largely silent.

The mice were presented with visual stimuli both while motionless and while moving, and measurements showed that walking could increase the response of V1 neurons by more than 30 percent. Moreover, V1 responses to these stimuli increased or declined in tandem with the activity of VIP neurons, and with the starting or stopping of walking by the mice.

To firmly establish that VIP neurons were responsible for these changes, the researchers used optogenetic techniques, inserting light-sensitive proteins exclusively into VIP neurons. Using light to stimulate just this population of cells, the team found that they could emulate the effects of locomotion – when VIP cells were activated, V1 cells responded more strongly to stimuli, regardless of whether the animals were moving. Conversely, when the researchers specifically targeted and disabled VIP cells, locomotion-induced increases in the response of other V1 cells were abolished.

Scientists catch brain damage in the act

Scientists have uncovered how inflammation and lack of oxygen conspire to cause brain damage in conditions such as stroke and Alzheimer’s disease.

The discovery, published today in Neuron, brings researchers a step closer to finding potential targets to treat neurodegenerative disorders.

Chronic inflammation and hypoxia, or oxygen deficiency, are hallmarks of several brain diseases, but little was known about how they contribute to symptoms such as memory loss.

The study used state-of-the-art techniques that reveal the movements of microglia, the brain’s resident immune cells. Brain researcher Brian MacVicar had previously captured how they moved to areas of injury to repair brain damage.

The new study shows that the combination of inflammation and hypoxia activates microglia in a way that persistently weakens the connection between neurons. The phenomenon, known as long-term depression, has been shown to contribute to cognitive impairment in Alzheimer’s disease.

“This is a never-before-seen mechanism among three key players in the brain that interact together in neurodegenerative disorders,” says MacVicar with the Djavad Mowafaghian Centre for Brain Health at UBC and Vancouver Coastal Health Research Institute.

“Now we can use this knowledge to start identifying new potential targets for therapy.”

(Image caption: This image shows a PC12 cell growing onto a randomly textures surface. Note how the cell is spreading out in all directions.)

Surface Characteristics Influence Cellular Growth on Semiconductor Material

Changing the texture and surface characteristics of a semiconductor material at the nanoscale can influence the way that neural cells grow on the material.

The finding stems from a study performed by researchers at North Carolina State University, the University of North Carolina at Chapel Hill and Purdue University, and may have utility for developing future neural implants.

“We wanted to know how a material’s texture and structure can influence cell adhesion and differentiation,” says Lauren Bain, lead author of a paper describing the work and a Ph.D. student in the joint biomedical engineering program at NC State and UNC-Chapel Hill. “Basically, we wanted to know if changing the physical characteristics on the surface of a semiconductor could make it easier for an implant to be integrated into neural tissue – or soft tissue generally.”

The researchers worked with gallium nitride (GaN), because it is one of the most promising semiconductor materials for use in biomedical applications. They also worked with PC12 cells, which are model cells used to mimic the behavior of neurons in lab experiments.

In the study, the researchers grew PC12 cells on GaN squares with four different surface characteristics: some squares were smooth; some had parallel grooves (resembling an irregular corduroy pattern); some were randomly textured (resembling a nanoscale mountain range); and some were covered with nanowires (resembling a nanoscale bed of nails).

Very few PC12 cells adhered to the smooth surface. And those that did adhere grew normally, forming long, narrow extensions. More PC12 cells adhered to the squares with parallel grooves, and these cells also grew normally.

About the same number of PC12 cells adhered to the randomly textured squares as adhered to the parallel grooves. However, these cells did not grow normally. Instead of forming narrow extensions, the cells flattened and spread across the GaN surface in all directions.

More PC12 cells adhered to the nanowire squares than to any of the other surfaces, but only 50 percent of the cells grew normally. The other 50 percent spread in all directions, like the cells on the randomly textured surfaces.

“This tells us that the actual shape of the surface characteristics influences the behavior of the cells,” Bain says. “It’s a non-chemical way of influencing the interaction between the material and the body. That’s something we can explore as we continue working to develop new biomedical technologies.”