Neuroscience

Eating disorders like anorexia nervosa and bulimia often run in families, but identifying specific genes that increase a person’s risk for these complex disorders has proved difficult.

Now scientists from the University of Iowa and University of Texas Southwestern Medical Center have discovered—by studying the genetics of two families severely affected by eating disorders—two gene mutations, one in each family, that are associated with increased risk of developing eating disorders.

Moreover, the new study shows that the two genes interact in the same signaling pathway in the brain, and that the two mutations produce the same biological effect. The findings suggest that this pathway might represent a new target for understanding and potentially treating eating disorders.

"If you’re considering two randomly discovered genes, the chance that they will interact is small. But, what really sealed the deal for us that the association was real was that the mutations have the same effect," says Michael Lutter, UI assistant professor of psychiatry and senior author of the study.

Overall, the study, published Oct. 8 in the Journal of Clinical Investigation, suggests that mutations that decrease the activity of a transcription factor—a protein that turns on the expression of other genes—called estrogen-related receptor alpha (ESRRA) increase the risk of eating disorders.

The challenge of finding genes for complex diseases

Anorexia nervosa and bulimia nervosa are fairly common, especially among women. They affect between 1 and 3 percent of women. They also are among the most lethal of all psychiatric diseases; about 1 in 1,000 women will die from anorexia.

Finding genes associated with complex diseases like eating disorders is challenging. Scientists can analyze the genetics of thousands of people and use statistics to find common, low-risk gene variations, the accumulation of which causes complex disorders from psychiatric conditions like eating disorders to conditions like heart disease or obesity.

On the other end of the spectrum are very rare gene variants, which confer an almost 100 percent risk of getting the disease. To track down these variants, researchers turn to large families that are severely affected by an illness.

Lutter and his colleagues were able to work with two such families to identify the two new genes associated with eating disorders.

"It’s basically a matter of finding out what the people with the disorder share in common that people without the disease don’t have," Lutter explains. "From a theoretical perspective, it’s straightforward. But the difficulty comes in having a large enough group to find these rare genes. You have to have large families to get the statistical power."

In the new study, 20 members from three generations of one family (10 affected individuals and 10 unaffected), and eight members of a second family (six affected and two unaffected) were analyzed.

Two genes, one pathway

The gene discovered in the larger family was ESRRA, a transcription factor that turns on the expression of other genes. The mutation associated with eating disorders decreases ESSRA activity.

The gene found in the second family is a transcriptional repressor called histone deacetylase 4 (HDAC4), which turns off transcription factors, including ESRRA. This mutation is unusual in the sense that it increases the gene’s activity—most mutations decrease or destroy a gene’s activity.

Importantly, the team also found that the two affected proteins interacted with one another; HDAC4 binds to ESRRA and inhibits it.

"The fact that the HDAC4 mutation happens to increase the gene activity and happens to increase its ability to repress the ESSRA protein we found in the other family was just beyond coincidence," Lutter says.

The two genes are already known to be involved in metabolic pathways in muscle and fat tissue. They also are both regulated by exercise.

In the brain, HDAC4 is very important for regulating genes that form connections between neurons. However, there’s almost nothing known about ESRRA in the brain, although it is expressed in many brain regions that are disrupted in anorexia.

Lutter and his colleagues plan to study the role of these genes in mice and in cultured neurons to find out exactly what they are doing in the brain. They will also look for ways to modify the genes’ activity, with the long-term goal of finding small molecules that might be developed into therapies for eating disorders.

They also plan to study patients with eating disorders and see if other genes associated with the ESSRA/HDAC4 brain pathway are affected in humans.

Scientists at the Montreal Neurological Institute and Hospital-The Neuro, McGill University, have made important discoveries about a cellular process that occurs during normal brain development and may play an important role in neurodegenerative diseases. The study’s findings, published in Cell Reports, a leading scientific journal, point to new pathways and targets for novel therapies for Alzheimer’s, Parkinson’s, ALS and other neurodegenerative diseases that affect millions of people world-wide.

Research into neurodegenerative disease has traditionally concentrated on the death of nerve cell bodies. However, it is now certain that in most cases that nerve cell body death represents the final event of an extended disease process. Studies have shown that protecting cell bodies from death has no impact on disease progression whereas blocking preceding axon breakdown has a significant benefit.  The new study by researchers at The Neuro shifts the focus to the loss or degeneration of axons, the nerve-cell ‘branches’ that receive and distribute neurochemical signals among neurons.

During early development, axons are pruned to ensure normal growth of the nervous system. Emerging evidence suggests that this pruning process becomes reactivated in neurodegenerative disease, leading to the aberrant loss of axons and dendrites. Axonal pruning in development is significantly influenced by proteins called caspases. “The idea that caspases are even involved in axonal degeneration during development is very recent” said Dr. Philip Barker, a principal investigator at The Neuro and senior author of the study.

Dr. Barker and his colleagues show that the activity of certain ’executioner’ caspases (caspase-3 and caspase-9) induce axonal degeneration and that their action is suppressed by a protein termed XIAP (X-linked inhibitor of apoptosis). “We found that caspase-3- and -9 play crucial roles in axonal degeneration and that their activities are regulated by XIAP. XIAP acts as a brake on caspase activity and must be removed for degeneration to proceed” added Dr. Barker.  

This balancing act between caspases and XIAP ensure that caspases do not cause unnecessary or excessive destruction. However, this balance may shift during neurodegenerative disease. “If we understand the pathways that regulate XIAP levels, we may be able to develop therapies that reduce caspase-dependent degeneration during neurodegenerative disease”.

In a breakthrough for understanding brain evolution, neuroscientists have shown that differences between primate brains - from the tiny marmoset to human – can be largely explained as consequences of the same genetic program.

In research published in the Journal of Neuroscience, Professor Marcello Rosa and his team at Monash University’s School of Biomedical Sciences and colleagues at Universidade Federal do Rio de Janeiro, in Brazil, used computer modelling to demonstrate that the substantial enlargement of some areas of the human brain, vital to advanced cognition, reflected a consistent pattern that is seen across primate species of all sizes.

This finding suggests how the neural circuits responsible for traits that we consider uniquely human – such as the ability to plan, make complex decisions and speak – could have emerged simply as a natural consequence of the evolution of larger brains.

“We have known for a long time that certain areas of the human brain are much larger than one would expect based on how monkey brains are organised,” Professor Rosa said. 

“What no one had realised is that this selective enlargement is part of a trend that has been present since the dawn of primates.”

Using publicly available brain maps, MRI imaging data and modelling software, the neuroscientists compared the sizes of different brain areasin humans and three monkey species: marmosets, capuchins and macaques. They found that two regions, the lateral prefrontal cortex and the temporal parietal junction, expand disproportionally to the rest of the brain.

The prefrontal cortex is related to long term planning, personality expression, decision-making, and behaviour modification. The temporal parietal junction is related to self-awareness and self-other distinction.

Lead author Tristan Chaplin, from the Department of Physiology will commence his PhD next year. He said the findings showed that those areas of the brain grew disproportionately in a predictable way.

“We found that the larger the brain is, the larger these areas get,” Tristan said.

“When you go from a small to big monkey - the marmoset to macaque - the prefrontal cortex and temporal parietal junction get larger relative to the rest of the cortex, and we see the same thing again when you compare macaques to humans.”

“This trend argues against the view that specific human mutations gave us these larger areas and advanced cognition and behaviour, but are a consequence of what happens in development when you grow a larger brain,” Tristan said.

Professor Rosa said the pattern held for primate species that evolved completely separately.

"If you compare the capuchin of South America and the macaque of Asia, their brains are almost identical, although they developed on opposite sides of the world. They both reflect the genetic plan of how a primate brain grows," Professor Rosa said.

This is the first computational comparative study conducted across several primate species. Tristan now hopes, in collaboration with zoos, to check if our closest primate relatives, the chimpanzees and gorillas, also have brain areas organised as his theory predicts.

Subtle body cues allow people to identify others with surprising accuracy when faces are difficult to differentiate. This skill may help researchers improve person-recognition software and expand their understanding of how humans recognize each other.

A study published in Psychological Science by researchers at The University of Texas at Dallas demonstrates that humans rely on non-facial cues, such as body shape and build, to identify people in challenging viewing conditions, such as poor lighting.

“Psychologists and computer scientists have concentrated almost exclusively on the role of the face in person recognition,” explains lead researcher Allyson Rice. “Our results show that the body can also provide important and sometimes sufficient identity information for person recognition.”

During several experiments, researchers asked college-age participants to look at images of two people side-by-side and identify whether the images showed the same person. Some pairs looked similar despite showing different people, while other image pairs showed the same person with a different appearance. The researchers used computer face recognition systems to find pairs of pictures in which facial characteristics were difficult to use for identity.

Overall, participants accurately discerned whether the images showed the same person when they were provided complete images that showed both the face and body. Participants were just as accurate in identifying people in the image pairs when the faces were blocked out and only the bodies were shown. But, similarly to the computer-based face recognition system, participants had trouble identifying images of the subjects’ faces without their bodies.

Image: Above are pairs of photographs that face-recognition software failed to identify correctly. The top two photos are of the same person, while the bottom two photos are of different people

When asked, participants thought they were using primarily facial features to identify the subjects. To unravel the paradox, the researchers used eye-tracking equipment to determine where participants were actually looking. They found participants spent more time looking at the body whenever the face did not provide enough information to identify the subjects.

“People’s recognition strategies were inaccessible to their conscious awareness,” Rice said. “This provides a cautionary tale in ascribing credibility to people’s subjective reports of how they came to an identity decision.”

Dr. Alice O’Toole, Aage and Margareta Møller Professor in the School of Behavioral and Brain Sciences, has worked on facial recognition for over 15 years and supervised the project.

“Given the widespread use of face recognition systems in security settings, it is important for these systems to make use of all potentially helpful information,” O’Toole said. “Our work shows that the body can be surprisingly useful for identification, especially when the face fails to provide the necessary identity information.”

TAU researchers find chemicals in marijuana could help treat MS

Multiple sclerosis is an inflammatory disease in which the immune system attacks the nervous system. The result can be a wide range of debilitating motor, physical, and mental problems. No one knows why people get the disease or how to treat it.

In a new study published in the Journal of Neuroimmune Pharmacology, Drs. Ewa Kozela, Ana Juknat, Neta Rimmerman and Zvi Vogel of Tel Aviv University’s Dr. Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases and Sackler Faculty of Medicine demonstrate that some chemical compounds found in marijuana can help treat MS-like diseases in mice by preventing inflammation in the brain and spinal cord.

"Inflammation is part of the body’s natural immune response, but in cases like MS it gets out of hand," says Kozela. "Our study looks at how compounds isolated from marijuana can be used to regulate inflammation to protect the nervous system and its functions." Researchers from the Weizmann Institute of Science co-authored the study.

Mind-altering findings

Israel has a strong tradition of marijuana research. Israeli scientists Raphael Mechoulam and Yechiel Gaoni discovered THC, or tetrahydrocannabinol, in 1964, kick-starting the scientific study of the plant and its chemical constituents around the world. Since then, scientists have identified about 70 compounds — called cannabinoids — that are unique to cannabis and have interesting biological effects. In the 1990s, Prof. Vogel was among the first researchers to describe endocannabinoids, molecules that act like THC in the body.

Besides THC, the most plentiful and potent cannabinoid in marijuana is cannabidiol, or CBD. The TAU researchers are particularly interested in CBD, because it offers medicinal benefits without the controversial mind-altering effects of THC.

In a 2011 study, they showed that CBD helps treat MS-like symptoms in mice by preventing immune cells in their bodies from transforming and attacking the insulating covers of nerve cells in the spinal cord. After inducing an MS-like condition in mice — partially paralyzing their limbs — the researchers injected them with CBD. The mice responded by regaining movement, first twitching their tails and then beginning to walk without a limp. The researchers noted that the mice treated with CBD had much less inflammation in the spinal cord than their untreated counterparts.

High hopes for humans

In the latest study, the researchers set out to see if the known anti-inflammatory properties of CBD and THC could also be applied to the treatment of inflammation associated with MS — and if so, how. This time they turned to the immune system.

The researchers took immune cells isolated from paralyzed mice that specifically target and harm the brain and spinal cord, and treated them with either CBD or THC. In both cases, the immune cells produced fewer inflammatory molecules, particularly one called interleukin 17, or IL-17, which is strongly associated with MS and very harmful to nerve cells and their insulating covers. The researchers concluded that the presence of CBD or THC restrains the immune cells from triggering the production of inflammatory molecules and limits the molecules’ ability to reach and damage the brain and spinal cord.

Further research is needed to prove the effectiveness of cannabinoids in treating MS in humans, but there are reasons for hope, the researchers say. In many countries, CBD and THC are already prescribed for the treatment of MS symptoms, including pain and muscle stiffness.

"When used wisely, cannabis has huge potential," says Kozela, who previously studied opiates like morphine, derived from the poppy plant. "We’re just beginning to understand how it works."

Researchers discover that an important clue to diagnosing Parkinson’s disease may lie just beneath the skin

Although Parkinson’s disease is the second most prevalent neurodegenerative disorder in the U.S., there are no standard clinical tests available to identify this widespread condition. As a result, Parkinson’s disease often goes unrecognized until late in its progression, when the brain’s affected neurons have already been destroyed and telltale motor symptoms such as tremor and rigidity have already appeared.

Now researchers from Beth Israel Deaconess Medical Center (BIDMC) have discovered that an important clue to diagnosing Parkinson’s may lie just beneath the skin.

In a study scheduled to appear in the October 29 print issue of the journal Neurology and currently published on-line, the investigators report that elevated levels of a protein called alpha-synuclein can be detected in the skin of Parkinson’s patients, findings that offer a possible biomarker to enable clinicians to identify and diagnose PD before the disease has reached an advanced stage.

Parkinson’s disease affects more than 1 million individuals throughout the U.S. Diagnosis is currently made through neurological history and examination, often by a patient’s primary care physician.

“Even the experts are wrong in diagnosing Parkinson’s disease a large percentage of the time,” says senior author Roy Freeman, MD, Director of the Autonomic and Peripheral Nerve Laboratory at BIDMC and Professor of Neurology at Harvard Medical School. “A reliable biomarker could help doctors in more accurately diagnosing Parkinson’s disease at an earlier stage and thereby offer patients therapies before the disease has progressed.”

Alpha-synuclein is a protein found throughout the nervous system. Although its function is unknown, it is the primary component of protein clumps known as Lewy bodies, which are considered the hallmark of Parkinson’s disease. There is accumulating evidence that the protein plays a role in Parkinson’s disease development.

“Alpha-synuclein deposition occurs early in the course of Parkinson’s disease and precedes the onset of clinical symptoms,” explains Freeman, who with his coauthors suspected that the protein was elevated in the skin’s structures with autonomic innervation.

“Symptoms related to the autonomic nervous system, including changes in bowel function, temperature regulation, and blood pressure control may antedate motor symptoms in Parkinson’s patients,” he explains. “Skin-related autonomic manifestations, including excessive and diminished sweating and changes in skin color and temperature, occur in almost two-thirds of patients with Parkinson’s disease. The skin can provide an accessible window to the nervous system and based on these clinical observations, we decided to test whether examination of the nerves in a skin biopsy could be used to identify a PD biomarker.”

To test this hypothesis, the research team enrolled 20 patients with Parkinson’s disease and 14 control subjects of similar age and gender. The participants underwent examinations, autonomic testing and skin biopsies in three locations on the leg. Alpha-synuclein deposition and density of cutaneous sensory, sudomotor and pilomotor nerve fibers were measured.

As predicted, their results showed that alpha-synuclein was increased in the cutaneous nerves supplying the sweat glands and pilomotor muscles in the Parkinson’s patients. Higher alpha-synuclein deposition in the nerves supplying the skin’s autonomic structures was associated with more advanced Parkinson’s disease and worsening autonomic function.

“There is a strong and unmet need for a biomarker for Parkinson’s disease,” says Freeman. “Alpha-synuclein deposition within the skin has the potential to provide a safe, accessible and repeatable biomarker. Our next steps will be to test whether this protein is present in the cutaneous nerves of individuals at risk for Parkinson’s disease, and whether measurement of alpha-synuclein deposition in the skin can differentiate Parkinson’s disease from other neurodegenerative disorders.”

Babies learn how to anticipate touch while in the womb, according to new research.

Using 4-d scans psychologists at Durham and Lancaster universities found, for the first time, that fetuses were able to predict, rather than react to, their own hand movements towards their mouths as they entered the later stages of gestation compared to earlier in a pregnancy.

The Durham-led team of researchers said that the latest findings could improve understanding about babies, especially those born prematurely, their readiness to interact socially and their ability to calm themselves by sucking on their thumb or fingers.

They said the results could also be a potential indicator of how prepared babies are for feeding.

The researchers carried out a total of 60 scans of 15 healthy fetuses at monthly intervals between 24 weeks and 36 weeks gestation.

Fetuses in the earlier stage of gestation more frequently touched the upper part and sides of their heads.

As the fetuses matured they began to increasingly touch the lower, more sensitive, part of their faces including their mouths.

By 36 weeks a significantly higher proportion of fetuses were observed opening their mouths before touching them, suggesting that later in pregnancy they were able to anticipate that their hands were about to touch their mouths, rather than reacting to the touch of their hands, the researchers said.

Increased sensitivity around a fetus’ mouth at this later stage of pregnancy could mean that they have more “awareness” of mouth movement, they added.

Previous theories have suggested that movement in sequence could form the basis for the development of intention in fetuses.

The researchers said their findings could potentially be an indicator of healthy development, as arguably fetuses who are delayed in this development due to illness, such as growth restriction, might not show the same behaviour observed during the study.

The research, published in the journal Developmental Psychobiology, involved eight girls and seven boys and the researchers noticed no difference in behaviour between boys and girls.

Lead author Dr Nadja Reissland, in the Department of Psychology, at Durham University, said: “Increased touching of the lower part of the face and mouth in fetuses could be an indicator of brain development necessary for healthy development, including preparedness for social interaction, self-soothing and feeding.

“What we have observed are sequential events, which show maturation in the development of fetuses, which is the basis for life after birth.

“The findings could provide more information about when babies are ready to engage with their environment, especially if born prematurely.”

Brian Francis, Professor of Social Statistics at Lancaster, added: “This effect is likely to be evolutionally determined, preparing the child for life outside the womb. Building on these findings, future research could lead to more understanding about how the child is prepared prenatally for life, including their ability to engage with their social environment, regulate stimulation and being ready to take a breast or bottle.”

The study builds on previous research by Durham and Lancaster into fetal development. Earlier this year another of their studies showed that unborn babies practise facial expressions in the womb in what is thought to be preparation for communicating after birth.

And in 2012 Dr Reissland published research showing that unborn babies yawn in the womb, suggesting that yawning is a developmental process which could potentially give doctors another index of a fetus’ health.

It’s a question that has long fascinated and flummoxed those who study human behavior: From whence comes the impulse to dream? Are dreams generated from the brain’s “top” — the high-flying cortical structures that allow us to reason, perceive, act and remember? Or do they come from the brain’s “bottom” — the unheralded brainstem, which quietly oversees such basic bodily functions as respiration, heart rate, salivation and temperature control?

At stake is what to make of the funny, sexual, scary and just plain bizarre mental scenarios that play themselves out in our heads while we sleep. Are our subconsious fantasies coming up for a breath of air, as Sigmund Freud believed? Is our brain consolidating lessons learned and pitching out unneeded data, as neuroscientists suggest? Or are dreams no more meaningful than a spontaneous run of erratic heartbeats, a hot flash, or the frisson we feel at the sight of an attractive passer-by?

A study published this week in the journal Brain suggests that the impulse to dream may be little more than a tickle sent up from the brainstem to the brain’s sensory cortex.

The full dream experience — the complex scenarios, the feelings of fear, delight or longing — may require the further input of the brain’s higher-order cortical areas, the new research suggests. But even people with grievous injury to the brain’s prime motivational machinery are capable of dreams, the study found.

The latest research looked for sleep-time “mentation” — thoughts, essentially — in a small group of very unusual patients. These patients — 13 in all — had suffered damage within their brains’ limbic system, the seat of our basic desires and motivations — for sex, for food, for pleasurable sensations brought on by drugs and friendship and whatever else turns us on.

As a result of that damage, they had a neuropsychological syndrome called auto-activation deficit, or AAD: Even while fully conscious, they could sit completely idle and mute for hours if they were not prodded to action or speech by caregivers. In fact, they were more than unmotivated to do anything; when asked about their thoughts, they would frequently report that their mind was completely blank. When prompted, they could often do math, sing a song or conjure up memories. But left on their own, these patients might have no spontaneous thoughts at all.

Do these people dream? The answer might suggest the answer to the question of where dreams come from.

Indeed, they do dream — or at least some of them did, in an experiment that compared the nighttime mentations of normal, healthy subjects with subjects who suffered from AAD. When awakened from rapid eye movement (REM) sleep — the sleep stage at which dreams are thought to be most common and complex — four of the patients with AAD — 31% of them — reported mentations.

That was a lot less dreaming than was happening in the healthy subjects, 92% of whom reported dreams — and much more colorful and bizarre ones — when they were awakened from REM sleep.

In the AAD patients, the dreams were rarer, shorter and less complex: they said they dreamed of things like shaving, taking a walk or seeing a relative. But even these rudimentary dreams cast them in situations that, in a conscious state, they were unlikely to think of unprompted.

That these inert patients could generate dreams was a “most unexpected result,” said the study’s authors, a team of French neurologists, neuroscientists and sleep specialists based in several institutes in Paris. It supports the hypothesis that “dreams are generated through bottom-up processes,” they concluded.

The “top-down theory” — that dreams originate from the brain’s higher-order cortex, the place from which imagination springs — “is not supported here,” the authors said, “as patients with AAD who have a mental emptiness and no imagination during wakefulness do report some dream mentations upon emerging from sleep.”

Of course, the dreams of healthy subjects may be enbellished by input from the cortical areas that are the seats of perception, memory, emotion and reason, the authors said: That is demonstrated by the vastly richer dreams described by normal subjects.

A lot of dream research in humans has been based on subjects with bizarre damage to the brain. People who have had frontal lobotomies, for instance, report an abrupt cessation of dream activity — an observation that had rallied the top-down view of the dream impulse.

It’s an imperfect method of research, since such subjects are rare and no two have exactly the same injuries. So, while the rest of us dream away unbothered, this intriguing debate is likely to remain open for some time to come.

An inhibitory neuron type is found to specifically suppress the activation of other inhibitory neurons in cerebral cortex.

The cerebral cortex contains two major types of neurons: principal neurons that are excitatory and interneurons that are inhibitory, all interconnected within the same network. New research now reveals that one class of inhibitory neurons – called VIP interneurons — specializes in inhibiting other inhibitory neurons in multiple regions of cortex, and does so under specific behavioral conditions.

The new research finds that VIP interneurons, when activated, release principal cells from inhibition, thus boosting their responses. This provides an additional layer of control over cortical processing, much like a dimmer switch can fine-tune light levels.

The discovery was made by a team of neuroscientists at Cold Spring Harbor Laboratory (CSHL) led by Associate Professor Adam Kepecs, Ph.D. Their research, published online today in Nature, shows that neurons expressing vasoactive intestinal polypeptide, or VIP, provide disinhibition in the auditory cortex and the medial prefrontal cortex. 

The researchers used molecular tagging techniques developed by team member Z. Josh Huang, a CSHL Professor, to single out VIP-expressing neurons in the vast diversity of cortical neurons. This enabled Kepecs’ group, led by postdocs Hyun Jae Pi and Balazs Hangya, to employ advanced optogenetic techniques using color-coded laser light to specifically activate VIP neurons. The activity of the cells was monitored via electrophysiological recordings in behaving animals to study their function, and in vitro to probe their circuit properties.

These VIP neurons are long sought “disinhibitory” cells: they inhibit other classes of inhibitory neurons; but they do not directly cause excitation to occur in brain. Dr. Kepecs and colleagues propose that the disinhibitory control mediated by VIP neurons represents a fundamental “motif” in cerebral cortex.

The difference between neural excitation and disinhibition is akin to the difference between hitting the gas pedal and taking your foot off the breaks. Cells that specialize in releasing the brakes, Dr. Kepecs explains, provide the means for balancing between excitation and inhibition. Kepecs calls this function “gain modulation,” which brings to mind the fine control that a dimmer switch provides.

The team wondered when VIP neurons are activated during behavior. When, in other words, is the “cortical dimmer switch” engaged? To learn the answer the scientists recorded VIP neurons while mice were making simple decisions, discriminating between sounds of different pitches. When they made correct choices, the mice earned a drop of water; for incorrect choices, a mild puff of air. Surprisingly, the team found that in auditory cortex, a region involved in processing sounds, VIP neurons were activated by rewards and punishments. Thus these neurons appeared to mediate the impact of reinforcements and “turn up the lights” on principal cells, to use the dimmer-switch analogy.

“Linking specific neuronal types to well-defined behaviors has proved extremely difficult,” says Kepecs. These results, he says, potentially link the circuit-function of VIP neurons in gain control to an important behavioral function: learning.

It’s not visible to the naked eye and you can’t feel it, but up to 40 per cent of your body’s energy goes into supplying the microscopic sodium-potassium pump with the energy it needs. The pump is constantly doing its job in every cell of all animals and humans. It works much like a small battery which, among other things, maintains the sodium balance which is crucial to keep muscles and nerves working.

The sodium-potassium pump transports sodium out and potassium into the cell in a fixed cycle. During this process the structure of the pump changes. It is well-established that the pump has a sodium and a potassium form. But the structural differences between the two forms have remained a mystery, and researchers have been unable to explain how the pump distinguishes sodium from potassium.

Structure solves the mystery

Thanks to the international collaboration between Professor Chikashi Toyoshima’s group at the University of Tokyo and researchers from Aarhus University, the structure of the sodium-bound form of the protein has now been described. For the first time ever, the sodium ions can be studied at a resolution so high - 0.28 nanometres - that researchers can actually see the sodium ions and observe where they bind in the structure of the pump. In 2000, Professor Chikashi Toyoshima’s group described the structure of a calcium-pump for the first time, and in 2007 and 2009 research groups from Aarhus University and Toyoshima’s group described the potassium-bound form of the sodium-potassium pump.

"The new protein structure shows how the smaller sodium ions are bound and subsequently transported out of the cell, whereas the access of the slightly larger potassium ions is blocked. We now understand how the pump distinguishes between sodium and potassium at the molecular level. This is a great leap forward for research into ion pumps and may help us understand and treat serious neurological conditions associated with mutations of the sodium-potassium pump, including a form of Parkinsonism and alternating hemiplegia of childhood in which sodium binding is defective," explains Bente Vilsen, a professor at Aarhus University who spearheaded the project’s activities in Aarhus with Associate Professor Flemming Cornelius.

Impressed Nobel Prize winner

The vital pump was discovered in 1957 by Professor Jens Christian Skou of Aarhus University, who received the Nobel Prize for his discovery in 1997. The new result is the culmination of five or six decades of research aimed at the mechanism behind this vital motor of the cells.

"Years ago, when the first electron microscopic images were taken in which the enzyme was but a millimetre-sized dot at 250,000 magnifications, I thought, how on earth will we ever be able to establish the structure of the enzyme. The pump transports potassium into and sodium out of the cells, so it must be capable of distinguishing between the two ions. But until now, it has been a mystery how this was possible," says retired Professor Jens Christian Skou, who - even at 94 years of age - keeps up to date with new developments in the field of research which he initiated more than 50 years ago.

"Now, the researchers have described the structure that allows the enzyme to identify sodium and this may pave the way for a more detailed understanding of how the pump works. It is an impressive achievement and something I haven’t even dared dream of," concludes Jens Christian Skou.

Study brings to 110 known risk factors and provides important insight into disease mechanism

Scientists of the International Multiple Sclerosis Genetics Consortium (IMSGC) have identified an additional 48 genetic variants influencing the risk of developing multiple sclerosis. This work nearly doubles the number of known genetic risk factors and thereby provides additional key insights into the biology of this debilitating neurological condition. The genes implicated by the newly identified associations underline the central role played by the immune system in the development of multiple sclerosis and show substantial overlap with genes known to be involved in other autoimmune diseases.

Published online September 29 in the journal Nature Genetics, the study, “Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis,” is the largest investigation of multiple sclerosis genetics to date. Led by the University of Miami Miller School of Medicine, this study relied upon an international team of 193 investigators from 84 research groups in 13 countries and was funded by more than 40 local and national agencies and foundations.

Multiple sclerosis (MS) is a chronic disabling neurological condition that affects over 2.5 million individuals worldwide. The disease results in patchy inflammation and damage to the central nervous system that causes problems with mobility, balance, sensation and cognition depending upon where the damage to the central nervous system occurs. Neurological symptoms are often intermittent in the early stages of the disease but tend to persist and progressively worsen with the passage of time for the majority of patients. The risk of developing multiple sclerosis is increased in those who have a family history of the disease. Research studies in twins and adopted individuals have shown that this increased risk is primarily the result of genetic risk factors.

The findings released in this study nearly double the number of confirmed susceptibility loci, underline the critical role played by the immune system in the development of multiple sclerosis, and highlight the marked similarities between the genetic architecture underlying susceptibility to this and the many other autoimmune diseases.

The present study takes advantage of custom designed technology known as ImmunoChip—a high-throughput genotyping array specifically designed to interrogate a targeted set of genetic variants linked to one or more autoimmune diseases. IMSGC researchers used the ImmunoChip platform to analyze the DNA from 29,300 individuals with multiple sclerosis and 50,794 unrelated healthy controls, making this the largest genetics study ever performed for multiple sclerosis. In addition to identifying 48 new susceptibility variants, the study also confirmed and further refined a similar number of previously identified genetic associations.

With these new findings, there are now 110 genetic variants associated with MS. Although each of these variants individually confers only a very small risk of developing multiple sclerosis, collectively they explain approximately 20 percent of the genetic component of the disease.

Explaining the significance of the work and the nature of the collaboration, the Miller School’s Jacob McCauley, Ph.D., who led the study on behalf of the IMSGC, said, “With the release of these new data, our ongoing effort to elucidate the genetic components of this complex disease has taken a major step forward. Describing the genetic underpinnings of any complex disease is a complicated but critical step. By further refining the genetic landscape of multiple sclerosis and identifying novel genetic associations, we are closer to being able to identify the cellular and molecular processes responsible for MS and therefore the specific biological targets for future drug treatment strategies. These results are the culmination of a thoroughly collaborative effort. A study of this size and impact is only possible because of the willingness of so many hard working researchers and thousands of patients to invest their time and energy in a shared goal.”

Scientists discover key function in molecule that regulates sleep, metabolism and hunger

Why does hunger keep us awake and a full belly make us tired? Why do people with sleep disorders such as insomnia often binge eat late at night? What can sleep patterns tell us about obesity?

Sleep, hunger and metabolism are closely related, but scientists are still struggling to understand how they interact. Now, Brandeis University researchers have discovered a function in a molecule in fruit flies that may provide insight into the complicated relationship between sleep and food.

In the October issue of the journal Neuron, Brandeis scientists report that sNPF, a neuropeptide long known to regulate food intake and metabolism, is also an important component in regulating and promoting sleep. When researchers activated sNPF in fruit flies, the insects fell asleep almost immediately, awaking only long enough to eat before nodding off again. The flies were so sleepy that once they found a food source, they slept right on top of it for days — like falling asleep on a giant hamburger bun and waking up long enough to take a few nibbles before falling back to sleep.

When researchers returned sNPF functions to normal, the flies resumed their normal level of activity, leaving behind their couch potato ways.

The researchers, led by professor of biology Leslie Griffith, concluded that sNPF has an important regulatory function in sleep in addition to its previously known function coordinating behaviors such as eating and metabolism.

"This paper provides a nice bridge between feeding behavior and sleep behavior with just a single molecule," says Nathan Donelson, a post doctoral fellow in Griffith’s lab and one of the study’s lead authors.

Neurons use neuropeptides to communicate a range of brain functions including learning, metabolism, memory and social behaviors. In humans, Neuropeptide Y functions similarly to sNPF and has been studied as a possible drug target for obesity treatment.

But scientists don’t fully understand how regulating neuropeptide function at specific times and in specific cells affects sleeping and eating. By studying sNPF in fruit flies, scientists can learn which cells, neurotransmitters and genes are involved in eating and sleeping; what processes turn on and inhibit the behaviors, and how sleep cells are relevant to hunger drive.

"Our paper makes a significant step into tying all these things together," says Donelson, "and that is extremely important down the road to our understanding of human health."

The membranes surrounding and inside cells are involved in every aspect of biological function. They separate the cell’s various metabolic functions, compartmentalize the genetic material, and drive evolution by separating a cell’s biochemical activities. They are also the largest and most complex structures that cells synthesize.

Understanding the myriad biochemical roles of membranes requires the ability to prepare synthetic versions of these complex multi-layered structures, which has been a long-standing challenge.

In a study published this week by Nature Chemistry, scientists at The Scripps Research Institute (TSRI) report a highly programmable and controlled platform for preparing and experimentally probing synthetic cellular structures.

“Layer-by-layer membrane assembly allows us to create synthetic cells with membranes of arbitrary complexity at the molecular and supramolecular scale,” said TSRI Assistant Professor Brian Paegel, who authored the study with Research Associate Sandro Matosevic. “We can now control the molecular composition of the inner and outer layers of a bilayer membrane, and even assemble multi-layered membranes that resemble the envelope of the cell nucleus.”

Starting with a technique commonly used to deposit molecules on a solid surface, Langmuir-Blodgett deposition, the scientists repurposed the approach to work on liquid objects.

The scientists engineered a microfluidic device containing an array of microscopic cups, each trapping a single droplet of water bathed in oil and lipids, the molecules that make up cellular membranes. The trapped droplets are then ready to serve as a foundation for building up a series of lipid layers like coats of paint.

The lipid-coated water droplets are first bathed in water. As the water/oil interface encounters the trapped droplets, a second lipid layer coats the droplets and transforms them into what are known as unilamellar or single-layer vesicles. Bathing the vesicles in oil/lipid deposits a third lipid layer, and followed by a final layer of lipids that is deposited on the trapped drops to yield double-bilayer vesicles.

“The computer-controlled microfluidic circuits we have constructed will allow us to assemble synthetic cells not only from biologically derived lipids, but from any amphiphile and to measure important chemical and physical parameters, such as permeability and stability,” said Paegel.

A team of scientists led by Dr. Antoine Adamantidis, a researcher at the Douglas Mental Health University Institute and an assistant professor at McGill University, has released the findings from their latest study, which will appear in the October issue of the prestigious scientific journal Nature Neuroscience.

(Image: iStockphoto)

Previous studies had established an association between the activity of certain types of neurons and the phase of sleep known as REM (rapid eye movement). Researchers on the team of Dr. Antoine Adamantidis identified, for the first time, a precise causal link between neuronal activity in the lateral hypothalamus (LH) and the state of REM sleep. Using optogenetics, they were able to induce REM sleep in mice and modulate the duration of this sleep phase by activating the neuronal network in this area of the brain.

This achievement is an important contribution to the understanding of sleep mechanisms in the brains of mammals, as well as the underlying neuronal network, which is still not well understood despite recent breakthroughs in neuroscience.

Better understanding how sleep is modulated to reduce sleep disorders

“These research findings could help us better grasp how the brain controls sleep and better understand the role of sleep in humans. These results could also lead to new therapeutic strategies to treat sleep disorders along with associated neuropsychiatric problems,” stated Dr. Antoine Adamantidis, who is also the Canada Research Chair in Neural Circuits and Optogenetics.

What is REM (rapid eye movement) sleep?

There are two types of sleep: REM and non-REM sleep. In humans, non-REM sleep has four stages. REM sleep, or deep sleep, is generally associated with dreaming and is a phase when the brain is very active, even though people are in a heavy sleep, their eyes move rapidly (hence the name), and their bodies have an almost total loss of muscle tonus.
Although our understanding of the mechanisms that control the wake and sleep cycle has progressed in recent years, many frontiers remain unexplored. However, we do know that a disruption in sleep can lead to adverse effects on physical and mental health in humans.

Optogenetics, a revolutionary technology

In 2010 in the journal Nature, optogenetics was recognized as one of the coming decade’s most promising techniques to better understand brain function. This new field of research and application integrates optics and genetics methodologies to modulate the activity of neural circuits. Optogenetics involves controlling neuronal activity with light. This technique is therefore used to manipulate a specific type of cell without affecting neighbouring cells. A researcher who uses optogenetics is therefore like a conductor who decides to change the sheet music for an instrument to observe the effects, however insignificant they may seem, on the orchestra’s entire performance.

As Baby Boomers age, many experience difficulty in hearing and understanding conversations in noisy environments such as restaurants. People who are hearing-impaired and who wear hearing aids or cochlear implants are even more severely impacted. Researchers know that the ability to locate the source of a sound with ease is vital to hear well in these types of situations, but much more information is needed to understand how hearing works to be able to design devices that work better in noisy environment.  

Researchers from the Eaton-Peabody Laboratories of the Massachusetts Eye and Ear, Harvard Medical School, and Research Laboratory of Electronics, Massachusetts Institute of Technology have gained new insight into how localized hearing works in the brain. Their research is published in the Oct. 2, 2013 issue of the Journal of  Neuroscience. 

“Most people are able to locate the source of a sound with ease, for example, a snapping twig on the left, or a honking horn on the right. However this is actually a difficult problem for the brain to solve,” said Mitchell L. Day, Ph.D., investigator in the Eaton-Peabody Laboratories at Mass. Eye and Ear and instructor of Otology and Laryngology at Harvard Medical School “The higher levels of the brain that decide the direction a sound is coming from do not have access to the actual sound, but only the representation of that sound in the electrical activity of neurons at lower levels in the brain. How higher levels of the brain use information contained in the electrical activity of these lower-level neurons to create the perception of sound location is not known.” 

In the experiment, researchers recorded the electrical activity of individual neurons in an essential lower-level auditory brain area called the inferior colliculus (IC) while an animal listened to sounds coming from different directions. They found that the location of a sound source could be accurately predicted from the pattern of activation across a population of less than 100 IC neurons – i.e., a particular pattern of IC activation indicated a particular location in space. Researchers further found that the pattern of IC activation could correctly distinguish whether there was a single sound source present or two sources coming from different directions – i.e., the pattern of IC activation could segregate concurrent sources. 

“Our results show that higher levels of the brain may be able to accurately segregate and localize sound sources based on the detection of patterns in a relatively small population of IC neurons,” said Dr. Day. “We hope to learn more so that someday we can design devices that work better in noisy environments.”

Johns Hopkins researchers, working with mice, say they have identified a chemical compound that reduces the risk of dangerous, potentially stroke-causing blood vessel spasms that often occur after the rupture of a bulging vessel in the brain.

They say their findings offer clues about the biological mechanisms that cause vasospasm, or constriction of blood vessels that reduces oxygen flow to the brain, as well as potential means of treating the serious condition in humans.

When an aneurysm — essentially a blister-like bulge in the wall of a blood vessel — bursts, blood spills into the fluid-filled space that cushions the brain inside the skull. If a patient survives a ruptured aneurysm, between 20 and 40 percent of the time, this brain bleed, called a subarachnoid hemorrhage, will lead to an ischemic stroke within four to 21 days, even when the aneurysm is surgically clipped.

“We’re a long way from applying this to humans, but it’s a good start,” says Johns Hopkins neurosurgery resident Tomas Garzon-Muvdi, M.D., M.Sc., one of the authors of the study led by Rafael J. Tamargo, M.D., and described in the October issue of the journal Neurosurgery.

To conduct their experiments, Garzon-Muvdi and his colleagues took blood from mouse leg arteries and injected it behind their necks to mimic what happens in a subarachnoid hemorrhage. Then they gave the mice a compound called (S)-4-carboxyphenylglycine (S-4-CPG), a placebo or nothing at all. The mice given S-4-CPG developed less vasospasm, looked better and were more active than those in the other two groups.

The scientists also found concentrations of the drug in the brains of the mice, showing that it was able to cross the often impermeable blood-brain barrier. The researchers chose the compound because it is similar to drugs that have been used in stroke research in rodents. It is not approved for any use in humans.

Garzon-Muvdi explains that when blood vessels break anywhere but the brain, the body’s immune cells easily clear the blood cells and their remnants from the area. This is what happens with a bruise, when immune cells rush to the area, and a chemical cascade scavenges and disperses the remnants of excess blood components.

When a blood vessel bursts in the space around the brain, however, the blood is trapped. A subsequent inflammatory response brings key immune system cells into the space, where they secrete the neurotransmitter glutamate outside of the blood vessels where it shouldn’t be, promoting dangerous vasospasm in those blood vessels. This can lead to ischemic stroke, the most common type of stroke, caused by a blockage of a blood vessel in the brain. Death or serious disability may result.

The Johns Hopkins researchers say S-4-CPG keeps glutamate “in check,” prevents or reduces vasospasm and allows oxygen-filled blood to continue flowing into the brain.

According to the National Institutes of Health, subarachnoid hemorrhage caused by a cerebral aneurysm that breaks open occurs in about 40 to 50 out of 100,000 people over age 30. Patients may die immediately, but those who survive are still at elevated risk for developing an ischemic stroke in the days afterward. These patients are often watched very carefully in the intensive care unit for one to two weeks to search for early signs of vasospasm so that doctors can take steps to prevent or limit damage from a stroke.

In the ICU, doctors can order regular angiograms or ultrasounds to measure blood flow in vessels. If need be, they can increase blood pressure to send blood through vessels faster in the hopes of counteracting the constriction.

A drug to prevent stroke after a serious subarachnoid hemorrhage that follows the rupture of an aneurysm would improve quality of life for patients, Garzon-Muvdi says, and could potentially save millions of dollars in health care costs if patients don’t have to endure extensive hospital stays to monitor for a delayed stroke.

A group of really brainy scientists have moved closer to growing “therapeutic” brain cells in the laboratory that can be re-integrated back into patients’ brains to treat a wide range of neurological conditions. According to new research published online in The FASEB Journal, brain cells from a small biopsy can be used to grow large numbers of new personalized cells that are not only “healthy,” but also possess powerful attributes to preserve and protect the brain from future injury, toxins and diseases. Scientists are hopeful that ultimately these cells could be transformed in the laboratory to yield specific cell types needed for a particular treatment, or to cross the “blood-brain barrier” by expressing specific therapeutic agents that are released directly into the brain.

"This work is an example of how integrating basic science and clinical care may reveal privileged opportunities for biomedical research," said Matthew O. Hebb, M.D., Ph.D., FRCSC, a researcher involved in the work from the Departments of Clinical Neurological Sciences (Neurosurgery), Oncology and Otolaryngology at the University of Western Ontario in Ontario, Canada. "It is our hope that the results of this study provide a footing for further advancement of personalized, cell-based treatments for currently incurable and devastating neurological disorders."

Scientists enrolled patients with Parkinson’s disease who were scheduled to have deep brain stimulation (DBS) surgery, a commonly used procedure that involves placing electrodes into the brain. Before the electrodes were implanted, small biopsies were removed near the surface of the brain and multiplied in culture to generate millions of patient-specific cells that were then subjected to genetic analysis. These cells were complex in their make-up, but exhibited regeneration and characteristics of a fundamental class of brain cells, called glia. They expressed a broad array of natural and potent protective agents, called neurotrophic factors.

"From an extremely small amount of brain tissue, we will one day be able to do very big things," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “For centuries, treating the brain effectively and safely has been elusive. This advance opens the doors to not only new therapies for a myriad of brain diseases, but new ways of delivering therapies as well.”

Researchers at The University of Texas at Dallas have taken a step toward developing a new treatment to aid the recovery of limb function after strokes.

In a study published online in the journal Neurobiology of Disease, researchers report the full recovery of forelimb strength in animals receiving vagus nerve stimulation.

“Stroke is a leading cause of disability worldwide,” said Dr. Navid Khodaparast, a postdoctoral researcher in the School of Behavioral and Brain Sciences and lead author of the study. “Every 40 seconds, someone in the U.S. has a stroke. Our results mark a major step in the development of a possible treatment.”

Vagus nerve stimulation (VNS) is an FDA-approved method for treating various illnesses, such as depression and epilepsy. It involves sending a mild electric pulse through the vagus nerve, which relays information about the state of the body to the brain.

Khodaparast and his colleagues used vagus nerve stimulation precisely timed to coincide with rehabilitative movements in rats. Each of the animals had previously experienced a stroke that impaired their ability to pull a handle.

Stimulation of the vagus nerve causes the release of chemicals in the brain known to enhance learning and memory called neurotransmitters, specifically acetylcholine and norepinephrine. Pairing this stimulation with rehabilitative training allowed Khodaparast and colleagues to improve recovery.

Many rehabilitative interventions try to enhance neuroplasticity (the brain’s ability to change) in conjunction with physical rehabilitation to drive the recovery of lost functions, according to Khodaparast. Unfortunately, up to 70 percent of stroke patients still display long-term impairment in arm function after traditional rehabilitation.

“For years, the majority of stroke patients have received treatment with various drugs and/or physical rehabilitation,” Khodaparast said. “Medications can have widespread effects in the brain and the effects can last for long periods of time. In some cases the side effects outweigh the benefits. Through the use of VNS, we are able to use the brain’s natural way of changing its neural circuitry and provide specific and long lasting effects.”

Khodaparast acknowledged the study has some limitations. For example, the animals were young and lacked some of the other illnesses that accompany an aged human population, such as diabetes or hypertension. But Khodaparast and his colleagues said they are optimistic about vagus nerve stimulation as a future tool. They will continue testing in chronically impaired animals with the hopes of translating the technique for stroke patients. Working with MicroTransponder Inc., a partner company in the current study, researchers at the University of Glasgow in Scotland have begun a small-scale trial in humans.

“There is strong evidence that VNS can be used safely in stroke patients because of its extensive use in the treatment of other neurological conditions,” said Dr. Michael Kilgard, professor in neuroscience at UT Dallas and senior author of the study.

Kilgard is also conducting clinical trials using vagus nerve stimulation to treat tinnitus, the medical condition of unexplained ringing in the ears. Kilgard’s lab first demonstrated the ability of vagus nerve stimulation to enhance brain adaptability in a 2011 Nature paper.

About 70 percent of a person’s intelligence can be explained by their DNA — and those genetic influences only get stronger with age, according to new research from The University of Texas at Austin.

The study, authored by psychology researchers Elliot Tucker-Drob, Daniel Briley and Paige Harden, shows how genes can be stimulated or suppressed depending on the child’s environment and could help bridge the achievement gap between rich and poor students. The findings are published online in Current Directions in Psychological Science.

To investigate the underlying mechanisms at work, Tucker-Drob and his colleagues analyzed data from several studies tracking the cognitive ability and environmental circumstances of twin and sibling pairs. According to the findings, genetic factors account for 80 percent of cognition for children in economically advantaged households. Yet disadvantaged children – who rank lower in cognitive performance across the board – show almost no progress attributable to their genetic makeup.

This doesn’t mean disadvantaged children are genetically inferior. Instead, they have less high-quality opportunities, such as learning resources and parental involvement, to reach their genetic potential, Tucker-Drob says. 

“Genetic influences on cognitive ability are maximized when people are free to select their own learning experiences,” says Tucker-Drob, who is an assistant professor of psychology. “We were born with blueprints; the question is how are we using our experiences to build upon our genetic makeup?”

In a related study, Daniel Briley, a psychology doctoral student, examined how genetic and environmental influences on cognition change over time. Using meta-analytic procedures — the statistical methods used to analyze and combine results from previous, related literature — Briley examined genetic and environmental influences on cognition in twin and sibling pairs from infancy to adolescence.

According to his findings, published in the July issue of Psychological Science, genes influencing cognition become activated during the first decade of life and accelerate over time. The results emphasize the importance of early literacy and education during the first decade of life.

“As children get older, their parents and teachers give them increasing autonomy to do their homework to the best of their ability, pay attention in class, and choose their peer group,” says Briley. “Each of these behaviors likely influences their academic development. If these types of behaviors are influenced by genes, then it would explain why the heritability of cognitive ability increases as children age.”

Tucker-Drob says this research highlights the possibilities for bridging the achievement gap between the rich and poor.

“The conventional view is that genes place an upper limit on the effects of social intervention on cognitive development,” says Tucker-Drob. “This research suggests the opposite. As social, educational and economic opportunities increase in a society, more children will have access to the resources they need to maximize their genetic potentials.”

Findings in bacteria, yeast, mice show how flawed transport gene contributes to the condition

Researchers say it’s clear that some cases of autism are hereditary, but have struggled to draw direct links between the condition and particular genes. Now a team at the Johns Hopkins University School of Medicine, Tel Aviv University and Technion-Israel Institute of Technology has devised a process for connecting a suspect gene to its function in autism.

In a report in the Sept. 25 issue of Nature Communications, the scientists say mutations in one such autism-linked gene, dubbed NHE9, which is involved in transporting substances in and out of structures within the cell, causes communication problems among brain cells that likely contribute to autism.

“Autism is considered one of the most inheritable neurological disorders, but it is also the most complex,” says Rajini Rao, Ph.D., a professor of physiology in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. “There are hundreds of candidate genes to sort through, and a single genetic variant may have different effects even within the same family. This makes it difficult to separate the chaff from the grain, to distinguish harmless variations from disease-causing mutations. We were able to use a new process to screen variants in one candidate gene that has been linked to autism, and figure out how they might contribute to the disorder.”

An estimated one in 88 children in the United States is affected by autism spectrum disorders, a group of neurological development conditions marked by varying degrees of social, communication and behavioral problems. Scientists for years have looked for the biological roots of the problem using tools such as genome-wide association studies and gene-linkage analysis, which crunch genetic and health data from thousands of people in an effort to pinpoint disease-causing genetic variants. But while such techniques have turned up a number of gene mutations that may be linked to autism, none of them appear in more than 1 percent of people with the condition. With numbers that low, researchers need a way to screen variants in order to make a definitive link, Rao says.

For the new study, Rao and her collaborators focused on NHE9, which other researchers had flagged as a suspect in attention-deficit hyperactivity disorder, addiction and epilepsy as well as autism spectrum disorders. The gene was already known to be involved in transporting hydrogen, sodium and potassium ions in and out of cellular compartments called endosomes, and the team wondered how this function might be related to neurological conditions.

Rao’s collaborators at Tel Aviv University and Technion-Israel Institute of Technology constructed a computer model of the NHE9 protein based on previous research on a distant relative in bacteria. They then used the model to predict how autism-linked variants in the NHE9 gene would affect the protein’s shape and function. Some of them were predicted to cause dramatic changes, while other changes appeared to be more subtle.

Rao’s team next tested how these variant forms of NHE9 would affect a relatively simple organism often used in genetic studies: yeast. “Using yeast to screen the function of variants was a quick, easy and inexpensive way of figuring out which were worth further study, and which we could ignore because they didn’t have any effect,” Rao says. To do that, the team engineered the yeast form of NHE9 to have the variants seen in autistic people.

For those mutations that did have a detectable effect on the yeast, the team moved on to a third and more challenging step, in mouse brains. They homed in on astrocytes, a type of brain cell that clears the signaling molecule glutamate out of the way after it has performed its job of delivering a message across a synapse between two nerve cells. Using lab-grown mouse astrocytes with variant forms of NHE9, the researchers found a change in the pH (acidity) inside cellular compartments called endosomes, which in turn altered the ability of cells to take up glutamate. Because endosomes are the vehicles that deliver cargo essential for communication between brain cells, changing their pH alters traffic to and from the cell surface, which could affect learning and memory, Rao says. “Elevated glutamate levels are known to trigger seizures, perhaps explaining why autistic patients with mutations in NHE9 and related genes also have seizures,” she notes.

Rao and her team hope that pinpointing the importance of this trafficking mechanism in autism spectrum disorders may lead to the development of new drugs for autism that alter endosomal pH. As the use of genomic data becomes increasingly commonplace in the future, the step-wise strategy devised by her team can be used to screen gene variants and identify at-risk patients, she says.