Neuroscience

A research team led by Jackson Laboratory Professor and Howard Hughes Investigator Susan Ackerman, Ph.D., has pinpointed a surprising mechanism behind neurodegeneration in mice, one that involves a defect in a key component of the cellular machinery that makes proteins, known as transfer RNA or tRNA.

The researchers report in the journal Science that a mutation in a gene that produces tRNAs operating only in the central nervous system results in a “stalling” or pausing of the protein production process in the neuronal ribosomes. When another protein the researchers identified, GTPBP2, is also missing, neurodegeneration results.

“Our study demonstrates that individual tRNA genes can be tissue-specifically expressed in vertebrates,” Ackerman says, “and mutations in such genes may cause disease or modify other phenotypes. This is a new area to look for disease mechanisms.”

Neurodegeneration—the process through which mature neurons decay and ultimately die—is poorly understood, yet it underlies major human diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease).

While the causes of neurodegeneration are still coming to light, there is mounting evidence that neurons are exquisitely sensitive—much more so than other types of cells—to disruptions in how proteins are made and how they fold.

tRNAs are critical in translating the genetic code into proteins, the workhorses of the cell. tRNAs possess a characteristic cloverleaf shape with two distinct “business” ends—one that reads out the genetic code in three-letter increments (or triplets), and another that transports the protein building block specified by each triplet (known as an amino acid).

In higher organisms, tRNAs are strikingly diverse. For example, while there are 61 distinct triplets that are recognized by tRNAs in humans, the human genome contains roughly 500 tRNA genes. To date little is known about why they are so numerous, whether they carry out overlapping or redundant functions, or whether they possibly have roles beyond the making of proteins.

“Multiple genes encode almost all tRNA types,” Ackerman says. “In fact, AGA codons are decoded by five tRNAs in mice. Until now, this apparent redundancy has caused us to completely overlook the disease-causing potential of mutations in tRNAs, as well as other repetitive genes.”

Ackerman and her colleagues at The Jackson Laboratory in Bar Harbor, Maine, and Farmington, Conn., The Scripps Research Institute in LaJolla, Calif., and Kumamoto University in Japan pinpointed a mutation in the tRNA gene n-Tr20 as a genetic culprit behind the neurodegeneration observed in mice lacking GTPBP2.

Remarkably, the tRNA’s activity is confined to the brain and other parts of the central nervous system, in both mice and humans. The tRNA encoded by n-Tr20 recognizes the triplet code, AGA (which specifies the amino acid arginine).

The n-Tr20 defect disrupts how proteins are made. Specifically, it causes the “factories” responsible for synthesizing proteins, called ribosomes, to stall when they encounter an AGA triplet.

Such stalling can be largely overcome, thanks to the work of a partner protein called GTPBP2. But when this partner is missing—as it is in the mutant mice that Ackerman and her colleagues studied—the stalling intensifies. This is thought to be a driving force behind the neurodegeneration seen in these mice.

Unlocking the secrets to better treating the pernicious disorders of obesity and dementia reside in the brain, according to a paper from American University’s Center for Behavioral Neuroscience. In the paper, researchers make the case for treating obesity with therapies aimed at areas of the brain responsible for memory and learning. Furthermore, treatments that focus on the hippocampus could play a role in reducing certain dementias.

"In the struggle to treat these diseases, therapies and preventive measures often fall short. This is a new way for providers who treat people with weight problems and for researchers who study dementias to think about obesity and cognitive decline," said Prof. Terry Davidson, center director and lead study author.

In the paper, published in the journal Physiology & Behavior, Davidson and colleague Ashley A. Martin review research findings linking obesity with cognitive decline, including the center’s findings about the “vicious cycle” model, which explains how weight-challenged individuals who suffer from particular kinds of cognitive impairment are more susceptible to overeating.

Obesity, Memory Deficits and Lasting Effects

It is widely accepted that overconsumption of dietary fats, sugar and sweeteners can cause obesity. These types of dietary factors are also linked to cognitive dysfunction. Foods that are risk factors for cognitive impairment (i.e., foods high in saturated fats and simple carbohydrates that make up the modern Western diet) are so widespread and readily available in today’s food environment, their consumption is all but encouraged, Davidson said.

Across age groups, evidence reveals links between excess food intake, body weight and cognitive dysfunction. Childhood obesity and consumption of the Western diet can have lasting effects, as seen through the normal aging process, cognitive deficits and brain pathologies. Several analyses of cases of mild cognitive impairment progressing to full-blown cases of Alzheimer’s disease show that the first signs of brain disease can occur at least 50 years prior to the emergence of serious cognitive dysfunction. These signs originate in the hippocampus, the area of the brain where memory, learning, decision making, behavior control and other cognitive functions come into play.

Still, most research on the role of the brain in obesity focuses on areas thought to be involved with hunger motivation (e.g., hypothalamus), taste (e.g., brain stem), reinforcement (e.g., striatum) and reward (e.g., nucleus accumbens) or with hormonal or metabolic disorders. This research has not yet been successful in generating therapies that are effective in treating or preventing obesity, Davidson says.

Vicious Cycle

Experiments in rats by Davidson and colleagues show that overconsumption of the Western diet can damage or change the blood-brain barrier, the tight network of blood vessels protecting the brain and substrates for cognition. Certain kinds of dementias are known to arise from the breakdown in these brain substrates.

"Breakdown in the blood-brain barrier is more rationale for treating obesity as a learning and memory disorder," Davidson said. "Treating obesity successfully may also reduce the incidence of dementias, because the deterioration in the brain is often produced by the same diets that promote obesity."

The “vicious cycle” model AU researchers put forth says eating a Western diet high in saturated fats, sugar and simple carbohydrates produces pathologies in brain structures and circuits, ultimately changing brain pathways and disrupting cognitive abilities.

It works like this: People become less able to resist temptation when they encounter environmental cues (e.g., food itself or the sight of McDonald’s Golden Arches) that remind them of the pleasures of consumption. They then eat more of the same type of foods that produce the pathological changes in the brain, leading to progressive deterioration in those areas and impairments in cognitive processes important for providing control over one’s thoughts and behaviors. These cognitive impairments can weaken a person’s ability to resist thinking about food, making them more easily distracted by food cues in the environment and more susceptible to overeating and weight gain.

"People have known at least since the time of Hippocrates that one key to a healthy life is to eat in moderation. Yet many of us are unable to follow that good advice," Davidson said. "Our work suggests that new therapeutic interventions that target brain regions involved with learning and memory may lead to success in controlling both the urge to eat, as well as the undesirable consequences produced by overeating."

Mozart, Beethoven or even Shakespeare — pregnant mothers have been known to expose their babies to many forms of auditory stimulation. But according to researchers at the University of Florida, all a baby really needs is the music of mom’s voice.

Research published in the most recent issue of the journal Infant Behavior and Development shows that babies in utero begin to respond to the rhythm of a nursery rhyme — showing evidence of learning — by 34 weeks of pregnancy and are capable of remembering a set rhyme until just prior to birth. Nursing researcher Charlene Krueger and her team studied pregnant women who recited a rhyme to their babies three times a day for six weeks, beginning at 28 weeks’ gestational age, which is the start of the third trimester of pregnancy.

“The mother’s voice is the predominant source of sensory stimulation in the developing fetus,” said Krueger, an associate professor in the UF College of Nursing. “This research highlights just how sophisticated the third trimester fetus really is and suggests that a mother’s voice is involved in the development of early learning and memory capabilities. This could potentially affect how we approach the care and stimulation of the preterm infant.”

Krueger’s team recruited 32 pregnant women during their 28th week of pregnancy, as determined by fetal ultrasound. The participants were between 18 and 39 years of age, spoke English as a primary language and were pregnant with their first baby. Once recruited, the women were randomly assigned to either an experimental or a control group. The mean age of the women in the group was 25. In addition, 68 percent of the women were white, 28 percent were black and 4 percent were of another race or ethnicity.

From 28 to 34 weeks of pregnancy, all mothers in the study recited a passage or nursery rhyme out loud twice a day and then came in for testing at 28, 32, 33 and 34 weeks’ gestation. To determine whether the fetus could remember the pattern of speech at 34 weeks of age, all mothers were asked to stop speaking the passage. Then the fetuses were tested again at 36 and 38 weeks’ gestational age.

During testing, researchers used a fetal heart monitor, similar to what is used during traditional labor and delivery, to record heart rate and determine any changes. Researchers interpret a small heart rate deceleration in the fetus as an indicator of learning or familiarity with a stimulus.

At testing, the fetuses in the experimental group were played a recording of the same rhyme their mother had been reciting at home but spoken by a female stranger. Those in the control group heard a different rhyme also spoken by a stranger. This was to help determine if the fetus was responding simply to its mother’s voice or to a familiar pattern of speech, which is a more difficult task, Krueger said.

The researchers found that the fetus’ heart rate began to respond to the familiar rhyme recited by a stranger’s voice by 34 weeks of gestational age — once the mother had spoken the rhyme out loud at home for six weeks. They continued to respond with a small cardiac deceleration for as long as four weeks after the mother had stopped saying the rhyme until about 38 weeks. At 38 weeks, there was a statistically significant difference between the two groups in responding to the strangers’ recited rhymes — the experimental group who heard the original rhyme responded with a deeper and more sustained cardiac deceleration, whereas the control group who heard a new rhyme responded with a cardiac acceleration.

Further research is needed to more fully understand how ongoing development affects learning and memory, Krueger said. Her aim is to recognize how this type of research can influence care in preterm infants and their long-term outcomes.

“This study helped us understand more about how early a fetus could learn a passage of speech and whether the passage could be remembered weeks later even without daily exposure to it,” Krueger said. “This could have implications to those preterm infants who are born before 37 weeks of age and the impact an intervention such as their mother’s voice may have on influencing better outcomes in this high-risk population.”

Contrary to previous assumptions, researchers find that preschoolers are able to gauge the strength of their memories and make decisions based on their self-assessments. The study findings are published in Psychological Science, a journal of the Association for Psychological Science.

“Previously, developmental researchers assumed that preschoolers did not introspect much on their mental states, and were not able to reflect on their own uncertainty when problem solving,” says psychological scientist Emily Hembacher of the University of California, Davis, lead author of the study. “This is partly because young children are not usually able to tell us much about their own mental processes due to verbal limitations.”

In several previous studies in their lab, Hembacher and co-author Simona Ghetti observed that preschoolers reported feeling uncertain after giving wrong answers during tasks, suggesting the preschoolers were capable of metacognition — the ability to evaluate one’s own thoughts and mental states.

The researchers decided to examine preschoolers’ metacognition about their memories, given its importance for learning.  They investigated whether kids could assess their confidence in their memories and use those assessments in deciding whether to exclude answers they had generated but were unsure of when given the option.

Eighty-one children ages 3, 4, and 5 participated in the study.  The preschoolers viewed a series of drawings of various items, such as a piano or a balloon.  Half of the images were presented once, and the other half were shown twice.  Next, the children were presented with a pair of images: one they had seen, and a new one they had not seen.  The children were instructed to pick which image they’d seen before in the previous task.

After making their choice, the preschoolers rated how confident they were that their choice was correct.  They then sorted their answers into two boxes.  One box was for the responses that children were confident about and wanted researchers to evaluate for a prize.  The other one was for responses the children thought might be mistaken and that they didn’t want researchers to see.

The data revealed that only 4- and 5-year-olds reported being less confident in their incorrect than their correct memory responses.  They were also more confident about images they’d seen twice, suggesting that they could distinguish between stronger and weaker memories. Older preschoolers were also more likely to decide whether they wanted researchers to see their answers based on their confidence level.

Although 3-year-olds didn’t display the same kind of metacognitive capability on individual responses, the data showed that 3-year-olds who had scored well reported higher confidence overall than kids who hadn’t scored as well.

When the researchers analyzed just the correct answers, they found that preschoolers of all ages sorted responses they weren’t as confident about to the box they didn’t want researchers to evaluate.  So, while they may not be as advanced as their older peers, even children as young as 3 seem to display some ability to reflect on their own knowledge.

The findings contribute to research on the reliability of children’s eyewitness testimony in a court of law, and they carry important implications for educational practices.

“Previous emphasis on the development of metacognition during middle childhood has influenced education practices aimed at strengthening children’s monitoring and control of their own learning,” says Hembacher. “Now we know that some of these ideas may be adapted to meet preschoolers’ learning needs.”

A type of immune cell widely believed to exacerbate chronic adult brain diseases, such as Alzheimer’s disease and multiple sclerosis (MS), can actually protect the brain from traumatic brain injury (TBI) and may slow the progression of neurodegenerative diseases, according to Cleveland Clinic research published today in the online journal Nature Communications.

The research team, led by Bruce Trapp, PhD, Chair of the Department of Neurosciences at Cleveland Clinic’s Lerner Research Institute, found that microglia can help synchronize brain firing, which protects the brain from TBI and may help alleviate chronic neurological diseases. They provided the most detailed study and visual evidence of the mechanisms involved in that protection.

"Our findings suggest the innate immune system helps protect the brain after injury or during chronic disease, and this role should be further studied," Dr. Trapp said. "We could potentially harness the protective role of microglia to improve prognosis for patients with TBI and delay the progression of Alzheimer’s disease, MS, and stroke. The methods we developed will help us further understand mechanisms of neuroprotection."

Microglias are primary responders to the brain after injury or during illness. While researchers have long believed that activated microglia cause harmful inflammation that destroys healthy brain cells, some speculate a more protective role. Dr. Trapp’s team used an advanced technique called 3D electron microscopy to visualize the activation of microglia and subsequent events in animal models.

They found that when chemically activated, microglia migrate to inhibitory synapses, connections between brain cells that slow the firing of impulses. They dislodge the synapse (called “synaptic stripping”), thereby increasing neuronal firing and leading to a cascade of events that enhance survival of brain cells.

Trapp is internationally known for his work on mechanisms of neurodegeneration and repair in multiple sclerosis. His past research has included investigation of the cause of neurological disability in MS patients, cellular mechanisms of brain repair in neurodegenerative diseases, and the molecular biology of myelination in the central and peripheral nervous systems.

With enough practice, some learners of a second language can process their new language as well as native speakers, research at the University of Kansas shows.

(Credit: bigstockphoto)

Using brain imaging, a trio of KU researchers was able to examine to the millisecond how the brain processes a second language. They then compared their findings with their previous results for native speakers and saw both followed similar patterns.

The research by Robert Fiorentino and Alison Gabriele, both associate professors in the linguistics department, and José Alemán Bañón, a former KU graduate student who is now a postdoctoral researcher at the University of Reading in the United Kingdom, was published this month in the journal Second Language Research.

For years, linguists have debated whether second-language learners would ever resemble native speakers in their ability to process language properties that differ between the first and second language, such as gender agreement, which is a property of Spanish but not English. In Spanish, all nouns are categorized as masculine or feminine, and various elements in the sentence, such as adjectives, need to carry the gender feature of the noun as well.

Some researchers argued that even those who spoke a second language with a high level of accuracy were using a qualitatively different mechanism than native speakers.

“We realized that these different theories proposing that either second-language learners use the same mechanism, or a different mechanism could actually be teased apart by using brain-imaging techniques,” Gabriele said.

The team studied 26 high-level Spanish speakers who hadn’t learned to speak Spanish until after age 11 and grew up with English as the majority language. The speakers used Spanish on a daily basis and had spent an average of a year and a half in a Spanish-speaking country.

They were compared with 24 native speakers, who were raised in Spanish-speaking countries and stayed in their home country until age 17.

To measure language processing as it happens, the team used a method known as electroencephalography (EEG), which uses an array of electrodes placed on the scalp to detect patterns of brain activity with high accuracy in timing.

Once hooked up to the EEG, the test subjects were asked to read sentences, some of which had grammatical errors in either number agreement or gender agreement.

The researchers then compared the results of the second-language learners to native speakers. They found that the highly proficient second-language speakers showed the same patterns of brain activity as native speakers when processing grammatical violations in sentences.

“We show that the learners’ brain activity looks qualitatively similar to that of native speakers, suggesting that they are using the same mechanisms,” Fiorentino said.

The study highlights the brain’s plasticity and its ability to acquire a new complex system even in adulthood.

“A lot of researchers have argued that there is some sort of language learning mechanism that might atrophy over the life span, particularly before puberty. And, we certainly have a lot of evidence that it is difficult to process your second language at nativelike levels and you have to go through quite a bit of effort to find people who can,” Gabriele said. “But I think what this paper shows is that it is possible.”

Gabriele and Fiorentino are working on a second phase of the research, studying how the brain processes a second language at the initial stages of exposure. Their preliminary results suggest that properties that are shared between the first and second language show patterns of brain activity that are very similar in learners and native speakers. This suggests that learners build on the representation for language that is already in place when learning a second language.

Scientists from the Sloan-Kettering Institute for Cancer Research in New York with the help of  Plymouth University Peninsula Schools of Medicine and Dentistry have completed research which for the first time brings us nearer to understanding how some cells in the brain and nervous system become cancerous.

The results of their study are published in the prestigious journal Cancer Cell.

The research team led by Sloan-Kettering researchers studied a tumour suppressor called Merlin. 

The results of the study have identified a new  mechanism whereby Merlin suppresses tumours, and that the mechanism operates within the nucleus. The research team has discovered that unsuppressed tumour cells increase via a core signalling system, the hippo pathway, and they have identified the route and method by which this signalling occurs.

By identifying the signalling system and understanding how, when present, Merlin suppresses it, the way is open for research into drug therapies which may suppress the signalling in a similar way to Merlin. 

Tumour suppressors exist in cells to prevent abnormal cell division in our bodies. The loss of Merlin leads to tumours in many cell types within our nervous systems. There are two copies of a tumour suppressor, one on each chromosome that we inherit from our parents. The loss of Merlin can be caused by random loss of both copies in a single cell, causing sporadic tumours, or by inheriting one abnormal copy and losing the second copy throughout our lifetime as is seen in the inherited condition of neurofibromatosis type 2 (NF2). 

No effective therapy for these tumours exists, other than repeated invasive surgery aiming at a single tumour at a time and which is unlikely to eradicate the full extent of the tumours, or radiotherapy.

Professor Oliver Hanemann, Director of the Institute of Translational and Stratified Medicine at Plymouth University Peninsula Schools of Medicine and Dentistry, and who led the Plymouth aspect of the study, commented:

“We have known for some time that the loss of the tumour suppressor Merlin resulted in the development of nervous system tumours, and we have come tantalisingly close to understanding how this occurs. Our joint study with colleagues at the Sloan-Kettering Institute for Cancer Research shows for the first time how this mechanism works. By understanding the mechanism, we can use this knowledge to develop effective drug therapies – in some cases adapting existing drugs – to treat patients for whom current therapies are limited and potentially devastating.”

A recent scientific discovery showed that mutations in prickle genes cause epilepsy, which in humans is a brain disorder characterized by repeated seizures over time. However, the mechanism responsible for generating prickle-associated seizures was unknown.

A new University of Iowa study, published online July 14 in the Proceedings of the National Academy of Sciences, reveals a novel pathway in the pathophysiology of epilepsy. UI researchers have identified the basic cellular mechanism that goes awry in prickle mutant flies, leading to the epilepsy-like seizures.

“This is to our knowledge the first direct genetic evidence demonstrating that mutations in the fly version of a known human epilepsy gene produce seizures through altered vesicle transport,” says John Manak, senior author and associate professor of biology in the College of Liberal Arts and Sciences and pediatrics in the Carver College of Medicine.

Seizure suppression in flies

A neuron has an axon (nerve fiber) that projects from the cell body to different neurons, muscles, and glands. Information is transmitted along the axon to help a neuron function properly.

Manak and his fellow researchers show that seizure-prone prickle mutant flies have behavioral defects (such as uncoordinated gait) and electrophysiological defects (problems in the electrical properties of biological cells) similar to other fly mutants used to study seizures. The researchers also show that altering the balance of two forms of the prickle gene disrupts neural information flow and causes epilepsy.

Further, they demonstrate that reducing either of two motor proteins responsible for directional movement of vesicles (small organelles within a cell that contain biologically important molecules) along tracks of structural proteins in axons can suppress the seizures.

“The reduction of either of two motor proteins, called Kinesins, fully suppressed the seizures in the prickle mutant flies,” says Manak, faculty member in the Interdisciplinary Graduate Programs in Genetics, Molecular and Cellular Biology, and Health Informatics. “We were able to use two independent assays to show that we could suppress the seizures, effectively ‘curing’ the flies of their epileptic behaviors.”

Genetic link between epilepsy and Alzheimer’s

This new epilepsy pathway was previously shown to be involved in neurodegenerative diseases, including Alzheimer’s and Parkinson’s.

Manak and his colleagues note that two Alzheimer’s-associated proteins, amyloid precursor protein and presenilin, are components of the same vesicle, and mutations in the genes encoding these proteins in flies affect vesicle transport in ways that are strikingly similar to how transport is impacted in prickle mutants.

“We are particularly excited because we may have stumbled upon one of the key genetic links between epilepsy and Alzheimer’s, since both disorders are converging on the same pathway,” Manak says. “This is not such a crazy idea. In fact, Dr. Jeff Noebels, a leading epilepsy researcher, has presented compelling evidence suggesting a link between these disorders. Indeed, patients with inherited forms of Alzheimer’s disease also present with epilepsy, and this has been documented in a number of published studies.”

Manak adds, “If this connection is real, then drugs that have been developed to treat neurodegenerative disorders could potentially be screened for anti-seizure properties, and vice versa.”

Manak’s future research will involve treating seizure-prone flies with such drugs to see if he can suppress their seizures.

Dysfunction in dopamine signaling profoundly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders, such as schizophrenia, according to UC Irvine scientists.

This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioral and physiological functions regulated in the prefrontal cortex.

The study, led by Emiliana Borrelli, a UCI professor of microbiology & molecular genetics, appears online in the journal Molecular Psychiatry.

“Our work presents new leads to understanding neuropsychiatric disorders,” Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”

Dopamine is a neurotransmitter that acts within certain brain circuitries to help manage functions ranging from movement to emotion. Changes in the dopaminergic system are correlated with cognitive, motor, hormonal and emotional impairment. Excesses in dopamine signaling, for example, have been identified as a trigger for neuropsychiatric disorder symptoms.

Borrelli and her team wanted to understand what would happen if dopamine signaling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release.

The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of basic DNA proteins called histones – particularly those associated with reduced gene activity.

Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviors in the mutant mice and that prolonged treatment with a dopamine activator restored regular signaling, pointing to one possible therapeutic approach.

The researchers are continuing their work to gain more insights into the genes altered by this dysfunctional dopamine signaling.

A study of 473 sets of twins followed since birth found that compared with single-born children, 47 percent of 24-month-old identical twins had language delay compared with 31 percent of nonidentical twins. Overall, twins had twice the rate of late language emergence of single-born children. None of the children had disabilities affecting language acquisition.

The results of the study were published in the June 2014 Journal of Speech, Language, and Hearing Research.

University of Kansas Distinguished Professor Mabel Rice, lead author, said that all of the language traits analyzed in the study—vocabulary, combining words and grammar—were significantly heritable with genes accounting for about 43 percent of the overall twins’ deficit.

The “twinning effect” — a lower level of language performance for twins than single-born children — was expected to be comparable for both kinds of twins, but was greater for identical twins, said Rice, strengthening the case for the heritability of language development.

“This finding disputes hypotheses that attribute delays in early language acquisition of twins to mothers whose attention is reduced due to the demands of caring for two toddlers,” Rice said. “This should reassure busy parents who worry about giving sufficient individual attention to each child.”

However, said Rice, prematurity and birth complications, more common in identical twins, could also affect their higher rates of language delay. A study of pregnancy and birth risks for late talking in twins is currently under way by the study authors.

Further, the study will continue at least until 2017 to continue to follow the twins through preschool and school years up to adolescence to answer the question of whether late-talking twins do catch up to their peers.

“Twin studies provide unique opportunities to study inherited and environmental contributions to language acquisition,” Rice said. “The outcomes inform our understanding of how these influences contribute to language acquisition in single-born children as well.”

Late language emergence means that a child’s language is below age and gender expectations in the number of words they speak and combining two or more words into sentences. In this study, 71 percent of 2-year-old twins were not combining words compared with 17 percent of single-born children.

While previous behavioral genetics studies of toddlers have largely focused on vocabulary, the researchers introduced an innovative measure of early grammatical ability on the correct use of the past tense and the “to be” and “to do” verbs. The measure was inspired by the Rice/Wexler Test of Early Grammar Impairment, developed in 2001 by Rice and Kenneth Wexler, Massachusetts Institute of Technology professor. It was the first test to detect the subtle but common language disorder, specific language impairment.

Rice’s collaborators in the international longitudinal project that began in 2002 are Professors Cate Taylor and Stephen Zubrick from the Telethon Kids Institute in Perth, Western Australia, and Professor Shelley Smith at the University of Nebraska Medical Center.

The study population is located in the vicinity of Perth, Western Australia, because it is demographically identical to Kansas City and several other U.S. Midwestern states. But in Australian health records are available, and the Western Australia Twin Registry is a unique resource for researchers since it is a record of all multiple births, Rice said.

The research group has followed the development of 1,000 sets of Western Australian twins from their first words. In 2012, the group was granted $2.8 million by the National Institute for Deafness and Other Communication Disorders for a fourth five-year-cycle that will enable researchers to continue to monitor the twins as they develop through adolescence. In addition to formal language tests, researchers have collected genetic and environmental data as well as assessments with the twins’ siblings.

Investigators at The Feinstein Institute for Medical Research have utilized a new image-based strategy to identify and measure placebo effects in randomized clinical trials for brain disorders. The findings are published in the August issue of The Journal of Clinical Investigation.

Parkinson’s disease is the second most common neurodegenerative disease in the US. Those who suffer from Parkinson’s disease most often experience tremors, slowness of movement (bradykinesia), rigidity, and impaired balance and coordination. Patients may have difficulty walking, talking or completing simple daily tasks. They may also experience depression and difficulty sleeping due to the disease. The current standard for diagnosis of Parkinson’s disease relies on a skilled healthcare professional, usually an experienced neurologist, to determine through clinical examination that someone has it. There currently is no cure for Parkinson’s disease, but medications can improve symptoms.

A team of researchers at the Feinstein Institute’s Center for Neurosciences, led by David Eidelberg, MD, has developed a method to identify brain patterns that are abnormal or indicate disease using imaging techniques. To date, this approach has been used successfully to identify specific networks in the brain that indicate a patient has or is at risk for Parkinson’s disease and other neurodegenerative disorders.

"One of the major challenges in developing new treatments for neurodegenerative disorders such as Parkinson’s disease is that it is common for patients participating in clinical trials to experience a placebo or sham effect," noted Dr. Eidelberg. "When patients involved in a clinical trial commonly experience benefits from placebo, it’s difficult for researchers to identify if the treatment being studied is effective. In a new study conducted by my colleagues and myself, we have used a new image-based strategy to identify and measure placebo effects in brain disorder clinical trials."

In the current study, the researchers used their network mapping technique to identify specific brain circuits underlying the response to sham surgery in Parkinson’s disease patients participating in a gene therapy trial. The expression of this network measured under blinded conditions correlated with the sham subjects’ clinical outcome; the network changes were reversed when the subjects learned of their sham treatment status. Finally, an individual subject’s network expression value measured before the treatment predicted his/her subsequent blinded response to sham treatment. This suggests that this novel image-based measure of the sham-related network can help to reduce the number of subjects assigned to sham treatment in randomized clinical trials for brain disorders by excluding those subjects who are more likely to display placebo effects under blinded conditions.

Obesity is the main culprit in the worldwide avalanche of type 2 diabetes. But how excess weight drives insulin resistance, the condition that may lead to the disease, is only partly understood. Scientists at Joslin Diabetes Center now have uncovered a new way in which obesity wreaks its havoc, by altering the production of proteins that affect how other proteins are spliced together. Their finding, published in Cell Metabolism, may point toward novel targets for diabetes drugs.

Scientists in the lab of Mary-Elizabeth Patti, M.D., began by examining the levels of proteins in the livers of obese people, and finding decreases in number for certain proteins that regulate RNA splicing.

“When a gene is transcribed by the cell, it generates a piece of RNA,” explains Dr. Patti, who is also an Assistant Professor of Medicine at Harvard Medical School. “That piece of RNA can be split up in different ways, generating proteins that have different functions.”

“In the case of these proteins whose production drops in the livers of obese people, this process changes the function of other proteins that can cause excess fat to be made in the liver,” she adds. “That excess fat is known to be a major contributor to insulin resistance.”

Additionally, the researchers showed that these RNA splicing proteins are diminished in samples of muscle from obese people.

The investigators went on to examine a representative RNA-splicing protein called SFRS10 whose levels drop in muscle and liver both in obese people and in over-fed mice. Working in human cells and in mice, they demonstrated that SFRS10 helps to regulate a protein called LPIN1 that plays an important role in synthesizing fat. Among their results, mice in which they suppressed production of SFRS10 made more triglycerides, a type of fat circulating in the blood.

“More broadly, this work adds a novel insight into how obesity may induce insulin resistance and diabetes risk by changing critical functions of cells, including splicing,” says Dr. Patti. “This information should stimulate the search for other genes for which differences in splicing may contribute to risk for type 2 diabetes. Ultimately, we hope that modifying these pathways with nutritional or drug therapies could limit the adverse consequences of obesity.”

With its first comprehensive set of results published today, the Great Brain Experiment, a free mobile app run by neuroscientists at the Wellcome Trust Centre for Neuroimaging at UCL, uses ‘gamified’ neuroscience experiments to address scientific questions on a scale that would not be possible using traditional approaches. The app investigates memory, impulsivity, risk-taking and happiness. By playing the games, anyone can anonymously compare their abilities to the wider population and contribute to real scientific research. More than 60,000 people have taken part so far.

The results, published in the journal PLOS ONE, demonstrate that mobile games can be used to reliably conduct research in psychology and neuroscience, reproducing well-known findings from laboratory studies. The small size of standard laboratory studies means they can be limited in their ability to investigate variability in the population at large. With data sent in from many thousands of participants, the scientists at UCL can now investigate how factors such as age and education affect cognitive functions. This new way of doing science enables questions to be addressed which would not previously have been practical.

Writing in the journal PLOS ONE, the researchers explained: “Smartphone users represent a participant pool far larger and more diverse than could ever be studied in the laboratory. By 2015, there will be an estimated two billion smartphone users worldwide. In time, data from simple apps could be combined with medical, genetic or lifestyle information to provide a novel tool for risk prediction and health monitoring.”

The Great Brain Experiment was funded by the Wellcome Trust and first released as part of last year’s Brain Awareness Week. Building on its initial success, the researchers have recently added four new games, including a “coconut shy” which tests people’s ability to perform under pressure. From this, the scientists hope to better understand how people make accurate movements in difficult situations. Going forward, they are calling on the public to download the app and throw coconuts to help science.

Rick Adams, a developer of The Great Brain Experiment based at the Wellcome Trust Centre for Neuroimaging at UCL, said: “The initial aim was simply to make the public more aware of cognitive neuroscience experiments, and how they are conducted. However, with such large numbers of people downloading the app and submitting their results, it rapidly became clear that there was the potential for studying task performance at an unprecedented scale.”

Harriet Brown, a researcher at the Wellcome Trust Centre for Neuroimaging at UCL, said: “It is hoped that carefully measuring performance on a range of tasks may give rise to a better understanding of common mechanisms that underlie performance on these different tasks. Through better understanding of these common mechanisms, we may be able to characterise how they are altered in neurological and psychiatric disease.”

Research from the University of Copenhagen is shedding new light on the brain’s complicated barrier tissue. The blood-brain barrier is an effective barrier which protects the brain, but which at the same time makes it difficult to treat diseases such as Alzheimer’s. In an in vitro blood-brain barrier, researchers can recreate the brain’s transport processes for the benefit of the development of new pharmaceuticals for the brain. The new research findings are published in the AAPS Journal.

Ninety-five per cent of all tested pharmacological agents for treating brain disorders fail, because they cannot cross the blood-brain barrier. It is therefore important to find a possible method for transporting drugs past the brain’s efficient outpost and fervent protector.

Researchers at the Department of Pharmacy at the University of Copenhagen have recreated the complex blood-brain barrier in a laboratory model, which is based on cells from animals. In a new study, the researchers have studied the obstreperous bouncer proteins in the barrier tissue. The proteins protect the brain, but also prevent the treatment of brain diseases:

"The blood-brain barrier is chemically tight because the cells contain transporter proteins which make sure that substances entering the cells are thrown straight back out into the bloodstream again. We have shown that the barrier which we have created in the laboratory contains the same bouncer proteins – and that they behave in the same way as in a ‘real’ brain. This is important, because the model can be used to test drive the difficult way into the brain. Complex phenomena – which we have so far only been able to study in live animals –can now be investigated in simple laboratory experiments using cultivated cells," says postdoc Hans Christian Cederberg Helms from the Department of Pharmacy.

The research team has shown that the transporter proteins P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein 1 are active in the artificially created barrier tissue. The proteins pump pharmacological agents from the ‘brain side’ to the ‘blood side’ in the same way as in the human blood-brain barrier.

Collaboration finds a way

The new findings have resulted from collaboration with industrial scientists from the pharmaceutical company H. Lundbeck A/S. “It is important to the treatment of brain diseases such as Alzheimer’s that we find a way of circumventing the brain’s effective defence. The university and industry must work together to overcome the fundamental challenges inherent in developing pharmaceuticals for the future,” says Lassina Badolo, Principal Scientist with H. Lundbeck A/S and an expert on the absorption of medicines in the body.

Associate Professor Birger Brodin adds: “We have shown that the models have the same bouncer proteins as the ones found in the intact barrier. We are now in the process of studying the proteins in the blood-brain barrier that accept pharmacological agents instead of throwing them out. If we can combine a beneficial substance which the brain needs with a so-called ‘absorber protein’, we will in the long term be able to smuggle pharmacological agents across the blood-brain barrier.”

Birger Brodin heads the Drug Transporters in ADME research group which is responsible for the in vitro blood-brain barrier.

The area of the brain that plays a primary role in emotional learning and the acquisition of fear – the amygdala – may hold the key to who is most vulnerable to post-traumatic stress disorder.

Researchers at the University of Washington, Boston Children’s Hospital, Harvard Medical School and Boston University collaborated on a unique opportunity to study whether patterns of brain activity predict teenagers’ response to a terrorist attack.

The team had already performed brain scans on Boston-area adolescents for a study on childhood trauma. Then in April 2013 two bombs went off at the finish line of the Boston Marathon, killing three people and injuring hundreds more. Even people who were nowhere near the bombing reported distress about the attack and the days-long manhunt for the suspects.

So, one month after the attack, Katie McLaughlin, then at Boston Children’s Hospital and Harvard Medical School and now an assistant professor of psychology at the UW; co-author Margaret Sheridan, of Boston Children’s Hospital and Harvard Medical School; and their fellow researchers sent online surveys to teenagers who had previously participated in studies to assess PTSD symptoms related to the attack.

By using functional Magnetic Resonance Imaging scans from before the attack and survey data from after, the researchers found that heightened amygdala reaction to negative emotional stimuli was a risk factor for later developing symptoms of PTSD.

The research study was published July 3 in the journal Depression and Anxiety.

“The amygdala responds to both negative and positive stimuli, but it’s particularly attuned to identifying potential threats in the environment,” said McLaughlin, the study’s first author. “In the current study of adolescents the more their amygdala responded to negative images, the more likely they were to have symptoms of PTSD following the terrorist attacks.”

The brain scans were conducted during the year prior to the bombing. At that time, the teens were evaluated for their responses to emotional stimuli by viewing neutral and negative images. Neutral images included items such as a chair or button. Negative images showed people who were sad, fighting or threatening someone else. Participants rated the degree of emotion they felt while looking at each image. The MRIs measured whether blood flow increased to the amygdala and the hippocampus when viewing negative images as compared to neutral images.

In the follow-up survey the teens were asked whether they were at the finish line during the bombing, how much media exposure they had after the attack, whether they were part of the lockdown at home or school while authorities searched for the suspects, and how their parents responded to the incident. They also were asked about specific PTSD symptoms, such as how often they had trouble concentrating and whether they kept thinking about the bombing when they tried not to.

Researchers found a significant association between amygdala activation while viewing negative images and whether the teens developed PTSD symptoms after the bombing.

McLaughlin said a number of previous studies have shown that people with PTSD had heightened amygdala responses to negative emotions, but researchers didn’t know whether that came before or after the trauma.

“It’s often really difficult to collect neurobiological markers before a traumatic event has occurred,” she said. By scanning the adolescents’ brains before the bombing, she and her fellow researchers were able to show that “amygdala reactivity before a traumatic event predicts your response to that traumatic event.”

While two-thirds of Americans will be exposed to some kind of traumatic event during their lifetime, most, fortunately, will not develop PTSD.

“The more we understand the underlying neurobiological systems that shape reactions to traumatic events, the closer we move to understanding a person’s increased vulnerability to them,” McLaughlin said. “That could help us develop early interventions to help people who might develop PTSD later.”

A team of researchers at the Neuroscience Institute at Georgia State University has discovered that hidden differences in the properties of neural circuits can account for whether animals are behaviorally susceptible to brain injury. These results could have implications for the treatment of brain trauma.

People vary in their responses to stroke and trauma, which impedes the ability of physicians to predict patient outcomes. Damage to the brain and nervous system can lead to severe disabilities, including epilepsy and cognitive impairment.

If doctors could predict outcomes with greater accuracy, patients might benefit from more tailored treatments. Unfortunately, the complexity of the human brain hinders efforts to explain why similar brain damage can affect each person differently.

The researchers used a unique research animal, a sea slug called Tritonia diomedea, to study this question. This animal was used because unlike humans, it has a small number of neurons and its behavior is simple. Despite this simplicity, the animals varied in how neurons were connected.

Under normal conditions, this variability did not matter to the animals’ behavior, but when a major pathway in the brain was severed, some of the animals showed little behavioral deficit, while others could not produce the behavior being studied. Remarkably, the researchers could artificially rewire the neural circuit using computer-generated connections and make animals susceptible or invulnerable to the injury.

“This study is important in light of the current Obama BRAIN initiative, which seeks to map all of the connections in the human brain,” said Georgia State professor, Paul Katz, who led the research project. “it shows that even in a simple brain, small differences that have no effect under normal conditions, have major implications when the nervous system is challenged by injury or trauma.”

Results of this study were published in the most recent edition of the journal eLife. The lead author on the study, Dr. Akira Sakurai, made this discovery in the course of doing basic research. He was assisted by Ph.D. student Arianna Tamvacakis from Dr. Katz’s lab.