Neuroscience

Articles and news from the latest research reports.

153 notes

Geneticists Show How Molecular Switches Coordinate the Nervous System

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

image

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

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

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

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

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

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

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

(Source: tcd.ie)

Filed under neurodegeneration nervous system neurons genetics neuroscience science

158 notes

Seizing Control of Brain Seizures A few years after serving in the Israeli army during the first Gulf War, Daniela Kaufer made a startling discovery about the effect of psychological stress on the brain. As a graduate student at the Hebrew University she showed that the kind of extreme stress experienced in combat can break down the physiological barriers that normally protect the brain. She could not have known it then, but the finding would eventually lead her to uncover a key change in brain chemistry that triggers epileptic seizures. The Bakar Fellows Program is now helping her refine a strategy to block the threat and protect the brain from damage caused by physical trauma and other insults. A physiological line of defense normally prevents circulating blood from entering the brain. Known as the blood-brain barrier, the tightly controlled system buffers the brain from exposure to bacteria and other blood-borne invaders. Kaufer’s research has revealed how brain trauma can disrupt brain function once the barrier is breached. In lab research as a postdoc at Stanford in 2002, Kaufer and her Israeli colleague Alon Friedman examined what happens in the brain when the barrier is compromised. They found that seizures were likely if – and only if – the brain came in contact with blood that had been circulating in the body. They showed that a very common protein in blood called albumin accelerates signaling between neurons to abnormal levels. Neurons become overexcited and can cause seizures. “We were surprised, even a little disappointed, that it was such a common component of the blood  – nothing exotic at all  – that led to epilepsy,” recalls Kaufer, associate professor of integrative biology. She and Friedman went to on to show that albumin interacts with a ubiquitous cell protein called TGF-Beta receptor to cause the damage. In the healthy brain, TGF-Beta signaling affects activity of star-shaped sister cells of neurons called astrocytes, which normally limit neuron-to-neuron firing signals across the synapse. But when albumin stimulates TGF-Beta receptors, astrocytes lose some of their control. Neuron signaling spikes dangerously, and promotes the development of epileptic seizures. “Researchers knew that following traumatic brain injury the risk of epilepsy was great, but they didn’t know why,” Kaufer says. As luck would have it, a prescription drug for hypertension blocks TGF-Beta signaling.  With support from the Bakar Fellows program, Kaufer is now carrying out research to confirm that blocking abnormal TGF-Beta activity can prevent epilepsy from a range of insults. She expects that her and Friedman’s lab research, coupled with clinical studies, will demonstrate the drug’s ability to protect the brain and move it into use in emergency medicine to prevent victims of brain trauma from becoming epileptic. Kaufer and Friedman’s research is suggesting too that a number of assaults besides physical trauma – from brain infections to stroke – can also weaken the blood-brain barrier, and lead to the development of epilepsy through TGF-beta signaling. Emergency medicine physicians need only determine if the barrier has been breached to know if a patient is at risk for seizures. Fortunately, the condition of the blood-brain barrier can be assessed using a safe and  straightforward FDA-approved MRI protocol, so screening for epilepsy risk is within reach, says Kaufer. “Right now, if someone comes to the emergency room with traumatic brain injury, they have a 10 to 50 percent chance of developing epilepsy. But you don’t know which ones, nor do you have a way of preventing it. And epilepsy from brain injuries is the type most unresponsive to drugs. “I’m very hopeful and that our research can spare these patients the added trauma of epilepsy.”

Seizing Control of Brain Seizures

A few years after serving in the Israeli army during the first Gulf War, Daniela Kaufer made a startling discovery about the effect of psychological stress on the brain. As a graduate student at the Hebrew University she showed that the kind of extreme stress experienced in combat can break down the physiological barriers that normally protect the brain.

She could not have known it then, but the finding would eventually lead her to uncover a key change in brain chemistry that triggers epileptic seizures. The Bakar Fellows Program is now helping her refine a strategy to block the threat and protect the brain from damage caused by physical trauma and other insults.

A physiological line of defense normally prevents circulating blood from entering the brain. Known as the blood-brain barrier, the tightly controlled system buffers the brain from exposure to bacteria and other blood-borne invaders. Kaufer’s research has revealed how brain trauma can disrupt brain function once the barrier is breached.

In lab research as a postdoc at Stanford in 2002, Kaufer and her Israeli colleague Alon Friedman examined what happens in the brain when the barrier is compromised. They found that seizures were likely if – and only if – the brain came in contact with blood that had been circulating in the body.

They showed that a very common protein in blood called albumin accelerates signaling between neurons to abnormal levels. Neurons become overexcited and can cause seizures.

“We were surprised, even a little disappointed, that it was such a common component of the blood  – nothing exotic at all  – that led to epilepsy,” recalls Kaufer, associate professor of integrative biology.

She and Friedman went to on to show that albumin interacts with a ubiquitous cell protein called TGF-Beta receptor to cause the damage.

In the healthy brain, TGF-Beta signaling affects activity of star-shaped sister cells of neurons called astrocytes, which normally limit neuron-to-neuron firing signals across the synapse. But when albumin stimulates TGF-Beta receptors, astrocytes lose some of their control. Neuron signaling spikes dangerously, and promotes the development of epileptic seizures.

“Researchers knew that following traumatic brain injury the risk of epilepsy was great, but they didn’t know why,” Kaufer says.

As luck would have it, a prescription drug for hypertension blocks TGF-Beta signaling.  With support from the Bakar Fellows program, Kaufer is now carrying out research to confirm that blocking abnormal TGF-Beta activity can prevent epilepsy from a range of insults.

She expects that her and Friedman’s lab research, coupled with clinical studies, will demonstrate the drug’s ability to protect the brain and move it into use in emergency medicine to prevent victims of brain trauma from becoming epileptic.

Kaufer and Friedman’s research is suggesting too that a number of assaults besides physical trauma – from brain infections to stroke – can also weaken the blood-brain barrier, and lead to the development of epilepsy through TGF-beta signaling. Emergency medicine physicians need only determine if the barrier has been breached to know if a patient is at risk for seizures.

Fortunately, the condition of the blood-brain barrier can be assessed using a safe and  straightforward FDA-approved MRI protocol, so screening for epilepsy risk is within reach, says Kaufer.

“Right now, if someone comes to the emergency room with traumatic brain injury, they have a 10 to 50 percent chance of developing epilepsy. But you don’t know which ones, nor do you have a way of preventing it. And epilepsy from brain injuries is the type most unresponsive to drugs.

“I’m very hopeful and that our research can spare these patients the added trauma of epilepsy.”

Filed under epilepsy epileptic seizures blood-brain barrier albumin neuroscience science

80 notes

Surprising culprit found in cell recycling defect

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

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

image

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

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

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

image

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

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

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

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

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

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

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

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

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

(Source: news.wustl.edu)

Filed under lysosomes mucolipidosis III genetic diseases phosphotransferase proteins medicine science

100 notes

Researchers provide standardized nomenclature for the architecture of insect brains When you’re talking about something as complex as the brain, the task isn’t any easier if the vocabulary being used is just as complex. An international collaboration of neuroscientists has not only tripled the number of identified brain structures, but created a simple lexicon to talk about them, which will be enormously helpful for future research on brain function and disease. Nick Strausfeld and Linda Restifo, both professors in the Department of Neuroscience at the University of Arizona, worked with colleagues in Japan who led the project, and colleagues in Germany and in the UK to produce a comprehensive atlas of neuroanatomical centers and computational centers of the insect brain. In the process, the team identified many previously unknown structures. By providing the research community with a unified system of terminology, they set the stage for a systematic effort to elucidate brain structures and functions that carry over to functions of the human brain. An article about the work appears in the scientific journal Neuron, regarded by many as one of the flagship publications of neuroscience; the online version includes an 80-page data supplement. The data will be publicly available within 6 months and include hundreds of images and 3-D video animations – amounting to an invaluable resource that will enable neuroscientists to work more efficiently, compare their results and obtain more meaningful interpretations. "This effort provides a three-dimensional road map for describing structures for all insect brains, and enables comparisons with other arthropods," said Strausfeld, director of the UA Center for Insect Science. "It has huge value in describing network relationships between computational centers in the brain." Read more

Researchers provide standardized nomenclature for the architecture of insect brains

When you’re talking about something as complex as the brain, the task isn’t any easier if the vocabulary being used is just as complex. An international collaboration of neuroscientists has not only tripled the number of identified brain structures, but created a simple lexicon to talk about them, which will be enormously helpful for future research on brain function and disease.

Nick Strausfeld and Linda Restifo, both professors in the Department of Neuroscience at the University of Arizona, worked with colleagues in Japan who led the project, and colleagues in Germany and in the UK to produce a comprehensive atlas of neuroanatomical centers and computational centers of the insect brain. In the process, the team identified many previously unknown structures. By providing the research community with a unified system of terminology, they set the stage for a systematic effort to elucidate brain structures and functions that carry over to functions of the human brain.

An article about the work appears in the scientific journal Neuron, regarded by many as one of the flagship publications of neuroscience; the online version includes an 80-page data supplement. The data will be publicly available within 6 months and include hundreds of images and 3-D video animations – amounting to an invaluable resource that will enable neuroscientists to work more efficiently, compare their results and obtain more meaningful interpretations.

"This effort provides a three-dimensional road map for describing structures for all insect brains, and enables comparisons with other arthropods," said Strausfeld, director of the UA Center for Insect Science. "It has huge value in describing network relationships between computational centers in the brain."

Read more

Filed under insects insect brain fruit flies neuroscience science

189 notes

Study reveals workings of working memory Keep this in mind: Scientists say they’ve learned how your brain plucks information out of working memory when you decide to act. Say you’re a busy mom trying to wrap up a work call now that you’ve arrived home. While you converse on your Bluetooth headset, one kid begs for an unspecified snack, another asks where his homework project has gone, and just then an urgent e-mail from your boss buzzes the phone in your purse. During the call’s last few minutes these urgent requests — snack, homework, boss — wait in your working memory. When you hang up, you’ll pick one and act. When you do that, according to Brown University psychology researchers whose findings appear in the journal Neuron, you’ll employ brain circuitry that links a specific chunk of the striatum called the caudate and a chunk of the prefrontal cortex centered on the dorsal anterior premotor cortex. Selecting from working memory, it turns out, uses similar circuits to those involved in planning motion. In lab experiments with 22 adult volunteers, the researchers used magnetic resonance imaging to track brain activity during a carefully designed working memory task. They also measured how quickly the subjects could choose from working memory — a phenomenon the scientists called “output gating.” “In the immediacy of what we’re doing we have this small working memory capacity where we can hang on to a few things that are going to be useful in a few moments, and that’s where output gating is crucial,” said study senior author David Badre, professor of cognitive, linguistic, and psychological sciences at Brown. From the perspective of cognition, said lead author and postdoctoral scholar Christopher Chatham, input gating — choosing what goes into working memory — and output gating allow people to maintain a course of action (e.g., finish that Bluetooth call) while being flexible enough to account for context in planning what’s next. Of cognition and wingdings In their experiments Badre, Chatham, and co-author Michael Frank, associate professor of cognitive, linguistic, and psychological sciences, provided their volunteers with four different versions of a similar working memory task. The versions distinguished output gating from input gating so that the anatomical action observed in the MRI could reliably associate with output gating behavior. In each round, volunteers saw a sequence of characters — either letters of the alphabet or wingdings (typographical symbols like stars and snowflakes). Before or after the sequence, the volunteers were also given a context cue in the form of a numeral that told them which kind of character would be relevant at end of the task (e.g., “1” might mean a wingding while “2” might mean a letter). The last step for volunteers was to select between groups of characters on the screen that included whichever contextually relevant character they had seen in the sequence (e.g., if the subject had seen a “1” and later a snowflake during the sequence, they should select the group that included a snowflake). When the context numeral came first, say a “2,” volunteers would “input gate” only letters into their working memory. When it came time to make a selection, they’d simply “output gate” the correct letter from the letters in working memory. If the context came last, people would have to input gate everything they saw into working memory, making all the real thinking a matter of output gating. If the context cue came last, they would carry a higher load of characters in working memory. To address this disparity, the experimenters created two more conditions in which a global context indicator, “3,” required people to keep everything they saw in working memory whether it came before the sequence or after. With this experimental design the researchers could measure performance and monitor brain activity with subjects who had distinct moments of input and output gating, regardless of the character load in working memory. People accomplished the tasks with a range of speeds, which the researchers regarded as a proxy for the amount of cognitive work volunteers had to do. People were slowest in making a selection when they got the context cue last and then had to gate just one specific symbol out of memory (e.g., they saw the sequence, then saw a 1, and then had to choose the option with a wingding they had seen). People were fastest at making a selection when they were given the context first and then had to pick the one character of that kind that they saw (e.g., they saw a “2,” then the sequence in which only letters mattered, and then had to choose the option with a letter they had seen). In analyzing the results, Chatham and his co-authors found that the caudate and the dorsal anterior premotor cortex, contributed distinctly to the reaction times they saw. These separate roles in the partnership agree with computational models of how the brain works. “The division of labor that’s specifically posited by these computational models is one in which there is a basically a context being represented in the prefrontal cortex that determines the overall efficiency of going from stimulus to response – like a route,” Chatham said. “The striatum is involved in the actual gating of that flow of information,” he said, “like traffic lights along the route.” So the cortex interprets the context, while the striatum implements the gating. When the context is unhelpfully general and the gating is very specific, for example, the task takes a lot of time. The findings help advance studies of how cognition works in the brain and could help psychiatrists analyze behavior in people where those areas of the brain have been injured, the researchers said. It also highlights how similar brain circuits can execute different functions – motion and working memory gating.

Study reveals workings of working memory

Keep this in mind: Scientists say they’ve learned how your brain plucks information out of working memory when you decide to act.

Say you’re a busy mom trying to wrap up a work call now that you’ve arrived home. While you converse on your Bluetooth headset, one kid begs for an unspecified snack, another asks where his homework project has gone, and just then an urgent e-mail from your boss buzzes the phone in your purse. During the call’s last few minutes these urgent requests — snack, homework, boss — wait in your working memory. When you hang up, you’ll pick one and act.

When you do that, according to Brown University psychology researchers whose findings appear in the journal Neuron, you’ll employ brain circuitry that links a specific chunk of the striatum called the caudate and a chunk of the prefrontal cortex centered on the dorsal anterior premotor cortex. Selecting from working memory, it turns out, uses similar circuits to those involved in planning motion.

In lab experiments with 22 adult volunteers, the researchers used magnetic resonance imaging to track brain activity during a carefully designed working memory task. They also measured how quickly the subjects could choose from working memory — a phenomenon the scientists called “output gating.”

“In the immediacy of what we’re doing we have this small working memory capacity where we can hang on to a few things that are going to be useful in a few moments, and that’s where output gating is crucial,” said study senior author David Badre, professor of cognitive, linguistic, and psychological sciences at Brown.

From the perspective of cognition, said lead author and postdoctoral scholar Christopher Chatham, input gating — choosing what goes into working memory — and output gating allow people to maintain a course of action (e.g., finish that Bluetooth call) while being flexible enough to account for context in planning what’s next.

Of cognition and wingdings

In their experiments Badre, Chatham, and co-author Michael Frank, associate professor of cognitive, linguistic, and psychological sciences, provided their volunteers with four different versions of a similar working memory task. The versions distinguished output gating from input gating so that the anatomical action observed in the MRI could reliably associate with output gating behavior.

In each round, volunteers saw a sequence of characters — either letters of the alphabet or wingdings (typographical symbols like stars and snowflakes). Before or after the sequence, the volunteers were also given a context cue in the form of a numeral that told them which kind of character would be relevant at end of the task (e.g., “1” might mean a wingding while “2” might mean a letter). The last step for volunteers was to select between groups of characters on the screen that included whichever contextually relevant character they had seen in the sequence (e.g., if the subject had seen a “1” and later a snowflake during the sequence, they should select the group that included a snowflake).

When the context numeral came first, say a “2,” volunteers would “input gate” only letters into their working memory. When it came time to make a selection, they’d simply “output gate” the correct letter from the letters in working memory. If the context came last, people would have to input gate everything they saw into working memory, making all the real thinking a matter of output gating. If the context cue came last, they would carry a higher load of characters in working memory. To address this disparity, the experimenters created two more conditions in which a global context indicator, “3,” required people to keep everything they saw in working memory whether it came before the sequence or after.

With this experimental design the researchers could measure performance and monitor brain activity with subjects who had distinct moments of input and output gating, regardless of the character load in working memory.

People accomplished the tasks with a range of speeds, which the researchers regarded as a proxy for the amount of cognitive work volunteers had to do. People were slowest in making a selection when they got the context cue last and then had to gate just one specific symbol out of memory (e.g., they saw the sequence, then saw a 1, and then had to choose the option with a wingding they had seen). People were fastest at making a selection when they were given the context first and then had to pick the one character of that kind that they saw (e.g., they saw a “2,” then the sequence in which only letters mattered, and then had to choose the option with a letter they had seen).

In analyzing the results, Chatham and his co-authors found that the caudate and the dorsal anterior premotor cortex, contributed distinctly to the reaction times they saw. These separate roles in the partnership agree with computational models of how the brain works.

“The division of labor that’s specifically posited by these computational models is one in which there is a basically a context being represented in the prefrontal cortex that determines the overall efficiency of going from stimulus to response – like a route,” Chatham said. “The striatum is involved in the actual gating of that flow of information,” he said, “like traffic lights along the route.”

So the cortex interprets the context, while the striatum implements the gating. When the context is unhelpfully general and the gating is very specific, for example, the task takes a lot of time.

The findings help advance studies of how cognition works in the brain and could help psychiatrists analyze behavior in people where those areas of the brain have been injured, the researchers said. It also highlights how similar brain circuits can execute different functions – motion and working memory gating.

Filed under working memory prefrontal cortex brain circuitry caudate nucleus neuroscience psychology science

295 notes

Scientists identify the switch that says it’s time to sleep

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

image

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Source: ox.ac.uk)

Filed under sleep nerve cells fruit flies sleep homeostasis homeostat neuroscience science

95 notes

Scientists identify new Huntington disease pathway

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

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

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

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

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

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

“One of the early observations was that enhanced HACE1 expression rescued cells from mutant Huntingtin (the mutant protein that is responsible for Huntington disease) toxicity. We knew then that we had to figure out how HACE1 can protect these cells.
“Our evidence points towards a previously unknown role of HACE1 in Huntington disease and possibly other forms of neurodegeneration. It’s very early days, but if we were able to find a way to boost this pathway, we might be able to develop a treatment that halts, or even reverses progression of Huntington disease.”

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

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

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

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

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

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

(Source: mrc.ac.uk)

Filed under huntington disease HACE1 oxidative stress genes neurodegeneration neuroscience science

276 notes

The Musical Brain: Novel Study of Jazz Players Shows Common Brain Circuitry Processes Both Music and Language The brains of jazz musicians engrossed in spontaneous, improvisational musical conversation showed robust activation of brain areas traditionally associated with spoken language and syntax, which are used to interpret the structure of phrases and sentences. But this musical conversation shut down brain areas linked to semantics - those that process the meaning of spoken language, according to results of a study by Johns Hopkins researchers. The study used functional magnetic resonance imaging (fMRI) to track the brain activity of jazz musicians in the act of “trading fours,” a process in which musicians participate in spontaneous back and forth instrumental exchanges, usually four bars in duration. The musicians introduce new melodies in response to each other’s musical ideas, elaborating and modifying them over the course of a performance. The results of the study suggest that the brain regions that process syntax aren’t limited to spoken language, according to Charles Limb, M.D., an associate professor in the Department of Otolaryngology-Head and Neck Surgery at the Johns Hopkins University School of Medicine. Rather, he says, the brain uses the syntactic areas to process communication in general, whether through language or through music. Limb, who is himself a musician and holds a faculty appointment at the Peabody Conservatory, says the work sheds important new light on the complex relationship between music and language. "Until now, studies of how the brain processes auditory communication between two individuals have been done only in the context of spoken language," says Limb, the senior author of a report on the work that appears online Feb. 19 in the journal PLOS ONE. “But looking at jazz lets us investigate the neurological basis of interactive, musical communication as it occurs outside of spoken language. "We’ve shown in this study that there is a fundamental difference between how meaning is processed by the brain for music and language. Specifically, it’s syntactic and not semantic processing that is key to this type of musical communication. Meanwhile, conventional notions of semantics may not apply to musical processing by the brain." To study the response of the brain to improvisational musical conversation between musicians, the Johns Hopkins researchers recruited 11 men aged 25 to 56 who were highly proficient in jazz piano performance. During each 10-minute session of trading fours, one musician lay on his back inside the MRI machine with a plastic piano keyboard resting on his lap while his legs were elevated with a cushion. A pair of mirrors was placed so the musician could look directly up while in the MRI machine and see the placement of his fingers on the keyboard. The keyboard was specially constructed so it did not have metal parts that would be attracted to the large magnet in the fMRI. The improvisation between the musicians activated areas of the brain linked to syntactic processing for language, called the inferior frontal gyrus and posterior superior temporal gyrus. In contrast, the musical exchange deactivated brain structures involved in semantic processing, called the angular gyrus and supramarginal gyrus. "When two jazz musicians seem lost in thought while trading fours, they aren’t simply waiting for their turn to play," Limb says. "Instead, they are using the syntactic areas of their brain to process what they are hearing so they can respond by playing a new series of notes that hasn’t previously been composed or practiced."

The Musical Brain: Novel Study of Jazz Players Shows Common Brain Circuitry Processes Both Music and Language

The brains of jazz musicians engrossed in spontaneous, improvisational musical conversation showed robust activation of brain areas traditionally associated with spoken language and syntax, which are used to interpret the structure of phrases and sentences. But this musical conversation shut down brain areas linked to semantics - those that process the meaning of spoken language, according to results of a study by Johns Hopkins researchers.

The study used functional magnetic resonance imaging (fMRI) to track the brain activity of jazz musicians in the act of “trading fours,” a process in which musicians participate in spontaneous back and forth instrumental exchanges, usually four bars in duration. The musicians introduce new melodies in response to each other’s musical ideas, elaborating and modifying them over the course of a performance.

The results of the study suggest that the brain regions that process syntax aren’t limited to spoken language, according to Charles Limb, M.D., an associate professor in the Department of Otolaryngology-Head and Neck Surgery at the Johns Hopkins University School of Medicine. Rather, he says, the brain uses the syntactic areas to process communication in general, whether through language or through music.

Limb, who is himself a musician and holds a faculty appointment at the Peabody Conservatory, says the work sheds important new light on the complex relationship between music and language.

"Until now, studies of how the brain processes auditory communication between two individuals have been done only in the context of spoken language," says Limb, the senior author of a report on the work that appears online Feb. 19 in the journal PLOS ONE. “But looking at jazz lets us investigate the neurological basis of interactive, musical communication as it occurs outside of spoken language.

"We’ve shown in this study that there is a fundamental difference between how meaning is processed by the brain for music and language. Specifically, it’s syntactic and not semantic processing that is key to this type of musical communication. Meanwhile, conventional notions of semantics may not apply to musical processing by the brain."

To study the response of the brain to improvisational musical conversation between musicians, the Johns Hopkins researchers recruited 11 men aged 25 to 56 who were highly proficient in jazz piano performance. During each 10-minute session of trading fours, one musician lay on his back inside the MRI machine with a plastic piano keyboard resting on his lap while his legs were elevated with a cushion. A pair of mirrors was placed so the musician could look directly up while in the MRI machine and see the placement of his fingers on the keyboard. The keyboard was specially constructed so it did not have metal parts that would be attracted to the large magnet in the fMRI.

The improvisation between the musicians activated areas of the brain linked to syntactic processing for language, called the inferior frontal gyrus and posterior superior temporal gyrus. In contrast, the musical exchange deactivated brain structures involved in semantic processing, called the angular gyrus and supramarginal gyrus.

"When two jazz musicians seem lost in thought while trading fours, they aren’t simply waiting for their turn to play," Limb says. "Instead, they are using the syntactic areas of their brain to process what they are hearing so they can respond by playing a new series of notes that hasn’t previously been composed or practiced."

Filed under music brain activity inferior frontal gyrus angular gyrus jazz musicians neuroscience psychology science

147 notes

Study uncovers surprising differences in brain activity of alcohol-dependent women

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

image

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Source: news.indiana.edu)

Filed under alcohol dependence addiction brain activity neuroimaging dopamine decision making neuroscience science

161 notes

A circuit for change To answer the seemingly simple question “Have I been here before?” we must use our memories of previous experiences to determine if our current location is familiar or novel. In a new study published in the Journal of Neuroscience researchers from the RIKEN Brain Science Institute have identified a region of the hippocampus, called CA2, which is sensitive to even small changes in a familiar context. The results provide the first clue to the contributions of CA2 to memory and may help shed light on why this area is often found to be abnormal in the schizophrenic brain. Change comes in many flavors; if we move to a new country, city or house it is easy to recognize the novelty of the environment, but if we come home to find the furniture rearranged or a new piece of art on the wall, this recognition may be much slower. Scientists believe this is because memory formation requires comparing current information with previous experience and the larger the overlap, the more difficult the distinction. It has long been known that the hippocampus is a region of the brain crucial for this type of memory, however the identification of neurons responsible for this comparison has remained elusive. In this study Marie Wintzer, Roman Boehringer, Denis Polygalov and Thomas McHugh used genetically modified mice and advanced cell imaging techniques to demonstrate that while the entire hippocampus is capable of detecting large changes in context, the small and often overlooked CA2 region is exquisitely sensitive to small changes. Mice were familiarized with one context and then placed either in a much different context or back in the original with small alterations, such as several new small objects. By detecting the expression of activity induced genes Wintzer and colleagues were able to demonstrate that just a few new objects in the otherwise unchanged context completely altered the pattern of active cells specifically in CA2. Mice that had been genetically engineered to lack this CA2 response explored the new context much less than their normal siblings. “CA2 has often been overlooked or simply grouped together with its more prominent neighbors, but these data suggest it’s unique and important for recognizing and reacting to changes in our environments” explains Dr. McHugh, the leader of the study. Compared to rodents, human CA2 is proportionally larger, but still as mysterious. One intriguing finding has been that early in the onset of schizophrenia and bipolar disorder there is a loss of inhibitory neurons specifically in CA2. In addition to the memory problems that accompany these diseases, patients often exhibit a hyper-sensitivity to changes in environment and routine. This study suggests there may be a functional relationship between this sensitivity and CA2 dysfunction, hinting at a new circuit to target in our attempts to understand the function of both the normal and diseased brain.

A circuit for change

To answer the seemingly simple question “Have I been here before?” we must use our memories of previous experiences to determine if our current location is familiar or novel. In a new study published in the Journal of Neuroscience researchers from the RIKEN Brain Science Institute have identified a region of the hippocampus, called CA2, which is sensitive to even small changes in a familiar context. The results provide the first clue to the contributions of CA2 to memory and may help shed light on why this area is often found to be abnormal in the schizophrenic brain.

Change comes in many flavors; if we move to a new country, city or house it is easy to recognize the novelty of the environment, but if we come home to find the furniture rearranged or a new piece of art on the wall, this recognition may be much slower. Scientists believe this is because memory formation requires comparing current information with previous experience and the larger the overlap, the more difficult the distinction. It has long been known that the hippocampus is a region of the brain crucial for this type of memory, however the identification of neurons responsible for this comparison has remained elusive.

In this study Marie Wintzer, Roman Boehringer, Denis Polygalov and Thomas McHugh used genetically modified mice and advanced cell imaging techniques to demonstrate that while the entire hippocampus is capable of detecting large changes in context, the small and often overlooked CA2 region is exquisitely sensitive to small changes.

Mice were familiarized with one context and then placed either in a much different context or back in the original with small alterations, such as several new small objects. By detecting the expression of activity induced genes Wintzer and colleagues were able to demonstrate that just a few new objects in the otherwise unchanged context completely altered the pattern of active cells specifically in CA2. Mice that had been genetically engineered to lack this CA2 response explored the new context much less than their normal siblings.

“CA2 has often been overlooked or simply grouped together with its more prominent neighbors, but these data suggest it’s unique and important for recognizing and reacting to changes in our environments” explains Dr. McHugh, the leader of the study.

Compared to rodents, human CA2 is proportionally larger, but still as mysterious. One intriguing finding has been that early in the onset of schizophrenia and bipolar disorder there is a loss of inhibitory neurons specifically in CA2. In addition to the memory problems that accompany these diseases, patients often exhibit a hyper-sensitivity to changes in environment and routine. This study suggests there may be a functional relationship between this sensitivity and CA2 dysfunction, hinting at a new circuit to target in our attempts to understand the function of both the normal and diseased brain.

Filed under hippocampus memory schizophrenia neurons CA2 psychology neuroscience science

free counters