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  • richardmitnick 10:04 am on January 11, 2018 Permalink | Reply
    Tags: , , Blue Brain Nexus, Brain Studies, ,   

    From EPFL: “Blue Brain Nexus: an open-source tool for data-driven science” 

    EPFL bloc

    École Polytechnique Fédérale de Lausanne

    11.01.18
    BBP communications

    1
    © iStockphotos

    Knowledge sharing is an important driving force behind scientific progress. In an open-science approach, EPFL’s Blue Brain Project has created and open sourced Blue Brain Nexus that allows the building of data integration platforms. Blue Brain Nexus enables data-driven science through searching, integrating and tracking large-scale data and models.

    EPFL’s Blue Brain Project today announces the release of its open source software project ‘Blue Brain Nexus’, designed to enable the FAIR (Findable, Accessible, Interoperable, and Reusable) data management principles for the Neuroscience and broader scientific community. It is part of EPFL’s open-science initiative, which seeks to maximize the reach and impact of research conducted at the school.

    The aim of the Blue Brain Project is to build accurate, biologically detailed, digital reconstructions and simulations of the rodent brain and, ultimately the human brain. Blue Brain Nexus is instrumental in supporting all stages of Blue Brain’s data-driven modelling cycle including, but not limited to experimental data, single cell models, circuits, simulations and validations. The brain is a complex multi-level system and is one of the biggest ‘Big Data’ problems we have today. Therefore, Blue Brain Nexus has been built to organize, store and process exceptionally large volumes of data and support usage by a broad number of users.

    At the heart of Blue Brain Nexus is the Knowledge Graph, which acts as a data repository and metadata catalogue. It also remains agnostic of the domain to be represented by allowing users to design arbitrary domains, which enables other scientific initiatives (e.g. astronomy, medical research and agriculture) to reuse Blue Brain Nexus as the core of their data platforms. Blue Brain Nexus services are already being evaluated for integration into the Human Brain Project’s Neuroinformatics Platform.

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    Specific to enabling scientific progress, Blue Brain Nexus’s Knowledge Graph treats provenance as a first-class citizen, thus facilitating the tracking of the origin of data as well as how it is being used. This allow users to assess the quality of data, and consequently to enable them to build trust. Another key feature of Blue Brain Nexus is its semantic search capability, whereby search is integrated over data and its provenance to enable scientists to easily discover and access new relevant data.

    EPFL Professor Sean Hill commented: “We see that nearly all sciences are becoming data-driven. Blue Brain Nexus represents the culmination of many years of research into building a state-of-the-art semantic data management platform. We can’t wait to see what the community will do with Blue Brain Nexus.”

    Blue Brain Nexus is available under the Apache 2 license, at https://github.com/BlueBrain/nexus

    For more information, please contact:

    EPFL Communications, emmanuel.barraud@epfl.ch, +41 21 693 21 90

    Blue Brain Project communications, kate.mullins@epfl.ch, +41 21 695 51 41

    See the full article here .

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    EPFL is Europe’s most cosmopolitan technical university. It receives students, professors and staff from over 120 nationalities. With both a Swiss and international calling, it is therefore guided by a constant wish to open up; its missions of teaching, research and partnership impact various circles: universities and engineering schools, developing and emerging countries, secondary schools and gymnasiums, industry and economy, political circles and the general public.

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  • richardmitnick 3:45 pm on January 8, 2018 Permalink | Reply
    Tags: , Brain Studies, , New Technology Will Create Brain Wiring Diagrams, The TRACT method   

    From Caltech: “New Technology Will Create Brain Wiring Diagrams” 

    Caltech Logo

    Caltech

    01/08/2018
    Lori Dajose
    (626) 395-1217
    ldajose@caltech.edu

    Technique allows for maps of the neural connections of entire insect brains, which was previously not possible with other methods.

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    The TRACT method allows for the identification of neurons connected by synapses in a brain circuit. This image shows the olfactory receptor neurons (red) activating the production of a green protein in their synaptically-connected downstream partners. Credit: Courtesy of the Lois Laboratory.

    The human brain is composed of billions of neurons wired together in intricate webs and communicating through electrical pulses and chemical signals. Although neuroscientists have made progress in understanding the brain’s many functions—such as regulating sleep, storing memories, and making decisions—visualizing the entire “wiring diagram” of neural connections throughout a brain is not possible using currently available methods. But now, using Drosophila fruit flies, Caltech researchers have developed a method to easily see neural connections and the flow of communications in real time within living flies. The work is a step forward toward creating a map of the entire fly brain’s many connections, which could help scientists understand the neural circuits within human brains as well.

    A paper describing the work appears online in the December 12 issue of eLife. The research was done in the laboratory of Caltech research professor Carlos Lois.

    “If an electrical engineer wants to understand how a computer works, the first thing that he or she would want to figure out is how the different components are wired to each other,” says Lois. “Similarly, we must know how neurons are wired together in order to understand how brains work.”

    When two neurons connect, they link together with a structure called a synapse, a space through which one neuron can send and receive electrical and chemical signals to or from another neuron. Even if multiple neurons are very close together, they need synapses to truly communicate.

    The Lois laboratory has developed a method for tracing the flow of information across synapses, called TRACT (Transneuronal Control of Transcription). Using genetically engineered Drosophila fruit flies, TRACT allows researchers to observe which neurons are “talking” and which neurons are “listening” by prompting the connected neurons to produce glowing proteins.

    With TRACT, when a neuron “talks”—or transmits a chemical or electrical signal across a synapse—it will also produce and send along a fluorescent protein that lights up both the talking neuron and its synapses with a particular color. Any neurons “listening” to the signal receive this protein, which binds to a so-called receptor molecule—genetically built-in by the researchers—on the receiving neuron’s surface. The binding of the signal protein activates the receptor and triggers the neuron it’s attached to in order to produce its own, differently colored fluorescent protein. In this way, communication between neurons becomes visible. Using a type of microscope that can peer through a thin window installed on the fly’s head, the researchers can observe the colorful glow of neural connections in real time as the fly grows, moves, and experiences changes in its environment.

    Many neurological and psychiatric conditions, such as autism and schizophrenia, are thought to be caused by altered connections between neurons. Using TRACT, scientists can monitor the neuronal connections in the brains of hundreds of flies each day, allowing them to make comparisons at different stages of development, between the sexes, and in flies that have genetic mutations. Thus, TRACT could be used to determine how different diseases perturb the connections within brain circuits. Additionally, because neural synapses change over time, TRACT allows the monitoring of synapse formation and destruction from day to day. Being able to see how and when neurons form or break synapses will be critical to understanding how the circuits in the brain assemble as the animal grows, and how they fall apart with age or disease.

    TRACT can be localized to focus in on the wiring of any particular neural circuit of interest, such as those that control movement, hunger, or vision. Lois and his group tested their method by examining neurons within the well-understood olfactory circuit, the neurons responsible for the sense of smell. Their results confirmed existing data regarding this particular circuit’s wiring diagram. In addition, they examined the circadian circuit, which is responsible for the waking and sleeping cycle, where they detected new possible synaptic connections.

    TRACT, however, can do more than produce wiring diagrams. The transgenic flies can be genetically engineered so that the technique prompts receiving neurons to produce proteins that have a function, rather than colorful proteins that simply trace connections.

    “We could use functional proteins to ask, ‘What happens in the fly if I silence all the neurons that receive input from this one neuron?'” says Lois. “Or, conversely, ‘What happens if I make the neurons that are connected to this neuron hyperactive?’ Our technique not only allows us to create a wiring diagram of the brain, but also to genetically modify the function of neurons in a brain circuit.”

    Previous methods for examining neural connections were time consuming and labor intensive, involving thousands of thin slices of a brain reconstructed into a three-dimensional structure. A laboratory using these techniques could only yield a diagram for a single, small piece of fruit-fly brain per year. Additionally, these approaches could not be performed on living animals, making it impossible to see how neurons communicated in real time.

    Because the TRACT method is completely genetically encoded, it is ideal for use in laboratory animals such as Drosophila and zebrafish; ultimately, Lois hopes to implement the technique in mice to enable the neural tracing of a mammalian brain. “TRACT is a new tool that will allow us to create wiring diagrams of brains and determine the function of connected neurons,” he says. “This information will provide important clues towards understanding the complex workings of the human brain and its diseases.”

    The paper is titled “Tracing neuronal circuits in transgenic animals by transneuronal control of transcription (TRACT).” Other Caltech coauthors include graduate students Ting- Hao Huang and Antuca Callejas; AMGEN undergraduate visiting scholar Peter Niesman; Khorana undergraduate visiting scholar Deepshika Arasu; research technicians Aubrie De La Cruz and Daniel Lee; and Elizabeth Hong (BS ’02), the Clare Boothe Luce Assistant Professor of Neuroscience. Funding was provided by BRAIN award UO1 MH109147 from the National Institutes of Health.

    See the full article here .

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    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”

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  • richardmitnick 10:32 am on December 22, 2017 Permalink | Reply
    Tags: , Brain Studies, Physicists Overturn a 100-Year-Old Assumption on How Brains Work, , , The human brain contains a little over 80-odd billion neurons each joining with other cells to create trillions of connections called synapses   

    From Science Alert: “Physicists Overturn a 100-Year-Old Assumption on How Brains Work” 

    ScienceAlert

    Science Alert

    22 DEC 2017
    MIKE MCRAE

    1
    (Kateryna Kon/Shutterstock)

    This is how neurons actually fire.

    The human brain contains a little over 80-odd billion neurons, each joining with other cells to create trillions of connections called synapses.

    The numbers are mind-boggling, but the way each individual nerve cell contributes to the brain’s functions is still an area of contention. A new study in Scientific Reports has overturned a hundred-year-old assumption on what exactly makes a neuron ‘fire’, posing new mechanisms behind certain neurological disorders.

    A team of physicists from Bar-Ilan University in Israel conducted experiments on rat neurons grown in a culture to determine exactly how a neuron responds to the signals it receives from other cells.

    To understand why this is important, we need to go back to 1907 when a French neuroscientist named Louis Lapicque proposed a model to describe how the voltage of a nerve cell’s membrane increases as a current is applied.

    Once reaching a certain threshold, the neuron reacts with a spike of activity, after which the membrane’s voltage resets.

    What this means is a neuron won’t send a message unless it collects a strong enough signal.

    Lapique’s equations weren’t the last word on the matter, not by far. But the basic principle of his integrate-and-fire model has remained relatively unchallenged in subsequent descriptions, today forming the foundation of most neuronal computational schemes.

    According to the researchers, the lengthy history of the idea has meant few have bothered to question whether it’s accurate.

    “We reached this conclusion using a new experimental setup, but in principle these results could have been discovered using technology that has existed since the 1980s,” says lead researcher Ido Kanter.

    “The belief that has been rooted in the scientific world for 100 years resulted in this delay of several decades.”

    The experiments approached the question from two angles – one exploring the nature of the activity spike based on exactly where the current was applied to a neuron, the other looking at the effect multiple inputs had on a nerve’s firing.

    Their results suggest the direction of a received signal can make all the difference in how a neuron responds.

    A weak signal from the left arriving with a weak signal from the right won’t combine to build a voltage that kicks off a spike of activity. But a single strong signal from a particular direction can result in a message.

    This potentially new way of describing what’s known as spatial summation could lead to a novel method of categorising neurons, one that sorts them based on how they compute incoming signals or how fine their resolution is, based on a particular direction.

    Better yet, it could even lead to discoveries that explain certain neurological disorders.

    It’s important not to throw out a century of wisdom on the topic on the back of a single study. The researchers also admit they’ve only looked at a type of nerve cell called pyramidal neurons, leaving plenty of room for future experiments.

    But fine-tuning our understanding of how individual units combine to produce complex behaviours could spread into other areas of research. With neural networks inspiring future computational technology, identifying any new talents in brain cells could have some rather interesting applications.

    See the full article here .

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  • richardmitnick 8:20 am on December 19, 2017 Permalink | Reply
    Tags: A small electrical jolt to the right brain region at just the right time derails impulsive behavior, , Brain Studies, DBS is in clinical trials for depression obsessive-compulsive disorder and multiple other disorders of the brain, DBS-deep brain stimulation, ,   

    From Stanford Scope blog: “A small electrical jolt to the right brain region at just the right time derails impulsive behavior” 

    Stanford University Name
    Stanford University

    stanford-scope-icon

    Stanford Scope blog

    December 18, 2017
    Bruce Goldman

    1

    Just imagine if you could predict and prevent a burst of binge eating or alcohol intake, a heroin injection, a sudden bout of uncontrolled rage or a suicide attempt. The world would be a better place.

    Long journeys start with first steps. In a study published in Proceedings of the National Academy of Sciences, Stanford researchers led by neurosurgeon Casey Halpern, MD, have identified, both in mice and in a human subject, a signature pattern of electrical activity in a small but important deep-brain region called the nucleus accumbens just a second or two before a burst of impulsive behavior.

    The nucleus accumbens is the hub of the brain’s reward circuitry, which evolution has engineered to reinforce survival-promoting actions by inducing pleasure in anticipation or performance of those actions. The researchers showed in mice that supplying a small electrical jolt to the nucleus accumbens as soon as the electrical signature manifested there stopped the mice from overindulging in fatty food — without messing up the rest of their natural activities.

    “Impulses are normal and absolutely necessary for survival,” Halpern said when I interviewed him for our news release on the new study. “They convert our feelings about what’s rewarding into concrete action to obtain food, sex, sleep and defenses against rivals or predators.”

    But in some contexts, impulsive behavior can be pathological, manifesting as a marked tendency to make poor decisions and act on them. One need look no further than the rash of recent reports about sexual predators perched in powerful positions in Hollywood, the media, finance and politics to see blatant examples of a fundamentally healthy drive — sexual appetite — taken to a pathological level.

    Halpern focuses on deep-brain stimulation, whereby devices deliver electrical pulses to targeted brain regions in which they’ve been implanted. Tens of thousands of DBS devices are in current use for treating symptoms of Parkinson’s disease and essential tremor, and DBS is in clinical trials for depression, obsessive-compulsive disorder, and multiple other disorders of the brain.

    But DBS devices in use today are inflexible; they just keep firing away nonstop on a preprogrammed basis. In the new study, the scientists fitted the mice with new-generation DBS devices that can fire or not fire, depending on feedback they get from sensors in the brain region they target — in this case, the nucleus accumbens. They identified a particular pattern of electrical activity that arose there just as mice were about to plunge into a pile of high-fat food to which they’d become quite fond, to the point of pigging out on it. But whenever the implanted device detected this pre-gluttony signal, it zapped the nucleus accumbens with an electrical pulse equivalent to a standard DBS pulse. That snuffed a mouse’s high-fat food bingeing — but not its intake of normal food, social behavior or other physical activity.

    The study’s findings offer the promise, Halpern told me, of an implantable device that monitors the nucleus accumbens for the telltale signal preceding a burst of impulsivity and immediately delivers a measured dose of electricity. This intervention may prevent impulsive and sometimes life-threatening actions by high-risk people for whom all noninvasive therapies have failed.

    Halpern is hoping to find out whether this kind of feedback could be helpful for obese patients who’ve been unable to curb their dietary intake even after bariatric surgery. The findings could also lead to less noninvasive methods of countering substance-abuse disorders, pathological gambling, sexual addiction or intermittent explosive disorder, a psychiatric condition marked by impromptu outbursts of inappropriate ferocity.

    See the full article here .

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    Scope is an award-winning blog founded in 2009 and produced by the Stanford University School of Medicine. If you’re curious about the latest advances in medicine and health and enjoy compelling, fresh and easily digestible news and features, then we’ve got just the thing. We’ve written quite a bit (7,000 posts and counting!), and we’re quite proud of it — so please enjoy.

    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 4:41 pm on December 18, 2017 Permalink | Reply
    Tags: , Brain Studies, Engineers develop microfluidic devices- microelectrodes for gentle implantation, , Nanotubes go with the flow to penetrate brain tissue, , The device uses the force applied by fast-moving fluids that gently advance insulated flexible fibers into brain tissue without buckling, The electrode is like a cooked noodle that you’re trying to put into a bowl of Jell-O” said Rice engineer Jacob Robinson   

    From Rice: “Nanotubes go with the flow to penetrate brain tissue” 

    Rice U bloc

    Rice University

    December 18, 2017
    Mike Williams

    Rice scientists, engineers develop microfluidic devices, microelectrodes for gentle implantation.

    Rice University researchers have invented a device that uses fast-moving fluids to insert flexible, conductive carbon nanotube fibers into the brain, where they can help record the actions of neurons.

    The Rice team’s microfluidics-based technique promises to improve therapies that rely on electrodes to sense neuronal signals and trigger actions in patients with epilepsy and other conditions.

    Eventually, the researchers said, nanotube-based electrodes could help scientists discover the mechanisms behind cognitive processes and create direct interfaces to the brain that will allow patients to see, to hear or to control artificial limbs.

    The device uses the force applied by fast-moving fluids that gently advance insulated flexible fibers into brain tissue without buckling. This delivery method could replace hard shuttles or stiff, biodegradable sheaths used now to deliver wires into the brain. Both can damage sensitive tissue along the way.

    The technology is the subject of a paper in the American Chemical Society journal Nano Letters.

    Lab and in vivo experiments showed how the microfluidic devices force a viscous fluid to flow around a thin fiber electrode. The fast-moving fluid slowly pulls the fiber forward through a small aperture that leads to the tissue. Once it crosses into the tissue, tests showed the wire, though highly flexible, stays straight.

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    Fast-moving fluid pulls a fiber through a microfluidic device to be inserted into brain tissue. The device invented at Rice University could provide a gentler method to implant wires into patients with neurological diseases and help scientists explore cognitive processes and develop implants to help people to see, to hear and to control artificial limbs. Courtesy of the Robinson Lab.

    “The electrode is like a cooked noodle that you’re trying to put into a bowl of Jell-O,” said Rice engineer Jacob Robinson, one of three project leaders. “By itself, it doesn’t work. But if you put that noodle under running water, the water pulls the noodle straight.”

    The wire moves slowly relative to the speed of the fluid. “The important thing is we’re not pushing on the end of the wire or at an individual location,” said co-author Caleb Kemere, a Rice electrical and computer engineer who specializes in neuroscience. “We’re pulling along the whole cross-section of the electrode and the force is completely distributed.”

    “It’s easier to pull things that are flexible than it is to push them,” Robinson said.

    “That’s why trains are pulled, not pushed,” said chemist Matteo Pasquali, a co-author. “That’s why you want to put the cart behind the horse.”

    The fiber moves through an aperture about three times its size but still small enough to let very little of the fluid through. Robinson said none of the fluid follows the wire into brain tissue (or, in experiments, the agarose gel that served as a brain stand-in).

    There’s a small gap between the device and the tissue, Robinson said. The small length of fiber in the gap stays on course like a whisker that remains stiff before it grows into a strand of hair. “We use this very short, unsupported length to allow us to penetrate into the brain and use the fluid flow on the back end to keep the electrode stiff as we move it down into the tissue,” he said.

    “Once the wire is in the tissue, it’s in an elastic matrix, supported all around by the gel material,” said Pasquali, a carbon nanotube fiber pioneer whose lab made a custom fiber for the project. “It’s supported laterally, so the wire can’t easily buckle.”

    Carbon nanotube fibers conduct electrons in every direction, but to communicate with neurons, they can be conductive at the tip only, Kemere said. “We take insulation for granted. But coating a nanotube thread with something that will maintain its integrity and block ions from coming in along the side is nontrivial,” he said.

    Sushma Sri Pamulapati, a graduate student in Pasquali’s lab, developed a method to coat a carbon nanotube fiber and still keep it between 15 to 30 microns wide, well below the width of a human hair. “Once we knew the size of the fiber, we fabricated the device to match it,” Robinson said. “It turned out we could make the exit channel two or three times the diameter of the electrode without having a lot of fluid come through.”

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    Rice University researchers have developed a method using microfluidics to implant conductive, thin, flexible fibers into brain tissue. Implanted wires could help patients with neurological diseases and help scientists explore cognitive processes and develop implants to help people to see, to hear and to control artificial limbs. Click on the image for a larger version. Courtesy of the Robinson Lab.

    The researchers said their technology may eventually be scaled to deliver into the brain at once multiple microelectrodes that are closely packed; this would make it safer and easier to embed implants. “Because we’re creating less damage during the implantation process, we might be able to put more electrodes into a particular region than with other approaches,” Robinson said.

    Flavia Vitale, a Rice alumna and now a research instructor at the University of Pennsylvania, and Daniel Vercosa, a Rice graduate student, are lead authors of the paper. Co-authors are postdoctoral fellow Alexander Rodriguez, graduate students Eric Lewis, Stephen Yan and Krishna Badhiwala and alumnus Mohammed Adnan of Rice; postdoctoral researcher Frederik Seibt and Michael Beierlein, an associate professor of neurobiology and anatomy at McGovern Medical School at the University of Texas Health Science Center at Houston; and Gianni Royer-Carfagni, a professor of structural mechanics at the University of Parma, Italy.

    Robinson and Kemere are assistant professors of electrical and computer engineering and adjunct assistant professors at Baylor College of Medicine. Pasquali is a professor of chemical and biomolecular engineering, of materials science and nanoengineering and of chemistry and chair of Rice’s Department of Chemistry.

    Supporting the research are the Defense Advanced Research Projects Agency, the Welch Foundation, the National Science Foundation, the Air Force Office of Scientific Research, the American Heart Association, the National Institutes of Health, the Citizens United for Research in Epilepsy Taking Flight Award and the Dan L. Duncan Family Foundation.

    See the full article here .

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    Rice U campus

    In his 1912 inaugural address, Rice University president Edgar Odell Lovett set forth an ambitious vision for a great research university in Houston, Texas; one dedicated to excellence across the range of human endeavor. With this bold beginning in mind, and with Rice’s centennial approaching, it is time to ask again what we aspire to in a dynamic and shrinking world in which education and the production of knowledge will play an even greater role. What shall our vision be for Rice as we prepare for its second century, and how ought we to advance over the next decade?

    This was the fundamental question posed in the Call to Conversation, a document released to the Rice community in summer 2005. The Call to Conversation asked us to reexamine many aspects of our enterprise, from our fundamental mission and aspirations to the manner in which we define and achieve excellence. It identified the pressures of a constantly changing and increasingly competitive landscape; it asked us to assess honestly Rice’s comparative strengths and weaknesses; and it called on us to define strategic priorities for the future, an effort that will be a focus of the next phase of this process.

     
  • richardmitnick 5:52 pm on December 17, 2017 Permalink | Reply
    Tags: , Brain Studies, Dheeraj Roy, Existing theories about memory formation and storage are wrong or at least incomplete, Light-Triggered Genes Reveal the Hidden Workings of Memory, Nobel laureate Susumu Tonegawa, , , The brain creates multiple copies of memories at once — even though it hides the long-term copy from our awareness at first, Tracking Memories Cell by Cell   

    From Quanta: “Light-Triggered Genes Reveal the Hidden Workings of Memory” 

    Quanta Magazine
    Quanta Magazine

    December 14, 2017
    Elizabeth Svoboda

    1
    Eero Lampinen for Quanta Magazine

    Neuroscientists gained several surprising insights into memory this year, including the discovery that the brain creates multiple copies of memories at once — even though it hides the long-term copy from our awareness at first.

    Nobel laureate Susumu Tonegawa’s lab is overturning old assumptions about how memories form, how recall works and whether lost memories might be restored from “silent engrams.”

    Susumu Tonegawa’s presence announces itself as soon as you walk through the door of the Massachusetts Institute of Technology’s Picower Institute for Learning and Memory. A three-foot-high framed photograph of Tonegawa stands front and center in the high-ceilinged lobby, flanked by a screen playing a looping rainbow-hued clip of recent research highlights.

    The man in the portrait, however, is anything but a spotlight-seeker. Most days, he’s ensconced in the impenetrable warren of labs and offices that make up Picower’s fifth floor. His hair, thick and dark in the photo, is now a subdued silver, and today, a loosely draped blue cardigan replaces the impeccable suit jacket. His accommodating, soft-spoken manner belies his reputation as a smasher of established dogma, or at least as a poker of deep and abiding holes.

    Along with his MIT neuroscientist colleague Dheeraj Roy and others, Tonegawa is upending basic assumptions in brain science. Early this year, he reported that memory storage and retrieval happen on two different brain circuits, not on the same one as was long thought. His team also showed that memories of an event form at the same time in the brain’s short-term and long-term storage areas, rather than moving to long-term storage later on. Most recently (and tantalizingly), his lab demonstrated what could someday be a way to bring currently irretrievable memories back into conscious awareness.

    Tonegawa, now MIT’s Picower Professor of Biology and Neuroscience, first carved out his maverick identity back in the 1980s. While at the Basel Institute for Immunology in Switzerland, he published a theory — first seen as heretical, then brilliant — that immune cells reshuffle their DNA to create millions of different antibodies from a small number of genes. His discovery won him the Nobel Prize in 1987, which explains the oversized lobby portrait. Most researchers would have stayed in the field and basked in the attention, but Tonegawa left immunology behind entirely. He spent the next couple of decades reinventing himself as a master of memory’s workings at the cellular level.

    Despite his professional stature, Tonegawa is no TED-circuit regular or fount of startup concepts. Instead of selling his ideas or his persona, he prefers to let his data speak for themselves. And they do, perhaps more loudly than some of his colleagues would like. “The way he continues to disrupt and innovate is really striking,” said Sheena Josselyn, a neuroscientist at Toronto’s Hospital for Sick Children who also studies memory formation. “He tackles the tough questions. He doesn’t do something that is easy and expected.”

    Tracking Memories Cell by Cell

    Upon meeting Tonegawa, I sensed that he considers his fame a slightly cumbersome side effect of his vocation. The day I visited his office, he was immersed in research banter with a colleague, breaking away only reluctantly to revisit his own journey. The whole immunology sideline, he told me, was something of an accident — his real love has always been molecular biology, and immunology was a fascinating expression of that. He ended up at Basel mostly because his U.S. work permit had run out. “Immunology was a transient interest for me,” he said. “I wanted to do something new.”

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    After making Nobel Prize-winning contributions to immunology, Susumu Tonegawa, now a professor of biology and neuroscience at the Massachusetts Institute of Technology, focused his passion for molecular biology on the brain. Tonegawa Lab.

    That “something” turned out to be neuroscience, which Francis Crick and other well-known biologists were touting as the wave of the future. In the late 1980s and early ’90s, researchers knew relatively little about how the cellular and molecular workings of the brain underpin its capabilities, and nothing excited Tonegawa more than mapping unexplored territory.

    Tonegawa’s venture into brain science wasn’t a complete turnabout, though, because he brought some of his investigative techniques with him. He had been using transgenic (genetically modified) mice in his immunology studies, knocking out particular genes and observing the physical effects, and he used a similar approach to uncover the biological basis of learning and memory. In an early MIT study, he bred mice that did not produce a particular enzyme thought to be important in cementing long-term memories. Although the behavior of the mutant mice seemed mostly normal, further testing showed that they had deficiencies in spatial learning, confirming the enzyme’s key role in that process.

    With that high-profile result, Tonegawa was off and running. About 10 years ago, he was able to take his work to a new level of precision in part by employing a technique called optogenetics. Developed by the Stanford University bioengineer Karl Deisseroth and others, the technique involves modifying the genes of lab animals so that their cells express a light-sensitive protein called channelrhodopsin, derived from green algae. Researchers can then activate these cells by shining light on them through optical fibers. Tonegawa and his colleagues use optogenetics to generate neural activity on command in specified regions of the brain.

    This method has allowed Tonegawa to show that existing theories about memory formation and storage are wrong, or at least incomplete. This past summer, along with Roy and other colleagues, he reported that — contrary to neuroscience dogma — the neural circuit in the brain structure called the hippocampus that makes a particular memory is not the same circuit [Cell] that recalls the memory later. Instead, retrieving a memory requires what the scientists call a “detour circuit” in the hippocampus’s subiculum, located just off the main memory-formation circuit.

    To illustrate the discovery for me, Roy called up an image of a magnified brain slice in the lab. “What you’re looking at is the hippocampus section of a mouse,” he said. He gestured to a dense cloud of glowing green neurons in the upper right — the subiculum itself — and explained that his team had genetically engineered the mouse to produce channelrhodopsin only in the subiculum’s neurons. He and his team could then activate or deactivate these subiculum neurons with piped-in laser light, leaving the surrounding neurons unaffected.

    4
    Studies have shown that the hippocampus (red) is essential for creating new memories. But short-term recall of those memories depends on a “detour circuit” involving a specialized area called the subiculum (green). Dheeraj Roy/Tonegawa Lab, MIT.

    Armed with this biological switch, the researchers turned the subiculum neurons on and off to see what would happen. To their surprise, they saw that mice trained to be afraid when inside a certain cage stopped showing that fear when the subiculum neurons were turned off. The mice were unable to dredge up the fearful memory, which meant that the subiculum was needed for recall. But if the researchers turned off the subiculum neurons only while teaching the fearful association, the mice later recalled the memory with ease. A separate part of the hippocampus must therefore have encoded the memory. Similarly, when the team turned the main hippocampal circuit on and off, they found that it was responsible for memory formation, but not for recall.

    To explain why the brain would form and recall memories using different circuits, Roy framed it in part as a matter of expediency. “We think these parallel circuits help us quickly update memories,” he said. If the same hippocampal circuit were used for both storage and retrieval, encoding a new memory would take hundreds of milliseconds. But if one circuit adds new information while the detour circuit simultaneously calls up similar memories, it’s possible to apply past knowledge to your current situation much more quickly. “Now you can update on the order of tens of milliseconds,” Roy said.

    That difference might prove crucial to creatures in danger, for whom a few hundred milliseconds could mean the difference between getting away from a predator scot-free and becoming its dinner. The parallel circuits may also help us integrate present information with older memories just as speedily: Memories of a new conversation with your friend Shannon, for instance, can be added seamlessly to your existing memories of Shannon.

    Reassessing How Memories Form

    In addition to revealing that different mechanisms control memory formation and recall, Tonegawa, Roy and their colleague Takashi Kitamura (who recently moved from MIT to the University of Texas Southwestern Medical Center) have shown that memory formation itself is unexpectedly complex. Their work concerned the brain changes involved in the transformation of short-term memories to long-term memories. (In mouse experiments, short-term memory refers to recollections of events from within the past few days — what is sometimes called recent memory to distinguish it from more transient neural impressions that flicker out after only minutes or hours. Long-term memory holds events that happened on the order of two weeks or more ago.)

    For decades in neuroscience, the most widely accepted model posited that short-term memories form rapidly in the hippocampus and are later transferred to the prefrontal cortex near the brain’s surface for long-term storage. But Tonegawa’s team recently reported in Science that new memories form at both locations at the same time.

    The road to that discovery started back in 2012, when Tonegawa’s lab came up with a way to highlight brain cells known as engram cells, which hold a unique memory. He knew that when mice take in new surroundings, certain genes activate in their brains. His team therefore linked the expression of these “experiential-learning” genes in the mice to a channelrhodopsin gene, so that the precise cells that activated during a learning event would glow. “You can demonstrate those are the cells really holding this memory,” Tonegawa said, “because if you reactivate only those neurons with laser light, the animal behaves as if recalling that memory.”

    5
    In this magnified slice of brain tissue enhanced with an optogenetic protein, the green glow shows which engram cells in the hippocampus stored a short-term memory. Dheeraj Roy, Tonegawa Lab/MIT.

    In the new Science study, the team used this technique to create mice whose learning cells would respond to light. They herded each mouse into a special cage and delivered a mild electric shock to its foot, leading the mouse to form a fearful memory of the cage. A day later, they returned each mouse to the cage and illuminated its brain to activate the brain cells storing the memory.

    As expected, hippocampal cells involved in short-term memory responded to the laser light. But surprisingly, a handful of cells in the prefrontal cortex responded as well. Cortical cells had formed memories of the foot shock almost right away, well ahead of the anticipated schedule.

    Yet the researchers noticed that even though the cortical cells could be activated early on with laser light, they did not fire spontaneously when the mice returned to the cage where the foot shock happened. The researchers called these cortical cells “silent engrams” because they contained the memory but did not respond to a natural recall cue. Over the next couple of weeks, however, these cells seemingly matured and became integral for recalling the memory.

    “The dynamic is, the hippocampal engram is active [at first] and goes down, and the prefrontal-cortex engram is silent at the beginning and slowly becomes active,” Tonegawa said. This detailed understanding of how memories are laid down and stored could inform the development of drugs that aid formation of new memories.

    7
    Lucy Ikkanda-Reading/Quanta Magazine

    Some in the neuroscience community, however, think it’s prudent to be cautious in interpreting the significance of findings like these. Last year, Tonegawa’s MIT colleagues Andrii Rudenko and Li-Huei Tsai emphasized that engram science is still so new that we don’t know exactly how engram cells might work together, nor which cells contain which parts of memories. “In these early days of functional memory engram investigation,” they wrote BMC Biology, “we still do not have satisfactory answers to many important questions.”

    Tonegawa has asserted that brains contain silent engrams that could potentially be externally activated — an idea that strikes a few neuroscientists as overblown even as it excites others, according to Josselyn. “It really forces the scientific community to either update our thinking or try experiments to challenge that,” she said.

    Bringing Silent Memories to Life

    Despite the uncertainty that surrounds it, the silent-engram concept offers us the fascinating prospect of gaining access to hidden memories — a prospect that Roy, in particular, continues to explore. In October, he published a paper with Tonegawa [PNAS]that generated a flurry of excited emails from scientists and nonscientists alike. One of the paper’s blockbuster findings was that, at least in mice, it was possible to awaken silent engrams without using a laser light or optical fibers.

    8
    Dheeraj Roy, a postdoctoral associate at MIT, has collaborated with Tonegawa on several recent studies that have overturned old ideas about how memory works. Vicky Roy.

    The question the team asked themselves, Roy said, was whether they could make hidden memories permanently active with a noninvasive treatment. A cellular protein called PAK1 stimulates the growth of dendritic spines, or protrusions, that allow communication between neurons, and Roy had a hunch that this protein — when transported into brain cells — might help bring silent engrams back into direct awareness. “Can we artificially put [in] more of one gene that would make more protrusions?” he asked, excitedly noting that this approach might be simpler than optogenetics.

    To test this possibility, the researchers first gave mild shocks to mice in a cage while also suppressing their ability to make the proteins that normally cement long-term memories. When these mice returned to the same cage later on, they showed no fear, indicating that they did not naturally recall the shock in response to a cue. Yet laser light could still switch on the mice’s fearful response, which meant the memory was still there in silent-engram form.

    When the team injected these mice with the PAK1 gene to make them overproduce the protein, the animals froze up spontaneously when entering the dreaded cage. They were recalling the memory of the cage all on their own: The silent engram was coming to life. When PAK1 is administered, “you just wait four days, [and] they recover it with natural cues,” Roy said. In the future, he added, a therapeutic injection of PAK1 molecules that enter the brain’s memory cells could awaken people’s silent memories as well.

    “So it would just be an injected protein?” I asked.

    “That’s right — one molecular transporter that has one protein. People already have ways to put proteins into brain cells. I don’t think we’re that far [away] anymore.”

    It’s amazing to think that all of our minds hold hundreds or thousands of silent memories that are just waiting for the right activation to re-emerge into conscious awareness. If Roy’s findings hold true in humans, the retrieval of hidden memories might someday be as easy to initiate as getting a flu shot. “What would happen if you did that to a normal person? What would come flooding back?” I asked. “What would that experience be like?”

    “Very sci-fi, even for me,” Roy said. “My family says, ‘Is this all real?’ I say, ‘Yeah, I’m not lying to you!’”

    A few minutes later, back in Tonegawa’s office, I posed more or less the same question to him. Reactivating silent engrams could allow people with memory issues — like Alzheimer’s sufferers, soldiers who have survived explosive blasts and concussed athletes in contact sports — to regain memories that have become inaccessible. (To be sure, these people would often need to get such treatments early, before their conditions progressed and too many brain cells died.) Roy and Tonegawa’s past research [PubMed] suggests that people with cognitive difficulties have many stored memories that they simply can’t recall. But what about the rest of us who just want to mine our memories, to excavate what’s buried deep within?

    Tonegawa paused to consider. “It could be these silent memories could come out,” he said. “If you artificially increase the spine density, inject enzymes which promote spine formation, then the silent engram can be converted to active engram.”

    When I pressed him further, though, he exuded caution. It was as if he was used to hearing people like me run away with the possibilities and wanted to tamp down my expectations. Even though his lab successfully reactivated mice’s silent engrams after a few days, that’s no guarantee that silent engrams last very long, he said. And once the cells that encode particular memories die off from old age or dementia, it might be game over, no matter what kind of proteins you inject. Tonegawa pointed to Roy, who was sitting across from him. “I won’t remember his name.”

    His patience seemed to be running out. The contrarian in him, I could tell, wanted to assert that he was a student of the essential nature of things, not a pursuer of drug patents or quick cures or even the ideal of perfect recall. “I know a joke,” he said cryptically. “Not injecting protein or genes, but I keep an external brain. I hold the information in that brain.” He pointed to Roy again — the person he counts on to remember things he can’t. “The only thing I have to do is have a relationship with that person,” he explained. It’s comforting, in a way, to know that the wizard of tracing and unlocking memories also believes that no brain is an island. “It’s better,” he said, “not to memorize everything.”

    See the full article here .

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    Formerly known as Simons Science News, Quanta Magazine is an editorially independent online publication launched by the Simons Foundation to enhance public understanding of science. Why Quanta? Albert Einstein called photons “quanta of light.” Our goal is to “illuminate science.” At Quanta Magazine, scientific accuracy is every bit as important as telling a good story. All of our articles are meticulously researched, reported, edited, copy-edited and fact-checked.

     
  • richardmitnick 2:29 pm on November 4, 2017 Permalink | Reply
    Tags: , Brain Studies, Brain waves, , ,   

    From INVERSE: For All of my Friernds in Neuroscience: “Nobody Knows Where Brainwaves Come From” 

    INVERSE

    INVERSE

    August 7, 2017 [Just now in social media]
    Rafi Letzter

    Wub-wub-wub-wub. Brainwaves are electromagnetic proof that we are alive. Decades of research have shown that these pulses of electrical potential reflect events at the root of our impulses and thoughts. As such, they underlie one of humanity’s weightiest moral decisions: deciding whether or not a person is officially dead. If a person goes 30 minutes without producing brainwaves, even a functioning heartbeat can’t convince doctors they’re alive.

    But as much as brainwaves loom in our understanding of the brain, not a single scientist has any idea where they come from.

    At least one researcher, Michael X. Cohen, Ph.D., an assistant professor at the Donders Institute for Brain, Cognition, and Behavior in the Netherlands, thinks it’s time to fix that. In an April op-ed in the journal Trends in Neurosciences, Cohen argued that the time has come for researchers to figure out what those brainwaves they’ve been recording for decades are really all about.

    “This is maybe the most important question for neuroscience right now,” he said to Inverse, but he added that it will be a challenge to convince his colleagues that it matters at all.

    Today, as Facebook races to read your brainwaves, roboticists use them to develop mind control systems, and cybersecurity experts race to protect yours from hackers, it’s clear that Cohen’s sense of urgency is justified.

    1
    Connecting brainwaves to neuron behavior is the next great challenge in neuroscience. No image credit

    What we do know about brainwaves is that when doctors stick silver chloride dots to a person’s scalp and hook the connected electrodes up to an electroencephalography (EEG) machine, the curves that appear on its screen represent the electrical activity inside our skulls. The German neuroscientist Hans Berger spotted the first type of brainwave — alpha waves — back in 1924.

    Researchers soon discovered more of these strange oscillations. There’s the slow, powerful delta wave, which shows up when we’re in deep sleep. There’s the low spikes of the theta wave, whose functions remain largely mysterious. Faster and even stranger is the gamma wave, which some researchers suspect plays a role in consciousness.

    These waves are at the root of our understanding of the shape and structure of human thought, as well as the methods doctors use to figure out how brains break down. It’s thought that alpha waves, for example, are a sign the brain is inhibiting certain mental systems to free up bandwidth for other tasks, like sleeping or imagining. But where does it come from in the first place?

    So far, there’s been no satisfactory answer to this question, but Cohen is determined to find it.

    2
    An alpha brainwave resembles a sine wave. No image credit.

    As one of the world’s leading researchers on the brain’s electrical activity, he hooks people up to EEG machines to figure out how their brains behave when they see a bird, think through a complex decision, or feel sad. But Cohen is the first to admit that what’s lacking in his research is context. Not understanding how those patterns relate to the actual meat of the brain — neurons firing or not firing, getting excited, or shutting down — leaves a huge mystery right at the center of brainwave neuroscience, he says.

    “Over time it started bothering me more and more,” Cohen told Inverse. “There’s so much complexity going on at smaller spatial scales, and we have literally no fucking clue how to get from this big spatial scale to this smaller spatial scale.”

    Part of the reason why it’s so hard to understand neuroscience research in the context of the brain, Cohen explains, is because neuroscientists themselves work in discrete, isolated sub-fields based on how big a chunk of the brain they study. Researchers studying the brain at the smallest level peel open individual neurons and watch the proteins inside them fold. Microcircuit neuroscientists map out the connections between neurons. Cohen zooms out a little further, connecting electrical patterns and human thought, rarely concerning himself with single cells or small groups of neurons.

    But as we begin to fully grasp how complex the brain really is, Cohen says, it’s increasingly imperative to find a way to bridge the research that happens at the macro and micro scales. Finally understanding brainwaves, he says, could be the key to doing so.

    3
    No image caption or credit.

    That’s because brainwaves pulse at every single level of the brain, from the tiniest neuron to the entire 3-pound organ. “If you’re recording from just one neuron, you’ll see oscillations,” Cohen says, using the scientific term for wobbling brainwaves.

    “If you’re recording from a small ensemble of neurons, you’ll see them. And if you’re recording from tens of millions of neurons, you’ll see oscillations.”

    For Cohen, brainwaves are the common thread that can unify neuroscience. But the problem is, most research deals only with the electrical activity produced from tens of millions of neurons at a time, which is the highest resolution a typical EEG machine can capture without needlessly cutting into an innocent study subject’s head. The problem is that this big, rough EEG research in humans isn’t very compatible with the intricate, neuron-scale research done in lab rats. Consequently, we have plenty of information about the brain’s parts but no understanding of how they work together as a whole.

    “It’s the difference between ‘What do Americans like?’ and ‘What does any individual American like?’” Cohen said. “And that’s a huge difference — between what any individual does and what you can say as a generality about an entire culture.”

    While we know that all that electrical activity is the result of charged chemicals sloshing around in our brains in rhythmic, patterned waves, that doesn’t tell us anything about the most important question: Why they’re generated in the first place.

    “The problem with these answers is that they’re totally meaningless from a neuroscience perspective,” Cohen says. “These answers tell you about how it’s physically possible, how the universe is constructed such that we can make these measurements. But there’s a totally different question, which is, what do these measurements mean? What do they tell us about the kinds of computations that are taking place in the brain? And that’s a huge explanatory gap.”

    4
    Despite some puzzlement from fellow scientists, Cohen plans to collect brainwave data from rodents. No image credit.

    There are a few ways to bridge that gap. Scientists like those at the Blue Brain Project in Switzerland are trying to do so by building a computerized brain simulation that’s detailed enough to include the whole organ, as well as individual neurons, which they hope can reveal a kind of cell activity that would cause different kinds of common EEG patterns to appear. The one huge challenge to this approach, however, is that there’s no computer that can simulate a brain’s computations in real time; just a millisecond of one neuron’s time in a simulation can take 10 seconds of real-world time for a computer to figure out. It’s certainly possible, but doing so would cost billions of dollars.

    Cohen’s plan, which relies on real-world experiments, is much simpler.

    Since you can’t cut open a human brain and start sticking electrodes in there to record activity (even in “human rights-challenged places,” Cohen says), he’s relying on rodents instead. But what makes his work different is that he’s hooking those rodents up to EEG machines, which researchers don’t usually do. “They say, why are you wasting your time recording EEG from rats? EEG is for when you don’t have access to the brain, so you record from outside,” he says.

    But rodents have brainwaves, too, and their data can provide much-needed insight into how to bridge the neuron-brainwave divide. His experiments will create two huge data sets that researchers can cross-reference to figure out how neuron function and EEG behavior relate to one another. With the help of some deep-learning algorithms, they’ll then pore over that data to build a map of how individual sparks of neural activity add up to recognizable brainwaves. If Cohen’s experiments are very successful, his team will be able to look at a rodent’s EEG and predict — with what he hopes is more than 98 percent accuracy — exactly how the neural circuits are behaving in its brain.

    “I think we’re not that far away from breakthroughs. Some of these kinds of questions are not so difficult to answer, it’s just that no one has really looked,” he said. But he admits that he’s worried that the segmentation of neuroscience research will get in the way of this whole-brain approach.

    “So this is very terrifying for me and also very difficult, because I have very little experience in the techniques that i think are necessary,” he said.

    Having to admit on his grant applications that his work would employ unfamiliar techniques he has never used made it difficult to get funding, but Cohen ultimately received a grant from the European Union. Now, with the aid of a lab fully staffed with experts in rodent brains, Cohen is ready to get to work.

    Soon enough, we might finally get some answers to one of the oldest and strangest mysteries in neuroscience: where all those wub-wubs really come from and what they really mean.

    See the full article here .

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  • richardmitnick 11:33 am on November 3, 2017 Permalink | Reply
    Tags: , Brain Studies, , For this study the researchers focused primarily on the calcium sodium potassium and other ions in cerebral fluid, LMIS4-Microsystems Laboratory 4, , Reading our brain chemistry   

    From EPFL: “Reading our brain chemistry” 

    EPFL bloc

    École Polytechnique Fédérale de Lausanne EPFL

    03.11.17
    Clara Marc

    1
    © Guillaume Petit-Pierre – Perfusion microdroplet allowing the extraction of interstitial liquid using the system developed by EPFL researchers.

    Researchers at EPFL have developed a new device and analysis method that let doctors measure the neurochemicals in a patient’s brain. The Microsystems Laboratory 4 (LMIS4)’s system involves collecting microdroplets of cerebral fluid and analyzing them to obtain chemical data that can help doctors diagnose and treat neurodegenerative diseases.

    Neurologists often use electrical impulses to stimulate and read brain signals. But the chemicals that neurons produce in response to these impulses are poorly understand at this point, even though they can provide valuable information for understanding the mechanisms behind neurodegenerative diseases like Alzheimer’s and Parkinson’s. “Neurons can be read two ways: electrically or chemically,” says Guillaume Petit-Pierre, a post-doc researcher at LMIS4 and one of the study’s authors. “Reading their electrical behavior can provide some limited information, such as the frequency and pace at which neurons communicate. However, reading their neurochemistry gives insight into the proteins, ions and neurotransmitters in a patient’s cerebral fluid.” By analyzing this fluid, doctors can obtain additional information – beyond that provided by neurons – and get a complete picture of a patient’s brain tissue metabolism.

    Collecting information through microchannels

    The EPFL researchers developed a system that can both collect a patient’s neurochemical feedback and form electrical connections with brain tissue. Their device is made up of electrodes and microchannels that are about half a hair in diameter. Once the device is placed inside brain tissue, the microchannels draw in cerebral fluid while the electrodes, which are located right at the fluid-collection interface, make sure that the measurements are taken at very precise locations. The microchannels subsequently create highly concentrated microdroplets of cerebral fluid. “The microdroplets form directly at the tip of the device, giving us a very high temporal resolution, which is essential if we want to accurately analyze the data,” says Petit-Pierre. The microdroplets are then placed on an analytical instrument that was also developed by scientists at the LMIS4 and the nearby University Centre of Legal Medicine which has expertise in this type of complex analysis. As a last step, the microdroplets are vaporized with a laser and the gas residue is analyzed. Both the researchers’ device and their analysis method are totally new. “Today there is only one method for performing neurochemical analyses: microdialysis. But it isn’t very effective in terms of either speed or resolution,” says Petit-Pierre. Another advantage of the researchers’ method is that it is a minimally invasive way to collect data. Currently scientists have to work directly on the brains of rats afflicted with neurodegenerative diseases, meaning the rats must be sacrificed to take the measurements. Their research was published in Nature Communications.

    Direct applications

    For this study, the researchers focused primarily on the calcium, sodium, potassium and other ions in cerebral fluid. They worked with EPFL’s Neurodegenerative Disease Laboratory to compare the measurements they took on rats with those reported in the literature – and found that the results were well correlated. The next step will be to develop a method for analyzing the proteins and neurotransmitters in cerebral fluid, so that their implications in neurodegenerative diseases can be further studied. “Doctors could measure neurochemical responses to help them make diagnoses, such as for epilepsy, when they use electricity to measure signals from a patient’s cortex,” says Guillaume, “or to improve the efficiency of treatments like deep brain stimulation (DBS) for Parkinson’s disease.” Their research could also soon find direct applications in other medical fields. Guillaume currently works on a start-up project to develop a catheter for patients affected by hemorrhagic stroke. Based on a similar technology, his catheter would let doctors treat a common yet serious complication of this condition and thereby reduce the risk of death.

    This research was carried out jointly by EPFL’s Laboratory of Microsystems 4 (LMIS4), EPFL’s Neurodegenerative Disease Laboratory (LEN), the Unit of Toxicology at the University Centre of Legal Medicine (CURML, CHUV and HUG) and the University of Lausanne’s Faculty of Biology and Medicine (FBM, UNIL).

    See the full article here .

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    EPFL campus

    EPFL is Europe’s most cosmopolitan technical university with students, professors and staff from over 120 nations. A dynamic environment, open to Switzerland and the world, EPFL is centered on its three missions: teaching, research and technology transfer. EPFL works together with an extensive network of partners including other universities and institutes of technology, developing and emerging countries, secondary schools and colleges, industry and economy, political circles and the general public, to bring about real impact for society.

     
  • richardmitnick 12:16 pm on November 1, 2017 Permalink | Reply
    Tags: , Brain Studies, Human chromosome 16p11.2 deletion syndrome is caused by the absence of about 27 genes on chromosome 16, , , R-Baclofen treatment   

    From MIT: “Promise seen in possible treatment for autism spectrum disorder” 

    MIT News
    MIT Widget

    MIT News

    October 31, 2017
    Picower Institute for Learning and Memory

    1
    In searching for a potential therapeutic for autism spectrum disorder, researchers have found that R-Baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11.2 deletion mice.

    Image courtesy of the Picower Institute for Learning and Memory.

    Studies in mice show improved social interaction and cognition from a potential therapeutic for a syndrome that often results in autism.

    Human chromosome 16p11.2 deletion syndrome is caused by the absence of about 27 genes on chromosome 16. This deletion is characterized by intellectual disability; impaired language, communication, and socialization skills; and autism spectrum disorder or ASD.

    Research from the laboratories of Mark Bear at MIT and Jacqueline Crawley at the University of California at Davis, has identified a potential therapeutic for ASD. Researchers found that R-Baclofen reverses cognitive deficits and improves social interactions in two lines of 16p11.2 deletion mice.

    The findings, published in the journal Neuropsychopharmacology, have the potential to treat humans with 16p11.2 deletion syndrome and ASD.

    “Our collaborative teams found that treatment with the drug R-baclofen improved scores on several learning and memory tasks, and on a standard assay of social behavior, in 16p11.2 mutant mice,” says Crawley, co-senior author of the paper along with Bear.

    “This unique corroboration of findings by two independent labs, using two distinct lines of mice with the same mutation, increases confidence that R-baclofen may be an effective pharmacological treatment for some of the symptoms of human 16p11.2 deletion syndrome, including intellectual impairment and autism,” she says.

    “These findings are particularly exciting on two fronts,” says Bear, who is the Picower Professor of Neuroscience at MIT. “First, the results show that diverse genetic causes of intellectual disability and autism may converge on a limited number of pathophysiological processes that can be ameliorated pharmacologically. Thus, a treatment for one genetically defined disorder may be beneficial for another with phenotypic overlap. Second, R-Baclofen has a well-understood safety profile and is well-tolerated in children and adults, making clinical studies feasible in the near future.”

    Growing knowledge about genetic mutations in people with autism is enabling researchers to evaluate hypothesis-driven pharmacological interventions in terms of their ability to reverse the biological and behavioral consequence of specific mutations that cause autism. One of the genes in the 16p11.2 deletion region regulates the inhibitory neurotransmitter GABA. Researchers tested the hypothesis that increasing GABA neurotransmission using R-baclofen, which binds to GABA-B receptors, could reverse analogous behavioral symptoms in a mouse model of 16p11.2 deletion syndrome.

    In the current paper, researchers report the results of animal model studies using two independently derived lines of mutant mice, each missing a chromosomal region analogous to human 16p11.2. Normal and mutant mice at both labs were tested after receiving R-baclofen in their drinking water on three tasks: novel object recognition, object location memory, and contextual recognition learning and memory. In addition, R-baclofen treated mutant mice scored better after treatment on each cognitive task than the untreated mutant mice. R-baclofen also increased scores on a standard assay of mouse social behaviors — male-female reciprocal social interactions — in the 16p11.2 mutant mice.

    This study suggests that R-baclofen should be explored for the treatment of cognitive phenotypes in affected humans.

    See the full article here .

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    The mission of MIT is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the MIT community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

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  • richardmitnick 3:16 pm on October 27, 2017 Permalink | Reply
    Tags: , , Brain Studies, , , Trans-Tango   

    From Brown: “Novel technology provides powerful new means for studying neural circuits” 

    Brown University
    Brown University

    [This post is dedicated to E.B.M., now at Brown]

    October 26, 2017
    David Orenstein
    david_orenstein@brown.edu


    Choreographing trans-Tango
    Developing trans-Tango, a system that works across neural connections called synapses to trace neurons in circuits, required decades of work and a dedicated team.
    Stephen Crocker

    2
    Motor and Sensory Regions of the Cerebral Cortex. This image was donated by Blausen Medical. Bruce Blaus

    With “trans-Tango,” a technology developed at Brown University and described in a new study in Neuron, scientists can bridge across the connections between neurons to trace — and in the future control — brain circuits.

    Finding out which neurons are connected with which others, and how they act together, is a huge challenge in neuroscience, and it’s crucial for understanding how brain circuits give rise to perception, motion, memory, and behavior. A new Brown University-developed technology called “trans-Tango” allows scientists to exploit the connections between pairs of neurons to make such discoveries in neuroscience. In a new study in Neuron, they used trans-Tango to illuminate connected neurons in fruit flies, revealing previously unmapped gustatory circuits that link the taste-sensing organs to brain regions known to govern feeding behavior and memory.

    The technology is widely applicable, the researchers say, because trans-Tango doesn’t depend on the neurotransmitters involved in a neural connection or on the types of neurons that are connected. As long as two neurons join at a synapse, trans-Tango allows scientists to label the cells connected to a starter neuron, experiments in the paper show.

    Moreover, because trans-Tango works by instigating the expression of genes in connected pairs of neurons, it also has the potential to enable scientists to control circuit functions, said senior and corresponding author Gilad Barnea, an associate professor of neuroscience at Brown who began looking for a precise, reliable and general way to visualize neural connections two decades ago. The application of trans-Tango that his team demonstrates in the new study is circuit tracing, but manipulations such as activating or shutting off connected neurons could become possible, too.

    “trans-Tango provides genetic accessibility in the context of connectivity,” Barnea said. “Our technique allows you to access the neurons that interact with the particular ‘starter’ cell you target. It therefore expands the use of molecular genetic techniques beyond the cell for which you have a marker to the ones it ‘talks’ to.”

    The team, which includes postdoctoral fellows, graduate students, research assistants and undergraduates, is now working on developing a host of other applications of trans-Tango. These include using the system to manipulate behavior, developing the equivalent technique in mice, and making it work in reverse so that it employs incoming connections from other neurons just like it does outgoing connections. That’s according to Mustafa Talay, a postdoctoral fellow who earned his Ph.D. in Barnea’s lab and is co-lead author with Ethan Richman, a former undergraduate at Brown who is now a graduate student at Stanford.

    In addition, the Barnea lab is collaborating on adapting the technology to study how cancer spreads.

    How it works

    trans-Tango works by genetically introducing an artificial signaling pathway into every neuron in the fly. The pathway acts like a switch in the neurons that can be thrown by exposure to a triggering protein. To operate trans-Tango, scientists genetically engineer the neurons of interest (starter neurons) to present this triggering protein on their synapses together with a protein that lights up the starter neurons in green. Expression of the trigger protein at the synapse causes connected neurons to light up in red, revealing the full extent of the connected neurons in the fly’s nervous system.

    In the gustatory system, for example, the team lit up connections extending all the way from peripheral taste-sensing starter neurons to connected neurons that projected into a brain region known to control feeding behavior as well as to other regions thought to regulate memory.


    trans-Tango reveals taste circuits
    Brown Unviersity scientists used trans-Tango to discover new connections linking taste-sensing organs in the fly body with specific regions in the brain.

    By design, the system stops after just one stage of connectivity because if it continued endlessly, it would eventually light up the whole nervous system, Talay said. After all, each neuron usually connects to many others, not just one or a few, and ultimately they are pretty much all connected.

    But the system is compatible with other cell imaging and targeting methods that can narrow down the number of connected neurons that respond to trans-Tango. In the new study, for example, the team combined trans-Tango with such techniques to specifically highlight individual connected neurons.

    “When we probe a circuit we have no idea about, we can first just use trans-Tango and see the totality of all the connections of a neuron,” Talay said. “After that, if we want to characterize a circuit in more detail, we can combine trans-Tango with other methods to basically dissect that circuit.”

    In many cases, revealing the full expanse that two connected neurons cover in a circuit can present deeply meaningful insights for neuroscientists. Not only did the team find novel connections in the gustatory circuitry of flies, but also they showed the different projections that various neurons in the olfactory system make, potentially clarifying how they carry out their distinct roles in connecting smell and behavior. Their experiments also highlighted connections that were already well known in the olfactory system, validating that the connections trans-Tango highlights are real.

    The technology’s triggering protein is not naturally found in the fly, and it doesn’t leave the neurons or the synapse. For this reason, the scientists said, the illumination that arises as a result of trans-Tango reveals cells that truly “talk” to each other rather than neighboring but irrelevant cells.

    How it was developed

    Barnea has sought to perform exactly this kind of circuit mapping since he joined the lab of Columbia University Professor Richard Axel as a postdoctoral researcher in 1996. They were studying the olfactory system, and Barnea wanted to map the olfactory circuits in the rodent brain.

    Tracing the connections of neurons within circuits in the brain is a fundamental but very difficult problem for neuroscientists. In all, the nervous systems of different organisms may involve many millions or billions of neurons with connections reaching into the trillions. It’s a lot to sort through.

    There are several other methods for mapping circuits, but they all suffer from drawbacks. Some are too noisy. Some are too expensive and laborious. Some are too specific to a tiny subset of connections or neurons. Some only reveal the synapses but not the full length of the cells that connect there. Some won’t work in a living organism. Barnea wanted to generate a system for circuit mapping that would be general, precise, simple to use and that would work in an organism rather than in extracted tissue.

    At Columbia, Barnea developed Tango [ PNAS], a method for studying cellular receptors that is the basis for the synthetic signaling pathway in trans-Tango. When he came to Brown in 2007, he continued this work and took on other projects. Barnea’s lab was not set for fly work, so its first fly incubator was an old egg incubator borrowed from biology professor Gary Wessel. The trans-Tango project was first supported by the Pew Charitable Trusts, then by the National Institutes of Health’s EUREKA program and subsequently by more conventional grants. The project also gained internal funding through the Innovation Award from the Brown Institute for Brain Science and Research Seed and Salomon awards from Brown’s Office of the Vice President for Research.

    2
    Flies on the wall
    Professor Gilad Barnea surveys shelves full of research flies in his Brown University lab.
    David Orenstein

    A key feature of trans-Tango is that it employs the human hormone glucagon as the trigger that switches the synthetic pathway on. Glucagon is engineered to localize to the synapse, and it is tethered in order to prevent it from diffusing away. Barnea credits the inspiration to use that form of glucagon to co-author John Szymanski, a former undergraduate student in his lab who is now a graduate student at Columbia. Szymanski first heard about the engineered form of glucagon at a party, Barnea said.

    In 2011, Barnea met Talay while visiting Boğaziçi University in Turkey, where Talay was a master’s student. Talay was also thinking about ways to trace neural circuits and he had crucial experience working in flies, where progress could be faster than in mice.

    Richman was interested in synthetic biology so he joined the Barnea lab to advance the development of the tracing technique. Talay and Richman led the charge to develop trans-Tango and make it work in flies, continually refining it with the help of several lab mates. This collaboration continued even after Richman graduated in 2013, when he decided to delay going to Stanford to see the project through.

    “I remember very clearly the excitement of seeing the first images appear indicating a functioning technique, and the pleasure of discussing those results with Gilad,” Richman said. “That happened in January, and in the subsequent spring I had gotten accepted to graduate school and was slated to start the next fall. By the summer, Mustafa and I had made progress optimizing the technique, and the excitement in the lab was building. Having spent so long getting the technique to work, I was tantalized by the opportunity to put it into action.”

    It was indeed a long time coming. Barnea points out that one of the paper’s co-authors, former undergraduate student Cambria Chou-Freed, is younger than the original idea he envisioned 21 years ago. In all, five of the paper’s authors were undergraduates in the lab, and all stayed in the lab after graduating to continue to work on this project.

    “Everyone on the list of authors contributed something unique to the success of this project,” Barnea said. “This was driven by individuals who were committed and obsessed with it, but it was also very nice teamwork.”

    The paper’s other authors are Nathaniel Snell, Griffin Hartmann, John Fisher, Altar Sorkaç, Juan Santoyo, Nived Nair and Mark Johnson.

    See the full article here .

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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.

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