Neuroscience

By examining the sense of touch in stroke patients, a University of Delaware cognitive psychologist has found evidence that the brains of these individuals may be highly plastic even years after being damaged.

The research is published in the March 6 edition of the journal Current Biology, in an article written by Jared Medina, assistant professor of psychology at UD, and Brenda Rapp of Johns Hopkins University’s Department of Cognitive Science. The findings, which are focused on patients who lost the sense of touch in their hands after a stroke, also have potential implications for other impairments caused by brain damage, Medina said.

“Our lab is interested in how the brain represents the body, not just in the sense of touch,” he said. “That involves a lot of different areas of the brain.”

For decades, scientists have been mapping the brain to determine which areas control certain functions, from movement to emotion to memory. In terms of representing the sense of touch, researchers know which specific parts of the brain are associated with representing specific parts of the body, Medina said.

Those scientists also know that, following the brain damage a stroke causes, patients often regain some of what they initially lost due to that damage.

“Even if every neuron has been killed in the part of the brain that represents touch on the hand, that doesn’t mean that you’re never going to feel anything on your hand again,” Medina said. “We’ve known that isn’t the case because the map can reorganize. The brain can change due to injury.”

But what the new research by Medina and Rapp found is that the brains of those stroke patients may change much more easily than the undamaged brains of healthy people — what they call “hyper-lability.”

The researchers worked with people who had had strokes in the past that affected their ability to localize touch. Each research participant, without being able to see his hand, was touched on the wrist and then on the fingertips. When asked to pinpoint the second touch, the stroke patients reported sensing the touch farther down their finger, toward the wrist, rather than in its actual location. 

Medina says that likely occurs because the neural map in the brain is shifting based on the earlier wrist touch — a phenomenon termed “experience-dependent plasticity.”

“Now what’s interesting about this is that when you and I [who haven’t had a stroke] are touched on the wrist, then the fingertips, we don’t have these changes that the brain-damaged individuals do,” he said. “This provides the counterintuitive finding that the maps in brain-damaged individuals are actually much more plastic than in you and me.”

Hyper-plasticity has positive and negative implications, he said.

“On the positive side, this plasticity may potentially be harnessed in rehabilitation to improve function” after a stroke or various other types of brain injury, Medina said. But, he added, the brain may also be so plastic in those cases that changes aren’t stable, creating additional problems.

That’s what he expects additional research to address.

“Now that we’ve found that these maps are more plastic than we thought, can certain strategies help the map become more stable and more accurate again? That’s one of the next questions, and we can only answer it by continuing to learn more about how the mind works.”

It may seem normal: As we age, we misplace car keys, or can’t remember a name we just learned or a meal we just ordered. But University of Florida researchers say memory trouble doesn’t have to be inevitable, and they’ve found a drug therapy that could potentially reverse this type of memory decline.

The drug can’t yet be used in humans, but the researchers are pursuing compounds that could someday help the population of aging adults who don’t have Alzheimer’s or other dementias but still have trouble remembering day-to-day items. Their findings will be published in today’s (March 5) issue of the Journal of Neuroscience.

The kind of memory responsible for holding information in the mind for short periods of time is called “working memory.” Working memory relies on a balance of chemicals in the brain. The UF study shows this chemical balance tips in older adults, and working memory declines. The reason? It could be because their brains are producing too much of a chemical that slows neural activity.

“Graduate student Cristina Banuelos’ work suggests that cells that normally provide the brake on neural activity are in overdrive in the aged prefrontal cortex,” said researcher Jennifer Bizon, Ph.D., an associate professor in the department of neuroscience and a member of UF’s Evelyn F. & William L. McKnight Brain Institute.

This chemical, an inhibitory brain neurotransmitter called GABA, is essential. Without it, brain cells can become too active, similar to what happens in the brains of people with schizophrenia and epilepsy. A normal level of GABA helps maintain the optimal levels of cell activation, said collaborator Barry Setlow, Ph.D., an associate professor in UF’s departments of psychiatry and neuroscience.

Working memory underlies many mental abilities and is sometimes referred to as the brain’s mental sketchpad, Bizon said. For example, Bizon said, you use your working memory in many everyday activities such as calculating your final bill at the end of dining at a restaurant. Most people can calculate a 15 percent tip and add it to the cost of their meal without pencil and paper. Central to this process is the ability to keep multiple pieces of information in mind for a short duration — such as remembering the cost of your dinner while calculating the amount needed for the tip.

“Almost all higher cognitive processes depend on this fundamental operation,” Bizon said.

To determine the culprit behind working memory decline, the researchers tested the memory of young and aged rats in a “Skinner box.” In the Skinner box, rats had to remember the location of a lever for short periods of up to 30 seconds. The scientists found that while both young and old rats could remember the location of the lever for brief periods of time, as those time periods lengthened, old rats had more difficulty remembering the location of the lever than young rats.

But not all older rats did poorly on the memory test, just as not all older adults have memory problems. The study shows the older brains of some people or rats with no memory problems might compensate for the overactive inhibitory system — they are able to produce fewer GABA receptors and therefore bind less of the inhibitory chemical.

Older rats with memory problems had more GABA receptors. The drug the researchers tested blocked GABA receptors, mimicking the lower number of those receptors that some older rats had naturally and restoring working memory in aged rats to the level of younger rats.

“Modern medicine has done a terrific job of keeping us alive for longer, and now we have to keep up and determine how to maximize the quality of life for seniors,” Bizon said. “A key aspect of that is going to be developing strategies and therapies that can maintain and improve cognitive health.”

Veterans exposed to explosions who do not report symptoms of traumatic brain injury (TBI) may still have damage to the brain’s white matter comparable to veterans with TBI, according to researchers at Duke Medicine and the U.S. Department of Veterans Affairs.

The findings, published in the Journal of Head Trauma Rehabilitation on March 3, 2014, suggest that a lack of clear TBI symptoms following an explosion may not accurately reflect the extent of brain injury.

Veterans of recent military conflicts in Iraq and Afghanistan often have a history of exposure to explosive forces from bombs, grenades and other devices, although relatively little is known about whether this injures the brain. However, evidence is building – particularly among professional athletes – that subconcussive events have an effect on the brain.

"Similar to sports injuries, people near an explosion assume that if they don’t have clear symptoms – losing consciousness, blurred vision, headaches – they haven’t had injury to the brain,” said senior author Rajendra A. Morey, M.D., associate professor of psychiatry and behavioral sciences at Duke University School of Medicine and a psychiatrist at the Durham Veterans Affairs Medical Center. “Our findings are important because they’re showing that even if you don’t have symptoms, there may still be damage.”

Researchers in the Mid-Atlantic Mental Illness Research, Education and Clinical Center at the W.G. (Bill) Hefner Veterans Affairs Medical Center in Salisbury, N.C., evaluated 45 U.S. veterans who volunteered to participate in the study. The veterans, who served since September 2001, were split into three groups: veterans with a history of blast exposure with symptoms of TBI; veterans with a history of blast exposure without symptoms of TBI; and veterans without blast exposure. The study focused on veterans with primary blast exposure, or blast exposure without external injuries, and did not include those with brain injury from direct hits to the head.

To measure injury to the brain, the researchers used a type of MRI called Diffusion Tensor Imaging (DTI). DTI can detect injury to the brain’s white matter by measuring the flow of fluid in the brain. In healthy white matter, fluid moves in a directional manner, suggesting that the white matter fibers are intact. Injured fibers allow the fluid to diffuse.

White matter is the connective wiring that links different areas of the brain. Since most cognitive processes involve multiple parts of the brain working together, injury to white matter can impair the brain’s communication network and may result in cognitive problems.

Both groups of veterans who were near an explosion, regardless of whether they had TBI symptoms, showed a significant amount of injury compared to the veterans not exposed to a blast. The injury was not isolated to one area of the brain, and each individual had a different pattern of injury.

Using neuropsychological testing to assess cognitive performance, the researchers found a relationship between the amount of white matter injury and changes in reaction time and the ability to switch between mental tasks. However, brain injury was not linked to performance on other cognitive tests, including decision-making and organization.

“We expected the group that reported few symptoms at the time of primary blast exposure to be similar to the group without exposure. It was a surprise to find relatively similar DTI changes in both groups exposed to primary blast,” said Katherine H. Taber, Ph.D., a research health scientist at the W.G. (Bill) Hefner Veterans Affairs Medical Center and the study’s lead author. “We are not sure whether this indicates differences among individuals in symptoms-reporting or subconcussive effects of primary blast. It is clear there is more we need to know about the functional consequences of blast exposures.”

Given the study’s findings, the researchers said clinicians treating veterans should take into consideration a person’s exposure to explosive forces, even among those who did not initially show symptoms of TBI. In the future, they may use brain imaging to support clinical tests.

“Imaging could potentially augment the existing approaches that clinicians use to evaluate brain injury by looking below the surface for TBI pathology,” Morey said.

The researchers noted that the results are preliminary, and should be replicated in a larger study.

TAU researchers discover a link between sharp vision and the brain’s processing speed

Middle-aged adults who suddenly need reading glasses, patients with traumatic brain injuries, and people with visual disorders such as “lazy eye” may have one thing in common — “visual crowding,” an inability to recognize individual items surrounded by multiple objects. Visual crowding makes it impossible to read, as single letters within words are rendered illegible. And basic cognitive functions such as facial recognition can also be significantly hampered. Scientists and clinicians currently attribute crowding to a disorder in peripheral vision.

Now Prof. Uri Polat, Maria Lev, and Dr. Oren Yehezkel of Tel Aviv University’s Goldschleger Eye Research Instituteat the Sackler Faculty of Medicine have discovered new evidence that correlates crowding in the fovea — a small part of the retina responsible for sharp vision — and the brain’s processing speed. These findings, published in Nature’s Scientific Reports, could greatly alter earlier models of visual crowding, which emphasized peripheral impairment exclusively. And for many adults lost without their reading glasses, this could improve their vision significantly.

"Current theories strongly stress that visual crowding does not exist in the fovea, that it’s a phenomenon that exists only in peripheral visual fields," said Prof. Polat. "But our study points to another part of the eye altogether — the fovea — and contributes to a unified model for how the brain integrates visual information."

A trained eye

According to Prof. Polat, vision is dynamic and changes rapidly, but it takes time for the brain to process this visual information. Rapidly moving tickers on TV, or traffic signs seen as the driver speeds past, are difficult for anyone to read. However, given enough time, someone with excellent vision can fully recognize the words. Those with slower processing speeds — usually the result of poor perceptive development or age — may not be able to decipher the tickers or the traffic signs. In the study, Prof. Polat employed his expertise in improving vision by retraining the brain and the foveal part of the eye, using exercises in which speed is a key element.

"Training adults to reduce foveal crowding leads to improved vision. A similar training we conducted two years ago allowed adults to eliminate their use of reading glasses altogether, using a technology provided by the GlassesOff company. Other patients who had lost sharp vision for whatever reason were also able to benefit from the same training and improve their processing speed and visual capabilities," said Prof. Polat.

Maria Lev, who performed the study as a part of her doctoral thesis, said one young subject had experienced significant limitations in school for years and had been unable to obtain a driver’s license due to severe visual impairment from foveal crowding. After undergoing training that emphasized a foveal rather than a peripheral focus, he was able to overcome the handicap.

"He finally managed to learn to read properly and found his way forward," said Lev. "I’m proud to say that today he is not only eligible for a driver’s license, he’s also been able to earn his master’s degree."

Prof. Polat and his team are currently exploring how visual integration and foveal crowding develop in various clinical cases.

New research from the University of Virginia School of Medicine has revealed the dramatic effect the immune system has on the brain development of young children. The findings suggest new and better ways to prevent developmental impairment in children in developing countries, helping to free them from a cycle of poverty and disease, and to attain their full potential.

U.Va. researchers working in Bangladesh determined that the more days infants suffered fever, the worse they performed on developmental tests at 12 and 24 months. They also found that elevated levels of inflammation-causing proteins in the blood were associated with worse performance, while higher levels of inflammation-fighting proteins were associated with improved performance.

“The problem we sought to address was why millions of young children in low- and middle-income countries are not attaining their full developmental potential,” said lead author Nona Jiang, who performed the research while an undergraduate student in the laboratory of Dr. William Petri Jr. “Early childhood is an absolutely critical time of brain development, and it’s also a time when these children are suffering from recurrent infections. Therefore, we asked whether these infections are contributing to the impaired development we observe in children growing up in adversity.”

Their findings offer a potential explanation for the developmental impairment seen in children living in poverty. They also offer important direction for doctors attempting to combat the problem: By preventing inflammation, physicians may be able to enhance children’s mental ability for a lifetime.

“We are interested in examining factors that predict healthy child development around the world,” said researcher Dr. Rebecca Scharf of U.Va.’s Department of Pediatrics. “By studying which early childhood influences are associated with hindrances to growth and learning, we will know better where to target interventions for the critical period of early childhood.”

In addition, the finding illuminates the complex relationship between the immune system and cognitive development, an increasingly important area of research that U.Va. has helped pioneer.

“This is a very interesting study, showing, probably for the first time, the link between peripheral cytokine levels and improved cognitive development in humans,” said Jonathan Kipnis, a professor of neuroscience and director of U.Va.’s Center for Brain Immunology & Glia. “What is of the most interest and of a great novelty is the fact that [inflammation-fighting cytokines] have positive correlation with cognitive function. My lab published results showing that these IL-4 cytokines are required for proper brain function in mice, and this work from Dr. Petri’s lab completely independently shows similar correlation in humans.

“I hope the scientific community will appreciate how dramatic the effects of the immune system are on the central nervous system and will invest more efforts in studying and better understanding these complex and intriguing interactions between the body’s two major systems.”

Johns Hopkins researchers report that people with chronic insomnia show more plasticity and activity than good sleepers in the part of the brain that controls movement.

"Insomnia is not a nighttime disorder," says study leader Rachel E. Salas, M.D., an assistant professor of neurology at the Johns Hopkins University School of Medicine. "It’s a 24-hour brain condition, like a light switch that is always on. Our research adds information about differences in the brain associated with it."

Salas and her team, reporting in the March issue of the journal Sleep, found that the motor cortex in those with chronic insomnia was more adaptable to change - more plastic - than in a group of good sleepers. They also found more “excitability” among neurons in the same region of the brain among those with chronic insomnia, adding evidence to the notion that insomniacs are in a constant state of heightened information processing that may interfere with sleep.

Researchers say they hope their study opens the door to better diagnosis and treatment of the most common and often intractable sleep disorder that affects an estimated 15 percent of the United States population.

To conduct the study, Salas and her colleagues from the Department of Psychiatry and Behavioral Sciences and the Department of Physical Medicine and Rehabilitation used transcranial magnetic stimulation (TMS), which painlessly and noninvasively delivers electromagnetic currents to precise locations in the brain and can temporarily and safely disrupt the function of the targeted area. TMS is approved by the U.S. Food and Drug Administration to treat some patients with depression by stimulating nerve cells in the region of the brain involved in mood control.

The study included 28 adult participants - 18 who suffered from insomnia for a year or more and 10 considered good sleepers with no reports of trouble sleeping. Each participant was outfitted with electrodes on their dominant thumb as well as an accelerometer to measure the speed and direction of the thumb.

The researchers then gave each subject 65 electrical pulses using TMS, stimulating areas of the motor cortex and watching for involuntary thumb movements linked to the stimulation. Subsequently, the researchers trained each participant for 30 minutes, teaching them to move their thumb in the opposite direction of the original involuntary movement. They then introduced the electrical pulses once again.

The idea was to measure the extent to which participants’ brains could learn to move their thumbs involuntarily in the newly trained direction. The more the thumb was able to move in the new direction, the more likely their motor cortexes could be identified as more plastic.

Because lack of sleep at night has been linked to decreased memory and concentration during the day, Salas and her colleagues suspected that the brains of good sleepers could be more easily retrained. The results, however, were the opposite. The researchers found much more plasticity in the brains of those with chronic insomnia.

Salas says the origins of increased plasticity in insomniacs are unclear, and it is not known whether the increase is the cause of insomnia. It is also unknown whether this increased plasticity is beneficial, the source of the problem or part of a compensatory mechanism to address the consequences of sleep deprivation associated with chronic insomnia. Patients with chronic phantom pain after limb amputation and with dystonia, a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements, also have increased brain plasticity in the motor cortex, but to detrimental effect.

Salas says it is possible that the dysregulation of arousal described in chronic insomnia - increased metabolism, increased cortisol levels, constant worrying - might be linked to increased plasticity in some way. Diagnosing insomnia is solely based on what the patient reports to the provider; there is no objective test. Neither is there a single treatment that works for all people with insomnia. Treatment can be a hit or miss in many patients, Salas says.

She says this study shows that TMS may be able to play a role in diagnosing insomnia, and more importantly, she says, potentially prove to be a treatment for insomnia, perhaps through reducing excitability.

So why do neurons respond in this remarkable way? A new study by Professor Jeff Bowers and colleagues at the University of Bristol argues that highly selective neural representations are well suited to co-activating multiple things, such as words, objects and faces, at the same time in short-term memory. 

The researchers trained an artificial neural network to remember words in short-term memory. Like a brain, the network was composed of a set of interconnected units that activated in response to inputs; the network ‘learnt’ by changing the strength of connections between units. The researchers then recorded the activation of the units in response to a number of different words.

When the network was trained to store one word at a time in short-term memory, it learned highly distributed codes such that each unit responded to many different words. However, when it was trained to store multiple words at the same time in short-term memory it learned highly selective (‘grandmother cell’) units – that is, after training, single units responded to one word but not any other. This is much like the neurons in the cortex that respond to one face amongst many.

Why did the network learn such highly specific representations when trained to co-activate multiple words at the same time? Professor Bowers and colleagues argue that the non-selective representations can support memory for a single word, given that a pattern of activation across many non-selective units can uniquely represent a specific word. However, when multiple patterns are mixed together, the resulting blend pattern is often ambiguous (the so-called ‘superposition catastrophe’).

This ambiguity is easily avoided, however, when the network learns to represent words in a highly selective manner, for example, if one unit codes for the word RACHEL, another for MONICA, and yet another JOEY, there is no ambiguity when the three units are co-activated.

Professor Bowers said: “Our research provides a possible explanation for the discovery that single neurons in the cortex respond to information in a highly selective manner. It’s possible that the cortex learns highly selective codes in order to support short-term memory.”

The study is published in Psychological Review.

Schizophrenia is one of the most disabling of all psychiatric illnesses. Sadly, it is not uncommon and it strikes early in life.

Many studies have looked into causes and potential interventions, and it has been long known that genetic factors play a role in determining the risk of developing schizophrenia. However, recent work has shown that there will be no simple answers as to why some people get schizophrenia: No single gene or small number of genes explains much of the risk for illness. Instead, future studies must focus on larger numbers of interacting genes.

In a new paper published in PLOS ONE, researchers led by Bruce Cohen of Harvard Medical School and McLean Hospital report promising evidence on what one of those important groups of genes may be.

Previous studies of schizophrenia have shown abnormalities in the brain’s white matter—its wiring and insulation—but these studies could not definitively separate inherited from environmental causes. For this study, researchers used previously discovered anomalies to select likely assortments of genes that, as a group, might be highly determinative of the risk for schizophrenia. The choice of genes was based on convergent results of past studies conducted locally and around the world, and included genes that control the insulation of the nerve cells in the brain.

The results of this study strongly suggest that the abnormalities of wiring and insulation are substantially determined by genes.

“There is abundant evidence from our center and from other laboratories that this insulation is compromised in schizophrenia,” said Cohen, HMS Robertson-Steele Professor of Psychiatry and director of the Shervert Frazier Research Institute at McLean Hospital. “Based on this lead, we tested whether the genes required for the activities of the cells that make this insulation (oligodendrocytes) were associated with schizophrenia. In a primary analysis, followed by three separate means of confirmatory analysis, we found strong evidence that genes for oligodendrocytes, as a group, were indeed associated with schizophrenia.”

The findings suggest a concrete reason why insulation is disrupted in the brain in schizophrenia. This disruption in turn may explain why thinking is altered in schizophrenia: Nerve cells are unable to pass exact messages if they lack proper insulation.

Further, the findings show that the abnormality in insulation is at least in part genetically determined, rather than solely due to environmental factors such as years of treatment, different life activities or exposure to toxins.

Finally, the results identify a specific cell-level abnormality, in oligodendrocytes, in schizophrenia.

Similar findings, using different techniques, were recently reported by an independent group of investigators, working separately but contemporaneously with the authors of this study.

“Knowing that one of the pathways of risk for schizophrenia is in this set of genes and in these cells may help identify who is at risk and in what way they are at risk,” said Cohen. “The cells themselves will next be studied to define the problem and seek methods to prevent or reverse it. Thus, the findings can point us towards new ways to reduce the risk and burden of schizophrenia.”

Additional researchers from HMS, Harvard School of Public Health, McLean Hospital, Massachusetts General Hospital, The Broad Institute of MIT and Harvard, and the Cardiff University School of Medicine in Wales contributed to the study.

A new study led by Weill Cornell Medical College scientists shows that the most common genetic form of mental retardation and autism occurs because of a mechanism that shuts off the gene associated with the disease. The findings, published today in Science, also show that a drug that blocks this silencing mechanism can prevent fragile X syndrome — suggesting similar therapy is possible for 20 other diseases that range from mental retardation to multisystem failure.

(Image caption: A key brain signaling protein, seen here in green, that is normally lost in Fragile X syndrome neurons is restored by an experimental drug. Image: Dilek Colak)

Fragile X syndrome occurs mostly in boys, causing intellectual disability as well as telltale physical, behavioral and emotional traits. While researchers have known for more than two decades that the culprit behind the disease is an unusual mutation characterized by the excess repetition of a particular segment of the genetic code, they weren’t sure why the presence of a large number of these repetitions — 200 or more — sets the disease process in motion.

Using stem cells from donated human embryos that tested positive for fragile X syndrome, the scientists discovered that early on in fetal development, messenger RNA — a template for protein production — begins sticking itself onto the fragile X syndrome gene’s DNA. This binding appears to gum up the gene, making it inactive and unable to produce a protein crucial to the transmission of signals between brain cells.

"Until 11 weeks of gestation, the fragile X syndrome gene is active — it produces its messenger RNA and protein normally. Then, all of a sudden it turns off, and stays off for the rest of the patient’s lifetime, causing fragile X syndrome. But scientists have not understood why this gene gets shut off," says senior author Dr. Samie Jaffrey, a professor of pharmacology at Weill Cornell Medical College. "We discovered that the messenger RNA can jam up one strand of the gene’s DNA, shutting down the gene — which was not known before.

"This is new biology — an interaction between the RNA and the DNA of the fragile X syndrome gene causes disease," Dr. Jaffrey says. "We are coming to understand that RNAs are powerful molecules that can regulate gene expression, but this mechanism is completely novel — and very exciting."

The malfunction occurs suddenly — before the end of the first trimester in humans and after 50 days in laboratory embryonic stem cells. At that point, the messenger RNA produced by the fragile X syndrome gene makes what the researchers call an RNA-DNA duplex — a particular arrangement of molecules in which the messenger RNA is stuck onto its DNA complement. (DNA produces two complementary strands of the genetic code responsible for human development and function. The four nucleic acids in the genomic code — A, C, G, T — have specific complements. In the case of fragile X syndrome, the repeat sequence in question is CGG. Therefore, RNA binds to its GCC complement on one strand of DNA.)

The RNA-DNA duplex then shuts down production of the fragile X syndrome gene, causing the loss of a protein needed for communication between brain cells. The gene then remains inactive for life. A normal fragile X gene — one with fewer than 200 CGG repeats — stays active in a person without the disorder, and produces the necessary protein. However, the mutant fragile X gene contains more than 200 CGG repeats, resulting in fragile X syndrome. Fragile X occurs in about 1 in 4,000 males and 1 in 8,000 females.

"Because the fragile X syndrome mutation is a repeat sequence, it is very easy for just a small portion of this sequence in the messenger RNA to find a matching repeat sequence on the DNA," Dr. Jaffrey says. "This is a unique feature of repeat sequences. When there are 200 or more repeats, the RNA-DNA interaction locks into place."

Hope for treatment — and other disorders

Dr. Jaffrey and his team, which includes researchers from The Scripps Research Institute in Florida and Albert Einstein College of Medicine in the Bronx, sought to find out why the disease is switched on when the CGG repeat is present in 200 to as many as 1,000 copies.

"Utilizing traditional ways to solve this puzzle has been impossible," he says. "Human fragile X syndrome genes introduced into mice and cells in the laboratory never turn off, no matter how many CGG repeats the genes have."

So the scientists turned to human embryonic stem cells. Co-authors Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and director of the Stem Cell Derivation Laboratory of Weill Cornell Medical College, and Dr. Nikica Zaninovic, assistant professor of reproductive medicine, generated stem cell lines from donated embryos that tested positive for fragile X syndrome. “These stem cells were critical to the success of this research, because they alone allowed us to mimic what happens to the fragile X gene during embryonic development,” says Dr. Dilek Colak, a postdoctoral scientist in Dr. Jaffrey’s laboratory and the first author of the study.

The stem cells were coaxed to become brain neurons, and at about 50 days, they differentiated in the same way that an embryo’s brain is developing at 11-plus weeks when the fragile X syndrome gene is switched off.

The researchers then used a drug developed by co-author Dr. Matthew Disney of the Scripps Research Institute that binds to CGG in the fragile X gene’s RNA before and after the 50-day switch. Strikingly, the gene never stopped producing its beneficial protein.

That suggests a potential prevention or treatment strategy for fragile X syndrome, Dr. Jaffrey says. “If a pregnant woman is told that her fetus carries the genetic mutation causing fragile X syndrome, we could potentially intervene and give the drug during gestation. This may delay or prevent the silencing of the fragile X gene, which could potentially significantly improve the outcome of these patients,” he says.

The researchers are now looking for similar RNA-DNA duplexes in other trinucleotide repeat diseases, including Huntington’s disease (a degenerative brain disease), myotonic dystrophy 1 and 2 (a multisystem progressive disease), Friedrich’s ataxia (a progressive nervous system disorder), Jacobsen syndrome (an intellectual disorder), and familial amyotrophic lateral sclerosis (a motor neuron disease), among others.

"This completely new mechanism by which RNAs can direct gene silencing may be involved in a lot of other diseases," Dr. Jaffrey says. "Our hope is that we can find drugs that interfere with this new type of disease process."

Researchers report that one tiny variation in the sequence of a gene may cause some people to be more impaired by traumatic brain injury (TBI) than others with comparable wounds.

The study, described in the journal PLOS ONE, measured general intelligence in a group of 156 Vietnam War veterans who suffered penetrating head injuries during the war. All of the study subjects had damage to the prefrontal cortex, a brain region behind the forehead that is important to cognitive tasks such as planning, problem-solving, self-restraint and complex thought.

The researchers controlled for the size and location of subjects’ brain injuries and other factors, such as intelligence prior to injury, which might have contributed to differences in cognitive function. (Prior to combat, the veterans had completed the Armed Forces Qualifications Test, which included measures of intelligence that provided a baseline for the new analysis.)

“We administered a large, cognitive battery of tests to investigate how they performed after their injury,” said study leader Aron Barbey, a professor of speech and hearing science, of psychology and of neuroscience at the University of Illinois. “And we had a team of neurologists who helped characterize the nature and scope of the patients’ brain injuries.”

The researchers also collected blood for a genetic analysis, focusing on a gene known as BDNF (brain-derived neurotrophic factor).

The team found that a single polymorphism (a difference in one “letter” of the sequence) in the BDNF gene accounted for significant differences in intelligence among those with similar injuries and comparable intelligence before being injured.

“BDNF is a basic growth factor and it’s related to neurogenesis, the production of new neurons,” Barbey said. “What we found is that if people have a specific polymorphism in the BDNF gene, they recovered to a greater extent than those with a different variant of the gene.”

The change in the gene alters the BDNF protein: The amino acid methionine (Met) is incorporated at a specific site in the protein instead of valine (Val). Since people inherit two versions of each gene, one from each parent, they have either Val/Val, Val/Met or Met/Met variants of the gene.

“The effects of this difference were large – very large,” Barbey said. “If an individual had the Val/Val combination, then their performance on a battery of cognitive tests (conducted long after the injury occurred) was remarkably lower than that of individuals who had the Val/Met or Met/Met combination.”

On average, those with the Val/Val polymorphism scored about eight IQ points lower on tests of general intelligence than those with the Val/Met or Met/Met variants, Barbey said. Those with the Val/Val variant also were significantly more impaired in “specific competencies for intelligence like verbal comprehension, perceptual organization, working memory and processing speed,” he said.

To test these results, the researchers did the analysis over again “in a subset of individuals who had very similar (brain injuries) to the other group,” Barbey said. “We found the same kind of effects, suggesting that lesion location isn’t a factor influencing the difference between the groups.”

The finding opens a new avenue of exploration for treatments to aid the process of recovery from TBI, Barbey said.

A team of international scientists, including a researcher from Simon Fraser University, has isolated a gene thought to play a causal role in the development of Alzheimer’s disease. The Proceedings of the National Academy of Sciences recently published the team’s study.

The newly identified gene affects accumulation of amyloid-beta, a protein believed to be one of the main causes of the damage that underpins this brain disease in humans.

The gene encodes a protein that is important for intracellular transportation. Each brain cell relies on an internal highway system that transports molecular signals needed for the development, communication, and survival of the cell. 

This system’s impairment can disrupt amyloid-beta processing, causing its eventual accumulation. This contributes to the development of amyloid plaques, which are a key hallmark of Alzheimer’s disease.

Teasing out contributing disease factors, whether genetic or environmental, has long posed a challenge for Alzheimer’s researchers.

“Alzheimer’s is a multifactorial disease where a build-up of subtle problems develop in the nervous system over a span of decades,” says Michael Silverman, an SFU biology associate professor. He worked on the study with a team of Japanese scientists led by Dr. Takashi Morihara at Osaka University.   

Identifying these subtle, yet perhaps critical genetic contributions is challenging. “Alzheimer’s, like many human disorders, has a genetic component, yet many environmental and lifestyle factors contribute to the disease as well,” says Silverman. “In a sense, it is like looking for a needle in a complex genetic haystack.”

Only a small fraction of cases have a strong hereditary component, for example early-onset Alzheimer’s.

This breakthrough in Alzheimer’s research could open new avenues for the design of therapeutics and pave the way for early detection by helping healthcare professionals identify those who are predisposed to the disease.

“One possibility is that a genetic test for a particular variant of this newly discovered gene, along with other variants of genes that contribute to Alzheimer’s, will help to give a person their overall risk for the disease.  

“Lifestyle changes, such as improved diet, exercise, and an increase in cognitive stimulation may then help to slow the progression of Alzheimer’s,” says Silverman.

University of Miami researchers develop a method to visualize protein interactions in a living organism’s brain

There are more than a trillion cells called neurons that form a labyrinth of connections in our brains. Each of these neurons contains millions of proteins that perform different functions. Exactly how individual proteins interact to form the complex networks of the brain still remains as a mystery that is just beginning to unravel.

For the first time, a group of scientists has been able to observe intact interactions between proteins, directly in the brain of a live animal. The new live imaging approach was developed by a team of researchers at the University of Miami (UM).

(Image caption: Photonic resonance energy transfer described by Förster, or FRET, occurs when two small proteins come within a very small distance of each other — eight nanometers or less. The fluorescence lifetime of the donor molecule will become shorter — from 3 nanosecond to, perhaps, 2.5 nanoseconds. We then interpret this as evidence that the two proteins of interest are physically interacting with each other — a molecular signaling event. Credit: Akira Chiba/University of Miami)

"Our ultimate goal is to create the systematic survey of protein interactions in the brain," says Akira Chiba, professor of Biology in the College of Arts and Sciences at UM and lead investigator of the project. "Now that the genome project is complete, the next step is to understand what the proteins coded by our genes do in our body."

The new technique will allow scientists to visualize the interactions of proteins in the brain of an animal, along different points throughout its development, explains Chiba, who likens protein interactions to the way organisms associate with each other.

"We know that proteins are one billionth of a human in size. Nevertheless, proteins make networks and interact with each other, like social networking humans do," Chiba says. "The scale is very different, but it’s the same behavior happening among the basic units of a given network."

The researchers chose embryos of the fruit fly (Drosophila melanogaster) as an ideal model for the study. Because of its compact and transparent body, it is possible to visualize processes inside the Drosophila cells using a fluorescence lifetime imaging microscope (FLIM). The results of the observations are applicable to other animal brains, including the human brain.

The Drosophila embryos in the study contained a pair of fluorescent labeled proteins: a developmentally essential and ubiquitously present protein called Rho GTPase Cdc42 (cell division control protein 42), labeled with green fluorescent tag and its alleged signaling partner, the regulatory protein WASp (Wiskot-Aldrich Syndrome protein), labeled with red fluorescent tag. Together, these specialized proteins are believed to help neurons grow during brain development. The proteins were selected because the same (homolog) proteins exist in the human brain as well.

Previous methods required chemical or physical treatments that most likely disturb or even kill the cells. That made it impossible to study the protein interactions in their natural environment.

(Image caption: FRET (Förster resonance energy transfer) between the two interacting protein partners occurs, Cdc42 and WASp, within neurons, during the time and space that coincides with the formation of new synapses in the brain of the baby insect. Synapses connect individual neurons in the brain. Credit: Akira Chiba / University of Miami)

The current study addresses these challenges by using the occurrence of a phenomenon called Förster resonance energy transfer, or FRET. It occurs when two small proteins come within a very small distance of each other, (eight nanometers). The event is interpreted as the time and place where the particular protein interaction occurs within the living animal.

(Image caption: Proteins are one billionth of a human in size. Nevertheless, proteins make networks and interact with each other, like social networking humans do,” says Akira Chiba, professor of Biology in the College of Arts and Sciences at the University of Miami. “The scale is very different, but it’s the same behavior happening among the basic units of a given network.” Credit: Akira Chiba / University of Miami)

The findings show that FRET between the two interacting protein partners occurs within neurons, during the time and space that coincides with the formation of new synapses in the brain of the baby insect. Synapses connect individual neurons in the brain.

"Previous studies have demonstrated that Cdc42 and WASp can directly bind to each other in a test-tube, but this is the first direct demonstration that these two proteins are interacting within the brain," Chiba says.

Pulling an “all-nighter” before a big test is practically a rite of passage in college. Usually, it’s no problem: You stay up all night, take the test, and then crash, rapidly catching up on lost sleep. But as we age, sleep patterns change, and our ability to recoup lost sleep diminishes.

Researchers at the Perelman School of Medicine, University of Pennsylvania, have been studying the molecular mechanisms underpinning sleep. Now they report that the pathways of aging and sleep intersect at the circuitry of a cellular stress response pathway, and that by tinkering with those connections, it may be possible to alter sleep patterns in the aged for the better – at least in fruit flies.

Nirinjini Naidoo, PhD, associate professor in the Center for Sleep and Circadian Neurobiology and the Division of Sleep Medicine, led the study with postdoctoral fellow Marishka Brown, PhD, which was published online before print in the journal Neurobiology of Aging.

Increasing age is well known to disrupt sleep patterns in all sorts of ways. Elderly people sleep at night less than their younger counterparts and also sleep less well. Older individuals also tend to nap more during the day. Naidoo’s lab previously reported that aging is associated with increasing levels of protein unfolding, a hallmark of cellular stress called the “unfolded protein response.”

Protein misfolding is also a characteristic of several age-related neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, and as it turns out, also associated with sleep deprivation. Naidoo and her team wanted to know if rescuing proper protein folding behavior might counter some of the detrimental sleep patterns in elderly individuals.

Using a video monitoring system to compare the sleep habits of “young” (9–12 days old) and “aged” (8 weeks old) fruit flies, they found that aged flies took longer to recover from sleep deprivation, slept less overall, and had their sleep more frequently interrupted compared to younger control animals. However, adding a molecule that promotes proper protein folding – a molecular “chaperone” called PBA — mitigated many of those effects, effectively giving the flies a more youthful sleep pattern. PBA (sodium 4-phenylbutyrate) is a compound currently used to treat such protein-misfolding-based diseases as Parkinson’s and cystic fibrosis.

The team also asked the converse question: Can protein misfolding induce altered sleep patterns in young animals. Another drug, tunicamycin, induces protein misfolding and stress, and when the team fed it to young flies, their sleep patterns shifted towards those of aged flies, with less sleep overall, more interrupted sleep at night, and longer recovery from sleep deprivation.

Molecular analysis of sleep-deprived and PBA-treated flies suggested that PBA acts through the unfolded protein response. PBA, Naidoo says, had two effects on aged flies: it “consolidated” baseline sleep, increasing the total amount of time slept and shifted recovery sleep, after sleep deprivation, to look more like that of a young fly.

“It rescued the sleep patterns in the older flies,” she explains.

These results, Naidoo says, suggest three key messages. First, sleep loss leads to protein misfolding and cellular stress, and as we age, our ability to recover from that stress decreases. Second, aging and sleep apparently form a kind of negative “chicken-and-egg” feedback loop, in which sleep loss or sleep fragmentation lead to cellular stress, followed by neuronal dysfunction, and finally even poorer-quality sleep.

Sleep recharges neuronal batteries, Naidoo explains, and if a person is forced to stay awake, those batteries run down. Dwindling physiological resources must be devoted to the most critical cell functions, which do not necessarily include protein homeostasis. “Staying awake has a cost, and one of those costs is problems with protein folding.”

Finally, and most importantly, she says these results suggest — assuming they can be replicated in mice and humans – that it may be possible using drugs such as PBA to “fix sleep” in aged or mutant animals.

“People know that sleep deteriorates with aging,” Naidoo says, “But this might be able to be stopped or reversed with molecular chaperones.” Her team is now looking to determine if a similar situation exists in mammals and if better sleep translates into longer lifespan.

Chronic stress that produces inflammation and anxiety in mice appears to prime their immune systems for a prolonged fight, causing the animals to have an excessive reaction to a single acute stressor weeks later, new research suggests.

After the mice recovered from the effects of chronic stress, a single stressful event 24 days later quickly returned them to a chronically stressed state in biological and behavioral terms. Mice that had not experienced the chronic stress were unaffected by the single acute stressor.

The study further showed that immune cells called to action as a result of chronic stress ended up on standby in the animals’ spleens and were launched from that organ to respond to the later stressor.

Mice without spleens did not experience the same reactivation with the second stressor, signifying the spleen’s role as a reservoir for primed immune cells to remain until they’re activated in response to another stressor.

The excessive immune response and anxiety initiated by a brief stressor mimic symptoms of post-traumatic stress disorder.

The Ohio State University scientists are cautious about extending their findings to humans. But they say their decade of work with this model of stress suggests that the immune system has a significant role in affecting behavior. And they are the first to study this re-establishment of anxiety in animals with a later acute stressor.

“No one else has done a study of this length to see what happens to recovered animals if we subject them again to stress,” said Jonathan Godbout, a lead author of the study and associate professor of neuroscience at Ohio State. “That retriggering is a component of post-traumatic stress. The previously stressed mice are living a normal rodent life, and then this acute stress brings everything back. Animals that have never been exposed to stress before were unaffected by that one event – it didn’t change behavioral or physiological properties.”

The research is published online in the journal Biological Psychiatry.

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Geneticists from Trinity College Dublin interested in ‘reverse engineering’ the nervous system have made an important discovery with wider implications for repairing missing or broken links. They found that the same molecular switches that induce originally non-descript cells to specialise into the billions of unique nerve cell types are also responsible for making these nerve cells respond differently to the environment. 

The geneticists are beginning to understand how these molecular switches, called ‘transcription factors’, turn on specific cellular labels to form complex bundles of nerves. These bundles function to ensure we respond and react appropriately to the incredible amount of information our brains encounter. Understanding how to precisely program nerve cells could help to target missing or broken links following serious injury or the onset of degenerative diseases such as Alzheimer’s or Parkinson’s.

Commenting on the importance and wider implications of this discovery, Assistant Professor in Genetics at Trinity, Juan Pablo Labrador said: “We know very little of how individual nerve cells are programmed to assemble into specific nerves in living organisms to make specific circuits, so our work is like reverse engineering the nervous system.” 

“To restore damaged or missing connections in the nervous system – for example, after spinal cord injuries or degenerative diseases such as Alzheimer’s or Parkinson’s – we need to know how nerve cells are programmed to make those connections in the first place. For that we require a complex ‘builder’s manual’ that tells us how to program the neurons to make the connections. What we are doing in my lab is trying to write this manual.” 

The nervous system can be thought of as an incredibly complex network of wires, which are all arranged into different, related bundles to coordinate complex tasks. The wires are the cellular extensions from the individual nerve cells that assemble into bundles to form specific nerves. The geneticists have begun to understand how varied combinations of transcription factors work to generate different nerve cells and direct their wiring to form specific nerves.

By studying the behaviour of individual nerve cells that make connections with muscles, the geneticists discovered specific ‘footprints’ of labels that induced these nerve cells to assemble into specific bundles that link to their target muscles. Individual transcription factors are only able to turn on specific labels to some extent. It is only the action of all of them together that programmes the nerve cells to turn on all the labels required. 

The research was just published in the high-profile journal Neuron. The team led by Assistant Professor Juan Pablo Labrador, found that the actions of the transcription factor influencing nerve cell differentiation in flies (‘Eve’) controls nerve cell surface labels.

The team also showed that if these labels, targeted by Eve, are expressed erroneously, the nerve cells will not form the correct nerves. Additionally, the team discovered that different combinations of transcription factors including Eve work as codes for different groups of labels that guide individual nerve development.

To remain healthy, the body’s cells must properly manage their waste recycling centers. Problems with these compartments, known as lysosomes, lead to a number of debilitating and sometimes lethal conditions.

Reporting in the Proceedings of the National Academy of Sciences (PNAS), researchers at Washington University School of Medicine in St. Louis have identified an unusual cause of the lysosomal storage disorder called mucolipidosis III, at least in a subset of patients. This rare disorder causes skeletal and heart abnormalities and can result in a shortened lifespan. But unlike most genetic diseases that involve dysfunctional or missing proteins, the culprit is a normal protein that ends up in the wrong place.

Image caption: In normal cells, phosphotransferase (green) is shown overlapping with the Golgi apparatus (red), which indicates that phosphotransferase is located in the Golgi, where it should be (Credit: Eline van Meel, PhD)

“There is a lot of interest and study about how cells distribute proteins to the right parts of the cell,” said senior author Stuart A. Kornfeld, MD, PhD, the David C. and Betty Farrell Professor of Medicine. “Our study has identified one of the few examples of a genetic disease caused by the misplacement of a protein. The protein functions just fine. It just doesn’t stay in the right place.”

The right place, in this case, is the Golgi apparatus, the cell’s protein packaging center. The protein in question – phosphotransferase – normally resides in the Golgi, where its job is to attach address labels to proteins bound for the lysosome. There are 60 such lysosomal proteins, and all of them must be properly labeled if they are to end up in a lysosome, where they recycle waste.

Image caption: In mutant cells, the protein phosphotransferase (green) is spread beyond the Golgi (red). Outside the Golgi, this wayward phosphotransferase is no longer able to perform its job of properly addressing enzymes bound for the lysosome (Credit: Eline van Meel, PhD)

Kornfeld and his colleagues, including first author Eline van Meel, PhD, postdoctoral research associate, showed that the phosphotransferase protein responsible for adding the address label starts out in the Golgi as it should, but seems to lack the signal to keep it there.

“Under normal circumstances, the phosphotransferase moves up through the Golgi, but then it’s recaptured and sent back,” Kornfeld said. “Our study shows that the mutant phosphotransferase moves up but is not recaptured. Ironically, the phosphotransferase that escapes the Golgi ends up in the lysosomes, where it is degraded.”

Because phosphotransferase gradually wanders away from the Golgi, a low level of lysosomal enzymes end up being properly addressed, but at perhaps 20 percent of the normal amount.

“In many lysosomal storage disorders, such as Tay-Sachs or Gaucher’s disease, only one out of the 60 enzymes is missing from the lysosome,” Kornfeld said. “But the mislocalization of phosphotranferase causes the misdirection of all 60 lysosomal enzymes.”

While the errant phosphotransferase ends up being degraded in the lysosome, the resulting misdirected lysosomal proteins end up in the bloodstream. As a result, children with this disorder have lysosomal proteins in their blood at levels 10 to 20 times higher than normal. But because some get to the lysosome at a low level, people with mucolipidosis III don’t have the most severe form of the disease.

“Type III patients live into adulthood, but they’re very impaired,” said Kornfeld. “They have joint and heart problems and have trouble walking. In the most severe form, type II, there is zero activity of phosphotransferase. None of the 60 enzymes are properly tagged, so these patients’ lysosomes are empty. Children with type II usually die by age 10.”

Having implicated wayward phosphotransferase in this lysosomal storage disorder, Kornfeld and his colleagues are investigating what goes wrong that allows it to escape the Golgi.

“We think there must be some protein in the cell that recognizes phosphotransferase when it gets to the end of the Golgi, binds it and takes it back,” said Kornfeld. “Now we’re trying to understand how that works.”