Risk of brain injury is genetic

University researchers have identified a link between injury to the developing brain and common variation in genes associated with schizophrenia and the metabolism of fat.

The study builds on previous research, which has shown that being born prematurely - before 37 weeks - is a leading cause of learning and behavioural difficulties in childhood.

Around half of infants weighing less than 1500g at birth go on to experience difficulties in learning and attention at school age.

Unique collaboration

Scientists at Edinburgh, Imperial College London and King’s College London studied genetic samples and MRI scans of more than 80 premature infants at the time of discharge from hospital.

The tests and scans revealed that variation in the genetic code of genes known as ARVCF and FADS2 influenced the risk of brain injury on MRI in the babies.

Global challenge

Premature births account for 10 per cent of all births worldwide, according to experts.

Earlier research has shown that being born preterm is closely related to abnormal brain development and poor neurodevelopmental outcome.

However, scientists say that they do not fully understand the processes that lead to these problems in some infants.

Researchers add that future studies could look at how changes in these genes may bring about this risk of - or resilience - to brain injury.

Environmental factors such as degree of prematurity at birth and infection play a part, but, as our study has found, they are not the whole story and genetic factors have a role in conferring risk or resilience. We hope that our findings will lead to new understanding about the mechanisms that lead to brain injury and ultimately new neuroprotective treatment strategies for preterm babies.-Dr James Boardman (Scientific director of the Jennifer Brown Research Laboratory at the MRC Centre for Reproductive Health at the University of Edinburgh)

(Image: Thinkstock)

Life Stressors Trigger Neurological Disorders

When mothers are exposed to trauma, illness, alcohol or other drug abuse, these stressors may activate a single molecular trigger in brain cells that can go awry and activate conditions such as schizophrenia, post-traumatic stress disorder and some forms of autism.

Until now, it has been unclear how much these stressors have impacted the cells of a developing brain. Past studies have shown that when an expectant mother exposes herself to alcohol or drug abuse or she experiences some trauma or illness, her baby may later develop a psychiatric disorder, including some forms of autism or post-traumatic stress disorder, later in life. But the new findings, published online in Neuron, identifies a molecular mechanism in the prenatal brain that may help explain how cells go awry when exposed to certain environmental conditions.

Kazue Hasimoto-Torii, PhD, Principal Investigator of the Center for Neuroscience, Children’s National Health System, and a Scott-Gentle Foundation investigator, is lead author of the paper. Torii was previously at Yale, whose researchers were co-authors in the report. The research was funded primarily through National Institutes of Health grants.

Researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures activate a single gene, HSF1, also known as heat shock factor, in cerebral cortex. The HSF1 “plays a crucial role in the response of brain cells to prenatal environmental insults,” the researchers reported. “The gene protects and enables brain cells to survive prenatal assaults. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth following exposures to very low levels of toxins.”

Even in mice where the HSF1 gene was properly activated to combat environmental insults, the molecular mechanism alone may permanently change how brain cells respond, and may be a reason why someone may be more susceptible to neuropsychiatric disorders later in life.

Innovative work with stem cells also provided findings that supported the theory that stress induces vulnerable cells to malfunction, the researchers reported. For the study, researchers created stem cells from biopsies of people diagnosed with schizophrenia. Stem cells are capable of becoming many different tissue types, including neurons. In the study, genes from the stem cells of those with schizophrenia responded more dramatically when exposed to environmental insults than stem cells from non-schizophrenic individuals.

While it has been generally accepted that exposure to harmful environmental factors increase the susceptibility of the brain to neurological and psychiatric disorders, new types of environmental agents are continuingly added to the mix, requiring evolving studies, Hasimoto-Torii says.

Hashimoto-Torii notes that autism rates have increased substantially and “more people are having these exposures to environmental stressors,” she says. While there have been many studies that have identified singular stressors, such as alcohol, there have not been enough studies to focus on many different environmental factors and their impacts, such as heavy metals as well as alcohol and other toxic exposure, she adds.

Identifying many risk factors helped Hashimoto-Torii and other researchers identify the gene that may be linked to neurological problems. “Different stressors may have different stress responses,” she says. She examined risk factors specifically involving epilepsy, ADHD, autism and schizophrenia. Eventually, it may open the door “to provide therapy in the future to reduce the risk” and protect vulnerable cells.

Lipid levels during prenatal brain development impact autism

In a groundbreaking York University study, researchers have found that abnormal levels of lipid molecules in the brain can affect the interaction between two key neural pathways in early prenatal brain development, which can trigger autism. And, environmental causes such as exposure to chemicals in some cosmetics and common over-the-counter medication can affect the levels of these lipids, according to the researchers.

“We have found that the abnormal level of a lipid molecule called Prostaglandin E2 in the brain can affect the function of Wnt proteins. It is important because this can change the course of early embryonic development,” explains Professor Dorota Crawford in the Faculty of Health and a member of the York Autism Alliance Research Group.

This is the first time research shows evidence for cross-talk between PGE2 and Wnt signalling in neuronal stem cells, according to the peer reviewed study published at Cell Communication and Signaling.

Lead researcher and York U doctoral student Christine Wong adds, “Using real-time imaging microscopy, we determined that higher levels of PGE2 can change Wnt-dependent behaviour of neural stem cells by increasing cell migration or proliferation. As a result, this could affect how the brain is organized and wired.  Moreover, we found that an elevated level of PGE2 can increase expression of Wnt-regulated genes — Ctnnb1, Ptgs2, Ccnd1, and Mmp9. “Interestingly, all these genes have been previously implicated in various autism studies.”

Autism is considered to be the primary disorder of brain development with symptoms ranging from mild to severe and including repetitive behaviour, deficits in social interaction, and impaired language. It is four times more prevalent in boys than in girls and the incidence continues to rise. The US Center for Disease Control and Prevention (CDC) data from 2010 estimates that 1 in 68 children now has autism.

“The statistics are alarming. It’s 30 per cent higher than the previous estimate of 1 in 88 children, up from only two years earlier. Perhaps we can no longer attribute this rise in autism incidence to better diagnostic tools or awareness of autism,” notes Crawford. “It’s even more apparent from the recent literature that the environment might have a greater impact on vulnerable genes, particularly in pregnancy. Our study provides some molecular evidence that the environment likely disrupts certain events occurring in early brain development and contributes to autism.”

According to Crawford, genes don’t undergo significant changes in evolution, so even though genetic factors are the main cause, environmental factors such as insufficient dietary supplementations of fatty acids, exposures to infections, various chemicals or drugs can change gene expression and contribute to autism.

(Image caption: The images show an early developmental stage of normal (top row) and BRCA1-deficient brains (bottom row). The imaged embryos show abundant proliferation of cell growth (red, first column) in both normal and BRCA1-deficient brains at this stage. However brains lacking BRCA1 exhibit high levels of cellular suicide (green, second column). The third column shows an overlay of the other columns. Credit: Courtesy of the Salk Institute for Biological Studies)

Scientists reveal potential link between brain development and breast cancer gene

Scientists at the Salk Institute have uncovered details into a surprising—and crucial—link between brain development and a gene whose mutation is tied to breast and ovarian cancer. Aside from better understanding neurological damage associated in a small percentage of people susceptible to breast cancers, the new work also helps to better understand the evolution of the brain.

The research, published this month in PNAS, shows that the gene known as BRCA1 has a significant role in creating healthy brains in mice and may provide a hint as to why some women genetically prone to breast cancer experience brain seizures.

"Previously, people associated mutations or deletions of BRCA1 with breast and ovarian cancer," says Inder Verma, a professor in Salk’s Laboratory of Genetics and American Cancer Society Professor of Molecular Biology. "Our paper goes beyond this link to explain the protective mechanism of BRCA1 in the brain."

Through a three–lab collaboration at the Salk Institute, which began over a water cooler conversation between adjacent lab researchers 10 years ago, the work has culminated in dramatic findings. The team found that eliminating BRCA1 in neural stems cells had profound effects: large swaths of brain were simply missing; the cortex, which typically has six layers, only developed two very rudimentary layers; the cerebellum, which is normally made up of many folds and creases, was almost completely smooth; and the olfactory bulb, which processes odor information, was severely disorganized and poorly developed. Neurons were dying rapidly shortly after forming, while ones that did last were often defective. In mouse models, this resulted in interference in balance, motor skills, and other core functions.

How exactly was the absence of BRCA1 leading to such a neural catastrophe? In a previous paper, the team showed that without the protein coded by the BRCA1 gene, DNA is not packaged properly, becoming fragile and more likely to break during DNA replication. In this new paper, the researchers reveal more about that mechanism, showing that without the protective ability of BRCA1, breaks in the DNA strands go unfixed, prompting the molecule ATM kinase to activate a cellular “suicide” pathway involving a protein called p53. This pathway helps to halt the replication of damaged cells and is important in cancer research.

"BRCA1 acts by conferring stability to the DNA and preventing it from breaking," says Carlos G. Perez–Garcia, a Salk researcher in the Molecular Neurobiology Lab. "BRCA1 is important for all healthy cells."

When the researchers eliminated both BRCA1 and p53, they found the neurons grew at a normal rate, but still disorderly, with cells pointed in the wrong direction.

"In this scenario, we recover a lot of neurons but there’s still a lot of abnormalities, such as cells that are sideways and pointed the wrong direction," says Gerald Pao, who, along with Quan Zhu and Perez–Garcia, is a primary contributor to the paper and Salk researcher.

This observation led the team to propose that BRCA1 has an additional role in assisting neurons in orienting: the gene acts on the centromere of DNA—essentially an anchor for the chromosome arms essential in cell replication—to tell the new cell in which direction to grow, providing guidance in developing the brain’s organized layers.

"It is remarkable that BRCA1 has such a significant effect on the brain, especially size. This work leads us to a better understanding of how to protect neurons," says Verma, who is also the Irwin and Joan Jacobs Chair in Exemplary Life Science. Because BRCA1 seems to regulate the centromere, studying the gene will help scientists to understand how mammalian brains have evolved over time.

"Now we have an explanation for why some patients with breast cancer also experienced brain seizures," adds Pao. This knowledge could potentially help identify breast cancer–susceptible patients predisposed to seizures and provide appropriate treatments.

Researchers find hand to mouth movement in humans likely hard-wired

A team of researchers in France has found evidence that suggests that human hand-to-mouth actions are hard-wired into the brain. In their paper published in Proceedings of the National Academy of Sciences, the researchers describe an experiment they conducted on adults undergoing brain surgery and why what they found could have profound implications on human brain development theories.

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Scientists discover a protein in nerves that determines which brain connections stay and which go

A newborn baby, for all its cooing cuddliness, is a data acquisition machine, absorbing information to finish honing the job of brain wiring that started before birth. This is true nowhere more so than the eyes, which start life peering at a blurry world and within months can make out a crisp, three-dimensional image of a mobile dangling overhead.

This process of refining the brain’s wiring involves cutting off some of the excess nerve connections we have at birth while strengthening connections we use all the time. Some estimates show that as many as half of the brain’s connections formed during development are clipped back as the final wiring takes shape.

Carla Shatz, the David Starr Jordan Director of Stanford Bio-X, and her team, including postdoctoral researcher Hanmi Lee and Bio-X Graduate Fellow Jaimie Adelson, recently found a protein that is essential for the brain to remove those excess connections. The team specifically showed a role for the protein in the developing visual system in mice, but the work appears to apply broadly across the developing brain. They published their findings online March 30 in the journal Nature.

Shatz said the discovery helps clear up something that has been a mystery to those who study brain development: How does the decision get made to eliminate some connections? It also settles a decade-long debate over whether the nervous system or the immune system is making those decisions. (Spoiler alert: It’s the nervous system.)

A single vision

"Vision is a challenging problem because you have two eyes and only one view of the world," said Shatz, who is the Sapp Family Provostial Professor and professor of biology and of neurobiology. "There’s a very beautiful set of wiring steps that makes sure the eyes are pointed at the same place and the two images get aligned."

Shatz said the rule of which connections the brain cuts back to create that single vision follows a simple mantra: “Fire together, wire together. Out of sync, lose your link.” Or rather, if early in life the left sides of both eyes see the same duck motif wallpaper, those neurons fire together and stay linked up. When the top of one eye and bottom of the other eye form a connection, the nerves fire out of sync, and the connection weakens and is eventually pruned back. Over time, the only connections that remain are between parts of the two eyes that are seeing the same thing.

The ability to detect which nerves fire out of sync and should therefore lose their link requires the protein Shatz’s team reported, which goes by the name of MHC Class I D, or D for short. This protein is one that is famous for its role in the immune system, but only in the past decade has Shatz’s team started building a case for D’s independent role in the brain.

Two camps, one protein

In 2000 Shatz first published work suggesting that a group of immune proteins called MHC in mice and HLA in people played a role in the developing nervous system. At the time, this caused a stir among immunologists, who were surprised to find their proteins showing up in the brain.

Lawrence Steinman, professor of neurology and neurological sciences and of pediatrics at Stanford School of Medicine, has followed Shatz’s work from the perspective of both a neurologist and immunologist. “One of the reasons that I think the research is so interesting is that it shows us that molecules thought to be the province of one group can be in another,” he said, adding, “It slowed the prevailing idea that people believed that some molecules were the domain of one camp.”

Shatz is in the privileged position of directing Stanford Bio-X, which includes faculty members and students from both immunology and the neurological sciences. She said being able to talk about her work and collaborate with this mix of colleagues has helped break down barriers in thinking about her unexpected findings.

After the initial discovery, Shatz went on to show that two of those MHC proteins – D and its sister protein K – seemed to be important in eliminating connections in the brain. Mice genetically engineered to lack both K and D had poorly functioning immune systems and also ended up with the visual system in a jumble, with unrelated parts of the two eyes forming connections. Without D and K the mice weren’t detecting which connections fired out of sync, so those connections didn’t lose their link.

After Shatz published that work, some immunologists argued that perhaps D and K were necessary for brain remodeling only because of their key function in the immune system. “They were saying that the immune system was telling the nervous system what to prune,” Shatz said.

It was a theory, but not one Shatz agreed with. Her feeling was that just because D and K were first found in the immune system didn’t mean they couldn’t have a unique role in the brain. “The nervous system has just as much right to these immune proteins as the immune system,” Shatz said. Her most recent work makes that point clear.

D on the brain

Shatz and her group worked with the mice that were lacking D and K everywhere, then used genetic engineering tricks to add D back, but only in the neurons. These mice still had poorly functioning immune systems, but had perfectly normal eye connections. In these mice, the nerves were able to determine which connections to cut and which to keep, even without the immune system.

Steinman said the work settles the issue of whether D is acting in the brain separate from its role in the immune system. “If Carla had studied MHC proteins before the immunologists, then we would consider them to be part of the nervous system. They clearly have major roles in both the nervous system and the immune system,” he said.

The group went on to show that the presence of D alters the composition of other proteins on the nerve cell surface that are in charge of receiving signals from other nerves. Her team thinks that it is this difference in how the nerve receives signals with or without D that makes the pruning process go awry.

Essentially, without D all nerve connections appear to be firing together and therefore they stay wired together.

Shatz says that in addition to explaining an important part of brain development, the work could also provide a new avenue for studying schizophrenia. Some studies have shown that people with mutations in the human genes related to D (called HLA genes) are more prone to the disease. Other studies have associated schizophrenia with improperly formed connections in the brain. Shatz suggests that this new role for D in the brain could mean that the pruning process has gone awry in schizophrenia. The group plans to explore this idea further, as well as to tease apart what D is doing to alter the composition of neurotransmitter receptors on the nerve cell surface.

Critical role of one gene to our brain development

New research from the University of Adelaide has confirmed that a gene linked to intellectual disability is critical to the earliest stages of the development of human brains.

Known as USP9X, the gene has been investigated by Adelaide researchers for more than a decade, but in recent years scientists have begun to understand its particular importance to brain development.

In a new paper published online in the American Journal of Human Genetics, an international research team led by the University of Adelaide’s Robinson Research Institute explains how mutations in USP9X are associated with intellectual disability. These mutations, which can be inherited from one generation to the next, have been shown to cause disruptions to normal brain cell functioning.

Speaking during Brain Awareness Week, senior co-author Dr Lachlan Jolly from the University of Adelaide’s Neurogenetics Research Program says the USP9X gene has shed new light on the mysteries of brain development and disability.

Dr Jolly says the base framework for the brain’s complex network of cells begins to form at the embryo stage.

"Not surprisingly, disorders that cause changes to this network of cells, such as intellectual disabilities, epilepsy and autism, are hard to understand, and treat," Dr Jolly says.

"By looking at patients with severe learning and memory problems, we discovered a gene - called USP9X - that is involved in creating this base network of nerve cells. USP9X controls both the initial generation of the nerve cells from stem cells, and also their ability to connect with one another and form the proper networks,” he says.

"This work is critical to understanding how the brain develops, and how it is altered in individuals with brain disorders.

"We hope that by learning more about genes such as USP9X, we will create new opportunities to understand brain disorders at a much deeper level than currently known, which could lead to future treatment opportunities.”

Brain development provides insights into adolescent depression

Lead research Professor Nick Allen from the Melbourne School of Psychological Sciences said, “It is well known that the brain continues to change and remodel itself during adolescence as part of healthy development.”

“In this study, we found that the pattern of development (such as changes in brain structure between ages twelve to sixteen) in several key brain regions differed between depressed and non-depressed adolescents,” Professor Allen said.

The brain regions involved include areas associated with the experience and regulation of emotion, as well as areas associated with learning and memory. 



“The findings are an important breakthrough for exploring possible causes of depression in adolescence. They also suggest that both prevention and treatment for depression (even for early signs and symptoms of depression) in adolescence is essential, especially targeting those in the early years of adolescence aged twelve to sixteen,” he said.

“We also observed some differences between males and females. For males, less growth in an area of the brain involved in processing threat and other unexpected events that is a critical part of the brain’s fear circuitry, was associated with depression. On the other hand, for females, greater growth of this area was found to be associated with depression.” 



“This is important information because depression becomes much more common amongst girls during adolescence, and these findings tell us about some of the neurobiological factors that might play a role in this gender difference,” he said.

Professor Allen says adolescence is a period during the lifespan where risk for developing depression dramatically increases.

The study examined eighty-six adolescents (41 female) with no history of depressive disorders before age 12 by using a Magnetic Resonance Imaging (MRI) scanner, which allowed researchers to measure the volume of particular brain regions of interest. 

Participants underwent an MRI scan first at age twelve and again at age sixteen, when rates of depression were beginning to increase. 

Researchers also conducted detailed interviews with each of the participants at four different time points between age twelve and age eighteen. Thirty participants experienced a first episode of a depressive disorder during the follow-up period.

These findings have recently been published in the American Journal of Psychiatry.