Monday, March 5th, 2018

Time	Event
10:59a	Viral tool traces long-term neuron activity For the past decade, neuroscientists have been using a modified version of the rabies virus to label neurons and trace the connections between them. Although this technique has proven very useful, it has one major drawback: The virus is toxic to cells and can’t be used for studies longer than about two weeks. Researchers at MIT and the Allen Institute for Brain Science have now developed a new version of this virus that stops replicating once it infects a cell, allowing it to deliver its genetic cargo without harming the cell. Using this technique, scientists should be able to study the infected neurons for several months, enabling longer-term studies of neuron functions and connections. “With the first-generation vectors, the virus is replicating like crazy in the infected neurons, and that’s not good for them,” says Ian Wickersham, a principal research scientist at MIT’s McGovern Institute for Brain Research and the senior author of the new study. “With the second generation, infected cells look normal and act normal for at least four months — which was as long as we tracked them — and probably for the lifetime of the animal.” Soumya Chatterjee of the Allen Institute is the lead author of the paper, which appears in the March 5 issue of Nature Neuroscience. Using two-photon microscopy, researchers can image fluorescent cells in the brains of live mice. These two images were taken of the same group of neurons in visual cortex at nine days (left) and 22 days (right) following injection of a first-generation rabies viral vector encoding a red fluorescent protein. The vast majority of infected neurons visible at the earlier time point are gone by the later imaging session. These two images show the same group of neurons in visual cortex at four weeks (left) and eight weeks (right) following injection of a second-generation rabies viral vector encoding Cre recombinase, which causes cells in these transgenic mice to express a red fluorescent protein. All neurons visible at the earlier time point are still present at the later one. Viral tracing Rabies viruses are well-suited for tracing neural connections because they have evolved to spread from neuron to neuron through junctions known as synapses. The viruses can also spread from the terminals of axons back to the cell body of the same neuron. Neuroscientists can engineer the viruses to carry genes for fluorescent proteins, which are useful for imaging, or for light-sensitive proteins that can be used to manipulate neuron activity. In 2007, Wickersham demonstrated that a modified version of the rabies virus could be used to trace synapses between only directly connected neurons. Before that, researchers had been using the rabies virus for similar studies, but they were unable to keep it from spreading throughout the entire brain. By deleting one of the virus’ five genes, which codes for a glycoprotein normally found on the surface of infected cells, Wickersham was able to create a version that can only spread to neurons in direct contact with the initially infected cell. This 2007 modification enabled scientists to perform “monosynaptic tracing,” a technique that allows them to identify connections between the infected neuron and any neuron that provides input to it. This first generation of the modified rabies virus is also used for a related technique known as retrograde targeting, in which the virus can be injected into a cluster of axon terminals and then travel back to the cell bodies of those axons. This can help researchers discover the location of neurons that send impulses to the site of the virus injection. Researchers at MIT have used retrograde targeting to identify populations of neurons of the basolateral amygdala that project to either the nucleus accumbens or the central medial amygdala. In that type of study, researchers can deliver optogenetic proteins that allow them to manipulate the activity of each population of cells. By selectively stimulating or shutting off these two separate cell populations, researchers can determine their functions. Reduced toxicity To create the second-generation version of this viral tool, Wickersham and his colleagues deleted the gene for the polymerase enzyme, which is necessary for transcribing viral genes. Without this gene, the virus becomes less harmful and infected cells can survive much longer. In the new study, the researchers found that neurons were still functioning normally for up to four months after infection. “The second-generation virus enters a cell with its own few copies of the polymerase protein and is able to start transcribing its genes, including the transgene that we put into it. But then because it’s not able to make more copies of the polymerase, it doesn’t have this exponential takeover of the cell, and in practice it seems to be totally nontoxic,” Wickersham says. The lack of polymerase also greatly reduces the expression of whichever gene the researchers engineer into the virus, so they need to employ a little extra genetic trickery to achieve their desired outcome. Instead of having the virus deliver a gene for a fluorescent or optogenetic protein, they engineer it to deliver a gene for an enzyme called Cre recombinase, which can delete target DNA sequences in the host cell’s genome. This virus can then be used to study neurons in mice whose genomes have been engineered to include a gene that is turned on when the recombinase cuts out a small segment of DNA. Only a small amount of recombinase enzyme is needed to turn on the target gene, which could code for a fluorescent protein or another type of labeling molecule. The second-generation viruses can also work in regular mice if the researchers simultaneously inject another virus carrying a recombinase-activated gene for a fluorescent protein. The new paper shows that the second-generation virus works well for retrograde labeling, not tracing synapses between cells, but the researchers have also now begun using it for monosynaptic tracing. The research was funded by the National Institute of Mental Health, the National Institute on Aging, and the National Eye Institute. (Comment on this)
11:00a	Insulator or superconductor? Physicists find graphene is both It’s hard to believe that a single material can be described by as many superlatives as graphene can. Since its discovery in 2004, scientists have found that the lacy, honeycomb-like sheet of carbon atoms — essentially the most microscopic shaving of pencil lead you can imagine — is not just the thinnest material known in the world, but also incredibly light and flexible, hundreds of times stronger than steel, and more electrically conductive than copper. Now physicists at MIT and Harvard University have found the wonder material can exhibit even more curious electronic properties. In two papers published today in Nature, the team reports it can tune graphene to behave at two electrical extremes: as an insulator, in which electrons are completely blocked from flowing; and as a superconductor, in which electrical current can stream through without resistance. Researchers in the past, including this team, have been able to synthesize graphene superconductors by placing the material in contact with other superconducting metals — an arrangement that allows graphene to inherit some superconducting behaviors. This time around, the team found a way to make graphene superconduct on its own, demonstrating that superconductivity can be an intrinsic quality in the purely carbon-based material. The physicists accomplished this by creating a “superlattice” of two graphene sheets stacked together — not precisely on top of each other, but rotated ever so slightly, at a “magic angle” of 1.1 degrees. As a result, the overlaying, hexagonal honeycomb pattern is offset slightly, creating a precise moiré configuration that is predicted to induce strange, “strongly correlated interactions” between the electrons in the graphene sheets. In any other stacked configuration, graphene prefers to remain distinct, interacting very little, electronically or otherwise, with its neighboring layers. The team, led by Pablo Jarillo-Herrero, an associate professor of physics at MIT, found that when rotated at the magic angle, the two sheets of graphene exhibit nonconducting behavior, similar to an exotic class of materials known as Mott insulators. When the researchers then applied voltage, adding small amounts of electrons to the graphene superlattice, they found that, at a certain level, the electrons broke out of the initial insulating state and flowed without resistance, as if through a superconductor. “We can now use graphene as a new platform for investigating unconventional superconductivity,” Jarillo-Herrero says. “One can also imagine making a superconducting transistor out of graphene, which you can switch on and off, from superconducting to insulating. That opens many possibilities for quantum devices.” A large-scale interpretation of the moiré patterns formed when one graphene lattice is slightly rotated at a “magic angle,” with respect to a second graphene lattice. A 30-year gap A material’s ability to conduct electricity is normally represented in terms of energy bands. A single band represents a range of energies that a material’s electrons can have. There is an energy gap between bands, and when one band is filled, an electron must embody extra energy to overcome this gap, in order to occupy the next empty band. A material is considered an insulator if the last occupied energy band is completely filled with electrons. Electrical conductors such as metals, on the other hand, exhibit partially filled energy bands, with empty energy states which the electrons can fill to freely move. Mott insulators, however, are a class of materials that appear from their band structure to conduct electricity, but when measured, they behave as insulators. Specifically, their energy bands are half-filled, but because of strong electrostatic interactions between electrons (such as charges of equal sign repelling each other), the material does not conduct electricity. The half-filled band essentially splits into two miniature, almost-flat bands, with electrons completely occupying one band and leaving the other empty, and hence behaving as an insulator. “This means all the electrons are blocked, so it’s an insulator because of this strong repulsion between the electrons, so nothing can flow,” Jarillo-Herrero explains. “Why are Mott insulators important? It turns out the parent compound of most high-temperature superconductors is a Mott insulator.” In other words, scientists have found ways to manipulate the electronic properties of Mott insulators to turn them into superconductors, at relatively high temperatures of about 100 Kelvin. To do this, they chemically “dope” the material with oxygen, the atoms of which attract electrons out of the Mott insulator, leaving more room for remaining electrons to flow. When enough oxygen is added, the insulator morphs into a superconductor. How exactly this transition occurs, Jarillo-Herrero says, has been a 30-year mystery. “This is a problem that is 30 years and counting, unsolved,” Jarillo-Herrero says. “These high-temperature superconductors have been studied to death, and they have many interesting behaviors. But we don’t know how to explain them.” A precise rotation Jarillo-Herrero and his colleagues looked for a simpler platform to study such unconventional physics. In studying the electronic properties in graphene, the team began to play around with simple stacks of graphene sheets. The researchers created two-sheet superlattices by first exfoliating a single flake of graphene from graphite, then carefully picking up half the flake with a glass slide coated with a sticky polymer and an insulating material of boron nitride. They then rotated the glass slide very slightly and picked up the second half of the graphene flake, adhering it to the first half. In this way, they created a superlattice with an offset pattern that is distinct from graphene’s original honeycomb lattice. The team repeated this experiment, creating several “devices,” or graphene superlattices, with various angles of rotation, between 0 and 3 degrees. They attached electrodes to each device and measured an electrical current passing through, then plotted the device’s resistance, given the amount of the original current that passed through. “If you are off in your rotation angle by 0.2 degrees, all the physics is gone,” Jarillo-Herrero says. “No superconductivity or Mott insulator appears. So you have to be very precise with the alignment angle.” At 1.1 degrees — a rotation that has been predicted to be a “magic angle” — the researchers found the graphene superlattice electronically resembled a flat band structure, similar to a Mott insulator, in which all electrons carry the same energy regardless of their momentum. “Imagine the momentum for a car is mass times velocity,” Jarillo-Herrero says. “If you’re driving at 30 miles per hour, you have a certain amount of kinetic energy. If you drive at 60 miles per hour, you have much higher energy, and if you crash, you could deform a much bigger object. This thing is saying, no matter if you go 30 or 60 or 100 miles per hour, they would all have the same energy.” “Current for free” For electrons, this means that, even if they are occupying a half-filled energy band, one electron does not have any more energy than any other electron, to enable it to move around in that band. Therefore, even though such a half-filled band structure should act like a conductor, it instead behaves as an insulator — and more precisely, a Mott insulator. This gave the team an idea: What if they could add electrons to these Mott-like superlattices, similar to how scientists doped Mott insulators with oxygen to turn them into superconductors? Would graphene assume superconducting qualities in turn? To find out, they applied a small gate voltage to the “magic-angle graphene superlattice,” adding small amounts of electrons to the structure. As a result, individual electrons bound together with other electrons in graphene, allowing them to flow where before they could not. Throughout, the researchers continued to measure the electrical resistance of the material, and found that when they added a certain, small amount of electrons, the electrical current flowed without dissipating energy — just like a superconductor. “You can flow current for free, no energy wasted, and this is showing graphene can be a superconductor,” Jarillo-Herrero says. Perhaps more importantly, he says the researchers are able to tune graphene to behave as an insulator or a superconductor, and any phase in between, exhibiting all these diverse properties in one single device. This is in contrast to other methods, in which scientists have had to grow and manipulate hundreds of individual crystals, each of which can be made to behave in just one electronic phase. “Usually, you have to grow different classes of materials to explore each phase,” Jarillo-Herrero says. “We’re doing this in-situ, in one shot, in a purely carbon device. We can explore all those physics in one device electrically, rather than having to make hundreds of devices. It couldn’t get any simpler.” This research was supported in part by the Gordon and Betty Moore Foundation and ther National Science Foundation. (Comment on this)
11:59p	Study reveals how the brain tracks objects in motion Catching a bouncing ball or hitting a ball with a racket requires estimating when the ball will arrive. Neuroscientists have long thought that the brain does this by calculating the speed of the moving object. However, a new study from MIT shows that the brain’s approach is more complex. The new findings suggest that in addition to tracking speed, the brain incorporates information about the rhythmic patterns of an object’s movement: for example, how long it takes a ball to complete one bounce. In their new study, the researchers found that people make much more accurate estimates when they have access to information about both the speed of a moving object and the timing of its rhythmic patterns. “People get really good at this when they have both types of information available,” says Mehrdad Jazayeri, the Robert A. Swanson Career Development Professor of Life Sciences and a member of MIT’s McGovern Institute for Brain Research. “It’s like having input from multiple senses. The statistical knowledge that we have about the world we’re interacting with is richer when we use multiple senses.” Jazayeri is the senior author of the study, which appears in the Proceedings of the National Academy of Sciences the week of March 5. The paper’s lead author is MIT graduate student Chia-Jung Chang. Objects in motion Much of the information we process about objects moving around us comes from visual tracking of the objects. Our brains can use information about an object’s speed and the distance it has to cover to calculate when it will reach a certain point. Jazayeri, who studies how the brain keeps time, was intrigued by the fact that much of the movement we see also has a rhythmic element, such as the bouncing of a ball.  “It occurred to us to ask, how can it be that the brain doesn’t use this information? It would seem very strange if all this richness of additional temporal structure is not part of the way we evaluate where things are around us and how things are going to happen,” Jazayeri says. There are many other sensory processing tasks for which the brain uses multiple sources of input. For example, to interpret language, we use both the sound we hear and the movement of the speaker’s lips, if we can see them. When we touch an object, we estimate its size based on both what we see and what we feel with our fingers. In the case of perceiving object motion, teasing out the role of rhythmic timing, as opposed to speed, can be difficult. “I can ask someone to do a task, but then how do I know if they’re using speed or they’re using time, if both of them are always available?” Jazayeri says. To overcome that, the researchers devised a task in which they could control how much timing information was available. They measured performance in human volunteers as they performed the task. During the task, the study participants watched a ball as it moved in a straight line. After traveling some distance, the ball went behind an obstacle, so the participants could no longer see it. They were asked to press a button at the time when they expected the ball to reappear. Performance varied greatly depending on how much of the ball’s path was visible before it went behind the obstacle. If the participants saw the ball travel a very short distance before disappearing, they did not do well. As the distance before disappearance became longer, they were better able to calculate the ball’s speed, so their performance improved but eventually plateaued. After that plateau, there was a significant jump in performance when the distance before disappearance grew until it was exactly the same as the width of the obstacle. In that case, when the path seen before disappearance was equal to the path the ball traveled behind the obstacle, the participants improved dramatically, because they knew that the time spent behind the obstacle would be the same as the time it took to reach the obstacle. When the distance traveled to reach the obstacle became longer than the width of the obstacle, performance dropped again. “It’s so important to have this extra information available, and when we have it, we use it,” Jazayeri says. “Temporal structure is so important that when you lose it, even at the expense of getting better visual information, people’s performance gets worse.” Integrating information The researchers also tested several computer models of how the brain performs this task, and found that the only model that could accurately replicate their experimental results was one in which the brain measures speed and timing in two different areas and then combines them. Previous studies suggest that the brain performs timing estimates in premotor areas of the cortex, which plays a role in planning movement; speed, which usually requires visual input, is calculated in visual cortex. These inputs are likely combined in parts of the brain responsible for spatial attention and tracking objects in space, which occurs in the parietal cortex, Jazayeri says. In future studies, Jazayeri hopes to measure brain activity in animals trained to perform the same task that human subjects did in this study. This could shed further light on where this processing takes place and could also reveal what happens in the brain when it makes incorrect estimates. The research was funded by the McGovern Institute for Brain Research. (Comment on this)

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