Neuroscience

Articles and news from the latest research reports.

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Experimental Compound Reverses Down Syndrome-Like Learning Deficits In Mice

Researchers at Johns Hopkins and the National Institutes of Health have identified a compound that dramatically bolsters learning and memory when given to mice with a Down syndrome-like condition on the day of birth. As they report in the Sept. 4 issue of Science Translational Medicine, the single-dose treatment appears to enable the cerebellum of the rodents’ brains to grow to a normal size.

The scientists caution that use of the compound, a small molecule known as a sonic hedgehog pathway agonist, has not been proven safe to try in people with Down syndrome, but say their experiments hold promise for developing drugs like it.

“Most people with Down syndrome have a cerebellum that’s about 60 percent of the normal size,” says Roger Reeves, Ph.D., a professor in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. “We treated the Down syndrome-like mice with a compound we thought might normalize the cerebellum’s growth, and it worked beautifully. What we didn’t expect were the effects on learning and memory, which are generally controlled by the hippocampus, not the cerebellum.”

Reeves has devoted his career to studying Down syndrome, a condition that occurs when people have three, rather than the usual two, copies of chromosome 21. As a result of this “trisomy,” people with Down syndrome have extra copies of the more than 300 genes housed on that chromosome, which leads to intellectual disabilities, distinctive facial features and sometimes heart problems and other health effects. Since the condition involves so many genes, developing treatments for it is a formidable challenge, Reeves says.

For the current experiments, Reeves and his colleagues used mice that were genetically engineered to have extra copies of about half of the genes found on human chromosome 21.
The mice have many characteristics similar to those of people with Down syndrome, including relatively small cerebellums and difficulty learning and remembering how to navigate through a familiar space. (In the case of the mice, this was tested by tracking how readily the animals located a platform while swimming in a so-called water maze.)
Based on previous experiments on how Down syndrome affects brain development, the researchers tried supercharging a biochemical chain of events known as the sonic hedgehog pathway that triggers growth and development. They used a compound — a sonic hedgehog pathway agonist — that could do just that.

The compound was injected into the Down syndrome-like mice just once, on the day of birth, while their cerebellums were still developing. “We were able to completely normalize growth of the cerebellum through adulthood with that single injection,” Reeves says.

But the research team went beyond measuring the cerebellums, looking for changes in behavior, too. “Making the animals, synthesizing the compound and guessing the right dose were so difficult and time-consuming that we wanted to get as much data out of the experiment as we could,” Reeves says. The team tested the treated mice against untreated Down syndrome-like mice and normal mice in a variety of ways, and found that the treated mice did just as well as the normal ones on the water maze test.

Reeves says further research is needed to learn why exactly the treatment works, because their examination of certain cells in the hippocampus known to be involved in learning and affected by Down syndrome appeared unchanged by the sonic hedgehog agonist treatment. One idea is that the treatment improved learning by strengthening communication between the cerebellum and the hippocampus, he says.

As for the compound’s potential to become a human drug, the problem, Reeves says, is that altering an important biological chain of events like sonic hedgehog would likely have many unintended effects throughout the body, such as raising the risk of cancer by triggering inappropriate growth. But now that the team has seen the potential of this strategy, they will look for more targeted ways to safely harness the power of sonic hedgehog in the cerebellum. Even if his team succeeds in developing a clinically useful drug, however, Reeves cautions that it wouldn’t constitute a “cure” for the learning and memory-related effects of Down syndrome. “Down syndrome is very complex, and nobody thinks there’s going to be a silver bullet that normalizes cognition,” he says. “Multiple approaches will be needed.”

(Source: newswise.com)

Filed under down syndrome trisomy sonic hedgehog pathway cerebellum animal model neuroscience science

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Space around others perceived just as our own A study from Karolinska Institutet in Sweden has shown that neurons in our brain ‘mirror’ the space near others, just as if this was the space near ourselves. The study, published in the scientific journal Current Biology, sheds new light on a question that has long preoccupied psychologists and neuroscientists regarding the way in which the brain represents other people and the events that happens to those people. "We usually experience others as clearly separated from us, occupying a very different portion of space," says Claudio Brozzoli, lead author of the study at the Department of Neuroscience. "However, what this study shows is that we perceive the space around other people in the same way as we perceive the space around our own body." The new research revealed that visual events occurring near a person’s own hand and those occurring near another’s hand are represented by the same region of the frontal lobe (premotor cortex). In other words, the brain can estimate what happens near another person’s hand because the neurons that are activated are the same as those that are active when something happens close to our own hand. It is possible that this shared representation of space could help individuals to interact more efficiently — when shaking hands, for instance. It might also help us to understand intuitively when other people are at risk of getting hurt, for example when we see a friend about to be hit by a ball. The study consists of a series of experiments in functional magnetic resonance imaging (fMRI) in which a total of forty-six healthy volunteers participated. In the first experiment, participants observed a small ball attached to a stick moving first near their own hand, and then near another person’s hand. The authors discovered a region in the premotor cortex that contained groups of neurons that responded to the object only if it was close to the individual’s own hand or close to the other person’s hand. In a second experiment, the authors reproduced their finding before going on to show that this result was not dependent on the order of stimulus presentation near the two hands. "We know from earlier studies that our brains represent the actions of other people using the same groups of neurons that represent our own actions; the so called mirror neuron system", says Henrik Ehrsson, co-author of the study. "But here we found a new class of these kinds of neuronal populations that represent space near others just as they represent space near ourselves." According to the scientists, this study provides a new perspective that could help facilitate the understanding of behavioural and emotional interactions between people, since — from the brain’s perspective — the space between us is shared.

Space around others perceived just as our own

A study from Karolinska Institutet in Sweden has shown that neurons in our brain ‘mirror’ the space near others, just as if this was the space near ourselves. The study, published in the scientific journal Current Biology, sheds new light on a question that has long preoccupied psychologists and neuroscientists regarding the way in which the brain represents other people and the events that happens to those people.

"We usually experience others as clearly separated from us, occupying a very different portion of space," says Claudio Brozzoli, lead author of the study at the Department of Neuroscience. "However, what this study shows is that we perceive the space around other people in the same way as we perceive the space around our own body."

The new research revealed that visual events occurring near a person’s own hand and those occurring near another’s hand are represented by the same region of the frontal lobe (premotor cortex). In other words, the brain can estimate what happens near another person’s hand because the neurons that are activated are the same as those that are active when something happens close to our own hand. It is possible that this shared representation of space could help individuals to interact more efficiently — when shaking hands, for instance. It might also help us to understand intuitively when other people are at risk of getting hurt, for example when we see a friend about to be hit by a ball.

The study consists of a series of experiments in functional magnetic resonance imaging (fMRI) in which a total of forty-six healthy volunteers participated. In the first experiment, participants observed a small ball attached to a stick moving first near their own hand, and then near another person’s hand. The authors discovered a region in the premotor cortex that contained groups of neurons that responded to the object only if it was close to the individual’s own hand or close to the other person’s hand. In a second experiment, the authors reproduced their finding before going on to show that this result was not dependent on the order of stimulus presentation near the two hands.

"We know from earlier studies that our brains represent the actions of other people using the same groups of neurons that represent our own actions; the so called mirror neuron system", says Henrik Ehrsson, co-author of the study. "But here we found a new class of these kinds of neuronal populations that represent space near others just as they represent space near ourselves."

According to the scientists, this study provides a new perspective that could help facilitate the understanding of behavioural and emotional interactions between people, since — from the brain’s perspective — the space between us is shared.

Filed under peripersonal space premotor cortex mirror neurons fMRI psychology neuroscience science

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Inner-Ear Disorders May Cause Hyperactivity Behavioral abnormalities are traditionally thought to originate in the brain. But a new study by researchers at Albert Einstein College of Medicine of Yeshiva University has found that inner-ear dysfunction can directly cause neurological changes that increase hyperactivity. The study, conducted in mice, also implicated two brain proteins in this process, providing potential targets for intervention. The findings were published today in the online edition of Science. For years, scientists have observed that many children and adolescents with severe inner-ear disorders – particularly disorders affecting both hearing and balance – also have behavioral problems, such as hyperactivity. Until now, no one has been able to determine whether the ear disorders and behavioral problems are actually linked. "Our study provides the first evidence that a sensory impairment, such as inner-ear dysfunction, can induce specific molecular changes in the brain that cause maladaptive behaviors traditionally considered to originate exclusively in the brain," said study leader Jean M. Hébert, Ph.D., professor in the Dominick P. Purpura Department of Neuroscience and of genetics at Einstein. The inner ear consists of two structures, the cochlea (responsible for hearing) and the vestibular system (responsible for balance). Inner-ear disorders are typically caused by genetic defects but can also result from infection or injury. The idea for the study arose when Michelle W. Antoine, a Ph.D. student at Einstein at the time, noticed that some mice in Dr. Hébert’s laboratory were unusually active – in a state of near-continual movement, chasing their tails in a circular pattern. Further investigation revealed that the mice had severe cochlear and vestibular defects and were profoundly deaf. “We then realized that these mice provided a good opportunity to study the relationship between inner-ear dysfunction and behavior,” said Dr. Hébert. The researchers established that the animals’ inner-ear problems were due to a mutation in a gene called Slc12a2, which mediates the transport of sodium, potassium, and chloride molecules in various tissues, including the inner ear and central nervous system (CNS). The gene is also found in humans. To determine whether the gene mutation was linked to the animals’ hyperactivity, the researchers took healthy mice and selectively deleted Slc12a2 from either the inner ear, various parts of the brain that control movement or the entire CNS. “To our surprise, it was only when we deleted the gene from the inner ear that we observed increased locomotor activity,” said Dr. Hébert. The researchers hypothesized that inner-ear defects cause abnormal functioning of the striatum, a central brain area that controls movement. Tests revealed increased levels of two proteins involved in a signaling pathway that controls the action of neurotransmitters: pERK (phosphorylated extracellular signal-regulated kinase) and pCREB (phospho-cAMP response-element binding protein), which is further down the signaling pathway from pERK. Increases in levels of the two proteins were seen only in the striatum and not in other forebrain regions. To discover whether increased pERK levels caused the abnormal increase in locomotor activity, Slc12a2-deficient mice were given injections of SL327, a pERK inhibitor. Administering SL327 restored locomotor activity to normal, without affecting activity levels in controls. The SL327 injections did not affect grooming, suggesting that increased pERK in the striatum selectively elevates locomotor activity and not general activity. According to the researchers, the findings suggest that hyperactivity in children with inner-ear disorders might be controllable with medications that directly or indirectly inhibit the pERK pathway in the striatum. "Our study also raises the intriguing possibility that other sensory impairments not associated with inner-ear defects could cause or contribute to psychiatric or motor disorders that are now considered exclusively of cerebral origin," said Dr. Hébert. "This is an area that has not been well studied."

Inner-Ear Disorders May Cause Hyperactivity

Behavioral abnormalities are traditionally thought to originate in the brain. But a new study by researchers at Albert Einstein College of Medicine of Yeshiva University has found that inner-ear dysfunction can directly cause neurological changes that increase hyperactivity. The study, conducted in mice, also implicated two brain proteins in this process, providing potential targets for intervention. The findings were published today in the online edition of Science.

For years, scientists have observed that many children and adolescents with severe inner-ear disorders – particularly disorders affecting both hearing and balance – also have behavioral problems, such as hyperactivity. Until now, no one has been able to determine whether the ear disorders and behavioral problems are actually linked.

"Our study provides the first evidence that a sensory impairment, such as inner-ear dysfunction, can induce specific molecular changes in the brain that cause maladaptive behaviors traditionally considered to originate exclusively in the brain," said study leader Jean M. Hébert, Ph.D., professor in the Dominick P. Purpura Department of Neuroscience and of genetics at Einstein.

The inner ear consists of two structures, the cochlea (responsible for hearing) and the vestibular system (responsible for balance). Inner-ear disorders are typically caused by genetic defects but can also result from infection or injury.

The idea for the study arose when Michelle W. Antoine, a Ph.D. student at Einstein at the time, noticed that some mice in Dr. Hébert’s laboratory were unusually active – in a state of near-continual movement, chasing their tails in a circular pattern. Further investigation revealed that the mice had severe cochlear and vestibular defects and were profoundly deaf. “We then realized that these mice provided a good opportunity to study the relationship between inner-ear dysfunction and behavior,” said Dr. Hébert.

The researchers established that the animals’ inner-ear problems were due to a mutation in a gene called Slc12a2, which mediates the transport of sodium, potassium, and chloride molecules in various tissues, including the inner ear and central nervous system (CNS). The gene is also found in humans.

To determine whether the gene mutation was linked to the animals’ hyperactivity, the researchers took healthy mice and selectively deleted Slc12a2 from either the inner ear, various parts of the brain that control movement or the entire CNS. “To our surprise, it was only when we deleted the gene from the inner ear that we observed increased locomotor activity,” said Dr. Hébert.

The researchers hypothesized that inner-ear defects cause abnormal functioning of the striatum, a central brain area that controls movement. Tests revealed increased levels of two proteins involved in a signaling pathway that controls the action of neurotransmitters: pERK (phosphorylated extracellular signal-regulated kinase) and pCREB (phospho-cAMP response-element binding protein), which is further down the signaling pathway from pERK. Increases in levels of the two proteins were seen only in the striatum and not in other forebrain regions.

To discover whether increased pERK levels caused the abnormal increase in locomotor activity, Slc12a2-deficient mice were given injections of SL327, a pERK inhibitor. Administering SL327 restored locomotor activity to normal, without affecting activity levels in controls. The SL327 injections did not affect grooming, suggesting that increased pERK in the striatum selectively elevates locomotor activity and not general activity. According to the researchers, the findings suggest that hyperactivity in children with inner-ear disorders might be controllable with medications that directly or indirectly inhibit the pERK pathway in the striatum.

"Our study also raises the intriguing possibility that other sensory impairments not associated with inner-ear defects could cause or contribute to psychiatric or motor disorders that are now considered exclusively of cerebral origin," said Dr. Hébert. "This is an area that has not been well studied."

Filed under hyperactivity inner-ear disorders gene mutation striatum neuroscience science

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“Seeing” Faces Through Touch

Our sense of touch can contribute to our ability to perceive faces, according to new research published in Psychological Science, a journal of the Association for Psychological Science.

“In daily life, we usually recognize faces through sight and almost never explore them through touch,” says lead researcher Kazumichi Matsumiya of Tohoku University in Japan. “But we use information from multiple sensory modalities in order to perceive many everyday non-face objects and events, such as speech perception or object recognition — these new findings suggest that even face processing is essentially multisensory.”

In a series of studies, Matsumiya took advantage of a phenomenon called the “face aftereffect” to investigate whether our visual system responds to nonvisual signals for processing faces. Inthe face aftereffect, we adapt to a face with a particular expression — happiness, for example — which causes us to perceive a subsequent neutral face as having the opposite facial expression (i.e., sadness).

Matsumiya hypothesized that if the visual system really does respond to signals from another modality, then we should see evidence for face aftereffects from one modality to the other. So, adaptation to a face that is explored by touch should produce visual face aftereffects.

To test this, Matsumiya had participants explore face masks concealed below a mirror by touching them. After this adaptation period, the participants were visually presented with a series of faces that had varying expressions and were asked to classify the faces as happy or sad. The visual faces and the masks were created from the same exemplar.

In line with his hypothesis, Matsumiya found that participants’ experiences exploring the face masks by touch shifted their perception of the faces presented visually compared to participants who had no adaptation period, such that the visual faces were perceived as having the opposite facial expression.

Further experiments ruled out other explanations for the results, including the possibility that the face aftereffects emerged because participants were intentionally imagining visual faces during the adaptation period.

And a fourth experiment revealed that the aftereffect also works the other way: Visual stimuli can influence how we perceive a face through touch.

According to Matsumiya, current views on face processing assume that the visual system only receives facial signals from the visual modality — but these experiments suggest that face perception is truly crossmodal.

“These findings suggest that facial information may be coded in a shared representation between vision and haptics in the brain,” notes Matsumiya, suggesting that these findings may have implications for enhancing vision and telecommunication in the development of aids for the visually impaired.

Filed under face perception face processing face aftereffects adaptation psychology neuroscience science

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Nasal inhalation of oxytocin improves face blindness

Prosopagnosia (face blindness) may be temporarily improved following inhalation of the hormone oxytocin.

This is the finding of research led by Dr Sarah Bate and Dr Rachel Bennetts of the Centre for Face Processing Disorders at Bournemouth University that will be presented today, Friday 6 September, at the British Psychological Society’s Joint Cognitive and Developmental annual conference at the University of Reading.

Dr Bate explained: “Prosopagnosia is characterised by a severe impairment in face recognition, whereby a person cannot identify the faces of their family or friends, or even their own face”

The researchers tested twenty adults (10 with prosopagnosia and 10 control participants). Each participant visited the laboratory on two occasions, approximately two weeks apart. On one visit they inhaled the oxytocin nasal spray, and on the other visit they inhaled the placebo spray. The two sprays were prepared by an external pharmaceutical company in identical bottles, and neither the participants nor the researchers knew the identity of the sprays until the data had been analysed.

Regardless of which spray the person inhaled, the testing sessions had an identical format. Participants inhaled the spray, then sat quietly for 45 minutes to allow the spray to take effect. They then participated in two face processing tests: one testing their ability to remember faces and the other testing their ability to match faces of the same identity.

The researchers found that the participants with prosopagnosia achieved higher scores on both face processing tests in the oxytocin condition. Interestingly, no improvement was observed in the control participants, suggesting the hormone may be more effective in those with impaired face recognition systems.

The initial ten participants with prosopagnosia had a developmental form of the condition. Individuals with developmental prosopagnosia have never experienced brain damage, and this form of face blindness is thought to be very common, affecting one in 50 people. Much more rarely, people can acquire prosopagnosia following a brain injury. At a later date, the researchers had the opportunity to test one person with acquired prosopagnosia, and also observed a large improvement following oxytocin inhalation in this individual.

Dr Bate said: “This study provides the first evidence that oxytocin may be used to temporarily improve face recognition in people with either developmental or acquired prosopagnosia. The effects of the hormone are thought to last 2-3 hours, and it may be that the nasal spray can be used to improve face recognition on a special occasion. However, much more research needs to be carried out, as we don’t currently know whether there are benefits or risks associated with longer-term inhalation of the hormone.”

(Source: alphagalileo.org)

Filed under prosopagnosia oxytocin face recognition psychology neuroscience science

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What Is the Brain Telling Us About the Diagnoses of Schizophrenia and Bipolar Disorder? We live in the most exciting and unsettling period in the history of psychiatry since Freud started talking about sex in public. On the one hand, the American Psychiatric Association has introduced the fifth iteration of the psychiatric diagnostic manual, DSM-V, representing the current best effort of the brightest clinical minds in psychiatry to categorize the enormously complex pattern of human emotional, cognitive, and behavioral problems. On the other hand, in new and profound ways, neuroscience and genetics research in psychiatry are yielding insights that challenge the traditional diagnostic schema that have long been at the core of the field. “Our current diagnostic system, DSM-V represents a very reasonable attempt to classify patients by their symptoms. Symptoms are an extremely important part of all medical diagnoses, but imagine how limited we would be if we categorized all forms of pneumonia as ‘coughing disease,” commented Dr. John Krystal, Editor of Biological Psychiatry. A paper by Sabin Khadka and colleagues that appears in the September 15th issue of Biological Psychiatry advances the discussion of one of these roiling psychiatric diagnostic dilemmas. One of the core hypotheses is that schizophrenia and bipolar disorder are distinct scientific entities. Emil Kraepelin, credited by many as the father of modern scientific psychiatry, was the first to draw a distinction between dementia praecox (schizophrenia) and manic depression (bipolar disorder) in the late 19th century based on the behavioral profiles of these syndromes. Yet, patients within each diagnosis can have a wide variation of symptoms, some symptoms appear to be in common across these diagnoses, and antipsychotic medications used to treat schizophrenia are very commonly prescribed to patients with bipolar disorder. But at the level of brain circuit function, do schizophrenia and bipolar differ primarily by degree or are there clear categorical differences? To answer this question, researchers from a large collaborative project called BSNIP looked at a large sample of patients diagnosed with schizophrenia or bipolar disorder, their healthy relatives, and healthy people without a family history of psychiatric disorder. They used a specialized analysis technique to evaluate the data from their multi-site study, which revealed abnormalities within seven different brain networks. Generally speaking, they found that schizophrenia and bipolar disorder showed similar disturbances in cortical circuit function. When differences emerged between these two disorders, it was usually because schizophrenia appeared to be a more severe disease. In other words, individuals with schizophrenia had abnormalities that were larger or affected more brain regions. Their healthy relatives showed subtle alterations that fell between the healthy comparison group and the patient groups. The authors highlight the possibility that there is a continuous spectrum of circuit dysfunction, spanning from individuals without any familial association with schizophrenia or bipolar to patients carrying these diagnoses. “These findings might serve as useful biological markers of psychotic illnesses in general,” said Khadka. Krystal agreed, adding, “It is evident that neither our genomes nor our brains have read DSM-V in that there are links across disorders that we had not previously imagined. These links suggest that new ways of organizing patients will emerge once we understand both the genetics and neural circuitry of psychiatric disorders sufficiently.” (Image: ALAMY)

What Is the Brain Telling Us About the Diagnoses of Schizophrenia and Bipolar Disorder?

We live in the most exciting and unsettling period in the history of psychiatry since Freud started talking about sex in public.

On the one hand, the American Psychiatric Association has introduced the fifth iteration of the psychiatric diagnostic manual, DSM-V, representing the current best effort of the brightest clinical minds in psychiatry to categorize the enormously complex pattern of human emotional, cognitive, and behavioral problems. On the other hand, in new and profound ways, neuroscience and genetics research in psychiatry are yielding insights that challenge the traditional diagnostic schema that have long been at the core of the field.

“Our current diagnostic system, DSM-V represents a very reasonable attempt to classify patients by their symptoms. Symptoms are an extremely important part of all medical diagnoses, but imagine how limited we would be if we categorized all forms of pneumonia as ‘coughing disease,” commented Dr. John Krystal, Editor of Biological Psychiatry.

A paper by Sabin Khadka and colleagues that appears in the September 15th issue of Biological Psychiatry advances the discussion of one of these roiling psychiatric diagnostic dilemmas.

One of the core hypotheses is that schizophrenia and bipolar disorder are distinct scientific entities. Emil Kraepelin, credited by many as the father of modern scientific psychiatry, was the first to draw a distinction between dementia praecox (schizophrenia) and manic depression (bipolar disorder) in the late 19th century based on the behavioral profiles of these syndromes. Yet, patients within each diagnosis can have a wide variation of symptoms, some symptoms appear to be in common across these diagnoses, and antipsychotic medications used to treat schizophrenia are very commonly prescribed to patients with bipolar disorder.

But at the level of brain circuit function, do schizophrenia and bipolar differ primarily by degree or are there clear categorical differences? To answer this question, researchers from a large collaborative project called BSNIP looked at a large sample of patients diagnosed with schizophrenia or bipolar disorder, their healthy relatives, and healthy people without a family history of psychiatric disorder.

They used a specialized analysis technique to evaluate the data from their multi-site study, which revealed abnormalities within seven different brain networks. Generally speaking, they found that schizophrenia and bipolar disorder showed similar disturbances in cortical circuit function. When differences emerged between these two disorders, it was usually because schizophrenia appeared to be a more severe disease. In other words, individuals with schizophrenia had abnormalities that were larger or affected more brain regions. Their healthy relatives showed subtle alterations that fell between the healthy comparison group and the patient groups.

The authors highlight the possibility that there is a continuous spectrum of circuit dysfunction, spanning from individuals without any familial association with schizophrenia or bipolar to patients carrying these diagnoses. “These findings might serve as useful biological markers of psychotic illnesses in general,” said Khadka.

Krystal agreed, adding, “It is evident that neither our genomes nor our brains have read DSM-V in that there are links across disorders that we had not previously imagined. These links suggest that new ways of organizing patients will emerge once we understand both the genetics and neural circuitry of psychiatric disorders sufficiently.”

(Image: ALAMY)

Filed under schizophrenia bipolar disorder psychiatric disorders endophenotype neuroscience science

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Image: A. Amyloid-beta plaques in Alzheimers B. Neurofibrillary tangles (tau) in Alzheimer’s C. Lewy bodies (alpha-synuclein) in Parkinson’s D. TDP-43 inclusions in motor neurons in ALS Prion-like proteins drive several diseases of aging Two leading neurology researchers have proposed a theory that could unify scientists’ thinking about several neurodegenerative diseases and suggest therapeutic strategies to combat them. The theory and backing for it are described in the September 5, 2013 issue of Nature. Mathias Jucker and Lary Walker outline the emerging concept that many of the brain diseases associated with aging, such as Alzheimer’s and Parkinson’s, are caused by specific proteins that misfold and aggregate into harmful seeds. These seeds behave very much like the pathogenic agents known as prions, which cause mad cow disease, chronic wasting disease in deer, scrapie in sheep, and Creutzfeldt-Jakob disease in humans. Walker is research professor at Yerkes National Primate Research Center, Emory University. Jucker is head of the Department of Cellular Neurology at the Hertie Institute for Clinical Brain Research at the University of Tübingen and the German Center for Neurodegenerative Diseases. Unlike prion diseases, which can be infectious, Alzheimer’s, Parkinson’s, and other neurodegenerative diseases can not be passed from person to person under normal circumstances. Once all of these diseases take hold in the brain, however, it is increasingly apparent that the clumps of misfolded proteins spread throughout the nervous system and disrupt its function. The authors were the first to show that a protein that is involved in Alzheimer’s disease – known as amyloid-beta – forms prion-like seeds that stimulate the aggregation of other amyloid-beta molecules in senile plaques and in brain blood vessels. Since then, a growing number of laboratories worldwide have discovered that proteins linked to other neurodegenerative disorders also share key features with prions. Age-related neurodegenerative disorders remain stubbornly resistant to the discovery of effective treatments. Jucker and Walker propose that the concept of pathogenic protein seeding not only could focus research strategies for these seemingly unrelated diseases, but it also suggests that therapeutic approaches designed to thwart prion-like seeds early in the disease process could eventually delay or even prevent the diseases.

Image: A. Amyloid-beta plaques in Alzheimers B. Neurofibrillary tangles (tau) in Alzheimer’s C. Lewy bodies (alpha-synuclein) in Parkinson’s D. TDP-43 inclusions in motor neurons in ALS

Prion-like proteins drive several diseases of aging

Two leading neurology researchers have proposed a theory that could unify scientists’ thinking about several neurodegenerative diseases and suggest therapeutic strategies to combat them.

The theory and backing for it are described in the September 5, 2013 issue of Nature.

Mathias Jucker and Lary Walker outline the emerging concept that many of the brain diseases associated with aging, such as Alzheimer’s and Parkinson’s, are caused by specific proteins that misfold and aggregate into harmful seeds. These seeds behave very much like the pathogenic agents known as prions, which cause mad cow disease, chronic wasting disease in deer, scrapie in sheep, and Creutzfeldt-Jakob disease in humans.

Walker is research professor at Yerkes National Primate Research Center, Emory University. Jucker is head of the Department of Cellular Neurology at the Hertie Institute for Clinical Brain Research at the University of Tübingen and the German Center for Neurodegenerative Diseases.

Unlike prion diseases, which can be infectious, Alzheimer’s, Parkinson’s, and other neurodegenerative diseases can not be passed from person to person under normal circumstances. Once all of these diseases take hold in the brain, however, it is increasingly apparent that the clumps of misfolded proteins spread throughout the nervous system and disrupt its function.

The authors were the first to show that a protein that is involved in Alzheimer’s disease – known as amyloid-beta – forms prion-like seeds that stimulate the aggregation of other amyloid-beta molecules in senile plaques and in brain blood vessels. Since then, a growing number of laboratories worldwide have discovered that proteins linked to other neurodegenerative disorders also share key features with prions.

Age-related neurodegenerative disorders remain stubbornly resistant to the discovery of effective treatments. Jucker and Walker propose that the concept of pathogenic protein seeding not only could focus research strategies for these seemingly unrelated diseases, but it also suggests that therapeutic approaches designed to thwart prion-like seeds early in the disease process could eventually delay or even prevent the diseases.

Filed under aging neurodegenerative diseases prion proteins amyloid beta neuroscience science

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Biologists Uncover Details of How We Squelch Defective Neurons Biologists at the University of California, San Diego have identified a new component of the cellular mechanism by which humans and animals automatically check the quality of their nerve cells to assure they’re working properly during development. In a paper published in this week’s issue of the journal Neuron, the scientists report the discovery in the laboratory roundworm C. elegans of a “quality check” system for neurons that uses two proteins to squelch the signals from defective neurons and marks them for either repair or destruction. “To be able to see, talk and walk, nerve cells in our body need to communicate with their right partner cells,” explains Zhiping Wang, the lead author in the team of researchers headed by Yishi Jin, a professor of neurobiology in UC San Diego’s Division of Biological Sciences and a professor of cellular and molecular medicine in its School of Medicine. “The communication is mediated by long fibers emitting from neurons called axons, which transmit electric and chemical signals from one cell to the other, just like cables connecting computers in a local wired network. In developing neurons, the journey of axons to their target cells is guided by a set of signals. These signals are detected by ‘mini-receivers’—proteins called guidance receptors—on axons and translated into ‘proceed,’ ‘stop,’ ‘turn left’ or ‘turn right.’  Thus, the quality of these receivers is very important for the axons to interpret the guiding signals.” Jin, who is also an Investigator of the Howard Hughes Medical Institute, says defective protein products and environmental stress, such as hyperthermia, can sometimes jeopardize the health and development of cells. “This may be one reason why pregnant women are advised by doctors to avoid saunas and hot tubs,” she adds. The scientists discovered the quality check system in roundworms, and presumably other animals including humans, consists of two parts: a protein-cleaning machine containing a protein called EBAX-1, and a well-known protein assembly helper called heat-shock protein 90 known as “hsp90.” “Hsp90 facilitates the assembly of guidance receivers during the production and also fixes flawed products whenever they are detected,” says Andrew Chisholm, a professor of neurobiology and cell and developmental biology, who also helped lead the study. “The EBAX-containing protein-cleaning machine is in charge of destroying any irreparable products so that they don’t hang around and affect the performance of functional receivers. The EBAX-1 protein plays as a defectiveness detector in this machine and a connector to Hsp90. It captures defective products and presents them for either repair or destruction.”  A human neurodevelopmental disorder called “horizontal gaze palsy with progressive scoliosis” is associated with the defective production of one of the protein guidance receivers. This team of researchers showed that the defective human protein can interact with EBAX proteins. The authors hope that by investigating the action of EBAX-1 protein, their findings will provide clues to develop remedies or drugs to retreat human disorders in the future.

Biologists Uncover Details of How We Squelch Defective Neurons

Biologists at the University of California, San Diego have identified a new component of the cellular mechanism by which humans and animals automatically check the quality of their nerve cells to assure they’re working properly during development.

In a paper published in this week’s issue of the journal Neuron, the scientists report the discovery in the laboratory roundworm C. elegans of a “quality check” system for neurons that uses two proteins to squelch the signals from defective neurons and marks them for either repair or destruction.

“To be able to see, talk and walk, nerve cells in our body need to communicate with their right partner cells,” explains Zhiping Wang, the lead author in the team of researchers headed by Yishi Jin, a professor of neurobiology in UC San Diego’s Division of Biological Sciences and a professor of cellular and molecular medicine in its School of Medicine. “The communication is mediated by long fibers emitting from neurons called axons, which transmit electric and chemical signals from one cell to the other, just like cables connecting computers in a local wired network. In developing neurons, the journey of axons to their target cells is guided by a set of signals. These signals are detected by ‘mini-receivers’—proteins called guidance receptors—on axons and translated into ‘proceed,’ ‘stop,’ ‘turn left’ or ‘turn right.’  Thus, the quality of these receivers is very important for the axons to interpret the guiding signals.”

Jin, who is also an Investigator of the Howard Hughes Medical Institute, says defective protein products and environmental stress, such as hyperthermia, can sometimes jeopardize the health and development of cells. “This may be one reason why pregnant women are advised by doctors to avoid saunas and hot tubs,” she adds.

The scientists discovered the quality check system in roundworms, and presumably other animals including humans, consists of two parts: a protein-cleaning machine containing a protein called EBAX-1, and a well-known protein assembly helper called heat-shock protein 90 known as “hsp90.”

“Hsp90 facilitates the assembly of guidance receivers during the production and also fixes flawed products whenever they are detected,” says Andrew Chisholm, a professor of neurobiology and cell and developmental biology, who also helped lead the study. “The EBAX-containing protein-cleaning machine is in charge of destroying any irreparable products so that they don’t hang around and affect the performance of functional receivers. The EBAX-1 protein plays as a defectiveness detector in this machine and a connector to Hsp90. It captures defective products and presents them for either repair or destruction.” 

A human neurodevelopmental disorder called “horizontal gaze palsy with progressive scoliosis” is associated with the defective production of one of the protein guidance receivers. This team of researchers showed that the defective human protein can interact with EBAX proteins. The authors hope that by investigating the action of EBAX-1 protein, their findings will provide clues to develop remedies or drugs to retreat human disorders in the future.

Filed under C. elegans nerve cells EBAX proteins Hsp90 protein neuroscience science

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Robots Could One Day Help Surgeons Remove Hard to Reach Brain Tumors

NIBIB-funded scientists and engineers are teaming up with neurosurgeons to develop technologies that enable less invasive, image-guided removal of hard-to-reach brain tumors. Their technologies combine novel imaging techniques that allow surgeons to see deep within the brain during surgery with robotic systems that enhance the precision of tissue removal.

A robot that worms its way in

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The median survival rate for patients with glioblastomas, or high grade primary brain cancer, is less than two years. One factor contributing to this low rate is the fact that many deep-seated and pervasive tumors are not entirely accessible or even visible when using current neurosurgical tools and imaging techniques.

But several years ago, J. Marc Simard, M.D., a professor of neurosurgery at the University of Maryland School of Medicine in Baltimore (UMB), had an insight that he hoped might address this problem. At the time, he had been watching a TV show in which plastic surgeons were using sterile maggots to remove damaged or dead tissue from a patient.

“Here you had a natural system that recognized bad from good and good from bad,” said Simard. “In other words, the maggots removed all the bad stuff and left all the good stuff alone and they’re really small. I thought, if you had something equivalent to that to remove a brain tumor that would be an absolute home run.”

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Image: Initial prototype for the minimally invasive neurosurgical intracranial robot. Image courtesy of University of Maryland.

And so Simard teamed up with Rao Gullapalli, Ph.D., professor of diagnostic radiology and nuclear medicine also at UMB, as well as Jaydev Desai, Ph.D., professor of mechanical engineering at the University of Maryland, College Park, to develop a small neurosurgical robot that could be used to remove deep-seated brain tumors.

Within four years, the team had designed, constructed, and tested their first prototype, a finger-like device with multiple joints, allowing it to move in many directions. At the tip of the robot is an electrocautery tool, which uses electricity to heat and ultimately destroy tumors, as well as a suction tube for removing debris.

“The idea was to have a device that’s small but that can do all the work a surgeon normally does,” said Simard. “You could place this small robotic device inside a tumor and have it work its way around from within, removing pieces of diseased tissue.”

A key component of the team’s device is its ability to be used while a patient is undergoing MRI. By replacing normal vision with continuously updated MRI, the surgeon is able to visualize deep-seated tumors and monitor the robot’s movement without having to create a large incision in the brain.

In addition to reducing incision size, Simard says the ability to view the brain under continuous MRI also helps surgeons keep track of tumor boundaries throughout an operation. “When we’re operating in a conventional way, we get an MRI on a patient before we do the surgery, and we use landmarks that can either be affixed to the scalp or are part of the skull to know where we are within the patient’s brain. But when the surgeon gets in there and starts to remove the tumor, the tissues shift around so that now the boundaries that were well-established when everything was in place don’t exist anymore, and you’re confronted once again with having to distinguish normal brain from tumor. This is very difficult for a surgeon using direct vision, but with MRI, the ability to discriminate tumor from non-tumor is much more powerful.”

Steve Krosnick, M.D., a program director at NIBIB, says real-time MRI guidance during brain tumor surgery would be a tremendous advantage. “Unlike pre-operative MRI or intermittent MRI, which requires interruption of the surgical procedure, real-time intra-operative MRI offers rapid delineation of normal tissue from tumor while accounting for brain shifts that occur during surgery.”

But designing a neurosurgical device that can be used inside an MRI magnet is no easy task. One of the first issues you have to consider, said Gullapalli, is a surgeon’s access to the brain. “When you scan a person’s brain during an MRI, he’s deep inside the machine’s tunnel. The problem is, how do you get your hands on the brain while the patient’s in the scanner?”

The team’s solution was to give the surgeon robotic control of the device in order to circumvent the need to access the brain directly. In other words, a surgeon can insert the robot into the brain while the patient is outside of the scanner. Then, when the patient moves into the scanner, the surgeon can sit in a different room and –while watching MRI images of the brain on a monitor—move the robot deep inside the brain and direct it to electrocauterize and aspirate the tissue.

Jaydev Desai, the team’s mechanical engineer, says the most challenging aspect of the project has been designing a robot that can be controlled inside the magnetic field of an MRI. While robots are often controlled via electromagnetic motors, this was not an option because, besides being magnetic, these motors create significant image distortion, making it impossible for the surgeon to perform the task. Other potential mechanisms such as hydraulic systems were off the table due to concerns about fluid leakage.

Instead, Desai decided to use shape memory alloy (SMA)—a material that alters its shape in response to changes in temperature—to control the robot’s movement. In the most recent prototype—developed by Desai and his team at the Robotics, Automation, and Medical Systems (RAMS) laboratory at the University of Maryland, College Park—a system of cables, pulleys and SMA springs are used. This cable and pulley system is an improvement from their previous prototype which caused some image distortion.

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Image: The newest prototype for the minimally invasive neurosurgical intracranial robot uses a system of pulleys and springs to move the robot. Source: Jaydev Desai, University of Maryland

With continued support from NIBIB, Desai and colleagues are now working to further reduce image distortion and to test the safety and efficacy of their device in swine as well as in human cadavers. Though it will be several years before their device finds its way into the operating room, Simard is excited by the prospect. “Advancing brain surgery to this level where tiny machines or robots could navigate inside people’s heads while being directed by neurosurgeons with the help of MRI imaging…It’s beyond anything that most people dream of.”

Scoping the brain

On the opposite side of the country, a different group of engineers and neurosurgeons is also working to develop an image-guided, robotically-controlled neurosurgical tool. Lead by Eric Seibel, Ph.D., a professor of mechanical engineering at the University of Washington, the team is attempting to adapt a scanning fiber endoscope—a tool initially developed by Seibel to image inside the narrow bile ducts of the liver—so that it can be used to visualize the brain during surgery.

An endoscope is a thin, tube-like instrument with a video camera attached to its end that can be inserted through a small incision or natural opening in the body to produce real-time video during surgery. Endoscopes are an essential component of minimally invasive surgeries because they allow surgeons to view the inside of the body on a monitor without having to make a large incision.

However, there are many parts of the body such as small vessels and ducts as well as areas deep in the brain that are inaccessible to conventional endoscopes. Although ultrathin endoscopes have recently been developed, Seibel says these smaller scopes come with the price of greatly reduced image resolution.

“Right now, with the current state of the art ultrathin endoscopes, I calculate based on the field of view and their resolution that the person looking at that display would see so little as to be classified in the US as legally blind,” said Seibel.

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Image: Microfabricated optical fiber scanner emitting red laser light, with scan amplitude of 1 mm peak-to-peak. Image courtesy of Eric Seibel, University of Washington

But with support from NIBIB over ten years ago, Seibel began working on a new type of endoscope that could fit into tiny crevices in the body while retaining high image quality. His end product was a new type of endoscope that, despite having the diameter of a toothpick, can provide doctors with microscopic views of the inside of the body.

Seibel retained image quality while significantly reducing the size of his scope by eschewing traditional endoscope models. Instead of a light source and a video camera, Seibel’s scope consists of a single optical fiber—approximately the size of a human hair—located in the middle of the scope. The fiber releases white laser light (a combination of green, red, and blue lasers) when vibrated at a particular frequency. By directing the laser light through a series of lenses in the scope, it can be reflected widely within the body, providing a 100 degree field of view. As the white laser light interacts with tissue, it picks up coloration and scatters it back to a ring of additional optical fibers which transmit this information to a monitor.

“It’s almost like putting your eyes inside the body so you can see with the wide field view of your human vision,” said Seibel.

In collaboration with three neurosurgeons and an electrical engineer, Seibel is now working to secure his novel endoscope to the tip of a robotically controlled micro-dissection neurosurgical tool.

As opposed to larger traditional endoscopes, Seibel say his scanning fiber endoscope is barely noticeable.

“It’ s like a piece of wet spaghetti,” said Seibel. “It’s even smaller then a piece of wet spaghetti in diameter, but it feels like that. So when it is actually at the tip of the surgeon’s tool, the surgeon wouldn’t feel it dragging behind her.”

One advantage of having the endoscope under robotic control is that the brain can be imaged at a higher magnification.

“A surgeon couldn’t hold a microscope steady in her hand while performing surgery, but the robot can,” said Seibel.

Microscopic detail is essential when trying to determine the border between healthy tissue—which if removed could lead to neurological deficits—and cancerous tissue—which if left in the brain could allow a tumor to return.

Krosnick says he’s excited by the combination of high-quality imaging and robotic enabled micro-neurosurgery. “It addresses a critical need, which is to discern tumor margins at high resolution while minimizing disruption to normal structures.”

Seibel believes this discrimination between cancerous and healthy tissue could be enhanced even further by taking advantage of the fact that his scanning endoscope is also able to detect fluorescence. One of the main focuses of his current research is a collaboration with Jim Olson, M.D., Ph.D. at the Fred Hutchinson Cancer Research Center, who is the inventor of a substance called “tumor paint”.

Tumor paint is a fluorescent probe that attaches to cancerous but not healthy cells when injected into the body. Seibel says the ultimate goal would be to give a patient an injection of tumor paint and then use his endoscope to create an image of the fluorescing cancer cells as well as a colored anatomic image of the brain. The two images could then be merged on a screen for the surgeon to view during an operation.“You would be able to see all the structure that a surgeon would see, but you’d also see those molecular pinpoints of light that are cancer cells…and from there the robot can be used to resect, or remove, these small cells of cancer, and it can do it very precisely because you don’t have the shaking of a human holding it.”

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Image: Tumor paint is made of a compound extracted from scorpion venom that can travel through the blood brain barrier and bind specifically to tumor cells. Source: iStockphoto

Seibel concluded by saying, “There’s a real niche for video-quality, high-resolution, multi-modal imaging that’s in a tiny package so that it can be put on microscopic tools for minimally invasive medicine. I really feel it’s an enabling technology that could move the whole field forward.”

Krosnick is enthusiastic about the progress the two teams have made so far. “These are innovative technologies that, if effective, could significantly add to the brain surgery armamentarium. They’re still early in development, but I think both show considerable promise.” He concluded by emphasizing that, like all new devices, these technologies would need to undergo a series of clinical trials to ensure that they are safe and effective before making their way into an operating room.

(Source: nibib.nih.gov)

Filed under brain tumors robotics glioblastoma neurosurgery neuroscience science

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TB and Parkinson’s Disease Linked By Unique Protein

UCSF Researchers Seek Way to Boost Parkin to Fight Both Diseases

A protein at the center of Parkinson’s disease research now also has been found to play a key role in causing the destruction of bacteria that cause tuberculosis, according to scientists led by UC San Francisco microbiologist and tuberculosis expert Jeffery Cox, PhD.

The protein, named Parkin, already is the focus of intense investigation in Parkinson’s disease, in which its malfunction is associated with a loss of nerve cells. Cox and colleagues now report that Parkin also acts on tuberculosis, triggering destruction of the bacteria by immune cells known as macrophages. Results appear online today (September 4, 2013) in the journal Nature.

The finding suggests that disease-fighting strategies already under investigation in pre-clinical studies for Parkinson’s disease might also prove useful in fighting tuberculosis, according to Cox. Cox is investigating ways to ramp up Parkin activity in mice infected with tuberculosis using a strategy similar to one being explored by his UCSF colleague Kevan Shokat, PhD, as a way to ward off neurodegeneration in Parkinson’s disease.

Globally, tuberculosis kills 1.4 million people each year, spreading from person to person through the air. Parkinson’s disease, the most common neurodegenerative movement disorder, also affects millions of mostly elderly people worldwide.

Cox homed in on the enzyme Parkin as a common element in Parkinson’s and tuberculosis through his investigations of how macrophages engulf and destroy bacteria. In a sense the macrophage — which translates from Greek as “big eater” — gobbles down foreign bacteria, through a process scientists call xenophagy.

Mycobacterium tuberculosis, along with a few other types of bacteria, including Salmonella and leprosy-causing Mycobacterium leprae, are different from other kinds of bacteria in that, like viruses, they need to get inside cells to mount a successful infection.

The battle between macrophage and mycobacterium can be especially intense. M. tuberculosis invades the macrophage, but then becomes engulfed in a sac within the macrophage that is pinched off from the cell’s outer membrane. The bacteria often escape this intracellular jail by secreting a protein that degrades the sac, only to be targeted yet again by molecular chains made from a protein called ubiquitin. Previously, Cox discovered molecules that escort these chained mycobacteria to more secure confinement within compartments inside cells called lysosomes, where the bacteria are destroyed.

The cells of non-bacterial organisms ranging in complexity from baker’s yeast to humans also use a similar mechanism — called autophagy — to dispose of their own unneeded molecules or worn out cellular components. Among the most abundant and crucial of these components are the cell’s mitochondria, metabolic powerhouses that convert food molecules into a source of energy that the cell can readily use to carry out its everyday housekeeping chores, as well as its more specialized functions.

Like other cellular components, mitochondria can wear out and malfunction, and often require replacement. The process through which mitochondria are disposed of, called mitophagy, depends on Parkin.

Cox became curious about the enzyme when he learned that specific, naturally occurring variations in the Parkin gene, called polymorphisms, are associated with increased susceptibility to tuberculosis infection.

“Because of the commonalities between mitophagy and the xenophagy of intracellular mycobacteria, as well as the links between Parkin gene polymorphisms and increased susceptibility to bacterial infection in humans, we speculated that Parkin may also be recruited to M. tuberculosis and target it for xenophagy,” Cox said.

In both mouse and human macrophages infected with M. tuberculosis in the lab, Parkin played a key role in fighting the bacteria, Cox and colleagues found. In addition, genetically engineered mice lacking Parkin died when infected with M. tuberculosis, while mice with normal Parkin survived infection.

The involvement of Parkin in targeting both damaged mitochondria and infectious mycobacteria arose long ago in evolution, Cox argues. As part of the Nature study, the research team found that Parkin-deficient mice and flies – creatures quite distant from humans in evolutionary time – also are more sensitive than normal mice and flies to intracellular bacterial infections.

Looking back more than 1 billion years, Cox noted that mitochondria evolved from bacteria that were taken up by cells in a symbiotic relationship.

In the same way that the immune system recognizes infectious bacteria as foreign, Cox said, “The evolutionary origin of mitochondria from bacteria suggests that perhaps mitochondrial dysfunction triggers the recognition of a mitochondrian as non-self.”

Having now demonstrated the importance of Parkin in fighting mycobacterial infection, Cox has begun working with Shokat to find a way to boost Parkin activity against cell-invading bacteria. “We are exploring the possibility that small-molecule drugs could be developed to activate Parkin to better fight tuberculosis infection,” Cox said.

(Source: newswise.com)

Filed under parkinson's disease tuberculosis parkin protein macrophages lysosomes medicine neuroscience science

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