Neuroscience
Month
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.”
10 August 2012 by Helen Thomson
A woman born missing a finger and a thumb has grown them back – albeit as part of a phantom limb. This extraordinary occurrence shows that our brain contains a fully functional map of our body image, regardless of what our limbs actually look like.
The woman, RN, was born with just three fingers on her right hand. Aged 18, RN had the hand amputated after a car accident. She later began to feel that her missing limb was still present, and developed a “phantom” hand.
"But here’s the interesting thing," says Paul McGeoch at the University of California, San Diego. "Her phantom hand didn’t have three digits, it had five."
RN was aware of a full complement of fingers, but her phantom thumb and index finger were less than half the usual length.
With training using a mirror box trick – a tool that creates the visual illusion of two hands – McGeoch and V.S Ramachandran, also at San Diego, managed to extend her short phantom finger and thumb to normal length.
McGeoch says this study indicates that there is a hardwired representation in the brain of what the body should look like, regardless of how it actually appears in real life. It shows us more about the balance between the external and innate representations of a limb, he says.
"The presence of the deformed hand was suppressing the brain’s innate representation of her fingers which is why they appeared shorter, but after the hand was removed and the inhibition taken away, the innate representation kicks in again."
Matthew Longo at Birkbeck, University of London, says it is a fascinating case study. “It contributes to a growing literature suggesting that our conscious experience of our body is, at least in part, dependent on the intrinsic organisation of the brain, rather than a result of experience.”
Source: NewScientist
August 10, 2012
Scientists affiliated with the UC Davis MIND Institute have discovered how a defective gene causes brain changes that lead to the atypical social behavior characteristic of autism. The research offers a potential target for drugs to treat the condition.
Earlier research already has shown that the gene is defective in children with autism, but its effect on neurons in the brain was not known. The new studies in mice show that abnormal action of just this one gene disrupted energy use in neurons. The harmful changes were coupled with antisocial and prolonged repetitive behavior — traits found in autism.
The research is published online today in the scientific journal PLoS ONE.
"A number of genes and environmental factors have been shown to be involved in autism, but this study points to a mechanism — how one gene defect may trigger this type of neurological behavior," said study senior author Cecilia Giulivi, professor of molecular biosciences in the UC Davis School of Veterinary Medicine and a researcher affiliated with the UC Davis MIND Institute.
"Once you understand the mechanism, that opens the way for developing drugs to treat the condition," she said.
The defective gene appears to disrupt neurons’ use of energy, Giulivi said, the critical process that relies on the cell’s molecular energy factories called mitochondria.
In the research, a gene called pten was tweaked in the mice so that neurons lacked the normal amount of pten’s protein. The scientists detected malfunctioning mitochondria in the mice as early as 4 to 6 weeks after birth.
By 20 to 29 weeks, DNA damage in the mitochondria and disruption of their function had increased dramatically. At this time the mice began to avoid contact with their litter mates and engage in repetitive grooming behavior. Mice without the single gene change exhibited neither the mitochondria malfunctions nor the behavioral problems.
The antisocial behavior was most pronounced in the mice at an age comparable in humans to the early teenage years, when schizophrenia and other behavioral disorders become most apparent, Giulivi said.
The research showed that, when defective, pten’s protein interacts with the protein of a second gene known as p53 to dampen energy production in neurons. This severe stress leads to a spike in harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus — brain regions critical for social behavior and cognition.
Pten mutations previously have been linked to Alzheimer’s disease as well as a spectrum of autism disorders. The new research shows that when pten protein was insufficient, its interaction with p53 triggered deficiencies and defects in other proteins that also have been found in patients with learning disabilities including autism.
Source: UCDavis
ScienceDaily (Aug. 9, 2012) — Manipulating a group of hormone-producing cells in the brain can control blood sugar levels in the body — a discovery that has dramatic potential for research into weight-loss drugs and diabetes treatment.
Erik Johnson uses the fruit fly, Drosophila, to look at an enzyme called AMP-activated kinase and its role in signaling the hormone that elevates the level of sugar in the blood. (Credit: Image courtesy of Wake Forest University)
In a paper published in the October issue of Genetics and available online now, neurobiologists at Wake Forest University examine how fruit flies (Drosophila) react when confronted with a decreased diet.
Reduced diet or starvation normally leads to hyperactivity in fruit flies — a hungry fly buzzes around feverishly, looking for more food. That happens because an enzyme called AMP-activated kinase stimulates the secretion of the adipokinetic hormone, which is the functional equivalent of glucagon. This hormone acts opposite of insulin, as it tells the body to release the sugar, or food, needed to fuel that hyperactivity. The body uses up its energy stores until it finds food.
But when Wake Forest’s Erik Johnson, an associate professor of biology, and his research team turned off AMP-activated kinase, the cells decreased sugar release and the hyperactive response stopped almost completely — even in the face of starvation.
"Since fruit flies and humans share 30 percent of the same genes and our brains are essentially wired the same way, it suggests that this discovery could inform metabolic research in general and diabetes research specifically," said Johnson, the study’s principal investigator. "The basic biophysical, biochemical makeup is the same. The difference in complexity is in the number of cells. Why flies are so simple is that they have approximately 100,000 neurons versus the approximately 11 billion in humans."
Medical advances as a result of this research might include:
• Diabetes research: Adipokinetic hormone is the insect equivalent to the hormone glucagon in the human pancreas. Glucagon raises blood sugar levels; insulin reduces them. However, it is difficult to study glucagon systems because the pancreatic cells are hard to pull apart. Studying how this similar system works in the fruit fly could pave the way to a drug that targets the cells that cause glucagon to tell the body to release sugar into the blood — thus reducing the need for insulin shots in diabetics.
• Weight-loss drugs: An “exercise drug” would turn on all AMP-activated kinase in the body and trick the body into thinking it was exercising. “Exercise stimulates AMP-activated kinase, so manipulation of this molecule may lead to getting the benefits of exercise without exercising,” Johnson said. In previous research published in the online journal PLoS ONE, Johnson and his colleagues found that, when you turn off AMP-activated kinase, you get fruit flies that “eat a lot more than normal flies, move around a lot less, and end up fatter.”
Source: Science Daily
THURSDAY, Aug. 9 (HealthDay News) — Researchers report that they have created a device able to short-circuit epileptic seizures in rats.
Similar in design to an implantable defibrillator, the device is placed in the brain and reacts only when a seizure starts to occur, essentially aborting the seizure’s electrical activity.
The self-adjusting device electrically stimulates the brain at the beginning of a short but frequent type of seizure in rats, and then automatically shuts itself off. The research was published in the Aug. 10 issue of the journal Science.
"It works like a ping-pong game," explained study author Dr. Gyorgy Buzsaki, a professor of neural science at New York University. "Every time a ball is coming your way, you apply an interfering pattern to whack it away."
Epilepsy is a brain disorder in which a person has repeated seizures over time. It affects nearly 3 million Americans, according to the Epilepsy Foundation, making it the third most common neurological disorder in the United States, after Alzheimer’s and stroke.
People with epilepsy can suffer from two different kinds of seizures: petit mal seizures, which last for just a few seconds but can occur frequently, and grand mal seizures, which are rare but involve violent muscle contractions and a loss of consciousness.
Seizures are episodes of disturbed brain activity that cause changes in attention or behavior. Brain cells keep firing instead of acting in an organized way. The malfunctioning electrical system of the brain causes surges of energy that can cause unconsciousness and muscle contractions.
The researchers tested the new device against petit mal seizures in rats because this type of seizure occurs hundreds of times a day. The sheer volume of the seizures allowed the scientists to effectively test the system they designed. People with petit mal seizures are typically treated effectively with drugs, so the device would not be used to treat that type of seizure.
In what Buzsaki describes as a simple, closed-loop system, the firing of brain neurons creates a spike in neurological activity that is followed by a wave and detected by the device, which fires back only when necessary. The system, called transcranial electrical stimulation, leaves other aspects of brain function unaffected. “The system doesn’t prevent seizures, it just treats them right away,” said Buzsaki. The stimulation reduced the length of a seizure by about 60 percent.
In humans, two plates about the size of a pocket watch could be placed in the skull in a position designed to target the affected area of the brain. The electrodes would be powered by ultralight electrical circuits implanted in the skull, Buzsaki explained.
The goal is to apply the system that worked in rats to people with complex partial seizures — epileptic seizures that affect both sides of the brain and cause a loss of consciousness, Buzsaki said. Although the device worked in rats, the results may not translate to humans.
This type of seizure also can occur with head injuries, brain infection and stroke. The cause is typically unknown.
In 20 percent to 40 percent of people who have complex partial seizures, drugs are ineffective and there are no remedies, Buzsaki said. “It’s not clear what kind of stimulation to deliver and where exactly in the brain the stimulation should go,” he explained.
Dr. Orrin Devinsky, director of the epilepsy program at New York University, said the research has enormous potential for treating epilepsy and other neurological problems. “What’s unique about this technique is that it’s a sophisticated way to identify the rhythmicity of the seizure itself and interrupt the cycle with precision,” he said. “Existing [deep brain stimulation] devices don’t finesse the timing this way.”
Devinsky, who was not associated with the study, said the research could potentially be applicable to people with tremors, Parkinson’s disease and even those with serious depression and other psychological disorders.
Source: HealthDay