Dr. Cornelia “Cori” Bargmann of The Rockefeller University delivered the fourth annual Sharp Lecture in Neural Circuits on Tuesday, March 2, 2015. Bargmann studies how genes, experience and neural circuits influence behavior in the nematode worm C. elegans.
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Translational Neuroscience Seminar Series: Raquel Gur, M.D. PhD
McGovern Institute awards prize to vision scientist Charles Gilbert
The McGovern Institute for Brain Research at MIT announced today that Charles D. Gilbert of The Rockefeller University is the winner of the 2015 Edward M. Scolnick Prize in Neuroscience. The Prize is awarded annually by the McGovern Institute to recognize outstanding advances in any field of neuroscience.
“Charles Gilbert has been a pioneer in understanding the function of visual cortex,” says Robert Desimone, director of the McGovern Institute and chair of the selection committee. “His work addresses fundamental questions about visual perception, and has also provided important insights into how the brain recovers from injury and degenerative disease.”
Gilbert is currently the Arthur and Janet Ross Professor and head of the laboratory of neurobiology at The Rockefeller University. He received his MD and PhD from Harvard University, where he later became an assistant professor before joining the Rockefeller faculty in 1983. He was elected to the American Academy of Arts and Sciences in 2001 and to the National Academy of Sciences in 2006.
While at Harvard, Gilbert began a longstanding collaboration with Torsten Wiesel, who shared the 1981 Nobel Prize for his work with David Hubel on the function of the visual cortex. Together with Wiesel, Gilbert described the lateral neuronal connections within the cortex, which are central to our current understanding of cortical function. The primary visual cortex contains a topographic map of the visual field that is transmitted from the retina, with each neuron responding to stimuli at a particular location in visual space, known as its receptive field. But as Gilbert’s work revealed, the cortex also contains an extensive network of lateral connections that allow neurons to respond not just to the stimuli in their primary receptive fields, but also to contextual information from other parts of the image. This is central to our ability to perceive large-scale features within the clutter of natural visual scenes.
Gilbert went on on to discover that these horizontal connections play an important role in the brain’s plasticity. If a blind patch is created on retina, the corresponding patch of cortex is initially unresponsive, but soon begins to respond to stimuli delivered to the surrounding part of the visual field, causing us to be unaware of any perceptual gap. Gilbert discovered the mechanism underlying this form of plasticity, demonstrating the anatomical growth of horizontal connections within the previously inactive patch of cortex and describing the intricate changes in connectivity that follow. These studies focused on the visual cortex, but similar circuits and mechanisms are thought to exist throughout the brain, and to underlie its ability to recover after damage or disease.
The plasticity of these horizontal connections is important not only for recovery after injury, but also for perceptual learning, a form of brain plasticity that persists throughout life. It has long been recognized that visual perceptual abilities (for example, the ability to do perceptual grouping of scene components) can improve with practice, and Gilbert has studied the neural basis of this phenomenon. He identified changes in the functional properties of cortical neurons that correlate with perceptual learning, and showed that these changes are seen only during the performance of the specific learned task, indicating that they are controlled by top-down influences such as attention and expectation that depend on behavioral context. This work has led to a new view of cortical neurons as ‘adaptive processors’ that can select task-relevant inputs through an interaction between top-down signals and local cortical connections.
The McGovern Institute will award the Scolnick Prize to Dr Gilbert on Friday March 20, 2015. At 4.00 pm he will deliver a lecture entitled “The Dynamic Brain,” to be followed by a reception, at the McGovern Institute in the Brain and Cognitive Sciences Complex, 43 Vassar Street (Building 46, Room 3002) in Cambridge. The event is free and open to the public.
About the Edward M. Scolnick Prize in Neuroscience:
The Scolnick Prize, awarded annually by the McGovern Institute, is named in honor of Dr. Edward M. Scolnick, who stepped down as President of Merck Research Laboratories in December 2002 after holding Merck’s top research post for 17 years. Dr. Scolnick is now a core member of the Broad Institute, where he is chief scientist at the Stanley Center for Psychiatric Research. He also serves as a member of the McGovern Institute’s governing board. The prize, which is endowed through a gift from Merck to the McGovern Institute, consists of a $100,000 award, plus an inscribed gift. Previous winners are Huda Zoghbi (Baylor College of Medicine), Thomas Jessell (Columbia University), Roger Nicoll (University of California, San Francisco), Bruce McEwen (Rockefeller University), Lily and Yuh-Nung Jan (University of California, San Francisco), Jeremy Nathans (Johns Hopkins University), Michael Davis (Emory University), David Julius (University of California, San Francisco), Michael Greenberg (Harvard Medical School), Judith Rapoport (National Institute of Mental Health) and Mark Konishi (California Institute of Technology).
2015 Scolnick Prize Lecture: Dr. Charles Gilbert
One young actor’s “Curious” Broadway role
Jane Pauley, host of CBS Sunday Morning interviews McGovern Investigator John Gabrieli about the brain basis of autism.
Colloquium: David Ginty
Translational Neuroscience Seminar Series: Tyrone D. Cannon, PhD
2015 Sharp Lecture in Neural Circuits: Dr. Cornelia Bargmann
Tasting light
Human taste receptors are specialized to distinguish several distinct compounds: sugars taste sweet, salts taste salty, and acidic compounds taste sour. Now a new study from MIT finds that the worm Caenorhabditis elegans has taken its powers of detection a step further: The worm can taste hydrogen peroxide, triggering it to stop eating the potentially dangerous substance.
Being able to taste hydrogen peroxide allows the worm to detect light, which generates hydrogen peroxide and other harmful reactive oxygen compounds both within the worm and in its environment.
“This is potentially a brand-new mechanism of sensing light,” says Nikhil Bhatla, the lead author of the paper and a postdoc in MIT’s Department of Biology. “All of the mechanisms of light detection we know about involve a chromophore — a small molecule that absorbs a photon and changes shape or transfers electrons. This seems to be the first example of behavioral light-sensing that requires the generation of a chemical in the process of detecting the light.”
Bhatla and Robert Horvitz, the David H. Koch Professor of Biology, describe the new hydrogen peroxide taste receptors in the Jan. 29 online issue of the journal Neuron.
Though it is not yet known whether there is a human equivalent of this system, the researchers say their discovery lends support to the idea that there may be human taste receptors dedicated to flavors other than the five canonical ones — sweet, salty, bitter, sour, and savory. It also opens the possibility that humans might be able to sense light in ways that are fundamentally different from those known to act in vision.
“I think we have underestimated our biological abilities,” Bhatla says. “Aside from those five, there are other flavors, such as burnt. How do we taste something as burnt? Or what about spicy, or metallic, or smoky? There’s this whole new area that hasn’t really been explored.”
Beyond bitter and sweet
One of the major functions of the sense of taste is to determine whether something is safe, or advantageous, to eat. For humans and other animals, bitterness often serves as a warning of poison, while sweetness can help to identify foods that are rich in energy.
For worms, hydrogen peroxide can be harmful because it can cause extensive cellular trauma, including damaging proteins, DNA, and other molecules in the body. In fact, certain strains of bacteria produce hydrogen peroxide that can kill C. elegans after being eaten. Worms might also ingest hydrogen peroxide from the soil where they live.
Bhatla and Horvitz found that worms stop eating both when they taste hydrogen peroxide and when light shines on them — especially high-energy light, such as violet or ultraviolet. The authors found the exact same feeding response when worms were exposed to either hydrogen peroxide or light, which suggested to them that the same mechanism might be controlling responses to both stimuli.
Worms are known to be averse to light: Previous research by others has shown that they flee when light shines on them. Bhatla and Horvitz have now found that this escape response, like the feeding response to light, is likely caused by light’s generation of chemicals such as hydrogen peroxide.
The C. elegans worm has a very simple and thoroughly mapped nervous system consisting of 302 neurons, 20 of which are located in the pharynx, the feeding organ that ingests and grinds food. Bhatla found that one pair of pharyngeal neurons, known as the I2 neurons, controls the animal’s response to both light and hydrogen peroxide. A particular molecular receptor in that neuron, gustatory receptor 3 (GUR-3), and a molecularly similar receptor found in other neurons (LITE-1) are critical to the response. However, each receptor appears to function in a slightly different way.
GUR-3 detects hydrogen peroxide, whether it is found naturally in the environment or generated by light. There are many GUR-3 receptors in the I2 neuron, and through a mechanism that remains unknown, hydrogen peroxide stimulation of GUR-3 causes the pharynx to stop grinding. Another molecule called peroxiredoxin, an antioxidant, appears to help GUR-3 detect hydrogen peroxide.
While the GUR-3 receptor responds much more strongly to hydrogen peroxide than to light, the LITE-1 receptor is much more sensitive to light than to hydrogen peroxide. LITE-1 has previously been implicated in detecting light, but until now, it has been a mystery how a taste receptor could respond to light. The new study suggests that like GUR-3, LITE-1 indirectly senses light by detecting reactive oxygen compounds generated by light — including, but not limited to, hydrogen peroxide.
Kenneth Miller of the Oklahoma Medical Research Foundation published a paper in 2008 describing LITE-1 and hypothesizing that it might work by detecting a chemical product of light interaction. “This paper goes one step beyond that and identifies molecules that LITE-1 could be sensing to identify the presence of light,” says Miller, who was not part of the new study. “I thought it was a fascinating look at the complex gustatory sensory mechanism for molecules like hydrogen peroxide.”
Not found in humans
The molecular family of receptors that includes GUR-3 and LITE-1 is specific to invertebrates, and is not found in humans. However, peroxiredoxin is found in humans, particularly in the eye, so the researchers suspect that peroxiredoxin might play a role in detecting reactive oxygen species generated by light in the eye.
The researchers are now trying to figure out the exact mechanism of hydrogen peroxide detection: For example, how exactly do these gustatory receptors detect reactive oxygen compounds? The researchers are also working to identify the neural circuit diagram that defines how the I2 neurons interact with other neurons to control the worms’ feeding behavior. Such neural circuit diagrams should provide insight into how the brains of worms, and people, generate behavior.
The research was funded by the National Science Foundation, the National Institutes of Health, and the Howard Hughes Medical Institute.
MIT team enlarges brain samples, making them easier to image
Beginning with the invention of the first microscope in the late 1500s, scientists have been trying to peer into preserved cells and tissues with ever-greater magnification. The latest generation of so-called “super-resolution” microscopes can see inside cells with resolution better than 250 nanometers.
A team of researchers from MIT has now taken a novel approach to gaining such high-resolution images: Instead of making their microscopes more powerful, they have discovered a method that enlarges tissue samples by embedding them in a polymer that swells when water is added. This allows specimens to be physically magnified, and then imaged at a much higher resolution.
This technique, which uses inexpensive, commercially available chemicals and microscopes commonly found in research labs, should give many more scientists access to super-resolution imaging, the researchers say.
“Instead of acquiring a new microscope to take images with nanoscale resolution, you can take the images on a regular microscope. You physically make the sample bigger, rather than trying to magnify the rays of light that are emitted by the sample,” says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT.
Boyden is the senior author of a paper describing the new method in the Jan. 15 online edition of Science. Lead authors of the paper are graduate students Fei Chen and Paul Tillberg.
Physical magnification
Most microscopes work by using lenses to focus light emitted from a sample into a magnified image. However, this approach has a fundamental limit known as the diffraction limit, which means that it can’t be used to visualize objects much smaller than the wavelength of the light being used. For example, if you are using blue-green light with a wavelength of 500 nanometers, you can’t see anything smaller than 250 nanometers.
“Unfortunately, in biology that’s right where things get interesting,” says Boyden, who is a member of MIT’s Media Lab and McGovern Institute for Brain Research. Protein complexes, molecules that transport payloads in and out of cells, and other cellular activities are all organized at the nanoscale.
Scientists have come up with some “really clever tricks” to overcome this limitation, Boyden says. However, these super-resolution techniques work best with small, thin samples, and take a long time to image large samples. “If you want to map the brain, or understand how cancer cells are organized in a metastasizing tumor, or how immune cells are configured in an autoimmune attack, you have to look at a large piece of tissue with nanoscale precision,” he says.
To achieve this, the MIT team focused its attention on the sample rather than the microscope. Their idea was to make specimens easier to image at high resolution by embedding them in an expandable polymer gel made of polyacrylate, a very absorbent material commonly found in diapers.
Before enlarging the tissue, the researchers first label the cell components or proteins that they want to examine, using an antibody that binds to the chosen targets. This antibody is linked to a fluorescent dye, as well as a chemical anchor that can attach the dye to the polyacrylate chain.
Once the tissue is labeled, the researchers add the precursor to the polyacrylate gel and heat it to form the gel. They then digest the proteins that hold the specimen together, allowing it to expand uniformly. The specimen is then washed in salt-free water to induce a 100-fold expansion in volume. Even though the proteins have been broken apart, the original location of each fluorescent label stays the same relative to the overall structure of the tissue because it is anchored to the polyacrylate gel.
“What you’re left with is a three-dimensional, fluorescent cast of the original material. And the cast itself is swollen, unimpeded by the original biological structure,” Tillberg says.
The MIT team imaged this “cast” with commercially available confocal microscopes, commonly used for fluorescent imaging but usually limited to a resolution of hundreds of nanometers. With their enlarged samples, the researchers achieved resolution down to 70 nanometers. “The expansion microscopy process … should be compatible with many existing microscope designs and systems already in laboratories,” Chen adds.
Large tissue samples
Using this technique, the MIT team was able to image a section of brain tissue 500 by 200 by 100 microns with a standard confocal microscope. Imaging such large samples would not be feasible with other super-resolution techniques, which require minutes to image a tissue slice only 1 micron thick and are limited in their ability to image large samples by optical scattering and other aberrations.
“The exciting part is that this approach can acquire data at the same high speed per pixel as conventional microscopy, contrary to most other methods that beat the diffraction limit for microscopy, which can be 1,000 times slower per pixel,” says George Church, a professor of genetics at Harvard Medical School who was not part of the research team.
“The other methods currently have better resolution, but are harder to use, or slower,” Tillberg says. “The benefits of our method are the ease of use and, more importantly, compatibility with large volumes, which is challenging with existing technologies.”
The researchers envision that this technology could be very useful to scientists trying to image brain cells and map how they connect to each other across large regions.
“There are lots of biological questions where you have to understand a large structure,” Boyden says. “Especially for the brain, you have to be able to image a large volume of tissue, but also to see where all the nanoscale components are.”
While Boyden’s team is focused on the brain, other possible applications for this technique include studying tumor metastasis and angiogenesis (growth of blood vessels to nourish a tumor), or visualizing how immune cells attack specific organs during autoimmune disease.
The research was funded by the National Institutes of Health, the New York Stem Cell Foundation, Jeremy and Joyce Wertheimer, the National Science Foundation, and the Fannie and John Hertz Foundation.