Cellular choreography, not molecular prepattern, creates repeated segments of vertebrate embryo

In a study that combines state-of-the-art biological imaging with gene expression analysis, scientists at the California Institute of Technology have uncovered a fundamental insight into the way embryonic cells and tissue move about to form key structures along the vertebrate axis. The study, which could lead to a better understanding of human development, takes advantage of the accessibility of chick embryos to embryonic manipulation.

The study by Caltech biologists Scott Fraser and Paul Kulesa, appearing in the November 1 issue of the journal Science, centers on segments known as somites, which form along either side of the future spinal cord of an embryo. Somites give rise to mature structures such as ribs, individual vertebrae, and even skin. The key role of somite segmentation in the patterning of the nervous system and the vertebral column has been long known. But the question of precisely how an individual somite buds off from a block of tissue in a pattern that is repeated all along the animal's torso, from head to tail, is poorly understood.

"Developmental biologists have had a difficult time getting a handle on how cell movements and gene expression patterns are coordinated to form complex structures, in this case the segmented units called somites," says Kulesa, a postdoctoral scholar in Fraser's lab and lead author of the paper. "The problems have been due to limitations in obtaining cellular resolution of tissue deep within living vertebrate embryos and difficulty in coordinating the cell movements and tissue shaping in living tissue with gene expression patterns typically obtained at one time point from fixed, non-living tissue."

The new insight of the paper is that the factors that determine the embryo's ultimate form as well as the eventual position of its cells involve a complicated set of motions of the cells themselves. Previous models of embryonic patterning had suggested that there was a molecular prepattern that subdivided the tissues, somewhat like a "paint-by-numbers" piece of art. The study thus shows the action of a more complex coordination between physical forces within the tissue and gene expression patterns that determine where an embryonic cell will go and what type of structure it will help form.

Kulesa and Fraser's study is made possible with a new culture technique combined with confocal time-lapse microscopy, an advanced form of imaging that allows the tissue of a living, developing embryo to be studied in intricate detail at the cellular level. Time-lapse imaging involves, first, labeling the tissue so that it will fluoresce when exposed to laser light, then passing a laser through the tissue, then reconstructing the fluorescent patterns of individual cells to form a three-dimensional microscopic image. The laser scans over the tissue of the developing embryo every minute or so, which allows the researchers to gather the hundreds of images taken during a several-hour run into a time-lapse video.

Using fertilized eggs, the researchers placed an embryo into a specially designed chamber to allow for high-resolution time-lapse imaging, and afterwards performed gene expression analyses on the same embryo. Thus, they were both videotaping cell movements for 6-to-12 hours as well as analyzing the expression of several genes, including EphA4 and c-Meso1, both thought to play a role in determining future somite boundary sites.

The results showed that the straight-line patterns of gene expression, which were thought to correlate with a simple, periodic slicing of the tissue into blocks, did not predict the complex cell movements. Time-lapse imaging showed that a ball-and-socket separation of tissue takes places in a series of six repeatable steps.

"It turns out that a somite pulls apart from the block of tissue, and cells move in anterior and posterior directions near the forming somite boundary," Kulesa says. "This is contrary to many models of somite segmentation which assume that gene expression boundaries that correlate with presumptive somite boundaries allocate cells into a particular block with very little cell movement.

"This study tells us that we have to be careful about assuming that gene expression patterns strictly determine a cell's fate and position."

Kulesa says the next step is to do the work in mouse embryos, which pose considerably more difficult challenges for developmental imaging, but have a tremendous advantage over chick-embryo imaging in attempting to isolate the role of key genes through gene manipulation.

 

 

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Caltech Professor Awarded Wilson Medal for Insights Into the Life Cycle of Cells

Ubiquitin is the Swiss Army knife of proteins. Long known to be ubiquitous in all organisms (hence the name, of course), it plays important roles in cell growth, division, and death, in DNA repair, and in the body's response to stress.

For his discovery of the ubiquitin system and its crucial physiological functions, the California Institute of Technology's Alexander Varshavsky has been named the co-recipient of the 2002 E. B. Wilson Medal, the highest scientific honor given by the American Society for Cell Biology (ASCB).

Varshavsky, the Smits Professor of Cell Biology, will share the award with Avram Hershko of the Technion—Israel Institute of Technology. Working separately, the pair made complementary discoveries of ubiquitin's many unique functions.

Ubiquitin is a small protein that attaches itself to other proteins within a cell that have outlived their usefulness, marking them for destruction. Hershko's initial studies uncovered ubiquitin's role in protein degradation in extracts derived from whole cells. Then, using cells from mice and baker's yeast as model organisms, Varshavsky proved that it is indeed ubiquitin that's essential for this natural process to take place. His laboratory also discovered that the ubiquitin system plays major roles in a number of biological processes, including cell growth and division, DNA repair, and responses to stress.

Subsequent work by numerous laboratories uncovered many other functions of this remarkable system, including its multiple roles in the functioning of the brain (for example, memory formation), in the development of most organs in the body, and in the regulation of general metabolism.

Scientists are now striving to understand the role of ubiquitin in many human diseases, including cancer, bacterial and viral infections, and neurodegenerative syndromes like Parkinson's and Alzheimer's diseases. Varshavsky's work on the ubiquitin system was instrumental in making possible the current efforts to devise new classes of drugs to attack such diseases.

Varshavsky is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Philosophical Society. He has received many of the top international prizes in biology and medicine, including the Wolf Prize, the Horwitz Prize, and the Merck Award, (all in 2001), the 2000 Sloan Prize from the General Motors Cancer Research Foundation, the 2000 Albert Lasker Award, and the 1999 Gairdner Award.

The ASCB's E. B. Wilson Medal, named for an early 20th-century pioneer of American biology who advocated the chromosomal theory of inheritance, is awarded by scientific peers to those who have made highly significant and far-reaching contributions to cell biology over the course of a career. The society will present its award to Varshavsky and Hershko on December 15 in San Francisco, during the 42nd ASCB Annual Meeting.

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Humans and chimps have 95 percent DNA compatibility, not 98.5 percent, research shows

Genetic studies for decades have estimated that humans and chimpanzees possess genomes that are about 98.5 percent similar. In other words, of the three billion base pairs along the DNA helix, nearly 99 of every 100 would be exactly identical.

However, new work by one of the co-developers of the method used to analyze genetic similarities between species says the figure should be revised downward to 95 percent.

Roy Britten, a biologist at the California Institute of Technology, reports in the current issue of the journal Proceedings of the National Academy of Sciences that the large amount of sequencing that has been done in recent years on both the human and chimp genomes—and improvements in the techniques themselves—allow for the issue to be revisited. In the article, he describes the method he used, which involved writing a special computer program to compare nearly 780,000 base pairs of the human genome with a similar number from the chimp genome.

To describe exactly what Britten did, it is helpful to explain the old method as it was originally used to determine genetic similarities between two species. Called hybridization, the method involved collecting tiny snips of the DNA helix from the chromosomes of the two species to be studied, then breaking the ladder-like helixes apart into strands. Strands from one species would be radioactively labeled, and then the two strands recombined.

The helix at this point would contain one strand from each species, and from there it was a fairly straightforward matter to "melt" the strands to infer the number of good base pairs. The lower the melting temperature, the less compatibility between the two species because of the lower energy required to break the bonds.

In the case of chimps and humans, numerous studies through the years have shown that there is an incidence of 1.2 to 1.76 percent base substitutions. This means that these are areas along the helix where the bases (adenine, thymine, guanine, and cytosine) do not correspond and hence do not form a bond at that point.

The problem with the old studies is that the methods did not recognize differences due to events of insertion and deletion that result in parts of the DNA being absent from the strands of one or the other species. These are different from the aforementioned substitutions. Such differences, called "indels," are readily recognized by comparing sequences, if one looks beyond the missing regions for the next regions that do match.

To accomplish the more complete survey, Britten wrote a Fortran program that did custom comparisons of strands of human and chimp DNA available from GenBank. With nearly 780,000 suitable base pairs available to him, Britten was able to better infer where the mismatches would actually be seen if an extremely long strand could be studied. Thus, the computer technique allowed Britten to look at several long strands of DNA with 780,000 potential base pairings.

As expected, he found a base substitution rate of about 1.4 percent—well in keeping with earlier reported results—but also an incidence of 3.9 percent divergence attributable to the presence of indels. Thus, he came up with the revised figure of 5 percent.

As for the implications, Britten says the new work should help biologists with future work on precisely how species branch off from each other, and why. "The basic question you would like to answer is what makes the chimp different from humans—what were the basic changes in the genome that mattered.

"A large number of these 5 percent of variations are relatively unimportant. But what matters, according to everyone's idea, is regulation of the genes, which is controlled by the genes that are actually expressed. So to address this issue, you first have to know how different the genomes are, and second, where the differences are located.

The article is available from PNAS by contacting Jill Locantore, the public information officer, at jlocantore@nas.edu, or by calling 202-334-1310.

Contact: Robert Tindol (626) 395-3631

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Five Caltech Faculty Members Elected to Membership in the American Academy of Arts and Sciences

PASADENA, Calif. — The American Academy of Arts and Sciences has announced that five members of the Caltech faculty have been elected to membership in the academy for contributions to their respective scientific fields.

The Caltech faculty members who have been elected are Richard Andersen, Boswell Professor of Neuroscience; David Anderson, professor of biology and investigator with the Howard Hughes Medical Institute (HHMI); Ronald Drever, professor of physics, emeritus; Mary Kennedy, Davis Professor of Biology; and Mark Wise, McCone Professor of High Energy Physics.

Richard Andersen is receiving recognition for his work in the fields of neuroscience, cognitive science, and behavioral biology. With the assistance of his postdoctoral and graduate students, he has examined the functions of the brain in relation to seeing, hearing, orientation, balance, and movement planning.

The author of more than 130 scholarly articles on the functions of the brain, Andersen has been honored with the Spencer Award from Columbia University, the McKnight Foundation Scholars Award, a Sloan Foundation Fellowship, a Regent's Fellowship, and an Abraham Rosenberg Fellowship, and is a Fellow of the American Association for the Advancement of Science.

David Anderson is being honored for his work in the fields of neurobiology, developmental biology, and genetics, where he has been able to make advances in stem-cell research that he hopes will eventually help fight brain diseases and spinal-cord injuries. Anderson has also made important discoveries in the field of angiogenesis, the study of blood vessel formation.

Anderson, who has authored more than 140 scholarly publications in the field of genetics and neuroscience, has also been honored with the Searle Scholars Award, the Charles Judson Herrick Award in Comparative Neurology, and the W. Alden Spencer Award in Developmental Neurobiology from Columbia University. His current affiliations include the American Association for the Advancement of Science, the Society for Neuroscience, and the Neuron editorial board.

Ronald Drever is being recognized for his work relating to gravitational physics and for his pioneering research on gravitational radiation detection. His group carried out early searches for gravitational waves, and he was cofounder of the Laser Interferometer Gravitational-Wave Observatory, a project shared by Caltech and MIT. Drever invented many of the techniques in gravitational-wave detection, including a high-precision method for controlling laser frequency now widely used in many science and technology applications.

Drever is a Fellow of the American Physical Society and is a former vice president of the Royal Astronomical Society.

Mary Kennedy is being honored for her contributions to the field of brain biochemistry and the mechanisms of learning and memory. Her research group is studying the effects of proteins in the brain and their relation to how memories are stored.

Kennedy holds numerous memberships and has been the recipient of several grants, as well as publishing a number of scientific works. Her honors include a McKnight Neuroscience Development Award, and she is an elected councilor of the Society for Neuroscience. Kennedy has also received a Faculty Award for Women Scientists and Engineers, and she is a member of the scientific advisory board of the Hereditary Disease Foundation, and the Scientific Advisory Board of the French Foundation for Alzheimer Research.

Mark Wise is receiving membership for his involvement in the field of high-energy physics, where he has developed information on the essential characteristics of particles and how they interact with each other to create the physical world.

Wise has been the recipient of a Sloan Foundation research grant and the Sakurai Prize, which reflects the admiration of his peers for his work and accomplishments in his field. Wise is also a member of the American Physical Society.

Founded in 1780 in Cambridge, Massachusetts, the American Academy of Arts and Sciences serves as a hub for complex study and discussion of multidisciplinary problems. This year, the academy elected 177 fellows and 30 foreign honorary members.

CONTACT: Ken Watson, Media Relations (626) 395-3227 Visit the Caltech Media Relations Web site: http://pr.caltech.edu/media

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Two Caltech Professors Elected to American Philosophical Society

PASADENA, Calif. — The American Philosophical Society (APS) recently announced that Pamela J. Bjorkman, professor of biology at Caltech and investigator of the Howard Hughes Medical Institute (HHMI), and Peter B. Dervan, Bren Professor of Chemistry, are two of the 37 new members elected in this year.

Bjorkman is being recognized for her work with molecules needed for cell-surface recognition, and their role in the immune system. Her lab is responsible for the discovery of the three-dimensional structure of a protein implicated in cachexia, the syndrome that causes AIDS and cancer patients to lose body mass.

With a BA from the University of Oregon in 1978 and a PhD from Harvard in 1984, Bjorkman joined the Caltech staff in 1989 as an assistant professor of biology. She became a full professor in 1998, and also a full investigator for the HHMI in 2000.

In addition to the APS, Bjorkman is also a member of the National Academy of Sciences, and has been awarded the Gairdner Foundation International Award, which recognizes contributions to the medical sciences, the William B. Coley Award for Distinguished Research in Fundamental Immunology, and the Paul Ehrlich and Ludwig Darmstaedter Award.

Dervan's research is aimed at the bioorganic chemistry of nucleic acids and the recognition of DNA by small molecules. Using synthesis, biology, and physical chemistry, he and his colleagues have created synthetic molecules that are similar to natural proteins in their ability to recognize predetermined DNA sequences.

A Boston native, Dervan received his BS from Boston College in 1967 and a PhD from Yale University in 1972. He held a postdoctoral fellowship at Stanford University before joining Caltech in 1973 as an assistant professor of chemistry. He was named Bren Professor of Chemistry in 1988.

His election to the APS adds to Dervan's list of professional honors, which includes membership in the National Academy of Sciences and the Institute of Medicine, and foreign membership in the French Academy of Sciences.

The American Philosophical Society was founded over 250 years ago by Benjamin Franklin, making it the oldest learned society in the United States. The organization supports the search for functional knowledge in the fields of sciences and humanities through collaboration between members and the community as a whole.

CONTACT: Ken Watson, Media Relations (626) 395-3227

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Caltech Researcher Granted $500,000 Career Award

PASADENA, Calif.- As a young medical student, Matthew Porteus recalls his frustration when admitting his first patient with chronic pain caused by sickle-cell anemia. There was little medicine could do to help her in a sustained and meaningful way. The experience influenced his decision to study the basic mechanisms of "gene targeting," one possible way to cure such diseases, which are caused by a single mutation in a cell. Now Porteus will be assisted in his studies thanks to a grant from the Burroughs Wellcome Fund.

The Career Award in the Biomedical Sciences is a five-year, $500,000 grant that consists of two parts – a two-year postdoctoral portion, and a three-year faculty portion. The program is intended to develop biomedical researchers early in their careers as they make the transition to becoming independent investigators.

Porteus is currently a postdoctoral researcher in the lab of Caltech president David Baltimore. Porteus's work is focused on developing techniques to increase the efficiency and specificity of gene targeting in human somatic cells. Gene targeting is a technique in which a gene is introduced into a cell to replace a specific gene that's been damaged.

Porteus notes there are now scores of diseases that are caused by mutations in single genes. Sickle-cell anemia, for example, is caused by a single mutation in the protein that carries oxygen in the blood. Cystic fibrosis, in which there is a small mutation in a channel that regulates salt and water flux into cells, is another.

Gene targeting is one promising approach to curing such diseases. Researchers like Porteus can introduce genetic change into a cell by creating subtle differences between the introduced gene and the target gene. Gene targeting is now widely used in the generation of "knockout" mice, in which genes are "knocked out" or disrupted, then replaced by genes from other organisms that are inserted into a particular genetic location. But gene targeting has had an extremely low success rate in human somatic cells. Porteus's work is focused on understanding the mechanism and regulation of gene targeting, with the goal of developing it as a technique for gene correction therapy.

To study gene targeting, Porteus and his colleagues have developed a system in which they can correct a mutation in a specific gene called GFP. From this, they have established several of the key parameters that regulate gene targeting in human somatic cells. The first major parameter is the role of DNA double-stranded breaks. As the name implies, these are a form of DNA damage in which both strands of the DNA molecule are broken. Porteus confirmed what others have shown, that the presence of a DNA double-stranded break in the target gene can stimulate the process of gene targeting by over 10,000-fold; that increases the success rate from one in a million to 3 to 5 percent. Porteus is currently working on ways to generate double-stranded breaks in a target gene.

The second major parameter is the role of random integration. When a gene is introduced into a cell it can either be integrated into the genome of the cell in a random fashion, or replace a specific gene. In human somatic cells the relative rate of gene targeting is very low, in part because the random integration rate is high. Porteus is working to understand the factors behind this, since, in other cell types, he's found that the relative rate of gene targeting is high because random integration is low. Besides studying the factors that affect the rate of random integration, he is developing techniques to block it as well.

Porteus believes that such focused study will eventually lead to gene targeting becoming a tool for gene correction therapy, and for a potential cure for people suffering from diseases that are caused by mutations in single genes.

The Burroughs Wellcome Fund is an independent private foundation dedicated to advancing the medical sciences by supporting research and other scientific and educational activities. Within this broad mandate, BWF's general strategy is to help scientists early in their careers develop as independent investigators, and to support investigators who are working in or entering fields in the basic medical sciences that are undervalued or in need of encouragement.-

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Brain oscillations compress odor representations as signals pass through olfactory networks

Most natural smells are complex blends of many individual chemicals. Freshly ground coffee, for example, contains about 300 individual volatile components. A typical perfume also contains tens of ingredients, although the recipes are tightly locked in secret vaults.

The percepts that such complex blends evoke in us are, however, astonishingly singular: ground coffee smells like coffee, not like a hopeless mess of hundreds of ingredients; Gio or Allure also have unique signatures (often associated with other memories). This contrast between a physical object's complexity and the uniqueness of how we perceive it is the expression of what brains do best: "bind" features together into highly recognizable patterns.

This is as true of smell as it is for the other senses: a person can immediately recognize his mother's face or voice. How this useful and effortless compression of information is accomplished by the brain is one of the deep mysteries of neuroscience. In addition, understanding the mechanisms of compression would help in the design of computerized pattern recognizers (e.g., face recognition devices), a very difficult task with many important applications.

This issue is the subject of new research from neurobiologist Gilles Laurent and his team in the California Institute of Technology's computation and neural systems program. In a paper appearing in the July 19 issue of the journal Science, the Laurent team reports that the complicated wiring in grasshoppers between the antennal lobe (the insect analog of the olfactory bulb in humans) and the mushroom body (the insect analog of the olfactory cortex) is arranged and functions in such a way that highly detailed information in the former is bound or compressed for future memory use in the latter.

To better explain the details of their discovery, it's probably best to first explain the organs of smell in grasshoppers. The first area associated with smell are the receptor cells that are the front line of cells coming into contact with the chemical elements of a smell. Information from the receptor neurons converge in the antenna lobe, which, in grasshoppers, comprises about 1,000 individual neurons. The signal then goes to the mushroom body, which comprises about 50,000 neurons.

By intricately wiring glass, silicon, and platinum wire electrode arrays into the brains of hundreds of grasshoppers to record activity from their neurons, then exposing the insects to a variety of smells, the Laurent team has demonstrated some of the fine details of this wiring and its consequences for odor encoding.

When a specific odor is detected by a grasshopper, the antennal lobe neurons, wired to the peripheral detector array, start a complicated "dance" that engages about half of its 1,000 neurons. Each individual odor evokes a different dance or spatio-temporal pattern that involves partially overlapping subsets of neurons activated at varying times. Hence, determining from these patterns the odor's identity is a very difficult task; it requires that an observer decode the details of the dance, identify the correlations between the activities of all the neurons, and put all this back together into a coherent whole. Said differently, the informative value of any antennal lobe neuron in isolation is close to zero: valuable information comes only from deciphering the message carried by the population.

Population decoding is precisely what is done by the downstream neurons (called Kenyon cells, in the mushroom body). Those neurons, using a complicated combination of wiring, biophysical properties, brain oscillations, and loops of inhibition, manage to compress the information carried by many antennal lobe neurons into highly specific and sparse signals. Thus, individual Kenyon cells are silent most of the time and produce a signal only in response to very specific odors. The signals from these neurons, when given out, are thus highly informative, Laurent says.

"If you observe Kenyon cell No. 2,976 and see that it produced one single pulse, you can be pretty confident that the animal has just detected a certain odor mixture and not another," he explains. Each Kenyon cell thus has a very limited, but highly specific repertoire of "preferred stimuli."

At the same time, this compression eliminates much of the information about the individual chemical elements that make up an odor. "Knowing that Kenyon cell No. 2,976 fired may tell me that the (grasshopper) just smelled a cherry blend, but it tells me nothing about the chemical composition of that smell."

This may explain why these individual elements cannot be perceived; the encoding and decoding of an odor as a whole (cherry or Gio) is done at a cost: detail is lost. The advantage, however, is that the storage and retrieval of this odor's representation has become very simple, fast, and manageable: Each odor, however complex, is now represented by very few, highly specific neurons. Because the mushroom body has many neurons (and our olfactory cortex has even more), a huge number of such memories can be stored.

"There are many reasons to think that odor perception may work in similar ways in vertebrates, including humans," Laurent says, explaining that the antennal lobe in insects, including flies, is very similar to the mammalian olfactory bulb, except that it possesses many fewer cells; and that the mushroom body is likewise similar to the human olfactory cortex.

"In the case of humans as well as animals, the brain is not doing analytical chemistry by pulling out individual components," he says. "Instead, you have a very good memory for odors, however complex, even though you lose information about details. After all, throwing away information is one of the most important things that brains do, but it must be done carefully.

"In olfaction as well as in vision and the other senses, the brain must represent and memorize a huge number of complicated patterns. One should expect that evolution has found an optimal way of solving this task. Our work provides the beginnings of a solution, although whether it applies to other senses remains to be seen."

In addition to Laurent, the other authors of the study, all members of Caltech's Division of Biology, are Javier Perez-Orive, Ofer Mazor, Glenn C. Turner, Stijn Cassenaer, and Rachel I. Wilson.

The paper is available online at http://www.sciencemag.org.

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New Clues to the Processing of Memories

PASADENA, Calif.- Quick! Memorize this sentence: The temporoammonic (TA) pathway is a entorhinal cortex (EC) input that consists of axons from layer III EC neurons that make synaptic contacts on the distal dendrites of CA1 neurons.

If by chance you can't memorize this, say two researchers from the California Institute of Technology, it may be due to this very TA pathway that is modulating what your brain remembers.

In another clue toward understanding the processing of memories, graduate student Miguel Remondes and Erin M. Schuman, an associate professor of biology at Caltech and an assistant investigator of the Howard Hughes Medical Institute, have now gleaned two possible roles for the TA pathway that until now were not known. The research is reported in the April 18 issue of the journal Nature.

Using rat hippocampal slices, they've found that this pathway may be part of the brain's decision-making process about whether to keep a particular input and form a memory, or reject it.

Input from the senses—an odor, a sight, or a sound, say, is first received by the brain's cortex. Then, via a specific pathway of nerve fibers long known to scientists, the signals are sent on to the hippocampus. That organ processes the signals, then sends them back to the cortex, probably for long-term storage.

Scientists have also known about the TA pathway, but not its function. Now Remondes and Schuman report that the TA pathway may serve as a memory gatekeeper that can either enhance or diminish the signals of the specific set of neurons that form a memory. Further, they've shown that this pathway may also provide the hippocampus with the information it needs to form so-called place-selective cells; that is, cells that help animals to know where they are in their environments.

The hippocampal formation comprises several structures in the brain and includes the seahorse-shaped hippocampus and a second organ called the dentate gyrus. The formation is involved in saving and retrieving long-term memories. Scientists divide the hippocampus into four divisions, from CA1 to CA4. CA1 and CA3 play major roles in processing memory.

In their quest to understand how communication between neurons contributes to memory, scientists have focused on the "trisynaptic circuit." When input from the senses reaches the cortex, it's sent on to the dentate gyrus, then on to the hippocampus. There, the signals are serially processed by synapses in areas CA3 and CA1 of the hippocampus (synapses are gaps between two neurons that function as the site of information transfer from one neuron to another). Finally, the hippocampus sends a signal back to the cortex. That's the trisynaptic circuit.

Remondes and Schuman found that the TA pathway also sends signals. But its input comes from a different part of the cortex and goes directly to the CA1 section of the hippocampus. The TA pathway reacts depending on how close in time the synaptic signals from the hippocampus are from the original signal sent by the trisynaptic circuit. If it is close, within 40 milliseconds, the TA pathway will act as a signal (and thus a memory) enhancer; that is, it will allocate a stronger synaptic signal from the hippocampus. If it is far, more than 400 milliseconds, it will inhibit the signal.

"So the brain sends the information to the hippocampus," says Remondes, "and instead of just collecting the result of its activity, the hippocampus may very well perform 'quality control' on the potential memory. And it may be doing this by using the direct cortical input from the TA pathway." Perhaps, then, this is a further clue to how memories are stored—or forgotten.

In addition, although the scientists have not done any specific spatial memory experiments, their work may have relevance to how the brain forms place-selective cells. Since other studies previously established that the trisynaptic circuit is not necessary for spatial memory, some of the important information entering the hippocampus may actually be provided by the TA pathway.

"The TA pathway has been briefly described in the past, but not really acknowledged as a 'player' in the memory debate," says Remondes. "Hopefully, these findings will bring new insight into how we form, or don't form, memories."

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Gaining a Better Understanding of the Brain

PASADENA, Calif. — A panel of experts who conduct a wide range of brain research will come together for California Institute of Technology's annual Biology Forum, "Gray Matters: Perception, Intention, Memory, and Dysfunction in the Brain," April 25 at 8 p.m. in Beckman Auditorium, 332 S. Michigan Ave, Pasadena. The event is free and open to the public.

The speakers for the program, which is sponsored by Caltech and Huntington Memorial Hospital and co-sponsored by the San Gabriel Valley Newspaper Group, will discuss topics as diverse as the dynamics of smell, moving robotic limbs using brain signals, and pinpointing and excising the spot in the brain where epilepsy seizures occur.

"Our speakers exemplify the world-class work that is being done on the brain right here in Pasadena," says Paul Patterson, biology professor and Biology Forum coordinator. Three of the four speakers are Caltech faculty and one is a Huntington Hospital neurosurgeon.

The speakers are:

Richard Andersen, James G. Boswell Professor of Neuroscience at Caltech. Andersen and his colleagues are beginning to decipher neuron firing patterns in the visuomotor part of the brain preceding arm movement. Using this code they can now predict where the arm will be moved. The eventual goal of this research is to develop a neural prosthesis that records this intended-movement signal from paralyzed patients, enabling them to operate a robot limb or other external devices.

Gilles Laurent, professor of biology and computation and neural systems at Caltech. Laurent studies neural coding in the brain. He focuses on the dynamics of neuronal circuits, brain oscillations, and the sense of smell, in insects, fish, and rodents. His laboratory studies the general problem of olfactory representations: how is an odor represented by brain circuits? What are the neuronal elements of the memory of a smell? What do brain circuits do to optimize those representations?

Adam Mamelak, neurosurgical director of the Epilepsy and Brain Mapping Program at Huntington Memorial Hospital, and associate professor of neurosurgery at City of Hope Cancer Center. The Huntington Brain Mapping Program is one of a handful of comprehensive epilepsy centers in the country. Through the program, patients' seizures and normal brain functions are mapped, the source of seizures is pinpointed, and the damaged portion of the brain is excised. It provides the most advanced and successful seizure evaluation and treatment available today.

Steven Quartz, assistant professor of philosophy at Caltech. Quartz uses experimental and theoretical methods from neuroscience to study traditional problems of mind, ranging from the formal learning properties of neurally constrained developing systems to the nature of moral decision-making.

The moderator of the program will be Robert Lee Hotz, a Pulitzer Prize-winning science writer with the Los Angeles Times.

For more information, call (626) 395-4652 or toll-free 1-888-222-5832. Persons with disabilities can call (626) 395-4688 (voice) or (626) 395-3700 (TDD) weekdays, 9 a.m. to 4 p.m.

CONTACT: Jill Perry, Media Relations Director (626) 395-3226 jperry@caltech.edu

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Caltech and Purdue scientists determinestructure of the Dengue fever virus

Scientists at the California Institute of Technology and Purdue University have determined the fine-detail structure of the virus that causes dengue fever. This advance could lead to newer and more focused strategies for devising a vaccine to protect the world against a viral illness that causes 20,000 deaths each year.

Reporting in the March 8 issue of the journal Cell, Caltech biology professor James H. Strauss, lead author Richard J. Kuhn of Purdue (a former postdoctoral scholar in Strauss's lab), and Michael G. Rossman and Timothy S. Baker, both of Purdue, describe the structure of the virus they obtained with a cryoelectron microscope. The detailed electron-density map shows the inner RNA core of the virus as well as the other spherical layers that cover it. At the surface is the glycoprotein scaffolding thought to allow the virus to interact with the receptor and invade a host cell.

This is the first time the structure of one of the flaviviruses has been described, Strauss says. The flaviviruses are a class of viruses that include the yellow fever, West Nile, tick-borne encephalitis, and Japanese encephalitis viruses. All are enclosed with a glycoprotein outer layer that includes minor projections out of the lipid layer due to the geometry of the scaffolding.

"Most viruses that cause serious illness are enveloped, including influenza, hantaviruses, West Nile virus, smallpox, and herpes—though not polio," Strauss says.

The surprise for the researchers was the unusual manner in which the glycoproteins are arranged. Details from the Caltech and Purdue computer-generated images show a highly variegated structure of glycoprotein molecules that are evenly dispersed, but with a surprisingly complicated pattern.

"It's symmetrical, but not with the obvious symmetry of most symmetric viruses," Strauss explains. "This was not an expected result."

Strauss says it's still unclear what the odd symmetry will ultimately mean for future research aimed at controlling the disease, because the precise function of the different structural domains of the glycoproteins are still not known. Those that have been false-colored blue in the image are the domain of glycoproteins thought to be involved in receptor binding—and thus responsible for the virus's entry into a cell. The glycoprotein structures coded yellow are an elongated domain thought to be responsible for holding the scaffolding together; and the ones coded red have a function that is not yet known.

But a more detailed view of these structures is the beginning of a more informed strategy for a focused medical or pharmaceutical attack, Strauss says. "You can think of the protease inhibitors for HIV. Those in large part came from knowing the structure of the HIV enzymes you were trying to interfere with."

Thus, the new work could lead to drugs that will bind to the virus to prevent it from entering the cell, or perhaps from reassembling once it is already inside the cell.

Dengue fever is a mosquito-spread disease that has been known for centuries, but was first isolated in the 1940s after it became a significant health concern for American forces in the Pacific theater. A worldwide problem, the disease is found throughout Latin America, the Caribbeans, Southeast Asia, and India, and is currently at epidemic levels in Hawaii.

Especially virulent is the closely related dengue hemorrhagic fever, which is responsible for most of the deaths. The disease is a leading cause of infant mortality in Thailand, where there is an especially vigorous program to find an effective vaccine.

More information can be found on the Center for Disease Control Web site at http://www.cdc.gov/ncidod/dvbid/dengue/index.htm.

Contact: Robert Tindol (626) 395-3631

Writer: 
RT

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