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BRAINWORK the Neuroscience Newsletter THE DANA FOUNDATION’S BRAINWORK The Neuroscience Newsletter Vol. 15 No. 4 July-August 2005 SPECIAL FOCUS: NEUROIMAGING Peering into the Brain: News New Frontiers in Neural Imaging FROM THE FRONTIER BY BRENDA PATOINE ••• Vaccine boosts activity of ew technologies—and the the fast-emerging frontier of optical chemotherapy in brain cancer. Clinical innovative ways in which sci- imaging, or, more precisely, two-pho- trials show that patients with glioblas- Nentists have harnessed them— ton excitation microscopy combined toma multiforme, a particularly aggres- have driven advances in neural imaging with fluorescent dyes that label indi- sive brain cancer, survived longer if beyond what any expert predicted 10 vidual molecules in living tissue. Scien- they were treated with a vaccine fol- years ago. Ever more sophisticated tists are applying these tools to track lowed by chemotherapy than did those images from brain scans and new brain function in living animals in real patients treated with either the vaccine microscopy techniques are offering a time, right down to the level of synap- or chemotherapy alone. The finding strikingly clear glimpse of what’s going tic connections and beyond. continues recent progress in immune on underneath the bumpy surface of A recent meeting on neural imaging treatments for brain tumors (see “Brain our skulls. at Cold Spring Harbor Laboratory in Tumor Researchers Let Slip the Some of the greatest excitement in New York was testimony to the results Immune Cells of War,” May-June neural imaging right now surrounds possible using so-called “light 2005 BrainWork). microscopy” approaches. The vaccine appears to kill off A few dozen of the world’s chemotherapy-resistant cells, leaving leading experts in imaging behind a population of cells that can be gathered to compare notes, treated with chemotherapy, report John debate technical hurdles, and S. Yu, co-director of the Comprehensive share some of the most Brain Tumor Program at Cedars-Sinai remarkable video and still Medical Center in Los Angeles, and col- images of mammalian brains leagues in the August issue of Oncogene. in action. To make the vaccine, dendritic cells Two-photon microscopes were harvested from each patient’s use longer wavelengths of blood, grown in a dish that contained light, supplied by lasers, to proteins from glioblastoma tumors, and penetrate tissue more deeply then injected back into the patient’s and with less damage than bloodstream. The process generates other optical imaging modes. A critical advance that pushed (Continued on page 7) the field forward was the identification and cloning of Inside: the gene for green fluores- Economic Pathways Page 4 Green fluorescent protein, or GFP, is expressed in the cent protein (GFP), reported Alzheimer’s Detection Page 5 visual cortex of a transgenic mouse, as shown in this in a landmark Science paper in Sleep Signals Page 6 two-photon microscopy image. This type of imaging is 1994. GFP is a naturally advancing scientists’ understanding of the brain. (Continued on page 2) BRAINWORK / July-August 2005 SPECIAL FOCUS: NEUROIMAGING (NEURAL IMAGING, continued from page 1) “The genetics has gotten to the synaptic connections, Kleinfeld says occurring protein that essentially makes point where you can target cells pretty optical imaging now makes it possible cell tissue light up like a neon sign precisely with a fluorescent protein,” “to observe how different sensory and when viewed with light microscopy. says David Kleinfeld, a University of motor patterns sculpt and resculpt the Roger Tsien at the University of California, San Diego, neurophysicist connectivity.” California, San Diego, and others have who attended the meeting. “You can Some of the most cutting-edge developed a whole spectrum of GFP go back to the same cell every time and work with light microscopy involves variants, a broad pallet of colors that determine its functional identity. Does finding ways to identify neuronal func- neuroscientists worldwide are now using the cell report the same sensory features tion in a manner that is rational, quan- to characterize neuronal structure and time and time again, or does its role in tifiable, and reproducible. The ulti- activity to a degree never before possible. a circuit evolve with experience? You mate goal is to use different types of can now study the same animals over GFP-based indicators of neuronal ‘No Competition’ time, which is particularly critical when function in various types of neurons in Among alternative methods, you’re studying brain development.” order to understand how they inter- “there’s no competition for optical connect and influence one another. imaging,” says Karel Svoboda of Cold Grappling with Circuits “What you’re really after is to record Spring Harbor, who co-chaired the These new methods are also making something that tells you about the meeting. “Using genetic tricks with a huge impact on systems neuro- state of the neuron: is it sending an GFP and its dozens of variants, you can science, which seeks to construct output signal or not; what are its input now put into neurons fluorescent “wiring diagrams” that correlate brain signals like; what is its sense of histo- markers of structure, of specific mole- activity to specific behaviors. Much of ry?” says Kleinfeld. Each of these states cules, or of cellular function. This has the Cold Spring Harbor meeting can be understood by looking at specif- enabled a better understanding not focused on the challenge of under- ic physiological indicators that can now only of the structural biology of the standing neural circuits, Svoboda says. be visualized with optical imaging. brain at the level of synaptic circuits, “In the mammalian brain, you have Josh Sanes, a neurobiologist and but also has begun to help us learn a million upon millions of neurons,” head of Harvard’s new Center for Sys- about the function of populations of he says. “If you think of it from an tems Neuroscience, describes his neurons in the intact brain.” engineering standpoint, the brain is an dream scenario: “to label 10, 20, 30 electrical signaling device, and neurons different neuronal types with different are the signaling units. Any engineer colors, and do it such a way that when The Neuroscience Newsletter will tell you that if you want to under- the neuron fires it would change Editorial Advisory Board stand a circuit, you need to have a cir- color.” This would make it possible to Leslie L. Iversen, Ph.D. cuit diagram. You not only need a list track neural activity throughout the Kay Redfield Jamison, Ph.D. of components, but you also need to circuit, with different cell types and Pierre Magistretti, M.D., Ph.D know how neurons connect with one functional characteristics clearly Robert C. Malenka, M.D., Ph.D. Bruce McEwen, Ph.D. another and with what probability.” demarcated. Then, individual cells or Donald L. Price, M.D. There has been good progress on the even genes could be turned off or on Editor “parts list,” but understanding the to understand their roles in the circuit. Dan Gordon connection matrix is still at a “primi- Such studies are just beginning, and Design tive stage,” he says. many technical hurdles remain. Still, FTM Design Studio One reason: until now, the standard Svoboda says, “We’ve made remark- technique for constructing a diagram able progress.” For example, his group A PUBLICATION OF THE DANA PRESS of a neural circuit had changed little has pioneered in vivo imaging of neu- Jane Nevins, Editor in Chief since the late 1800s, when Spanish rons over long periods, even months at Walter Donway, Director anatomist Santiago Ramon e Cajal a time, something that was “just a pipe Editorial office: pioneered it. The technique essentially dream 10 years ago.” The Dana Center 900 15th Street, NW involves staining single neurons, iden- Washington, D.C. 20005 tifying where axons and dendrites Birth of Modern Imaging E-mail: [email protected] overlap, and marking those junctures Such advances were unimaginable DANA is a federally registered trademark. as synapses. back in the 1970s, when the advent of THE DANA FOUNDATION A problem with this approach, Svo- computerized tomography (CT) scan- 745 Fifth Avenue Suite 900 boda says, is that “there’s no function- ning marked the beginning of the mod- New York, NY 10151 al context. You don’t really know ern era of neural imaging. “CT was a For free subscription or change of address: whether or not and to what extent remarkable advance, because it was the [email protected], or fax to 202-408-5599. these neurons ‘synapse’ onto one first time you could look into the brain BrainWork on the Internet: www.dana.org another.” While electrical recording of a living person,” says Arthur Toga, © 2005 DANA PRESS studies can measure activity across who heads the Laboratory of Neuro BRAINWORK / July-August 2005 / 2 SPECIAL FOCUS: NEUROIMAGING Imaging at the University of California, “New Techniques Detect Alzheimer’s Imaging and Behavior: Los Angeles. Before Symptoms Develop,” this issue.) Reality Check Magnetic resonance imaging (MRI) and positron emission tomography Integration Is Key The visual appeal of imaging studies, (PET) followed CT. These powerful Toga encapsulates what he finds coupled with their relevance to things tools have enabled an unprecedented most exciting about the current state people care about, such as memory and emotion, can leave the work open to look not only at the brain’s anatomical of neuroimaging in one word: integra- less-than-critical interpretation. Experts structure, but also, in the case of PET tion. “We have made tremendous say findings on imaging and human and functional MRI (fMRI), at the progress in terms of the technological behavior come with a few caveats. patterns of brain activity that underlie advances to acquire images that Marcus Raichle of the Washington mental functions and pathological describe one part of the brain or anoth- University School of Medicine acknowl- states.
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