Neuroscience

Articles and news from the latest research reports.

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Pair bonding reinforced in the brain In addition to their song, songbirds also have an extensive repertoire of calls. While the species-specific song must be learned as a young bird, most calls are, as in the case of all other birds, innate. Researchers at the Max Planck Institute in Seewiesen have now discovered that in zebra finches the song control system in the brain is also active during simple communication calls. This relationship between unlearned calls and an area of the brain responsible for learned vocalisations is important for understanding the evolution of song learning in songbirds. Almost half of all bird species are songbirds. Only they have the ability to learn complicated vocal patterns which are described generally as song. Several studies prove that the songs of songbirds serve mainly to select a partner and defend a territory. In the temperate zones of the Northern hemisphere, usually only the male birds sing. However, all birds, both male and female, have calls - including species such as the zebra finch, where the female never sings. Apart from a few exceptions, the calls do not have to be learned and are used for communication purposes. They are mostly associated with a specific purpose as in the case of alarm calls and contact calls, for example. The songbird’s song is of great interest for neurobiologists as it is controlled by a network of nuclei in the forebrain. Neuroscientists study this network to investigate general rules that determine how the brain controls behaviour. Using specially designed methods to record song and brain activity, a team of researchers at the Max Planck Institute for Ornithology in Seewiesen has now found the neuronal basis of unlearned call communication. The researchers developed ultra-light microphone transmitters which they attached with rubber bands to the backs of zebra finch couples like rucksacks. They also attached a wireless recording system to the males to measure brain activity. Thanks to this miniature telemetry technology, the animals could move freely in groups in large aviaries so that the scientists were able to continuously register the animals’ entire behavioural repertoire. In their experiment, the researchers concentrated on so-called “stack” calls. They discovered that these calls mainly promote cohesion between males and females within bonded pairs. “Constant contact with a partner is important, as the zebra finches live in large social groups,” says Lisa Trost, co-author of the study. Surprisingly, not every call produces an answer in the partner, which initially presented the researchers with a problem during the analysis. They determined that a call from a partner only qualifies as an answer if it is made within two seconds. “We were thus able to create a matrix that clearly showed that almost without exception the two partners exchange calls with one another, which underlines the important social component of this ‘stack’ call,” says Andries Ter Maat, lead author of the study. When the researchers analysed the activity in an area of the brain that is important for the production of song – an area known as nucleus RA – they found a clear correlation between its activity pattern and the occurrence of the “stack” call. “This connection between an innate call and the activity of a brain area important to learned vocalisations suggests that during the evolution of songbirds, the role of the song area in the brain changed from being a simple vocalisation system for innate calls to a specialised neural network for learned songs,” concludes Manfred Gahr, coordinator of the study.

Pair bonding reinforced in the brain

In addition to their song, songbirds also have an extensive repertoire of calls. While the species-specific song must be learned as a young bird, most calls are, as in the case of all other birds, innate. Researchers at the Max Planck Institute in Seewiesen have now discovered that in zebra finches the song control system in the brain is also active during simple communication calls. This relationship between unlearned calls and an area of the brain responsible for learned vocalisations is important for understanding the evolution of song learning in songbirds.

Almost half of all bird species are songbirds. Only they have the ability to learn complicated vocal patterns which are described generally as song. Several studies prove that the songs of songbirds serve mainly to select a partner and defend a territory. In the temperate zones of the Northern hemisphere, usually only the male birds sing.

However, all birds, both male and female, have calls - including species such as the zebra finch, where the female never sings. Apart from a few exceptions, the calls do not have to be learned and are used for communication purposes. They are mostly associated with a specific purpose as in the case of alarm calls and contact calls, for example. The songbird’s song is of great interest for neurobiologists as it is controlled by a network of nuclei in the forebrain. Neuroscientists study this network to investigate general rules that determine how the brain controls behaviour.

Using specially designed methods to record song and brain activity, a team of researchers at the Max Planck Institute for Ornithology in Seewiesen has now found the neuronal basis of unlearned call communication. The researchers developed ultra-light microphone transmitters which they attached with rubber bands to the backs of zebra finch couples like rucksacks. They also attached a wireless recording system to the males to measure brain activity.

Thanks to this miniature telemetry technology, the animals could move freely in groups in large aviaries so that the scientists were able to continuously register the animals’ entire behavioural repertoire. In their experiment, the researchers concentrated on so-called “stack” calls. They discovered that these calls mainly promote cohesion between males and females within bonded pairs. “Constant contact with a partner is important, as the zebra finches live in large social groups,” says Lisa Trost, co-author of the study.

Surprisingly, not every call produces an answer in the partner, which initially presented the researchers with a problem during the analysis. They determined that a call from a partner only qualifies as an answer if it is made within two seconds. “We were thus able to create a matrix that clearly showed that almost without exception the two partners exchange calls with one another, which underlines the important social component of this ‘stack’ call,” says Andries Ter Maat, lead author of the study.

When the researchers analysed the activity in an area of the brain that is important for the production of song – an area known as nucleus RA – they found a clear correlation between its activity pattern and the occurrence of the “stack” call. “This connection between an innate call and the activity of a brain area important to learned vocalisations suggests that during the evolution of songbirds, the role of the song area in the brain changed from being a simple vocalisation system for innate calls to a specialised neural network for learned songs,” concludes Manfred Gahr, coordinator of the study.

Filed under songbirds vocalization mating neurons communication neuroscience science

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(Image caption: Pale green cells are CNiFERs implanted in mouse brain. Traces in white illustrate shifts in the timing of dopamine release with learning, a change the CNiFERs allowed researchers to track in real time. Credit: Kleinfeld Lab) Real-time Readout of Neurochemical Activity Scientists have created cells with fluorescent dyes that change color in response to specific neurochemicals. By implanting these cells into living mammalian brains, they have shown how neurochemical signaling changes as a food reward drives learning, they report in Nature Methods online October 26. These cells, called CNiFERs (pronounced “sniffers”) can detect small amounts of a neurotransmitter, either dopamine or norepinephrine, with fine resolution in both location and timing. Dopamine has long been of interest to neuroscientists for its role in learning, reward, and addiction. “Dopamine is a ubiquitous molecule in the brain that signals ‘mission accomplished.’ It serves as the key indicator during almost all aspects of learning and the formation of new memories,” said David Kleinfeld professor of physics at UC San Diego, who directed the work. “Disruptions to dopamine signaling lie at the heart of schizophrenia and addiction.” Kleinfeld also holds appointments in neurobiology, and electrical and computer engineering. Neuroscientists have long sought to measure dopamine in the brain during controlled conditions. But the chemistry of dopamine is so close to that of norepinephrine that fast and accurate measurements of dopamine, not confounded by other molecules, have eluded scientists.  Kleinfeld and Paul Slesinger, a professor of neuroscience at Icahn School of Medicine at Mount Sinai, New York, developed CNiFERs to meet this challenge. These modified cells can be inserted into the brains of animals to observe changes in neural signalling in real time. Arnaud Muller and Victory Joseph, working Kleinfeld’s laboratory, implanted CNiFERs into the frontal cortex in mice, then watched how signaling changed as the mice learned to associate a sound with a sweet reward.  This is classical conditioning, in which a tone that reliably preceded a drop of sweet water came to elicit anticipatory licking over time. The researchers found that release of dopamine, but not norepinephrine, tracked this change. That is, dopamine was initially released with the reward, but began to be released earlier, with the tone, as the mice learned to associate this previously neutral signal with something pleasant. In mice that failed to learn or made only a weak association, the anticipatory release of dopamine was reduced as well. Brain researchers have long suspected this link. But because the design of these cellular reporters is quite versatile, a number of different chemical signals of interest could be tracked using the same approach. “This work provides a path for the design of cells that report a large and diverse group of signaling molecules in the brain,” Kleinfeld said.

(Image caption: Pale green cells are CNiFERs implanted in mouse brain. Traces in white illustrate shifts in the timing of dopamine release with learning, a change the CNiFERs allowed researchers to track in real time. Credit: Kleinfeld Lab)

Real-time Readout of Neurochemical Activity

Scientists have created cells with fluorescent dyes that change color in response to specific neurochemicals. By implanting these cells into living mammalian brains, they have shown how neurochemical signaling changes as a food reward drives learning, they report in Nature Methods online October 26.

These cells, called CNiFERs (pronounced “sniffers”) can detect small amounts of a neurotransmitter, either dopamine or norepinephrine, with fine resolution in both location and timing. Dopamine has long been of interest to neuroscientists for its role in learning, reward, and addiction.

“Dopamine is a ubiquitous molecule in the brain that signals ‘mission accomplished.’ It serves as the key indicator during almost all aspects of learning and the formation of new memories,” said David Kleinfeld professor of physics at UC San Diego, who directed the work. “Disruptions to dopamine signaling lie at the heart of schizophrenia and addiction.” Kleinfeld also holds appointments in neurobiology, and electrical and computer engineering.

Neuroscientists have long sought to measure dopamine in the brain during controlled conditions. But the chemistry of dopamine is so close to that of norepinephrine that fast and accurate measurements of dopamine, not confounded by other molecules, have eluded scientists. 

Kleinfeld and Paul Slesinger, a professor of neuroscience at Icahn School of Medicine at Mount Sinai, New York, developed CNiFERs to meet this challenge. These modified cells can be inserted into the brains of animals to observe changes in neural signalling in real time.

Arnaud Muller and Victory Joseph, working Kleinfeld’s laboratory, implanted CNiFERs into the frontal cortex in mice, then watched how signaling changed as the mice learned to associate a sound with a sweet reward. 

This is classical conditioning, in which a tone that reliably preceded a drop of sweet water came to elicit anticipatory licking over time. The researchers found that release of dopamine, but not norepinephrine, tracked this change. That is, dopamine was initially released with the reward, but began to be released earlier, with the tone, as the mice learned to associate this previously neutral signal with something pleasant. In mice that failed to learn or made only a weak association, the anticipatory release of dopamine was reduced as well.

Brain researchers have long suspected this link. But because the design of these cellular reporters is quite versatile, a number of different chemical signals of interest could be tracked using the same approach.

“This work provides a path for the design of cells that report a large and diverse group of signaling molecules in the brain,” Kleinfeld said.

Filed under neurotransmitters CNiFERs norepinephrine dopamine neuroscience science

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Whites of Their Eyes: Study Finds Infants Respond to Social Cues From Sclera

Humans are the only primates with large, highly visible sclera – the white part of the eye.

The eye plays a significant role in the expressiveness of a face, and how much sclera is shown can indicate the emotions or behavioral attitudes of a person. Wide-open eyes, exposing a lot of white, indicate fear or surprise. A thinner slit of exposed eye, such as when smiling, expresses happiness or joy. Averted eyes, as well as direct eye contact, can mean several things. So the eye white, or how much of it is shown and at what angle, plays a role in the social and cooperative interactions among humans.

Adult humans are well-attuned to social cues involving the eye and use them, along with a great range of other facial and body features, to respond appropriately during social interactions. This sensitivity to eye cues is hard-wired into the brain of adults as they respond to social eye cues even without consciously seeing them.

But it is unclear whether the ability to unconsciously distinguish between different social cues indicated by the eyes exists early in development and can therefore be considered a key feature of the human social makeup.

A new University of Virginia and Max Planck Institute study, published online this week in the journal Proceedings of the National Academy of Sciences, finds that the ability to respond to eye cues apparently develops during infancy – at seven or so months.

“Our study provides developmental evidence for the notion that humans possess specific brain processes that allow them to automatically respond to eye cues,” said Tobias Grossmann, a University of Virginia developmental psychologist and one of the study’s authors.

Grossmann and his Max Planck Institute colleague Sarah Jessen used electroencephalography, or EEG, to measure the brain activity of 7-month-old infants while showing images of eyes wide open, narrowly opened, and with direct or averted gazes.

They found that the infants’ brains responded differently depending on the expression suggested by the eyes they viewed, which were shown absent of other facial features. They viewed the eye images for only 50 milliseconds – which is much less time than needed for an infant of this age to consciously perceive this kind of visual information.

“Their brains clearly responded to social cues conveyed through the eyes, indicating that even without conscious awareness, human infants are able to detect subtle social cues,” Grossmann said.

The infants’ brain responses displayed a different pattern to sclera depicting fearful expressions (wide-eyed) to non-fearful sclera. They also showed brain responses that differed when viewing direct gaze eyes compared to averted gaze.

“This demonstrates that, like adults, infants are sensitive to eye expressions of fear and direction of focus, and that these responses operate without conscious awareness,” Grossmann said. “The existence of such brain mechanisms in infants likely provides a vital foundation for the development of social interactive skills in humans.”

The infants in the study wore an EEG cap, like a small hat, which included sensors that could detect brain signals. Infants were sitting in the laps of their parents during the testing.

Filed under social perception social interaction brain activity infants EEG sclera neuroscience science

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Researchers observe brain development in utero New investigation methods using functional magnetic resonance tomography (fMRT) offer insights into fetal brain development. These “in vivo” observations will uncover different stages of the brain’s development. A research group at the Computational Imaging Research Lab from the MedUni Vienna has observed that parts of the brain that are later responsible for sight are already active at this stage. To obtain insights into the development of the human brain in utero, the study group observed 32 fetuses from the 21st to 38th week of pregnancy (an average pregnancy lasts 40 weeks). The architecture of the brain is developed particularly during the middle trimester of pregnancy. Using functional magnetic resonance tomography, it was possible to measure activity and thereby gain information about the most important cortical and sub-cortical structures of the developing brain. During the period of the 26th to 29th week of pregnancy in particular, short-range neuronal connections developed especially actively, while in contrast to this, long-range nerve connections exhibited more linear growth during pregnancy. “It became apparent that the areas responsible for sensory perception are developed first and only then, around four weeks later, do the areas responsible for more complex, cognitive skills come along,” says first author Andras Jakab from the Computational Imaging Research Lab at the MedUni Vienna, explaining the results. In another study, the study group led by Veronika Schöpf and Georg Langs was able to demonstrate for a correlation of eye movement and areas of the brain which are later responsible to process vision as early as the 30th to the 36th weeks of pregnancy. The fact that newborn babies first have to learn to “process” visual stimuli after birth is already known. It has now been possible to demonstrate that this important development starts even before birth. The research group investigated the relationship between eye movements and brain activity. Even at this stage of development, motor visual movement is linked to the areas in the visual cortex of the brain responsible for processing optical signals. “The relationship between eye movement and the responsible areas of the brain has therefore been demonstrated for the first time in utero”, explains first author Veronika Schöpf.

Researchers observe brain development in utero

New investigation methods using functional magnetic resonance tomography (fMRT) offer insights into fetal brain development. These “in vivo” observations will uncover different stages of the brain’s development. A research group at the Computational Imaging Research Lab from the MedUni Vienna has observed that parts of the brain that are later responsible for sight are already active at this stage.

To obtain insights into the development of the human brain in utero, the study group observed 32 fetuses from the 21st to 38th week of pregnancy (an average pregnancy lasts 40 weeks). The architecture of the brain is developed particularly during the middle trimester of pregnancy. Using functional magnetic resonance tomography, it was possible to measure activity and thereby gain information about the most important cortical and sub-cortical structures of the developing brain. During the period of the 26th to 29th week of pregnancy in particular, short-range neuronal connections developed especially actively, while in contrast to this, long-range nerve connections exhibited more linear growth during pregnancy. “It became apparent that the areas responsible for sensory perception are developed first and only then, around four weeks later, do the areas responsible for more complex, cognitive skills come along,” says first author Andras Jakab from the Computational Imaging Research Lab at the MedUni Vienna, explaining the results.

In another study, the study group led by Veronika Schöpf and Georg Langs was able to demonstrate for a correlation of eye movement and areas of the brain which are later responsible to process vision as early as the 30th to the 36th weeks of pregnancy. The fact that newborn babies first have to learn to “process” visual stimuli after birth is already known. It has now been possible to demonstrate that this important development starts even before birth. The research group investigated the relationship between eye movements and brain activity. Even at this stage of development, motor visual movement is linked to the areas in the visual cortex of the brain responsible for processing optical signals. “The relationship between eye movement and the responsible areas of the brain has therefore been demonstrated for the first time in utero”, explains first author Veronika Schöpf.

Filed under brain development prenatal development brain activity visual cortex eye movement neuroscience science

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(Image caption: Three-dimensional reconstruction of a synapse in the mouse brain. Readily releasable fusionable synaptic vesicles (blue, around 45 millionths of a millimetre in diameter) are docked at the cell membrane. Credit: © MPI f. Experimental Medicine/ Benjamin H. Cooper) Synapses always on the starting blocks While neurons rapidly propagate information in their interior via electrical signals, they communicate with each other at special contact points known as the synapses. Chemical messenger substances, the neurotransmitters, are stored in vesicles at the synapses. When a synapse becomes active, some of these vesicles fuse with the cell membrane and release their contents. To ensure that valuable time is not lost, synapses always have some readily releasable vesicles on standby. With the help of high-resolution, three-dimensional electron microscopy, scientists at the Max Planck Institute of Experimental Medicine in Göttingen succeeded in demonstrating that these fusionable vesicles have a very special characteristic: they already have close contact with the cell membrane long before the actual fusion occurs. In addition, the research team also decoded the molecular machinery that facilitates the operation of this docking mechanism. The fusion of the neurotransmitter vesicles with the cell membrane involves close cooperation between numerous protein components, which monitor each other and ensure that every single ‘participant’ is always in the right place. This is referred to as the fusion machinery and the comparison is an apt one: if a cogwheel in a clock mechanism is broken, the hands do not move. In a similar way, faulty or missing molecules impair synaptic operations. In research studies carried out some years ago, Nils Brose and his colleague JeongSeop Rhee from the Max Planck Institute of Experimental Medicine in Göttingen already demonstrated that the transmission of information at the synapses in genetically modified mice, in which all known genes of the Munc13 or CAPS proteins had been switched off, is severely defective. Although the neurons of the genetically modified mice do not differ from those of healthy mice when examined under an optical microscope, if Munc13 is missing, the release of neurotransmitters actually grinds to a halt completely. Brose and Rhee’s findings showed that to be able to react immediately to signals at all times, each synapse must keep a small number of ‘readily releasable’ fusionable vesicles on standby. But how do Munc13 and CAPS convert the vesicles to this kind of fusionable state? To answer this question, the Göttingen-based scientists studied the synaptic contacts in the minutest possible detail. To do this, neurobiologists Cordelia Imig and Ben Cooper, who have been working with Brose and Rhee for many years, used a high-pressure freezing process. This involves the rapid freezing of neurons in the brain tissue under high pressure so that no disruptive ice crystals are formed and the fine structure of the cells is particularly well conserved. The samples obtained in this way were then analysed using electron tomography. Using this method, electron microscope images of a structure are recorded from many different angles, in a similar way to the process used in medical computed tomography. The individual images can then be combined on the computer to give a high-resolution three-dimensional image – of a synapse in this case (see image). “Our results showed that readily releasable vesicles in healthy synapses touch the cell membrane,” explains Cooper. “However, if Munc13 and CAPS proteins are missing, the vesicles do not reach the active zone and accumulate a few nanometres away from it.” To their astonishment, the researchers also observed that SNARE proteins, which collaborate with Munc13 and CAPS in the nerve endings, are also involved in this docking process. SNARE proteins are found in the cell and vesicle membranes of healthy synapses and control the fusion of the two membranes during neurotransmitter release. When a vesicle approaches the cell membrane, the individual SNARE molecules line up opposite each other like the sides of a zip and pull the membranes close to each other in this way. The vesicles await the starting gun for their fusion in this state – in the starting blocks, so to speak. The findings of the neurobiologists in Göttingen prove that Munc13, CAPS and SNARE proteins closely align the vesicle and cell membrane in the synapse, long before the signal for fusion is given. This is the only way that the fast and controlled transmission of information at the synapse can be guaranteed, thanks to which we can react specifically to information from our environment. “It had long been clear that synapses have to be extremely fast to carry out all of the many complex brain functions. Our study shows for the first time how this is managed at the molecular level and on the level of the synaptic vesicles,” says Brose. Because almost all of the protein components involved in this process also play a role in neurological and psychiatric diseases, the Göttingen-based scientists believe that their discovery will soon benefit medical research.

(Image caption: Three-dimensional reconstruction of a synapse in the mouse brain. Readily releasable fusionable synaptic vesicles (blue, around 45 millionths of a millimetre in diameter) are docked at the cell membrane. Credit: © MPI f. Experimental Medicine/ Benjamin H. Cooper)

Synapses always on the starting blocks

While neurons rapidly propagate information in their interior via electrical signals, they communicate with each other at special contact points known as the synapses. Chemical messenger substances, the neurotransmitters, are stored in vesicles at the synapses. When a synapse becomes active, some of these vesicles fuse with the cell membrane and release their contents. To ensure that valuable time is not lost, synapses always have some readily releasable vesicles on standby. With the help of high-resolution, three-dimensional electron microscopy, scientists at the Max Planck Institute of Experimental Medicine in Göttingen succeeded in demonstrating that these fusionable vesicles have a very special characteristic: they already have close contact with the cell membrane long before the actual fusion occurs. In addition, the research team also decoded the molecular machinery that facilitates the operation of this docking mechanism.

The fusion of the neurotransmitter vesicles with the cell membrane involves close cooperation between numerous protein components, which monitor each other and ensure that every single ‘participant’ is always in the right place. This is referred to as the fusion machinery and the comparison is an apt one: if a cogwheel in a clock mechanism is broken, the hands do not move. In a similar way, faulty or missing molecules impair synaptic operations.

In research studies carried out some years ago, Nils Brose and his colleague JeongSeop Rhee from the Max Planck Institute of Experimental Medicine in Göttingen already demonstrated that the transmission of information at the synapses in genetically modified mice, in which all known genes of the Munc13 or CAPS proteins had been switched off, is severely defective. Although the neurons of the genetically modified mice do not differ from those of healthy mice when examined under an optical microscope, if Munc13 is missing, the release of neurotransmitters actually grinds to a halt completely. Brose and Rhee’s findings showed that to be able to react immediately to signals at all times, each synapse must keep a small number of ‘readily releasable’ fusionable vesicles on standby.

But how do Munc13 and CAPS convert the vesicles to this kind of fusionable state? To answer this question, the Göttingen-based scientists studied the synaptic contacts in the minutest possible detail. To do this, neurobiologists Cordelia Imig and Ben Cooper, who have been working with Brose and Rhee for many years, used a high-pressure freezing process. This involves the rapid freezing of neurons in the brain tissue under high pressure so that no disruptive ice crystals are formed and the fine structure of the cells is particularly well conserved. The samples obtained in this way were then analysed using electron tomography. Using this method, electron microscope images of a structure are recorded from many different angles, in a similar way to the process used in medical computed tomography. The individual images can then be combined on the computer to give a high-resolution three-dimensional image – of a synapse in this case (see image).

“Our results showed that readily releasable vesicles in healthy synapses touch the cell membrane,” explains Cooper. “However, if Munc13 and CAPS proteins are missing, the vesicles do not reach the active zone and accumulate a few nanometres away from it.” To their astonishment, the researchers also observed that SNARE proteins, which collaborate with Munc13 and CAPS in the nerve endings, are also involved in this docking process. SNARE proteins are found in the cell and vesicle membranes of healthy synapses and control the fusion of the two membranes during neurotransmitter release. When a vesicle approaches the cell membrane, the individual SNARE molecules line up opposite each other like the sides of a zip and pull the membranes close to each other in this way. The vesicles await the starting gun for their fusion in this state – in the starting blocks, so to speak.

The findings of the neurobiologists in Göttingen prove that Munc13, CAPS and SNARE proteins closely align the vesicle and cell membrane in the synapse, long before the signal for fusion is given. This is the only way that the fast and controlled transmission of information at the synapse can be guaranteed, thanks to which we can react specifically to information from our environment. “It had long been clear that synapses have to be extremely fast to carry out all of the many complex brain functions. Our study shows for the first time how this is managed at the molecular level and on the level of the synaptic vesicles,” says Brose. Because almost all of the protein components involved in this process also play a role in neurological and psychiatric diseases, the Göttingen-based scientists believe that their discovery will soon benefit medical research.

Filed under neurotransmitters synapses Munc13 SNARE cell membrane neuroscience science

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(Image caption: In the top image, cells from a mouse model of amyotrophic lateral sclerosis caused normal healthy brain cells (green) to die. But when scientists blocked an enzyme in the cells from the mouse model, more of the normal cells and their branches survived (bottom)) Heart drug may help treat ALS Digoxin, a medication used in the treatment of heart failure, may be adaptable for the treatment of amyotrophic lateral sclerosis (ALS), a progressive, paralyzing disease, suggests new research at Washington University School of Medicine in St. Louis. ALS, also known as Lou Gehrig’s disease, destroys the nerve cells that control muscles. This leads to loss of mobility, difficulty breathing and swallowing and eventually death. Riluzole, the sole medication approved to treat the disease, has only marginal benefits in patients. But in a new study conducted in cell cultures and in mice, scientists showed that when they reduced the activity of an enzyme or limited cells’ ability to make copies of the enzyme, the disease’s destruction of nerve cells stopped. The enzyme maintains the proper balance of sodium and potassium in cells. “We blocked the enzyme with digoxin,” said senior author Azad Bonni, MD, PhD. “This had a very strong effect, preventing the death of nerve cells that are normally killed in a cell culture model of ALS.” The findings appear online Oct. 26 in Nature Neuroscience. The results stemmed from Bonni’s studies of brain cells’ stress responses in a mouse model of ALS. The mice have a mutated version of a gene that causes an inherited form of the disease and develop many of the same symptoms seen in humans with ALS, including paralysis and death. Efforts to monitor the activity of a stress response protein in the mice unexpectedly led the scientists to another protein: sodium-potassium ATPase. This enzyme ejects charged sodium particles from cells and takes in charged potassium particles, allowing cells to maintain an electrical charge across their outer membranes. Maintenance of this charge is essential for the normal function of cells. The particular sodium-potassium ATPase highlighted by Bonni’s studies is found in nervous system cells called astrocytes. In the ALS mice, levels of the enzyme are higher than normal in astrocytes. Bonni’s group found that the increase in sodium-potassium ATPase led the astrocytes to release harmful factors called inflammatory cytokines, which may kill motor neurons. Recent studies have suggested that astrocytes may be crucial contributors to neurodegenerative disorders such as ALS, and Alzheimer’s, Huntington’s and Parkinson’s diseases. For example, placing astrocytes from ALS mice in culture dishes with healthy motor neurons causes the neurons to degenerate and die. “Even though the neurons are normal, there’s something going on in the astrocytes that is harming the neurons,” said Bonni, the Edison Professor of Neurobiology and head of the Department of Anatomy and Neurobiology. How this happens isn’t clear, but Bonni’s results suggest the sodium-potassium ATPase plays a key role. When he conducted the same experiment but blocked the enzyme in ALS astrocytes using digoxin, the normal motor nerve cells survived. Digoxin blocks the ability of sodium-potassium ATPase to eject sodium and bring in potassium. In mice with the mutation for inherited ALS, those with only one copy of the gene for sodium-potassium ATPase survived an average of 20 days longer than those with two copies of the gene. When one copy of the gene is gone, cells make less of the enzyme. “The mice with only one copy of the sodium-potassium ATPase gene live longer and are more mobile,” Bonni said. “They’re not normal, but they can walk around and have more motor neurons in their spinal cords.” Many important questions remain about whether and how inhibitors of the sodium-potassium ATPase enzyme might be used to slow progressive paralysis in ALS, but Bonni said the findings offer an exciting starting point for further studies.

(Image caption: In the top image, cells from a mouse model of amyotrophic lateral sclerosis caused normal healthy brain cells (green) to die. But when scientists blocked an enzyme in the cells from the mouse model, more of the normal cells and their branches survived (bottom))

Heart drug may help treat ALS

Digoxin, a medication used in the treatment of heart failure, may be adaptable for the treatment of amyotrophic lateral sclerosis (ALS), a progressive, paralyzing disease, suggests new research at Washington University School of Medicine in St. Louis.

ALS, also known as Lou Gehrig’s disease, destroys the nerve cells that control muscles. This leads to loss of mobility, difficulty breathing and swallowing and eventually death. Riluzole, the sole medication approved to treat the disease, has only marginal benefits in patients.

But in a new study conducted in cell cultures and in mice, scientists showed that when they reduced the activity of an enzyme or limited cells’ ability to make copies of the enzyme, the disease’s destruction of nerve cells stopped. The enzyme maintains the proper balance of sodium and potassium in cells.

“We blocked the enzyme with digoxin,” said senior author Azad Bonni, MD, PhD. “This had a very strong effect, preventing the death of nerve cells that are normally killed in a cell culture model of ALS.”

The findings appear online Oct. 26 in Nature Neuroscience.

The results stemmed from Bonni’s studies of brain cells’ stress responses in a mouse model of ALS. The mice have a mutated version of a gene that causes an inherited form of the disease and develop many of the same symptoms seen in humans with ALS, including paralysis and death.

Efforts to monitor the activity of a stress response protein in the mice unexpectedly led the scientists to another protein: sodium-potassium ATPase. This enzyme ejects charged sodium particles from cells and takes in charged potassium particles, allowing cells to maintain an electrical charge across their outer membranes.

Maintenance of this charge is essential for the normal function of cells. The particular sodium-potassium ATPase highlighted by Bonni’s studies is found in nervous system cells called astrocytes. In the ALS mice, levels of the enzyme are higher than normal in astrocytes.

Bonni’s group found that the increase in sodium-potassium ATPase led the astrocytes to release harmful factors called inflammatory cytokines, which may kill motor neurons.

Recent studies have suggested that astrocytes may be crucial contributors to neurodegenerative disorders such as ALS, and Alzheimer’s, Huntington’s and Parkinson’s diseases. For example, placing astrocytes from ALS mice in culture dishes with healthy motor neurons causes the neurons to degenerate and die.

“Even though the neurons are normal, there’s something going on in the astrocytes that is harming the neurons,” said Bonni, the Edison Professor of Neurobiology and head of the Department of Anatomy and Neurobiology.

How this happens isn’t clear, but Bonni’s results suggest the sodium-potassium ATPase plays a key role. When he conducted the same experiment but blocked the enzyme in ALS astrocytes using digoxin, the normal motor nerve cells survived. Digoxin blocks the ability of sodium-potassium ATPase to eject sodium and bring in potassium.

In mice with the mutation for inherited ALS, those with only one copy of the gene for sodium-potassium ATPase survived an average of 20 days longer than those with two copies of the gene. When one copy of the gene is gone, cells make less of the enzyme.

“The mice with only one copy of the sodium-potassium ATPase gene live longer and are more mobile,” Bonni said. “They’re not normal, but they can walk around and have more motor neurons in their spinal cords.”

Many important questions remain about whether and how inhibitors of the sodium-potassium ATPase enzyme might be used to slow progressive paralysis in ALS, but Bonni said the findings offer an exciting starting point for further studies.

Filed under ALS Lou Gehrig’s disease neurodegeneration SOD1 digoxin neuroscience science

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Ultra-high-field MRI reveals language centres in the brain in much more detail In a new investigation by the University Department of Neurology, it has been possible for the first time to demonstrate that the areas of the brain that are important for understanding language can be pinpointed much more accurately using ultra-high-field MRI (7 Tesla) than with conventional clinical MRI scanners. This helps to protect these areas more effectively during brain surgery and avoid accidentally damaging it. Before brain surgery, it is important to precisely understand the areas of the brain required for language in order to avoid injuring them during the procedure. Their position can shift considerably, especially in patients with tumours or brain injuries. The brain’s flexibility also means that language centres can shift to other regions. If the areas responsible for language control and processing are injured during a brain operation, the patient can be left unable to communicate. In order to create a “map” of the language control centres prior to the operation, functional magnetic resonance imaging (fMRI) is used these days. A multi-centre study from 2013 demonstrated the advantages of fMRI-assisted localisation of the motor centres in the brain. In a new investigation by the working group led by Roland Beisteiner (University Department of Neurology), it has been possible for the first time to demonstrate that the areas of the brain that are important for understanding language can be pinpointed even more accurately using ultra-high-field MRI (7 Tesla) than with conventional clinical MRI scanners. The focus lies on the two most important language centres in the brain known as Wernicke’s area (which controls the understanding of language) and Broca’s area (which controls the motor functions involved with speech). The brain is scanned for activity while the patient is carrying out speech exercises. This allows the areas required for speech to be localised much more accurately than previously. “Ultra-high-field MR offers much greater sensitivity than classic MRI scanners”, explains Roland Beisteiner, “allowing even very weak signals to be recorded in areas that would otherwise have been missed.”

Ultra-high-field MRI reveals language centres in the brain in much more detail

In a new investigation by the University Department of Neurology, it has been possible for the first time to demonstrate that the areas of the brain that are important for understanding language can be pinpointed much more accurately using ultra-high-field MRI (7 Tesla) than with conventional clinical MRI scanners. This helps to protect these areas more effectively during brain surgery and avoid accidentally damaging it.

Before brain surgery, it is important to precisely understand the areas of the brain required for language in order to avoid injuring them during the procedure. Their position can shift considerably, especially in patients with tumours or brain injuries. The brain’s flexibility also means that language centres can shift to other regions. If the areas responsible for language control and processing are injured during a brain operation, the patient can be left unable to communicate. In order to create a “map” of the language control centres prior to the operation, functional magnetic resonance imaging (fMRI) is used these days.

A multi-centre study from 2013 demonstrated the advantages of fMRI-assisted localisation of the motor centres in the brain. In a new investigation by the working group led by Roland Beisteiner (University Department of Neurology), it has been possible for the first time to demonstrate that the areas of the brain that are important for understanding language can be pinpointed even more accurately using ultra-high-field MRI (7 Tesla) than with conventional clinical MRI scanners. The focus lies on the two most important language centres in the brain known as Wernicke’s area (which controls the understanding of language) and Broca’s area (which controls the motor functions involved with speech).

The brain is scanned for activity while the patient is carrying out speech exercises. This allows the areas required for speech to be localised much more accurately than previously. “Ultra-high-field MR offers much greater sensitivity than classic MRI scanners”, explains Roland Beisteiner, “allowing even very weak signals to be recorded in areas that would otherwise have been missed.”

Filed under neuroimaging fMRI brain activity language neuroscience science

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Activity in dendrites is critical in memory formation Why do we remember some things and not others? In a unique imaging study, two Northwestern University researchers have discovered how neurons in the brain might allow some experiences to be remembered while others are forgotten. It turns out, if you want to remember something about your environment, you better involve your dendrites. Using a high-resolution, one-of-a-kind microscope, Daniel A. Dombeck and Mark E. J. Sheffield peered into the brain of a living animal and saw exactly what was happening in individual neurons called place cells as the animal navigated a virtual reality maze. The scientists found that, contrary to current thought, the activity of a neuron’s cell body and its dendrites can be different. They observed that when cell bodies were activated but the dendrites were not activated during an animal’s experience, a lasting memory of that experience was not formed by the neurons. This suggests that the cell body seems to represent ongoing experience, while dendrites, the treelike branches of a neuron, help to store that experience as a memory. "There are a lot of theories on memory but very little data as to how individual neurons actually store information in a behaving animal," said Dombeck, assistant professor of neurobiology in the Weinberg College of Arts and Sciences and the study’s senior author. "Now we have uncovered signals in dendrites that we think are very important for learning and memory. Our findings could explain why some experiences are remembered and others are forgotten." In the brain’s hippocampus, there are hundreds of thousands of place cells — neurons essential to the brain’s GPS system. Dombeck and Sheffield are the first to image the activity of individual dendrites in place cells. Their findings contribute to our understanding of how the brain represents the world around it and also point to dendrites as a new potential target for therapeutics to combat memory deficits and debilitating diseases, such as Alzheimer’s disease (AD). Disruption to the brain’s GPS system is one of the first symptoms of AD, with many patients unable to find their way home. Understanding how place cells and their dendrites store these types of memories could help us find new ways to treat the disease. The Northwestern study will be published Oct. 26 by the journal Nature. Neuroscientist John O’Keefe discovered place cells in 1971 (and received this year’s Nobel Prize in physiology and medicine), but it is only in the last few years that scientists, such as Dombeck and Sheffield, have been able to image these neurons that represent a map of where we are in our environment. In their study, Dombeck and Sheffield found dendrite signals that could explain how an animal can experience something without storing the experience as a memory. They saw that dendrites are not always activated when the cell body is activated in a neuron. Signals produced in the dendrites (used to store information) and signals within the neuron cell body (used to compute and transmit information) can be either highly synchronized or desynchronized depending on how well the neurons remember different features of the maze. Scientists have long believed that the neuronal tasks of computing and storing information are connected — when neurons compute information, they are also storing it, and vice versa. The Northwestern study provides evidence against this classic view of neuronal function. "We experience events all the time, which must be represented in the brain by the activity of neurons, but not all these events can be recalled later," said Mark E. J. Sheffield, a postdoctoral fellow in Dombeck’s lab and first author of the study. "A daily commute to work, for example, requires the activity of millions of neurons, but you would be hard pressed to remember what was happening halfway through your commute last Tuesday," Sheffield said. "How is it then that the neurons could be activated during the commute without storing that information in the brain? Now we may have an explanation for how this occurs." Dombeck and Sheffield built their own laser scanning microscope that can image neurons on multiple planes. They then studied individual animals navigating (on a trackball) a virtual reality maze constructed using the video game Quake II. Each lit-up structure seen in the images they took indicate a neuron firing action potentials. The activity of these neurons represents an animal’s experience of where it is in the environment, the researchers said. Whether the neurons store this experience or not appears to depend on the activity of the neurons’ dendrites. (Image credit)

Activity in dendrites is critical in memory formation

Why do we remember some things and not others? In a unique imaging study, two Northwestern University researchers have discovered how neurons in the brain might allow some experiences to be remembered while others are forgotten. It turns out, if you want to remember something about your environment, you better involve your dendrites.

Using a high-resolution, one-of-a-kind microscope, Daniel A. Dombeck and Mark E. J. Sheffield peered into the brain of a living animal and saw exactly what was happening in individual neurons called place cells as the animal navigated a virtual reality maze.

The scientists found that, contrary to current thought, the activity of a neuron’s cell body and its dendrites can be different. They observed that when cell bodies were activated but the dendrites were not activated during an animal’s experience, a lasting memory of that experience was not formed by the neurons. This suggests that the cell body seems to represent ongoing experience, while dendrites, the treelike branches of a neuron, help to store that experience as a memory.

"There are a lot of theories on memory but very little data as to how individual neurons actually store information in a behaving animal," said Dombeck, assistant professor of neurobiology in the Weinberg College of Arts and Sciences and the study’s senior author. "Now we have uncovered signals in dendrites that we think are very important for learning and memory. Our findings could explain why some experiences are remembered and others are forgotten."

In the brain’s hippocampus, there are hundreds of thousands of place cells — neurons essential to the brain’s GPS system. Dombeck and Sheffield are the first to image the activity of individual dendrites in place cells.

Their findings contribute to our understanding of how the brain represents the world around it and also point to dendrites as a new potential target for therapeutics to combat memory deficits and debilitating diseases, such as Alzheimer’s disease (AD). Disruption to the brain’s GPS system is one of the first symptoms of AD, with many patients unable to find their way home. Understanding how place cells and their dendrites store these types of memories could help us find new ways to treat the disease.

The Northwestern study will be published Oct. 26 by the journal Nature.

Neuroscientist John O’Keefe discovered place cells in 1971 (and received this year’s Nobel Prize in physiology and medicine), but it is only in the last few years that scientists, such as Dombeck and Sheffield, have been able to image these neurons that represent a map of where we are in our environment.

In their study, Dombeck and Sheffield found dendrite signals that could explain how an animal can experience something without storing the experience as a memory.

They saw that dendrites are not always activated when the cell body is activated in a neuron. Signals produced in the dendrites (used to store information) and signals within the neuron cell body (used to compute and transmit information) can be either highly synchronized or desynchronized depending on how well the neurons remember different features of the maze.

Scientists have long believed that the neuronal tasks of computing and storing information are connected — when neurons compute information, they are also storing it, and vice versa. The Northwestern study provides evidence against this classic view of neuronal function.

"We experience events all the time, which must be represented in the brain by the activity of neurons, but not all these events can be recalled later," said Mark E. J. Sheffield, a postdoctoral fellow in Dombeck’s lab and first author of the study.

"A daily commute to work, for example, requires the activity of millions of neurons, but you would be hard pressed to remember what was happening halfway through your commute last Tuesday," Sheffield said. "How is it then that the neurons could be activated during the commute without storing that information in the brain? Now we may have an explanation for how this occurs."

Dombeck and Sheffield built their own laser scanning microscope that can image neurons on multiple planes. They then studied individual animals navigating (on a trackball) a virtual reality maze constructed using the video game Quake II.

Each lit-up structure seen in the images they took indicate a neuron firing action potentials. The activity of these neurons represents an animal’s experience of where it is in the environment, the researchers said. Whether the neurons store this experience or not appears to depend on the activity of the neurons’ dendrites.

(Image credit)

Filed under place cells memory formation dendrites hippocampus neurons neuroscience science

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Just 30 minutes of exercise has benefits for the brain University of Adelaide neuroscientists have discovered that just one session of aerobic exercise is enough to spark positive changes in the brain that could lead to improved memory and coordination of motor skills. A study conducted by researchers in the University’s Robinson Research Institute has found changes in the brain that were likely to make it more “plastic” after only 30 minutes of vigorous exercise. The study involved a small group of healthy people aged in their late 20s to early 30s who rode exercise bikes. They were monitored for changes in the brain immediately after the exercise and again 15 minutes later. "We saw positive changes in the brain straight away, and these improvements were sustained 15 minutes after the exercise had ended," says research leader Associate Professor Michael Ridding. "Plasticity in the brain is important for learning, memory and motor skill coordination. The more ‘plastic’ the brain becomes, the more it’s able to reorganise itself, modifying the number and strength of connections between nerve cells and different brain areas." Associate Professor Ridding says past research has shown that regular physical activity can have positive effects on brain function and plasticity, but it was unknown whether a stand-alone session of exercise would also have similar positive effects. "We now have evidence suggesting that it does," he says. "This exercise-related change in the brain may, in part, explain why physical activity has a positive effect on memory and higher-level functions." Associate Professor Ridding says there is now mounting evidence that engaging in aerobic exercise positively influences brain function in many ways - at cellular and molecular levels, as well as in the brain’s architecture. "Although this was a small sample group, it helps us to better understand the overall picture of how exercise influences the brain," he says. "We know that plasticity is also important for recovery from brain damage, so this opens up potential therapeutic avenues for patients. "Further research will be required to see what the possible long-term benefits could be for patients as well as healthy people."

Just 30 minutes of exercise has benefits for the brain

University of Adelaide neuroscientists have discovered that just one session of aerobic exercise is enough to spark positive changes in the brain that could lead to improved memory and coordination of motor skills.

A study conducted by researchers in the University’s Robinson Research Institute has found changes in the brain that were likely to make it more “plastic” after only 30 minutes of vigorous exercise.

The study involved a small group of healthy people aged in their late 20s to early 30s who rode exercise bikes. They were monitored for changes in the brain immediately after the exercise and again 15 minutes later.

"We saw positive changes in the brain straight away, and these improvements were sustained 15 minutes after the exercise had ended," says research leader Associate Professor Michael Ridding.

"Plasticity in the brain is important for learning, memory and motor skill coordination. The more ‘plastic’ the brain becomes, the more it’s able to reorganise itself, modifying the number and strength of connections between nerve cells and different brain areas."

Associate Professor Ridding says past research has shown that regular physical activity can have positive effects on brain function and plasticity, but it was unknown whether a stand-alone session of exercise would also have similar positive effects.

"We now have evidence suggesting that it does," he says. "This exercise-related change in the brain may, in part, explain why physical activity has a positive effect on memory and higher-level functions."

Associate Professor Ridding says there is now mounting evidence that engaging in aerobic exercise positively influences brain function in many ways - at cellular and molecular levels, as well as in the brain’s architecture.

"Although this was a small sample group, it helps us to better understand the overall picture of how exercise influences the brain," he says.

"We know that plasticity is also important for recovery from brain damage, so this opens up potential therapeutic avenues for patients.

"Further research will be required to see what the possible long-term benefits could be for patients as well as healthy people."

Filed under exercise memory plasticity physical activity brain function neuroscience science

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Dietary Flavanols Reverse Age-Related Memory Decline

Dietary cocoa flavanols—naturally occurring bioactives found in cocoa—reversed age-related memory decline in healthy older adults, according to a study led by Columbia University Medical Center (CUMC) scientists. The study, published today in the advance online issue of Nature Neuroscience, provides the first direct evidence that one component of age-related memory decline in humans is caused by changes in a specific region of the brain and that this form of memory decline can be improved by a dietary intervention.

As people age, they typically show some decline in cognitive abilities, including learning and remembering such things as the names of new acquaintances or where they parked the car or placed their keys. This normal age-related memory decline starts in early adulthood but usually does not have any noticeable impact on quality of life until people reach their fifties or sixties. Age-related memory decline is different from the often-devastating memory impairment that occurs with Alzheimer’s, in which a disease process damages and destroys neurons in various parts of the brain, including the memory circuits.

Previous work, including by the laboratory of senior author Scott A. Small, MD, had shown that changes in a specific part of the brain—the dentate gyrus—are associated with age-related memory decline. Until now, however, the evidence in humans showed only a correlational link, not a causal one. To see if the dentate gyrus is the source of age-related memory decline in humans, Dr. Small and his colleagues tested whether compounds called cocoa flavanols can improve the function of this brain region and improve memory. Flavanols extracted from cocoa beans had previously been found to improve neuronal connections in the dentate gyrus of mice.

Dr. Small is the Boris and Rose Katz Professor of Neurology (in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, the Sergievsky Center, and the Departments of Radiology and Psychiatry) and director of the Alzheimer’s Disease Research Center in the Taub Institute at CUMC.

A cocoa flavanol-containing test drink prepared specifically for research purposes was produced by the food company Mars, Incorporated, which also partly supported the research, using a proprietary process to extract flavanols from cocoa beans. Most methods of processing cocoa remove many of the flavanols found in the raw plant.

In the CUMC study, 37 healthy volunteers, ages 50 to 69, were randomized to receive either a high-flavanol diet (900 mg of flavanols a day) or a low-flavanol diet (10 mg of flavanols a day) for three months. Brain imaging and memory tests were administered to each participant before and after the study. The brain imaging measured blood volume in the dentate gyrus, a measure of metabolism, and the memory test involved a 20-minute pattern-recognition exercise designed to evaluate a type of memory controlled by the dentate gyrus.

“When we imaged our research subjects’ brains, we found noticeable improvements in the function of the dentate gyrus in those who consumed the high-cocoa-flavanol drink,” said lead author Adam M. Brickman, PhD, associate professor of neuropsychology at the Taub Institute.

The high-flavanol group also performed significantly better on the memory test. “If a participant had the memory of a typical 60-year-old at the beginning of the study, after three months that person on average had the memory of a typical 30- or 40-year-old,” said Dr. Small. He cautioned, however, that the findings need to be replicated in a larger study—which he and his team plan to do.    

Flavanols are also found naturally in tea leaves and in certain fruits and vegetables, but the overall amounts, as well as the specific forms and mixtures, vary widely.

The precise formulation used in the CUMC study has also been shown to improve cardiovascular health. Brigham and Women’s Hospital in Boston recently announced an NIH-funded study of 18,000 men and women to see whether flavanols can help prevent heart attacks and strokes.

The researchers point out that the product used in the study is not the same as chocolate, and they caution against an increase in chocolate consumption in an attempt to gain this effect.

Two innovations by the investigators made the study possible. One was a new information-processing tool that allows the imaging data to be presented in a single three-dimensional snapshot, rather than in numerous individual slices. The tool was developed in Dr. Small’s lab by Usman A. Khan, an MD-PhD student in the lab, and Frank A. Provenzano, a biomedical engineering graduate student at Columbia. The other innovation was a modification to a classic neuropsychological test, allowing the researchers to evaluate memory function specifically localized to the dentate gyrus. The revised test was developed by Drs. Brickman and Small.

Besides flavanols, exercise has been shown in previous studies, including those of Dr. Small, to improve memory and dentate gyrus function in younger people. In the current study, the researchers were unable to assess whether exercise had an effect on memory or on dentate gyrus activity. “Since we didn’t reach the intended VO2max (maximal oxygen uptake) target,” said Dr. Small, “we couldn’t evaluate whether exercise was beneficial in this context. This is not to say that exercise is not beneficial for cognition. It may be that older people need more intense exercise to reach VO2max levels that have therapeutic effects.”

Filed under aging memory decline flavanols dentate gyrus cognition memory neuroscience science

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