Neuroscience

A team of international scientists, including a researcher from Simon Fraser University, has isolated a gene thought to play a causal role in the development of Alzheimer’s disease. The Proceedings of the National Academy of Sciences recently published the team’s study.

The newly identified gene affects accumulation of amyloid-beta, a protein believed to be one of the main causes of the damage that underpins this brain disease in humans.

The gene encodes a protein that is important for intracellular transportation. Each brain cell relies on an internal highway system that transports molecular signals needed for the development, communication, and survival of the cell. 

This system’s impairment can disrupt amyloid-beta processing, causing its eventual accumulation. This contributes to the development of amyloid plaques, which are a key hallmark of Alzheimer’s disease.

Teasing out contributing disease factors, whether genetic or environmental, has long posed a challenge for Alzheimer’s researchers.

“Alzheimer’s is a multifactorial disease where a build-up of subtle problems develop in the nervous system over a span of decades,” says Michael Silverman, an SFU biology associate professor. He worked on the study with a team of Japanese scientists led by Dr. Takashi Morihara at Osaka University.   

Identifying these subtle, yet perhaps critical genetic contributions is challenging. “Alzheimer’s, like many human disorders, has a genetic component, yet many environmental and lifestyle factors contribute to the disease as well,” says Silverman. “In a sense, it is like looking for a needle in a complex genetic haystack.”

Only a small fraction of cases have a strong hereditary component, for example early-onset Alzheimer’s.

This breakthrough in Alzheimer’s research could open new avenues for the design of therapeutics and pave the way for early detection by helping healthcare professionals identify those who are predisposed to the disease.

“One possibility is that a genetic test for a particular variant of this newly discovered gene, along with other variants of genes that contribute to Alzheimer’s, will help to give a person their overall risk for the disease.  

“Lifestyle changes, such as improved diet, exercise, and an increase in cognitive stimulation may then help to slow the progression of Alzheimer’s,” says Silverman.

University of Miami researchers develop a method to visualize protein interactions in a living organism’s brain

There are more than a trillion cells called neurons that form a labyrinth of connections in our brains. Each of these neurons contains millions of proteins that perform different functions. Exactly how individual proteins interact to form the complex networks of the brain still remains as a mystery that is just beginning to unravel.

For the first time, a group of scientists has been able to observe intact interactions between proteins, directly in the brain of a live animal. The new live imaging approach was developed by a team of researchers at the University of Miami (UM).

(Image caption: Photonic resonance energy transfer described by Förster, or FRET, occurs when two small proteins come within a very small distance of each other — eight nanometers or less. The fluorescence lifetime of the donor molecule will become shorter — from 3 nanosecond to, perhaps, 2.5 nanoseconds. We then interpret this as evidence that the two proteins of interest are physically interacting with each other — a molecular signaling event. Credit: Akira Chiba/University of Miami)

"Our ultimate goal is to create the systematic survey of protein interactions in the brain," says Akira Chiba, professor of Biology in the College of Arts and Sciences at UM and lead investigator of the project. "Now that the genome project is complete, the next step is to understand what the proteins coded by our genes do in our body."

The new technique will allow scientists to visualize the interactions of proteins in the brain of an animal, along different points throughout its development, explains Chiba, who likens protein interactions to the way organisms associate with each other.

"We know that proteins are one billionth of a human in size. Nevertheless, proteins make networks and interact with each other, like social networking humans do," Chiba says. "The scale is very different, but it’s the same behavior happening among the basic units of a given network."

The researchers chose embryos of the fruit fly (Drosophila melanogaster) as an ideal model for the study. Because of its compact and transparent body, it is possible to visualize processes inside the Drosophila cells using a fluorescence lifetime imaging microscope (FLIM). The results of the observations are applicable to other animal brains, including the human brain.

The Drosophila embryos in the study contained a pair of fluorescent labeled proteins: a developmentally essential and ubiquitously present protein called Rho GTPase Cdc42 (cell division control protein 42), labeled with green fluorescent tag and its alleged signaling partner, the regulatory protein WASp (Wiskot-Aldrich Syndrome protein), labeled with red fluorescent tag. Together, these specialized proteins are believed to help neurons grow during brain development. The proteins were selected because the same (homolog) proteins exist in the human brain as well.

Previous methods required chemical or physical treatments that most likely disturb or even kill the cells. That made it impossible to study the protein interactions in their natural environment.

(Image caption: FRET (Förster resonance energy transfer) between the two interacting protein partners occurs, Cdc42 and WASp, within neurons, during the time and space that coincides with the formation of new synapses in the brain of the baby insect. Synapses connect individual neurons in the brain. Credit: Akira Chiba / University of Miami)

The current study addresses these challenges by using the occurrence of a phenomenon called Förster resonance energy transfer, or FRET. It occurs when two small proteins come within a very small distance of each other, (eight nanometers). The event is interpreted as the time and place where the particular protein interaction occurs within the living animal.

(Image caption: Proteins are one billionth of a human in size. Nevertheless, proteins make networks and interact with each other, like social networking humans do,” says Akira Chiba, professor of Biology in the College of Arts and Sciences at the University of Miami. “The scale is very different, but it’s the same behavior happening among the basic units of a given network.” Credit: Akira Chiba / University of Miami)

The findings show that FRET between the two interacting protein partners occurs within neurons, during the time and space that coincides with the formation of new synapses in the brain of the baby insect. Synapses connect individual neurons in the brain.

"Previous studies have demonstrated that Cdc42 and WASp can directly bind to each other in a test-tube, but this is the first direct demonstration that these two proteins are interacting within the brain," Chiba says.

Pulling an “all-nighter” before a big test is practically a rite of passage in college. Usually, it’s no problem: You stay up all night, take the test, and then crash, rapidly catching up on lost sleep. But as we age, sleep patterns change, and our ability to recoup lost sleep diminishes.

Researchers at the Perelman School of Medicine, University of Pennsylvania, have been studying the molecular mechanisms underpinning sleep. Now they report that the pathways of aging and sleep intersect at the circuitry of a cellular stress response pathway, and that by tinkering with those connections, it may be possible to alter sleep patterns in the aged for the better – at least in fruit flies.

Nirinjini Naidoo, PhD, associate professor in the Center for Sleep and Circadian Neurobiology and the Division of Sleep Medicine, led the study with postdoctoral fellow Marishka Brown, PhD, which was published online before print in the journal Neurobiology of Aging.

Increasing age is well known to disrupt sleep patterns in all sorts of ways. Elderly people sleep at night less than their younger counterparts and also sleep less well. Older individuals also tend to nap more during the day. Naidoo’s lab previously reported that aging is associated with increasing levels of protein unfolding, a hallmark of cellular stress called the “unfolded protein response.”

Protein misfolding is also a characteristic of several age-related neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, and as it turns out, also associated with sleep deprivation. Naidoo and her team wanted to know if rescuing proper protein folding behavior might counter some of the detrimental sleep patterns in elderly individuals.

Using a video monitoring system to compare the sleep habits of “young” (9–12 days old) and “aged” (8 weeks old) fruit flies, they found that aged flies took longer to recover from sleep deprivation, slept less overall, and had their sleep more frequently interrupted compared to younger control animals. However, adding a molecule that promotes proper protein folding – a molecular “chaperone” called PBA — mitigated many of those effects, effectively giving the flies a more youthful sleep pattern. PBA (sodium 4-phenylbutyrate) is a compound currently used to treat such protein-misfolding-based diseases as Parkinson’s and cystic fibrosis.

The team also asked the converse question: Can protein misfolding induce altered sleep patterns in young animals. Another drug, tunicamycin, induces protein misfolding and stress, and when the team fed it to young flies, their sleep patterns shifted towards those of aged flies, with less sleep overall, more interrupted sleep at night, and longer recovery from sleep deprivation.

Molecular analysis of sleep-deprived and PBA-treated flies suggested that PBA acts through the unfolded protein response. PBA, Naidoo says, had two effects on aged flies: it “consolidated” baseline sleep, increasing the total amount of time slept and shifted recovery sleep, after sleep deprivation, to look more like that of a young fly.

“It rescued the sleep patterns in the older flies,” she explains.

These results, Naidoo says, suggest three key messages. First, sleep loss leads to protein misfolding and cellular stress, and as we age, our ability to recover from that stress decreases. Second, aging and sleep apparently form a kind of negative “chicken-and-egg” feedback loop, in which sleep loss or sleep fragmentation lead to cellular stress, followed by neuronal dysfunction, and finally even poorer-quality sleep.

Sleep recharges neuronal batteries, Naidoo explains, and if a person is forced to stay awake, those batteries run down. Dwindling physiological resources must be devoted to the most critical cell functions, which do not necessarily include protein homeostasis. “Staying awake has a cost, and one of those costs is problems with protein folding.”

Finally, and most importantly, she says these results suggest — assuming they can be replicated in mice and humans – that it may be possible using drugs such as PBA to “fix sleep” in aged or mutant animals.

“People know that sleep deteriorates with aging,” Naidoo says, “But this might be able to be stopped or reversed with molecular chaperones.” Her team is now looking to determine if a similar situation exists in mammals and if better sleep translates into longer lifespan.

Chronic stress that produces inflammation and anxiety in mice appears to prime their immune systems for a prolonged fight, causing the animals to have an excessive reaction to a single acute stressor weeks later, new research suggests.

After the mice recovered from the effects of chronic stress, a single stressful event 24 days later quickly returned them to a chronically stressed state in biological and behavioral terms. Mice that had not experienced the chronic stress were unaffected by the single acute stressor.

The study further showed that immune cells called to action as a result of chronic stress ended up on standby in the animals’ spleens and were launched from that organ to respond to the later stressor.

Mice without spleens did not experience the same reactivation with the second stressor, signifying the spleen’s role as a reservoir for primed immune cells to remain until they’re activated in response to another stressor.

The excessive immune response and anxiety initiated by a brief stressor mimic symptoms of post-traumatic stress disorder.

The Ohio State University scientists are cautious about extending their findings to humans. But they say their decade of work with this model of stress suggests that the immune system has a significant role in affecting behavior. And they are the first to study this re-establishment of anxiety in animals with a later acute stressor.

“No one else has done a study of this length to see what happens to recovered animals if we subject them again to stress,” said Jonathan Godbout, a lead author of the study and associate professor of neuroscience at Ohio State. “That retriggering is a component of post-traumatic stress. The previously stressed mice are living a normal rodent life, and then this acute stress brings everything back. Animals that have never been exposed to stress before were unaffected by that one event – it didn’t change behavioral or physiological properties.”

The research is published online in the journal Biological Psychiatry.

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Geneticists from Trinity College Dublin interested in ‘reverse engineering’ the nervous system have made an important discovery with wider implications for repairing missing or broken links. They found that the same molecular switches that induce originally non-descript cells to specialise into the billions of unique nerve cell types are also responsible for making these nerve cells respond differently to the environment. 

The geneticists are beginning to understand how these molecular switches, called ‘transcription factors’, turn on specific cellular labels to form complex bundles of nerves. These bundles function to ensure we respond and react appropriately to the incredible amount of information our brains encounter. Understanding how to precisely program nerve cells could help to target missing or broken links following serious injury or the onset of degenerative diseases such as Alzheimer’s or Parkinson’s.

Commenting on the importance and wider implications of this discovery, Assistant Professor in Genetics at Trinity, Juan Pablo Labrador said: “We know very little of how individual nerve cells are programmed to assemble into specific nerves in living organisms to make specific circuits, so our work is like reverse engineering the nervous system.” 

“To restore damaged or missing connections in the nervous system – for example, after spinal cord injuries or degenerative diseases such as Alzheimer’s or Parkinson’s – we need to know how nerve cells are programmed to make those connections in the first place. For that we require a complex ‘builder’s manual’ that tells us how to program the neurons to make the connections. What we are doing in my lab is trying to write this manual.” 

The nervous system can be thought of as an incredibly complex network of wires, which are all arranged into different, related bundles to coordinate complex tasks. The wires are the cellular extensions from the individual nerve cells that assemble into bundles to form specific nerves. The geneticists have begun to understand how varied combinations of transcription factors work to generate different nerve cells and direct their wiring to form specific nerves.

By studying the behaviour of individual nerve cells that make connections with muscles, the geneticists discovered specific ‘footprints’ of labels that induced these nerve cells to assemble into specific bundles that link to their target muscles. Individual transcription factors are only able to turn on specific labels to some extent. It is only the action of all of them together that programmes the nerve cells to turn on all the labels required. 

The research was just published in the high-profile journal Neuron. The team led by Assistant Professor Juan Pablo Labrador, found that the actions of the transcription factor influencing nerve cell differentiation in flies (‘Eve’) controls nerve cell surface labels.

The team also showed that if these labels, targeted by Eve, are expressed erroneously, the nerve cells will not form the correct nerves. Additionally, the team discovered that different combinations of transcription factors including Eve work as codes for different groups of labels that guide individual nerve development.

To remain healthy, the body’s cells must properly manage their waste recycling centers. Problems with these compartments, known as lysosomes, lead to a number of debilitating and sometimes lethal conditions.

Reporting in the Proceedings of the National Academy of Sciences (PNAS), researchers at Washington University School of Medicine in St. Louis have identified an unusual cause of the lysosomal storage disorder called mucolipidosis III, at least in a subset of patients. This rare disorder causes skeletal and heart abnormalities and can result in a shortened lifespan. But unlike most genetic diseases that involve dysfunctional or missing proteins, the culprit is a normal protein that ends up in the wrong place.

Image caption: In normal cells, phosphotransferase (green) is shown overlapping with the Golgi apparatus (red), which indicates that phosphotransferase is located in the Golgi, where it should be (Credit: Eline van Meel, PhD)

“There is a lot of interest and study about how cells distribute proteins to the right parts of the cell,” said senior author Stuart A. Kornfeld, MD, PhD, the David C. and Betty Farrell Professor of Medicine. “Our study has identified one of the few examples of a genetic disease caused by the misplacement of a protein. The protein functions just fine. It just doesn’t stay in the right place.”

The right place, in this case, is the Golgi apparatus, the cell’s protein packaging center. The protein in question – phosphotransferase – normally resides in the Golgi, where its job is to attach address labels to proteins bound for the lysosome. There are 60 such lysosomal proteins, and all of them must be properly labeled if they are to end up in a lysosome, where they recycle waste.

Image caption: In mutant cells, the protein phosphotransferase (green) is spread beyond the Golgi (red). Outside the Golgi, this wayward phosphotransferase is no longer able to perform its job of properly addressing enzymes bound for the lysosome (Credit: Eline van Meel, PhD)

Kornfeld and his colleagues, including first author Eline van Meel, PhD, postdoctoral research associate, showed that the phosphotransferase protein responsible for adding the address label starts out in the Golgi as it should, but seems to lack the signal to keep it there.

“Under normal circumstances, the phosphotransferase moves up through the Golgi, but then it’s recaptured and sent back,” Kornfeld said. “Our study shows that the mutant phosphotransferase moves up but is not recaptured. Ironically, the phosphotransferase that escapes the Golgi ends up in the lysosomes, where it is degraded.”

Because phosphotransferase gradually wanders away from the Golgi, a low level of lysosomal enzymes end up being properly addressed, but at perhaps 20 percent of the normal amount.

“In many lysosomal storage disorders, such as Tay-Sachs or Gaucher’s disease, only one out of the 60 enzymes is missing from the lysosome,” Kornfeld said. “But the mislocalization of phosphotranferase causes the misdirection of all 60 lysosomal enzymes.”

While the errant phosphotransferase ends up being degraded in the lysosome, the resulting misdirected lysosomal proteins end up in the bloodstream. As a result, children with this disorder have lysosomal proteins in their blood at levels 10 to 20 times higher than normal. But because some get to the lysosome at a low level, people with mucolipidosis III don’t have the most severe form of the disease.

“Type III patients live into adulthood, but they’re very impaired,” said Kornfeld. “They have joint and heart problems and have trouble walking. In the most severe form, type II, there is zero activity of phosphotransferase. None of the 60 enzymes are properly tagged, so these patients’ lysosomes are empty. Children with type II usually die by age 10.”

Having implicated wayward phosphotransferase in this lysosomal storage disorder, Kornfeld and his colleagues are investigating what goes wrong that allows it to escape the Golgi.

“We think there must be some protein in the cell that recognizes phosphotransferase when it gets to the end of the Golgi, binds it and takes it back,” said Kornfeld. “Now we’re trying to understand how that works.”

The switch works by regulating the activity of a handful of sleep-promoting nerve cells, or neurons, in the brain. The neurons fire when we’re tired and need sleep, and dampen down when we’re fully rested.

‘When you’re tired, these neurons in the brain shout loud and they send you to sleep,’ says Professor Gero Miesenböck of Oxford University, in whose laboratory the new research was performed.

Although the research was carried out in fruit flies, or Drosophila, the scientists say the sleep mechanism is likely to be relevant to humans.

Dr Jeffrey Donlea, one of the lead authors of the study, explains: ‘There is a similar group of neurons in a region of the human brain. These neurons are also electrically active during sleep and, like the flies’ cells, are the targets of general anaesthetics that put us to sleep. It’s therefore likely that a molecular mechanism similar to the one we have discovered in flies also operates in humans.’

The researchers say that pinpointing the sleep switch might help us identify new targets for novel drugs – potentially to improve treatments for sleep disorders.

But there is much still to find out, and further research could give insight into the big unanswered question of why we need to sleep at all, they say.

‘The big question now is to figure out what internal signal the sleep switch responds to,’ says Dr Diogo Pimentel of Oxford University, the other lead author of the study. ‘What do these sleep-promoting cells monitor while we are awake?

‘If we knew what happens in the brain during waking that requires sleep to reset, we might get closer to solving the mystery of why all animals need to sleep.’

The findings are reported in the journal Neuron. The work of the Centre for Neural Circuits and Behaviour is funded by the Wellcome Trust and the Gatsby Charitable Foundation. This study was also supported by the UK Medical Research Council, the US National Institutes of Health, and the Human Frontier Science Program.

The body uses two mechanisms to regulate sleep. One is the body clock, which attunes humans and animals to the 24 hour cycle of day and night. The other mechanism is the sleep ‘homeostat’: a device in the brain that keeps track of your waking hours and puts you to sleep when you need to reset. This mechanism represents an internal nodding off point that is separate from external factors. When it is turned off or out of use, sleep deficits build up.

What makes us go to sleep at night is probably a combination of the two mechanisms,’ says Professor Miesenböck. ‘The body clock says it’s the right time, and the sleep switch has built up pressure during a long waking day.’

The work in fruit flies allowed the critical part of the sleep switch to be discovered. ‘We discovered mutant flies that couldn’t catch up on their lost sleep after they had been kept awake all night,’ says Dr Jeffrey Donlea.

Flies stop moving when they go to sleep and require more disturbance to get them up. Sleep-deprived flies are prone to nodding off and are cognitively impaired – they have severe learning and memory deficits, much as sleep loss in humans leads to problems.

Professor Miesenböck says: ‘The sleep homeostat is similar to the thermostat in your home. A thermostat measures temperature and switches on the heating if it’s too cold. The sleep homeostat measures how long a fly has been awake and switches on a small group of specialized cells in the brain if necessary. It’s the electrical output of these nerve cells that puts the fly to sleep.’

In the mutant flies, the researchers were able to show a key molecular component of the electrical activity switch is broken and the sleep-inducing neurons are always off, causing insomnia.

An international group of researchers has identified a major new pathway thought to be involved in the development of Huntington disease. The findings, published in the Proceedings of the National Academy of Sciences journal, could eventually lead to new treatments for the disease, which currently has no cure.

Scientists at the BC Cancer Agency Research Centre and the Centre for Molecular Medicine and Therapeutics in Vancouver, Canada, and the MRC Toxicology Unit in Leicester, UK, studied mice and human tissue and found that the HACE1 gene is essential for mopping up toxic molecules during periods of oxidative stress, where harmful ‘reactive oxygen species’ build up in the cell.

Oxidative stress is thought to be involved in the development of a number of diseases including cancer and neurodegenerative disorders like Alzheimer’s and Parkinson’s disease. Therefore finding out how this process occurs in the body is important for understanding the course of disease.

The body has evolved highly effective defence mechanisms that sense and respond to oxidative stress to protect the cells from damage. One of these protective mechanisms is controlled by a molecule called NRF2 which springs into action and switches on the production of proteins and enzymes that detoxify the cell.

In this study, scientists found that the HACE1 also plays a vital role in this detoxification process, by activating NRF2. The authors believe that this mechanism goes wrong in Huntington’s disease, leading to gradual destruction of nerve cells in the brain.

Lead author Dr Barak Rotblat, of the MRC Toxicology Unit, said:

“One of the early observations was that enhanced HACE1 expression rescued cells from mutant Huntingtin (the mutant protein that is responsible for Huntington disease) toxicity. We knew then that we had to figure out how HACE1 can protect these cells.

“Our evidence points towards a previously unknown role of HACE1 in Huntington disease and possibly other forms of neurodegeneration. It’s very early days, but if we were able to find a way to boost this pathway, we might be able to develop a treatment that halts, or even reverses progression of Huntington disease.”

HACE1 is already known to play a protective role against tumour formation, but its role in neurodegeneration has not been investigated before.

Dr Poul Sorensen, the senior author of the work from the BC Cancer Agency Research Centre and a Professor at the University of British Columbia, said:

“This is a glowing example of how work in one field, namely childhood cancers, where we first identified the HACE1 gene, has applications to a completely different disease, Huntington disease”.

In this study, researchers looked at mice with and without the HACE1 gene and found that those without the gene had more oxidative stress in the brain, and their response to this was impaired. Depleting HACE1 in cells also resulted in reduced NRF2 activity, leading to lower tolerance against oxidative stress triggers.

The scientists also looked at human brain samples from Huntington disease patients and found a striking reduction of HACE1 levels in the striatum – the area of the brain where the disease develops and is most damaged.

Finally, they looked at HACE1 in a cellular model of Huntington disease. They found that upping expression of the gene in nerve precursor cells protected them against oxidative stress.

A new Indiana University study that examines the brain activity of alcohol-dependent women compared to women who were not addicted found stark and surprising differences, leading to intriguing questions about brain network functions of addicted women as they make risky decisions about when and what to drink.

The study used functional magnetic resonance imaging, or fMRI, to study differences between patterns of brain network activation in the two groups of women. The findings indicate that the anterior insular region of the brain may be implicated in the process, suggesting a possible new target of treatment for alcohol-dependent women.

"We see that the network dynamics of alcohol-dependent women may be really different from that of healthy controls in a drinking-related task," said Lindsay Arcurio, a graduate student in the Department of Psychological and Brain Sciences. "We have evidence to suggest alcohol-dependent women have trouble switching between networks of the brain."

The research is part of a larger new effort to understand the differences between men and women with respect to alcohol. Arcurio said most of the research on alcohol dependence has been conducted with men or groups of men and women. Yet several factors make looking at women “really important.”

One such factor is that the physiological effects of drinking alcohol, which include liver damage, heart disease or breast cancer, set in much earlier in women than in men. For this reason, the suggested limit on the number of drinks per week that women can safely consume is eight, whereas for men, it is 14. Secondly, binge-drinking in women is on the rise. One in five adolescent girls is binge-drinking three times a month. In women between the ages of 18 and 54, that number is one in eight.

A ‘sledgehammer’ approach to defining differences in brain network activation

Research on decision-making mechanisms in alcohol-dependent individuals typically involves a general risk-taking situation in which money or points are at stake. In this study, participants were placed in the fMRI brain scanner and asked to consider low-risk and high-risk situations specifically related to alcohol — what the researchers describe as “ecological” tasks. Participants were then asked to make decisions regarding control stimuli — food as well as a presumably neutral stimuli, a stapler — to observe whether risky behavior was greater with respect to drinking than with these other items. The same picture cues were used to present high-risk and low-risk scenarios, and these two extremes were as follows:

For the low-risk situation, participants were told: Imagine you are at a bar. You are offered a drink, already paid for, with two shots of alcohol, and you have a safe ride home. For the high-risk, they were told: You are at a bar and are offered a drink already paid for, with six shots of alcohol, but you do not have a safe ride home.

The reason for such an extreme contrast between the two situations, Arcurio said, is that “as one of the first ecological tasks used in the scanner, we wanted to take a sledgehammer approach to really find the differences between cases that are definitely high-risk and those that are definitely low-risk.”

The findings, however, reflect an equally sharp contrast in differences between the brain network activation in alcohol-dependent women versus the controls.

For the control group, high-risk decisions to drink led to the deactivation of regions associated with “approach behavior,” deciding to take the drink in a risky situation. Conversely, women in the control group activate regions associated with the default mode network, a region traditionally thought to involve resting-state behavior or inactive or relaxed mental state, but which some now speculate plays a role in conceptualizing one’s future.

"It gets really interesting," Arcurio said, "comparing this pattern of activation to those in alcohol-dependent women, who behaviorally say they’re more likely to take the high-risk drink compared to the controls. They don’t deactivate anything. In contrast to the controls, alcohol-dependent women activate all three regions in question. They activate regions associated with reward (which release dopamine). They also activate frontal control regions involved in cognitive control and regions associated with the default mode network, involved in resting-state behavior. They are activating everything."

The investigators infer from these findings that alcohol-dependent women have trouble switching between networks. Being unable to activate one region and deactivate another in response to an alcohol-related situation means they are unable to use one strategy over another.

Furthermore, Arcurio said, “a lot of evidence suggests that switching between networks is influenced by the anterior insular and anterior cingulate regions of the brain, and we did find major differences in the insula between the alcohol-dependent women and controls. We’re thinking the issue is pinpointed to that region.”

The researchers are now running analyses to test the hypothesis that the insula helps in this process, which could offer new possibilities for intervention, with both behavioral therapy and medication.

The research is part of a whole research program, both planned and in the works, to further explore the questions about risky decision-making in alcohol-dependent women: studies of adolescent drinking, risky sexual behavior in alcohol-dependent women, the interaction of visual networks with decision-making networks, as well as the way music (or auditory networks) interacts with decision-making mechanisms in alcohol-dependent women. In the latter experiment, college-age participants choose a song that they associate with drinking and one with quiet reflection.

"There’s a lot of Miley Cyrus in the first category," Arcurio said.

Hyperactivity of our immune system can cause a state of chronic inflammation. If chronic, the inflammation will affect our body and result in disease. In the devastating disease multiple sclerosis, hyperactivity of immune cells called T-cells induce chronic inflammation and degeneration of the brain. Researchers at BRIC, the University of Copenhagen, have identified a new type of regulatory blood cells that can combat such hyperactive T-cells in blood from patients with multiple sclerosis. By stimulating the regulatory blood cells, the researchers significantly decreased the level of brain inflammation and disease in a biological model. The results are published in the journal Nature Medicine.

Molecule activate anti-inflammatory blood cells

The new blood cells belong to the group of our white blood cells called lymphocytes. The cells express a molecule called FoxA1 that the researchers found is responsible for the cells’ development and suppressive functions.

"We knew that some unidentified blood cells were able to inhibit multiple sclerosis-like disease in mice and through gene analysis we found out, that these cells are a subset of our lymphocytes expressing the gene FoxA1. Importantly, when inserting FoxA1 into normal lymphocytes with gene therapy, we could change them to actively regulate inflammation and inhibit multiple sclerosis", explains associated professor Yawei Liu leading the experimental studies.

Image caption: Tissue sections from an untreated diseased brain and a FoxA1-treated brain from the researchers biological model. (Photo: Yawei Liu)

Activating own blood cells for treatment of disease

FoxA1 expressing lymphocytes were not known until now, and this is the first documentation of their importance in controlling multiple sclerosis. The number of people living with this devastating disease around the world has increased by 10 percent in the past five years to 2.3 million. It affects women twice more than men and no curing treatment exists. The research group headed by professor Shohreh Issazadeh-Navikas from BRIC examined blood of patients with multiple sclerosis, before and after two years of treatment with the drug interferon-beta. They found that patients who benefit from the treatment increase the number of this new blood cell type, which fight disease.

Image caption: FoxA1-lymphocytes. (Photo: Yawei Liu)

“From a therapeutic viewpoint, our findings are really interesting and we hope that they can help finding new treatment options for patients not benefiting from existing drugs, especially more chronic and progressive multiple sclerosis patients. In our model, we could activate lymphocytes by chemical stimulation and gene therapy, and we are curios whether this can be a new treatment strategy”, says professor Shohreh Issazadeh-Navikas.

And this is exactly what the research group will focus on at next stage of their research. They have already started to test whether the new FoxA1-lymphocytes can prevent degradation of the nerve cell’s myelin layer and brain degeneration in a model of progressive multiple sclerosis. Besides multiple sclerosis, knowledge on how to prevent chronic inflammation will also be valuable for other autoimmune diseases like type 1 diabetes, inflammatory bowel disease and rheumatoid arthritis, where inflammation is a major cause of the disease.

Boys are at greater risk for delayed language development than girls, according to a new study using data from the Norwegian Mother and Child Cohort Study. The researchers also found that reading and writing difficulties in the family gave an increased risk.

“We show for the first time that reading and writing difficulties in the family can be the main reason why a child has a speech delay that first begins between three to five years of age,” says Eivind Ystrøm, senior researcher at the Norwegian Institute of Public Health.

Ystrøm was supervisor of Imac Maria Zambrana, a former PhD student at the Norwegian Institute of Public Health who conducted the research in this study as part of her doctoral research.

The researchers used data from questionnaires completed by the mothers who are participating in the Norwegian Mother and Child Cohort Study (MoBa). The study included more than 10,000 children from week 17 of pregnancy up to five years of age.

“MoBa is a large study with a normal cross-section of the population. It gives us a unique opportunity to examine changes over time, the scope and any risk factors for delayed language development,” says Ystrøm.

Mostly boys

The researchers classified the language difficulties at three and five years of age in three groups: persistent delayed language development (present at both times), transient delayed language development (only present at three years) and delayed language development first identified at five years old.

Boys are in the majority for the groups with persistent and transient language difficulties. Ystrøm explains that boys are biologically at greater risk for developmental disorders in utero than girls. British scientists have measured the male sex hormone (testosterone) in amniotic fluid and they found that the levels were related to the development of both autism and language disorders. Ystrøm points out that boys are generally a little later in language development than girls, but that most catch up during the first year. Therefore, many boys could be at risk of persistent language impairment and increasingly have transient language difficulties that disappear before school age.

The researchers found that gender was irrelevant for the third group who have language difficulties that begin sometime between three and five years of age.

Hereditary factors

We have good knowledge about normal language development in children. Many genes are important for language development and research suggests that different genes are involved in different types of language difficulty.

“Reading and writing difficulties in the family are the predominant risk factors for late-onset language difficulties. We see no language problems when the child is between 18 months and three years old. They are latent” says Ystrøm.

The researchers believe that both specific genes and factors in the child’s external environment can lead to delays in language development at three to five years of age.

What can we do?

Ystrøm believes that children with delayed language development must be identified as early as possible. Parents, health care workers and child care staff should be aware of the language development of children and encourage an enabling language environment, in some cases with specially adapted measures. In particular, they must be aware of children who have sustained disabilities, or who have had normal language development up to three years and then unexpectedly began to have difficulties.

“Professionals and caregivers must be vigilant. It is difficult to detect language difficulties when language becomes more complex in older children. They must be trained so that they are confident in how to spot language difficulties and how to encourage a child’s language. We need more research into the needs of children with different trajectories”, says Ystrøm.

Parents who are concerned about their child’s language development should consult their doctor. They should also raise the issue at the regular check-ups at the health clinic when the child is between two and four years old.

“The checks must take place at the appropriate time. It is important that they are not delayed or not implemented at all,” says Ystrøm.

A few years ago, a survey by the Health and Welfare Department in Oslo showed that few of the health centres in Oslo met the required 14 consultations for each child from birth to school stipulated by the Norwegian Directorate of Health.

Further research

In addition to researchers at the Norwegian Institute of Public Health, researchers at the University of Oslo and the University of Melbourne in Australia participated in this study. The work is funded by the Extra Foundation for Health and Rehabilitation.

“We hope to continue this research and specifically look at the relationship between gender and language. We need more research into the needs of children with various types of language delay”, says Eivind Ystrøm.

Reference

Zambrana, IM, Pons, F., Eadie, P. and Ystrom, E. (2013). Trajectories of language delay from age 3 to 5: persistence, recovery and late onset. International Journal of Language & Communication

Researchers at the University of Bristol and University College London found that lactate – essentially lactic acid – causes cells in the brain to release more noradrenaline (norepinephrine in US English), a hormone and neurotransmitter which is fundamental for brain function. Without it people can hardly wake up or focus on anything.

Production of lactate can be triggered by muscle use, which reinforces the connection between exercise and positive mental wellbeing.

Lactate was first discovered in sour milk by Swedish chemist, Carl Wilhelm Scheele in 1780. It is produced naturally by the body, for example when muscles are at work. In the brain, it has always been regarded as an energy source which can be delivered to neurones as fuel to keep them working when brain activity increases.

This research, published today [11 February] in Nature Communications, identifies a secondary function for lactate as a signal between brain cells. It implies that there is an as yet unknown receptor for lactate in the brain which must be present on noradrenaline cells to make them sensitive to lactate.

Professor Sergey Kasparov, from Bristol University’s School of Physiology and Pharmacology, said: “Our findings suggest that lactate has more than one incarnation - in addition to its role as an energy source, it is also a signal to neurones to release more noradrenaline.”

Dr Anja Teschemacher, also from the University of Bristol, added: “The next big task is to identify the receptor which mediates this effect because this will help to design drugs to block or stimulate this response. If we can regulate the release of noradrenaline – which is absolutely fundamental for brain function - then this could have important implications for the treatment of major health problems such as stress, blood pressure, pain and depression.”

Astrocytes, small non-neuronal star-shaped cells in the brain and spinal cord, are the principle source of brain lactate. The discovery that astrocytes communicate directly with neurones opens up a whole new area of pharmacology which has been little explored.

For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study is published today in Molecular Psychiatry and may help scientists understand biological mechanisms behind some forms of intellectual impairment. 

The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified. 

An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence. 

Dr Sylvane Desrivières, from the MRC Social, Genetic and Developmental Psychiatry Centre at King’s College London’s Institute of Psychiatry and lead author of the study, said: “We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity – how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.”

She adds: “It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.” 

The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate. 

To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. The researchers found that the NPTN gene had a different activity in the left and right hemispheres of the brain, which may cause the left hemisphere to be more sensitive to the effects of NPTN mutations. Their findings suggest that some differences in intellectual abilities can result from the decreased function of the NPTN gene in particular regions of the left brain hemisphere.

The genetic variation identified in this study only accounts for an estimated 0.5% of the total variation in intelligence. However, the findings may have important implications for the understanding of biological mechanisms underlying several psychiatric disorders, such as schizophrenia, autism, where impaired cognitive ability is a key feature of the disorder.