Neuroscience

Articles and news from the latest research reports.

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Newly found ‘volume control’ in the brain promotes learning, memory

Scientists have long wondered how nerve cell activity in the brain’s hippocampus, the epicenter for learning and memory, is controlled — too much synaptic communication between neurons can trigger a seizure, and too little impairs information processing, promoting neurodegeneration. Researchers at Georgetown University Medical Center say they now have an answer. In the January 10 issue of Neuron, they report that synapses that link two different groups of nerve cells in the hippocampus serve as a kind of “volume control,” keeping neuronal activity throughout that region at a steady, optimal level.

"Think of these special synapses like the fingers of God and man touching in Michelangelo’s famous fresco in the Sistine Chapel," says the study’s senior investigator, Daniel Pak, PhD, an associate professor of pharmacology. "Now substitute the figures for two different groups of neurons that need to perform smoothly. The touching of the fingers, or synapses, controls activity levels of neurons within the hippocampus."

The hippocampus is a processing unit that receives input from the cortex and consolidates that information in terms of learning and memory. Neurons known as granule cells, located in the hippocampus’ dentate gyrus, receive transmissions from the cortex. Those granule cells then pass that information to the other set of neurons (those in the CA3 region of the hippocampus, in this study) via the synaptic fingers.

Those fingers dial up, or dial down, the volume of neurotransmission from the granule cells to the CA3 region to keep neurotransmission in the learning and memory areas of the hippocampus at an optimal flow — a concept known as homeostatic plasticity. “If granule cells try to transmit too much activity, we found, the synaptic junction tamps down the volume of transmission by weakening their connections, allowing the proper amount of information to travel to CA3 neurons,” says Pak. “If there is not enough activity being transmitted by the granule cells, the synapses become stronger, pumping up the volume to CA3 so that information flow remains constant.”

There are many such touching fingers in the hippocampus, connecting the so-called “mossy fibers” of the granule cells to neurons in the CA3 region. But importantly, not every one of the billions of neurons in the hippocampus needs to set its own level of transmission from one nerve cell to the other, says Pak.

To explain, he uses another analogy. “It had previously been thought that neurons act separately like cars, each working to keep their speed at a constant level even though signal traffic may be fast or slow. But we wondered how these neurons could process learning and memory information efficiently, while also regulating the speed by which they process and communicate that information.

"We believe, based on our study, that only the mossy fiber synapses on the CA3 neurons control the level of activity for the hippocampus — they are like the engine on a train that sets the speed for all the other cars, or neurons, attached to it," Pak says. "That frees up the other neurons to do the job they are tasked with doing — processing and encoding information in the forms of learning and memory."

Not only does the study offer a new model for how homeostatic plasticity in the hippocampus can co-exist with learning and memory, it also suggests a new therapeutic avenue to help patients with uncontrollable seizures, he says.

"The CA3 region is highly susceptible to seizures, so if we understand how homeostasis is maintained in these neurons, we could potentially manipulate the system. When there is an excessive level of CA3 neuronal activity in a patient, we could learn how to therapeutically turn it down."

(Source: eurekalert.org)

Filed under learning memory neurotransmission nerve cells neuronal activity neuron neuroscience science

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How the brain stays receptive: RUB researchers and colleagues examine the role of channel protein in learning The channel protein Pannexin1 keeps nerve cells flexible and thus the brain receptive for new knowledge. Together with colleagues from Canada and the U.S., researchers at the Ruhr-Universität Bochum led by the junior professor Dr. Nora Prochnow from the Department of Molecular Brain Research describe these results in PLoS ONE. In the study, mice comprising no Pannexin1 in memory-related brain structures displayed symptoms similar to autism. Their nerve cells lacked synaptic plasticity, i.e. the ability to form new synaptic contacts or give up old contacts based on the level of usage. Pannexins are abundant in the central nervous system of vertebrates Pannexins traverse the cell membrane of vertebrate animals and form large pored channels. They are permeable for certain signalling molecules, such as the energy storage molecule ATP (adenosine triphosphate). The best known representative is Pannexin1, which occurs in abundance in the brain and spinal cord and among others in the hippocampus - a brain structure that is critical for long-term memory. Malfunctions of the pannexins play a role in the development of epilepsy and strokes. No more scope in long-term potentiation The research team studied mice in which the gene for Pannexin1 was lacking. Using cell recordings carried out on isolated brain sections, they analysed the long-term potentiation in the hippocampus. Long-term potentiation usually occurs when new memory content is built - the contacts between nerve cells are strengthened; they communicate more effectively with each other. In mice without Pannexin1, the long-term potentiation occurred earlier and was more prolonged than in mice with Pannexin1. “It looks at first glance like a gain in long-term memory”, says Nora Prochnow. “But precise analysis shows that there was no more scope for upward development.” Due to the lack of Pannexin1, the cell communication in general was increased to such an extent that a further increase through the learning of new knowledge was no longer possible. The synaptic plasticity was thus extremely restricted. “The plasticity is essential for learning processes in the brain”, Nora Prochnow explains. “It helps you to organise, keep or even to forget contents in a positive sense, to gain room for new inputs.” Autistic-like behaviour without Pannexin1 The absence of Pannexin1 also had an impact on behaviour: when solving simple problems, the animals were quickly overwhelmed in terms of content. Their spatial orientation was limited, their attention impaired and an increased probability for seizure generation occurred. “The behavioural patterns are reminiscent of autism. We should therefore consider the Pannexin1 channel more closely with regard to the treatment of such diseases”, says the neurobiologist from Bochum. Theory: feedback regulation gets out of hand without Pannexin1  According to the scientists’ theory, nerve cells lack a feedback mechanism without Pannexin1. Normally the channel protein releases ATP, which binds to specific receptors and thus reduces the release of the neurotransmitter glutamate. Without Pannexin1 more glutamate is released, which leads to increased long-term potentiation. This causes the cell to lose its dynamic equilibrium, which is needed for an efficient learning process.

How the brain stays receptive: RUB researchers and colleagues examine the role of channel protein in learning

The channel protein Pannexin1 keeps nerve cells flexible and thus the brain receptive for new knowledge. Together with colleagues from Canada and the U.S., researchers at the Ruhr-Universität Bochum led by the junior professor Dr. Nora Prochnow from the Department of Molecular Brain Research describe these results in PLoS ONE. In the study, mice comprising no Pannexin1 in memory-related brain structures displayed symptoms similar to autism. Their nerve cells lacked synaptic plasticity, i.e. the ability to form new synaptic contacts or give up old contacts based on the level of usage.

Pannexins are abundant in the central nervous system of vertebrates

Pannexins traverse the cell membrane of vertebrate animals and form large pored channels. They are permeable for certain signalling molecules, such as the energy storage molecule ATP (adenosine triphosphate). The best known representative is Pannexin1, which occurs in abundance in the brain and spinal cord and among others in the hippocampus - a brain structure that is critical for long-term memory. Malfunctions of the pannexins play a role in the development of epilepsy and strokes.

No more scope in long-term potentiation

The research team studied mice in which the gene for Pannexin1 was lacking. Using cell recordings carried out on isolated brain sections, they analysed the long-term potentiation in the hippocampus. Long-term potentiation usually occurs when new memory content is built - the contacts between nerve cells are strengthened; they communicate more effectively with each other. In mice without Pannexin1, the long-term potentiation occurred earlier and was more prolonged than in mice with Pannexin1. “It looks at first glance like a gain in long-term memory”, says Nora Prochnow. “But precise analysis shows that there was no more scope for upward development.” Due to the lack of Pannexin1, the cell communication in general was increased to such an extent that a further increase through the learning of new knowledge was no longer possible. The synaptic plasticity was thus extremely restricted. “The plasticity is essential for learning processes in the brain”, Nora Prochnow explains. “It helps you to organise, keep or even to forget contents in a positive sense, to gain room for new inputs.”

Autistic-like behaviour without Pannexin1

The absence of Pannexin1 also had an impact on behaviour: when solving simple problems, the animals were quickly overwhelmed in terms of content. Their spatial orientation was limited, their attention impaired and an increased probability for seizure generation occurred. “The behavioural patterns are reminiscent of autism. We should therefore consider the Pannexin1 channel more closely with regard to the treatment of such diseases”, says the neurobiologist from Bochum.

Theory: feedback regulation gets out of hand without Pannexin1 

According to the scientists’ theory, nerve cells lack a feedback mechanism without Pannexin1. Normally the channel protein releases ATP, which binds to specific receptors and thus reduces the release of the neurotransmitter glutamate. Without Pannexin1 more glutamate is released, which leads to increased long-term potentiation. This causes the cell to lose its dynamic equilibrium, which is needed for an efficient learning process.

Filed under brain brain structure nerve cells synaptic plasticity LTM neuroscience science

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How insulin binds to cells A landmark discovery about how insulin docks on cells could help in the development of improved types of insulin for treating both type 1 and type 2 diabetes. For the first time, researchers have captured the intricate way in which insulin uses the insulin receptor to bind to the surface of cells. This binding is necessary for the cells to take up sugar from the blood as energy. The research team was led by the Walter and Eliza Hall Institute and used the Australian Synchrotron in Melbourne. The study was published in the journal Nature. For more than 20 years scientists have been trying to solve the mystery of how insulin binds to the insulin receptor. A research team led by Associate Professor Mike Lawrence, Dr Colin Ward and Dr John Menting have now found the answer. Associate Professor Lawrence from the institute’s Structural Biology division said the team was excited to reveal for the first time a three-dimensional view of insulin bound to its receptor. “Understanding how insulin interacts with the insulin receptor is fundamental to the development of novel insulins for the treatment of diabetes,” Associate Professor Lawrence said. “Until now we have not been able to see how these molecules interact with cells. We can now exploit this knowledge to design new insulin medications with improved properties, which is very exciting.” The Australian Synchrotron’s MX2 microcrystallography beamline was critical to the project’s success. “If we did not have this fantastic facility in Australia and their staff available to help us, we would simply not have been able to complete this project,” Associate Professor Lawrence said. Associate Professor Lawrence assembled an international team of project collaborators, including researchers from Case Western Reserve University, the University of Chicago, the University of York and the Institute of Organic Chemistry and Biochemistry in Prague. “Collaborations in this field are essential,” he said. “No one laboratory has all the resources, expertise and experience to take on a project as difficult as this one.” “We have now found that the insulin hormone engages its receptor in a very unusual way,” Associate Professor Lawrence said. “Both insulin and its receptor undergo rearrangement as they interact – a piece of insulin folds out and key pieces within the receptor move to engage the insulin hormone. You might call it a ‘molecular handshake’.” Australia is facing an increasing epidemic of type 2 diabetes. There are now approximately one million Australians living with diabetes and around 100,000 new diagnoses each year. “Insulin controls when and how glucose is used in the human body,” Associate Professor Lawrence said. “The insulin receptor is a large protein on the surface of cells to which the hormone insulin binds. The generation of new types of insulin have been limited by our inability to see how insulin docks into its receptor in the body. “Insulin is a key treatment for diabetics, but there are many ways that its properties could potentially be improved,” Associate Professor Lawrence said. “This discovery could conceivably lead to new types of insulin that could be given in ways other than injection, or an insulin that has improved properties or longer activity so that it doesn’t need to be taken as often. It may also have ramifications for diabetes treatment in developing nations, by creating insulin that is more stable and less likely to degrade when not kept cold, an angle being pursued by our collaborators. Our findings are a new platform for developing these kinds of medications.”

How insulin binds to cells

A landmark discovery about how insulin docks on cells could help in the development of improved types of insulin for treating both type 1 and type 2 diabetes.

For the first time, researchers have captured the intricate way in which insulin uses the insulin receptor to bind to the surface of cells. This binding is necessary for the cells to take up sugar from the blood as energy.

The research team was led by the Walter and Eliza Hall Institute and used the Australian Synchrotron in Melbourne. The study was published in the journal Nature.

For more than 20 years scientists have been trying to solve the mystery of how insulin binds to the insulin receptor. A research team led by Associate Professor Mike Lawrence, Dr Colin Ward and Dr John Menting have now found the answer.

Associate Professor Lawrence from the institute’s Structural Biology division said the team was excited to reveal for the first time a three-dimensional view of insulin bound to its receptor. “Understanding how insulin interacts with the insulin receptor is fundamental to the development of novel insulins for the treatment of diabetes,” Associate Professor Lawrence said. “Until now we have not been able to see how these molecules interact with cells. We can now exploit this knowledge to design new insulin medications with improved properties, which is very exciting.”

The Australian Synchrotron’s MX2 microcrystallography beamline was critical to the project’s success. “If we did not have this fantastic facility in Australia and their staff available to help us, we would simply not have been able to complete this project,” Associate Professor Lawrence said.

Associate Professor Lawrence assembled an international team of project collaborators, including researchers from Case Western Reserve University, the University of Chicago, the University of York and the Institute of Organic Chemistry and Biochemistry in Prague. “Collaborations in this field are essential,” he said. “No one laboratory has all the resources, expertise and experience to take on a project as difficult as this one.”

“We have now found that the insulin hormone engages its receptor in a very unusual way,” Associate Professor Lawrence said. “Both insulin and its receptor undergo rearrangement as they interact – a piece of insulin folds out and key pieces within the receptor move to engage the insulin hormone. You might call it a ‘molecular handshake’.”

Australia is facing an increasing epidemic of type 2 diabetes. There are now approximately one million Australians living with diabetes and around 100,000 new diagnoses each year.

“Insulin controls when and how glucose is used in the human body,” Associate Professor Lawrence said. “The insulin receptor is a large protein on the surface of cells to which the hormone insulin binds. The generation of new types of insulin have been limited by our inability to see how insulin docks into its receptor in the body.

“Insulin is a key treatment for diabetics, but there are many ways that its properties could potentially be improved,” Associate Professor Lawrence said. “This discovery could conceivably lead to new types of insulin that could be given in ways other than injection, or an insulin that has improved properties or longer activity so that it doesn’t need to be taken as often. It may also have ramifications for diabetes treatment in developing nations, by creating insulin that is more stable and less likely to degrade when not kept cold, an angle being pursued by our collaborators. Our findings are a new platform for developing these kinds of medications.”

Filed under diabetes type II diabetes insulin insulin receptor glucose cells science

88 notes

Mass. Eye and Ear Researchers Regenerate Sensory Hair Cells, Restore Hearing to Noise-Damaged Ears Hearing loss is a significant public health problem affecting almost 50 million people in the United States alone. Sensorineural hearing loss is the most common form and is caused by the loss of sensory hair cells in the cochlea. Hair cell loss results from a variety of factors including noise exposure, aging, toxins, infections, and certain antibiotics and anti-cancer drugs.  Although hearing aids and cochlear implants can ameliorate the symptoms somewhat, there are no known treatments to restore hearing, because auditory hair cells in mammals, unlike those in birds or fish, do not regenerate once lost. Auditory hair cell replacement holds great promise as a treatment that could restore hearing after loss of hair cells. In the Jan. 10 issue of Neuron, Massachusetts Eye and Ear and Harvard Medical School researchers demonstrate for the first time that hair cells can be regenerated in an adult mammalian ear by using a drug to stimulate resident cells to become new hair cells, resulting in partial recovery of hearing in mouse ears damaged by noise trauma. This finding holds great potential for future therapeutic application that may someday reverse deafness in humans. “Hair cells are the primary receptor cells for sound and are responsible for the sense of hearing,” explains senior author, Dr. Albert Edge, of Harvard Medical School and Mass. Eye and Ear. “We show that hair cells can be generated in a damaged cochlea and that hair cell replacement leads to an improvement in hearing.” In the experiment, the researchers applied a drug to the cochlea of deaf mice. The drug had been selected for its ability to generate hair cells when added to stem cells isolated from the ear. It acted by inhibiting an enzyme called gamma-secretase that activates a number of cellular pathways. The drug applied to the cochlea inhibited a signal generated by a protein called Notch on the surface of cells that surround hair cells. These supporting cells turned into new hair cells upon treatment with the drug. Replacing hair cells improved hearing in the mice, and the improved hearing could be traced to the areas in which supporting cells had become new hair cells. “The missing hair cells had been replaced by new hair cells after the drug treatment, and analysis of their location allowed us to correlate the improvement in hearing to the areas where the hair cells were replaced,” Dr. Edge said. This is the first demonstration of hair cell regeneration in an adult mammal.  “We’re excited about these results because they are a step forward in the biology of regeneration and prove that mammalian hair cells have the capacity to regenerate,” Dr. Edge said. “With more research, we think that regeneration of hair cells opens the door to potential therapeutic applications in deafness.”

Mass. Eye and Ear Researchers Regenerate Sensory Hair Cells, Restore Hearing to Noise-Damaged Ears

Hearing loss is a significant public health problem affecting almost 50 million people in the United States alone. Sensorineural hearing loss is the most common form and is caused by the loss of sensory hair cells in the cochlea. Hair cell loss results from a variety of factors including noise exposure, aging, toxins, infections, and certain antibiotics and anti-cancer drugs.  Although hearing aids and cochlear implants can ameliorate the symptoms somewhat, there are no known treatments to restore hearing, because auditory hair cells in mammals, unlike those in birds or fish, do not regenerate once lost. Auditory hair cell replacement holds great promise as a treatment that could restore hearing after loss of hair cells.

In the Jan. 10 issue of Neuron, Massachusetts Eye and Ear and Harvard Medical School researchers demonstrate for the first time that hair cells can be regenerated in an adult mammalian ear by using a drug to stimulate resident cells to become new hair cells, resulting in partial recovery of hearing in mouse ears damaged by noise trauma. This finding holds great potential for future therapeutic application that may someday reverse deafness in humans.

“Hair cells are the primary receptor cells for sound and are responsible for the sense of hearing,” explains senior author, Dr. Albert Edge, of Harvard Medical School and Mass. Eye and Ear. “We show that hair cells can be generated in a damaged cochlea and that hair cell replacement leads to an improvement in hearing.”

In the experiment, the researchers applied a drug to the cochlea of deaf mice. The drug had been selected for its ability to generate hair cells when added to stem cells isolated from the ear. It acted by inhibiting an enzyme called gamma-secretase that activates a number of cellular pathways. The drug applied to the cochlea inhibited a signal generated by a protein called Notch on the surface of cells that surround hair cells. These supporting cells turned into new hair cells upon treatment with the drug. Replacing hair cells improved hearing in the mice, and the improved hearing could be traced to the areas in which supporting cells had become new hair cells.

“The missing hair cells had been replaced by new hair cells after the drug treatment, and analysis of their location allowed us to correlate the improvement in hearing to the areas where the hair cells were replaced,” Dr. Edge said.

This is the first demonstration of hair cell regeneration in an adult mammal.  “We’re excited about these results because they are a step forward in the biology of regeneration and prove that mammalian hair cells have the capacity to regenerate,” Dr. Edge said. “With more research, we think that regeneration of hair cells opens the door to potential therapeutic applications in deafness.”

Filed under hearing sensory hair cells hair cell regeneration cochlear implants neuroscience science

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First Alzheimer’s case has full diagnosis 106 years later More than a hundred years after Alois Alzheimer identified Alzheimer’s disease in a patient an analysis of that original patient’s brain has revealed the genetic origin of their condition. The brain specimen tested was discovered in a university basement late last century after a search by rival teams of academics. "It is extremely satisfying to place this last piece in the medical puzzle that Auguste Deter, the first ever Alzheimer patient, presented us with,” said Professor Manuel Graeber, from the University of Sydney. "It is not only of historical interest, however, as it ends any speculation about whether the disease is correctly named after Alois Alzheimer. Alzheimer’s ability to recognise this dementia more than a century ago provides compelling support for specialisation in medicine. Alzheimer was a founding father of neuropathology, an important medical specialty that is still underrepresented." Professor Graeber, from the University’s Brain and Mind Research Institute, Sydney Medical School and the Faculty of Health Sciences, collaborated with Professor Ulrich Müller’s team from the Institute of Human Genetics of the University of Giessen in Germany to produce the molecular diagnosis recently published in Lancet Neurology. For years scientists have been wondering whether the first case of Alzheimer’s disease had a genetic cause. In 1901 Auguste Deter, a middle-aged female patient at the Frankfurt Asylum with unusual symptoms, including short-term memory loss, came to the attention of Dr Alzheimer. When she died, Dr Alzheimer examined her brain and described the distinctive damage indicating a form of presenile dementia. For decades the more than 200 slides that Alzheimer prepared from Deter’s brain were lost. Then in 1992, after Professor Graeber uncovered new information pointing to their location, two teams of medical researchers began a dramatic race to find them. One team searched in Frankfurt but it was a team headed by Professor Graeber, then working at the Max Planck Institute for Neurobiology that finally located the material at the University of Munich in 1997. The slides were examined and confirmed beyond doubt that Deter was suffering from Alzheimer’s disease, with large numbers of amyloid plaques and neurofribrillary tangles in the brain that are hallmarks of the disease. Until now a more sophisticated DNA analysis of the small amount of fragile material in single slides has not been possible. Since their rediscovery, a significant number of brain slides have been under the official custodianship of Professor Graeber who has been at the University of Sydney since 2010. He is preparing a book on the material. "We found a mutation whose ultimate effect is the formation of amyloid plaques. These plaques, which form between nerve cells and seem to suffocate them are the key diagnostic landmark of the disease." Alzheimer’s disease represents one of the greatest health problems in industrialised societies today. An estimated 100 million dementia sufferers are predicted worldwide by 2050, the vast majority of whom will have Alzheimer’s disease. 95 percent of Alzheimer’s patients suffer late onset of the illness after they turn 65. Five percent fall ill before that age (early onset) and Auguste Deter belongs to this group. "We have revealed that Auguste Deter is one of those in which early onset of the disease is caused by mutation in a single gene," said Professor Graeber.

First Alzheimer’s case has full diagnosis 106 years later

More than a hundred years after Alois Alzheimer identified Alzheimer’s disease in a patient an analysis of that original patient’s brain has revealed the genetic origin of their condition.

The brain specimen tested was discovered in a university basement late last century after a search by rival teams of academics.

"It is extremely satisfying to place this last piece in the medical puzzle that Auguste Deter, the first ever Alzheimer patient, presented us with,” said Professor Manuel Graeber, from the University of Sydney.

"It is not only of historical interest, however, as it ends any speculation about whether the disease is correctly named after Alois Alzheimer. Alzheimer’s ability to recognise this dementia more than a century ago provides compelling support for specialisation in medicine. Alzheimer was a founding father of neuropathology, an important medical specialty that is still underrepresented."

Professor Graeber, from the University’s Brain and Mind Research Institute, Sydney Medical School and the Faculty of Health Sciences, collaborated with Professor Ulrich Müller’s team from the Institute of Human Genetics of the University of Giessen in Germany to produce the molecular diagnosis recently published in Lancet Neurology.

For years scientists have been wondering whether the first case of Alzheimer’s disease had a genetic cause. In 1901 Auguste Deter, a middle-aged female patient at the Frankfurt Asylum with unusual symptoms, including short-term memory loss, came to the attention of Dr Alzheimer. When she died, Dr Alzheimer examined her brain and described the distinctive damage indicating a form of presenile dementia.

For decades the more than 200 slides that Alzheimer prepared from Deter’s brain were lost. Then in 1992, after Professor Graeber uncovered new information pointing to their location, two teams of medical researchers began a dramatic race to find them.

One team searched in Frankfurt but it was a team headed by Professor Graeber, then working at the Max Planck Institute for Neurobiology that finally located the material at the University of Munich in 1997.

The slides were examined and confirmed beyond doubt that Deter was suffering from Alzheimer’s disease, with large numbers of amyloid plaques and neurofribrillary tangles in the brain that are hallmarks of the disease. Until now a more sophisticated DNA analysis of the small amount of fragile material in single slides has not been possible.

Since their rediscovery, a significant number of brain slides have been under the official custodianship of Professor Graeber who has been at the University of Sydney since 2010. He is preparing a book on the material.

"We found a mutation whose ultimate effect is the formation of amyloid plaques. These plaques, which form between nerve cells and seem to suffocate them are the key diagnostic landmark of the disease."

Alzheimer’s disease represents one of the greatest health problems in industrialised societies today. An estimated 100 million dementia sufferers are predicted worldwide by 2050, the vast majority of whom will have Alzheimer’s disease.

95 percent of Alzheimer’s patients suffer late onset of the illness after they turn 65. Five percent fall ill before that age (early onset) and Auguste Deter belongs to this group.

"We have revealed that Auguste Deter is one of those in which early onset of the disease is caused by mutation in a single gene," said Professor Graeber.

Filed under alzheimer's disease Auguste Deter dementia genetics mutation history science

92 notes

Dark matter made visible before the final cut Research findings from the University of North Carolina School of Medicine are shining a light on an important regulatory role performed by the so-called dark matter, or “junk DNA,” within each of our genes. The new study reveals snippets of information contained in dark matter that can alter the way a gene is assembled. “These small sequences of genetic information tell the gene how to splice, either by enhancing the splicing process or inhibiting it. The research opens the door for studying the dark matter of genes. And it helps us further understand how mutations or polymorphisms affect the functions of any gene,” said study senior author, Zefeng Wang, PhD, assistant professor of pharmacology in the UNC School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center. The study is described in a report published in the January 2013 issue of the journal Nature Structural & Molecular Biology. 

Dark matter made visible before the final cut

Research findings from the University of North Carolina School of Medicine are shining a light on an important regulatory role performed by the so-called dark matter, or “junk DNA,” within each of our genes.

The new study reveals snippets of information contained in dark matter that can alter the way a gene is assembled.

“These small sequences of genetic information tell the gene how to splice, either by enhancing the splicing process or inhibiting it. The research opens the door for studying the dark matter of genes. And it helps us further understand how mutations or polymorphisms affect the functions of any gene,” said study senior author, Zefeng Wang, PhD, assistant professor of pharmacology in the UNC School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center.

The study is described in a report published in the January 2013 issue of the journal Nature Structural & Molecular Biology. 

Filed under junk DNA dark matter genetics mutations splicing process science

69 notes

Cheap and easy technique to snip DNA could revolutionize gene therapy A simple, precise and inexpensive method for cutting DNA to insert genes into human cells could transform genetic medicine, making routine what now are expensive, complicated and rare procedures for replacing defective genes in order to fix genetic disease or even cure AIDS. Discovered last year by Jennifer Doudna and Martin Jinek of the Howard Hughes Medical Institute and University of California, Berkeley, and Emmanuelle Charpentier of the Laboratory for Molecular Infection Medicine-Sweden, the technique was labeled a “tour de force” in a 2012 review in the journal Nature Biotechnology. That review was based solely on the team’s June 28, 2012, Science paper, in which the researchers described a new method of precisely targeting and cutting DNA in bacteria. Two new papers published last week in the journal Science Express (1 , 2) demonstrate that the technique also works in human cells. A paper by Doudna and her team reporting similarly successful results in human cells has been accepted for publication by the new open-access journal eLife. “The ability to modify specific elements of an organism’s genes has been essential to advance our understanding of biology, including human health,” said Doudna, a professor of molecular and cell biology and of chemistry and a Howard Hughes Medical Institute Investigator at UC Berkeley. “However, the techniques for making these modifications in animals and humans have been a huge bottleneck in both research and the development of human therapeutics. “This is going to remove a major bottleneck in the field, because it means that essentially anybody can use this kind of genome editing or reprogramming to introduce genetic changes into mammalian or, quite likely, other eukaryotic systems.” “I think this is going to be a real hit,” said George Church, professor of genetics at Harvard Medical School and principal author of one of the Science Express papers. “There are going to be a lot of people practicing this method because it is easier and about 100 times more compact than other techniques.” “Based on the feedback we’ve received, it’s possible that this technique will completely revolutionize genome engineering in animals and plants,” said Doudna, who also holds an appointment at Lawrence Berkeley National Laboratory. “It’s easy to program and could potentially be as powerful as the Polymerase Chain Reaction (PCR).” The latter technique made it easy to generate millions of copies of small pieces of DNA and permanently altered biological research and medical genetics.

Cheap and easy technique to snip DNA could revolutionize gene therapy

A simple, precise and inexpensive method for cutting DNA to insert genes into human cells could transform genetic medicine, making routine what now are expensive, complicated and rare procedures for replacing defective genes in order to fix genetic disease or even cure AIDS.

Discovered last year by Jennifer Doudna and Martin Jinek of the Howard Hughes Medical Institute and University of California, Berkeley, and Emmanuelle Charpentier of the Laboratory for Molecular Infection Medicine-Sweden, the technique was labeled a “tour de force” in a 2012 review in the journal Nature Biotechnology.

That review was based solely on the team’s June 28, 2012, Science paper, in which the researchers described a new method of precisely targeting and cutting DNA in bacteria.

Two new papers published last week in the journal Science Express (1 , 2) demonstrate that the technique also works in human cells. A paper by Doudna and her team reporting similarly successful results in human cells has been accepted for publication by the new open-access journal eLife.

“The ability to modify specific elements of an organism’s genes has been essential to advance our understanding of biology, including human health,” said Doudna, a professor of molecular and cell biology and of chemistry and a Howard Hughes Medical Institute Investigator at UC Berkeley. “However, the techniques for making these modifications in animals and humans have been a huge bottleneck in both research and the development of human therapeutics.

“This is going to remove a major bottleneck in the field, because it means that essentially anybody can use this kind of genome editing or reprogramming to introduce genetic changes into mammalian or, quite likely, other eukaryotic systems.”

“I think this is going to be a real hit,” said George Church, professor of genetics at Harvard Medical School and principal author of one of the Science Express papers. “There are going to be a lot of people practicing this method because it is easier and about 100 times more compact than other techniques.”

“Based on the feedback we’ve received, it’s possible that this technique will completely revolutionize genome engineering in animals and plants,” said Doudna, who also holds an appointment at Lawrence Berkeley National Laboratory. “It’s easy to program and could potentially be as powerful as the Polymerase Chain Reaction (PCR).”

The latter technique made it easy to generate millions of copies of small pieces of DNA and permanently altered biological research and medical genetics.

Filed under Cas9 gene therapy DNA DNA cleavage bacteria genetics genome science

64 notes

Stem cell materials could boost research into key diseases Stem cell manufacturing for drug screening and treatments for diseases such as Huntington’s and Parkinson’s could be boosted by a new method of generating stem cells, a study suggests. Scientists have developed a family of compounds that can support the growth of human embryonic stem cells on a large scale for use in drug testing or treatments. The new materials, which are water-based gels, act as a tiny scaffold to which cells can cling as they grow. Normally cells must be grown on expensive biological surfaces that can carry pathogens and contaminate cells. Once cells have multiplied sufficiently for their intended purpose, the gels can be cooled, enabling the stem cells to drop off the scaffold without becoming damaged. The new approach surpasses existing techniques of separating cells by mechanical or chemical means, which carry a greater risk of damage to cells. Scientists say the materials could offer a means of enabling the stem cells to be produced in large numbers efficiently and without the risk of inadvertent contamination, facilitating research, drug screening programmes and clinical applications that call for large numbers of cells. Researchers at the University of Edinburgh developed the new materials by screening hundreds of potential compounds for their ability to support stem cell growth. From a shortlist of four, one has been found to be effective, and researchers say the remaining three show similar potential. Stem cells provide a powerful tool for screening drugs as they can be used to show the effects of drugs on cells and systems within the body. The study, published in Nature Communications, was supported by the European Union Framework 7 Grant Funding. The gels are being developed under licence by technology company Ilika. Dr Paul de Sousa, of the University of Edinburgh’s Scottish Centre for Regenerative Medicine, said: “This development could greatly enhance automated production of embryonic stem cells, which would improve the efficiency and reduce the cost of stem cell manufacturing. We are also looking into whether this work could help develop pluripotent stem cells induced from adult cells.”

Stem cell materials could boost research into key diseases

Stem cell manufacturing for drug screening and treatments for diseases such as Huntington’s and Parkinson’s could be boosted by a new method of generating stem cells, a study suggests.

Scientists have developed a family of compounds that can support the growth of human embryonic stem cells on a large scale for use in drug testing or treatments.

The new materials, which are water-based gels, act as a tiny scaffold to which cells can cling as they grow. Normally cells must be grown on expensive biological surfaces that can carry pathogens and contaminate cells.

Once cells have multiplied sufficiently for their intended purpose, the gels can be cooled, enabling the stem cells to drop off the scaffold without becoming damaged.

The new approach surpasses existing techniques of separating cells by mechanical or chemical means, which carry a greater risk of damage to cells.

Scientists say the materials could offer a means of enabling the stem cells to be produced in large numbers efficiently and without the risk of inadvertent contamination, facilitating research, drug screening programmes and clinical applications that call for large numbers of cells.

Researchers at the University of Edinburgh developed the new materials by screening hundreds of potential compounds for their ability to support stem cell growth. From a shortlist of four, one has been found to be effective, and researchers say the remaining three show similar potential.

Stem cells provide a powerful tool for screening drugs as they can be used to show the effects of drugs on cells and systems within the body.

The study, published in Nature Communications, was supported by the European Union Framework 7 Grant Funding. The gels are being developed under licence by technology company Ilika.

Dr Paul de Sousa, of the University of Edinburgh’s Scottish Centre for Regenerative Medicine, said: “This development could greatly enhance automated production of embryonic stem cells, which would improve the efficiency and reduce the cost of stem cell manufacturing. We are also looking into whether this work could help develop pluripotent stem cells induced from adult cells.”

Filed under neurodegerative disorders stem cells embryonic stem cells drug screening medicine science

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Does listening to Mozart really boost your brainpower?

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It is said that classical music could make children more intelligent, but when you look at the scientific evidence, the picture is more mixed.

You have probably heard of the Mozart effect. It’s the idea that if children or even babies listen to music composed by Mozart they will become more intelligent. A quick internet search reveals plenty of products to assist you in the task. Whatever your age there are CDs and books to help you to harness the power of Mozart’s music, but when it comes to scientific evidence that it can make you more clever, the picture is more mixed. 

The phrase “the Mozart effect” was coined in 1991, but it is a study described two years later in the journal Nature that sparked real media and public interest about the idea that listening to classical music somehow improves the brain. It is one of those ideas that feels plausible. Mozart was undoubtedly a genius himself, his music is complex and there is a hope that if we listen to enough of it, a little of that intelligence might rub off on us.

The idea took off, with thousands of parents playing Mozart to their children, and in 1998 Zell Miller, the Governor of the state of Georgia in the US, even asked for money to be set aside in the state budget so that every newborn baby could be sent a CD of classical music. It’s not just babies and children who were deliberately exposed to Mozart’s melodies. When Sergio Della Sala, the psychologist and author of the book Mind Myths, visited a mozzarella farm in Italy, the farmer proudly explained that the buffalos were played Mozart three times a day to help them to produce better milk.

I’ll leave the debate on the impact on milk yield to farmers, but what about the evidence that listening to Mozart makes people more intelligent? Exactly what was it was that the authors of the initial study discovered that took public imagination by storm?

When you look back at the original paper, the first surprise is that the authors from the University of California, Irvine are modest in their claims and don’t even use the “Mozart effect” phrase in the paper. The second surprise is that it wasn’t conducted on children at all: it was in fact conducted with those stalwarts of psychological studies – young adult students. Only 36 students took part. On three occasions they were given a series of mental tasks to complete, and before each task, they listened either to ten minutes of silence, ten minutes of a tape of relaxation instructions, or ten minutes of Mozart’s sonata for two pianos in D major (K448).

The students who listened to Mozart did better at tasks where they had to create shapes in their minds. For a short time the students were better at spatial tasks where they had to look at folded up pieces of paper with cuts in them and to predict how they would appear when unfolded. But unfortunately, as the authors make clear at the time, this effect lasts for about fifteen minutes. So it’s hardly going to bring you a lifetime of enhanced intelligence.

Brain arousal

Nevertheless, people began to theorise about why it was that Mozart’s music in particular could have this effect. Did the complexity of music cause patterns of cortical firing in the brain similar to those associated with solving spatial puzzles?

More research followed, and a meta-analysis of sixteen different studies confirmed that listening to music does lead to a temporary improvement in the ability to manipulate shapes mentally, but the benefits are short-lived and it doesn’t make us more intelligent.

Then it began to emerge that perhaps Mozart wasn’t so special after all. In 2010 a larger meta-analysis of a greater number of studies again found a positive effect, but that other kinds of music worked just as well. One study found that listening to Schubert was just as good, and so was hearing a passage read out aloud from a Stephen King novel. But only if you enjoyed it. So, perhaps enjoyment and engagement are key, rather than the exact notes you hear.

Although we tend to associate the Mozart effect with babies and small children, most of these studies were conducted on adults, whose brains are of course at a very different stage of development. But in 2006 a large study was conducted in Britain involving eight thousand children. They listened either to ten minutes of Mozart’s String Quintet in D Major, a discussion about the experiment or to a sequence of three pop songs: Blur’s “Country House,” “Return of the Mack,” by Mark Morrison and PJ and Duncan’s “Stepping Stone”. Once again music improved the ability to predict paper shapes, but this time it wasn’t a Mozart effect, but a Blur effect. The children who listened to Mozart did well, but with pop music they did even better, so prior preference could come into it.

Whatever your musical choice, it seems that all you need to do a bit better at predictive origami is some cognitive arousal. Your mind needs to get a little more active, it needs something to get it going and that’s going to be whichever kind of music appeals to you. In fact, it doesn’t have to be music. Anything that makes you more alert should work just as well – doing a few star jumps or drinking some coffee, for instance.

There is a way in which music can make a difference to your IQ, though. Unfortunately it requires a bit more effort than putting on a CD. Learning to play a musical instrument can have a beneficial effect on your brain. Jessica Grahn, a cognitive scientist at Western University in London, Ontario says that a year of piano lessons, combined with regular practice can increase IQ by as much as three points.

So listening to Mozart won’t do you or your children any harm and could be the start of a life-long love of classical music. But unless you and your family have some urgent imaginary origami to do, the chances are that sticking on a sonata is not going to make you better at anything.

(Source: bbc.com)

Filed under brain intelligence Mozart effect brain activity music psychology neuroscience science

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First Oral Drug for Spinal Cord Injury Improves Movement in Mice

An experimental oral drug given to mice after a spinal cord injury was effective at improving limb movement after the injury, a new study shows.

The compound efficiently crossed the blood-brain barrier, did not increase pain and showed no toxic effects to the animals.

“This is a first to have a drug that can be taken orally to produce functional improvement with no toxicity in a rodent model,” said Sung Ok Yoon, associate professor of molecular & cellular biochemistry at Ohio State University and lead author of the study. “So far, in the spinal cord injury field with rodent models, effective treatments have included more than one therapy, often involving invasive means. Here, with a single agent, we were able to obtain functional improvement.”

The small molecule in this study was tested for its ability to prevent the death of cells called oligodendrocytes. These cells surround and protect axons, long projections of a nerve cell, by wrapping them in myelin. In addition to functioning as axon insulation, myelin allows for the rapid transmission of signals between nerve cells.

The drug preserved oligodendrocytes by inhibiting the activation of a protein called p75. Yoon’s lab previously discovered that p75 is linked to the death of these specialized cells after a spinal cord injury. When they die, axons that are supported by them degenerate.

“Because we know that oligodendrocytes continue to die for a long period of time after an injury, we took the approach that if we could put a brake on that cell death, we could prevent continued degeneration of axons,” she said. “Many researchers in the field are focusing on regeneration of neurons, but we specifically targeted a different type of cells because it allows a relatively long therapeutic window.”

An additional benefit of targeting oligodendrocytes is that it can amplify the therapeutic effect because a single oligodendrocyte myelinates multiple axons.

A current acute treatment for humans, methylprednisolone, must be administered within eight but not more than 24 hours after the injury to be effective at all. An estimated 1.3 million people in the United States are living with spinal cord injuries, experiencing paralysis and complications that include bladder, bowel and sexual dysfunction and chronic pain.

The experimental drug, called LM11A-31, was developed by study co-author Frank Longo, professor of neurology and neurological sciences at Stanford University. The drug is the first to be developed with a specific target, p75, as a potential therapy for spinal cord injury.

The research is published in the Jan. 9, 2013, issue of The Journal of Neuroscience.

Researchers gave three different oral doses of LM11A-31, as well as a placebo, to different groups of mice beginning four hours after injury and then twice daily for a 42-day experimental period. The scientists analyzed the compound’s effectiveness at improving limb movement and preventing myelin loss.

The spinal cord injuries in mice mimicked those caused in humans by the application of extensive force and pressure, resulting in loss of hind-limb and bladder function andexperimentally calibrated baseline difficulty in walking and swimming.

The researchers determined that the mice did not experience more pain than the placebo group at all the doses tested, suggesting that LM11A-31 does not worsen nerve pain after spinal cord injury.

Analysis showed that the extent of myelin sparing was dependent on the dose of the drug. Each dose – 10, 25 or 100 milligrams per kilogram of body weight – led to increasing myelin sparing, with the highest dose demonstrating the greatest effect.

The injury in the animals caused a loss of about 75 percent of myelinated axons in the lesion area in the placebo group. This loss was reduced so that myelinated axons reached more than half of the normal levels with LM11A-31 at 100 mg/kg. That was correlated with about a 50 percent increase in surviving oligodendrotcytes compared to those in the placebo group, Yoon said.

In behavior tests, only the highest dose of the compound led to improvements in motor function. Mice were tested in both weight-bearing and non-weight-bearing activities over the 42 days to evaluate their functional recovery.

Mice receiving the highest dose could walk with well-coordinated steps. In swimming tests, scientists saw similar improvements, with mice receiving the highest dose most able to coordinate hind-limb crisscross movement. The other treatment groups exhibited difficulty in walking and swimming.

Yoon said the findings may suggest that myelin sparing needs to reach a threshold of roughly 50 percent of normal levels before motor function improvements become measurable.

“The cellular analysis of the myelin profile detects small changes. Behavior is more complex, and we don’t think functional behavior necessarily improves in a linear fashion,” she said. “Still, these results clearly show that this is the first oral drug in spinal cord injury that works alone to improve function.”

(Source: researchnews.osu.edu)

Filed under limb movement spinal cord spinal cord injury toxicity experimental drug neuroscience science

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