Neuroscience

Articles and news from the latest research reports.

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Low Omega-3 could explain why some children struggle with reading

An Oxford University study has shown that a representative sample of UK schoolchildren aged seven to nine years had low levels of key Omega-3 fatty acids in their blood. Furthermore, the study found that children’s blood levels of the long-chain Omega-3 DHA (the form found in most abundance in the brain) ‘significantly predicted’ how well they were able to concentrate and learn. Oxford University researchers explained the findings, recently published in the journal PLOS ONE, at a conference in London on 4 September.

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The study was presented at the conference by co-authors Dr Alex Richardson and Professor Paul Montgomery from Oxford University’s Centre for Evidence-Based Intervention in the Department of Social Policy and Intervention. It is one of the first to evaluate blood Omega-3 levels in UK schoolchildren. The long-chain Omega-3 fats (EPA and DHA) found in fish, seafood and some algae, are essential for the brain’s structure and function as well as for maintaining a healthy heart and immune system. Parents also reported on their child’s diet, revealing to the researchers that almost nine out of ten children in the sample ate fish less than twice a week, and nearly one in ten never ate fish at all. The government’s guidelines for a healthy diet recommend at least two portions of fish a week. This is because like vitamins, omega-3 fats have to come from our diets – and although humans can in theory make some EPA and DHA from shorter-chain omega-3 (found in some vegetable oils), research has shown this conversion is not reliable, particularly for DHA, say the researchers.

Blood samples were taken from 493 schoolchildren, aged between seven and nine years, from 74 mainstream schools in Oxfordshire. All of the children were thought to have below-average reading skills, based on national assessments at the age of seven or their teachers’ current judgements. Analyses of their blood samples showed that, on average, just under two per cent of the children’s total blood fatty acids were Omega-3 DHA (Docosahexaenoic acid) and 0.5 per cent were Omega-3 EPA (Eicosapentaenoic acid), with a total of 2.45 per cent for these long-chain Omega-3 combined. This is below the minimum of 4 per cent recommended by leading scientists to maintain cardiovascular health in adults, with 8-12 per cent regarded as optimal for a healthy heart, the researchers reported.

Co-author Professor Paul Montgomery said: ‘From a sample of nearly 500 schoolchildren, we found that levels of Omega-3 fatty acids in the blood significantly predicted a child’s behaviour and ability to learn. Higher levels of Omega-3 in the blood, and DHA in particular, were associated with better reading and memory, as well as with fewer behaviour problems as rated by parents and teachers. These results are particularly noteworthy given that we had a restricted range of scores, especially with respect to blood DHA but also for reading ability, as around two-thirds of these children were still reading below their age-level when we assessed them. Although further research is needed, we think it is likely that these findings could be applied generally to schoolchildren throughout the UK.’

Co-author Dr Alex Richardson added: ‘The longer term health implications of such low blood Omega-3 levels in children obviously can’t be known. But this study suggests that many, if not most UK children, probably aren’t getting enough of the long-chain Omega-3 we all need for a healthy brain, heart and immune system. That gives serious cause for concern  because we found that lower blood DHA was linked with poorer behaviour and learning in these children.
‘Most of the children we studied had blood levels of long-chain Omega-3 that in adults would indicate a high risk of heart disease. This was consistent with their parents’ reports that most of them failed to meet current dietary guidelines for fish and seafood intake. Similarly, few took supplements or foods fortified with these Omega-3.’

The current findings build on earlier work by the same researchers, showing that dietary supplementation with Omega-3 DHA improved both reading progress and behaviour in children from the general school population who were behind on their reading. Their previous research has already shown benefits of supplementation with long-chain omega-3 (EPA+DHA) for children with ADHD, Dyspraxia, Dyslexia, and related conditions. The DHA Oxford Learning and Behaviour (DOLAB) Studies have now extended these findings to children from the general school population.

‘Technical advances in recent years have enabled the measurement of individual Omega-3 and other fatty acids from fingerstick blood samples. ‘These new techniques have been revolutionary – because in the past, blood samples from a vein were needed for assessing fatty acids, and that has seriously restricted research into the blood Omega-3 status of healthy UK children until now,’ said Dr Richardson.

(Source: ox.ac.uk)

Filed under omega-3 fatty acids school children reading neuroscience science

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Researchers Pinpoint Molecular Path that Makes Antidepressants Act Quicker in Mouse Model

Understanding alternate pathways for how mental meds work could lead to faster-acting drug targets

The reasons behind why it often takes people several weeks to feel the effect of newly prescribed antidepressants remains somewhat of a mystery – and likely, a frustration to both patients and physicians.

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(Image: Mouse hippocampus expressing the Cre- virus. Credit: Julie Blendy, PhD; Brigitta Gunderson, PhD; Perelman School of Medicine, University of Pennsylvania)

Julie Blendy, PhD, professor of Pharmacology, at the Perelman School of Medicine, University of Pennsylvania; Brigitta Gunderson, PhD, a former postdoctoral fellow in the Blendy lab, and colleagues, have been working to find out why and if there is anything that can be done to shorten the time in which antidepressants kick in.

“Our goal is to find ways for antidepressants to work faster,” says Blendy.  

The proteins CREB and CREM are both transcription factors, which bind to specific DNA sequences to control the “reading” of genetic information from DNA to messenger RNA (mRNA). Both CREB and CREM bind to the same 8-base-pair DNA sequence in the cell nucleus. But, the comparative influence of CREM versus CREB on the action of antidepressants is a “big unknown,” says Blendy.

CREB, and CREM to some degree, has been implicated in the pathophysiology of depression, as well as in the efficacy of antidepressants. However, whenever CREB is deleted, CREM is upregulated, further complicating the story.

Therefore, how an antidepressant works on the biochemistry and behavior in a mouse in which the CREB protein is deleted only in the hippocampus versus a wild type mouse in which CREM is overexpressed let the researchers tease out the relative influence of CREB and CREM on the pharmacology of an antidepressant. They saw the same results in each type of mouse line – increased nerve-cell generation in the hippocampus and a quicker response to the antidepressant. Their findings appear in the Journal of Neuroscience.

“This is the first demonstration of CREM within the brain playing a role in behavior, and specifically in behavioral outcomes, following antidepressant treatment,” says Blendy.

A Flood of Neurotransmitters

Antidepressants like SSRIs, NRIs, and older tricyclic drugs work by causing an immediate flood of neurotransmitters like serotonin, norepinephrine, and in some cases dopamine, into the synaptic space. However, it can take three to four weeks for patients to feel changes in mental state. Long-term behavioral effects of the drugs may take longer to manifest themselves, because of the need to activate CREB downstream targets such as BDNF and trkB, or as of yet unidentified targets, which could also be developed as new antidepressant drug targets.

The Penn team compared the behavior of the control, wild-type mice to the CREB mutant mice using a test in which the mouse is trained to eat a treat – Reese’s Pieces, to be exact – in the comfort of their home cage. The treat-loving mice are then placed in a new cage to make them anxious. They are given the treat again, and the time it takes for the mouse to approach the treat is recorded.

Animals that receive no drug treatment take a long time to venture out into the anxious environment to retrieve the treat, however, if given an antidepressant drug for at least three weeks, the time it takes a mouse to get the treat decreases significantly, from about 400 seconds to 100 seconds. In mice in which CREB is deleted or in mice in which CREM is upregulated, this reduction happens in one to two days versus the three weeks seen in wild-type mice.

The accelerated time to approach the treat in mice on the medication was accompanied by an increase in new nerve growth in the hippocampus.

“Our results suggest that activation of CREM may provide a means to accelerate the therapeutic efficacy of current antidepressant treatment,” says Blendy. Upregulation of CREM observed after CREB deletion, appears to functionally compensate for CREB loss at a behavioral level and leads to maintained or increased expression of some CREB target genes. The researchers’ next step is to identify any unique CREM target genes in brain areas such as the hippocampus, which may lead to the development of faster-acting antidepressants.

(Source: uphs.upenn.edu)

Filed under antidepressants hippocampus nerve cells dopamine norepinephrine serotonin SSRIs neuroscience science

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Insulin plays a role in mediating worms’ perceptions and behaviors Using salt-sniffing roundworms, Salk scientists help explain how the nervous system processes sensory information In the past few years, as imaging tools and techniques have improved, scientists have been working tirelessly to build a detailed map of neural connections in the human brain—with the ultimate hope of understanding how the mind works. But determining how cells in the brain are physically connected is only the first clue for decoding our perceptions and behaviors. We also need to know the precise routes that information takes in the brain in a given context. Now, publishing their results September 8, 2013, in the journal Nature Neuroscience, researchers at the Salk Institute for Biological Studies have shown a striking example of the flexibility in neural circuitry and its influence on behaviors in worms, depending on the animals’ environment. The roundworm Caenorhabditis elegans has exactly 302 neurons—far less than the estimated 100 billion neurons a person has—and we already know how each of them is connected. That, in addition to how easily the tiny creature’s cells can be manipulated, allows researchers to ask what sort of information passes through the circuits—in molecular-and circuit-level detail—and what are the behavioral consequences of this information flow. Even with a comprehensive map of the worm’s neuronal connections in hand, however, scientists still don’t know how the animal can interact with its environment in thousands of different ways. That’s one big question that Sreekanth Chalasani, an assistant professor in Salk’s Molecular Neurobiology Laboratory and Sarah Leinwand, a doctoral student at the University of California, San Diego, sought to answer. In C. elegans, thanks to studies performed more than 20 years ago, many sensory neurons were identified to have distinct roles such as sensing temperature, pheromones, salt and odors. To know what these cells did, scientists had zapped them one-by-one with a laser and measured the worms’ behaviors. These studies implicated one neuron in the detection of increased salt in the worm’s surroundings. In the new study, rather than ablating individual sensory neurons, Leinwand and Chalasani imaged worms that expressed genetically encoded calcium indicators in their neurons, which caused the cells to light up when active. Surprisingly, after exposure to an attractive but high concentration of salt, the worms’ olfactory sensory neuron lit up. "We were extremely surprised to see that with these new tools, these new calcium sensors, we could discover that there was more than one type of neuron involved in processing sensory cues that people had thought were only sensed by single neurons," says Leinwand. Using additional genetic manipulations and behavioral assays, the researchers showed that the olfactory neuron—while still important for sensing odorants—was crucial for the worm’s movement toward salt within a certain concentration range. Unexpectedly, this neuron’s response to salt also required the previously identified salt-sensing neuron. In fact, the olfactory neuron was not directly sensing salt but instead was being activated by the salt sensory neuron, they found. What information was the salt-sensing neuron sending to the olfactory neuron? Neurons communicate with each other by sending chemical and electrical signals through close contacts with their neighbors. By testing worms whose signaling molecules had been genetically knocked out, Chalasani and Leinwand could see which were playing a role in transmission when the worm was stimulated by higher salt. From these experiments, they saw that a neuropeptide, a small protein present in neurons, was being released by the salt-sensing neuron to shape the animal’s behavior. Identifying the neuropeptide (or neuropeptides) responsible for the context-dependent signaling was the most challenging part of the study, because the worm has 115 genes that code for some 250 neuropeptides, Chalasani says. Luckily, there are only four different molecular machines that process all of these peptides; by using genetic knockouts of each of the four, Leinwand and Chalasani were quickly able to narrow the list down to about 40 genes which coded for insulin neuropeptides. One by one, the team tracked olfactory neuron responses to high salt in worms missing each gene, finding that worms lacking the gene for an insulin neuropeptide known as INS-6 did not respond to increases in salt. Putting this peptide back restored the animal’s normal responses to high salt. "It was rewarding to see that, while there might be more than one peptide signal, the contributions from INS-6 are certainly significant," Leinwand says. She and Chalasani also found the specific receptor on the receiving end of the olfactory neurons. That insulin was the main signaling molecule recruiting the olfactory neuron into a salt-sensing circuit was a big surprise. "Traditionally, neuropeptides have been thought to modulate neuronal function over many seconds to many minutes," Chalasani says. "But in this particular instance, it looks like the insulin is acting in less than a second to transfer information from the salt-sensing neuron to the neuron which normally responds to odor." Similar neuropeptide communication may also create flexible neural circuits that mediate the diverse behaviors that other animals and people perform in their environments. Insulin has many roles in people—it has been implicated in aging and metabolism, for example—but so far it has only been shown to function on a slower, minute time-scale. Chalasani and Leinwand plan to investigate whether there are other fast neural circuit switches in worms—and if so, whether those switches act through neuropeptide signaling or some other mechanism. They’re also interested in how the circuit switch changes as the animal ages. “You would expect that as the animal is aging, some of this communication becomes less efficient,” Chalasani says.

Insulin plays a role in mediating worms’ perceptions and behaviors

Using salt-sniffing roundworms, Salk scientists help explain how the nervous system processes sensory information

In the past few years, as imaging tools and techniques have improved, scientists have been working tirelessly to build a detailed map of neural connections in the human brain—with the ultimate hope of understanding how the mind works.

But determining how cells in the brain are physically connected is only the first clue for decoding our perceptions and behaviors. We also need to know the precise routes that information takes in the brain in a given context. Now, publishing their results September 8, 2013, in the journal Nature Neuroscience, researchers at the Salk Institute for Biological Studies have shown a striking example of the flexibility in neural circuitry and its influence on behaviors in worms, depending on the animals’ environment.

The roundworm Caenorhabditis elegans has exactly 302 neurons—far less than the estimated 100 billion neurons a person has—and we already know how each of them is connected. That, in addition to how easily the tiny creature’s cells can be manipulated, allows researchers to ask what sort of information passes through the circuits—in molecular-and circuit-level detail—and what are the behavioral consequences of this information flow.

Even with a comprehensive map of the worm’s neuronal connections in hand, however, scientists still don’t know how the animal can interact with its environment in thousands of different ways. That’s one big question that Sreekanth Chalasani, an assistant professor in Salk’s Molecular Neurobiology Laboratory and Sarah Leinwand, a doctoral student at the University of California, San Diego, sought to answer.

In C. elegans, thanks to studies performed more than 20 years ago, many sensory neurons were identified to have distinct roles such as sensing temperature, pheromones, salt and odors. To know what these cells did, scientists had zapped them one-by-one with a laser and measured the worms’ behaviors. These studies implicated one neuron in the detection of increased salt in the worm’s surroundings.

In the new study, rather than ablating individual sensory neurons, Leinwand and Chalasani imaged worms that expressed genetically encoded calcium indicators in their neurons, which caused the cells to light up when active. Surprisingly, after exposure to an attractive but high concentration of salt, the worms’ olfactory sensory neuron lit up.

"We were extremely surprised to see that with these new tools, these new calcium sensors, we could discover that there was more than one type of neuron involved in processing sensory cues that people had thought were only sensed by single neurons," says Leinwand.

Using additional genetic manipulations and behavioral assays, the researchers showed that the olfactory neuron—while still important for sensing odorants—was crucial for the worm’s movement toward salt within a certain concentration range. Unexpectedly, this neuron’s response to salt also required the previously identified salt-sensing neuron. In fact, the olfactory neuron was not directly sensing salt but instead was being activated by the salt sensory neuron, they found.

What information was the salt-sensing neuron sending to the olfactory neuron? Neurons communicate with each other by sending chemical and electrical signals through close contacts with their neighbors. By testing worms whose signaling molecules had been genetically knocked out, Chalasani and Leinwand could see which were playing a role in transmission when the worm was stimulated by higher salt. From these experiments, they saw that a neuropeptide, a small protein present in neurons, was being released by the salt-sensing neuron to shape the animal’s behavior.

Identifying the neuropeptide (or neuropeptides) responsible for the context-dependent signaling was the most challenging part of the study, because the worm has 115 genes that code for some 250 neuropeptides, Chalasani says. Luckily, there are only four different molecular machines that process all of these peptides; by using genetic knockouts of each of the four, Leinwand and Chalasani were quickly able to narrow the list down to about 40 genes which coded for insulin neuropeptides.

One by one, the team tracked olfactory neuron responses to high salt in worms missing each gene, finding that worms lacking the gene for an insulin neuropeptide known as INS-6 did not respond to increases in salt. Putting this peptide back restored the animal’s normal responses to high salt.

"It was rewarding to see that, while there might be more than one peptide signal, the contributions from INS-6 are certainly significant," Leinwand says. She and Chalasani also found the specific receptor on the receiving end of the olfactory neurons.

That insulin was the main signaling molecule recruiting the olfactory neuron into a salt-sensing circuit was a big surprise.

"Traditionally, neuropeptides have been thought to modulate neuronal function over many seconds to many minutes," Chalasani says. "But in this particular instance, it looks like the insulin is acting in less than a second to transfer information from the salt-sensing neuron to the neuron which normally responds to odor."

Similar neuropeptide communication may also create flexible neural circuits that mediate the diverse behaviors that other animals and people perform in their environments. Insulin has many roles in people—it has been implicated in aging and metabolism, for example—but so far it has only been shown to function on a slower, minute time-scale.

Chalasani and Leinwand plan to investigate whether there are other fast neural circuit switches in worms—and if so, whether those switches act through neuropeptide signaling or some other mechanism. They’re also interested in how the circuit switch changes as the animal ages. “You would expect that as the animal is aging, some of this communication becomes less efficient,” Chalasani says.

Filed under sensory neurons neural circuitry C. elegans calcium sensors insulin neuropeptides neuroscience science

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Making memories Modifying the activity of neuronal networks that encode spatial memories leads to the formation of an incorrect fear memory in mice The formation and retrieval of memories allows all kinds of organisms, including humans, to learn and thrive in their environment. Yet our memories are not always accurate, and mistaken remembrances can have important consequences, such as in the justice system and in our navigation of the world. Susumu Tonegawa, Steve Ramirez, Xu Liu and colleagues at the RIKEN-MIT Center for Neural Circuit Genetics, have gained insight into the creation of mistaken memories by using light activation of neurons to generate an incorrect fear memory in mice. The researchers allowed mice to explore a novel location and used genetic techniques to label neurons in the hippocampus—a part of the brain linked to spatial memory—that were activated in the process with a special channel called channelrhodopsin-2. The cells that expressed this channel could then be artificially activated by light. In this way, the researchers were able to reactivate neurons that fired in that particular location, even if the mice were no longer there. They then moved the mice to another location where they were exposed to foot shocks, causing the mice to exhibit immobility, a fear behavior. At the same time, the researchers used light to activate the channelrhodopsin-2-expressing neurons that had fired in the first location. When Tonegawa and his colleagues moved the animals to a third location, they did not show fear behavior. Yet when the mice went back to the first location, where they had never experienced a foot shock, the mice now exhibited prominent freezing behavior. The researchers had generated a ‘false memory’ in the mice of foot shocks in a location in which they had never been exposed to them. The researchers showed that light reactivation of neuronal networks in the central area of the hippocampus, called the dentate gyrus, could create false memories, while reactivation of the outer ‘CA1’ area of the hippocampus could not. Tonegawa and his colleagues suggest that this is because mouse exploration of different locations leads to activation of more overlapping neuronal networks in the CA1 than in the dentate gyrus. “This may reflect the fundamental differences of how memories are encoded in these two regions,” explains Liu. The findings provide insight into how the brain encodes and processes memories and could one day lead to treatments for post-traumatic stress disorder. “Our work may also have implications for situations where patients mix reality with their own imaginations, such as in schizophrenia,” says Liu.

Making memories

Modifying the activity of neuronal networks that encode spatial memories leads to the formation of an incorrect fear memory in mice

The formation and retrieval of memories allows all kinds of organisms, including humans, to learn and thrive in their environment. Yet our memories are not always accurate, and mistaken remembrances can have important consequences, such as in the justice system and in our navigation of the world. Susumu Tonegawa, Steve Ramirez, Xu Liu and colleagues at the RIKEN-MIT Center for Neural Circuit Genetics, have gained insight into the creation of mistaken memories by using light activation of neurons to generate an incorrect fear memory in mice.

The researchers allowed mice to explore a novel location and used genetic techniques to label neurons in the hippocampus—a part of the brain linked to spatial memory—that were activated in the process with a special channel called channelrhodopsin-2. The cells that expressed this channel could then be artificially activated by light. In this way, the researchers were able to reactivate neurons that fired in that particular location, even if the mice were no longer there.

They then moved the mice to another location where they were exposed to foot shocks, causing the mice to exhibit immobility, a fear behavior. At the same time, the researchers used light to activate the channelrhodopsin-2-expressing neurons that had fired in the first location.

When Tonegawa and his colleagues moved the animals to a third location, they did not show fear behavior. Yet when the mice went back to the first location, where they had never experienced a foot shock, the mice now exhibited prominent freezing behavior. The researchers had generated a ‘false memory’ in the mice of foot shocks in a location in which they had never been exposed to them.

The researchers showed that light reactivation of neuronal networks in the central area of the hippocampus, called the dentate gyrus, could create false memories, while reactivation of the outer ‘CA1’ area of the hippocampus could not. Tonegawa and his colleagues suggest that this is because mouse exploration of different locations leads to activation of more overlapping neuronal networks in the CA1 than in the dentate gyrus. “This may reflect the fundamental differences of how memories are encoded in these two regions,” explains Liu.

The findings provide insight into how the brain encodes and processes memories and could one day lead to treatments for post-traumatic stress disorder. “Our work may also have implications for situations where patients mix reality with their own imaginations, such as in schizophrenia,” says Liu.

Filed under memory formation hippocampus false memory dentate gyrus PTSD neuroscience science

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Researchers Find Surprising Role of Critical Brain Protein

If the violins were taken away from the musicians performing Beethoven’s 9th symphony, the resulting composition would sound very different. If the violins were left on stage but the violinists were removed, the same mutant version of the symphony would be heard.

But what if it ended up sounding like “Hey Jude” instead?

This sort of surprise is what scientists from the Virginia Tech Carilion Research Institute had during what they assumed to be a routine experiment in neurodevelopment. Previous studies had shown that the glycoprotein Reelin is crucial to developing healthy neural networks. Logically, taking away the two receptors that Reelin is known to act on early in the brain’s development should create the same malformations as taking away Reelin itself.

It didn’t.

“We conducted the experiment thinking we’d see the same defects for both cases – Reelin deficiency and its receptors’ deletion – but we didn’t,” said Michael Fox, an associate professor at the research institute and the lead author of the study. “If you take away the receptors instead of the targeting molecule, you get an entirely separate set of abnormalities. The results raise the question of the identity of other molecules with which Reelin and the two receptors are interacting.”

The study, first published online in June in Neural Development, could prove useful for the development of therapies and diagnostics to combat brain disease.

In the early stages of neural development, neurons grow from the retina to a small portion of the brain called the thalamus. All sensory information coming into the brain gets routed through this region, before being transmitted to the cerebral cortex for further processing. Because these retinal neurons carry specific types of information, they must connect to specific places in the thalamus, which Reelin helps them find.

In the experiment, the scientists bred mice lacking both Reelin receptors known to be critical for neurons to navigate their targets during development. The scientists expected the neurons in the mutants to become lost and unable to find their targets, which is what happens in Reelin-deficient mice. Instead, the neurons were able to locate their targets, but those targets had wandered off.

While these results were surprising, they weren’t the most interesting of the experiment. Although most neurons look the same to people without advanced training in neuroscience, many different types are intermixed in distinct regions with strict borders. How these borders are formed, however, is still an open question.

“Many of us have questioned how you can have such a crisp boundary between two regions of the brain,” said Jianmin Su, a research assistant professor at the research institute and first author of the study. “I always thought it was a large number of cells creating some kind of cue or environment, but that isn’t what this experiment indicates.”

In the mice without the Reelin receptors, neurons from one part of the thalamus migrated to an area where they weren’t supposed to be. Even though only a handful of neurons were misplaced, they did not mingle with their new neighbors. They stayed separate.

“The result is a baffling curiosity that nobody in the lab expected – just how distinct these little regions can be,” Fox said. “How do just a few cells create such a barrier? How many cells does it take? Maybe these little islands can teach us something about how you create boundaries between larger regions of functionally similar cells.”

This experiment isn’t the only example Fox has had recently of neurons invading regions in which they weren’t supposed to be. In a second experiment, researchers examined how neurons from the cortex connect to the thalamus during the initial stages of development.

And neurons seem to be polite.

The results showed that neurons from the cortex grow to the edge of the part of the thalamus dedicated to visual signals, called the dorsal lateral geniculate nucleus, but then stop. In fact, they stay on standby for nearly two weeks before making their way into the region. It seems as though they’re waiting for the retinal neurons to make their connections before beginning to make their own. If researchers surgically removed the eyes or genetically removed the retinal cells connecting the eyes to the thalamus, neurons from the cortex invaded more than a week earlier than they were supposed to.

“It turns out that the cortical neurons are waiting for the retinal axons to mature and find the most appropriate spots to connect before they’re allowed to come in,” said Fox. “There’s some form of instructional role that retinal axons play in the timing of the cortical axons entering.”

(Source: newswise.com)

Filed under brain development reelin retinal neurons intergeniculate nucleus cortical neurons neuroscience science

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Alzheimer’s patients show striking individual differences in molecular basis of disease

Alzheimer’s disease is thought to be caused by the buildup of abnormal, thread-like protein deposits in the brain, but little is known about the molecular structures of these so-called beta-amyloid fibrils. A study published by Cell Press September 12th in the journal Cell has revealed that distinct molecular structures of beta-amyloid fibrils may predominate in the brains of Alzheimer’s patients with different clinical histories and degrees of brain damage. The findings pave the way for new patient-specific strategies to improve diagnosis and treatment of this common and debilitating disease.

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"This work represents the first detailed characterization of the molecular structures of beta-amyloid fibrils that develop in the brains of patients with Alzheimer’s disease," says senior study author Robert Tycko of the National Institutes of Health. "This detailed structural model may be used to guide the development of chemical compounds that bind to these fibrils with high specificity for purposes of diagnostic imaging, as well as compounds that inhibit fibril formation for purposes of prevention or therapy."

Tycko and his team had previously noticed that beta-amyloid fibrils grown in a dish have different molecular structures, depending on the specific growth conditions. Based on this observation, they suspected that fibrils found in the brains of patients with Alzheimer’s disease are also variable and that these structural variations might relate to each patient’s clinical history. But it has not been possible to directly study the structures of fibrils found in patients because of their low abundance in the brain.

To overcome this hurdle, Tycko and his collaborators developed a new experimental protocol. They extracted beta-amyloid fibril fragments from the brain tissue of two patients with different clinical histories and degrees of brain damage and then used these fragments to grow a large quantity of fibrils in a dish. They found that a single fibril structure prevailed in the brain tissue of each patient, but the molecular structures were different between the two patients.

"This may mean that fibrils in a given patient appear first at a single site in the brain, then spread to other locations while retaining the identical molecular structure," Tycko says. "Our study also shows that certain fibril structures may be more likely than others to cause Alzheimer’s disease, highlighting the importance of developing imaging agents that target specific fibril structures to improve the reliability and specificity of diagnosis."

(Source: eurekalert.org)

Filed under alzheimer's disease beta-amyloid fibrils brain damage brain tissue neuroscience science

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Scientists Pinpoint Proteins Vital to Long-Term Memory

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found a group of proteins essential to the formation of long-term memories.

The study, published online ahead of print on September 12, 2013 by the journal Cell Reports, focuses on a family of proteins called Wnts. These proteins send signals from the outside to the inside of a cell, inducing a cellular response crucial for many aspects of embryonic development, including stem cell differentiation, as well as for normal functioning of the adult brain.

“By removing the function of three proteins in the Wnt signaling pathway, we produced a deficit in long-term but not short-term memory,” said Ron Davis, chair of the TSRI Department of Neuroscience. “The pathway is clearly part of the conversion of short-term memory to the long-term stable form, which occurs through changes in gene expression.”

The findings stem from experiments probing the role of Wnt signaling components in olfactory memory formation in Drosophila, the common fruit fly—a widely used doppelgänger for human memory studies. In the new study, the scientists inactivated the expression of several Wnt signaling proteins in the mushroom bodies of adult flies—part of the fly brain that plays a role in learning and memory.

The resulting memory disruption, Davis said, suggests that Wnt signaling participates actively in the formation of long-term memory, rather than having some general, non-specific effect on behavior.

“What is interesting is that the molecular mechanisms of adult memory use the same processes that guide the early development of the organism, except that they are repurposed for memory formation,” he said. “One difference, however, is that during early development the signals are intrinsic, while in adults they require an outside stimulus to create a memory.”

(Source: scripps.edu)

Filed under memory formation long-term memory learning Wnts proteins neuroscience science

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Dreaming is still possible even when the mind is blank

Isabelle Arnulf and colleagues from the Sleep Disorders Unit at the Université Pierre et Marie Curie (UPMC) have outlined case studies of patients with Auto-Activation Deficit who reported dreams when awakened from REM sleep – even when they demonstrated a mental blank during the daytime. This paper proves that even patients with Auto-Activation Disorder have the ability to dream and that it is the “bottom-up” process that causes the dream state.

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In a new paper for the neurology journal Brain, Arnulf et al compare the dream states of patients with Auto-Activation Deficit (AAD) with those of healthy, control patients. AAD is caused by bilateral damage to the basal ganglia and it is a neuro-physical syndrome characterized by a striking apathy, a lack of spontaneous activation of thought, and a loss of self-driven behaviour. AAD patients must be stimulated by their care-givers in order to take part in everyday tasks like standing up, eating, or drinking. If you were to ask an AAD patient: “what are you thinking?” they would report that they have no thoughts.

During sleep, the brain is operating on an exclusively internal basis. In REM sleep, the higher cortex areas are internally stimulated by the brainstem. When awakened, most normal subjects will remember some dreams that were associated with their previous sleep state, especially in REM sleep. Would the self-stimulation of the cortex by the brainstem be sufficient to stimulate spontaneous dreams during sleep in AAD patients?

Discovering the answer to this question would go some way to proving either the top-down or bottom-up theories of dreaming. The top-down theory stipulates that dreaming begins in higher cortex memory structures and then proceeds backwards as imagination develops during wakefulness. The bottom-up theory posits that the brainstem structures which elicit rapid eye movements and cortex activation during REM sleep result in the emotional, visual, sensory, and auditory elements of dreaming.

Thirteen patients with AAD agreed to participate in the study and record their dreams in dream diaries during the week leading up to the evaluation. These patients were compared with thirteen non-medicated, healthy control subjects. Video and sleep monitoring were performed on all twenty six participants for two consecutive nights. The first night evaluated the patient’s sleep duration, structure, and architecture of their dreams. During the second night of sleep evaluation, the researchers woke the subjects up as they entered the second non-REM sleep cycle, and again after 10 min of established REM sleep during the following sleep cycle, and asked them what they were dreaming before being woken up. The dream reports were then independently analysed and scored according to; complexity of dream, bizarreness, and elaboration.

Four of the thirteen patients with AAD reported dreaming when awakened from REM sleep, even though they demonstrated a mental blank during the daytime. This is compared to 12 out of 13 of the control patients. However, the four AAD patients’ dreams were devoid of any complex, bizarre, or emotional elements. The presence of simple yet spontaneous dreams in REM sleep, despite the absence of thoughts during wakefulness in AAD patients, supports the notion that simple dream imagery is generated by brainstem stimulation and sent to the sensory cortex. The lack of complexity in the dreams of the four AAD patients, as opposed to the complexity of the control patients’ dreams, demonstrates that the full dreaming process require these sensations to be interpreted by a higher-order cortical area.

Therefore, this study shows for the first time that it is the bottom-up process that causes the dream state.

Yet, despite the simplicity of the dreams, Isabelle Arnulf commented that the banal tasks that the AAD patients dreamt about were fascinating. For instance, Patient 10 dreamt of shaving – an activity he never initiated during the daytime without motivation from his caregivers, and an activity he could not do by himself due to severe hand dystonia. Similarly, Patient 5 dreamt about writing even though he would never write in the daytime without being invited by his caregivers to do so.

Interestingly, there were no real differences in the sleep measures between the AAD patients and the control patients apart from 46% of the AAD patients had a complete absence of sleep spindles (a burst of oscillatory brain activity visible on an EEG that occurs during stage 2 sleep). The striking absence of sleep spindles in localized lesions in the basal ganglia of these 6 AAD patients highlights the role of the pallidum and striatum in spindling activity during non-REM sleep. This is a key distinction between the AAD patients and the control patients; all thirteen control subjects displayed signs of sleep spindles.

(Source: alphagalileo.org)

Filed under auto-activation deficit brain activity REM sleep sensory cortex basal ganglia neuroscience science

113 notes

Stunted neuron branching restored in mice In a new study in Neuron, Brown University researchers report that mutation of a gene associated with some autism forms in humans can hinder the proper growth and connectivity of brain cells in mice. They also show how that understanding allowed them to restore proper cell growth in the lab. Brown University researchers have traced a genetic deficiency implicated in autism in humans to specific molecular and cellular consequences that cause clear deficits in mice in how well neurons can grow the intricate branches that allow them to connect to brain circuits. The researchers also show in their study (online Sep. 12, 2013, in Neuron) that they could restore proper neuronal growth by compensating for the errant molecular mechanisms they identified. The study involves the gene that produces a protein called NHE6. Mutation of the gene is directly associated with a rare and severe autism-related condition known as Christianson syndrome. But scientists, including senior author Dr. Eric Morrow, have also associated the protein with more general autism. “In generalized autism this protein is downregulated,” said Morrow, assistant professor of biology in the Department of Molecular Biology, Cellular Biology, and Biochemistry at Brown and a psychiatrist who sees autism patients at the Bradley Hospital in East Providence. “That meant to us that downregulation of NHE6 is relevant to a sizeable subset of autism.” The NHE6 protein helps to regulate acidity in the endosomes of cells. These endosomes are responsible for transporting material around cells and for degrading proteins including ones that signal neurons to grow the elaborately branched axons and dendrites that form neural connections. In their experiments the researchers measured acidity in the endosomes of brain cells of normal mice and in mice with mutations in the NHE6 gene. They found that the mutant mice had significantly higher endosome acidity. The mutant mice with the higher endosome acidity also had more degradation of a receptor protein, called TrkB, that responds a neurotrophic factor called BDNF. Together they signal axon and dendrite growth and branching. Did the higher acidity and lower levels of TrkB signaling affect the neurons? Morrow and his colleagues were able to show directly in the mouse brain that the neuronal branching was diminished as were the number and maturity of connections between neurons, called synapses. Further still, working with co-author Julie Kauer, professor of medical science in the Department of Molecular Pharmacology, Physiology, and Biotechnology, they looked at synaptic and circuit function in the mice, and they found deficits corresponding to those anatomical findings. “One of the overriding problems in disorders like autism, we think, is that it’s a problem of communication between different areas of the brain and neurons communicating with each other in networks,” said Morrow, who is affiliated with the Brown Institute for Brain Science. Searching for a rescue Having discovered a specific chain of events by which NHE6 mutations undermine neural branching and connectivity, Morrow and lead authors Qing Ouyang and Sofia Lizarraga sought to find out why and whether they could fix it. Sometimes acidity in the endosome can activate protein-degrading enzymes called proteases. The team hypothesized that perhaps the acidity resulting from the absence of NHE6 was leading proteases to degrade TrkB, reducing its levels in mutant neurons compared to normal ones. When they treated mutant cells with a protease inhibitor called leupeptin, they found that the TrkB levels and signaling returned to levels close to those found in the normal cells. Given that TrkB’s job is to bind with BDNF, the researchers also hypothesized that if the problem of NHE6 mutation was a reduction of TrkB, perhaps a suitable end-run around the problem would be to administer BDNF to cells directly. Indeed they found that NHE6 mutant cells, if given extra BDNF, produced axon and dendrite growth and branching that was more like normal neurons. “In this paper we show that BDNF signaling is attenuated in the mutant mice, but it’s not blocked,” Morrow said. “You can rescue the [neuronal growth] by turning up the signaling.” There are already drugs developed to deliver doses of chemicals that increase or mimic BDNF in the body, Morrow said, but many more tests beyond this study would have to be done before scientists and doctors could know whether a BDNF-related drug could have a therapeutic effect for patients with Christianson syndrome or any related form of autism. “We don’t think that this is everything about the condition,” Morrow said. “But if we were able to treat this one mechanism by adding exogenous drug, would it repair enough or some element of it?” Christianson syndrome and perhaps only a subset of autism appears to relate to deficits in neural branching. Some forms of autism, in fact, may result from too much branch growth. Moreover, doctors have no precise ways to tell whether a child diagnosed with autism has too much or too little neural branching. But given the study results suggesting that NHE6 may play a role in some autism forms perhaps by hindering neural branching, the new research suggests a target for addressing it.

Stunted neuron branching restored in mice

In a new study in Neuron, Brown University researchers report that mutation of a gene associated with some autism forms in humans can hinder the proper growth and connectivity of brain cells in mice. They also show how that understanding allowed them to restore proper cell growth in the lab.

Brown University researchers have traced a genetic deficiency implicated in autism in humans to specific molecular and cellular consequences that cause clear deficits in mice in how well neurons can grow the intricate branches that allow them to connect to brain circuits. The researchers also show in their study (online Sep. 12, 2013, in Neuron) that they could restore proper neuronal growth by compensating for the errant molecular mechanisms they identified.

The study involves the gene that produces a protein called NHE6. Mutation of the gene is directly associated with a rare and severe autism-related condition known as Christianson syndrome. But scientists, including senior author Dr. Eric Morrow, have also associated the protein with more general autism.

“In generalized autism this protein is downregulated,” said Morrow, assistant professor of biology in the Department of Molecular Biology, Cellular Biology, and Biochemistry at Brown and a psychiatrist who sees autism patients at the Bradley Hospital in East Providence. “That meant to us that downregulation of NHE6 is relevant to a sizeable subset of autism.”

The NHE6 protein helps to regulate acidity in the endosomes of cells. These endosomes are responsible for transporting material around cells and for degrading proteins including ones that signal neurons to grow the elaborately branched axons and dendrites that form neural connections.

In their experiments the researchers measured acidity in the endosomes of brain cells of normal mice and in mice with mutations in the NHE6 gene. They found that the mutant mice had significantly higher endosome acidity. The mutant mice with the higher endosome acidity also had more degradation of a receptor protein, called TrkB, that responds a neurotrophic factor called BDNF. Together they signal axon and dendrite growth and branching.

Did the higher acidity and lower levels of TrkB signaling affect the neurons? Morrow and his colleagues were able to show directly in the mouse brain that the neuronal branching was diminished as were the number and maturity of connections between neurons, called synapses. Further still, working with co-author Julie Kauer, professor of medical science in the Department of Molecular Pharmacology, Physiology, and Biotechnology, they looked at synaptic and circuit function in the mice, and they found deficits corresponding to those anatomical findings.

“One of the overriding problems in disorders like autism, we think, is that it’s a problem of communication between different areas of the brain and neurons communicating with each other in networks,” said Morrow, who is affiliated with the Brown Institute for Brain Science.

Searching for a rescue

Having discovered a specific chain of events by which NHE6 mutations undermine neural branching and connectivity, Morrow and lead authors Qing Ouyang and Sofia Lizarraga sought to find out why and whether they could fix it.

Sometimes acidity in the endosome can activate protein-degrading enzymes called proteases. The team hypothesized that perhaps the acidity resulting from the absence of NHE6 was leading proteases to degrade TrkB, reducing its levels in mutant neurons compared to normal ones. When they treated mutant cells with a protease inhibitor called leupeptin, they found that the TrkB levels and signaling returned to levels close to those found in the normal cells.

Given that TrkB’s job is to bind with BDNF, the researchers also hypothesized that if the problem of NHE6 mutation was a reduction of TrkB, perhaps a suitable end-run around the problem would be to administer BDNF to cells directly. Indeed they found that NHE6 mutant cells, if given extra BDNF, produced axon and dendrite growth and branching that was more like normal neurons.

“In this paper we show that BDNF signaling is attenuated in the mutant mice, but it’s not blocked,” Morrow said. “You can rescue the [neuronal growth] by turning up the signaling.”

There are already drugs developed to deliver doses of chemicals that increase or mimic BDNF in the body, Morrow said, but many more tests beyond this study would have to be done before scientists and doctors could know whether a BDNF-related drug could have a therapeutic effect for patients with Christianson syndrome or any related form of autism.

“We don’t think that this is everything about the condition,” Morrow said. “But if we were able to treat this one mechanism by adding exogenous drug, would it repair enough or some element of it?”

Christianson syndrome and perhaps only a subset of autism appears to relate to deficits in neural branching. Some forms of autism, in fact, may result from too much branch growth. Moreover, doctors have no precise ways to tell whether a child diagnosed with autism has too much or too little neural branching.

But given the study results suggesting that NHE6 may play a role in some autism forms perhaps by hindering neural branching, the new research suggests a target for addressing it.

Filed under ASD autism neurons neuronal growth Christianson syndrome neurotrophic factor neuroscience science

2,281 notes

"Brainbow" zebra fish. Neurons are labeled in multiple colors with Brainbow fluorescence microscopy. Three fluorescent proteins (cyan, yellow and red) are randomly taken up by various neurons, offering a palette of dozens of colors to help scientists follow complex neural pathways. Shown here is a five-day-old zebra fish larva viewed from the dorsal side, captured using a 20X objective. Image credit: Dr. Albert Pan, Harvard University, Cambridge, Mass., U.S.

"Brainbow" zebra fish.

Neurons are labeled in multiple colors with Brainbow fluorescence microscopy. Three fluorescent proteins (cyan, yellow and red) are randomly taken up by various neurons, offering a palette of dozens of colors to help scientists follow complex neural pathways. Shown here is a five-day-old zebra fish larva viewed from the dorsal side, captured using a 20X objective.

Image credit: Dr. Albert Pan, Harvard University, Cambridge, Mass., U.S.

(Source: scientificamerican.com)

Filed under zebrafish brainbow fluorescence microscopy neurons neuroscience Olympus BioScapes 2008 science

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