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ScienceDaily (Aug. 15, 2012) — Acute stress alters the methylation of the DNA and thus the activity of certain genes. This is reported by researchers at the Ruhr-Universität Bochum together with colleagues from Basel, Trier and London for the first time in the journal Translational Psychiatry. “The results provide evidence how stress could be related to a higher risk of mental or physical illness,” says Prof. Dr. Gunther Meinlschmidt from the Clinic of Psychosomatic Medicine and Psychotherapy at the LWL University Hospital of the RUB. The team looked at gene segments which are relevant to biological stress regulation.
In stressful social situations, the methylation patterns (bright spheres) of the DNA change. (Credit: Illustration: Christoph Unternährer and Christian Horisberger)
Epigenetics — the “second code” — regulates gene activity
Our genetic material, the DNA, provides the construction manual for the proteins that our bodies need. Which proteins a cell produces depends on the cell type and the environment. So-termed epigenetic information determines which genes are read, acting quasi as a biological switch. An example of such a switch is provided by methyl (CH3) groups that attach to specific sections of the DNA and can remain there for a long time — even when the cell divides. Previous studies have shown that stressful experiences and psychological trauma in early life are associated with long-term altered DNA methylation. Whether the DNA methylation also changes after acute psychosocial stress, was, however, previously unknown.
Two genes tested
To clarify this issue, the research group examined two genes in particular: the gene for the oxytocin receptor, i.e. the docking site for the neurotransmitter oxytocin, which has become known as the “trust hormone” or “anti-stress hormone”; and the gene for the nerve growth factor Brain-Derived Neurotrophic Factor (BDNF), which is mainly responsible for the development and cross-linking of brain cells. The researchers tested 76 people who had to participate in a fictitious job interview and solve arithmetic problems under observation — a proven means for inducing acute stress in an experiment. For the analysis of the DNA methylation, they took blood samples from the subjects before the test as well as ten and ninety minutes afterwards.
DNA methylation changes under acute psychosocial stress
Stress had no effect on the methylation of the BDNF gene. In a section of the oxytocin receptor gene, however, methylation already increased within the first ten minutes of the stressful situation. This suggests that the cells formed less oxytocin receptors. Ninety minutes after the stress test, the methylation dropped below the original level before the test. This suggests that the receptor production was excessively stimulated.
Possible link between stress and disease
Stress increases the risk of physical or mental illness. The stress-related costs in Germany alone amount to many billions of Euros every year. In recent years, there have been indications that epigenetic processes are involved in the development of various chronic diseases such as cancer or depression. “Epigenetic changes may well be an important link between stress and chronic diseases” says Prof. Meinlschmidt, Head of the Research Department of Psychobiology, Psychosomatics and Psychotherapy at the LWL University Hospital. “We hope to identify more complex epigenetic stress patterns in future and thus to be able to determine the associated risk of disease. This could provide information on new approaches to treatment and prevention.” The work originated within the framework of an interdisciplinary research consortium with the University of Trier, the University of Basel and King’s College London. The German Research Foundation and the Swiss National Science Foundation supported the study.
Source: Science Daily
The first genome-wide searches for the genes responsible for Tourette syndrome and obsessive-compulsive disorder have uncovered a few clues to the underpinnings of both disorders.
Tourette syndrome is a neurological disorder characterized by muscle and vocal tics such as eye blinking, throat clearing and uttering taboo words or phrases. Tourette’s often co-occurs with obsessive-compulsive disorder (OCD), a mental illness marked by repetitive behaviors and anxiety-producing intrusive thoughts.
Neither Tourette syndrome nor OCD are simple enough to be traced to a single gene, but two new studies detailed today (Aug. 14) in the journal Molecular Psychiatry find several locations on the human chromosome that may contribute to the conditions.
A DNA molecule.
CREDIT: Giovanni Cancemi | Shutterstock
"Both disorders clearly have a complex underlying genetic architecture, and these two studies lay the foundation for understanding the underlying genetic etiology of Tourette syndrome and OCD," said Jeremiah Scharf, a neurologist at Massachusetts General Hospital in Boston, who worked on both projects.
Genetics of Tourette Syndrome
In the Tourette syndrome study, Scharf and his colleagues compared the genomes of more than 1,200 people with the disorder with the genomes of nearly 5,000 healthy individuals. They conducted what’s called a genome-wide association study, scanning hundreds of thousands of genetic variants from across the genomes to see if any were more common in the people with the disorder.
They found that no single genetic signal was significantly different between the two genomes, meaning that the researchers could not rule out random chance as the reason for any given difference. But among the top genetic variations, the researchers found an unusually high number that influence levels of gene expression in the frontal lobe of the brain — a region important in both Tourette syndrome and OCD, Scharf said.
One intriguing gene that varied the most between Tourette- and non-Tourette genomes was called COL27A1, a gene that encodes a collagen protein found in cartilage. The same gene is also active in the cerebellum, a brain region important for motor control during development. More research will be necessary to find what link, if any, COL27A1 has to Tourette syndrome, Scharf said.
The architecture of OCD
In a separate study, the scientists carried out the same analysis on healthy genomes as well as about 1,500 people with obsessive-compulsive disorder. Again, no one gene rose to the top as a definitive OCD gene, but the results revealed a good candidate near a gene called BTBD3, which is involved in multiple cellular functions. BTBD3 is very active in the brain during childhood and adolescent development, when OCD often first appears. It’s also related to a gene called BTBD9, which has been linked to Tourette syndrome in the past.
This first genome-wide pass is bound to turn up some false positives, Scharf said, so researchers will now need to home in on the intriguing genes in larger samples of people. They are also merging the two studies to look for genetic linkages that might explain why Tourette syndrome and OCD so frequently co-occur.
"The important thing this study does is that it really brings Tourette syndrome and OCD into the company of a number of other psychiatric diseases, which people have studied using genome-wide association," Scharf said, citing autism, schizophrenia and bipolar disorder as examples. “Now that we have these data for Tourette syndrome and OCD, we can work with investigators who are studying those other diseases to try to see what we can learn about what variants are shared between different neurodevelopment disorders.”
Source: Live Science
By Sabrina Richards | August 13, 2012
Researchers use UV light to stimulate protein production in nano-sized delivery capsules in mice.
Nanoparticles expressing a GFP reporter.
Device: Science is one step closer to producing drugs in the right place at the right time in the body, avoiding the collateral damage of untargeted treatments. Researchers led by Daniel Anderson at the Massachusetts Institute of Technology have designed nanoparticles that can be stimulated via UV light to produce proteins on demand in vivo.
The new method, which involves packaging the molecular machinery for making proteins into a membraned capsule, allows the researchers to spatially and temporally regulate protein production, said Zhen Gu, who also researches nanoparticle drug delivery at North Carolina State and University of North Carolina, Chapel Hill, but did not participate in the research. “They can control generation of a protein at any time with a trigger of light.”
The scientists created the nano-sized “protein factories” by using lipids to encapsulate polymerase and other machinery necessary for protein production from E. coli, along with a DNA plasmid containing a gene of interest. To block transcription until the right moment, they added a DNA “photo-labile cage” to the plasmid—a small chemical that inhibits transcription but is cleaved by exposure to UV light.
To test the principle in vivo, the researchers used luciferase as the reporter protein and injected mice with the nanovesicles. After zapping them with UV light at the site of injection, they were able to measure a local burst of luminescence.
What’s new: Protein expression in liposomes has been possible for at least 10 years, said Mitchel Doktycz, a synthetic biologist at Oak Ridge National Laboratory in Tennessee. What is new, said Doktycz, who did not participate in the research, is being able to control the timing of protein expression in an animal. “They can do it remotely,” he said.
And that switch is not limited to UV light, added Gu, but will likely work with other wavelengths using different chemical ligands.
Avi Schroeder
Importance: Many life-saving drugs, such as chemotherapy, can have nasty and toxic effects outside the tissues they’re designed to treat. The goal of remotely-controlled factories like Anderson’s is to produce a drug in a specific place (such as a tumor) at a specific time (after enough particles have accumulated to produce a therapeutic effect). Anderson’s group is “trying to deliver a payload, [and] activate [it] in a specific spot, so they’re not dosing everywhere,” Doktycz explained—which has the potential to minimize side effects while maximizing therapeutic benefit.
Needs improvement: “We have a long way to go still before we have a drug factory that will land in a target tissue to produce a drug of interest,” noted Anderson. The study has proved the principle of the first step—getting the protein expressed on signal—but future research will need to ensure that the nanoparticles and the proteins they produce aren’t toxic in the wrong place, and that they get to the right location. Targeting the nanoparticles to the appropriate tissues might be achieved by “decorating” the surface of the vesicles with specific proteins, said Gu.
Furthermore, although most of the materials in the current particles are probably safe, some are microorganism-derived, Anderson pointed out, and most likely need to be switched to human alternatives. Finally, getting the drug expressed is also just one part of the problem, said Doktycz. So far the system has no way to re-cage the DNA to halt protein production when it’s no longer needed. “Turning on is one thing, but turning off is another,” he said.
August 13, 2012
Researchers at Mount Sinai School of Medicine may have discovered why certain drugs to treat schizophrenia are ineffective in some patients. Published online in Nature Neuroscience, the research will pave the way for a new class of drugs to help treat this devastating mental illness, which impacts one percent of the world’s population, 30 percent of whom do not respond to currently available treatments.
A team of researchers at Mount Sinai School of Medicine set out to discover what epigenetic factors, or external factors that influence gene expression, are involved in this treatment-resistance to atypical antipsychotic drugs, the standard of care for schizophrenia. They discovered that, over time, an enzyme in the brains of schizophrenic patients analyzed at autopsy begins to compensate for the prolonged chemical changes caused by antipsychotics, resulting in reduced efficacy of the drugs.
"These results are groundbreaking because they show that drug resistance may be caused by the very medications prescribed to treat schizophrenia, when administered chronically," said Javier Gonzalez-Maeso, PhD, Assistant Professor of Psychiatry and Neurology at Mount Sinai School of Medicine and lead investigator on the study.
They found that an enzyme called HDAC2 was highly expressed in the brain of mice chronically treated with antipsychotic drugs, resulting in lower expression of the receptor called mGlu2, and a recurrence of psychotic symptoms. A similar finding was observed in the postmortem brains of schizophrenic patients. The research team administered a chemical called suberoylanilide hydroxamic acid (SAHA), which inhibits the entire family of HDACs. They found that this treatment prevented the detrimental effect of the antipsychotic called clozapine on mGlu2 expression, and also improved the therapeutic effects of atypical antipsychotics in mouse models.
Previous research conducted by the team showed that chronic treatment with the antipsychotic clozapine causes repression of mGlu2 expression in the frontal cortex of mice, a brain area key to cognition and perception. The researchers hypothesized that this effect of clozapine on mGlu2 may play a crucial role in restraining the therapeutic effects of antipsychotic drugs.
"We had previously found that chronic antipsychotic drug administration causes biochemical changes in the brain that may limit the therapeutic effects of these drugs,"said Dr. Gonzalez-Maeso. "We wanted to identify the molecular mechanism responsible for this biochemical change, and explore it as a new target for new drugs that enhance the therapeutic efficacy of antipsychotic drugs."
Mitsumasa Kurita, PhD, a postdoctoral fellow at Mount Sinai and the lead author of the study, said, “We found that atypical antipsychotic drugs trigger an increase of HDAC2 in frontal cortex of individuals with schizophrenia, which then reduces the presence of mGlu2, and thereby limits the efficacy of these drugs,” said
Dr. Gonzalez-Maeso’s team is now developing compounds that specifically inhibit HDAC2 as adjunctive treatments to antipsychotics. The study was funded by the National Institutes of Health.
Source: The Mount Sinai Hospital
12 August 2012
Certain brain regions in people with major depression are smaller and less dense than those of their healthy counterparts. Now, researchers have traced the genetic reasons for this shrinkage.
A series of genes linked to the function of synapses, or the gaps between brain cells crucial for cell-to-cell communication, can be controlled by a single genetic “switch” that appears to be overproduced in the brains of people with depression, a new study finds.
"We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated," study researcher Ronald Duman, a professor of psychiatry at Yale University, said in a statement.
Shrinking brain
Brain-imaging studies, post-mortem examinations of human brains and animal studies have all found that in depression, a part of the brain called the dorsolateral prefrontal cortex shrinks. The neurons in this region, which is responsible for complex tasks from memory and sensory integration to the planning of actions, are also smaller and less dense in depressed people compared with healthy people.
Duman and his colleagues suspected that these neuronal abnormalities would include problems with the synapses, the points where brain cells “talk” to one another. At synapses, neurons release neurotransmitters that are picked up by their neighbors, carrying signals from cell to cell at rapid speed.
The researchers conducted gene profiling on the postmortem brain tissue of both depressed and mentally healthy subjects. They found a range of genes that were significantly less active in depressed people’s dorsolateral prefrontal cortexes, particularly five related to synaptic function: synapsin 1, Rab3A, calmodulin 2, Rab4B and TUBB4.
Synaptic damage
These genes are all involved in either the chemical signaling that occurs at synapses or the cellular recycling and regeneration processes that keep the synapse-system humming. All five are regulated by a single transcription factor called GATA1, which was overproduced in depressed brains.
The researchers activated GATA1 in the brains of rats and found that the factor decreased the complexity of the long, branchlike projections, or dendrites, of brain cells. These projections are the telephone lines that carry synaptic messages, integrating all the information a cell receives.
Extra GATA1 also increased depression-like behavior in the rats. For example, when given a swimming task, rats with extra GATA1 stayed immobile in the water longer, a signal of despair, than normal-GATA1 rats, the researchers report today (Aug. 12) in the journal Nature Medicine.
The researchers believe the damage could be a result of chronic stress, and they hope the findings lead to new depression treatments.
"We hope that by enhancing synaptic connections, either with novel medications or behavioral therapy, we can develop more effective antidepressant therapies," Duman said.
Source: Live Science
August 10, 2012
Most people have been in a situation that suddenly feels strangely familiar, while also realizing that they have never been in that specific place before. These experiences are called ‘déjà vu’ and the phenomenon has inspired countless books, songs and movies.
What is remarkable about déjà vu, says Western University graduate student Chris Martin, is that the impression of familiarity is accompanied by a sense that the current environment or situation should in fact feel new. But how can it be that a scene or an experience evokes a sense of familiarity but at the same time a feeling that this familiarity is wrong?
Despite the curiosity and excitement about déjà vu in popular culture, these subjective experiences remain poorly understood in scientific terms. Studying déjà vu has proven difficult due to the fleeting nature of these obscure occurrences, and due to the lack of experimental procedures to elicit them in the psychological laboratory.
In an article published online by Neuropsychologia, “Déjà Vu in Unilateral Temporal-Lobe Epilepsy is Associated with Selective Familiarity Impairments on Experimental Tasks of Recognition Memory,” Martin and psychology professor Stefan Köhler were able to shed light on this fascinating phenomenon by examining a rare group of neurological patients that experience déjà vu as an early sign of advancing seizures.
Due to lasting underlying brain pathology, most patients with temporal lobe epilepsy exhibit subtle impairments in memory even at times when no seizures are present. Köhler and his team built on this link by seeking behavioural markers of déjà vu on specific memory tasks that were designed to probe feelings of familiarity. The researchers discovered a pattern of performance that clearly distinguished patients with déjà vu from those without.
Specifically, familiarity was selectively impaired only in individuals with déjà vu in their seizure profile. In an experiment that placed different types of memories in conflict, patients with déjà vu were still able to counteract inappropriate feelings of familiarity with their ability to recollect pertinent information about previous actual events.
These findings, say Köhler and Martin, open a new window towards understanding the psychological and neural mechanisms that give rise to fleeting, subjective feelings of déjà vu. Köhler says they remind us that even when lasting for just a split second, memory experiences reflect the interplay of many different, sometimes competing processes. On another level, these findings are also of clinical relevance in the surgical treatment of temporal lobe epilepsy.
Source: University of Western Ontario
August 11th, 2012
By Laura Sanders
Lifting neural constraints could turn back time, making way for youthful flexibility
Michael Morgenstern
A baby’s brain is a thirsty sponge, slurping up words, figuring out faces and learning which foods are good and bad to eat. Information about the world flooding into a young brain begins to carve out traces, like rushing water over soft limestone. As the outside world sculpts the growing brain, important connections between nerve cells become strong rivers, while smaller unused tributaries quietly disappear.
In time, these brain connections crystallize, forming indelible patterns etched into marble. Impressionable brain systems that allowed a child to easily learn a language, for instance, go away, abandoned for the speed and strength that come with rigidity. In a fully set brain, signals fly around effortlessly, making commonplace tasks short work. A master of efficiency, the adult brain loses the exuberance of childhood.
But the adult brain need not remain in this petrified state. In a feat of neural alchemy, the brain can morph from marble back to limestone.
The potential for this metamorphosis has galvanized scientists, who now talk about a mind with the power to remake itself. In the last few years, researchers have found ways to soften the stone, recapturing some of the lost magic of a young brain.
“There’s been a very, very significant change,” says Richard Davidson of the University of Wisconsin–Madison. “I don’t think the import of that basic fact has fully expressed itself.”
Though this research is still in its early stages, studies suggest techniques that dissolve structures that pin brain cells in place, interrupt molecular stop signals and tweak the rush of nerve cell activity can restore the brain’s youthful glow. Scientists are already attempting to reverse brain rigidity, boosting what’s known as “plasticity” in people with a vision disorder once thought to be irreversible in adults.
These efforts are not an exercise in neural vanity. A malleable brain, researchers hope, can heal after a stroke, combat the decline in vision that comes with old age and perhaps even repair a severed spinal cord. An end to childhood — and the prodigal learning that comes with it — does not need to eliminate the brain’s capacity for change. “There are still windows of opportunity out there,” says neuroscientist Daphné Bavelier of the University of Rochester in New York. “It may require a little more work to open them, though.”