Neuroscience

Articles and news from the latest research reports.

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New High-Tech Lab Records the Brain and Body in Action

Until recently, the answers to basic questions of how diseases affect the brain – much less the ways to treat them – were lost to the limitations on how scientists could study brain function under real-world conditions. Most technology immobilized subjects inside big, noisy machines or tethered them to computers that made it impossible to simulate what it’s really like to live and interact in a complex world.

But now UC San Francisco neuroscientist Adam Gazzaley, MD, PhD, is hoping to paint a fuller picture of what is happening in the minds and bodies of those suffering from brain disease with his new lab, Neuroscape, which bridges the worlds of neuroscience and high-tech.

In the Neuroscape lab, wireless and mobile technologies set research participants free to move around and interact inside 3-D environments, while scientists make functional recordings with an array of technologies. Gazzaley hopes this will bring his field closer to understanding how complex neurological and psychiatric diseases really work and help doctors like him repurpose technologies built for fitness or fun into targeted therapies for their patients.

“I want us to have a platform that enables us to be more creative and aggressive in thinking how software and hardware can be a new medicine to improve brain health,” said Gazzaley, an associate professor of neurology, physiology and psychiatry and director of the UCSF Neuroscience Imaging Center. “Often, high-tech innovations take a decade to move beyond the entertainment industry and reach science and medicine. That needs to change.”

As a demonstration of what Neuroscape can do, Gazzaley’s team created new imaging technology that he calls GlassBrain, in collaboration with the Swartz Center at UC San Diego and Nvidia, which makes high-end computational computer chips. GlassBrain creates vivid, color visualizations of the structures of the brain and the white matter that connects them, as they pulse with electrical activity in real time.

These brain waves are recorded through electroencephalography (EEG), which measures electrical potentials on the scalp. Ordinary EEG recordings look like wavy horizontal lines, but GlassBrain turns the data into bursts of rhythmic activity that speed along golden spaghetti-like connections threading through a glowing, multi-colored glass-like image of a brain. Gazzaley is now looking at how to feed this information back to his subjects, for example by using the data from real-time EEG to make video games that adapt as people play them to selectively challenge weak brain processes. 

Gazzaley has already used the technology to image the brain of former Grateful Dead drummer Mickey Hart as he plays a hypnotic, electronic beat on a Roland digital percussion device with NeuroDrummer, a game the Gazzaley Lab is designing to enhance brain function through rhythmic training. Hart, whose brain is healthy, is collaborating with Gazzaley to develop the game and performed on NeuroDrummer while immersed in virtual reality on an Oculus Rift at the Neuroscape lab opening on March 5.

Filed under virtual reality electroencephalography NeuroDrummer neuroscience science

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Discovery sheds new light on marijuana’s anxiety relief effects An international group led by Vanderbilt University researchers has found cannabinoid receptors, through which marijuana exerts its effects, in a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight response. This is the first time cannabinoid receptors have been identified in the central nucleus of the amygdala in a mouse model, they report in the current issue of the journal Neuron. The discovery may help explain why marijuana users say they take the drug mainly to reduce anxiety, said Sachin Patel, M.D., Ph.D., the paper’s senior author and professor of Psychiatry and of Molecular Physiology and Biophysics. Led by first author Teniel Ramikie, a graduate student in Patel’s lab, the researchers also showed for the first time how nerve cells in this part of the brain make and release their own natural “endocannabinoids.” The study “could be highly important for understanding how cannabis exerts its behavioral effects,” Patel said. As the legalization of marijuana spreads across the country, more people — and especially young people whose brains are still developing — are being exposed to the drug. Previous studies at Vanderbilt and elsewhere, Patel said, have suggested the following: • The natural endocannabinoid system regulates anxiety and the response to stress by dampening excitatory signals that involve the neurotransmitter glutamate. • Chronic stress or acute, severe emotional trauma can cause a reduction in both the production of endocannabinoids and the responsiveness of the receptors. Without their “buffering” effect, anxiety goes up. • While marijuana’s “exogenous” cannabinoids also can reduce anxiety, chronic use of the drug down-regulates the receptors, paradoxically increasing anxiety. This can trigger “a vicious cycle” of increasing marijuana use that in some cases leads to addiction. In the current study, the researchers used high-affinity antibodies to “label” the cannabinoid receptors so they could be seen using various microscopy techniques, including electron microscopy, which allowed very detailed visualization at individual synapses, or gaps between nerve cells. “We know where the receptors are, we know their function, we know how these neurons make their own cannabinoids,” Patel said. “Now can we see how that system is affected by … stress and chronic (marijuana) use? It might fundamentally change our understanding of cellular communication in the amygdala.” (Image: Shutterstock)

Discovery sheds new light on marijuana’s anxiety relief effects

An international group led by Vanderbilt University researchers has found cannabinoid receptors, through which marijuana exerts its effects, in a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight response.

This is the first time cannabinoid receptors have been identified in the central nucleus of the amygdala in a mouse model, they report in the current issue of the journal Neuron.

The discovery may help explain why marijuana users say they take the drug mainly to reduce anxiety, said Sachin Patel, M.D., Ph.D., the paper’s senior author and professor of Psychiatry and of Molecular Physiology and Biophysics.

Led by first author Teniel Ramikie, a graduate student in Patel’s lab, the researchers also showed for the first time how nerve cells in this part of the brain make and release their own natural “endocannabinoids.”

The study “could be highly important for understanding how cannabis exerts its behavioral effects,” Patel said. As the legalization of marijuana spreads across the country, more people — and especially young people whose brains are still developing — are being exposed to the drug.
Previous studies at Vanderbilt and elsewhere, Patel said, have suggested the following:

• The natural endocannabinoid system regulates anxiety and the response to stress by dampening excitatory signals that involve the neurotransmitter glutamate.

• Chronic stress or acute, severe emotional trauma can cause a reduction in both the production of endocannabinoids and the responsiveness of the receptors. Without their “buffering” effect, anxiety goes up.

• While marijuana’s “exogenous” cannabinoids also can reduce anxiety, chronic use of the drug down-regulates the receptors, paradoxically increasing anxiety. This can trigger “a vicious cycle” of increasing marijuana use that in some cases leads to addiction.

In the current study, the researchers used high-affinity antibodies to “label” the cannabinoid receptors so they could be seen using various microscopy techniques, including electron microscopy, which allowed very detailed visualization at individual synapses, or gaps between nerve cells.

“We know where the receptors are, we know their function, we know how these neurons make their own cannabinoids,” Patel said. “Now can we see how that system is affected by … stress and chronic (marijuana) use? It might fundamentally change our understanding of cellular communication in the amygdala.”

(Image: Shutterstock)

Filed under anxiety cannabis cannabinoid receptors amygdala glutamate neuroscience science

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Scientists Create Most Detailed Picture Ever of Membrane Protein Linked to Learning, Memory, Anxiety, Pain and Brain Disorders Researchers at The Scripps Research Institute (TSRI) and Vanderbilt University have created the most detailed 3-D picture yet of a membrane protein that is linked to learning, memory, anxiety, pain and brain disorders such as schizophrenia, Parkinson’s, Alzheimer’s and autism. "This receptor family is an exciting new target for future medicines for treatment of brain disorders," said P. Jeffrey Conn, PhD, Lee E. Limbird Professor of Pharmacology and director of the Vanderbilt Center for Neuroscience Drug Discovery, who was a senior author of the study with Raymond Stevens, PhD, a professor in the Department of Integrative Structural and Computational Biology at TSRI. "This new understanding of how drug-like molecules engage the receptor at an atomic level promises to have a major impact on new drug discovery efforts." The research—which focuses on the mGlu1 receptor—was reported in the March 6, 2014 issue of the journal Science. A Family of Drug Targets The mGlu1 receptor, which helps regulate the neurotransmitter glutamate, belongs to a superfamily of molecules known as G protein-coupled receptors (GPCRs). GPCRs sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters and light. After binding these molecules, GPCRs trigger a specific response inside the cell. More than one-third of therapeutic drugs target GPCRs—including allergy and heart medications, drugs that target the central nervous system and anti-depressants. The Stevens lab’s work has revolved around determining the structure and function of GPCRs. GPCRs are not well understood and many fundamental breakthroughs are now occurring due to the understanding of GPCRs as complex machines, carefully regulated by cholesterol and sodium.  When the Stevens group decided to pursue the structure of mGlu1 and other key members of the mGlu family, it was natural the scientists reached out to the researchers at Vanderbilt. “They are the best in the world at understanding mGlu receptors,” said Stevens. “By collaborating with experts in specific receptor subfamilies, we can reach our goal of understanding the human GPCR superfamily and how GPCRs control human cell signaling.” Colleen Niswender, PhD, director of Molecular Pharmacology and research associate professor of Pharmacology at the Vanderbilt Center for Neuroscience Drug Discovery, also thought the collaboration made sense. “This work leveraged the unique strengths of the Vanderbilt and Scripps teams in applying structural biology, molecular modeling, allosteric modulator pharmacology and structure-activity relationships to validate the receptor structure,” she said. The Challenge of the Unknown mGlu1 was a particularly challenging research topic. In general, GPCRs are exceedingly flimsy, fragile proteins when not anchored within their native cell membranes. Coaxing them to line up to form crystals, so that their structures can be determined through X-ray crystallography, has been a formidable challenge. And the mGlu1 receptor is particularly tricky as, in addition to the domain spanning the membrane, it has a large domain extending into the extracellular space. Moreover, two copies of this multidomain receptor associating in a dimer are needed to transmit glutamate’s signal across the membrane.    The task was made more difficult because there was no template for mGlu1 from closely related GPCR proteins to guide the researchers. “mGlu1 belongs to class C GPCRs, of which no structure has been solved before,” said TSRI graduate student Chong Wang, a first author of the new study with TSRI graduate student Huixian Wu. “This made the project much harder. We could not use other GPCRs as a template to design constructs for expression and stabilization or to help interpret diffraction data. The structure was so different that old school methods in novel protein structure determination had to be used.” Surprising Results The team decided to try to determine the structure of mGlu1 bound to novel “allosteric modulators” of mGlu1 contributed by the Vanderbilt group. Allosteric modulators bind to a site far away from the binding site of the natural activator (in this case, presumably the glutamate molecule), but change the shape of the molecule enough to affect receptor function. In the case of allosteric drug candidates, the hope is that the compounds affect the receptor function in a desirable, therapeutic way. "Allosteric modulators are promising drug candidates as they can ‘fine-tune’ GPCR function,” said Karen Gregory, a former postdoctoral fellow at Vanderbilt University, now at Monash Institute of Pharmaceutical Sciences. “However, without a good idea of how drug-like compounds interact with the receptor to adjust the strength of the signal, discovery efforts are challenging." The team proceeded to apply a combination of techniques, including X-ray crystallography, structure-activity relationships, mutagenesis and full-length dimer modeling. At the end of the study, they had achieved a high-resolution image of mGlu1 in complex with one of the drug candidates, as well as a deeper understanding of the receptor’s function and pharmacology. The findings show that mGlu1 possesses structural features both similar to and distinct from those seen in other GPCR classes, but in ways that would have been impossible to predict in advance. “Most surprising is that the entrance to a binding pocket in the transmembrane domain is almost completely covered by loops, restricting access for the binding of allosteric modulators,” said Vsevolod “Seva” Katritch, assistant professor of molecular biology at TSRI and a co-author of the paper. “This is very important for understanding action of the allosteric modulator drugs and may partially explain difficulties in screening for such drugs. “The mGlu1 receptor structure now provides a solid platform for much more reliable modeling of closely related receptors,” he continued, “some of which are equally important in drug discovery.”

Scientists Create Most Detailed Picture Ever of Membrane Protein Linked to Learning, Memory, Anxiety, Pain and Brain Disorders

Researchers at The Scripps Research Institute (TSRI) and Vanderbilt University have created the most detailed 3-D picture yet of a membrane protein that is linked to learning, memory, anxiety, pain and brain disorders such as schizophrenia, Parkinson’s, Alzheimer’s and autism.

"This receptor family is an exciting new target for future medicines for treatment of brain disorders," said P. Jeffrey Conn, PhD, Lee E. Limbird Professor of Pharmacology and director of the Vanderbilt Center for Neuroscience Drug Discovery, who was a senior author of the study with Raymond Stevens, PhD, a professor in the Department of Integrative Structural and Computational Biology at TSRI. "This new understanding of how drug-like molecules engage the receptor at an atomic level promises to have a major impact on new drug discovery efforts."

The research—which focuses on the mGlu1 receptor—was reported in the March 6, 2014 issue of the journal Science.

A Family of Drug Targets

The mGlu1 receptor, which helps regulate the neurotransmitter glutamate, belongs to a superfamily of molecules known as G protein-coupled receptors (GPCRs).

GPCRs sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters and light. After binding these molecules, GPCRs trigger a specific response inside the cell. More than one-third of therapeutic drugs target GPCRs—including allergy and heart medications, drugs that target the central nervous system and anti-depressants.

The Stevens lab’s work has revolved around determining the structure and function of GPCRs. GPCRs are not well understood and many fundamental breakthroughs are now occurring due to the understanding of GPCRs as complex machines, carefully regulated by cholesterol and sodium. 

When the Stevens group decided to pursue the structure of mGlu1 and other key members of the mGlu family, it was natural the scientists reached out to the researchers at Vanderbilt. “They are the best in the world at understanding mGlu receptors,” said Stevens. “By collaborating with experts in specific receptor subfamilies, we can reach our goal of understanding the human GPCR superfamily and how GPCRs control human cell signaling.”

Colleen Niswender, PhD, director of Molecular Pharmacology and research associate professor of Pharmacology at the Vanderbilt Center for Neuroscience Drug Discovery, also thought the collaboration made sense. “This work leveraged the unique strengths of the Vanderbilt and Scripps teams in applying structural biology, molecular modeling, allosteric modulator pharmacology and structure-activity relationships to validate the receptor structure,” she said.

The Challenge of the Unknown

mGlu1 was a particularly challenging research topic.

In general, GPCRs are exceedingly flimsy, fragile proteins when not anchored within their native cell membranes. Coaxing them to line up to form crystals, so that their structures can be determined through X-ray crystallography, has been a formidable challenge. And the mGlu1 receptor is particularly tricky as, in addition to the domain spanning the membrane, it has a large domain extending into the extracellular space. Moreover, two copies of this multidomain receptor associating in a dimer are needed to transmit glutamate’s signal across the membrane.   

The task was made more difficult because there was no template for mGlu1 from closely related GPCR proteins to guide the researchers.

“mGlu1 belongs to class C GPCRs, of which no structure has been solved before,” said TSRI graduate student Chong Wang, a first author of the new study with TSRI graduate student Huixian Wu. “This made the project much harder. We could not use other GPCRs as a template to design constructs for expression and stabilization or to help interpret diffraction data. The structure was so different that old school methods in novel protein structure determination had to be used.”

Surprising Results

The team decided to try to determine the structure of mGlu1 bound to novel “allosteric modulators” of mGlu1 contributed by the Vanderbilt group. Allosteric modulators bind to a site far away from the binding site of the natural activator (in this case, presumably the glutamate molecule), but change the shape of the molecule enough to affect receptor function. In the case of allosteric drug candidates, the hope is that the compounds affect the receptor function in a desirable, therapeutic way.

"Allosteric modulators are promising drug candidates as they can ‘fine-tune’ GPCR function,” said Karen Gregory, a former postdoctoral fellow at Vanderbilt University, now at Monash Institute of Pharmaceutical Sciences. “However, without a good idea of how drug-like compounds interact with the receptor to adjust the strength of the signal, discovery efforts are challenging."

The team proceeded to apply a combination of techniques, including X-ray crystallography, structure-activity relationships, mutagenesis and full-length dimer modeling. At the end of the study, they had achieved a high-resolution image of mGlu1 in complex with one of the drug candidates, as well as a deeper understanding of the receptor’s function and pharmacology.

The findings show that mGlu1 possesses structural features both similar to and distinct from those seen in other GPCR classes, but in ways that would have been impossible to predict in advance.

“Most surprising is that the entrance to a binding pocket in the transmembrane domain is almost completely covered by loops, restricting access for the binding of allosteric modulators,” said Vsevolod “Seva” Katritch, assistant professor of molecular biology at TSRI and a co-author of the paper. “This is very important for understanding action of the allosteric modulator drugs and may partially explain difficulties in screening for such drugs.

“The mGlu1 receptor structure now provides a solid platform for much more reliable modeling of closely related receptors,” he continued, “some of which are equally important in drug discovery.”

Filed under neurodegeneration learning memory glutamate genetics neuroscience science

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Motion-Sensing Cells in the Eye Let the Brain ‘Know’ About Directional Changes How do we “know” from the movements of speeding car in our field of view if it’s coming straight toward us or more likely to move to the right or left? Scientists have long known that our perceptions of the outside world are processed in our cortex, the six-layered structure in the outer part of our brains. But how much of that processing actually happens in cortex? Do the eyes tell the brain a lot or a little about the content of the outside world and the objects moving within it? In a detailed study of the neurons linking the eyes and brains of mice, biologists at UC San Diego discovered that the ability of our brains and those of other mammals to figure out and process in our brains directional movements is a result of the activation in the cortex of signals that originate from the direction-sensing cells in the retina of our eyes. “Even though direction-sensing cells in the retina have been known about for half a century, what they actually do has been a mystery- mostly because no one knew how to follow their connections deep into the brain,” said Andrew Huberman, an assistant professor of neurobiology, neurosciences and ophthalmology at UC San Diego, who headed the research team, which also involved biologists at the Salk Institute for Biological Sciences. “Our study provides the first direct link between direction-sensing cells in the retina and the cortex and thereby raises the new idea that we ‘know’ which direction things are moving specifically because of the activation of these direction-selective retinal neurons.” The study, recently published online, will appear in the March 20 print issue of Nature. The discovery of the link between direction-sensing cells in the retina and the cortex has a number of practical implications for neuroscientists who treat disabilities in motion processing, such as dysgraphia, a condition sometimes associated with dyslexia that affects direction-oriented skills. “Understanding the cells and neural circuits involved in sensing directional motion may someday help us understand defects in motion processing, such as those involved dyslexia, and it may inform strategies to treat or even re-wire these circuits in response to injury or common neurodegenerative diseases, such as glaucoma or Alzheimer’s,” said Huberman. He and his team discovered the link in mice by using new types of modified rabies viruses that were pioneered by Ed Callaway, a professor at the Salk Institute, and by imaging the activity of neurons deep in the brain during visual experience.

Motion-Sensing Cells in the Eye Let the Brain ‘Know’ About Directional Changes

How do we “know” from the movements of speeding car in our field of view if it’s coming straight toward us or more likely to move to the right or left?

Scientists have long known that our perceptions of the outside world are processed in our cortex, the six-layered structure in the outer part of our brains. But how much of that processing actually happens in cortex? Do the eyes tell the brain a lot or a little about the content of the outside world and the objects moving within it?

In a detailed study of the neurons linking the eyes and brains of mice, biologists at UC San Diego discovered that the ability of our brains and those of other mammals to figure out and process in our brains directional movements is a result of the activation in the cortex of signals that originate from the direction-sensing cells in the retina of our eyes.

“Even though direction-sensing cells in the retina have been known about for half a century, what they actually do has been a mystery- mostly because no one knew how to follow their connections deep into the brain,” said Andrew Huberman, an assistant professor of neurobiology, neurosciences and ophthalmology at UC San Diego, who headed the research team, which also involved biologists at the Salk Institute for Biological Sciences. “Our study provides the first direct link between direction-sensing cells in the retina and the cortex and thereby raises the new idea that we ‘know’ which direction things are moving specifically because of the activation of these direction-selective retinal neurons.” The study, recently published online, will appear in the March 20 print issue of Nature.

The discovery of the link between direction-sensing cells in the retina and the cortex has a number of practical implications for neuroscientists who treat disabilities in motion processing, such as dysgraphia, a condition sometimes associated with dyslexia that affects direction-oriented skills.

“Understanding the cells and neural circuits involved in sensing directional motion may someday help us understand defects in motion processing, such as those involved dyslexia, and it may inform strategies to treat or even re-wire these circuits in response to injury or common neurodegenerative diseases, such as glaucoma or Alzheimer’s,” said Huberman.

He and his team discovered the link in mice by using new types of modified rabies viruses that were pioneered by Ed Callaway, a professor at the Salk Institute, and by imaging the activity of neurons deep in the brain during visual experience.

Filed under vision visual cortex retina retinal ganglion cells lateral geniculate nucleus neuroscience science

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Researchers find drug therapy that could eventually reverse memory decline in seniors

It may seem normal: As we age, we misplace car keys, or can’t remember a name we just learned or a meal we just ordered. But University of Florida researchers say memory trouble doesn’t have to be inevitable, and they’ve found a drug therapy that could potentially reverse this type of memory decline.

The drug can’t yet be used in humans, but the researchers are pursuing compounds that could someday help the population of aging adults who don’t have Alzheimer’s or other dementias but still have trouble remembering day-to-day items. Their findings will be published in today’s (March 5) issue of the Journal of Neuroscience.

The kind of memory responsible for holding information in the mind for short periods of time is called “working memory.” Working memory relies on a balance of chemicals in the brain. The UF study shows this chemical balance tips in older adults, and working memory declines. The reason? It could be because their brains are producing too much of a chemical that slows neural activity.

“Graduate student Cristina Banuelos’ work suggests that cells that normally provide the brake on neural activity are in overdrive in the aged prefrontal cortex,” said researcher Jennifer Bizon, Ph.D., an associate professor in the department of neuroscience and a member of UF’s Evelyn F. & William L. McKnight Brain Institute.

This chemical, an inhibitory brain neurotransmitter called GABA, is essential. Without it, brain cells can become too active, similar to what happens in the brains of people with schizophrenia and epilepsy. A normal level of GABA helps maintain the optimal levels of cell activation, said collaborator Barry Setlow, Ph.D., an associate professor in UF’s departments of psychiatry and neuroscience.

Working memory underlies many mental abilities and is sometimes referred to as the brain’s mental sketchpad, Bizon said. For example, Bizon said, you use your working memory in many everyday activities such as calculating your final bill at the end of dining at a restaurant. Most people can calculate a 15 percent tip and add it to the cost of their meal without pencil and paper. Central to this process is the ability to keep multiple pieces of information in mind for a short duration — such as remembering the cost of your dinner while calculating the amount needed for the tip.

“Almost all higher cognitive processes depend on this fundamental operation,” Bizon said.

To determine the culprit behind working memory decline, the researchers tested the memory of young and aged rats in a “Skinner box.” In the Skinner box, rats had to remember the location of a lever for short periods of up to 30 seconds. The scientists found that while both young and old rats could remember the location of the lever for brief periods of time, as those time periods lengthened, old rats had more difficulty remembering the location of the lever than young rats.

But not all older rats did poorly on the memory test, just as not all older adults have memory problems. The study shows the older brains of some people or rats with no memory problems might compensate for the overactive inhibitory system — they are able to produce fewer GABA receptors and therefore bind less of the inhibitory chemical.

Older rats with memory problems had more GABA receptors. The drug the researchers tested blocked GABA receptors, mimicking the lower number of those receptors that some older rats had naturally and restoring working memory in aged rats to the level of younger rats.

“Modern medicine has done a terrific job of keeping us alive for longer, and now we have to keep up and determine how to maximize the quality of life for seniors,” Bizon said. “A key aspect of that is going to be developing strategies and therapies that can maintain and improve cognitive health.”

(Source: ufhealth.org)

Filed under aging prefrontal cortex memory memory decline GABA neuroscience science

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Plumes in the sleeping avian brain When we drift into deep slow-wave sleep (SWS), waves of neuronal activity wash across our neocortex. Birds also engage in SWS, but they lack this particular brain structure. Researchers from the Max Planck Institute for Ornithology in Seewiesen, Germany together with colleagues from the Netherlands and Australia have gained deeper insight into the sleeping avian brain. They found complex 3D plumes of brain activity propagating through the brain that clearly differed from the two-dimensional activity found in mammals. These findings show that the layered neuronal organization of the neocortex is not required for waves to propagate, and raise the intriguing possibility that the 3D plumes of activity perform computations not found in mammals. Mammals, including humans, depend upon the processing power of the neocortex to solve complex cognitive tasks. This part of the brain also plays an important role in sleep. During SWS, slow neuronal oscillations propagate across the neocortex as a traveling wave, much like sports fans performing the wave in a stadium. It is thought that this wave might be involved in coordinating the processing of information in distant brain regions. Birds have mammalian-like cognitive abilities, but yet different neuronal organization. They lack the elegant layered arrangement of neurons characteristic of the neocortex. Instead, homologous neurons are packaged in unlayered, seemingly poorly structured nuclear masses of neurons. Researchers from the Max Planck Institute for Ornithology in Seewiesen together with colleagues from the Netherlands and Australia now investigated in female zebra finches how brain activity changed over space and time during sleep. “When we first looked at the recordings, it appeared that the slow waves were occurring simultaneously in all recording sites. However, when we visualized the data as a movie and slowed it down, a fascinating picture emerged!” says Gabriël Beckers from Utrecht University, who developed the high-resolution recording method at the Max Planck Institute for Ornithology in Seewiesen. The waves were moving across the two-dimensional recording array as rapidly changing arcs of activity. Rotating the orientation of the array by 90 degrees revealed similar patterns, and thereby established the 3D nature of the plumes propagating through the brain. The researchers found similar patterns in distant brain regions involved in processing different types of information, suggesting that this type of activity is a general feature of the sleeping avian brain. In addition to revealing how neurons in the avian brain behave during sleep, this research also adds to our understanding of the sleeping neocortex. “Our findings demonstrate that the traveling nature of slow waves is not dependent upon the layered organization of neurons found in the neocortex, and is unlikely to be involved in functions unique to this pattern of neuronal organization,” says Niels Rattenborg, head of the Avian Sleep Group in Seewiesen. “In this respect, research on birds refines our understanding of what is and is not special about the neocortex.” Finally, the researchers wonder whether the 3D geometry of wave propagation in the avian brain reflects computational properties not found in the neocortex. While this idea is clearly speculative, the authors note that during the course of evolution, birds replaced the three-layered cortex present in their reptilian ancestors with nuclear brain structures. “Presumably, there are benefits to the seemingly disorganized, nuclear arrangement of neurons in the avian brain that we are far from understanding. Whether this relates to what we have observed in the sleeping bird brain is a wide open question,” says Rattenborg.

Plumes in the sleeping avian brain

When we drift into deep slow-wave sleep (SWS), waves of neuronal activity wash across our neocortex. Birds also engage in SWS, but they lack this particular brain structure. Researchers from the Max Planck Institute for Ornithology in Seewiesen, Germany together with colleagues from the Netherlands and Australia have gained deeper insight into the sleeping avian brain. They found complex 3D plumes of brain activity propagating through the brain that clearly differed from the two-dimensional activity found in mammals. These findings show that the layered neuronal organization of the neocortex is not required for waves to propagate, and raise the intriguing possibility that the 3D plumes of activity perform computations not found in mammals.

Mammals, including humans, depend upon the processing power of the neocortex to solve complex cognitive tasks. This part of the brain also plays an important role in sleep. During SWS, slow neuronal oscillations propagate across the neocortex as a traveling wave, much like sports fans performing the wave in a stadium. It is thought that this wave might be involved in coordinating the processing of information in distant brain regions. Birds have mammalian-like cognitive abilities, but yet different neuronal organization. They lack the elegant layered arrangement of neurons characteristic of the neocortex. Instead, homologous neurons are packaged in unlayered, seemingly poorly structured nuclear masses of neurons.

Researchers from the Max Planck Institute for Ornithology in Seewiesen together with colleagues from the Netherlands and Australia now investigated in female zebra finches how brain activity changed over space and time during sleep. “When we first looked at the recordings, it appeared that the slow waves were occurring simultaneously in all recording sites. However, when we visualized the data as a movie and slowed it down, a fascinating picture emerged!” says Gabriël Beckers from Utrecht University, who developed the high-resolution recording method at the Max Planck Institute for Ornithology in Seewiesen. The waves were moving across the two-dimensional recording array as rapidly changing arcs of activity. Rotating the orientation of the array by 90 degrees revealed similar patterns, and thereby established the 3D nature of the plumes propagating through the brain. The researchers found similar patterns in distant brain regions involved in processing different types of information, suggesting that this type of activity is a general feature of the sleeping avian brain.

In addition to revealing how neurons in the avian brain behave during sleep, this research also adds to our understanding of the sleeping neocortex. “Our findings demonstrate that the traveling nature of slow waves is not dependent upon the layered organization of neurons found in the neocortex, and is unlikely to be involved in functions unique to this pattern of neuronal organization,” says Niels Rattenborg, head of the Avian Sleep Group in Seewiesen. “In this respect, research on birds refines our understanding of what is and is not special about the neocortex.” Finally, the researchers wonder whether the 3D geometry of wave propagation in the avian brain reflects computational properties not found in the neocortex. While this idea is clearly speculative, the authors note that during the course of evolution, birds replaced the three-layered cortex present in their reptilian ancestors with nuclear brain structures. “Presumably, there are benefits to the seemingly disorganized, nuclear arrangement of neurons in the avian brain that we are far from understanding. Whether this relates to what we have observed in the sleeping bird brain is a wide open question,” says Rattenborg.

Filed under sleep neurons neocortex avian brain brain structure neuroscience science

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Blasts May Cause Brain Injury Even Without Symptoms

Veterans exposed to explosions who do not report symptoms of traumatic brain injury (TBI) may still have damage to the brain’s white matter comparable to veterans with TBI, according to researchers at Duke Medicine and the U.S. Department of Veterans Affairs.

The findings, published in the Journal of Head Trauma Rehabilitation on March 3, 2014, suggest that a lack of clear TBI symptoms following an explosion may not accurately reflect the extent of brain injury.

Veterans of recent military conflicts in Iraq and Afghanistan often have a history of exposure to explosive forces from bombs, grenades and other devices, although relatively little is known about whether this injures the brain. However, evidence is building – particularly among professional athletes – that subconcussive events have an effect on the brain.

"Similar to sports injuries, people near an explosion assume that if they don’t have clear symptoms – losing consciousness, blurred vision, headaches – they haven’t had injury to the brain,” said senior author Rajendra A. Morey, M.D., associate professor of psychiatry and behavioral sciences at Duke University School of Medicine and a psychiatrist at the Durham Veterans Affairs Medical Center. “Our findings are important because they’re showing that even if you don’t have symptoms, there may still be damage.”

Researchers in the Mid-Atlantic Mental Illness Research, Education and Clinical Center at the W.G. (Bill) Hefner Veterans Affairs Medical Center in Salisbury, N.C., evaluated 45 U.S. veterans who volunteered to participate in the study. The veterans, who served since September 2001, were split into three groups: veterans with a history of blast exposure with symptoms of TBI; veterans with a history of blast exposure without symptoms of TBI; and veterans without blast exposure. The study focused on veterans with primary blast exposure, or blast exposure without external injuries, and did not include those with brain injury from direct hits to the head.

To measure injury to the brain, the researchers used a type of MRI called Diffusion Tensor Imaging (DTI). DTI can detect injury to the brain’s white matter by measuring the flow of fluid in the brain. In healthy white matter, fluid moves in a directional manner, suggesting that the white matter fibers are intact. Injured fibers allow the fluid to diffuse.

White matter is the connective wiring that links different areas of the brain. Since most cognitive processes involve multiple parts of the brain working together, injury to white matter can impair the brain’s communication network and may result in cognitive problems.

Both groups of veterans who were near an explosion, regardless of whether they had TBI symptoms, showed a significant amount of injury compared to the veterans not exposed to a blast. The injury was not isolated to one area of the brain, and each individual had a different pattern of injury.

Using neuropsychological testing to assess cognitive performance, the researchers found a relationship between the amount of white matter injury and changes in reaction time and the ability to switch between mental tasks. However, brain injury was not linked to performance on other cognitive tests, including decision-making and organization.

“We expected the group that reported few symptoms at the time of primary blast exposure to be similar to the group without exposure. It was a surprise to find relatively similar DTI changes in both groups exposed to primary blast,” said Katherine H. Taber, Ph.D., a research health scientist at the W.G. (Bill) Hefner Veterans Affairs Medical Center and the study’s lead author. “We are not sure whether this indicates differences among individuals in symptoms-reporting or subconcussive effects of primary blast. It is clear there is more we need to know about the functional consequences of blast exposures.”

Given the study’s findings, the researchers said clinicians treating veterans should take into consideration a person’s exposure to explosive forces, even among those who did not initially show symptoms of TBI. In the future, they may use brain imaging to support clinical tests.

“Imaging could potentially augment the existing approaches that clinicians use to evaluate brain injury by looking below the surface for TBI pathology,” Morey said.

The researchers noted that the results are preliminary, and should be replicated in a larger study.

(Source: dukehealth.org)

Filed under brain injury TBI diffusion tensor imaging white matter neuroimaging neuroscience science

317 notes

Brain development provides insights into adolescent depression A new study led by the University of Melbourne and Orygen Youth Health Research Centre is the first to discover that the brain develops differently in adolescents who experience depression. These brain changes also represent possible risk factors for developing depression during teenage years. Lead research Professor Nick Allen from the Melbourne School of Psychological Sciences said, “It is well known that the brain continues to change and remodel itself during adolescence as part of healthy development.” “In this study, we found that the pattern of development (such as changes in brain structure between ages twelve to sixteen) in several key brain regions differed between depressed and non-depressed adolescents,” Professor Allen said. The brain regions involved include areas associated with the experience and regulation of emotion, as well as areas associated with learning and memory. 

 “The findings are an important breakthrough for exploring possible causes of depression in adolescence. They also suggest that both prevention and treatment for depression (even for early signs and symptoms of depression) in adolescence is essential, especially targeting those in the early years of adolescence aged twelve to sixteen,” he said. “We also observed some differences between males and females. For males, less growth in an area of the brain involved in processing threat and other unexpected events that is a critical part of the brain’s fear circuitry, was associated with depression. On the other hand, for females, greater growth of this area was found to be associated with depression.” 

 “This is important information because depression becomes much more common amongst girls during adolescence, and these findings tell us about some of the neurobiological factors that might play a role in this gender difference,” he said. Professor Allen says adolescence is a period during the lifespan where risk for developing depression dramatically increases. The study examined eighty-six adolescents (41 female) with no history of depressive disorders before age 12 by using a Magnetic Resonance Imaging (MRI) scanner, which allowed researchers to measure the volume of particular brain regions of interest. 

Participants underwent an MRI scan first at age twelve and again at age sixteen, when rates of depression were beginning to increase. 

Researchers also conducted detailed interviews with each of the participants at four different time points between age twelve and age eighteen. Thirty participants experienced a first episode of a depressive disorder during the follow-up period. These findings have recently been published in the American Journal of Psychiatry.

Brain development provides insights into adolescent depression

A new study led by the University of Melbourne and Orygen Youth Health Research Centre is the first to discover that the brain develops differently in adolescents who experience depression. These brain changes also represent possible risk factors for developing depression during teenage years.

Lead research Professor Nick Allen from the Melbourne School of Psychological Sciences said, “It is well known that the brain continues to change and remodel itself during adolescence as part of healthy development.”

“In this study, we found that the pattern of development (such as changes in brain structure between ages twelve to sixteen) in several key brain regions differed between depressed and non-depressed adolescents,” Professor Allen said.

The brain regions involved include areas associated with the experience and regulation of emotion, as well as areas associated with learning and memory. 



“The findings are an important breakthrough for exploring possible causes of depression in adolescence. They also suggest that both prevention and treatment for depression (even for early signs and symptoms of depression) in adolescence is essential, especially targeting those in the early years of adolescence aged twelve to sixteen,” he said.

“We also observed some differences between males and females. For males, less growth in an area of the brain involved in processing threat and other unexpected events that is a critical part of the brain’s fear circuitry, was associated with depression. On the other hand, for females, greater growth of this area was found to be associated with depression.” 



“This is important information because depression becomes much more common amongst girls during adolescence, and these findings tell us about some of the neurobiological factors that might play a role in this gender difference,” he said.

Professor Allen says adolescence is a period during the lifespan where risk for developing depression dramatically increases.

The study examined eighty-six adolescents (41 female) with no history of depressive disorders before age 12 by using a Magnetic Resonance Imaging (MRI) scanner, which allowed researchers to measure the volume of particular brain regions of interest. 

Participants underwent an MRI scan first at age twelve and again at age sixteen, when rates of depression were beginning to increase. 

Researchers also conducted detailed interviews with each of the participants at four different time points between age twelve and age eighteen. Thirty participants experienced a first episode of a depressive disorder during the follow-up period.

These findings have recently been published in the American Journal of Psychiatry.

Filed under brain development depression adolescents neuroimaging psychology neuroscience science

200 notes

Off with Your Glasses

TAU researchers discover a link between sharp vision and the brain’s processing speed

image

Middle-aged adults who suddenly need reading glasses, patients with traumatic brain injuries, and people with visual disorders such as “lazy eye” may have one thing in common — “visual crowding,” an inability to recognize individual items surrounded by multiple objects. Visual crowding makes it impossible to read, as single letters within words are rendered illegible. And basic cognitive functions such as facial recognition can also be significantly hampered. Scientists and clinicians currently attribute crowding to a disorder in peripheral vision.

Now Prof. Uri Polat, Maria Lev, and Dr. Oren Yehezkel of Tel Aviv University’s Goldschleger Eye Research Instituteat the Sackler Faculty of Medicine have discovered new evidence that correlates crowding in the fovea — a small part of the retina responsible for sharp vision — and the brain’s processing speed. These findings, published in Nature’s Scientific Reports, could greatly alter earlier models of visual crowding, which emphasized peripheral impairment exclusively. And for many adults lost without their reading glasses, this could improve their vision significantly.

"Current theories strongly stress that visual crowding does not exist in the fovea, that it’s a phenomenon that exists only in peripheral visual fields," said Prof. Polat. "But our study points to another part of the eye altogether — the fovea — and contributes to a unified model for how the brain integrates visual information."

A trained eye

According to Prof. Polat, vision is dynamic and changes rapidly, but it takes time for the brain to process this visual information. Rapidly moving tickers on TV, or traffic signs seen as the driver speeds past, are difficult for anyone to read. However, given enough time, someone with excellent vision can fully recognize the words. Those with slower processing speeds — usually the result of poor perceptive development or age — may not be able to decipher the tickers or the traffic signs. In the study, Prof. Polat employed his expertise in improving vision by retraining the brain and the foveal part of the eye, using exercises in which speed is a key element.

"Training adults to reduce foveal crowding leads to improved vision. A similar training we conducted two years ago allowed adults to eliminate their use of reading glasses altogether, using a technology provided by the GlassesOff company. Other patients who had lost sharp vision for whatever reason were also able to benefit from the same training and improve their processing speed and visual capabilities," said Prof. Polat.

Maria Lev, who performed the study as a part of her doctoral thesis, said one young subject had experienced significant limitations in school for years and had been unable to obtain a driver’s license due to severe visual impairment from foveal crowding. After undergoing training that emphasized a foveal rather than a peripheral focus, he was able to overcome the handicap.

"He finally managed to learn to read properly and found his way forward," said Lev. "I’m proud to say that today he is not only eligible for a driver’s license, he’s also been able to earn his master’s degree."

Prof. Polat and his team are currently exploring how visual integration and foveal crowding develop in various clinical cases.

(Source: aftau.org)

Filed under vision visual crowding foveal crowding fovea neuroscience science

85 notes

Yeast model reveals Alzheimer’s drug candidate and its mechanism of action Using a yeast model of Alzheimer’s disease (AD), Whitehead Institute researchers have identified a drug that reduces levels of the toxic protein fragment amyloid-β (Aβ) and prevents at least some of the cellular damage caused when Ab accumulates in the brains of AD patients. “We can use this yeast model to find small molecules that will address the underlying cellular pathologies of Alzheimer’s, an age-related disease whose burden will become even more significant as our population grows older,” says Kent Matlack, a former staff scientist in Whitehead Member Susan Lindquist’s lab. “We need a no-holds-barred approach to find effective compounds, and we need information about their mechanism of action quickly. Our work demonstrates that using a yeast model of Ab toxicity is a valid way to do this.” The U.S. National Institute on Aging estimates that 5.1 million Americans may have AD, the most common form of dementia, which progressively robs patients of their memories, thinking, and reasoning skills. Research focused on the disease has been hampered by the affected cells’ location in the brain, where they cannot be studied until after an AD patient’s death. To explore the cellular processes compromised by AD, researchers in Lindquist’s lab created a yeast model, first described in the journal Science in 2011, that mimics in vivo the accumulation of Aβ that occurs in the human disease. In the current research, which is described in this week’s issue of the journal Proceedings of the National Academy of Sciences (PNAS), a team of scientists in Lindquist’s lab used the yeast model to screen approximately 140,000 compounds to identify those capable of rescuing the cells from Aβ toxicity. One of the more promising classes of compounds has previously shown efficacy in animal models of AD and is about to complete a second phase II trial for AD. The mechanism by which the best-studied member of this class, clioquinol, targets Ab within the cell – where a large portion of it is produced in neurons – was unclear.   “Our work in the yeast model shows that clioquinol decreases the amount of Aβ in the cells by 90%,” says Daniel Tardiff, a scientist in Lindquist’s lab. “That’s a strong decrease, and it’s dose-dependent. I’ve tested a lot of compounds before, and I’ve never seen anything as dramatic.” Clioquinol chelates copper, meaning that it selectively binds the metal. In many AD patients, Aβ aggregates have higher concentrations of copper and other metals than normal, healthy brain tissue. Biochemical experiments also show that copper makes Aβ more toxic. With clioquinol’s chelation capabilities in mind, Tardiff and Matlack, co-authors of the PNAS paper, tested clioquinol’s effect on Aβ-expressing cells in the presence of copper. The drug dramatically increased the degradation of Aβ in a copper-dependent manner, and even restored the cellular protein-trafficking process known as endocytosis, which is disrupted in both the yeast model and in AD-affected neurons. “The clioquinol probably has a slightly higher affinity for copper than Aβ does, but it is not a strong enough chelator to strip the cell’s normal metalloproteins of the copper they need,” says Matlack. “From what we’ve seen in the yeast model, we think the drug pulls the copper away from Aβ. That would alter Aβ’s structure and likely make it more susceptible to degradation, thus shortening its half-life in the cell.” The results from clioquinol in yeast and the clinical potential of closely related compounds are promising. While these compounds are not yet ready to serve as AD drugs in the clinic, the identification of an AD-relevant compound and cellular pathology – along with the Lindquist lab’s previous identification of human AD risk alleles that reduce Ab toxicity in yeast – suggests that this discovery platform will continue to yield information and lead to more compounds with equal or greater effectiveness, some of which will hopefully make a difference in human disease. “It is important to remember that this class of compounds was shown to work in mouse models and in a limited human trial,” says Lindqust, who is also a professor of biology at MIT and an investigator of the Howard Hughes Medical Institute. “We have validated the yeast model and shown that we can find such compounds at a speed that was inconceivable before—indeed we found some compounds that look even more effective.”

Yeast model reveals Alzheimer’s drug candidate and its mechanism of action

Using a yeast model of Alzheimer’s disease (AD), Whitehead Institute researchers have identified a drug that reduces levels of the toxic protein fragment amyloid-β (Aβ) and prevents at least some of the cellular damage caused when Ab accumulates in the brains of AD patients.

“We can use this yeast model to find small molecules that will address the underlying cellular pathologies of Alzheimer’s, an age-related disease whose burden will become even more significant as our population grows older,” says Kent Matlack, a former staff scientist in Whitehead Member Susan Lindquist’s lab. “We need a no-holds-barred approach to find effective compounds, and we need information about their mechanism of action quickly. Our work demonstrates that using a yeast model of Ab toxicity is a valid way to do this.”

The U.S. National Institute on Aging estimates that 5.1 million Americans may have AD, the most common form of dementia, which progressively robs patients of their memories, thinking, and reasoning skills. Research focused on the disease has been hampered by the affected cells’ location in the brain, where they cannot be studied until after an AD patient’s death. To explore the cellular processes compromised by AD, researchers in Lindquist’s lab created a yeast model, first described in the journal Science in 2011, that mimics in vivo the accumulation of Aβ that occurs in the human disease.

In the current research, which is described in this week’s issue of the journal Proceedings of the National Academy of Sciences (PNAS), a team of scientists in Lindquist’s lab used the yeast model to screen approximately 140,000 compounds to identify those capable of rescuing the cells from Aβ toxicity. One of the more promising classes of compounds has previously shown efficacy in animal models of AD and is about to complete a second phase II trial for AD. The mechanism by which the best-studied member of this class, clioquinol, targets Ab within the cell – where a large portion of it is produced in neurons – was unclear.  

“Our work in the yeast model shows that clioquinol decreases the amount of Aβ in the cells by 90%,” says Daniel Tardiff, a scientist in Lindquist’s lab. “That’s a strong decrease, and it’s dose-dependent. I’ve tested a lot of compounds before, and I’ve never seen anything as dramatic.”

Clioquinol chelates copper, meaning that it selectively binds the metal. In many AD patients, Aβ aggregates have higher concentrations of copper and other metals than normal, healthy brain tissue. Biochemical experiments also show that copper makes Aβ more toxic.

With clioquinol’s chelation capabilities in mind, Tardiff and Matlack, co-authors of the PNAS paper, tested clioquinol’s effect on Aβ-expressing cells in the presence of copper. The drug dramatically increased the degradation of Aβ in a copper-dependent manner, and even restored the cellular protein-trafficking process known as endocytosis, which is disrupted in both the yeast model and in AD-affected neurons.

“The clioquinol probably has a slightly higher affinity for copper than Aβ does, but it is not a strong enough chelator to strip the cell’s normal metalloproteins of the copper they need,” says Matlack. “From what we’ve seen in the yeast model, we think the drug pulls the copper away from Aβ. That would alter Aβ’s structure and likely make it more susceptible to degradation, thus shortening its half-life in the cell.”

The results from clioquinol in yeast and the clinical potential of closely related compounds are promising. While these compounds are not yet ready to serve as AD drugs in the clinic, the identification of an AD-relevant compound and cellular pathology – along with the Lindquist lab’s previous identification of human AD risk alleles that reduce Ab toxicity in yeast – suggests that this discovery platform will continue to yield information and lead to more compounds with equal or greater effectiveness, some of which will hopefully make a difference in human disease.

“It is important to remember that this class of compounds was shown to work in mouse models and in a limited human trial,” says Lindqust, who is also a professor of biology at MIT and an investigator of the Howard Hughes Medical Institute. “We have validated the yeast model and shown that we can find such compounds at a speed that was inconceivable before—indeed we found some compounds that look even more effective.”

Filed under alzheimer's disease yeast model endocytosis beta amyloid Ab toxicity neuroscience science

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