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* Genetic mutation causes ataxia in humans, dogs

Cerebellar ataxia is a condition of the cerebellum that causes an inability to coordinate muscle movements. A study publishing June 16 in Cell Reports now describes a new genetic mutation as an additional cause of ataxia in humans and mice. The mutation, in the gene CAPN1, affects the function of the enzyme calpain-1 and causes abnormal brain development. The same genetic mutation is also associated with ataxia in Parson Russell Terrier dogs.

“There are a number of genes linked to motor function that can be involved in ataxia when mutated,” says Michel Baudry, a neurobiologist at Western University of Health Sciences. “Not only have we identified another, but we’ve also refined our understanding of the calpain enzymes, which is important because several companies have been talking about using calpain inhibitors to treat neurodegenerative diseases.”

Calpain is an enzyme involved with learning, memory, and neurodegeneration in the brain, but it comes in two major forms–calpain-1 and calpain-2. “Nobody could make much progress on figuring out what each form of calpain was doing, because most of the pharmacological studies used molecules that inhibit both types at once” says Baudry. But about eight years ago, Baudry’s team obtained a line of mice genetically engineered to lack only calpain-1 to examine the differences.

Baudry’s mouse studies caught the attention of Henry Houlden, a neurologist at University College London, who was leading a team investigating ataxia. “Around two years ago, we identified two families with CAPN1 mutations with ataxia and spasticity,” Houlden explains. Once the researchers determined that the mutation affected calpain-1’s function, they looked up Baudry’s work on the calpain-1 knockout mice. “Together, we started to investigate the function of this gene,” says Houlden. The current study includes four families with members that have CAPN1 mutations and display symptoms of ataxia.

Baudry’s team started testing whether the knockout mice had ataxia by tracking their balance when placed on a rotating rod. “We had never looked at the cerebellum in our mice before,” says Baudry. “But sure enough, we found that they had mild cerebellar ataxia.”

The researchers demonstrated that during the first week after birth, the mice lacking calpain-1 had a much higher rate of neuronal death in their cerebellum, as compared to normal mice, and many of their synapses failed to mature.

“Calpain-1 is neuroprotective,” explains Baudry. “When the brain matures, excess neurons are supposed to be pruned–but calpain-1 prevents that process from getting out of control.” The team further determined that calpain-1 works normally by degrading an enzyme called PHLPP1, a protein phosphatase involved in programmed cell death. Injecting another compound involved in the pathway during the first postnatal week caused the newborn mice with CAPN1 mutations to develop normally.

Pharmacologically, the attempts to use calpain inhibitors in the clinic may not be working because they don’t discriminate between calpain-1 and calpain-2, says Baudry: “If you want to try to address neurodegeneration, you have to use a calpain-2 inhibitor.” Baudry is currently working with a team to develop calpain-2 inhibitors as neuroprotective drugs, under the umbrella of a new company called NeurAegis.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160616140715.htm Original web page at Science Daily

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Artificial synapse rivals biological ones in energy consumption

Creation of an artificial intelligence system that fully emulates the functions of a human brain has long been a dream of scientists. A brain has many superior functions as compared with super computers, even though it has light weight, small volume, and consumes extremely low energy. This is required to construct an artificial neural network, in which a huge amount (1014) of synapses is needed.

Most recently, great efforts have been made to realize synaptic functions in single electronic devices, such as using resistive random access memory (RRAM), phase change memory (PCM), conductive bridges, and synaptic transistors. Artificial synapses based on highly aligned nanostructures are still desired for the construction of a highly-integrated artificial neural network.

Prof. Tae-Woo Lee, research professor Wentao Xu, and Dr. Sung-Yong Min with the Dept. of Materials Science and Engineering at POSTECH have succeeded in fabricating an organic nanofiber (ONF) electronic device that emulates not only the important working principles and energy consumption of biological synapses but also the morphology. They recently published their findings in Science Advances, a new sister journal of Science.

The morphology of ONFs is very similar to that of nerve fibers, which form crisscrossing grids to enable the high memory density of a human brain. Especially, based on the e-Nanowire printing technique, highly-aligned ONFs can be massively produced with precise control over alignment and dimension. This morphology potentially enables the future construction of high-density memory of a neuromorphic system.

Important working principles of a biological synapse have been emulated, such as paired-pulse facilitation (PPF), short-term plasticity (STP), long-term plasticity (LTP), spike-timing dependent plasticity (STDP), and spike-rate dependent plasticity (SRDP). Most amazingly, energy consumption of the device can be reduced to a femtojoule level per synaptic event, which is a value magnitudes lower than previous reports. It rivals that of a biological synapse. In addition, the organic artificial synapse devices not only provide a new research direction in neuromorphic electronics but even open a new era of organic electronics.

This technology will lead to the leap of brain-inspired electronics in both memory density and energy consumption aspects. The artificial synapse developed by Prof. Lee’s research team will provide important potential applications to neuromorphic computing systems and artificial intelligence systems for autonomous cars (or self-driving cars), analysis of big data, cognitive systems, robot control, medical diagnosis, stock trading analysis, remote sensing, and other smart human-interactive systems and machines in the future.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160620100319.htm  Original web page at Science Daily

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Urban bird species risk dying prematurely due to stress

Birds of the species Parus Major (great tit) living in an urban environment are at greater risk of dying young than great tits living outside cities. Research results from Lund University in Sweden show that urban great tits have shorter telomeres than others of their own species living in rural areas. According to the researchers, the induced stress that the urban great tits are experiencing is what results in shorter telomeres and thereby increases their risk of dying young.

Telomeres are located at the end of each DNA strand in the body’s chromosomes, in both great tits and humans. The length of the telomeres can be described as a kind of age biomarker — short telomeres mean short life expectancy. According to the researchers, their study shows that the environment in which great tits grow up determines the length of their telomeres more than their genetics.

“Although there are advantages to living in cities, such as the access to food, they seem to be outweighed by the disadvantages, such as stress — at least in terms of how quickly the cells of the great tits age,” says biologist Pablo Salmón who conducts research in the field of evolutionary ecology at the Faculty of Science, Lund University.

The researchers obtained the results by studying great tit groups of siblings. Half of the siblings grew up in the countryside, half in Malmö. After 13 days, blood was taken to measure the length of their red cell telomeres. Pablo Salmón and his colleagues had partly anticipated the outcome, but were still surprised when they saw how big the difference in the length of the telomeres was after only 13 days.

“Previous studies have shown that genetics have an effect on the telomere length in individual birds. What we’re showing now is that growing up in a stressful environment has even more of an impact,” he says.

The study, which he conducted together with colleagues at the Faculty of Science, indicates the need for further studies to better understand how people can help birds in urban environments live longer.

“The impact that urbanisation has on wildlife must be studied much more, or we won’t be able to understand the threats that birds are exposed to in urban environments, and won’t be able to do anything about them. Our results also raise questions concerning the aging of other animals affected by urbanisation, and humans for that matter,” says Pablo Salmón. The study is published in an article in the scientific journal The Royal Society Journal Biology Letters.

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https://www.sciencedaily.com/releases/2016/06/160620112028.htm  Original web page at Science Daily

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New view of brain development: Striking differences between adult and newborn mouse brain

Findings reveal mismatch between neuronal activity and blood flow in the brains of newborn mice, shedding new light on how the growing brain feeds itself.

Columbia scientists have found that spikes in the activity of neurons in young mice do not spur corresponding boosts in blood flow — a discovery that stands in stark contrast to the adult mouse brain. This new study raises questions about how the growing human brain meets its energy needs, as well as how best to track brain development with functional magnetic resonance imaging, or fMRI, which relies on blood-flow changes to map neuronal activity in the brain. The research could also provide critical new insights for improving care for infants.

“In the adult brain, neuronal activity triggers a localized boost in blood flow. This relationship between neuronal activity and blood flow has long been assumed to be present from birth, but our findings in mice suggest the opposite: that instead it develops over time,” said Elizabeth Hillman, PhD, a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, associate professor of biomedical engineering and radiology at Columbia’s Fu Foundation School of Engineering and Applied Science and the paper’s senior author. Our study further suggests that this process is an essential part of building a healthy brain and could represent an unexplored factor in brain disorders that emerge in early childhood.”

Today’s study was motivated by previous fMRI studies in humans that reported vastly different responses in the brains of babies compared to the brains of adults.

“No one knew how to interpret blood-flow responses in the developing brain,” said Mariel Kozberg MD, PhD, a recent Columbia neurobiology graduate in Dr. Hillman’s lab and the paper’s first author. In this study, we needed to find out what was different between adult and newborn brains. Were the differences in neural activity itself, or did they lie in the relationship between this activity and local blood flow changes?”

To answer this question, Drs. Hillman and Kozberg developed a new imaging technique that simultaneously recorded neuronal activity and blood flow in the brains of mice of different ages (from newborn up to adult), tracking how the brain responded when they stimulated each animal’s hind paw.

“When we started to get data we were amazed by what we could see,” said Dr. Kozberg. First, the team’s innovative imaging methods revealed that, for the youngest mice, stimulating the hind paw caused a strong neuronal response, but this response was localized to one region. Then, as the animals got older, the neuronal response began to spread. By 10 days of age, stimulating the right paw first sparked activity on the left side of the brain before traveling to the right side, corresponding to the development of connections between the two hemispheres.

“We realized we were actually watching cells form connections with each other throughout the brain: the development of neural networks,” added Dr. Hillman, who is also a member of the Kavli Institute for Brain Science at Columbia.

The researchers’ second finding was even more startling. In the youngest mice, neuronal activity did not trigger an increase in blood flow, as occurs in the adult mouse brain. But as the animals matured, and their neural networks became more established, the brain’s blood-flow response gradually got stronger over time until the animal reached adulthood.

“It was like the brain was gradually learning to feed itself,” said Dr. Hillman, who notes that this finding makes a lot of sense. “It is hardly surprising that blood vessels — and the machinery linking them to brain activity — would mature in step with the development of neural activity itself.”

However, these results raised a worrying question. The job of blood vessels is to deliver oxygen-rich blood to the brain. So, can the newborn brain truly function and grow without subsequent increases in blood flow? To find out, Drs. Kozberg and Hillman used another optical imaging technique, called flavoprotein imaging, which measures how the newborn brain used oxygen.

“In the youngest animals, we confirmed that neurons were indeed consuming oxygen, but without a rush of fresh blood, they seemed to run out of fuel,” said Dr. Kozberg. “We further found that the neural activity actually caused localized drops in oxygen levels, known as hypoxias.”

Drs. Hillman and Kozberg propose several explanations for this surprising result. “Newborns make an incredible transition from being inside the womb to breathing air in the delivery room,” noted Dr. Hillman. “To survive those first few hours, the newborn brain must be well prepared to withstand enormous fluctuations in the availability of oxygen.”

Because the hypoxias seen in young mice appear to be part of the normal development process, the authors propose that it may in fact serve an important purpose.

“We know that a lack of oxygen can trigger the growth of blood vessels,” said Dr. Kozberg. “So in this case, neural activity in the newborn brain might actually be guiding blood vessels to grow in the right places.”

Moving forward, the team is preparing to compare their results in mice to the human brain. Dr. Hillman is working with researchers at Columbia’s Department of Psychiatry to analyze hundreds of fMRI scans previously collected from newborns, as well as from children of different ages.

“If we can find the same signatures of neurovascular development in human infants, we could turn fMRI into an even more powerful tool. For example, using it to better understand, detect and track the origins of developmental disorders in the newborn brain,” she said.

Dr. Hillman’s team is also eager to continue studying oxygen metabolism in newborns. Preterm infants exposed to high oxygen levels can suffer from retinopathy, a condition in which blood vessels in the eyes grow incorrectly. She hypothesizes that excessive oxygen could lead to the same disruptions to blood-vessel growth in the brain itself.

Added Dr. Hillman, “If we can learn more about the unique metabolic state of the developing brain, we might be able to improve treatment strategies for premature infants, while also gaining a deeper understanding of normal and abnormal brain development overall.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160621193102.htm Original web page at Science Daily

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Compound shown to reduce brain damage caused by anaesthesia in early study

An experimental drug prevented learning deficits in young mice exposed repeatedly to anaesthesia, according to a study led by researchers from NYU Langone Medical Center and published June 22 in Science Translational Medicine.

The study results may have implications for children who must have several surgeries, and so are exposed repeatedly to general anaesthesia. Past studies have linked such exposure to a higher incidence of learning disabilities, attention deficits and hyperactivity.

Specifically, the research team found that the experimental drug CX456, part of the AMPAkine class in clinical trials for several neurological conditions, counters for the dampening effect of anaesthesia on nerve signaling. The treatment bolstered nerve cell activity as well as learning ability in mice recovering from repeated exposure to general anaesthesia.

“Each year, in the United States alone, more than a million children under age four undergo surgical procedures that require anaesthesia, and the numbers are growing,” says the study’s senior investigator Guang Yang, PhD, assistant professor of anaesthesiology at NYU Langone. “There are currently no effective treatments to combat potential toxicity linked to repeated anaesthesia, and we would like to change that.”

Yang’s group took advantage of genetically engineered young mice that have protein markers which glow in response to changes in nerve function. Researchers then used advanced microscopy to visualize activity in their brains, comparing nerve signaling activity in those exposed to anaesthesia to those who were not.

The research team found that anaesthesia exposure resulted in a prolonged reduction of signal transmission among nerve cells following anaesthesia. They also observed that CX456 treatment enhances this transmission, along with learning and memory in mice exposed to anesthesia.

The team studied the anaesthetic ketamine, which blocks NMDA (N-methyl-D-aspartate) receptor proteins that enable charged particles like calcium to flow into nerve cells, like electric switches that trigger and shape messages. In contrast, CX546 increases nerve cell activity and calcium influx into nerve cells by enhancing the activity of proteins called AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors.

“We were able to counter anaesthesia-induced deficits in the formation of connections between nerve cells and related learning problems,” says Yang. “This work is an important proof-of-principle study, and opens the door to a new direction for preventing long-term neurocognitive deficits.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160622144816.htm  Original web page at Science

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Precise control of brain circuit alters mood

Pacemaker circuit keeps emotional centers working together. By combining super-fine electrodes and tiny amounts of a very specific drug, Duke University researchers have singled out a circuit in mouse brains and taken control of it to dial an animal’s mood up and down.

Stress-susceptible animals that behaved as if they were depressed or anxious were restored to relatively normal behavior by tweaking the system, according to a study appearing in the July 20 issue of Neuron.

“If you ‘turn the volume up’ on animals that hadn’t experienced stress, they start normal and then they have a problem,” said lead researcher Kafui Dzirasa, an assistant professor of psychiatry and behavioral sciences, and neurobiology. “But in the animals that had experienced stress and didn’t do well with it, you had to turn their volume up to get them back to normal. It looked like stress had turned the volume down.”

The circuit the team identified and altered is a connection the prefrontal cortex uses to keep time for the limbic system, which governs emotions and basic drives. To regulate mood, the prefrontal cortex acts as a pacemaker to coordinate the actions of the amygdala, which governs stress responses, and the ventral tegmental area, which plays a role in the brain’s reward circuitry.

“These subcortical circuits are the key regulators of our emotional life,” said Helen Mayberg, a professor of psychiatry, neurology and radiology at Emory University who was not involved in this research. “What’s great about this paper is that they use different approaches to see a circuit that’s relevant to a lot of disorders,” said Mayberg, who has been pioneering deep-brain stimulation of very specific sites in the human prefrontal cortex to treat mood disorders.

The emerging picture from this study and others is of a brain built of multi-part circuits that respond in concert and regulate one another. Specificity in understanding these circuits is going to be key to resolving different disorders, Dzirasa said.

“The prefrontal cortex is not just a blob of cells,” Mayberg said. “These findings give insight into which cells go to which area and allow researchers to kind of choreograph their actions.”

Dzirasa is an M.D. just finishing his residency in psychiatry and a Ph.D. neuroscientist with an engineering background. Postdoctoral researcher and first author Rainbo Hultman is a biochemist.

In addition to overcoming the challenges of understanding each other, they asked, “Could we go from a protein, to a signaling activity, to a cell, to a circuit, to this big activity that happens across the whole brain, to actual behavior?” Hultman said.

“Illness can happen at any one of these levels,” said Dzirasa, who is also a member of the Duke Institute for Brain Sciences.

The team started by precisely placing arrays of 32 electrodes in four brain areas of the mice. Then they recorded brain activity as these mice were subjected to a stressful situation called chronic social defeat. This allowed them to see activity between the prefrontal cortex and three areas of the limbic system that are implicated in major depression.

To interpret the complicated data coming from the electrodes, the neuroscientists then turned to Duke colleagues David Dunson of statistical science and Lawrence Carin of electrical engineering, who specialize in statistical analysis of noisy data to find important patterns. Using machine learning algorithms, they identified which parts of the data seemed to be the timing control signal between the prefrontal cortex and the amygdala and zeroed in on the individual neurons involved in that circuit.

“They came back with, ‘It’s this clock signature here that is responsible for which mice become susceptible to stress and which become resilient,'” Dzirasa said.

Hultman then turned to engineered molecules called DREADD developed by University of North Carolina at Chapel Hill pharmacologist Bryan Roth. These Designer Receptors Exclusively Activated by Designer Drug are very specific signal receptors that can be incorporated into the neural circuit’s control spots in very tiny amounts (0.5 microliter). A drug that attaches only to that DREADD is then administered to give the researchers control over the circuit.

This new combination of electronics and drugs to intervene in an individual brain circuit might be used to create mouse models of other mood disorders for other studies, Dzirasa said. But Emory’s Mayberg cautions that a mouse brain is not a human brain and to assess anything like “mood” in a mouse, one can only infer from its behaviors. “It’s hard to do, even in a human,” she said.

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https://www.sciencedaily.com/releases/2016/06/160623122942.htm  Original web page at Science Daily

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Human brain houses diverse populations of neurons, new research shows

A team of researchers has developed the first scalable method to identify different subtypes of neurons in the human brain. The research lays the groundwork for “mapping” the gene activity in the human brain and could help provide a better understanding of brain functions and disorders, including Alzheimer’s, Parkinson’s, schizophrenia and depression.

By isolating and analyzing the nuclei of individual human brain cells, researchers identified 16 neuronal subtypes in the cerebral cortex — the brain’s outer layer of neural tissue responsible for cognitive functions including memory, attention and decision making. The team, led by researchers at the University of California San Diego, The Scripps Research Institute (TSRI) and Illumina, published their findings in the June 24 online issue of the journal Science.

“We’re providing a unified framework to look at and compare individual neurons, which can help us find out how many unique types of neurons exist,” said Kun Zhang, bioengineering professor at the University of California, San Diego and a corresponding author of the study.

Researchers can use these different neuronal subtypes to build what Zhang calls a “reference map” of the human brain — a foundation to understand the differences between a healthy brain and a diseased brain.

“In the future, patients with brain disorders or abnormalities could be diagnosed and treated based on how they differ from the reference map. This is analogous to what’s being done with the reference human genome map,” Zhang said.

The new study reflects a growing understanding that individual brain cells are unique: they express different types of genes and perform different functions. To better understand this diversity, researchers analyzed more than 3,200 single human neurons in six Brodmann areas, which are regions of the cerebral cortex classified by their functions and arrangements of neurons.

Through an interdisciplinary collaborative effort, the team developed a new method to isolate and sequence individual cell nuclei. TSRI researchers led by neuroscience professor Jerold Chun obtained the samples from a post mortem brain and focused on isolating the neuronal nuclei. Zhang’s lab worked with Fluidigm, a manufacturer of microfluidic chips for single-cell studies, to develop a protocol to identify and quantify RNA molecules in individual neuronal nuclei. Scientists at San Diego-based Illumina sequenced the resulting RNA libraries. Researchers led by biochemistry professor Wei Wang at UC San Diego developed algorithms to cluster and identify 16 neuronal subtypes from the sequenced datasets.

Researchers deciphered what types of genes were “turned on” within each nucleus and revealed that various combinations of the 16 subtypes tended to cluster in cortical layers and Brodmann areas, helping explain why these regions look and function differently.

Neurons exhibited many differences in their transcriptomic profiles — the patterns of genes that are being actively expressed by these cells — revealing single neurons with shared, as well as unique, characteristics that likely lead to difference in cellular function.

“We’re finding new ways to understand the basic building blocks of the brain,” said Blue Lake, a postdoctoral researcher in Zhang’s lab and a co-first author of the study. “Our study opens the door to look at global gene expression patterns and how that defines cell types within a normal tissue, which can also be used to see what’s abnormal in terms of disease or disorders.”

In future studies, researchers aim to analyze neurons in other Brodmann areas of the brain and investigate what subtypes exist in other brain regions. They also plan to study neurons from multiple post mortem human brains (this study only involved one) to investigate neuronal diversity among individuals.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160623150111.htm  Original web page at Science Daily

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‘Baby talk’ can help songbirds learn their tunes

Adult songbirds modify their vocalizations when singing to juveniles in the same way that humans alter their speech when talking to babies. The resulting brain activity in young birds could shed light on speech learning and certain developmental disorders in humans, according to a study by McGill University researchers.

Lead author Jon Sakata, a professor of neurobiology at McGill, says that songbirds learn vocalizations like humans learn speech. “Songbirds first listen to and memorize the sound of adult songs and then undergo a period of vocal practice-in essence, babbling-to master the production of song.”

Researchers have been studying song learning in birds for some time. But the degree to which social interaction with adult birds contributes to that learning has been unclear. That’s because, unlike this current work, past studies didn’t control for the time exposed to song and the presence of other birds.

In this study, published in the journal Proceedings of the National Academy of Sciences, a group of juvenile zebra finches was allowed to interact with an adult. Another group simply heard adult songs played through a speaker. After a brief period of “tutoring” the juveniles were house individually for months as they practiced their tunes.

Sakata and his team found that avian pupils who socialized with an adult learned the adult’s song much better. That was true even if the social tutoring lasted just one day. In analyzing why this would be so, Sakata and his team made a surprising discovery.

Adult zebra finches change their vocalizations when singing to juveniles. Sakata says just as people speak more slowly and repeat words more often when speaking to infants, so do these birds. “We found that adult zebra finches similarly slow down their song by increasing the interval between song phrases and repeat individual song elements more often when singing to juveniles.”

What’s more, the researchers found that juvenile birds pay more attention to this “baby talk” compared to other songs. And the more the juveniles paid attention, the better they learned.

The researchers took their work a step further by examining the activity of certain neurons in parts of the brain associated with attention. They found that more neurons that produce the chemicals dopamine and norepinephrine were turned on after socially interacting with a singing adult than after simply hearing song through a speaker.

Dr. Sakata says this finding could have implications beyond the avian world. “Our data suggest that dysfunctions in these neurons could contribute to social and communicative disorders in humans. For example, children who suffer from autism spectrum disorders have difficulty processing social information and learning language, and these neurons might be potential targets for treating such disorders.”

Dr. Sakata is now testing whether raising dopamine and norepinephrine levels in the brain can help birds learn song when they only hear adult songs. As he puts it, “We are testing whether we can “trick” a bird’s brain into thinking that the bird is being socially tutored.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160531165239.htm Original web page at Science Daily

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Transmission of genetic disorder Huntington’s disease in normal animals

Mice transplanted with cells grown from a patient suffering from Huntington’s disease (HD) develop the clinical features and brain pathology of that patient, suggests a study published in the latest issue of Acta Neuropathologica by CHA University in Korea, in collaboration with researchers at Université Laval in Québec City, Canada.

“Our findings shed a completely new light onto our current understanding of how HD begins and develops. We believe that they will also lead to the development of a whole new range of therapies for neurodegenerative diseases of the central nervous system,” explains corresponding author of the study Jihwan Song, professor and director of Neural Regeneration and Therapy Group at the CHA Stem Cell Institute of CHA University.

The researchers have now provided further evidence for this new theory by showing that the abnormal protein coded for this genetic disorder can be transmitted to normal animals by the injection of diseased cells into their brain. “This is the first demonstration that cells carrying a genetic disease are capable of spreading into the normal mammalian brain and lead to the manifestation of behavioral abnormalities associated with the disease,” says Francesca Cicchetti, professor at the Université Laval Faculty of Medecine and researcher at Centre de recherche du CHU de Québec-Université Laval.

HD is an inherited chronic degenerative disorder of the brain characterized by major thinking and motor problems as well as psychiatric disturbances. There is no cure for HD and current treatments are of very limited efficacy. It is caused by a single gene abnormality which leads to the production of a mutant form of a protein called huntingtin (mHtt). The production of this protein in a nerve cell eventually kills it but it has long been thought that this protein cannot spread out of the cell and infect and kill neighbouring ones.

However, in recent post mortem analyses of HD patients who received transplants of non-HD tissue in an attempt to repair their brain, the researchers showed that the mHtt can be found in the graft itself. This suggests that the patient with HD transmitted the mHtt from their brain into the transplant.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160531104225.htm  Original web page at Science Daily

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The primate brain is ‘pre-adapted’ to face potentially any situation

Scientists have shown how the brain anticipates all of the new situations that it may encounter in a lifetime by creating a special kind of neural network that is “pre-adapted” to face any eventuality. This emerges from a new neuroscience study published in PLOS Computational Biology.

Enel et al at the INSERM in France investigate one of the most noteworthy properties of primate behavior, its diversity and adaptability. Human and non-human primates can learn an astonishing variety of novel behaviors that could not have been directly anticipated by evolution — we now understand that this ability to cope with new situations is due to the “pre-adapted” nature of the primate brain.

This study shows that this seemingly miraculous pre-adaptation comes from connections between neurons that form recurrent loops where inputs can rebound and mix in the network, like waves in a pond, thus called “reservoir” computing. This mix of the inputs allows a potentially universal representation of combinations of the inputs that can then be used to learn the right behaviour for a new situation.

The authors demonstrate this by training a reservoir network to perform a novel problem solving task. They then compared the activity of neurons in the model with activity of neurons in the prefrontal cortex of a research primate that was trained to perform the same task. Remarkably, there were striking similarities in the activation of neurons in both the reservoir model and the primate.

This breakthrough shows that we have taken big step towards understanding the local recurrent connectivity in the brain that prepares primates to face unlimited situations. This research shows that by allowing essentially unlimited combinations of internal representations in the network of the brain, one of them is always on hand for the given situation.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160610173512.htm  Original web page at Science Daily

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Mobilizing mitochondria may be key to regenerating damaged neurons

Researchers at the National Institute of Neurological Disorders and Stroke have discovered that boosting the transport of mitochondria along neuronal axons enhances the ability of mouse nerve cells to repair themselves after injury. The study, “Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits,” which has been published in The Journal of Cell Biology, suggests potential new strategies to stimulate the regrowth of human neurons damaged by injury or disease.

Neurons need large amounts of energy to extend their axons long distances through the body. This energy — in the form of adenosine triphosphate (ATP) — is provided by mitochondria, the cell’s internal power plants. During development, mitochondria are transported up and down growing axons to generate ATP wherever it is needed. In adults, however, mitochondria become less mobile as mature neurons produce a protein called syntaphilin that anchors the mitochondria in place. Zu-Hang Sheng and colleagues at the National Institute of Neurological Disorders and Stroke wondered whether this decrease in mitochondrial transport might explain why adult neurons are typically unable to regrow after injury.

Sheng and his research fellow Bing Zhou, the first author of the study, initially found that when mature mouse axons are severed, nearby mitochondria are damaged and become unable to provide sufficient ATP to support injured nerve regeneration. However, when the researchers genetically removed syntaphilin from the nerve cells, mitochondrial transport was enhanced, allowing the damaged mitochondria to be replaced by healthy mitochondria capable of producing ATP. Syntaphilin-deficient mature neurons therefore regained the ability to regrow after injury, just like young neurons, and removing syntaphilin from adult mice facilitated the regeneration of their sciatic nerves after injury.

“Our in vivo and in vitro studies suggest that activating an intrinsic growth program requires the coordinated modulation of mitochondrial transport and recovery of energy deficits. Such combined approaches may represent a valid therapeutic strategy to facilitate regeneration in the central and peripheral nervous systems after injury or disease,” Sheng says.

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https://www.sciencedaily.com/releases/2016/06/160607151233.htm Original web page at Science Daily

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* Scientists unpack how Toxoplasma infection is linked to neurodegenerative disease

Toxoplasma gondii, a protozoan parasite about five microns long, infects a third of the world’s population. Ingested via undercooked meat or unwashed vegetables, the parasite infects 15-30 percent of the US population. In France and Brazil, up to 80 percent of the population has the infection.

Particularly dangerous during pregnancy — infection in pregnant women can cause serious congenital defects and even death of the fetus — this chronic infection has two components: the unicellular parasite, and inflammation of tissues it causes.

Working on mice (like all mammals, a natural host for this parasite), a University of California, Riverside team of biomedical scientists reports in the journal PLOS Pathogens that Toxoplasma infection leads to a disruption of neurotransmitters in the brain and postulates that it triggers neurological disease in those already predisposed to such a disease.

They note that Toxoplasma infection leads to a significant increase in glutamate — the primary and most important neurotransmitter in the brain, which transmits excitatory signals between neurons. This glutamate increase is “extracellular,” meaning outside the cell, and is strictly controlled by specialized cells in the central nervous system (brain and spinal cord), called astrocytes. Glutamate buildup is seen in traumatic brain injury as well as highly pathological and neurodegenerating diseases such as epilepsy, multiple sclerosis and amyotrophic lateral sclerosis (ALS).

One role astrocytes play is to remove extracellular glutamate, lest it increase to pathological levels that could damage neurons. This is primarily achieved using a glutamate transporter, called GLT-1, tasked with regulating extracellular glutamate. GLT-1 soaks up glutamate released by neurons and converts it back into the safer substance glutamine, which can then be used by cells for energy.

“When a neuron fires it releases glutamate into the space between itself and a nearby neuron,” explained lead researcher Emma H. Wilson, an associate professor in the Division of Biomedical Sciences in the School of Medicine, who has worked on toxoplasmosis for more than 15 years. “The nearby neuron detects this glutamate which triggers a firing of the neuron. If the glutamate isn’t cleared by GLT-1 then the neurons can’t fire properly the next time and they start to die.”

Wilson and her team found that during toxoplasma infection, astrocytes swell and are not able to regulate extracellular glutamate concentrations. Further, GLT-1 is not expressed properly. This leads to a buildup of the glutamate released from neurons and the neurons misfire.

“These results suggest that in contrast to assuming chronic Toxoplasma infection as quiescent and benign, we should be aware of the potential risk to normal neurological pathways and changes in brain chemistry,” Wilson said.

When the researchers treated the infected mice with ceftriaxone, an antibiotic known to produce beneficial results in mouse models of ALS as well as neuroprotection in a variety of central nervous system injuries, they found that GLT-1 was upregulated. This restoration of GLT-1 expression significantly reduced extracellular glutamate from pathological to normal concentrations, returning neuronal function to a normal state.

“We have shown for the first time the direct disruption of a major neurotransmitter in the brain resulting from this infection,” Wilson said. “More direct and mechanistic research needs to be performed to understand the realities of this very common pathogen.”

Next, Wilson and her colleagues will research what initiates the downregulation of GLT-1 during chronic Toxoplasma infection.

“Despite the importance of this transporter to maintaining glutamate homeostasis, there is little understanding of the mechanism that governs its expression,” Wilson said. “We’d like to know how cells, including peripheral immune cells, control the parasite in the brain. Toxoplasma infection results in the lifelong presence of parasitic cysts within the neurons in the brain. We’d like to further develop a project focused on killing the cysts, which is where the parasite hides from the immune response for the rest of the infected person’s life. Getting rid of the cyst removes the threat of reactivation of the parasite and the risk of encephalitis while also allowing us to minimize chronic inflammation in the brain.”

Mysteriously, the parasite that causes toxoplasmosis can sexually reproduce only in cats. Asexually, it can replicate and live in any mammalian cell that has a nucleus. Indeed, the parasite has been found in every mammal ever tested.

Post-infection, a competent immune system is needed to prevent parasite reactivation and encephalitis. Infected people with compromised immune systems need to be on prophylactic drugs for life. Otherwise they are at risk of cyst reactivation and death. The parasite lives in areas of the brain that have the potential to disrupt certain behaviors such as risk-seeking (infected mice will run toward cat urine instead of away from it).

The parasite is not as latent or dormant as researchers once thought. Cases of congenital infection and retinal toxoplasmosis are on the rise (the brain and retina are closely linked). People who have schizophrenia are more likely to be infected with Toxoplasma. Infection shows some correlation with Alzheimer’s disease, Parkinson’s disease and epilepsy.

Nevertheless, Wilson notes that infection is no cause for major worry. “We have been living with this parasite for a long time,” she said. “It does not want to kill its host and lose its home. The best way to prevent infection is to cook your meat and wash your hands and vegetables. And if you are pregnant, don’t change the cat litter.”

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https://www.sciencedaily.com/releases/2016/06/160609150841.htm Original web page at Science Daily

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Antibody-based drug helps ‘bridge’ leukemia patients to curative treatmen

In a randomized Phase III study of the drug inotuzumab ozogamicin, a statistically significant percentage of patients with acute lymphoblastic leukemia (ALL) whose disease had relapsed following standard therapies, qualified for stem cell transplants.

Inotuzumab ozogamicin, also known as CMC-544, links an antibody that targets CD22, a protein found on the surface of more than 90 percent of ALL cells. Once the drug connects to CD22, the ALL cell draws it inside and dies.

The study, which revealed complete remission rates of nearly 81 percent and significantly longer progression-free and higher overall survival rates than with standard therapies, was conducted at The University of Texas MD Anderson Cancer Center. Study findings were reported in the June 12 online issue of the New England Journal of Medicine.

“Forty-one percent of ALL patients in the study were able to proceed to transplant after receiving inotuzumab ozogamicin compared with the 11 percent we have seen qualify through standard chemotherapy,” said Hagop Kantarjian, M.D., chair of Leukemia. “Given that stem cell transplant is considered the only curative treatment option, the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging.”

Donor stem cell transplants generally are considered curative for this aggressive form of leukemia with more than 6,500 American adults expected to be diagnosed with the disease in 2016. However, patients must be in complete remission before they are eligible for transplant.

Current therapies for adults with newly diagnosed B-cell ALL result in complete remission rates (CR) of 60 to 90 percent. However, many of those patients will relapse and only about 30 to 50 percent will achieve long-term, disease-free survival lasting more than three years.

“Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier, and just 18 to 25 percent in those who relapse later,” said Kantarjian. “Patients in the inotuzumab ozogamicin study had remission rates of 58 percent, higher than previously reported, possibly due to patients being treated later in the disease course.”

The study reported moderate side effects, the most common being cytopenia, a disorder that reduces blood cell production, and liver toxicity. Funding was provided by Pfizer, Inc.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160612105823.htm Original web page at Science Daily

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Neurologic symptoms common in early HIV infection

A team led by researchers from UCSF and Yale has found that half of people newly infected with HIV experience neurologic issues. These neurologic findings are generally not severe and usually resolve after participants started anti-retroviral therapy.

“We were surprised that neurologic findings were so pervasive in participants diagnosed with very recent HIV infection,” said study lead author, Joanna Hellmuth, MD, MHS, clinical fellow in UCSF’s Department of Neurology. “While the findings were mild, it is clear that HIV affects the nervous system within days of infection. Since the majority of these neurologic issues were resolved with treatment, our study reinforces recommendations that people at risk for HIV test often and start antiretroviral treatment immediately if they are infected.”

The research will be published in the June 10, 2016, issue of Neurology, the medical journal of the American Academy of Neurology.

The team examined 139 participants in the RV254 Thai cohort who were recently infected with HIV. The time from infection to entry into the study ranged from 3 to 56 days with a median of 19 days. At this stage, participants would not test positive on the common antibody tests for HIV since they have not been infected long enough for a robust specific immune response to take place. Fifty-three percent had neurologic findings, with a third experiencing cognitive deficits, a quarter having motor issues, and nearly 20 percent experiencing neuropathy. Many experienced more than one symptom. One participant was diagnosed with Guillain-Barré Syndrome, the only severe case found in the cohort.

“In the early days of the epidemic in San Francisco, approximately 10 percent of patients with recent HIV infection presented with dramatic neurological disease. But that was likely due to patients coming in early because of the severity of symptoms they were experiencing. The Thai cohort has given us an opportunity to look at a broad range of newly infected patients, analyze their neurological functioning systematically and follow them over time. We are gaining deeper insights into the degree to which early HIV affects the nervous system,” said study senior author, Serena Spudich, MD, Yale associate professor of neurology.

All participants were offered and commenced antiretroviral treatment at diagnosis. Ninety percent of the issues present at diagnosis were resolved after one month of treatment, but 9 percent of the participants had neurologic symptoms that were still not resolved six months after starting therapy. In addition, neurological symptoms were associated with higher levels of HIV found in participants’ blood.

The study participants underwent extensive neurologic assessments. Self reported symptoms were correlated with objective neuropsychological testing. In addition, a quarter of participants opted to undergo a lumbar puncture and almost half of the patients agreed to undergo a MRI.

“This is one of the first comprehensive studies scrutinizing the involvement of the nervous system in early infection. Since we have been able to maintain the cohort for five years now, we will be able to study whether there are any persistent abnormalities that need to be addressed. Additionally, the ubiquity of symptoms in early infection found in this study reinforces the need for the brain to be considered as a compartment containing latent HIV as we design cure studies,” said study co-author, Victor Valcour, MD, PhD, UCSF professor of neurology.

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https://www.sciencedaily.com/releases/2016/06/160613105753.htm Original web page at Science Daily

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Resistance mechanism of aggressive brain tumors revealed

Brain tumors subject to therapy can become resistant to it through interactions with their tumor microenvironment rather than because of anything intrinsic about the tumor itself, a new study in mice suggests.

The resistance mechanism outlined in the study involves a particular enzyme and can be overcome using other drugs that target this newly identified signaling pathway. Glioblastoma multiforme (GBM) is a common and aggressive type of adult brain tumor; current standard treatment only minimally prolongs survival.

Macrophages, types of white blood cell that ingest debris, are found in abundance in GMB tumors, and tend to express high levels of colony stimulating factor-1 (CSF-1).

Daniela Quail et al. showed that inhibiting CSF-1 with a drug called BLZ945 caused tumor regression in mice; however, the majority of GBM tumors ultimately developed resistance to BLZ945, a phenomenon of interest as cancer drugs targeting CSF-1 are currently in clinical trials in multiple settings.

Further investigation revealed that GMB recurrence correlated with elevated activity of a tumor enzyme called PI3-K, which was in turn driven by an environmental influence, macrophage-secreted IGF-1. Mice that were treated with BLZ945 plus a PI3-K or IGF-1 inhibitor benefited from significantly longer survival than control mice, the researchers showed.

By implanting BLZ945-resistant tumors into naïve mice, Quail et al. demonstrated that GBM tumors use this this PI3-K/IGF-1 mechanism to manipulate the surrounding microenvironment to their advantage.

Thus, they say, tumors can also develop resistance through microenvironment-dependent mechanisms, independent of the tumor itself. Whether the findings will translate to a human model of glioma remains to be seen.

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https://www.sciencedaily.com/releases/2016/05/160519144538.htm  Original web page at Science Daily

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* How brain connects memories across time

Neuroscientists boost ability of aging brain to recapture links between related memories. Using a miniature microscope that opens a window into the brain, UCLA neuroscientists have identified in mice how the brain links different memories over time. While aging weakens these connections, the team devised a way for the middle-aged brain to reconnect separate memories.

The findings, which were published in the advance online edition of Nature, suggest a possible intervention for people suffering from age-related memory problems.

“Until now, neuroscientists have focused on how the brain creates and stores single memories,” said principal investigator Alcino Silva, a professor of neurobiology at the David Geffen School of Medicine at UCLA. “We wanted to explore how the brain links two memories and whether the passage of time affects the strength of the connection.”

“In the real world, memories don’t happen in isolation,” said first author Denise Cai, a researcher in Silva’s lab. “Our past experiences influence the creation of new memories and help us predict what to expect and make informed decisions in the future.”

In an intricate experiment, the UCLA team tested in young and middle-aged mice whether the brain linked memories of experiences separated by five hours versus seven days.

The lab used a miniature microscope, called a Miniscope, which was developed by UCLA neuroscientists Dr. Peyman Golshani, Baljit Khakh and Silva with funding from the presidential BRAIN Initiative and the Geffen School. The instrument’s powerful camera allowed the scientists to peer into the brains of young and observe their cells in action. The tiny, head-mounted microscope illuminated the animals’ neurons firing as the mice moved freely in their natural environments.

For 10 minutes at a time, each mouse was placed in three boxes, all unique in terms of fragrance, shape, lighting and flooring. A week’s time separated placement in the first and second boxes. Only five hours separated time spent in the second and third boxes, where the mouse later received a small shock to the foot.

Two days later, the team returned each mouse to all three boxes. As expected, the mice froze with fear when it recognized the inside of the third box.

“The mouse also froze in the second box, where no shock occurred,” Silva observed. “This suggests that the mouse transferred its memory of the shock in the third box to its experience in the second box five hours earlier.”

When Silva and Cai examined the animals’ brains, the neural activity confirmed their hypothesis.

“The same brain cells that recorded the mouse’s shock in the third box also encoded its memory of the second box a few hours earlier,” Cai said. “We saw 20 percent more overlap in the neural circuits that recorded the animal’s experiences in the memories that unfolded closer in time.”

In other words, says Silva, “The memories became interrelated in how they were encoded and stored by the brain, such that the recall of one memory triggered the recall of another memory related in time.”

Based on an earlier Silva finding, the team knew that a cell is most likely to encode a memory when it’s aroused and ready to fire. Neuroscientists refer to this condition as excitability.

“The excitable brain is already warmed up,” Silva said. “It’s like stretching your muscles before exercise or revving your car engine before you drive.”

Suspecting that aging weakens neurons’ ability to fully excite, the UCLA researchers conducted a similar experiment in middle-aged mice. They introduced each of the mice to two boxes, five hours apart, and administered a foot shock in the second box.

When they returned the animals to the boxes two days later, the results could not have been more clear-cut.

“The older mice froze only in the box where they had received a shock,” Cai explained. “They did not react in the first box.”

A glimpse into the Miniscopes confirmed that the brains of the mice did not connect the two memories; each memory was encoded on its own neural circuit.

Next the team focused on boosting the older animals’ ability to link memories. Cai used a biological tool to excite neurons in a tiny part of the hippocampus — the memory center of the brain — before introducing the mice to the first box.

She stimulated the same cells before placing the mice in the first box and the second box, where they received a foot shock two days later.

“The proof in the pudding arrived when we reintroduced the middle-aged mice to the first box,” Silva said. “The animals froze — they now linked the shock that happened in the second box to the first. This suggests that increased excitability had reversed their age-related inability to link memories.”

Cai and Silva are currently testing an FDA-approved drug’s effect on the ability of middle-aged mice to connect memories.

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https://www.sciencedaily.com/releases/2016/05/160523113730.htm Original web page at Science Daily

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Male birds may sing, but females are faster at discriminating sounds

It may well be that only male zebra finches can sing, but the females are faster at learning to discriminate sounds. Leiden researchers publish their findings in the scientific journal Animal Behaviour.

The scientists reached this conclusion after a meta-analysis of different experiments with the songbirds. Combining the results of 14 separate studies gave them a population of 87 birds to work from. The aim of the research was to find out why some birds could recognize sounds faster than others.

The zebra finches heard one of two sound types after pecking at an LED sensor. If — after hearing the right sound (the ‘go sound’) — they pecked on the sensor again, they received a reward. Pecking on the sensor after hearing the so-called no-go sound gave them no reward, and even ‘punished’ the birds by leaving them in the dark for a short while.

Dr Pralle Kriengwatana: ‘Our meta-analysis shows that female zebra finches learn to discriminate sounds faster, which is surprising considering that females don’t sing. On the basis that male songbirds usually sing more than female songbirds, scientists have long assumed that the males must also be better at recognising and learning song (and perhaps also other sounds). It now seems that sex differences in producing complex sounds do not necessarily correlate exactly with the ability to perceive and discriminate these complex sounds.’

The scientists are still in the dark about the reasons why females learn better than males, although the female hormone oestrogen may play a role. According to Kriengwatana, further research is needed to determine the precise cause of the sex differences.

The researchers also discovered that the zebra finches try out different theories in their efforts to understand the test. In the first instance some birds stop pecking as soon as they hear new sounds, and then start pecking after each sound (both ‘go’ and ‘no-go’). Once they realise that pecking after the ‘no-go’ sound does not bring them any reward, they peck much less after this sound. The other group of birds also initially stop pecking, and then slowly but surely start pecking on the LED sensor again after both sounds. As soon as they understand that the ‘go’ sound gives them food, they peck more after hearing this sound.

Surprisingly enough, family size and body mass also seem to play a role. The finches from larger nests learned to distinguish sounds faster than birds with fewer siblings. The same applied for finches that weighed more at the age when they learned to eat by themselves and stop relying on parents for food. One explanation could be that more contact with other birds and better health may promote the faster recognition of sounds.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160512130332.htm  Original web page at Science Daily

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Second gene modifies effect of mutation in a dog model of ALS

Degenerative Myelopathy is a naturally occurring, progressive adult onset disorder of the spinal cord that leads to paralysis and death. In 2009, a SOD1 mutation was associated with risk of developing the disease (link to previous press release). However, not all dogs with the mutation became affected, prompting the hypothesis that additional genes could modify disease risk.

Genome-wide association analysis comparing affected and unaffected PWC with the SOD1 mutation identified a haplotype within the gene ‘SP110 nuclear body protein’ that was associated with increased risk of developing DM and early age of onset.

We discovered several variants in SP110 that were more common in the PWCs that developed DM says Emma Ivansson, former PostDoc at Uppsala University leading the study.

Our functional studies revealed that the variants alter expression of SP110 in blood cells continues Sergey Kozyrev, senior scientist at Uppsala University.

Whether SP110 affects the risk of DM also in other dog breeds requires further investigation, says Kate Megquier, veterinarian and PhD student at Uppsala University and Broad Institute.

SP110 is a regulator of gene expression, mainly in immune cells. It is known that the immune response is important in neurodegeneration, but inflammation can be either protective or damaging and the exact mechanisms are still unclear.

Many studies have investigated the role of immunity in ALS, and our finding that a gene regulating the immune response is important in this canine model of ALS could provide a new angle says Emma Ivansson.

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https://www.sciencedaily.com/releases/2016/05/160516181035.htm  Original web page at Science Daily

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Early-life stress causes digestive problems and anxiety in rats

Traumatic events early in life can increase levels of norepinephrine — the primary hormone responsible for preparing the body to react to stressful situations — in the gut, increasing the risk of developing chronic indigestion and anxiety during adulthood, a new study in American Journal of Physiology — Gastrointestinal and Liver Physiology reports.

Functional dyspepsia, also known as indigestion with no clear origin, affects an estimated 25 to 40 percent of adults. The most common symptoms include pain or discomfort in the upper abdomen, upset stomach, bloating and feeling full quickly while eating. Because the symptoms cannot be pinpointed to a cause, such as an ulcer or gastritis, functional dyspepsia is challenging to treat and many patients continue to experience symptoms years after diagnosis.

How functional dyspepsia develops is not well understood. Population studies have reported that early-life trauma — including abuse, psychological stress and gastrointestinal infections from sources such as contaminated food and water — increases the risk of developing functional dyspepsia in adulthood. Patients with functional dyspepsia also have a higher prevalence of anxiety, but whether functional dyspepsia and anxiety are linked is a contentious issue.

A research team from the University of Texas Medical Branch at Galveston reported in a previous study that inducing inflammation in the colon — such as what occurs during gastrointestinal infections — of neonatal rats caused gut hypersensitivity when the rats became adults. The researchers found that colon inflammation did so by increasing levels of stress hormone norepinephrine. Norepinephrine is produced in nerves all over the body. When stimulated, the nerves release norepinephrine into the blood stream, which affects cells in the surrounding area. This new study aimed to explain the increase in norepinephrine and determine whether rats were more susceptible to anxiety after having colon inflammation as newborns.

The researchers induced inflammation in the colons of 10-day-old rats. After six to eight weeks, the adult rats were evaluated for stomach hypersensitivity and anxiety-like behavior. The researchers found that colon inflammation increased the levels of tyrosine hydroxylase, a protein that makes norepinephrine, in the nerves in the upper abdomen. The nerves released more norepinephrine, increasing levels of norepinephrine in the upper abdomen. The rats also displayed anxiety-like behavior.

The study shows that increased norepinephrine release in the upper abdomen increases stomach sensitivity and susceptibility to anxiety-like behaviors in rats. “Our findings extend the clinical observations that adverse early-life experiences are risk factors for the development of functional dyspepsia symptoms,” says Sushil Sarna, PhD, of University of Texas Medical Branch at Galveston and lead investigator of the team.

The research group will continue to study the link between functional dyspepsia, anxiety and early-life stress. Anxiety worsens the symptoms of functional dyspepsia, but whether it causes or is a result of functional dyspepsia remains to be investigated, according to Sarna. The experimental method used in this study can be used to answer these questions, Sarna says. The research team is also working to identify potential targets for treating the condition and finding biomarkers to diagnose and evaluate the severity of functional dyspepsia symptoms.

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https://www.sciencedaily.com/releases/2016/05/160526152213.htm  Original web page at Science Daily

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Stress affects males, females differently

How does stress — which, among other things, causes our bodies to divert resources from non-essential functions — affect the basic exchange of materials that underlies our everyday life? Weizmann Institute of Science researchers investigated this question by looking at a receptor in the brains of mice, and they came up with a surprising answer. The findings, which recently appeared in Cell Metabolism, may in the future aid in developing better drugs for stress-related problems and eating disorders.

Dr. Yael Kuperman began this study as part of her doctoral research in the lab of Prof. Alon Chen of the Department of Neurobiology. Dr. Kuperman, presently a staff scientist in the Veterinary Resources Department, Prof. Chen, and research student Meira Weiss focused on an area of the brain called the hypothalamus, which has a number of functions, among them helping the body adjust to stressful situations, controlling hunger and satiety, and regulating blood glucose and energy production.

When stress hits, cells in the hypothalamus step up production of a receptor called CRFR1. It was known that this receptor contributes to the rapid activation of a stress-response sympathetic nerve network — increasing heart rate, for example. But since this area of the brain also regulates the body’s exchange of materials, the team thought that the CRFR1 receptor might play a role in this, as well.

Prof. Chen and his group characterized the cells in a certain area of the hypothalamus, finding that the receptor is expressed in around half of the cells that arouse appetite and suppress energy consumption. These cells comprise one of two main populations in the hypothalamus — the second promotes satiety and the burning of energy. “This was a bit of a surprise,” says Dr. Kuperman, “as we would instinctively expect the receptor to be expressed on the cells that suppress hunger.”

To continue investigating, the researchers removed the CRFR1 receptor in mice from just the cells that arouse appetite in the hypothalamus, and then observed how this affected the animals’ bodily functions. At first, the team did not see any significant changes, confirming that this receptor is saved for stressful situations. But when they exposed the mice to stress — cold or hunger — they got another surprise.

When exposed to cold, the sympathetic nervous system activates a unique type of fat called brown fat, which produces heat to maintain the body’s internal temperature. When the receptor was removed, the body temperature dropped dramatically — but only in the female mice. Their temperatures failed to stabilize even afterward the stressor was removed, while male mice showed hardly any change.

Fasting produced a similarly drastic response in the female mice. Normally, when food is scarce, the brain sends a message to the liver to produce glucose, conserving a minimum level in the blood. But when food was withheld from female mice missing the CRFR1 receptor, the amount of glucose their livers produced dropped significantly. In hungry male CRFR1-deficient mice, the result was similar to the effects of exposure to cold: the exchange of materials in their bodies was barely affected.

“We discovered that the receptor has an inhibitory effect on the cells, and this is what activates the sympathetic nervous system,” says Dr. Kuperman.

Among other things — revealing exactly how this receptor works and how it contributes to the stress response — the findings show that male and female bodies may exhibit significant differences in the ways that materials are exchanged under stress. Indeed, the fact that the receptor suppresses hunger in females may help explain why women are much more prone to eating disorders than men.

Because drugs can enter the hypothalamus with relative ease, the findings could be relevant to the development of treatments for regulating hunger or stress responses, including anxiety disorders or depression. Indeed, several pharmaceutical companies have already begun developing psychiatric drugs to block the CRFR1 receptor. The scientists caution, however, that because the cells are involved in the exchange of materials, blocking the receptor could turn out to have such side effects as weight gain.

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https://www.sciencedaily.com/releases/2016/05/160526190418.htm  Original web page at Science Daily

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* How prions kill neurons: New culture system shows early toxicity to dendritic spines

Prion diseases are fatal and incurable neurodegenerative conditions of humans and animals. Yet, how prions kill nerve cells (or neurons) remains unclear. A study published on May 26, 2016 in PLOS Pathogens describes a system in which to study the early assault by prions on brain cells of the infected host.

Some of the earliest and potentially most critical changes in prion-infected brains occur at the connections (synapses) between neurons, and specifically at so-called dendritic spines. Dendritic spines are protrusions on the post-synaptic branches of a neuron that receive signals from other neurons. However, to date there has been no experimentally tractable model system in which the early degenerative changes caused by prions can be studied in cell culture.

David Harris, from Boston University School of Medicine, USA, and colleagues have argued that the availability of a neuronal culture system susceptible to the toxic effects of prions is crucial for understanding the underlying mechanisms and for potentially identifying drugs that block neurodegeneration. In this study, they report such a system, which reproduces acute prion neurotoxicity through degeneration of dendritic spines on cultured hippocampal neurons.

The researchers started by culturing neurons isolated from the hippocampus (a brain region involved in learning and memory) of mice. These neurons can be maintained in culture for three weeks, during which time they develop mature dendrites studded with spines, which contain chemical receptors that receive signals from neighboring neurons.

When the cultured neurons were exposed to brain extracts from mice with prion disease (which are known to contain large amounts of infectious prions), they showed rapid and dramatic changes: Within hours, there was severe retraction of spines, reducing their overall density and the size of the remaining ones. These changes in spines occurred without large-scale destruction of the neurons, suggesting that they represented very early events that would affect the functioning of the neurons prior to their actual death. When the researchers used three different kinds of purified prion preparations, they saw similar dendritic spine retraction in the cultures.

It is known that the development of prion disease involves an alteration of the normal cellular prion protein (designated PrPC), such that it assumes an abnormal shape (designated PrPSc). The resulting PrPSc is toxic to neurons, and it can propagate an infection by corrupting the shape of additional molecules of PrPC in a kind of chain-reaction.

To test whether the effects of PrPSc in their cell cultures depended on the neurons’ normal PrPC, the researchers generated cultures of hippocampal neurons from mice that were genetically engineered to lack PrPC. These cultures, they found, were resistant to toxic prion exposure, i.e., they did not show any of the changes in dendritic spines seen in neurons from normal mice containing PrPC.

Finally, the researchers tested neurons from transgenic mice expressing mutant PrPC molecules that were missing a specific region that is thought to interact with toxic prions. And indeed, the researchers found that these neurons–just like neurons without any PrPC–were immune to prion toxicity.

The researchers summarize their results as follows: “We describe a new system that is capable of reproducing acute prion neurotoxicity, based on PrPSc-induced degeneration of dendritic spines on cultured hippocampal neurons.” The system, they state, “provides new insights into the mechanisms responsible for prion neurotoxicity, and it provides a platform for testing potential therapeutic agents.”

Because “dendritic spine loss is a common theme in many neurodegenerative conditions, including Alzheimer’s, Huntington’s, and Parkinson’s diseases, and has been suggested to contribute to clinical symptoms in patients,” the researchers also suggest that their system allows for “direct comparisons between pathogenic mechanisms involved in prion diseases and other neurodegenerative disorders.”

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https://www.sciencedaily.com/releases/2016/05/160526151738.htm Original web page at Science Daily

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Mimicking deep sleep brain activity improves memory

It is not surprising that a good night’s sleep improves our ability to remember what we learned during the day. Now, researchers at the RIKEN Brain Science Institute in Japan have discovered a brain circuit that governs how certain memories are consolidated in the brain during sleep. Published in the May 26 issue of Science magazine, the study shows how experimentally manipulating the identified neural connection during non-REM sleep (deep sleep) can prevent or enhance memory retention in mice.

The team led by Masanori Murayama studied the long-known phenomenon of memory consolidation during sleep by building off their recent study on tactile perception in which they found that perceiving texture requires signaling within a neural circuit from higher-level motor-related brain regions back to lower-level touch-related sensory areas. They reasoned that the same “top-down” pathway might also consolidate memories of textures. Explains Murayama, “There is a long standing hypothesis that top-down input is crucial for memory consolidation and that during sleep, neurons in sensory regions activated during the initial experience can “reactivate” by unknown pathways. We found such reactivation of the top-down pathway is critical for mice to encode memories of their tactile experiences.”

The researchers developed a task to assess memory retention that relies on the natural inclination of mice to spend more time investigating new items in their environment. First they allowed mice to explore objects in two rooms with smooth floors, then they changed one of the smooth floors to a textured floor and again allowed the mice to explore. With normal sleep, mice spent more time exploring the room with the textured floor, showing that they remembered the smooth room and were less interested in it. Typically, this behavior was observed as long as the second exploration occurred within two days.

To examine whether the top down circuit was responsible for memory consolidation during sleep, they manipulated the mice in several ways. First, they showed that sleep deprivation immediately following the first tactile experience caused mice to explore the textured room less often on the second exploration, indicating that they did not remember the smooth room. Next, they inactivated the top-down neural pathway during non-REM sleep shortly after the first exploration and found that during the second exploration, mice performed as if they had been sleep deprived. Silencing the top-down pathway when mice were awake or during non-REM sleep at later times had no effect on performance, indicating that memory consolidation happened in the first bout of non-REM sleep after the experience.

The importance of top-down circuit activation in non-REM sleep suggested that memory consolidation might involve synchronous slow wave brain activity between the two brain regions that is characteristic of non-REM sleep. To test this, they artificially applied synchronous or asynchronous activity in the higher and lower regions of the circuit during non-REM sleep after the first tactile experience. Mice with asynchronous activation were unable to consolidate memories, but synchronous activation allowed them to retain a strong memory of the smooth floor for at least 4 days or twice as long as normal. The synchronous treatment even rescued the typical lack of memory retention in sleep-deprived mice.

“Our findings on sleep deprivation are particularly interesting from a clinical perspective,” says Murayama. “Patients who suffer from sleep disorders often have impaired memory functions. Our findings suggest a route to therapy using transcortical magnetic or direct-current stimulation to top down cortical pathways to reactivate sleep-deprived neurons during non-REM sleep. Our next step is to test this in mouse models of sleep-disorders.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160526151749.htm  Original web page at Science Daily

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* Alternative odor receptors discovered in mice

Smell in mammals turns out to be more complex than we thought. Rather than one receptor family exclusively dedicated to detecting odors, a study in mice reports that a group of neurons surrounding the olfactory bulb use an alternative mechanism for catching scents. These “necklace” neurons, as they’re called, use this newly discovered olfactory detection system to respond to odors that elicit instinctive responses, such as pheromones and the smell of seeds and nuts. Harvard researchers report the finding May 26 in Cell.

“Our work suggests that mammalian mechanisms for smell are not monolithic in terms of mechanism or logic, but rather can take many forms and can be mediated by multiple types of receptors,” says senior author Sandeep Robert Datta, a neurobiologist at Harvard Medical School. “These findings revise our canonical view of how animals probe the chemical environment.”

Nobel Prize-winning work back in 1991 showed that, in mammals, each sensory neuron in the main olfactory system expresses one type of G-protein coupled receptor (GPCR), which is specialized to detect a specific type of odor. The pattern of activity of all sensory neurons in the olfactory system allows us to distinguish between different odors present in the environment. This one-GPCR-per-neuron pattern also exists in the vomeronasal olfactory system, which is specialized for recognizing pheromones, suggesting a common and general logic for processing smell. Yet, a third olfactory system consisting of necklace neurons, so-called due to the unique circular pattern of their projections to the brain, also responds to diverse odors. It has not been clear which receptors are expressed by these neurons and what role they play in odor perception.

In the new study, Datta and his team discovered that necklace neurons in mice do not express GPCRs, unlike all other types of olfactory sensory neurons in mammals. Rather, these neurons express the MS4A class of proteins, which were previously not known to play a role in odor perception. Moreover, each necklace neuron expresses multiple types of MS4A receptors, in stark contrast to the one-receptor-per-neuron rule that organizes insect and other mammalian olfactory systems. These receptors respond to fatty acids that are specifically found in nuts and seeds, as well as a pheromone known to be aversive to mice.

“This discovery strongly suggests that the brain must be interpreting information from these receptors using a very different strategy from the one used by the brain to discriminate most odors,” Datta says. “We speculate–but don’t have the evidence to back this idea yet–that the MS4As are used as a kind of alert system for the brain, letting it know that something of real importance is out there in the world, but not telling the brain explicitly what that thing is.”

By analyzing differences between Ms4a genes across mammalian species, the researchers found that the evolution of these genes preceded the advent of the mammalian receptors for taste and for pheromones. “The fact that the MS4As have been preserved for at least 400 million years suggests that these receptors play a crucial role in enabling animals to interact with the olfactory environment,” Datta says.

In humans, MS4A receptors have previously been found in the intestines, lung cells, and even sperm cells. Based on the pattern of expression of MS4A receptors in different tissues, and the type of odors they detect, Datta suspects that MS4A molecules represent an ancient mechanism for sensing ethologically salient small molecules in the environment. “It is possible that this is the main function of the MS4As across species, and that the olfactory function of the MS4As is actually more recently evolved,” Datta says.

For now, it is not clear whether MS4As in humans serve as odor receptors. In future studies, Datta and his team will examine whether MS4A proteins act as a primordial odor receptor across species. “This would be incredibly interesting, as it would suggest that many animals have a kind of hidden nose we were unaware of buried within their main olfactory system,” Datta says.

Because the MS4A proteins are expressed on many cells in the body, the researchers will also test whether they detect cues that are generated by the body itself. “If so, this would suggest that one reason that the Ms4As are so widespread across evolution is that they are generally well suited to the detection of small molecules in the environment, regardless of whether that environment is the external or the internal world,” Datta says.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160526124311.htm Original web page at Science Daily

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Quick test for Zika effectively detects virus in monkeys

A novel, inexpensive method for detecting the Zika virus could help slow spread of outbreak, and potentially other future pandemic diseases

An international, multi-institutional team of researchers led by synthetic biologist James Collins, Ph.D. at the Wyss Institute for Biologically Inspired Engineering at Harvard University, has developed a low-cost, rapid paper-based diagnostic system for strain-specific detection of the Zika virus, with the goal that it could soon be used in the field to screen blood, urine, or saliva samples.

“The growing global health crisis caused by the Zika virus propelled us to leverage novel technologies we have developed in the lab and use them to create a workflow that could diagnose a patient with Zika, in the field, within 2-3 hours,” said Collins, who is a Wyss Core Faculty member, and Termeer Professor of Medical Engineering & Science and Professor of Biological Engineering at the Massachusetts Institute of Technology (MIT)’s Department of Biological Engineering.

In October 2014, Collins’ team developed a breakthrough method for embedding synthetic gene networks — which could be used as programmable diagnostics and sensors — on portable, small discs of ordinary paper.

Stirred by the then-ongoing Ebola outbreak in Africa, they demonstrated a proof-of-concept color-changing diagnostic that could screen for Ebola by embedding in paper a novel kind of synthetic biomolecular sensor designed to screen for specific RNA sequences. These RNA sequences can mark not only the genetic signatures of Ebola but also other RNA viruses including Zika, SARS, measles, influenza, hepatitis C, and West Nile fever. The team believed that one day, the method could be applied in the field to identify viruses with blood, urine or saliva samples.

However, until recently, the team’s paper-based technology has been challenged by the extremely low concentration of virus that is normally found in blood, urine and saliva. Now, using blood samples from monkeys infected with Zika virus as well as virus recovered from cells infected in the laboratory, the team has validated a next generation technique that overcomes this problem.

“The vivid images in the news stemming from the ongoing Zika crisis are heartbreaking,” said Keith Pardee, Ph.D., one of the study’s co-first authors and an Assistant Professor in the Leslie Dan Faculty of Pharmacy at University of Toronto, who was formerly a Postdoctoral Fellow at the Wyss Institute and BU. “We hope a tool like this can help reduce the impact of the outbreak until a vaccine can be developed.”

With field use in mind, Collins’ team designed a simple modular workflow comprising three steps: amplification, Zika detection, and CRISPR-Cas9-aided strain identification. CRISPR-Cas9, a gene editing mechanism derived from the immune systems of bacteria, can be used to search entire sequences to find exclusive genetic markers. Leveraging CRISPR-Cas9’s talent for sequence recognition, the third part of the team’s system uses a CRISPR-Cas9-aided paper-based diagnostic to discriminate between strains whose genetic profiles differ by as little as one nucleotide.

Once a sample’s RNA has been amplified using a mixture of enzymes and “primers,” DNA sequences that trigger replication, a drop is administered to paper discs that are freeze-dried containing a mixture of cellular components and biological proteins. The droplet of amplified RNA activates the freeze-dried components so that the discs will change color to indicate a positive result for Zika virus. While the result can be read with the naked eye similar to a home pregnancy test, a specially designed electronic reader can also be used to get faster results and could, one day, quantify the amount of viral load in a sample.

If Zika is detected, the third step involves mixing a sample with a freeze-dried CRISPR-Cas9 cocktail and then using that mixture to wet another set of color-changing paper discs. Depending on the type of Zika strain contained in the sample, these discs undergo another set of visible color changes. Although synthetic biologists and genetic engineers usually put CRISPR-Cas9 to work inside living cells, Collins’ team discovered that it functions just as well — and even better in some cases — when freeze dried.

“We have tested our diagnostic systems against closely-related strains of the Dengue virus and found that within the first two steps, our system can readily distinguish Zika from Dengue,” said Alexander Green, Ph.D., co-first author on the study and an Assistant Professor in the Center for Molecular Design and Biomimetics at ASU’s Biodesign Institute and School of Molecular Sciences, who was formerly a Postdoctoral Fellow at the Wyss Institute and BU. “The addition of the third CRISPR-based step — deploying Cas9 on a paper-based platform for the first time — only enhances the accuracy of detection. As we prepare this technology for translation, we plan to validate our system against dozens or even hundreds of clinical samples.”

All components of the diagnostic system can be freeze-dried for storage and transport while retaining their efficacy. The ability to pinpoint a strain-specific diagnosis in the field could prove valuable to national and global health organizations for tracking the spread of a viral outbreak in real time and for preparing containment strategies and treatment plans.

The diagnostic system developed by Collins’ team could be tailored to identify a range of pathogens, and is an extremely cost effective diagnostic platform given its paper-based nature. What’s more — the method is robust and could be used to quickly respond and develop new diagnostics in the face of emerging outbreaks.

“In response to an emerging outbreak, we envision a custom-tailored diagnostic system could be ready for use within one week’s time,” said Collins. “We are currently pursuing multiple opportunities to secure private and public funding in order to commercialize this diagnostic system and make it available to the world’s health responders.”

“The ability to recapitulate the genetic machinery of living cells in ordinary freeze dried paper provides a way to develop revolutionary sensors and diagnostics in a fraction of the time and with higher sensitivity and specificity than more conventional assays. These inexpensive paper-based tests also can be easily transported out of the laboratory and distributed virtually anywhere around the world. The potential for applications in health and environmental screening, particularly in low resource areas, is huge,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160506132205.htm  Original web page at Science Daily

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Early life stress accelerates maturation of key brain region in male mice

Intuition is all one needs to understand that stress in early childhood can create lifelong psychological troubles, but scientists have only begun to explain how those emerge in the brain. They have observed, for example, that stress incurred early in life attenuates neural growth. Now a study in male mice exposed to stress shows that a particular region, the hippocampus, hits many developmental milestones early — essentially maturing faster in response to stress.

The findings, the first to track and report signs of stress-related early maturation in a brain region throughout mouse development, may lend some neuroscientific credence to the expression that children facing early adversity have to “grow up too fast.”

Lead author Kevin Bath, assistant professor of cognitive, linguistic and psychological sciences at Brown University, said he became curious about whether some brain regions were maturing faster because he and other researchers had made observations in humans and rodents all suggesting that certain traits — such as fear-driven learning and memory, sexual development and neural connectivity among some brain regions — were accelerated, rather than stunted, after early life stress (ELS). Some of these qualities, particularly memory and emotion regulation, involve the hippocampus.

“There were a number of different indicators that [early maturation] might be happening,” Bath said. “We wanted to carefully assess this and look at a number of different markers of not only growth, but also maturation of these animals, and to measure it not only at the behavioral level but also at the neuromolecular level.”

The study, co-authored by Brown graduate students Gabriela Manzano-Nieves and Haley Goodwill, appears online in the journal Hormones and Behavior.

The experimental stress introduced to the mice in the study was a period of fragmented maternal care — a condition comparable to one that might affect a child growing up in an economically challenged, single-parent household, for example.

At four days of age, pups and their mothers were moved from standard cages to ones where the materials available to the mother for nest building were inadequate. Food and water remained plentiful, but the mother responded anxiously and would frequently depart to search for anything that might work as nesting material. Pups therefore received less consistent and attentive care from their harried and distracted mothers than experimental controls who were never moved from standard cages. After just a week of exposure to this manipulation (a significant span of time for mice who mature from birth to adulthood in just eight weeks), the mice returned to cages with everything they needed.

By then, however, the effects of the ELS were underway. Bath and his co-authors made several measurements in mice aged four to 50 days (when mice reach young adulthood) to track how development in the hippocampus varied between mice with ELS and the unstressed controls.

What they found — from counting specific populations of cells, to measuring behavior, to gene expression — was that the hippocampus appeared to mature significantly faster in the ELS mice during their seven weeks from birth to early adulthood.

Based upon measures of gene expression and counting cells, the team saw that parvalbumin interneurons developed about a week early, attaining an abundance by day 21 in ELS mice that was not seen in control mice until day 28. In other measurements, the teams saw that developmental changes in synaptic receptor subunits that are important for developmental changes in learning occurred about nine days ahead of schedule. They also found that myelination, a key developmental process for neural communication, also started more than a week early.

They also looked at a behavioral trait controlled by the hippocampus. Mice can be conditioned to associate shocks with a particular location, such that they will freeze in fear when they come back to that place. But for about a week during the maturation of the hippocampus, that freezing behavior temporarily disappears, Bath has found. In the new study, he saw that this was still the case, but the temporary suspension of the fear response happened a week earlier in ELS mice than in control mice.

Also, in their study, the team confirmed the findings of previous researchers showing overall reduced neural growth.

The results showing reduced growth but faster hippocampus maturation appear to support an evolution-based hypothesis that mice — and perhaps people, too — interpret ELS as a cue to adapt brain development to match a world where long-term survival seems unlikely, Bath said.

“In the case of development, the stress may be providing a signal about the hospitability of the environment,” Bath said.

Rather than invest for the long run in optimally refined systems in the cortex for learning rules and suppressing emotional responses, mice may instead invest in accelerating the maturation of more primal systems, such as the hippocampus, to support short-term priorities. The priority, Bath speculates, becomes racing to survive long enough to reproduce at least once.

“The evolutionary push is for you to pass on your genes,” Bath said. “We hypothesize that stress drives a reallocation of developmental resources from development of the full brain to development of limbic structures that are important for reproduction.”

To know for sure — and to get hints about how mental health practitioners can help people who have experienced early life stress — much more work is needed, Bath said. He’s pursuing several lines of research including studying female mice, given observations that females are twice as prone as males to develop problems in response to stress, and that human girls who have experienced early life stress undergo menarche earlier. He’s also tracking the behavioral implications of accelerated maturational traits (e.g. the early abundance of parvalbumin interneurons), measuring whether maturation is accelerated or delayed in other areas in the brain, and looking at the genetic mechanisms underlying the accelerated maturation to understand why some humans are resilient to ELS exposure.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160510124824.htm  Original web page at Science Daily

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* Cells carry ‘memory’ of injury, which could reveal why chronic pain persists

A new study from King’s College London offers clues as to why chronic pain can persist, even when the injury that caused it has gone. Although still in its infancy, this research could explain how small and seemingly innocuous injuries leave molecular ‘footprints’ which add up to more lasting damage, and ultimately chronic pain.

All of us are likely to know someone who suffers from persistent pain — it is a very common condition, which can be caused by sports injuries, various diseases and the process of ageing. Treatment options are limited and doctors are often unable to offer anything more than partial relief with painkillers, leaving their patients resigned to suffering.

While chronic pain can have many different causes, the outcome is often the same: an overly sensitive nervous system which responds much more than it normally would. However, a question still remains as to why the nervous system should remain in this sensitive state over long periods of time, especially in instances where the underlying injury or disease has gone.

Researchers from King’s sought to answer this question by examining immune cells in the nervous system of mice, which are known to be important for the generation of persistent pain.

In the study, published today in Cell Reports, they found that nerve damage changes epigenetic marks on some of the genes in these immune cells. Epigenetics is the process that determines which gene is expressed and where. Some epigenetic signals have direct functional consequences, while others are just primers: flags that indicate a potential to act or be modified.

The cells examined in this King’s study still behaved as normal, but the existence of these novel epigenetic marks may mean that they carry a ‘memory’ of the initial injury.

Dr Franziska Denk, first author of the study, from the Wolfson Centre for Age Related Diseases at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, said: ‘We are ultimately trying to reveal why pain can turn into a chronic condition. We already knew that chronic pain patients have nerves that are more active, and we think this is probably due to various proteins and channels in those nerves having different properties.

However, it is unclear why these nerves should remain in this overactive, highly sensitive state, even when the initial injury or disease has gone: the back pain from two years ago that never quite went away or the joints that are still painful despite your rheumatoid arthritis being in remission.’

Dr Denk added: ‘We want to know why these proteins and channels should maintain their altered function over such a long period of time. Cells have housekeeping systems by which the majority of their content are replaced and renewed every few weeks and months — so why do crucial proteins keep being replaced by malfunctioning versions of themselves? Our study is the very first step towards trying to answer this question by exploring the possibility that changes in chronic pain may persist because of epigenetics. We hope that future research in this area could help in the search for novel therapeutic targets.’

Professor Stephen McMahon from the IoPPN at King’s College London said: ‘This research raises many interesting questions: do neurons also acquire epigenetic footprints as a result of nerve injury? Do these molecular footprints affect the function of proteins? And are they ultimately the reason that chronic pain persists in patients over such long periods of time?

‘The last question is particularly hard to answer, because to study epigenetics we need access to pure cell populations. Obviously, many of these are only accessible in postmortem tissue. However, colleagues at King’s are already doing this in psychiatry, through studies such as the The PsychENCODE project, so it is possible.’

Dr Giovanna Lalli, Neuroscience & Mental Health Senior Portfolio Developer at the Wellcome Trust, which part-funded the study, said: ‘People develop chronic pain for a huge variety of reasons. We therefore need an equally diverse range of treatments to tackle the different root causes.

‘The clues from this study, suggesting epigenetic changes may be involved in pain persisting, will hopefully lead us to better understand the mechanisms underlying chronic pain.’

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160512124930.htm  Original web page at Science Daily

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Slips of the lip stay all in the family: dogs included, but not the cat

It’s happened to many of us: While looking right at someone you know very well, you open your mouth and blurt out the wrong name. The name you blurt is not just any old name, though, says new research from Duke University that finds “misnaming” follows predictable patterns.

Among people who know each other well, the wrong name is usually plucked from the same relationship category, the study finds. Friends call each other by other friends’ names, and family members by other family members’ names. And that includes the family dog.

“It’s a cognitive mistake we make, which reveals something about who we consider to be in our group,” said Duke psychology and neuroscience professor David Rubin, one of the study authors. “It’s not just random.”

The new paper, based on five separate surveys of more than 1,700 respondents, appears online this week in the journal Memory and Cognition. Many of the patterns didn’t surprise lead author Samantha Deffler, a Ph.D. student at Duke. One did, though.

In addition to mixing up sibling for sibling and daughter for son, study participants frequently called other family members by the name of the family pet — but only when the pet was a dog. Owners of cats or other pets didn’t commit such slips of the tongue. Deffler says she was surprised how consistent that finding was, and how often it happened.

“I’ll preface this by saying I have cats and I love them,” Deffler says. “But our study does seem to add to evidence about the special relationship between people and dogs.

“Also, dogs will respond to their names much more than cats, so those names are used more often. Perhaps because of that, the dog’s name seems to become more integrated with people’s conceptions of their families.”

Phonetic similarity between names helps fuel mix-ups too, the authors found. Names with the same beginning or ending sounds, such as Michael and Mitchell or Joey and Mikey, were more likely to be swapped. So were names that shared phonemes, or sounds, such as John and Bob, which share the same vowel sound.

Physical similarities between people, on the other hand, played little to no role. For instance, parents were inclined to swap their children’s names even when the children looked nothing alike and were different genders. It’s not a question of aging, either: The authors found plenty of instances of misnaming among college undergraduates.

Although misnaming is a common theme in popular culture, Deffler said the new study is one of few describing how the phenomenon works.

Deffler is no stranger to the experience in her own life. Her graduate supervisor frequently swaps the names of his two graduate assistants. And growing up, she said, her mom often called her Rebecca, Jesse or Molly — the names of her sister, brother and the family pit bull.

“I’m graduating in two weeks and my siblings will all be there,” Deffler said. “I know my mom will make mistakes.”

Now she knows why.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160516181217.htm  Original web page at Science Daily

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* Deadly animal prion disease appears in Europe

A highly contagious and deadly animal brain disorder has been detected in Europe for the first time. Scientists are now warning that the single case found in a wild reindeer might represent an unrecognized, widespread infection.

Chronic wasting disease (CWD) was thought to be restricted to deer, elk (Cervus canadensis) and moose (Alces alces) in North America and South Korea, but on 4 April researchers announced that the disease had been discovered in a free-ranging reindeer (Rangifer tarandus tarandus) in Norway. This is both the first time that CWD has been found in Europe and the first time that it has been found in this species in the wild anywhere in the world.

“It’s worrying — of course, especially for animals. It’s a nasty disease,” says Sylvie Benestad, an animal-disease researcher at the Norwegian Veterinary Institute in Oslo who, along with colleague Turid Vikøren, diagnosed the diseased reindeer.

A key question now is whether this is a rare — even unique — case, or if the disease is widespread but so far undetected in Europe.

“If it’s similar to our prion disease in the United States and Canada, the disease is subtle and it would be easy to miss,” says Christina Sigurdson, a pathologist at the University of California, San Diego, who has shown that reindeer can contract CWD in a laboratory environment.

Like both bovine spongiform encephalopathy — also known as mad-cow disease — and variant Creutzfeldt-Jakob disease in humans, CWD occurs when cellular proteins called prions bend into an abnormal shape, inducing neighbouring, healthy proteins to do the same. The misfolded proteins aggregate in the brain and sometimes in other tissue, causing weight loss, coordination problems and behaviour changes. There is no cure or vaccine; as far as scientists know, CWD is always fatal.

Although the disease is not known to be transmissible to humans, it is highly contagious among deer, elk and related animals, which can shed infectious misfolded prion proteins in their saliva, urine and faeces. Animals infected with CWD have been found in more than 20 states in the United States and 2 provinces in Canada. The disease has also been detected in captive animals in South Korea, which imported CWD with a shipment of live elk brought into the country for farming in the late 1990s.

The brain of an ill reindeer from Norway was found to contain misfolded proteins called prions. The infected reindeer ended up on Vikøren’s necropsy table thanks to scientists with the Norwegian Institute for Nature Research in Trondheim. They found it as they used a helicopter to track a free-ranging herd from the Nordfjella population in the alpine regions of southern Norway. Their goal was to capture adult female reindeer and collar them for satellite tracking — but when the researchers landed, they discovered a sick animal that could not move and soon died.

During the necropsy, Benestad tested for the abnormally folded proteins as a matter of routine. Eventually, a total of three different antibody-based tests all confirmed the presence of prions.

“I was very afraid,” Benestad says. During her long career as a prion researcher she has heard scientists from the United States and Canada discuss CWD, how contagious it is and how hard it is to stamp out.

It is a mystery how this disease arrived on a mountaintop in Norway. Benestad and Vikøren think it unlikely that it was it imported. They suspect that it might have arisen spontaneously, or jumped the species barrier from a prion disease in sheep called scrapie, although such a jump has never been seen before.

“The $64,000 question is what is the origin of this case of CWD in Europe,” says Glenn Telling, a prion-disease researcher at Colorado State University in Fort Collins. “What we do know is that once CWD is detected in new locations, it typically takes a foothold in that location, and is difficult to eradicate.”

Nature doi:10.1038/nature.2016.19759

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/deadly-animal-prion-disease-appears-in-europe-1.19759  Original web page at Nature

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How a macaque’s brain knows it’s swinging

Any organism with a brain needs to make decisions about how it’s going to navigate through three-dimensional spaces. That’s why animals have evolved sensory organs in the ears to detect if they’re rotating or moving in a straight line. But how does an animal perceive curved motion, as in turning a corner? One explanation, published April 21 in Cell Reports, from researchers looking at macaques, is that curved motion is detected when sensory neurons in the brain receiving converging information about linear and rotational movement are activated.

The parts of the ear that help macaques and humans detect motion are the same ones that help us stay balanced. Otoliths are sphere-like organs that detect linear motion and gravitational pull. In contrast, semi-circular canals specifically detect rotational movement. Information about an animal’s motion collected by these organs are then sent to the central nervous system in the brain.

It’s known that two distinct sets of neurons help us sense linear and rotational movement, but the new study identified a third set of neurons in the macaque sensory cortex that respond optimally to curved motion.

“It’s a very interesting question as to why our brain evolved this way,” says corresponding author Yong Gu, a neuroscientist at the Shanghai Institutes for Biological Sciences and Chinese Academy of Sciences. “We don’t have to have these curved motion neurons in the sensory area of the brain; the information about translation and rotation could have converged at a higher level, e.g. association cortex which is important for sensory-motor transformation and decision making. Our hunch is that representation of curved motion in sensory cortex helps animals rapidly detect this type of movement, and save the working load of the decision centres for other important neural computations.”

Gu and lab member Zhixian Cheng made their discovery by placing macaques in moving platforms and attaching brain electrodes to individual neurons to measure how often and when they fired. “People have known that linear and rotational motion converged in the sensory cortex, and we found that certain neurons fire more spikes when the linear or rotational information are available at the same time for these neurons,” Gu says. “This might have been expected, but we now propose that these neurons could represent curvilinear motion.”

The experiments also mimicked a 1997 human study in which subjects were passively moved in various motion conditions (e.g, curvilinear motion versus moving in a straight line while rotating the body) and reported analogous curved-motion sensation as long as both linear and rotation signals are present simultaneously. The current macaque neurophysiological data show extremely similar patterns, thus could account for the human psychophysical data. “This is surprising,” Gu says. “In nature, we should be able to tell these two different types of motion during active navigation. Other signals in the brain, for example, the motor command signals may help.”

The past decade has seen a surge in papers on how the body senses motion, and Gu believes there are more surprises to come. In particular, he’s interested in learning how other sensory systems play a role in how primates know where they are going.

https://www.sciencedaily/  Science Daily

https://www.sciencedaily.com/releases/2016/04/160421133645.htm  Original web page at Science Daily

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Despite their small brains, ravens and crows may be just as clever as chimps, research suggests

A study led by researchers at Lund University in Sweden suggests that ravens can be as clever as chimpanzees, despite having much smaller brains, indicating that rather than the size of the brain, the neuronal density and the structure of the birds’ brains play an important role in terms of their intelligence.

“Absolute brain size is not the whole story. We found that corvid birds performed as well as great apes, despite having much smaller brains,” says Can Kabadayi, doctoral student in Cognitive Science.

Intelligence is difficult to test, but one aspect of being clever is inhibitory control, and the ability to override animal impulses and choose a more rational behaviour. Researchers at Duke University, USA, conducted a large-scale study in 2014, where they compared the inhibitory control of 36 different animal species, mainly primates and apes. The team used the established cylinder test, where food is placed in a transparent tube with openings on both sides. The challenge for the animal is to retrieve the food using the side openings, instead of trying to reach for it directly. To succeed, the animal has to show constraint and choose a more efficient strategy for obtaining the food.

The large-scale study concluded that great apes performed the best, and that absolute brain size appeared to be key when it comes to intelligence. However, they didn’t conduct the cylinder test on corvid birds.

Can Kabadayi, together with researchers from the University of Oxford, UK and the Max Planck Institute for Ornithology in Germany, therefore had ravens, jackdaws and New Caledonian crows perform the same cylinder test to better understand their inhibitory control.

The team first trained the birds to obtain a treat in an opaque tube with a hole at each end. Then they repeated the test with a transparent tube. The animal impulse would naturally be to go straight for the tube as they saw the food. However, all of the ravens chose to enter the tube from the ends in every try. The performance of the jackdaws and the crows came very close to 100%, comparable to a performance by bonobos and gorillas.

“This shows that bird brains are quite efficient, despite having a smaller absolute brain size. As indicated by the study, there might be other factors apart from absolute brain size that are important for intelligence, such as neuronal density,” says Can Kabadayi, and continues:

“There is still so much we need to understand and learn about the relationship between intelligence and brain size, as well as the structure of a bird’s brain, but this study clearly shows that bird brains are not simply birdbrains after all!”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/04/160426101527.htm Original web page at Science Daily