Neuroscience

Over the past decades, we have seen numerous tragic examples where the failure of institutions to meet the needs of infants for social contact and stimulation has led to the failure of these infants to thrive. 

Infancy and childhood are critical life periods that shape the development of the cortex. A generation of research suggests that enriched environments, full of interesting stimuli to explore, promote cortical development and cognitive function. In contrast, deprivation and stress may compromise cortical development and attenuate some cognitive functions.

Young children who are raised in environments of psychosocial neglect, such as those who grow up in institutions for orphaned or abandoned children, are at markedly elevated risk for developing a wide range of mental health problems, including attention-deficit/hyperactivity disorder (ADHD).

Now, new data from the Bucharest Early Intervention Project (BEIP), published in the current issue of Biological Psychiatry, suggests that this type of deprived early environment is associated with drastic changes in brain development in children. 

BEIP is a longitudinal study that has followed a sample of children raised from early infancy in institutions in Romania. The authors of the current report used data from 58 of those children and compared it with 22 typically-reared children from the same community. All children underwent a structural imaging scan and were assessed for symptoms of ADHD.

The researchers discovered that children raised in institutional settings exhibited widespread reductions in cortical thickness in multiple brain regions including the prefrontal, parietal, and temporal cortices relative to children raised in families in the community. 

The data also revealed that the reduced cortical thickness in several of those same brain regions was associated with greater ADHD symptoms of inattention and impulsivity.

This is consistent with previous research that has implicated those brain regions in regulating attention, memory, and other vital cognitive processes.

"Perhaps most importantly, the new findings indicate that the high rates of ADHD among children raised in these deprived environments are explained, in part, by these atypical patterns of brain development," explained first author Dr. Katie McLaughlin, Assistant Professor at the University of Washington.

"These disturbing data provide a mechanism that links institutional rearing to compromised cortical development," said Dr. John Krystal, Editor of Biological Psychiatry. “They suggest that society may have to choose between investing in enriching institutional environments and enhancing the capacity of these institutions to offer mental health support on the one hand and bearing the cost of ADHD and its impact on social and vocational productivity on the other.”

McLaughlin agrees and added, “The early caregiving environment has lasting effects on brain development in children. Identifying strategies for mitigating these effects is critical for improving mental health and educational outcomes among children raised in deprived environments.”

University of Queensland researchers have gained new insights into how the body sorts and transports protein ‘cargo’ within our cells, in a finding that could eventually lead to treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

An international research team co-led by Dr Brett Collins from UQ’s Institute for Molecular Bioscience has revealed the structure of a molecular transport hub that sorts, directs and transports protein to correct destinations in the cell.

Dr Collins said protein cargoes that failed to reach the correct destinations in cells created ‘traffic jams’ that could affect neuronal activity and brain function.

“Having an understanding of how these proteins work together to sort and transport cargo could be the first step in developing drugs that reverse the effects of toxic protein accumulation in neurodegenerative disease,” he said.

Dr Collins has been studying how cargo is sorted, packaged, and trafficked within human cells for more than a decade.

He said that developing drugs that fix faulty proteins such as the transport hub was a relatively new and exciting approach to treatment.

“Traditionally, drugs are developed to try to block or inhibit the function of proteins in the body,” Dr Collins said.

“The problem with drugs that completely stop the function of a protein is that you often get harmful side-effects.”

Dr Collins said the promising finding provided new avenues to target multiple parts of the transport hub to enhance its function by stabilising the protein.

“If we can enhance or improve the function of this protein we could potentially slow down the brain degeneration that occurs in diseases such as Alzheimer’s and Parkinson’s,” he said.

When young mice with the rodent equivalent of a rare autism spectrum disorder (ASD), called Rett syndrome, were fed a diet supplemented with the synthetic oil triheptanoin, they lived longer than mice on regular diets. Importantly, their physical and behavioral symptoms were also less severe after being on the diet, according to results of new research from The Johns Hopkins University.

(Image caption: Mitochondria (arrows) in muscle cells from mice with Rett syndrome improved in appearance after the mice were given triheptanoin oil. Top: Muscle from mice given regular food. Bottom: Muscle from mice given food supplemented with triheptanoin. Left: Healthy mice. Right: Mice with a genetic mutation that mimics Rett syndrome.)

Researchers involved in the study think that triheptanoin improved the functioning of mitochondria, energy factories common to all cells. Since mitochondrial defects are seen in other ASDs, the researchers say, the experimental results offer hope that the oil could help not just people with Rett syndrome, but also patients with other, more common ASDs.

A description of the research was published on Oct. 9 in the journal PLOS ONE.

ASDs affect an estimated one in 68 children under 8 years of age in the United States. Rett syndrome is a rare ASD caused by mutations in the MECP2 gene, which codes for methyl-CpG-binding-protein 2 (MeCP2). Rett syndrome includes autismlike signs, such as difficulty communicating, socializing and relating to others. Other hallmarks are seizures, decreased muscle tone, repetitive involuntary movements, and gastrointestinal and breathing problems. These other signs are also seen in some patients with other ASDs, suggesting underlying similarities in their causes. While the causes of most ASDs are unknown and thought to be complex, Rett syndrome is unique — and could be a source of insight for the others — because it is caused by an error in a single gene.

The research team used mice lacking the MeCP2 protein, which left them with severe Rett syndrome. In examining those mice, what stood out, according to Gabriele Ronnett, M.D., Ph.D., who led the research project at the Johns Hopkins University School of Medicine, was that they weighed the same as healthy mice but had large fat deposits accompanied by lower amounts of nonfat tissue, such as muscle. This suggested that calories were not being used to support normal tissue function but instead were being stored as fat.

This possibility led Ronnett and her research team to consider the role of mitochondria, which transform the building blocks of nutrients into a high-energy molecule, ATP. This molecule drives processes such as the building of muscle and the growth of nerve cells. Mitochondria use a series of biochemical reactions, collectively called the TCA cycle, to make this transformation possible. According to Susan Aja, Ph.D., a research associate and lead member of the research team, “If the components of the TCA cycle are low, nutrient building blocks are not processed well to create ATP. They are instead stored as fat.”

Ronnett suspected, she says, that some of Rett syndrome’s neurological symptoms could stem from metabolic deficiencies caused by faulty mitochondria and reduced energy for brain cells. “Rett syndrome becomes apparent in humans 6 to 18 months old, when the energy needs of the brain are particularly high, because a lot of new neural connections are being made,” says Ronnett. “If the mitochondria are already defective, stressed or damaged, the increased demand would be too much for them.”

Previous small clinical trials in people with a different metabolic disorder suggested that dietary intervention with triheptanoin could help. Triheptanoin is odorless, tasteless and a little thinner than olive oil. It is easily processed to produce one of the components of the TCA cycle.

When Rett syndrome mice were weaned at 4 weeks of age, they were fed a diet in which 30 percent of their calories came from triheptanoin, mixed in with their normal pelleted food. Though far from a cure, the results of the triheptanoin treatment were impressive, the researchers say. Treated mice had healthier mitochondria, improved motor function, increased social interest in other mice and lived four weeks — or 30 percent — longer than mice who did not receive the oil. The team also found that the diet normalized their body fat, glucose and fat metabolism.

“You can think of the mitochondria of the Rett syndrome model mice as damaged buckets with holes in them that allow TCA cycle components to leak out,” says Aja. “We haven’t figured out how to plug the holes, but we can keep the buckets full by providing triheptanoin to replenish the TCA cycle.”

“It is still too early to assume that this oil will work in humans with ASDs, but these results give us hope,” says Ronnett. “It’s exciting to think that we might be able to improve many ASDs without having to identify each and every contributing gene.”

According to Aja, additional mouse studies are needed to learn if female mice respond to the treatment, to perform a wider range of physiology and behavior tests, and, importantly, to assess the effects of triheptanoin treatment on the brain, which is considered the main driver of many Rett symptoms. The team would also like to provide triheptanoin at earlier ages, perhaps via the mothers’ milk, to mimic developmental ages at which most children are diagnosed with Rett syndrome.

Triheptanoin is currently made for research purposes only and is not available as a medicine or dietary supplement for humans.

Scientists at The University of Manchester have used a new way of working to identify a new gene linked to neurodegenerative diseases such as Alzheimer’s. The discovery fills in another piece of the jigsaw when it comes to identifying people most at risk of developing the condition.

Researcher David Ashbrook and colleagues from the UK and USA used two of the world’s largest collections of scientific data to compare the genes in mice and humans. Using brain scans from the ENIGMA Consortium and genetic information from The Mouse Brain Library, he was able to identify a novel gene, MGST3 that regulates the size of the hippocampus in both mouse and human, which is linked to a group of neurodegenerative diseases. The study has just been published in the journal BMC Genomics.

David, who works in Dr Reinmar Hager’s lab at the Faculty of Life Sciences, says: “There is already the ‘reserve hypothesis’ that a person with a bigger hippocampus will have more of it to lose before the symptoms of Alzheimer’s are spotted. By using ENIGMA to look at hippocampus size in humans and the corresponding genes and then matching those with genes in mice from the BXD system held in the Mouse Brain Library database we could identify this specific gene that influences neurological diseases.”

He continues: “Ultimately this could provide another biomarker in the toolkit for identifying those at greatest risk of developing diseases such as Alzheimer’s.”

Dr Hager, senior author of the study, says: “What is critical about this research is that we have not only been able to identify this specific gene but also the networks it uses to influence a disease like Alzheimer’s. We believe this information will be incredibly useful for future studies looking at treatments and preventative measures.”

The ENIGMA Consortium is led by Professor Paul Thompson based at the University of California, Los Angeles, and contains brain images and gene information from nearly 25,000 subjects. The Mouse Brain Library, established by Professor Robert Williams based at the University of Tennessee Health Science Center, contains data on over 10,000 brains and numerical data from just over 20,000 mice. 

David explains why combining the information held by both databases is so useful: “The key advantage of working this way is that it is much easier to identify a genetic variant in mice as they live in such controlled environments. By taking the information from mice and comparing it to human gene information we can identify the same variant much more quickly.”

And David thinks this way of working will be used more often in the future: “We are living in a big data world thanks to the likes of the Human Genome Project and post-genome technologies. A lot of that information is now widely shared so by mining what we already know we can learn so much more, advancing our knowledge of diseases and ultimately improving detection and treatment.”

It’s one of those ideas that seems to make perfect sense: the bigger the brain, the more intelligent the creature. While it is generally true, exceptions are becoming increasingly common. Yet the belief persists even among scientists. Most biologists, for example, assume that rats, with larger brains, are smarter than mice. Cold Spring Harbor Laboratory (CSHL) scientists now challenge this belief. They compared mice and rats and found very similar levels of intelligence, a result that could have powerful implications for researchers studying complex behaviors and learning.

Are rats really smarter than mice? The question is more important than it sounds. For more than a decade, rats have been the rodent of choice for scientists studying how the brain arrives at decisions. They are relatively inexpensive to keep and are the subject of extensive protocols for studying cognitive function. Yet the last few years have seen an explosion in the number of genetic tools available to study their smaller cousins, mice. These tools enable scientists to turn genes on and off within specific populations of neurons – specificity that is critical to understanding how complex behaviors arise. Many investigators have shied away from using these new tools, however, believing that mice simply are not as intelligent as rats.

CSHL Professor Anthony Zador and Santiago Jaramillo, Ph.D., were skeptical. “Mice have the potential to greatly accelerate our research. We didn’t want to discount a very powerful option based on anecdotal evidence of their inferiority,” explains Zador.

The team systematically compared how rats and mice learn to perform a moderately challenging auditory task and found that their performance was similar. “This was a task that tested perceptual ability as well as adaptability, and we were very surprised to see that mice and rats performed about the same,” says Jaramillo, a former postdoctoral researcher in the Zador lab who now heads his own lab at the University of Oregon.

The researchers were able to find only one difference: rats learned somewhat faster than mice. According to Zador and Jaramillo, the training protocol, which was developed and optimized specifically for rats, might account for the slight advantage.

The finding of roughly equal intelligence has broad implications for cognition research. “We’ve found that mice, and all the genetic tools available in them, can be used to study the neural mechanisms underlying decision-making, and they might be suitable for other cognitive tasks as well,” says Zador.

A new study from UCLA found that a drug being evaluated to treat an entirely different disorder helped slow the progression of Parkinson’s disease in mice.

The study, published in the October edition of the journal Neurotherapeutics, found that the drug, AT2101, which has also been studied for Gaucher disease, improved motor function, stopped inflammation in the brain and reduced levels of alpha-synuclein, a protein critically involved in Parkinson’s.

Although the exact cause of Parkinson’s is unknown, evidence points to an accumulation of alpha-synuclein, which has been found to be common to all people with the disorder. The protein is thought to destroy the neurons in the brain that make dopamine, a neurotransmitter that helps regulate a number of functions, including movement and coordination. Dopamine deficiency is associated with Parkinson’s disease.

Gaucher disease is a rare genetic disorder in which the body cannot produce enough of an enzyme called β-glucocerebrosidase, or GCase. Researchers seeking genetic factors that increase people’s risk for developing Parkinson’s have determined that there may be a close relationship between Gaucher and Parkinson’s due to a GCase gene. Mutation of this gene, which leads to decreased GCase activity in the brain, has been found to be a genetic risk factor for Parkinson’s, although the majority of patients with Parkinson’s do not carry mutations in the Gaucher gene.

“This is the first time a compound targeting Gaucher disease has been tested in a mouse model of Parkinson’s disease and was shown to be effective,” said the study’s senior author, Marie-Francoise Chesselet, the Charles H. Markham Professor of Neurology at UCLA and director of the UCLA Center for the Study of Parkinson’s Disease. “The promising findings in this study suggest that further investigation of this compound in Parkinson’s disease is warranted.”

In the study, the researchers used mice that were genetically engineered to make too much alpha-synuclein which, over time, led the animals to develop deficits similar to those observed in humans with Parkinson’s. The researchers found that the mice’s symptoms improved after they received AT2101 for four months.

The researchers also observed that AT2101 was effective in treating Parkinson’s in mice even though they did not carry a mutant version of the Gaucher gene, suggesting that the compound may have a clinical effect in the broader Parkinson’s population.

AT2101 is a first-generation “pharmacological chaperone” — a drug that can bind malfunctioning, mutated enzymes and lead them through the cell to their normal location, which allows the enzymes to carry on with their normal work. This was the first time that a pharmacological chaperone showed promise in a model of Parkinson’s, according to Chesselet.

Parkinson’s disease affects as many as 1 million Americans, and 60,000 new cases are diagnosed each year. The disorder continues to puzzle scientists. There is no cure and researchers have been unable to pin down its cause and no drug has been proven to stop the progression of the disease, which causes tremors, stiffness and other debilitating symptoms. Current Parkinson’s treatments only address its symptoms.

Studying rats as model subjects, scientists found that adolescents were at an increased risk of suffering negative health effects from sugar-sweetened beverage consumption.

Adolescent rats that freely consumed large quantities of liquid solutions containing sugar or high-fructose corn syrup (HFCS) in concentrations comparable to popular sugar-sweetened beverages experienced memory problems and brain inflammation, and became pre-diabetic, according to a new study from USC. Neither adult rats fed the sugary drinks nor adolescent rats who did not consume sugar had the same issues.

“The brain is especially vulnerable to dietary influences during critical periods of development, like adolescence,” said Scott Kanoski, corresponding author of the study and an assistant professor at the USC Dornsife College of Letters, Arts and Sciences.

Kanoski collaborated with USC’s Ted Hsu, Vaibhav Konanur, Lilly Taing, Ryan Usui, Brandon Kayser, and Michael Goran. Their study, which tested a total of 76 rats, was published online by the journal Hippocampus on Sept. 23.

About 35 to 40 percent of the rats’ caloric intake was from sugar or HFCS. For comparason, added sugars make up about 17 percent of the total caloric intake of teens in the U.S. on average, according to the CDC.

The rats were then tested in mazes that probe their spatial memory ability. Adolescent rats that had consumed the sugary beverages, particularly HFCS, performed worse on the test than any other group – which may be the result of the neuroinflammation detected in the hippocampus, Kanoski said.

The hippocampus is a part of the temporal lobe located deep within the brain that controls memory formation. People with Alzheimer’s Disease and other dementias often suffer damage to the hippocampus.

“Consuming a diet high in added sugars not only can lead to weight gain and metabolic disturbances, but can also negatively impact our neural functioning and cognitive ability.” Kanoski said. Next, Kanoski and his team plant to see how different monosaccharides (simple sugars) and HFCS affect the brain.

New research, led by King’s College London finds that the high heritability of exam grades reflects many genetically influenced traits such as personality, behaviour problems, and self-efficacy and not just intelligence.

The study, published today in the Proceedings of the National Academy of Sciences (PNAS), looked at 13,306 twins at age 16 who were part of the Medical Research Council (MRC) funded UK Twins Early Development Study (TEDS). The twins were assessed on a range of cognitive and non-cognitive measures, and the researchers had access to their GCSE (General Certificate of Secondary Education) scores.

In total, 83 scales were condensed into nine domains: intelligence, self-efficacy (confidence in one’s own academic ability), personality, well-being, home environment, school environment, health, parent-reported behaviour problems and child reported behaviour problems.

Identical twins share 100% of their genes, and non-identical twins (just as any other siblings) share 50% of the genes that vary between people. Twin pairs share the same environment (family, schools, teachers etc). By comparing identical and non-identical twins, the researchers were able to estimate the relative contributions of genetic and environmental factors. So, if overall, identical twins are more similar on a particular trait than non-identical twins, the differences between the two groups are due to genetics, rather than environment.

Eva Krapohl, joint first author of the study, from the MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s, says: “Previous work has already established that educational achievement is heritable. In this study, we wanted to find out why that is. What our study shows is that the heritability of educational achievement is much more than just intelligence – it is the combination of many traits which are all heritable to different extents.

“It is important to point out that heritability does not mean that anything is set in stone. It simply means that children differ in how easy and enjoyable they find learning and that much of these differences are influenced by genetics.”

The researchers found that the heritability of GCSE scores was 62%.  Individual traits were between 35% and 58% heritable, with intelligence being the most highly heritable. Together, the nine domains accounted for 75% of the heritability of GCSE scores.

Heritability is a population statistic which does not provide any information at an individual level. It describes the extent to which differences between children can be ascribed to DNA differences, on average, in a particular population at a particular time. 

Ache, agony, distress and pain draw more attention than non-pain related words when it comes to people who suffer from chronic pain, a York University research using state-of-the-art eye-tracking technology has found.

(Image credit)

“People suffering from chronic pain pay more frequent and longer attention to pain-related words than individuals who are pain-free,” says Samantha Fashler, a PhD candidate in the Faculty of Health and the lead author of the study. “Our eye movements — the things we look at — generally reflect what we attend to, and knowing how and what people pay attention to can be helpful in determining who develops chronic pain.”

Chronic pain currently affects about 20 per cent of the population in Canada.

The current study, “More than meets the eye: visual attention biases in individuals reporting chronic pain”, published in the Journal of Pain Research, incorporated an eye-tracker, which is a more sophisticated measuring tool to test reaction time than the previously used dot-probe task in similar studies.

“The use of an eye-tracker opens up a number of previously unavailable avenues for research to more directly tap what people with chronic pain attend to and how this attention may influence the presence of pain,” says Professor Joel Katz, Canada Research Chair in Health Psychology, the co-author of the study.

The researchers recorded both reaction time and eye movements of chronic pain (51) and pain-free (62) participants. Both groups viewed neutral and sensory pain-related words on a dot-probe task. They found reaction time did not indicate attention, but “the eye-tracking technology captured eye gaze patterns with millimetre precision,” according to Fashler. She points out that this helped researchers to determine how frequently and how long individuals looked at sensory pain words.

“We now know that people with and without chronic pain differ in terms of how, where and when they attend to pain-related words. This is a first step in identifying whether the attentional bias is involved in making pain more intense or more salient to the person in pain,” says Katz.