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  • richardmitnick 4:02 pm on January 16, 2017 Permalink | Reply
    Tags: , Brain Studies, Connectome project, , Multiregional brain-on-a-chip,   

    From Wyss: “Multiregional brain on a chip” 

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    Wyss Institute bloc
    Wyss Institute

    January 14, 2017
    Leah Burrows

    Model allows researchers to study how diseases like schizophrenia impact different regions of the brain simultaneously.

    Harvard University researchers have developed a multiregional brain-on-a-chip that models the connectivity between three distinct regions of the brain. The in vitro model was used to extensively characterize the differences between neurons from different regions of the brain and to mimic the system’s connectivity.

    The research was published in the Journal of Neurophysiology.

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    Three areas populated with neurons representing different regions of the brain are interconnected by thin neuronal process (in green) to allow the study of complex diseases. Credit: Disease Biophysics Group/Harvard University

    “The brain is so much more than individual neurons,” said Ben Maoz, co-first author of the paper and a Technology Development Fellow at the Wyss Institute for Biologically Inspired Engineering, and Postdoctoral Fellow in the Disease Biophysics Group in the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). “It’s about the different types of cells and the connectivity between different regions of the brain. When modeling the brain, you need to be able to recapitulate that connectivity because there are many different diseases that attack those connections.”

    “Roughly twenty-six percent of the US healthcare budget is spent on neurological and psychiatric disorders,” said Wyss Institute Core Faculty member Kit Parker and the Tarr Family Professor of Bioengineering and Applied Physics Building at SEAS. “Tools to support the development of therapeutics to alleviate the suffering of these patients is not only the human thing to do, it is the best means of reducing this cost.”

    Researchers from the Wyss Institute and the Disease Biophysics Group at SEAS modeled three regions of the brain most affected by schizophrenia — the amygdala, hippocampus and prefrontal cortex.

    They began by characterizing the cell composition, protein expression, metabolism, and electrical activity of neurons from each region in vitro.

    “It’s no surprise that neurons in distinct regions of the brain are different but it is surprising just how different they are,” said Stephanie Dauth, co-first author of the paper and former postdoctoral fellow in the Disease Biophysics Group. “We found that the cell-type ratio, the metabolism, the protein expression and the electrical activity all differ between regions in vitro. This shows that it does make a difference which brain region’s neurons you’re working with.”

    Next, the team looked at how these neurons change when they’re communicating with one another. To do that, they cultured cells from each region independently and then let the cells establish connections via guided pathways embedded in the chip.

    The researchers then measured cell composition and electrical activity again and found that the cells dramatically changed when they were in contact with neurons from different regions.

    “When the cells are communicating with other regions, the cellular composition of the culture changes, the electrophysiology changes, all these inherent properties of the neurons change,” said Maoz. “This shows how important it is to implement different brain regions into in vitro models, especially when studying how neurological diseases impact connected regions of the brain.”

    To demonstrate the chip’s efficacy in modeling disease, the team doped different regions of the brain with the drug Phencyclidine hydrochloride — commonly known as PCP — which simulates schizophrenia. The brain-on-a-chip allowed the researchers for the first time to look at both the drug’s impact on the individual regions as well as its downstream effect on the interconnected regions in vitro.

    The brain-on-a-chip could be useful for studying any number of neurological and psychiatric diseases, including drug addiction, post traumatic stress disorder, and traumatic brain injury.

    “To date, the Connectome project has not recognized all of the networks in the brain,” said Parker. “In our studies, we are showing that the extracellular matrix network is an important part of distinguishing different brain regions and that, subsequently, physiological and pathophysiological processes in these brain regions are unique. This advance will not only enable the development of therapeutics, but fundamental insights as to how we think, feel, and survive.”

    This research was coauthored by Sean P. Sheehy, Matthew A. Hemphill, Tara Murty, Mary Kate Macedonia, Angie M. Greer and Bogdan Budnik. It was supported by the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Defense Advanced Research Projects Agency.

    See the full article here .

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    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
  • richardmitnick 1:20 pm on January 6, 2017 Permalink | Reply
    Tags: , , Brain Studies, ,   

    From Stanford: “Stanford study shows that tissue in the brain, rather than being lost, grows across childhood and may underlie better face recognition” 

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    Stanford University

    January 5, 2017
    Taylor Kubota
    (650) 724-7707
    tkubota@stanford.edu

    A central tenet in neuroscience has been that the amount of brain tissue goes in one direction throughout our lives – from too much to just enough. A new study finds that in some cases the brain can add tissue as well.

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    Stanford Professor Kalanit Grill-Spector, left, research associate Kevin Weiner and graduate student Jesse Gomez study growth in brain tissue enabling face recognition. (Image credit: Brianna Jeska)

    People are born with brains riddled with excess neural connections. Those are slowly pruned back until early childhood when, scientists thought, the brain’s structure becomes relatively stable.

    Now a pair of studies, published in the Jan. 6, 2017, issue of Science and Nov. 30, 2016, in Cerebral Cortex, suggest this process is more complicated than previously thought. For the first time, the group found microscopic tissue growth in the brain continues in regions that also show changes in function.

    The work overturns a central thought in neuroscience, which is that the amount of brain tissue goes in one direction throughout our lives – from too much to just enough. The group made this finding by looking at the brains of an often-overlooked participant pool: children.

    “I would say it’s only in the last 10 years that psychologists started looking at children’s brains,” said Kalanit Grill-Spector, a professor of psychology at Stanford and senior author of both papers. “The issue is, kids are not miniature adults and their brains show that. Our lab studies children because there’s still a lot of very basic knowledge to be learned about the developing brain in that age range.”

    Grill-Spector and her team examined a region of the brain that distinguishes faces from other objects. In Cerebral Cortex, they demonstrate that brain regions that recognize faces have a unique cellular make-up. In Science, they find that the microscopic structures within the region change from childhood into adulthood over a timescale that mirrors improvements in people’s ability to recognize faces.

    “We actually saw that tissue is proliferating,” said Jesse Gomez, graduate student in the Grill-Spector lab and lead author of the Science paper. “Many people assume a pessimistic view of brain tissue: that tissue is lost slowly as you get older. We saw the opposite – that whatever is left after pruning in infancy can be used to grow.”

    Microscopic brain changes

    The group studied regions of the brain that recognize faces and places, respectively, because knowing who you are looking at and where you are is important for everyday function. In adults, these parts of the brain are close neighbors, but with some visible structural differences.

    “If you could walk across an adult brain and you were to look down at the cells, it would be like walking through different neighborhoods,” Gomez said. “The cells look different. They’re organized differently.”

    Curious about the deeper cellular structures not visible by magnetic resonance imaging (MRI), the Stanford group collaborated with colleagues in the Institute of Neuroscience and Medicine, Research Centre Jülich, in Germany, who obtained thin tissue slices of post-mortem brains. Over the span of a year, this international collaboration figured out how to match brain regions identified with functional MRI in living brains with the corresponding brain slices. This allowed them to extract the microscopic cellular structure of the areas they scanned with functional MRI, which is not yet possible to do in living subjects. The microscopic images showed visible differences in the cellular structure between face and place regions.

    “There’s been this pipe dream in the field that we will one day be able to measure cellular architecture in living humans’ brains and this shows that we’re making progress,” said Kevin Weiner, a Stanford social science research associate, co-author of the Science paper and co-lead author of the Cerebral Cortex paper with Michael Barnett, a former research assistant in the lab.

    Neighborhoods of the brain

    This work established that the two parts of the brain look different in adults, but Grill-Spector has been curious about these areas in brains of children, particularly because the skills associated with the face region improve through adolescence. To further investigate how development of these skills relates to brain development, the researchers used a new type of imaging technique.

    They scanned 22 children (ages 5 to 12) and 25 adults (ages 22 to 28) using two types of MRI, one that indirectly measures brain activity (functional MRI) and one that measures the proportion of tissue to water in the brain (quantitative MRI). This scan has been used to show changes in the fatty insulation surrounding the long neuronal wires connecting brain regions over a person’s lifetime, but this study is the first to use this method to directly assess changes in the cells’ bodies.

    What they found, published in Science, is that, in addition to seeing a difference in brain activity in these two regions, the quantitative MRI showed that a certain tissue in the face region grows with development. Ultimately, this development contributes to the tissue differences between face and place regions in adults. What’s more, tissue properties were linked with functional changes in both brain activity and face recognition ability, which they evaluated separately. There is no indication yet of which change causes the other or if they happen in tandem.

    A test bed

    Being able to identify familiar faces and places, while clearly an important skillset, may seem like an odd choice for study. The reason these regions are worth some special attention, said Grill-Spector, is because we can identify them in each person’s brain, even a 5-year-old child, which means research on these regions can include large pools of participants and produce results that are easy to compare across studies. This research also has health implications, as approximately 2 percent of the adult population is poor at recognizing faces, a disorder sometimes referred to as facial blindness.

    What’s more, the fusiform gyrus, an anatomical structure in the brain that contains face-processing regions, is only found in humans and great apes (gorillas, chimps, bonobos and orangutans).

    “If you had told me five or 10 years ago that we’d be able to actually measure tissue growth in vivo, I wouldn’t have believed it,” Grill-Spector said. “It shows there are actual changes to the tissue that are happening throughout your development. I think this is fantastic.”

    Additional Stanford co-authors on the Science paper are Michael Barnett, Vaidehi Natu and Aviv Mezer (now at Hebrew University in Jerusalem); other co-authors are Katrin Amunts, Karl Zilles and Nicola Palomero-Gallagher of Institute of Neuroscience and Medicine, Research Centre Jülich, Jülich, Germany.

    The Science research was funded by the National Science Foundation, the National Eye Institute, European Union Seventh Framework Programme and a NARSAD Young Investigator Grant.

    Additional co-authors on the Cerebral Cortex paper include Anthony Stigliani of Stanford University; Katrin Amunts, Karl Zilles, Simon Lorenz and Julian Caspers of the Institute of Neuroscience and Medicine, Research Centre Jülich, in Jülich, Germany; and Bruce Fischl of Harvard Medical School and the Massachusetts Institute of Technology.

    This research was funded by the National Eye Institute, European Union Seventh Framework Programme, the National Institute for Biomedical Imaging and Bioengineering, and the National Institute on Aging, the National Institute for Neurological Disorders and Stroke. It was also made possible by the resources provided by Shared Instrumentation Grants. Additional support was provided by the NIH Blueprint for Neuroscience Research, part of the multi-institutional Human Connectome Project.

    See the full article here .

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    Leland and Jane Stanford founded the University to “promote the public welfare by exercising an influence on behalf of humanity and civilization.” Stanford opened its doors in 1891, and more than a century later, it remains dedicated to finding solutions to the great challenges of the day and to preparing our students for leadership in today’s complex world. Stanford, is an American private research university located in Stanford, California on an 8,180-acre (3,310 ha) campus near Palo Alto. Since 1952, more than 54 Stanford faculty, staff, and alumni have won the Nobel Prize, including 19 current faculty members

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  • richardmitnick 9:15 pm on December 15, 2016 Permalink | Reply
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    From UCLA: “Analyzing brain patterns may help neuroscientists increase people’s confidence, reduce fear” 

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    UCLA

    December 15, 2016
    Stuart Wolpert

    1
    Study subjects were conditioned to fear certain color patterns, but researchers found that small rewards got them to subconsciously overcome those fears. Christelle Snow/UCLA

    A new technique of analyzing brain patterns appears to help people overcome fear and build self-confidence.

    The approach, developed by a UCLA-led team of neuroscientists, is described in two new papers, published in the journals Nature Communications and Nature Human Behaviour.

    Their method could have implications for treating people with depression, dementia and anxiety disorders, including post-traumatic stress disorder, said Hakwan Lau, a UCLA associate professor of psychology and the senior author of both studies. It could also play a role in improving leadership training for executives and managers.

    In the Nature Human Behaviour study, the researchers showed that they could reduce the brain’s manifestation of fear using a procedure called decoded neurofeedback, which involves identifying complex patterns of brain activity linked to a specific memory, and then giving feedback to the subject — for example, in the form of a reward — based on their brain activity.

    The researchers tested the technique on 17 undergraduate and graduate students in Japan. Participants were seated in a functional magnetic resonance imaging, or fMRI, scanner and shown patterns of vertical lines in four colors — red, green, blue and yellow. The blue and yellow images were always shown without shocks, but the red and green patterns were often accompanied by a small electrical shock administered to their feet.

    As a result, the subjects’ brain patterns began to register fear for the red and green images. But the scientists learned that they could use decoded neurofeedback to lessen the subjects’ fear of the red pattern. They did this by giving the subjects a small cash reward — the equivalent of about 10 cents — each time they spontaneously thought about the red lines (but gave no rewards for thinking about the green lines), which the scientists could determine in real time based on their brain activity.

    The following day, researchers tested whether the participants still had a fear response to the vertical lines. The red pattern, which had been frightening because it was paired with shocks, became less so because it now was paired with a positive outcome. With the reward as part of the equation, researchers found that participants perspired much less than when they had seen the red lines previously, and their brain’s fear signal, centered in the amygdala, was significantly reduced.

    “After just three days of training, we saw a significant reduction of fear,” Lau said. “We changed the association of the ‘fear object’ from negative to positive.”

    Participants were not told what they had to do to earn the money — only that the reward was based on their brain activity and that they should try to earn as much money as possible. And each time participants were told they had won money, their brains demonstrated more of the same pattern that had just won them the cash reward.

    Although participants tried to guess which of their thoughts were triggering the rewards — some guessed humming music or thinking about a girlfriend, for example — none actually figured out how they earned the money or recognized that the researchers had effectively reduced their fear of the red lines.

    “Their brain activity was completely unconscious,” Lau said. “That makes sense; a lot of our brain activity is unconscious.”

    Participants did still register fear on their fMRI scans when they saw the green pattern because, without the financial rewards, they still primarily associated the color with shocks.

    The findings could help improve upon standard behavioral therapy, in which a person who is afraid of a certain object is exposed to photos of that object, or even the object itself — which can be frightening enough that many people cannot complete treatment. Lau said using “unconscious fear reduction,” like in the experiment, could be more effective in many cases.

    Instilling confidence

    In the Nature Communications study, published today, Lau and his colleagues used decoded neurofeedback to increase people’s confidence levels.

    Ten participants were seated in an fMRI scanner and asked to watch a computer screen with hundreds of dots moving in different directions. Participants were asked whether the majority of dots were moving to the left or the right, and how confident they were in their responses. That initial feedback gave the researchers a chance to see how high confidence and low confidence were represented in brain patterns.

    Participants then were shown dots moving in random motion and told to think about anything — and that certain thoughts would earn them cash rewards. Every time the brain pattern looked like it was representing high confidence, the participant received a reward of up to the equivalent of 10 cents; subjects received smaller rewards if their brain activity indicated less confidence.

    Next, the researchers showed the students the images from the first phase of the experiment — with numerous dots primarily moving in one direction or the other. The scientists found that although students weren’t any better at guessing the primary direction of the dots’ motion, they had become more confident in their guesses.

    By studying brain patterns, Lau said, neuroscientists can decode people’s thoughts about food, love, money and many other concepts, which eventually could help them design treatments for eating disorders, gambling addiction and more. The researchers next will determine whether the techniques described in the papers can be used to help patients with real phobias.

    “We are cautiously optimistic,” he said.

    Co-authors of both studies include Mitsuo Kawato, professor and director of the ATR Brain Information Communication Research Laboratory Group in Kyoto, Japan; Ai Koizumi, a UCLA postdoctoral scholar; Ben Seymour, a neuroscientist at the University of Cambridge; and Aurelio Cortese, a doctoral student in Kawato’s laboratory.

    Lau’s research is funded mainly by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (grant R01NS088628).

    See the full article here .

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    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

     
  • richardmitnick 10:46 am on October 1, 2016 Permalink | Reply
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    From Brown: “BRAIN grant of $1.6 million powers study of neural signals” 

    Brown University
    Brown University

    September 29, 2016
    David Orenstein
    david_orenstein@brown.edu

    Three-year project will develop a software tool to help scientists and doctors understand how recorded brainwaves emerge from underlying neural activity.

    1
    Thinking cap. An array of electroencephalography sensors allows detailed sensing of neural signals. New software will help researchers understand that data better. Michael Cohea/Brown University

    In her research at Brown University, Stephanie Jones, research associate professor of neuroscience, has led the development of a unique computational model that explains how individual neurons and circuits of them produce the signals detected by external brainwave measurements, such as EEG or MEG sensors. Now, with a three-year, $1.6 million grant from the federal government’s BRAIN Initiative, she hopes to share her innovation with other scientists.

    “The aim of the grant is to turn the model into a user-friendly software tool that researchers and clinicians can use to test hypotheses about the neural origin of their MEG/EEG or electrocorticography data,” said Jones, a member of the Brown Institute for Brain Science. “We are calling this tool the ‘Human Neocortical Neurosolver.'”

    Jones leads the research, which officially starts Sept. 30 in collaboration with Dr. Matti Hamalainen at Massachusetts General Hospital and Dr. Michael Hines at Yale University.

    The team will also “integrate the neural model into existing source localization software so that researchers can study the location, time course and neural mechanisms of their human brain imaging data all in one software package,” Jones added.

    She said the software will not only aid neuroscience, but also future patient care.

    “While there are numerous studies connecting human MEG/EEG data to healthy and abnormal functions, the circuit level interpretation of the underlying neural dynamics is lacking,” she said. “This tool will foster the translational relevance of these technologies by allowing researchers to generate testable hypotheses that can guide further studies and ultimately novel therapeutics.”

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    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

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  • richardmitnick 8:52 am on September 17, 2016 Permalink | Reply
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    From U Colorado: “Landmark study on adolescent brain development begins” 

    U Colorado

    University of Colorado Boulder

    Sept. 12, 2016
    No writer credit found

    1
    An illustration of neurons in the brain. Credit: Institute of Cognitive Science / University of Colorado Boulder

    CU Boulder researchers will play a key role in a landmark National Institutes of Health (NIH) study of brain development and child health in the United States. The long-term study begins recruitment today.

    The Adolescent Brain Cognitive Development (ABCD) study will follow the biological and behavioral development of more than 10,000 children beginning at ages 9-10 through adolescence into early adulthood. Recruitment will be done over a two-year period through partnerships with public and private schools near research sites across the country as well as through twin registries.

    CU Boulder is one of 19 sites across the nation selected to host the study. Research will be led by the university’s Institute of Cognitive Science (ICS) which runs the campus’s neuroimaging center and the Institute for Behavioral Genetics (IBG).

    “Adolescence is a remarkable period of brain development, a time when the brain is particularly malleable and receptive to the environment,” said Marie Banich, director of the CU Boulder neuroimaging center and one of the principal investigators of the ABCD study. “The size and scope of this study will provide foundational research to understand how brain development enables the growth in mental and emotional functions that characterize the transition from childhood to adolescence to adulthood.”

    CU Boulder will also be one of just four study sites to focus on twin pairs, specifically looking at developmental behaviors that can be attributed to environmental influences compared to those that are inherited genetically.

    “The selection to participate in a national study of this caliber speaks to the strength of both the twin study resources we have developed and the reputation IBG has in this area,” said John Hewitt, director of IBG. IBG has maintained the statewide Colorado Twin Registry since 1968.

    The study, which is supported by the National Institute on Drug Abuse, may also shed new light on the effects of adolescent experiences on brain development, including experimentation with drugs and alcohol. For example, the study may provide information on whether there are certain sensitive periods during adolescence when the brain is particularly influenced or affected by such experiences.

    “Overall, we hope to gain a better understanding of the brain’s emotional and cognitive development at this crucial point in life,” said Banich, who is also a professor in CU Boulder’s Department of Psychology & Neuroscience. “The results will help provide scientific evidence that can be used to help design educational programs and guide public policy so that the youth of Colorado, as well as other teens across the country, can lead the happiest and healthiest lives possible.”

    The ABCD study is supported by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Cancer Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, the National Institute on Minority Health and Health Disparities, the National Institute of Neurological Disorders and Stroke, the NIH Office of Behavioral and Social Sciences Research and the Division of Adolescent and School Health at the Centers for Disease Control and Prevention.

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    As the flagship university of the state of Colorado, CU-Boulder is a dynamic community of scholars and learners situated on one of the most spectacular college campuses in the country. As one of 34 U.S. public institutions belonging to the prestigious Association of American Universities (AAU) – and the only member in the Rocky Mountain region – we have a proud tradition of academic excellence, with five Nobel laureates and more than 50 members of prestigious academic academies.

    CU-Boulder has blossomed in size and quality since we opened our doors in 1877 – attracting superb faculty, staff, and students and building strong programs in the sciences, engineering, business, law, arts, humanities, education, music, and many other disciplines.

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  • richardmitnick 8:59 pm on September 12, 2016 Permalink | Reply
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    From Salk: “The brain’s stunning genomic diversity revealed” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    September 9, 2016
    No writer credit found

    Multi-institutional collaboration led by the Salk Institute shows that half of our healthy neurons contain huge insertions or deletions in DNA

    1
    Using postmortem human brains and human embryonic stem cell models of brain development, Salk Institute researchers discover a new mechanism to generate DNA variation in human neurons. Here, human embryonic cell- derived neurons stained for a neurons specific marker (Tuj1, green, DNA show in red) show remarkable diversity. No image credit.

    Our brains contain a surprising diversity of DNA. Even though we are taught that every cell in our body has the same DNA, in fact most cells in the brain have changes to their DNA that make each neuron a little different.

    Now researchers at the Salk Institute and their collaborators have shown that one source of this variation—called long interspersed nuclear elements or L1s—are present in 44 to 63 percent of healthy neurons and can not only insert DNA but also remove it. Previously, these L1s were known to be small bits of DNA called “jumping genes” that copy and paste themselves throughout the genome, but the researchers found that they also cause large deletions of entire genes. What’s more, such variations can influence the expression of genes that are crucial for the developing brain.

    The findings, published September 12, 2016 in the journal Nature Neuroscience, may help explain what makes us each unique—why even identical twins can be so different from one other, for example—and how jumping genes can go awry and cause disease.

    “In 2013, we discovered that different neurons within the same brain have various complements of DNA, suggesting that they function slightly differently from each other even within the same person,” says the study’s senior investigator Rusty Gage, a professor in Salk’s Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. “This recent study reveals a new and surprising form of variation that will help us understand the role of L1s, not only in healthy brains but in those affected by schizophrenia and autism.”

    In 2005, Gage’s team discovered L1s as a mechanism of genome diversity in the brain. However, it was not until it became possible to sequence the entire genome of a single cell that scientists could get a handle on the amount and nature of these variations. Using single-cell sequencing detailed in a 2013 Science paper, Gage’s group showed that large chunks of DNA were inserted—or deleted—into the genomes of the cells.

    2
    The “jumping gene” L1 cuts DNA in human cells to generate neuronal genomic diversity. Cells expressing L1 (genomic DNA shown in red) have high levels of DNA breaks as visualized by 53BP1 staining (green) which repairs broken DNA. Credit: Salk Institute

    But even in that study the mechanisms responsible for causing insertions and deletions were unclear, making it difficult to decipher whether specific regions of the genome were more or less likely to be altered, as well as whether jumping genes were related to the deletions.

    In the new study, Gage, co-first authors Jennifer Erwin and Apuã Paquola, and collaborators developed a method to better capture the L1-associated variants in healthy neurons for sequencing and created a computational algorithm to distinguish the variations with greater accuracy than before.

    Using stem cells that are coaxed to differentiate into neurons in a dish, the team found that L1s are prone to DNA breaks. That’s because a specific enzyme that chews through L1 spots in the genome is particularly active during differentiation. People inherit some L1s from their parents, and the enzyme appears to cut near these spots, the group found.

    “The surprising part was that we thought all L1s could do was insert into new places. But the fact that they’re causing deletions means that they’re affecting the genome in a more significant way,” says Erwin, a staff scientist in Gage’s group.

    Gage believes that diversity can be good for the brain—after all, about half of our brain cells have large chunks of missing or inserted DNA caused by L1s alone—but that too much of it can cause disease.

    Recent evidence has shown that neurons derived from individuals with schizophrenia or the rare autism-associated disorder Rett syndrome harbor more than normal amounts of L1 variations in their genomes. In the new study, the team examined a schizophrenia-associated gene called DLG2, in which introducing L1 variations can change the gene’s expression and subsequent maturation of neurons. The group plans to explore the role of L1 variations in other genes and their effects on brain activity and disease.

    Other authors on the study are Tatjana Singer, Iryna Gallina, Carolina Quayle, Tracy Bedrosian, Cheyenne Butcher, Joseph Herdy and Anindita Sarkar of Salk; Mark Novotny and Roger Lasken of the J. Craig Venter Institute; Francisco Alves of the University of São Paulo in Brazil; and Alysson Muotri of the University of California, San Diego.

    The research was supported by George E. Hewitt Foundation for Medical Research, the California Institute for Regenerative Medicine, the National Institutes of Health (MH095741, MH088485), the G. Harold & Leila Y. Mathers Foundation, the Engman Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, the Paul G. Allen Family Foundation, the Glenn Center for Aging Research at the Salk Institute, and JPB Foundation.

    See the full article here .

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    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 5:25 pm on August 25, 2016 Permalink | Reply
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    From Salk: “Salk scientists map brain’s action center” 

    Salk Institute bloc

    Salk Institute for Biological Studies

    August 25, 2016
    No writer credit found

    New work dispels long-held notions about area involved in Parkinson’s and addiction

    1
    Salk Institute researchers employed novel genetic tools to map the connectivity of neurons within a part of the brain, called the striatum, that controls movement toward a goal or reward. The matrix neurons, highlighted in green, appear to avoid the patch neurons (in red), which are smaller clusters of neurons in the striatum. Credit: Salk Institute

    When you reach for that pan of brownies, a ball-shaped brain structure called the striatum is critical for controlling your movement toward the reward. A healthy striatum also helps you stop yourself when you’ve had enough.

    But when the striatum doesn’t function properly, it can lead to disorders such as Parkinson’s disease, obsessive-compulsive disorder or addiction.

    In fact, the exact functions of the striatum are by no means resolved, and it’s also a mystery how the structure can coordinate many diverse functions. Now, a new study published August 25, 2016 by Salk Institute researchers and their colleagues in the journal Neuron, delves into the anatomy and function of the striatum by employing cutting-edge strategies to comprehensively map one of the brain’s lesser-known forms of organization.

    “The most exciting result from this research is that we now have a new avenue to study long-standing questions about how the striatum controls movement in both healthy and diseased brains,” says the study’s senior investigator Xin Jin, an assistant professor in the Molecular Neurobiology Laboratory at Salk.

    Forty years ago, researchers discovered a unique way that the striatum is organized. It is dotted with patch neurons, which under the microscope look like tiny islands of cells. The ocean surrounding them is made up of neurons scientists collectively refer to as “matrix” cells.

    Over the course of four decades, scientists hypothesized about the role of patch and matrix neurons in neurodegenerative diseases. One idea was that patch cells were fed by the brain’s higher thought centers, suggesting they could play a role in cognition, whereas the matrix cells seemed to play a role in sensing and movement.

    2
    Using genetic engineering, cutting-edge neuronal tracing and electrophysiology, researchers decipher a lesser known form of organization in a deep, ball-shaped brain area that helps control movement toward a goal. In this artistic interpretation, patch neurons (red) sit as separate, small islands amid matrix neurons (green), but each cell type is well connected with the rest of the brain. Credit: Salk Institute

    In contrast, the new study dispels that idea, showing that both types of information are sent to the patch and matrix neurons, though patch cells tend to receive slightly more information from the brain’s emotion centers (these are included in the higher thought centers). But those results could help explain why, in the brains of patients with neurological disorders like Huntington’s disease (a progressive neurodegenerative disease affecting movement and other functions), patch cells and matrix cells are both affected, Jin says.

    “This is an elegant example demonstrating that we are in a new era of studying brain circuits in ever more refined detail,” said Daofen Chen, Ph.D., program director at the NIH’s National Institute of Neurological Disorders and Stroke. “As a result of emerging technologies and novel tools, we are gaining new insights into mechanisms of brain disorders.”

    Jin, together with the paper’s first authors Jared Smith, Jason Klug and Danica Ross, drew upon several technologies to uncover these new findings. The first was genetic engineering to selectively and precisely target the patch versus matrix neurons; traditionally, researchers used staining methods that were not as exact. Secondly, new neural tracing methods, including one generated by collaborator Edward Callaway and his group at Salk, allowed Jin’s team to chart the entire brain’s input to the patch and matrix cells and the output of each of the cell types as well. A third major approach, from the field of electrophysiology, enabled the scientists to confirm the connections they had mapped and to understand their strength.

    “Much of the previous work on patch and matrix cells inferred their functions based on connectivity with the rest of the brain, but most of those hypotheses were incorrect,” Smith says. “With a more precise map of the input and output of patch and matrix cells, we can now make more informed hypotheses.”

    Patch and matrix neurons are not the only way that neuroscientists understand the striatum. The striatum also contains cells that take two opposing routes—the direct and indirect pathways—that are thought to provide the gas and brakes on movement, so to speak. Those indirect and direct pathways are also crucial for certain behaviors, such as the formation of new habits.

    Interestingly, both patch and matrix groups contain both indirect and direct pathway cells. That makes the story of the striatum more complicated, Jin says, but in future studies his team can study the intersection of these two types of organization in the context of how the striatum controls actions in health and disease.

    Other authors on the study are Jason Klug, Danica Ross, Christopher Howard, Nick Hollon, Vivian Ko, Hilary Hoffman and Edward Callaway of the Salk Institute; and Charles Gerfen of the National Institute of Mental Health in Bethesda, Maryland.

    The research was supported by grants from the National Institutes of Health, the Dana Foundation, the Ellison Medical Foundation, and the Whitehall Foundation.

    See the full article here .

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    Salk Institute Campus

    Every cure has a starting point. Like Dr. Jonas Salk when he conquered polio, Salk scientists are dedicated to innovative biological research. Exploring the molecular basis of diseases makes curing them more likely. In an outstanding and unique environment we gather the foremost scientific minds in the world and give them the freedom to work collaboratively and think creatively. For over 50 years this wide-ranging scientific inquiry has yielded life-changing discoveries impacting human health. We are home to Nobel Laureates and members of the National Academy of Sciences who train and mentor the next generation of international scientists. We lead biological research. We prize discovery. Salk is where cures begin.

     
  • richardmitnick 11:03 am on August 23, 2016 Permalink | Reply
    Tags: , Brain Studies, ,   

    From Scripps: “A Look Deep Inside the Human Brain Reveals a Surprise” 

    Scripps
    Scripps Research Institute

    8.23.16
    No writer credit

    In the field of neuroscience, researchers often make the assumption that information they obtain from a tiny brain sample is true for the entire brain.

    Now, a team of scientists at The Scripps Research Institute (TSRI), University of California, San Diego (UC San Diego) and Illumina, Inc., has completed the first large-scale assessment of the way thousands of single neuronal nuclei produce proteins from genetic information (“transcription”) – revealing a surprising diversity in the process. The findings could improve both our understanding of the brain’s normal functioning and how it’s damaged by diseases such as Alzheimer’s, Parkinson’s, ALS and depression.

    [The study is published in Science.]

    The researchers accomplished this feat by isolating and analyzing 3,200 single human neurons, more than 10-fold greater than prior publications, from six Brodmann Areas (larger regions having functional roles) of the human brain.

    “Through a wonderful scientific collaboration, we found an enormous amount of transcriptomic diversity from cell to cell that will be relevant to understanding the normal brain and its diseases such as Alzheimer’s, Parkinson’s, ALS and depression,” said TSRI Professor and neuroscientist Jerold Chun, who co-led the study with bioengineers Kun Zhang and Wei Wang of UC San Diego and Jian-Bing Fan of Illumina.

    While parts of the cerebral cortex look different under a microscope – with different cell shapes and densities that form cortical layers and larger regions having functional roles called “Brodmann Areas” – most researchers treat neurons as a fairly uniform group in their studies. “From a tiny brain sample, researchers often make assumptions that obtained information is true for the entire brain,” said Dr. Chun.

    But the brain isn’t like other organs, Dr. Chun explained. There’s a growing understanding that individual brain cells are unique, and a possibility has been that the microscopic differences among cerebral cortical areas may also reflect unique transcriptomic differences – i.e., differences in the expressed genes, or messenger RNAs (mRNAs), which carry copies of the DNA code outside the nucleus and determine which proteins the cell makes.

    With the help of newly developed tools to isolate and sequence individual cell nuclei (where genetic material is housed in a cell), the researchers deciphered the minute quantities of mRNA within each nucleus, revealing that various combinations of the 16 subtypes tended to cluster in cortical layers and Brodmann Areas, helping explain why these regions look and function differently.

    Neurons exhibited anticipated similarities, yet also many differences in their transcriptomic profiles, revealing single neurons with shared, as well as unique, characteristics that likely lead to differences in cellular function.

    “Now we can actually point to an enormous amount of molecular heterogeneity in single neurons of the brain,” said Gwendolyn E. Kaeser, a UC San Diego Biomedical Sciences Graduate Program student studying in Dr. Chun’s lab at TSRI and co-first author of the study.

    Interestingly, some of these differences in gene expression have roots in very early brain development taking place before birth. The researchers found markers on some neurons showing that they originated from a specific region of fetal brain called the ganglionic eminence, which generates inhibitory neurons destined for the cerebral cortex. These neurons may have particular relevance to developmental brain disorders.

    In future studies, the researchers hope to investigate how single-neuron DNA and mRNA differ in single neurons, groups and between human brains – and how these may be influenced by factors such as stress, medications or disease.

    See the full article here .

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 2:42 pm on August 18, 2016 Permalink | Reply
    Tags: , Brain Studies, ,   

    From MIT Tech Review: “New Brain-Mapping Technique Captures Every Connection Between Neurons” 

    MIT Technology Review
    M.I.T Technology Review

    August 18, 2016
    Ryan Cross

    The human brain is among the universe’s greatest remaining uncharted territories. And as with any mysterious land, the secret to understanding it begins with a good map.

    Neuroscientists have now taken a huge step toward the goal of mapping the connections between neurons in the brain using bits of genetic material to bar-code each individual brain cell. The technique, called MAP-seq, could help researchers study disorders like autism and schizophrenia in unprecedented detail.

    “We’ve got the basis for a whole new technology with a gazillion applications,” says Anthony Zador, a neuroscientist at Cold Spring Harbor Laboratory who came up with the technique.

    Current methods for mapping neuronal connections, known as the brain’s connectome, commonly rely on fluorescent proteins and microscopes to visualize cells, but they are laborious and have difficultly following the connections of many neurons at once.

    MAP-seq works by first creating a library of viruses that contain randomized RNA sequences. This mixture is then injected into the brain, and approximately one virus enters each neuron in the injection area, granting each cell a unique RNA bar code. The brain is then sliced and diced into orderly sections for processing. A DNA sequencer reads the RNA bar codes, and researchers create a connectivity matrix that displays how individual neurons connect to other regions of the brain.

    The newly published study, which appears Thursday in the journal Neuron, follows the sprawling outbound connections from 1,000 mouse neurons in a brain region called the locus coeruleus to show that the technique works. But Zador says the results actually reconcile previously conflicting findings about how those neurons connect across the brain.

    Justus Kebschull, who worked with Zador in developing MAP-seq, says the technique is getting better. “We’re now mapping out 100,000 cells at a time, in one week, in one experiment,” he says. “That was previously only possible if you put a ton of work in.”

    Both autism and schizophrenia are viewed as disorders that may arise from dysfunctional brain connectivity. There are perhaps hundreds of genetic mutations that may slightly alter the brain’s wiring as it develops. “We are looking at mouse models where something is mucked up. And now that the method is so fast, we can look at many mouse models,” Kebschull says. By comparing the brain circuitry in mice with different candidate genes for autism, researchers expect, they’ll get new insight into the condition.

    “I think it is a great method that has a lot of room to grow,” says Je Hyuk Lee, a molecular biologist at Cold Spring Harbor Laboratory, who was not part of the MAP-seq study. Although other groups have used similar bar-coding to study individual differences between cells, no one knew if the bar codes would be able to travel along the neuronal connections across the brain. “That had been conjectured but never shown, especially not at this scale,” Lee says.

    Zador says that as of now, his lab is the only one bar-coding the brain, but he hopes others will start using MAP-seq to chart the brain’s circuitry. “Because the cost of sequencing is continuing to plummet, we can envision doing this quickly and cheaply,” he said. It may not be long, then, before a complete map of the brain is ready for its first explorer to use.

    See the full article here .

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    The mission of MIT Technology Review is to equip its audiences with the intelligence to understand a world shaped by technology.

     
  • richardmitnick 1:55 pm on August 14, 2016 Permalink | Reply
    Tags: , Brain Studies, This is your brain on sentences,   

    From Rochester: “This is your brain on sentences” 

    U Rochester bloc

    University of Rochester

    August 12, 2016
    Monique Patenaude
    monique.patenaude@rochester.edu

    Researchers at the University of Rochester have, for the first time, decoded and predicted the brain activity patterns of word meanings within sentences, and successfully predicted what the brain patterns would be for new sentences.

    The study used functional magnetic resonance imaging (fMRI) to measure human brain activation. “Using fMRI data, we wanted to know if given a whole sentence, can we filter out what the brain’s representation of a word is—that is to say, can we break the sentence apart into its word components, then take the components and predict what they would look like in a new sentence,” said Andrew Anderson, a research fellow who led the study as a member of the lab of Rajeev Raizada, assistant professor of brain and cognitive sciences at Rochester.

    “We found that we can predict brain activity patterns—not perfectly [on average 70% correct], but significantly better than chance,” said Anderson, The study is published in the journal Cerebral Cortex.

    Anderson and his colleagues say the study makes key advances toward understanding how information is represented throughout the brain. “First, we introduced a method for predicting the neural patterns of words within sentences—which is a more complex problem than has been addressed by previous studies, which have almost all focused on single words,” Anderson said. “And second, we devised a novel approach to map semantic characteristics of words that we then correlated to neural activity patterns.”

    Finding a word in a sentence

    To predict the patterns of particular words within sentences, the researchers used a broad set of sentences, with many words shared between them. For example: “The green car crossed the bridge,” “The magazine was in the car,” and “The accident damaged the yellow car.” fMRI data was collected from 14 participants as they silently read 240 unique sentences.

    “We estimate the representation of a word ‘car,’ in this case, by taking the neural activity pattern associated with all of the sentences which that word occurred in and we decomposed sentence level brain activity patterns to build an estimate of the representation of the word,” explained Anderson.

    1
    These brain maps show how accurately it was possible to predict neural activation patterns for new, previously unseen sentences, in different regions of the brain. The brighter the area, the higher the accuracy. The most accurate area, which can be seen as the bright yellow strip, is a region in the left side of the brain known as the Superior Temporal Sulcus. This region achieved statistically significant sentence predictions in 11 out of the 14 people whose brains were scanned. Although that was the most accurate region, several other regions, broadly distributed across the brain, also produced significantly accurate sentence predictions. (University of Rochester graphic / Andrew Anderson)

    What does the meaning of a word look like?

    “Coffee has a color, smell, you can drink it—coffee makes you feel good—it has sensory, emotional, and social aspects,” said senior author Raizada. “So we built upon a model created by Jeffrey Binder at the Medical College of Wisconsin, a coauthor on the paper, and surveyed people to tell us about the sensory, emotional, social and other aspects for a set of words. Together, we then took that approach in a new direction, by going beyond individual words to entire sentences.”

    The new semantic model employs 65 attributes—such as “color,” “pleasant,” “loud,” and “time.” Participants in the survey rated, on a scale of 0-6, the degree to which a given root concept was associate with a particular experience. For example, “To what degree do you think of ‘coffee’ as having a characteristic or defining temperature?” In total, 242 unique words were rated with each of the 65 attributes.

    “The strength of association of each word and its attributes allowed us to estimate how its meanings would be represented across the brain using fMRI,” said Raizada.

    The model captures a wider breadth of experience than previous semantic models, said Anderson, “which made it easier to interpret the relationship between the predictive model and brain activity patterns.”

    The team was then able to recombine activity patterns for individual words, in order to predict brain patterns for entire sentences built up out of new combinations of those words. For example, the computer model could predict the brain pattern for a sentence such as, “The family played at the beach,” even though it had never seen that specific sentence before. Instead, it had only seen other sentences containing those words in different contexts, such as “The beach was empty” and “The young girl played soccer.”

    The researchers said the study opens a new set of questions toward understanding how meaning is represented in the brain. “Not now, not next year, but this kind of research may eventually help individuals who have problems with producing language, including those who suffer from traumatic brain injuries or stroke,” said Anderson.

    2
    Brain activation patterns for different sensory and emotional aspects of the word “play.” The numbers to the left of each brain pattern show how strongly the word is associate with each feature. For example, “play” is positively associated with “Biomotion”, because playing often involves people moving their bodies. But it is negatively associated with “Unpleasant”, because play is rarely an unpleasant activity.” (University of Rochester graphic / Andrew Anderson)

    The Intelligence Advanced Research Projects Activity and the National Science Foundation supported the research.

    See the full article here .

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    U Rochester Campus

    The University of Rochester is one of the country’s top-tier research universities. Our 158 buildings house more than 200 academic majors, more than 2,000 faculty and instructional staff, and some 10,500 students—approximately half of whom are women.

    Learning at the University of Rochester is also on a very personal scale. Rochester remains one of the smallest and most collegiate among top research universities, with smaller classes, a low 10:1 student to teacher ratio, and increased interactions with faculty.

     
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