Neuroscience

Even with today’s technology, it still takes both a male and a female to make a baby. But is it important for both parents to raise that child? Many studies have outlined the value of a mother, but few have clearly defined the importance of a father, until now. New findings from the Research Institute of the McGill University Health Centre (RI-MUHC) show that the absence of a father during critical growth periods, leads to impaired social and behavioural abilities in adults. This research, which was conducted using mice, was published today in the journal Cerebral Cortex. It is the first study to link father absenteeism with social attributes and to correlate these with physical changes in the brain.

“Although we used mice, the findings are extremely relevant to humans,” says senior author Dr. Gabriella Gobbi, a researcher of the Mental Illness and Addiction Axis at the RI-MUHC and an associate professor at the Faculty of Medicine at McGill University. “We used California mice which, like in some human populations, are monogamous and raise their offspring together.” 

“Because we can control their environment, we can equalize factors that differ between them,” adds first author, Francis Bambico, a former student of Dr. Gobbi at McGill and now a post-doc at the Centre for Addiction and Mental Health (CAMH) in Toronto. “Mice studies in the laboratory may therefore be clearer to interpret than human ones, where it is impossible to control all the influences during development.”

Dr. Gobbi and her colleagues compared the social behaviour and brain anatomy of mice that had been raised with both parents to those that had been raised only by their mothers. Mice raised without a father had abnormal social interactions and were more aggressive than counterparts raised with both parents. These effects were stronger for female offspring than for their brothers. Females raised without fathers also had a greater sensitivity to the stimulant drug, amphetamine. 

“The behavioural deficits we observed are consistent with human studies of children raised without a father,” says Dr. Gobbi, who is also a psychiatrist at the MUHC. “These children have been shown to have an increased risk for deviant behaviour and in particular, girls have been shown to be at risk for substance abuse. This suggests that these mice are a good model for understanding how these effects arise in humans.” 

In pups deprived of fathers, Dr. Gobbi’s team also identified defects in the mouse prefrontal cortex, a part of the brain that helps control social and cognitive activity, which is linked to the behaviourial deficits.

“This is the first time research findings have shown that paternal deprivation during development affects the neurobiology of the offspring,” says Dr. Gobbi. These results should incite researchers to look more deeply into the role of fathers during critical stages of growth and suggest that both parents are important in children’s mental health development.

A UW-Madison research team reports today that the brain can produce and release estrogen — a discovery that may lead to a better understanding of hormonal changes observed from before birth throughout the entire aging process.

The new research shows that the hypothalamus can directly control reproductive function in rhesus monkeys and very likely performs the same action in women.

Scientists have known for about 80 years that the hypothalamus, a region in the brain, is involved in regulating the menstrual cycle and reproduction. Within the past 40 years, they predicted the presence of neural estrogens, but they did not know whether the brain could actually make and release estrogen.

Most estrogens, such as estradiol, a primary hormone that controls the menstrual cycle, are produced in the ovaries. Estradiol circulates throughout the body, including the brain and pituitary gland, and influences reproduction, body weight, and learning and memory. As a result, many normal functions are compromised when the ovaries are removed or lose their function after menopause.

"Discovering that the hypothalamus can rapidly produce large amounts of estradiol and participate in control of gonadotropin-releasing hormone neurons surprised us," says Ei Terasawa, professor of pediatrics at the UW School of Medicine and Public Health and senior scientist at the Wisconsin National Primate Research Center. "These findings not only shift the concept of how reproductive function and behavior is regulated but have real implications for understanding and treating a number of diseases and disorders."

For diseases that may be linked to estrogen imbalances, such as Alzheimer’s disease, stroke, depression, experimental autoimmune encephalomyelitis and other autoimmune disorders, the hypothalamus may become a novel area for drug targeting, Terasawa says. “Results such as these can point us in new research directions and find new diagnostic tools and treatments for neuroendocrine diseases.”

The study, published today in the Journal of Neuroscience, “opens up entirely new avenues of research into human reproduction and development, as well as the role of estrogen action as our bodies age,” reports the first author of the paper, Brian Kenealy, who earned his Ph.D. this summer in the Endocrinology and Reproductive Physiology Program at UW-Madison. Kenealy performed three studies. In the first experiment, a brief infusion of estradiol benzoate administered into the hypothalamus of rhesus monkeys that had surgery to remove their ovaries rapidly stimulated GnRH release. The brain took over and began rapidly releasing this estrogen in large pulsing surges.

In the second experiment, mild electrical stimulation of the hypothalamus caused the release of both estrogen and GnRH (thus mimicking how estrogen could induce a neurotransmitter-like action). Third, the research team infused letrazole, an aromatase inhibitor that blocks the synthesis of estrogen, resulting in a lack of estrogen as well as GnRH release from the brain. Together, these methods demonstrated how local synthesis of estrogen in the brain is important in regulating reproductive function.

The reproductive, neurological and immune systems of rhesus macaques have proven to be excellent biomedical models for humans over several decades, says Terasawa, who focuses on the neural and endocrine mechanisms that control the initiation of puberty. “This work is further proof that these animals can teach us about so many basic functions we don’t fully understand in humans.”

Leading up to this discovery, Terasawa said, recent evidence had shown that estrogen acting as a neurotransmitter in the brain rapidly induced sexual behavior in quails and rats. Kenealy’s work is the first evidence of this local hypothalamic action in primates, and in those that don’t even have ovaries.

"The discovery that the primate brain can make estrogen is key to a better understanding of hormonal changes observed during every phase of development, from prenatal to puberty, and throughout adulthood, including aging," Kenealy says.

In a new paper published in the current issue of Neuron, McLean Hospital and Harvard Medical School researchers report that increased activity in the medial prefrontal cortex (mPFC) of the brain is linked to decreased activity in the amygdala, the portion of the brain used in the creation of memories of events that scared those exposed.

According to author Vadim Bolshakov, PhD, director of the Cellular Neurobiology Laboratory at McLean and professor at Harvard Medical School, this finding is significant in that it could lead to better methods to prevent PTSD.

"A single exposure to something traumatic or scary can be enough to create a fear memory—causing someone to expect and be afraid in similar situations in the future," said Bolshakov. "What we’re seeing is that we may one day be able to prevent those fear memories."

Bolshakov and his colleagues tested their theory using animal models. Dividing the mice into two groups, some were taught to fear an auditory stimulus while in others fear memory was extinguished Increased activation of mPFC in extinguished animals led to inhibition of the amygdala and significant decreases in fear responses.

"For example, if a sound ended with an extremely loud shriek, a subject would come to expect that scary noise at the end of the sound," explained Bolshakov. "What we found was when we suppressed the fear memory by decreasing activity in the amygdala, the subjects were not afraid of the end of the auditory stimulus any longer."

Bolshakov notes that this work could have serious implications for the treatment of a number of conditions including PTSD.

"While there is still a great deal of research that needs to be done before our work can be translated to clinical trials, what we are showing has the potential to ensure that individuals exposed to trauma were not haunted by the conditions surrounding their initial stressor."

Fear, at the right level, can increase alertness and protect against dangers. Disproportionate fear, on the other hand, can disrupt the sensory perception, be disabling, reduce happiness and therefore become a danger in itself.  Anxiety disorders are therefore a psychiatric condition that should not be underestimated. In these disorders, the fear is so strong that there is tremendous psychological strain and living a normal life appears to be impossible. Researchers at the MedUni Vienna have now found a possible explanation as to how social phobias and fear can be triggered in the brain: a missing inhibitory connection or missing “brake” in the brain.

Inside the brain, the amygdala and the orbitofrontal cortex in the frontal lobe form an important control circuit for regulating the emotions. This control circuit is termed the brain’s emotional control centre. Whereas in healthy subjects, this circuit has “negative feedback” and “calmness” was identified, scientists used functional magnetic resonance imaging (MRI) on people with social phobias and found the opposite to be true: an important inhibitory connection is different in these patients, which may explain why they are unable to control their fears.

In collaboration with the Centre for Medical Physics and Biomedical Technology and the University Department of Psychiatry and Psychotherapy at the MedUni Vienna, the research team lead by Christian Windischberger was also able to discover through its recent study at the MedUni Vienna’s High Field MR Centre of Excellence how the areas of the brain that are involved with processing emotions are able to influence each other.

The study participants were shown a series of “emotional faces” while undergoing functional magnetic resonance imaging. fMRI is a non-invasive method which uses radio waves and magnetic fields to measure changes in the levels of oxygen in the blood and therefore neuronal activity in individual regions of the brain. An analysis method developed at University College London was used to provide new perspectives on the data obtained.

Breaking the circle of fear
When emotional facial expressions were shown - from laughing to crying, from happiness to anger - neuronal activity was triggered in the brain. The result: on a purely external basis, the test subjects looked no different, but the healthy subjects were kept calm thanks to their automatic “brake”, despite the emotional nature of the images. For the social phobics, on the other hand, the photographs put their brains into “overdrive”, triggering very strong neuronal activity. This was demonstrated very clearly using the new analysis method: “We have the opportunity not only to localise brain activity and compare it between groups, but we can now also make statements regarding functional connections within the brain. In psychiatric conditions especially, we can assume that there are not complete failures of these connections going on, but rather imbalances in complex regulatory processes,” says Ronald Sladky, the study’s primary author.

This better understanding of the neuronal mechanisms involved will now be used to develop new approaches to treatment. The aim is to understand what effect medications and psycho-therapeutic support have on the networks involved in order to help patients break out of their circles of fear.

The ability to localize the source of sound is important for navigating the world and for listening in noisy environments like restaurants, an action that is particularly difficult for elderly or hearing impaired people. Having two ears allows animals to localize the source of a sound. For example, barn owls can snatch their prey in complete darkness by relying on sound alone. It has been known for a long time that this ability depends on tiny differences in the sounds that arrive at each ear, including differences in the time of arrival: in humans, for example, sound will arrive at the ear closer to the source up to half a millisecond earlier than it arrives at the other ear. These differences are called interaural time differences. However, the way that the brain processes this information to figure out where the sound came from has been the source of much debate.

A recent paper by Mass. Eye and Ear/Harvard Medical School researchers in collaboration with researchers at the Ecole Normale Superieure, France, challenge the two dominant theories of how people localize sounds, explain why neuronal responses to sounds are so diverse and show how sound can be localized, even with the absence of one half of the brain. Their research is described on line in the journal eLife.

“Progress has been made in laboratory settings to understand how sound localization works, but in the real world people hear a wide range of sounds with background noise and reflections,” said Dan F. M. Goodman, lead author and post-doctoral fellow in the Eaton-Peabody Laboratories at Mass. Eye and Ear, Harvard Medical School. “Theories based on more realistic environments are important. The theme of the paper is that previous theories about this have been too idealized, and if you use more realistic data, you come to an entirely different conclusion.”

“Two theories have come to dominate our understanding of how the brain localizes sounds: the peak coding theory (which says that only the most strongly responding brain cells are needed), and the hemispheric coding theory (which says that only the average response of the cells in the two hemispheres of the brain are needed),” Goodman said. “What we’ve shown in this study is that neither of these theories can be right, and that the evidence they presented only works because their experiments used unnatural/idealized sounds. If you use more realistic, natural sounds, then they both do very badly at explaining the data.”

Researchers showed that to do well with realistic sounds, one needs to use the whole pattern of neural responses, not just the most strongly responding or average response. They showed two other key things: first, it has long been known that the responses of different auditory neurons are very diverse, but this diversity was not used in the hemispheric coding theory.

“We showed that the diversity is essential to the brain’s ability to localize sounds; if you make all the responses similar then there isn’t enough information, something that was not appreciated before because if one has unnatural/idealized sounds you don’t see the difference” Goodman said.

Second, previous theories are inconsistent with the well-known fact that people are still able to localize sounds if they lose one half of our brain, but only sounds on the other side (i.e. if one loses the left half of the brain, he or she can still localize sounds coming from the right), he added.

“We can explain why this is the case with our new theory,” Goodman said.

People who carry a high-risk gene for Alzheimer’s disease show changes in their brains beginning in childhood, decades before the illness appears, new research from the Centre for Addiction and Mental Health (CAMH) suggests.

The gene, called SORL1, is one of a number of genes linked to an increased risk of late-onset Alzheimer’s disease, the most common form of the illness. SORL1 carries the gene code for the sortilin-like receptor, which is involved in recycling some molecules in the brain before they develop into beta-amyloid a toxic Alzheimer protein. SORL1 is also involved in lipid metabolism, putting it at the heart of the vascular risk pathway for Alzheimer’s disease as well.

“We need to understand where, when and how these Alzheimer’s risk genes affect the brain, by studying the biological pathways through which they work,” says Dr. Aristotle Voineskos, head of the Kimel Family Translational Imaging-Genetics Laboratory at CAMH, who led the study. “Through this knowledge, we can begin to design interventions at the right time, for the right people.” The study was recently published online in Molecular Psychiatry with Dr. Voineskos’s graduate student, Daniel Felsky as first author, and was a collaborative effort with the Zucker Hillside Hospital/Feinstein Institute in New York and the Rush Alzheimer’s Disease Center in Chicago.

To understand SORL1’s effects across the lifespan, the researchers studied individuals both with and without Alzheimer’s disease. Their approach was to identify genetic differences in SORL1, and see if there was a link to Alzheimer’s-related changes in the brain, using imaging as well as post-mortem tissue analysis.

In each approach, a link was confirmed.

In the first group of healthy individuals, aged eight to 86, researchers used a brain imaging technique called diffusion tensor imaging (DTI). Even among the youngest participants in the study, those with a specific copy of SORL1 showed a reduction in white matter connections in the brain important for memory performance and executive function. 

The second sample included post-mortem brain tissue from 189 individuals less than a year old to 92 years, without Alzheimer’s disease. Among those with that same copy of the SORL1 gene, the brain tissue showed a disruption in the process by which the gene translated its code to become the sortilin-like receptor.

Finally, the third set of post-mortem brains came from 710 individuals, aged 66 to 108, of whom the majority had mild cognitive impairment or Alzheimer’s. In this case, the SORL1 risk gene was linked with the presence of amyloid-beta, a protein found in Alzheimer’s disease. 

Dr. Voineskos notes that risk for Alzheimer’s disease results from a combination of factors – unhealthy diet, lack of exercise, smoking, high blood pressure combined with a person’s genetic profile – which all contribute to the development of the illness. “The gene has a relatively small effect, but the changes are reliable, and may represent one ‘hit’, among a pathway of hits required to develop Alzheimer’s disease later in life”.

While it’s too early to provide interventions that may target these changes, “individuals can take measures in their own lifestyle to reduce the risk of late-onset Alzheimer’s disease.” Determining whether there is an interaction with this risk gene and lifestyle factors will be one important next step.

In order to develop genetically-based interventions to prevent Alzheimer’s disease, the biological pathways of other risk genes also need to be systematically analyzed, the researchers note.

This research does, however, build on a previous CAMH imaging-genetics study on another gene related to Alzheimer’s disease. That study showed that a genetic variation of brain-derived neurotrophic factor (BDNF) affected brain structures in Alzheimer’s.

“The interesting connection is that BDNF may have important therapeutic value. But there is data to suggest that the effects of BDNF won’t work unless SORL1 is present, so there is the possibility that if you boost the activity of one gene, the other will increase,” says Dr. Voineskos, adding that BDNF therapeutics are in development. A next stage in the research, he says, is to look at the interaction of BDNF and SORL1.

A new study led by University of Kentucky researchers suggests that a diet low in vitamin D causes damage to the brain.

In addition to being essential for maintaining bone health, newer evidence shows that vitamin D serves important roles in other organs and tissue, including the brain. Published in Free Radical Biology and Medicine, the UK study showed that middle-aged rats that were fed a diet low in vitamin D for several months developed free radical damage to the brain, and many different brain proteins were damaged as identified by redox proteomics. These rats also showed a significant decrease in cognitive performance on tests of learning and memory.

"Given that vitamin D deficiency is especially widespread among the elderly, we investigated how during aging from middle-age to old-age how low vitamin D affected the oxidative status of the brain," said lead author on the paper Allan Butterfield, professor in the UK Department of Chemistry, director of the Center of Membrane Sciences, faculty of Sanders-Brown Center on Aging, and director of the Free Radical Biology in Cancer Core of the Markey Cancer Center. “Adequate vitamin D serum levels are necessary to prevent free radical damage in brain and subsequent deleterious consequences."

Previously, low levels of vitamin D have been associated with Alzheimer’s disease, and it’s also been linked to the development of certain cancers and heart disease. In both the developed world and in areas of economic hardship where food intake is not always the most nutritious, vitamin D levels in humans are often low, particularly in the elderly population. Butterfield recommends persons consult their physicians to have their vitamin D levels determined, and if low that they eat foods rich in vitamin D, take vitamin D supplements, and/or get at least 10-15 minutes of sun exposure each day to ensure that vitamin D levels are normalized and remain so to help protect the brain.

Exposure to air pollution appears to increase the risk for autism among people who carry a genetic disposition for the neurodevelopmental disorder, according to newly published research led by scientists at the Keck School of Medicine of the University of Southern California (USC).

"Our research shows that children with both the risk genotype and exposure to high air pollutant levels were at increased risk of autism spectrum disorder compared to those without the risk genotype and lower air pollution exposure," said the study’s first author, Heather E. Volk, Ph.D., M.P.H., assistant professor of research in preventive medicine and pediatrics at the Keck School of Medicine of USC and principal investigator at The Saban Research Institute of Children’s Hospital Los Angeles.

The study, “Autism spectrum disorder: Interaction of air pollution with the MET receptor tyrosine kinase gene,” is scheduled to appear in the January 2014 edition of Epidemiology.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disability characterized by problems with social interaction, communication and repetitive behaviors. The Centers for Disease Control and Prevention estimates that one in 88 children in the United States has an ASD.

ASD is highly heritable, suggesting that genetics are an important contributing factor, but many questions about its causes remain. There currently is no cure for the disorder.

"Although gene-environment interactions are widely believed to contribute to autism risk, this is the first demonstration of a specific interaction between a well-established genetic risk factor and an environmental factor that independently contribute to autism risk," said Daniel B. Campbell, Ph.D., assistant professor of psychiatry and the behavioral sciences at the Keck School of Medicine of USC and the study’s senior author. "The MET gene variant has been associated with autism in multiple studies, controls expression of MET protein in both the brain and the immune system, and predicts altered brain structure and function. It will be important to replicate this finding and to determine the mechanisms by which these genetic and environmental factors interact to increase the risk for autism."

Independent studies by Volk and Campbell have previously reported associations between autism and air pollution exposure and between autism and a variant in the MET gene. The current study suggests that air pollution exposure and the genetic variant interact to augment the risk of ASD.

Campbell and Volk’s team studied 408 children between 2 and 5 years of age from the Childhood Autism Risks From Genetics and the Environment Study, a population-based, case-control study of preschool children from California. Of those, 252 met the criteria for autism or autism spectrum disorder. Air pollution exposure was determined based on the past residences of the children and their mothers, local traffic-related sources, and regional air quality measures. MET genotype was determined through blood sampling.

Campbell and Volk continue to study the interaction of air pollution exposure and the MET genotype in mothers during pregnancy.

Premature birth appears to trigger developmental processes in the white matter of the brain that could put children at higher risk of problems later in life, according to a study being presented next week at the annual meeting of the Radiological Society of North America (RSNA).

Preterm infants—generally those born 23 to 36 weeks after conception, as opposed to the normal 37- to 42-week gestation—face an increased risk of behavioral problems, ranging from impulsiveness and distractibility to more serious conditions like autism and attention deficit hyperactivity disorder (ADHD).

"In the United States, we have approximately 500,000 preterm births a year," said Stefan Blüml, Ph.D., director of the New Imaging Technology Lab at Children’s Hospital Los Angeles and associate professor of research radiology at the University of Southern California in Los Angeles. "About 60,000 of these babies are at high risk for significant long-term problems, which means that this is a significant problem with enormous costs."

Dr. Blüml and colleagues have been studying preterm infants to learn more about how premature birth might cause changes in brain structure that may be associated with clinical problems observed later in life. Much of the focus has been on the brain’s white matter, which transmits signals and enables communication between different parts of the brain. While some white matter damage is readily apparent on structural magnetic resonance imaging (MRI), Dr. Blüml’s group has been using magnetic resonance spectroscopy (MRS) to look at differences on a microscopic level.

In this study, the researchers compared the concentrations of certain chemicals associated with mature white matter and gray matter in 51 full-term and 30 preterm infants. The study group had normal structural MRI findings, but MRS results showed significant differences in the biochemical maturation of white matter between the term and preterm infants, suggesting a disruption in the timing and synchronization of white and gray matter maturation. Gray matter is the part of the brain that processes and sends out signals.

"The road map of brain development is disturbed in these premature kids," Dr. Blüml said. "White matter development had an early start and was ‘out of sync’ with gray matter development."

This false start in white matter development is triggered by events after birth, according to Dr. Blüml.

"This timeline of events might be disturbed in premature kids because there are significant physiological switches at birth, as well as stimulatory events, that happen irrespective of gestational maturity of the newborn," he said. "The most apparent change is the amount of oxygen that is carried by the blood."

Dr. Blüml said that the amount of oxygen delivered to the fetus’s developing brain in utero is quite low, and our brains have evolved to optimize development in that low oxygen environment. However, when infants are born, they are quickly exposed to a much more oxygen-rich environment.

"This change may be something premature brains are not ready for," he said.

While this change may cause irregularities in white matter development, Dr. Blüml noted that the newborn brain has a remarkable capacity to adapt or even “re-wire” itself—a concept known as plasticity. Plasticity not only allows the brain to govern new skills over the course of development, like learning to walk and read, but could also make the brains of preterm infants and young children more responsive to therapeutic interventions, particularly if any abnormalities are identified early.

"Our research points to the need to better understand the impact of prematurity on the timing of critical maturational processes and to develop therapies aimed at regulating brain development," Dr. Blüml said.

Asparagine, found in foods such as meat, eggs, and dairy products, was until now considered non-essential because it is produced naturally by the body. Researchers at the University of Montreal and its affiliated CHU Sainte-Justine Hospital found that the amino acid is essential for normal brain development. This is not the case for other organs. “The cells of the body can do without it because they use asparagine provided through diet. Asparagine, however, is not well transported to the brain via the blood-brain barrier,” said senior co-author of the study Dr. Jacques Michaud, who found that brain cells depend on the local synthesis of asparagine to function properly. First co-author José-Mario Capo-Chichi and colleague Grant Mitchell also made major contributions to the study.

In April 2009, a Quebec family experienced the worst tragedy for parents: before the age of one, one of their sons died of a rare genetic disease causing congenital microcephaly, intellectual disability, cerebral atrophy, and refractory seizures. The event was even more tragic because it was the third infant to die in this family from the same disease.

This tragedy led Dr. Michaud to discover the genetic abnormality responsible for this developmental disorder. “We are not at the verge of a miracle drug,” Michaud said, “but we at least know where to look.”

The team identified the gene affected by the mutation code for asparagine synthetase, the enzyme responsible for synthesizing the amino acid asparagine. The study is the first to associate a specific genetic variant with a deficiency of this enzyme. “In healthy subjects, it seems that the level of asparagine synthetase in the brain is sufficient to supply neurons,” Michaud said. “In individuals with the disability, the enzyme is not produced in sufficient quantity, and the resulting asparagine depletion affects the proliferation and survival of cells during brain development.”

Potential treatment

Children who are carriers of this mutation suffer, to varying degrees, from a variety of symptoms, including intellectual disability and cerebral atrophy, which can lead to death. The Quebec family lost three infant sons to this disorder. Two of their other children are alive and healthy.

Knowledge about gene mutations can be used to develop treatments. “Our results not only open the door to a better understanding of the disease,” Michaud said, “but they also give us valuable information about the molecular mechanisms involved in brain development, which is important for the development of new treatments.”

For example, asparagine supplement could be given to infants to ensure an adequate level of asparagine in the brain and the latter’s normal development. “The amount of supplementation remains to be determined, as well as its effectiveness,” said the geneticist. “Since these children are already born with neurological abnormalities, it is uncertain whether this supplementation would correct the neurological deficits.”

Creating a pediatric clinical genomics centre

To date, nine children from four different families have been identified as carriers of the mutation: three infants from Quebec, three from a Bengali family living in Toronto, and three Israelis, whose symptoms are less severe.

Dr. Michaud’s team discovered the genetic mutation by comparing the complete DNA of the Quebec family’s children with symptoms of the disease. The researchers then identified children, among other families, who carried the single candidate gene. The gene was revealed only in the affected children, but not in the unaffected children of the families studied.

The discovery comes at a time when CHU Sainte-Justine Mother and Child University Hospital has reached an agreement with Génome Québec to create the first pediatric clinical genomic centre in Canada. “This initiative will transform the quality of care for younger patients to ensure better prevention from childhood,” says Dr. Michaud. “More than 80% of genetic diseases occur in childhood or adolescence. “This new technology will allow us to sequence all the genes in the genome and obtain a genetic portrait of the children more quickly to know which disease they suffer from and to provide treatment, if available, or when it becomes available.”

A new discovery may help explain the surprisingly strong connections between sleep problems and neurodegenerative conditions such as Alzheimer’s disease. Sleep loss increases the risk of Alzheimer’s disease, and disrupted sleeping patterns are among the first signs of this devastating disorder.

Scientists at Washington University School of Medicine in St. Louis and the University of Pennsylvania have shown that brain cell damage similar to that seen in Alzheimer’s disease and other disorders results when a gene that controls the sleep-wake cycle and other bodily rhythms is disabled.

The researchers found evidence that disabling a circadian clock gene that controls the daily rhythms of many bodily processes blocks a part of the brain’s housekeeping cycle that neutralizes dangerous chemicals known as free radicals.

“Normally in the hours leading up to midday, the brain increases its production of certain antioxidant enzymes, which help clean up free radicals,” said first author Erik Musiek, MD, PhD, assistant professor of neurology at the School of Medicine. “When clock genes are disabled, though, this surge no longer occurs, and the free radicals may linger in the brain and cause more damage.”

Musiek conducted the research in the labs of Garret FitzGerald, MD, chairman of pharmacology at the University of Pennsylvania, and of David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology at Washington University School of Medicine, who are co-senior authors.

The study appears Nov. 25 in The Journal of Clinical Investigation.

Musiek studied mice lacking a master clock gene called Bmal1. Without this gene, activities that normally occur at particular times of day are disrupted.

“For example, mice normally are active at night and asleep during the day, but when Bmal1 is missing, they sleep equally in the day and in the night, with no circadian rhythm,” Musiek said. “They get the same amount of sleep, but it’s spread over the whole day. Rhythms in the way genes are expressed are lost.”

FitzGerald uses mice lacking Bmal1 to study whether clock cells have links to diabetes and heart disease. He has shown that clock genes influence blood pressure, blood sugar and lipid levels.

Several years ago, Musiek, who at the time was a neurology resident at the University of Pennsylvania, and FitzGerald decided to investigate how knocking out Bmal1 affects the brain. Holtzman, who has published pioneering work on sleep and Alzheimer’s disease, encouraged Musiek to continue and expand these studies when he came to Washington University as a postdoctoral fellow.

In the new study, Musiek found that as the mice aged, many of their brain cells became damaged and did not function normally. The patterns of damage were similar to those seen in Alzheimer’s disease and other neurodegenerative disorders.

“Brain cell injury in these mice far exceeded that normally seen in aging mice,” Musiek said. “Many of the injuries appear to be caused by free radicals, which are byproducts of metabolism. If free radicals come into contact with brain cells or other tissue, they can cause damaging chemical reactions.”

This led Musiek to examine the production of key antioxidant enzymes, which usually neutralize and help clear free radicals from the brain, thereby limiting damage. He found levels of several antioxidant proteins peak in the middle of the day in healthy mice. However, this surge is absent in mice lacking Bmal1. Without the surge, free radicals may remain in the brain longer, contributing to the damage Musiek observed.

“We’re trying to identify more specifics about how problems in clock genes contribute to neurodegeneration, both with and without influencing sleep,” Musiek said. “That’s a challenging distinction to make, but it needs to be made because clock genes appear to control many other functions in the brain in addition to sleeping and waking.”

A new study published 26th November in the open access journal PLOS Biology, identifies a new target in the search for therapeutic interventions for Huntington’s disease – a devastating late-onset neurodegenerative disorder.

The disease is genetic, affecting up to one person in 10,000, and from the age of about 35 leads to increasingly severe problems with movement, mental function, and behavior. Patients usually die within 20 years of onset, and there is to date no treatment that will modify the disease onset or progression.

Huntington’s disease is caused by an unusual type of mutation in a gene that encodes the “huntingtin” protein. These mutations create long stretches of the amino acid glutamine within the protein chain, preventing huntingtin from folding properly and making it more ‘sticky’. This causes huntingtin proteins to self-aggregate in both the nucleus and cytoplasm of cells, disrupting multiple aspects of cellular function and ultimately leading to the progressive death of nerve cells.

Nuclear huntingtin aggregates have been found to interfere with the transcription of many genes, and previous work has shown beneficial effects for Huntington’s disease of inhibiting a family of enzymes that are normally thought to regulate transcription – the histone deacetylases, or HDACs. However, humans have eleven different HDAC enzymes, and it’s been uncertain exactly which HDAC needs to be inhibited to see these benefits.

The new study from Michal Mielcarek, Gillian Bates and colleagues at King’s College London has pinpointed just one of these enzymes as the target – HDAC4 – but with an intriguing twist; everything is happening in the cytoplasm, not the nucleus, and HDAC4’s classic role in transcription has little to do with it.

The researchers noted that the HDAC4 protein naturally contains a region that, like mutant huntingtin, is rich in the amino acid glutamine. They show that HDAC4 can associate directly with huntingtin protein in a manner that depends on the length of the glutamine tracts, but that this association between HDAC4 and huntingtin occurs in the cytoplasm of nerve cells in the mouse brain, and – surprisingly – not in the nucleus, where HDAC4 is known to have its transcriptional role.

Bates and colleagues did their work in an aggressive disease mouse model of Huntington’s disease – the gold standard model for this type of study. They find that halving the levels of HDAC4 in the cells of Huntington’s disease mice can delay the aggregation of huntingtin in the cytoplasm, thereby identifying a new route to modulating the toxicity of mutant huntingtin protein. Crucially, reducing HDAC4 levels can also rescue the overall function of nerve cells and their synapses, with corresponding improvements seen in coordination of movement, neurological performance and lifespan of the mice. In agreement with the cytoplasmic association between HDAC4 and huntingtin, this all happens without any obvious improvement in the defective gene transcription in the nucleus.

There are currently no disease-modifying therapeutics available for Huntington’s disease. It is still very early days and it is important to note that the medical applications of any therapy arising from this study have not been studied in a clinical setting and are far from clear. However, one broad-brush HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) had previously been shown to improve movement defects in preclinical tests in this mouse model. The authors have shown in a related publication that, in addition to inhibiting HDAC enzyme function, SAHA decreases levels of the HDAC4 protein. Therefore it is hoped that the development of HDAC4-targeted compounds may be a promising strategy in improving the lot of Huntington’s disease patients.

A study published recently in the Journal of Neuroscience points, for the first time, to the gene trkC as a factor in susceptibility to the disease. The researchers define the specific mechanism for the formation of fear memories which will help in the development of new pharmacological and cognitive treatments.

Five out of every 100 people* in Spain suffer from panic disorder, one of the diseases included within the anxiety disorders, and they experience frequent and sudden attacks of fear that may influence their everyday lives, sometimes even rendering them incapable of things like going to the shops, driving the car or holding down a job.

It was known that this disease had a neurobiological and genetic basis and for some time the search had been on to discover which genes were involved in its development, with certain genes being implicated without their physiopathological contribution being understood. Now, for the first time, researchers from the Centre for Genomic Regulation (CRG) have revealed that the gene NTRK3, responsible for encoding a protein essential for the formation of the brain, the survival of neurones and establishing connections between them, is a factor in genetic susceptibility to panic disorder.

"We have observed that deregulation of NTRK3 produces changes in brain development that lead to malfunctions in the fear-related memory system", explains Mara Dierssen, head of the Cellular and Systems Neurobiology group at the CRG. “In particular, this system is more efficient at processessing information to do with fear, the thing that makes a person overestimate the risk in a situation and therefore feel more frightened and, also, that stores that information in a more lasting and consistent manner".

Different regions of the human brain are responsible for processing this feeling, although the hippocampus and amygdala play crucial roles. On the one hand, the hippocampus is responsible for forming memories and processing contextual information, which means that the person may be afraid of being in places where they could suffer a panic attack; and on the other, the amygdala is crucial in converting this information into a physiological fear response.

Although these circuits are activated in everyone in warning situations, what the CRG researchers have discovered is that “in those people who suffer from panic disorder there is overactivation of the hippocampus and altered activation in the amygdala circuitry, resulting in exaggerated formation of fear memories”, explains Davide D’Amico, a PhD student at the CRG, co-author of the work and the article published in the Journal of Neuosciences, together with Dierssen and the researcher Mónica Santos.

They have also found that Tiagabine, a drug that modulates the brain’s fear inhibition system, is able to reverse the formation of panic memories. Although it had already been observed to alleviate certain symptoms in some patients, “we have discovered that it specifically helps restore the fear memory system”, points out Dierssen.

Panic disorder

Panic attacks are a key symptom of panic disorder. They can last several minutes, be sudden and repeated, and the sufferer has a physical reaction similar to the alarm response to real danger, involving palpitations, cold sweats, dizziness, shortness of breath, tingling in the body, nausea and stomach pain. On top of this, they feel continuously anxious when faced with the prospect of suffering another attack.

This study by the CRG researchers reveals that the way in which the memories resulting from a panic attack are stored is what ultimately ends up producing the disorder, which usually appears between 20 and 30 years of age. Although it has a genetic basis, it is also influenced by other environmental factors, such as accumulated stress. This is why the authors of the paper consider elevated environmental stress in Spanish society to have led to an increase in the occurrence of these disorders.

Currently, there is no cure for this disease, which is treated with medicines that block the more serious symptoms, as well as with cognitive therapy, which aims to help the person learn to survive the attacks better. “The problem is that drugs have many side effects and psychotherapy is not really aimed at specific moments in the process of forming and forgetting fear memories. In our work we have defined a specific creation mechanism for these fear memories that could help in the development of new drugs and, also, in identifying the key moments for applying cognitive therapy”, indicates D’Amico.

Scientists are a step closer to understanding how some of the brain’s 100 billion nerve cells co-ordinate their communication. The study is published in the journal Cell Reports.

The University of Bristol research team investigated some of the chemical processes that underpin how brain cells co-ordinate their communication. Defects in this communication are associated with disorders such as epilepsy, autism and schizophrenia, and therefore these findings could lead to the development of novel neurological therapies.

Neurons in the brain communicate with each other using chemicals called neurotransmitters. This release of neurotransmitter from neurons is tightly controlled by many different proteins inside the neuron. These proteins interact with each other to ensure that neurotransmitter is only released when necessary. Although the mechanisms that control this release have been extensively studied, the processes that co-ordinate how and when the component proteins interact is not fully understood.

The School of Biochemistry researchers have now discovered that one of these proteins called ‘RIM1α’ is modified by a small protein named ‘SUMO’ which attaches to a specific region in RIM1α. This process acts as a ‘molecular switch’ which is required for normal neurotransmitter release.

Jeremy Henley, Professor of Molecular Neuroscience in the University’s Faculty of Medical and Veterinary Sciences and the study’s lead author, said: “These findings are important as they show that SUMO modification plays a vital and previously unsuspected role in normal brain function.”

The research builds on the team’s earlier work that identified a group of proteins in the brain responsible for protecting nerve cells from damage and could be used in future for therapies for stroke and other brain diseases.

Scientists have moved a step closer to understanding genetic changes that permitted humans and other mammals to develop such big brains.

During evolution, different mammal species have experienced variable degrees of expansion in brain size. An important goal of neurobiology is to understand the genetic changes underlying these extraordinary adaptations.

The process by which some species evolved larger brains – called encephalization – is not well understood by scientists. The puzzle is made more complex because evolving large brains comes at a very high cost.

Dr Humberto Gutierrez, from the School of Life Sciences, University of Lincoln, UK, led research which examined the genomes of 39 species of mammals with the aim of better understanding how brains became larger and more complex in mammals.

To do this, the scientists focussed on the size of gene families across these species. Gene families are groups of related genes which share similar characteristics, often linked with common or related biological functions. It is believed that large changes in the size of gene families can help to explain why related species evolved along different paths.

The researchers found a clear link between increased brain size and the expansion of gene families related to certain biological functions.

Dr Gutierrez said: “We found that brain size variations are associated with changes in gene number in a large proportion of families of closely related genes. These gene families are preferentially involved in cell communication and cell movement as well as immune functions and are prominently expressed in the human brain. Our results suggest that changes in gene family size may have contributed to the evolution of larger brains in mammals.”

Mammalian species in general tend to have large brains compared to their body size which represent an evolutionary costly adaptation as they require large amounts of energy to function.

Dr Gutierrez explained: “The brain is an extremely expensive organ consuming a large amount of energy in proportion to its volume, so large brains place severe metabolic demands on animals. Larger brains also demand higher parental investment. For example, humans require many years of nurturing and care before their brains are fully matured.”

Dr Gutierrez’s research concluded that variations in the size of gene families associated with encephalization provided an evolutionary support for the specific physiological demands associated with increased brain size in mammals.

Establishing links between genes, the brain and human behavior is a central issue in cognitive neuroscience research, but studying how genes influence cognitive abilities and behavior as the brain develops from childhood to adulthood has proven difficult.

Now, an international team of scientists has made inroads to understanding how genes influence brain structure and cognitive abilities and how neural circuits produce language.

The team studied individuals with a rare disorder known as Williams syndrome. By measuring neural activity in the brain associated with the distinct language skills and facial recognition abilities that are typical of the syndrome, they showed that Williams is due not to a single gene but to distinct subsets of genes, hinting that the syndrome is more complex than originally thought.

"Solutions to understanding the connections between genes, neural circuits and behavior are now emerging from a unique union of genetics and neuroscience," says Julie Korenberg, a University of Utah professor and an adjunct professor at the Salk Institute, who led the genetics aspects on the new study.

The study was led by Debra Mills, a professor of cognitive neuroscience at Bangor University in Wales. Ursula Bellugi, a professor at the Salk Institute for Biological Studies in La Jolla, was also integrally involved in the research.

Korenberg was convinced that with Mills’ approach of directly measuring the brain’s electrical firing they could solve the puzzle of precisely which genes were responsible for building the brain wiring underlying the different reaction to human faces in Williams syndrome.

"We also discovered," says Mills, "that in those with Williams syndrome, the brain processes language and faces abnormally from early childhood through middle age. This was a surprise because previous studies had suggested that part of the Williams brain functions normally in adulthood, with little understanding about how it developed."

The results of the study were published November 12, 2013 in Developmental Neuropsychology.

Williams syndrome is caused by the deletion of one of the two usual copies of approximately 25 genes from chromosome 7, resulting in mental impairment. Nearly everyone with the condition is missing these same genes, although a few rare individuals retain one or more genes that most people with Williams have lost. Korenberg was the early pioneer of studying these individuals with partial gene deletions as a way of gathering clues to the specific function of those genes and gene networks. The syndrome affects approximately 1 in 10,000 people around the world, including an estimated 20,000 to 30,000 individuals in the United States.

Although individuals with Williams experience developmental delays and learning disabilities, they are exceptionally sociable and possess remarkable verbal abilities and facial recognition skills in relation to their lower IQ. Bellugi has long observed that sociability also seems to drive language and has spent much of her career studying those with Williams syndrome.

"Williams offers us a window into how the brain works at many different levels," says Bellugi. "We have the tools to measure the different cognitive abilities associated with the syndrome, and thanks to Julie and Debbie we are now able to combine this with studies of the underlying genetic and neurological aspects."

Suspecting that specific genes might lie at the origins of brain plasticity, functional changes in the brain that occur with new knowledge or experiences, and that these genes might be linked to the unusual proficiencies of those with Williams, the team enrolled individuals of various ages in their study. They drew from children, adolescents and adults who all had the full genetic deletion for Williams syndrome and compared them with their non-affected peers. Their study is additionally significant for being one of the first to examine the brain structure and its functioning in children with Williams. And, as Korenberg predicted, a critical piece of the puzzle came from including in their study two adults with partial genetic deletions for Williams.

Using highly sensitive sensors to measure brain activity, the researchers, led by Mills, presented their study participants with both visual and auditory stimuli in the form of unfamiliar faces and spoken sentences. They charted the small changes in voltage generated by the areas of the brain responding to these stimuli, a process known as event-related potentials (ERPs). Mills was the first to publish studies on Williams syndrome using ERPs, developed the ERP markers for this study, and oversaw its design and analysis.

Mills identified ERP markers of brain plasticity in Williams syndrome in children and adults of varying ages and developmental stages. These findings are important because the brains of people with Williams are structured differently than those of people without the syndrome. In the Williams brain, the dorsal areas (along the back and top), which help control vision and spatial understanding, are undersized. The ventral areas (at the front and the bottom), which influence language, facial recognition, emotion and social drive, are relatively normal in size.

It was previously believed that in individuals with Williams, the ventral portion of the brain operated normally. What the team discovered, however, was that this area of the brain also processed information differently than those without the syndrome, and did so throughout development, from childhood to the adult years. This suggests that the brain was compensating in order to analyze information; in other words, it was exhibiting plasticity. Of additional importance, the distinct ERP markers identified by Mills are so characteristic of the different brain organization in Williams that this information alone is approximately 90 percent accurate when analyzing brain activity to identify someone with Williams syndrome.

Other key findings of the study resulted from comparing the ERPs of participants with full Williams deletion with those with partial genetic deletions. While psychological tests focused on facial recognition show no difference between these groups, the scientists found differences in these recognition abilities on the ERP measurements, which look directly at neural activity. Thus, the scientists were able to see how very slight genetic differences affected brain activity, which will allow them identify the roles of sub-sets of Williams genes in brain development and in adult facial recognition abilities.

By combining these one-in-a-million people with tools capable of directly measuring brain activity, the scientists now have the unprecedented opportunity to study the genetic underpinnings of mental disorders. The results of this study not only advance science’s understanding of the links between genes, the brain and behavior, but may lead to new insight into such disorders as autism, Down syndrome and schizophrenia.

"By greatly narrowing the specific genes involved in social disorders, our findings will help uncover targets for treatment and provide measures by which these and other treatments are successful in alleviating the desperation of autism, anxiety and other disorders," says Korenberg.

Our sense of smell is often the first response to environmental stimuli. Odors trigger neurons in the brain that alert us to take action. However, there is often more than one odor in the environment, such as in coffee shops or grocery stores. How does our brain process multiple odors received simultaneously?

Barani Raman, PhD, of the School of Engineering & Applied Science at Washington University in St. Louis, set out to find an answer. Using locusts, which have a relatively simple sensory system ideal for studying brain activity, he found the odors prompted neural activity in the brain that allowed the locust to correctly identify the stimulus, even with other odors present.

The results were published in Nature Neuroscience as the cover story of the December 2013 print issue.

The team uses a computer-controlled pneumatic pump to administer an odor puff to the locust, which has olfactory receptor neurons in its antennae, similar to sensory neurons in our nose. A few seconds after the odor puff is given, the locust gets a piece of grass as a reward, as a form of Pavlovian conditioning. As with Pavlov’s dog, which salivated when it heard a bell ring, trained locusts anticipate the reward when the odor used for training is delivered. Instead of salivating, they open their palps, or finger-like projections close to the mouthparts, when they predict the reward. Their response was less than half of a second. The locusts could recognize the trained odors even when another odor meant to distract them was introduced prior to the target cue.

“We were expecting this result, but the speed with which it was done was surprising,” says Raman, assistant professor of biomedical engineering. “It took only a few hundred milliseconds for the locust’s brain to begin tracking a novel odor introduced in its surrounding. The locusts are processing chemical cues in an extremely rapid fashion.”

“There were some interesting cues in the odors we chose,” Raman says. “Geraniol, which smells like rose to us, was an attractant to the locusts, but citral, which smells like lemon to us, is a repellant to them. This helped us identify principles that are common to the odor processing.

Raman has spent a decade learning how the human brain and olfactory system operate to process scent and odor signals. His research seeks to take inspiration from the biological olfactory system to develop a device for noninvasive chemical sensing. Such a device could be used in homeland security applications to detect volatile chemicals and in medical diagnostics, such as a device to test blood-alcohol level.

This study is the first in a series seeking to understand the principles of olfactory computation, Raman says.

“There is a precursory cue that could tell the brain there is a predator in the environment, and it has to predict what will happen next,” Raman says. “We want to determine what kinds of computations have to be done to make those predictions.”

In addition, the team is looking to answer other questions.

“Neural activity in the early processing centers does not terminate until you stop the odor pulse,” he says. “If you have a lengthy pulse – 5 or 10 seconds long – what is the role of neural activity that persists throughout the stimulus duration and often even after you terminate the stimulus? What are the roles of the neural activity generated at different points in time, and how do they help the system adapt to the environment? Those questions are still not clear.”