Owls perform a type of multiplicationin locating ground prey in dark, study shows

Owls have long been known for their stunning ability to swoop down in total darkness and grab unsuspecting prey for a midnight snack.

In the April 13 issue of the journal Science, neuroscientists from the California Institute of Technology report that an owl locates prey in the dark by processing two auditory signal cues to "compute" the position of the prey. This computation takes place in the midbrain and involves about a thousand specialized neurons.

"An owl can catch stuff in the dark because its brain determines the location of sound sources by using differences in arrival time and intensity between its two ears," says Mark Konishi, who is Bing Professor of Behavioral Biology at Caltech and coauthor of the Science paper.

For example, if a mouse on the ground is slightly to the right of a flying owl, the owl first hears the sound the mouse makes in its right ear, and a fraction of a second later, in its left ear. This information is transmitted to the specialized neurons in the midbrain.

Simultaneously, the owl's ears also pick up slight differences in the intensity of the sound. This information is transmitted to the same neurons of the midbrain, where the two cues are multiplied to provide a precise two-dimensional location of the prey.

"What we did not know was how the neural signals for time and intensity differences were combined in single neurons in the map of auditory space in the midbrain," Konishi says. "These neurons respond to specific combination of time and intensity differences. The question our paper answers is how this combination sensitivity is established."

"The answer is that these neurons multiply the time and intensity signals," he says.

Thus, the neurons act like switches. The neurons do not respond to time or intensity alone, but to particular combinations of them.

The reason the neural signals are multiplied rather than added is that, in an addition, a big input from the time pathway alone might drive the neuron to the firing level. In a multiplication, however, this possibility is less likely because a multiplication reduces the effects of a big input on one side.

It's not clear how the owl perceives the location of the mouse in the third dimension, Konishi says, but it could be that the owl simply remembers how far it is to the ground or how much noise a mouse generally makes, and somehow adds this information into the computation.

The lead author of the Science paper is José Luis Peña, a senior research fellow in biology at Caltech.

Contact: Robert Tindol (626) 395-3631

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Baxter Awards Caltech Professor $250,000

PASADENA, Calif.— The BioScience business of Baxter Healthcare Corporation, Hyland Immuno, has awarded $250,000 to a California Institute of Technology faculty member to continue his protein design research.

Glendale-based Baxter Hyland Immuno awarded the unrestricted grant to Dr. David Tirrell, the Ross McCollum - William H. Corcoran Professor of Chemistry and Chemical Engineering. Tirrell is also division chair for the Chemistry and Chemical Engineering Division at Caltech.

Tirrell's research addresses the design and synthesis of novel proteins and protein-like materials for applications in biology, biotechnology and medicine. He and his coworkers use biological cells to make proteins, just as nature does, but the cells are reprogrammed to produce specific materials that are targeted toward important biomedical technologies.

"I am delighted by this award, which will allow us to move our research forward much more rapidly," said Tirrell. "The link to Baxter will also help us connect our programs more directly to important clinical problems."

Said Norbert Riedel, PhD, president of Hyland Immuno's recombinant business, "One of our keys to growth is the collaboration with world-class academic research centers like Caltech. We are pleased to provide this grant to Dr. Tirrell to further his important work in protein design."

Founded in 1891, Caltech has an enrollment of some 2,000 students, and an academic staff of about 275 professorial faculty and 130 research faculty. The Institute has more than 19,000 alumni. Caltech employs a staff of more than 2,100 on campus and 4,800 at JPL. Over the years, 28 Nobel Prizes and four Crafoord Prizes have been awarded to faculty members and alumni. Forty-seven Caltech faculty members and alumni have received the National Medal of Science; and eight alumni (two of whom are also trustees), two additional trustees, and one faculty member have won the National Medal of Technology. Since 1958, 13 faculty members have received the annual California Scientist of the Year award. On the Caltech faculty there are 78 fellows of the American Academy of Arts and Sciences; and on the faculty and Board of Trustees, 70 members of the National Academy of Sciences and 48 members of the National Academy of Engineering.

Baxter Healthcare Corporation is the principal U.S. subsidiary of Baxter International Inc. (NYSE:BAX), a global medical products and services company that focuses on critical therapies for people with life-threatening conditions. Baxter's medical products and services include blood therapies, medication delivery and renal therapy, and are used by healthcare providers and their patients in more than 100 countries. The Hyland Immuno business of Baxter Healthcare Corporation develops and produces therapeutic proteins from plasma and through recombinant methods to treat hemophilia, immune deficiencies, and other blood-related disorders. Hyland Immuno's portfolio of therapies includes coagulation factors, immune globulins, albumin, wound management products and vaccines.

Contact: Deborah Williams-Hedges (626) 395-3227 debwms@caltech.edu

Visit the Caltech Media Relations Web site at: http://www.caltech.edu/~media

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Caltech Professor Awarded Wolf Foundation Prize for Insights Into the Life Cycle of Cells

PASADENA, Ca.-For his discovery of a critical protein system that regulates normal cell division and many other biological processes, the California Institute of Technology's Alexander Varshavsky has been named the co-recipient of the 2001 Wolf Foundation Prize in Medicine.

Varshavsky, the Smits Professor of Cell Biology at Caltech, will share the award with Avram Hershko of the Technion-Israel Institute of Technology. The Wolf Prize was established in 1978, and is designed to promote science and art for the benefit of mankind. Specifically, the pair is being honored for the discovery of the "ubiquitin system of intracellular protein degradation and the crucial functions of this system in cellular regulation." The prize includes an honorarium of $100,000 that will be split between the two awardees.

Proteins are biology's blue-collar workers. They are the catalysts that jump-start the various reactions of cellular life, telling cells when it's time to divide, change into other cell types, or die, and monitoring the timing of such events. When its specific job is done, it's often critical that a particular protein should be destroyed and thereby cease functioning.

Ubiquitin is a small protein that attaches itself to other proteins within a cell, marking them for degradation (or destruction) by proteases, still another kind of specialized protein. Ubiquitin is, well, ubiquitous in all organisms other than bacteria; hence its name. Using both mouse cells and baker's yeast as model organisms, Varshavsky proved that ubiquitin is essential for protein degradation in living cells. His laboratory also showed 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.

Conversely, malfunctions of the ubiquitin system often allow the cell's mechanisms to run amok. Therefore, these malfunctions play major roles 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 Academy of Microbiology. His other honors include the 1998 Merit Award from the National Institutes of Health; the 1998 Novartis-Drew Award in Biomedical Science; the 1999 Gairdner International Award from Canada's Gairdner Foundation; the 2000 Sloan Prize from the General Motors Cancer Research Foundation; the 2000 Albert Lasker Award in Basic Medical Research from the Lasker Foundation; and the 2001 Merck Award, from the American Society for Biochemistry and Molecular Biology.

 

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Baxter Awards Caltech Professor $250,000

PASADENA, Calif.— The Hyland Immuno division of Baxter Healthcare Corporation has awarded $250,000 to a California Institute of Technology faculty member to continue his protein design research.

Glendale-based Baxter Hyland Immuno awarded the unrestricted grant to Dr. David Tirrell, the Ross McCollum – William H. Corcoran Professor of Chemistry and Chemical Engineering. Tirrell is also division chair for the Chemistry and Chemical Engineering Division at Caltech.

Tirrell's research addresses the design and synthesis of novel proteins and protein-like materials for applications in biology, biotechnology and medicine. He and his coworkers use biological cells to make proteins, just as nature does, but the cells are reprogrammed to produce specific materials that are targeted toward important biomedical technologies.

"I am delighted by this award, which will allow us to move our research forward much more rapidly," said Tirrell. "The link to Baxter will also help us connect our programs more directly to important clinical problems."

Said Norbert Riedel, PhD, president of Hyland Immuno's recombinant business, "One of the reasons Baxter is in Southern California is the opportunity to collaborate with world-class academic research centers like Caltech. We are pleased to provide this grant to Dr. Tirrell to further his important work in protein design."

Baxter Healthcare Corporation is the principal U.S. subsidiary of Baxter International Inc. (NYSE:BAX), a global medical products and services company that focuses on critical therapies for people with life-threatening conditions. Baxter's medical products and services include blood therapies, medication delivery and renal therapy, and are used by healthcare providers and their patients in more than 100 countries. The Hyland Immuno business of Baxter Healthcare Corporation develops and produces therapeutic proteins from plasma and through recombinant methods to treat hemophilia, immune deficiencies, and other blood-related disorders. Hyland Immuno's portfolio of therapies includes coagulation factors, immune globulins, albumin, wound management products and vaccines.

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

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Researchers progress toward mutating a mousefor studying Parkinson's disease

Some inventors hope to build a better mousetrap, but California Institute of professor of biology Henry Lester's grand goal is to build a better mouse.

Not that the everyday laboratory mouse is inappropriate for a vast variety of biological and biomedical research. But for Parkinson's disease research, it has become clear that a strain of mutant mice with "slight" alterations would be a benefit in future medical studies. And not only would the mutant mice be useful for Parkinson's, but also for studies of anxiety and nicotine addiction.

Though Lester and his colleagues Johannes Schwarz and Cesar Labarca have not yet produced the mouse they envision, they have already achieved encouraging results by altering the molecules that form the receptors for nicotine in the mouse's brain. If they can just make these receptors overly sensitive in the right amount, they reason, the mice will develop Parkinson's disease after a few months of life.

Two earlier strains of mice were not ideal, but nonetheless convinced the Lester team members they were on the right track. One strain of mice suffered from nerve-cell degeneration too quickly, developing ion channels that opened literally before birth. These overly sensitive receptors essentially short-circuited some nerve cells. These mice usually do not survive birth, and never live long enough to reproduce.

Another strain developed modest nerve-cell degeneration in about a year, which is a long time in a mouse's life as well as a long time for a research project to wait for its test subjects. Lester wants the "Goldilocks mouse," with neurons that die "not before birth—that's too fast. Not at a year—that's too slow and incomplete. With a mouse strain that degenerates in three months, we could generate and test hypotheses several times per year."

Though they haven't achieved the "Goldilocks mouse" yet, the strain of mice developing modest degeneration after a year is particularly interesting. Tests showed that they were quite anxious, but tended to be calmed down by minuscule doses of nicotine. For reasons not entirely understood, humans who smoke are less likely to develop Parkinson's disease later in life, pointing to the likelihood that a mouse with hypersensitive nicotine receptors will be a good model for studying the disease.

In fact, the Lester team originally set out to build the strain of mice in order to study nicotine addiction and certain psychiatric diseases that might involve acetylcholine, a natural brain neurotransmitter that is mimicked by nicotine. The work in the past has been funded by the California Tobacco-Related Disease Research Program, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke (NINDS).

Once they had some altered mice, Schwarz (a neurologist who works with many Parkinson's patients) realized that the dopamine-containing nerve cells were dying fastest. The death of these cells is also a cause of Parkinson's disease. Because present mouse models for Parkinson's research are unsatisfactory, the researchers applied for and soon received funding from the National Parkinson Foundation, Inc. (NPF). Not only did the researchers receive the funding from the NPF, but they also were named recipients of the Richard E. Heikkila Research Scholar Award, which is presented for new directions in Parkinson's research.

"The Heikkila award is gratifying recognition for our new attempts to develop research at the intersection of clinical neuroscience and molecular neuroscience here at Caltech," says Lester.

Dr. Yuan Liu, program director at NINDS, says the Lester team's research is important not only because it is the first genetic manipulation of an ion channel that might lead to a mammalian model for Parkinson's disease, but also because the research is a pioneering effort in an emerging field called "channelopathy."

"Channelopathy addresses defects in ion channel function that causes diseases," Liu says. "Dr. Lester is one of the pioneers working in this field.

"We're excited about this development," she says, "because Parkinson's is a disease that affects such a large number of people—500,000 in the US. The research on Parkinson's is one of the research highlights that the NINDS is addressing."

The first results of the Lester team's research are reported in the current issue of the journal Proceedings of the National Academy of Sciences (PNAS).

In addition to Labarca, a member of the professional staff in the Caltech Department of Biology, and Schwarz, a visiting associate, the collaborators include groups led by professors James Boulter of UCLA and Jeanne Wehner of the University of Colorado.

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Caltech Professor Receives Ellison Award

PASADENA, Calif.—Giuseppe Attardi, the California Institute of Technology's Grace C. Steele Professor of Molecular Biology, has received the Ellison Medical Foundation Senior Scholar Award. The award is for $935,584 over four years.

Attardi's work encompasses research in the area of aging and in the detection of DNA that affects the aging processes. He is responsible for the discovery and development of new genetic research techniques that are used by laboratories internationally.

Attardi's career spans nearly a half century, including 35 years at Caltech. Prior to joining the Caltech faculty in 1963, Attardi was an assistant professor in histology and general embryology at the University of Padua, Italy. He received his MD from the University of Padua in 1947.

Throughout his career, Attardi has received numerous distinguished honors and awards.

The Ellison Medical Foundation is a nonprofit corporation that was established by a gift from Mr. Lawrence J. Ellison to support basic biomedical research on aging, relevant to understanding aging processes and age-related diseases and disabilities. The Ellison Medical Foundation stimulates basic biomedical research in multiple disciplines including molecular genetics, cell cycle regulation, cellular differentiation, genetic epidemiology, immunology, gene/environment and gene/gene interactions, metabolism, endocrinology, signal transduction, and integrative physiology. Through various award mechanisms, including the Senior Scholar and New Scholar Awards programs, the foundation fosters research by means of grants-in-aid to investigators at universities and laboratories within the United States.

Contact: Deborah Williams-Hedges (626) 395-3227 debwms@caltech.edu

Visit the Caltech Media Relations Web site at: http://www.caltech.edu/~media

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Odor recognition is a patterned, time-dependent process, research shows

PASADENA, Calif.-When Hamlet told the courtiers they would eventually "nose out" the hidden corpse of Polonius, he was perhaps a better neurobiologist than he realized. According to research by neuroscientists at the California Institute of Technology, the brain creates and uses subtle temporal codes to identify odors.

This research shows that the signals carried by certain neuron populations change over the duration of a sniff such that one first gets a general notion of the type of odor. Then, the wiring between these neurons performs work that leads to a more subtle discrimination, and thus, a precise recognition of the smell.

In the February 2 issue of the journal Science, Caltech biology and computation and neural systems professor Gilles Laurent and his colleague, postdoctoral scholar Rainer W. Friedrich, now at the Max Planck Institute in Heidelberg, Germany, report that the neurons of the olfactory bulb respond to an odor through a complicated process that evolves over a brief period of time. These neurons, called mitral cells because they resemble miters, thepointed hats worn by bishops, are found by the thousands in the olfactory bulb of humans.

"We're interested in how ensembles of neurons encode sensory information," explains Laurent, lead author of the study. "So we're less interested in where the relevant neurons lie, as revealed by brain mapping studies, than in the patterns of firing these neurons produce and in figuring out from these patterns how recognition, or decoding, works."

The researchers chose to use zebrafish in the study because these animals have comparatively few mitral cells and because much is already known about the types of odors that are behaviorally relevant to them. The Science study likely applies to other animals, including humans, because the olfactory systems of most living creatures appear to follow the same basic principles.

After placing electrodes in the brain of individual fish, the researchers subjected them sequentially to 16 amino-acid odors. Amino acids, the components of proteins, are found in the foods these fish normally go after in their natural environments.

By analyzing the signals produced by a population of mitral cells in response to each one of these odors, the researchers found that the information they could extract about the stimulus became more precise as time went by. The finding was surprising because the signals extracted from the neurons located upstream of the mitral cells, the receptors, showed no such temporal evolution.

"It looks as if the brain actively transforms static patterns into dynamic ones and in so doing, manages to amplify the subtle differences that are hard to perceive between static patterns," Laurent says.

"Music may provide a useful analogy. Imagine that the olfactory system is a chain of choruses-a receptor chorus, feeding onto a mitral-cell chorus and so on-and that each odor causes the receptor chorus to produce a chord.

"Two similar odors evoke two very similar chords from this chorus, making discrimination difficult to a listener," Laurent says. "What the mitral-cell chorus does is to transform each chord it hears into a musical phrase, in such a way that the difference between these phrases becomes greater over time. In this way, odors that, in this analogy, sounded alike, can progressively become more unique and more easily identified."

Applied to our own experience, this result could be described as follows: When we detect a citrus smell in a garden, for example, the odor is first conveyed by the receptors and the mitral cells. The initial firing of the cells allows for little more than the generic detection of the citrus nature of the smell.

Within a few tenths of a second, however, this initial activity causes new mitral cells to be recruited, leading the pattern of activity to change rapidly and become more unique. This quickly allows us to determine whether the citrus smell is actually a lemon or an orange.

However, the individual tuning of the mitral cells first stimulated by the citrus odor do not themselves become more specific. Instead, the manner in which the firing patterns unfold through the lateral circuitry of the olfactory bulb is ultimately responsible for the fine discrimination of the odor.

"Hence, as the system evolves, it loses information about the class of odors, but becomes able to convey information about precise identity," says Laurent. This study furthers progress toward understanding the logic of the olfactory coding.

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New research shows that the ears can sometimes trick the eyes

Though it seems to follow common sense that vision is the most dominant of the human senses, a new study by California Institute of Technology researchers shows that auditory signals can sometimes trick test subjects into misinterpreting what they have seen.

In a new study appearing in the Dec. 14 issue of the journal Nature, Caltech psychophysicists Ladan Shams, Yukiyasu Kamitani, and Shinsuke Shimojo report that auditory information can alter the perception of accompanying visual information, even when the visual input is otherwise unambiguous.

"We have discovered a visual illusion that is induced by sound," the authors write in the paper. Using a computer program that runs very short blips of light accompanied by beeps, the researchers asked test subjects to determine whether there was one or two flashes.

However, unknown to the subjects, the number of flashes mismatch that of beeps in some trials. When the subjects were shown the flash accompanied by one beep, everyone correctly stated that they had seen one flash. But when they were shown the flash with two very quick beeps spaced about 50 milliseconds apart, the subjects all erroneously reported that they had seen two flashes.

What's more, test subjects who were told that there was actually only one flash still continued to perceive two flashes when they heard two beeps.

According to Shimojo, a professor of biology at Caltech, the effect works only if the beeps are very rapid. When they are, "there's no way within the time window for vision to tell whether there's a single or double flash," he says.

According to Shams, a postdoctoral scholar working in Shimojo's lab and lead author of the paper, the results contribute to a shift in our view of visual processing from one "that is independent of other modalities, toward one that is more intertwined with other modalities, and can get as profoundly influenced by signals of other modalities as it influences them."

Contact: Robert Tindol (626) 395-3631

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Sequencing of Arabidopsis genome will havehuge payoffs, Caltech plant geneticist says

Whether or not the man was right when he said a mustard seed can move mountains, a poorer cousin of mustard named Arabidopsis has just been certified one of the heavy lifters of 21st-century biology.

With today's announcement that the international effort to sequence the Arabidopsis genome has been completed, plant biologists now have a powerful tool that is a triumph for biology as well as world agriculture, says Caltech plant geneticist Elliot Meyerowitz.

"Anything you learn in Arabidopsis is easily applied to crop plants," says Meyerowitz, in whose Caltech lab the first cloning and sequencing of an Arabidopsis gene took place.

"With knowledge from the genome sequencing, you might be able to make crops more resistant to disease and other plant problems," he said. "Fifty percent of all pre- and postharvest losses are due to pests, so if you could solve these problems, you could double the efficiency of world agriculture."

Arabidopsis is a nondescript weed of the mustard family that has a thin 6-inch-long stem, small green leaves, and tiny white blooms when it flowers. With no commercial, medicinal, decorative, or other practical uses, the plant is hardly even worth grubbing out of the flower bed when it springs up in its various habitats around the world.

But for geneticists, Arabidopsis is the powerhouse of the plant world. It is easy to plant and grow, maturing in a couple of weeks; it is small and thus requires little precious lab space; it is easy to clone and sequence its genes; and it produces plenty of seeds very quickly so that future generations—mutants and otherwise—can be studied. And now, Arabidopsis is the only plant species whose genome has been totally sequenced.

"Arabidopsis took off in the 1980s after it was demonstrated it has a very small genome, which makes it easier to clone genes," said Meyerowitz, a longtime supporter of and adviser to the international Arabidopsis genome project.

"One reason the plant was chosen was because it doesn't have that much DNA," he said. "Arabidopsis has about 125 million base pairs in the entire genome—and that's 20 times smaller than the human genome, and thus about 20 times less expensive to sequence. It's been a bargain."

The sequencing of the plant genome was originally proposed in 1994 for a 2004 completion, but experts later realized the project could be completed four years early—and under budget.

"Everybody shared the cost, and everybody will share the benefits—all the information is in the public domain," Meyerowitz says. "Taxpayers got a big bargain."

Sequencing Arabidopsis has benefits for the understanding of basic biological mechanisms, in much the same way that sequencing the roundworm or fruit fly has benefits. As a consequence of evolution, all organisms on Earth share a huge number of genes.

Thus, the information obtained from sequencing Arabidopsis as well as fruit flies and roundworms will contribute to advances in understanding how the genes of all living organisms are related. These underlying genetic interactions, in turn, will eventually lead to new treatments of human disease as well as the genetic engineering of agricultural products.

In addition to making crops more disease- and pest-resistant, genetic engineering could also change the time of flowering so that crops could be fitted to new environments; make plants more resistant to temperature changes; and possibly lengthen the roots so that plants could make more efficient use of nutrients.

Also, approximately one-fourth of all medicines were originally derived from plants, Meyerowitz says. So better understanding of the enzymes that create these pharmaceutical products could be used for creating new drugs as well as making existing drugs better and more efficient.

Contact: Robert Tindol (626) 395-3631

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Human brain employs the same neurons in seeing an objectand later imagining it

In a study of nine epilepsy patients awaiting brain surgery, researchers have discovered that humans use the same neurons to conjure up mental images that they use when they see the real object with their eyes.

In the November 16 issue of the journal Nature, UCLA neurosurgeon and neuroscientist Itzhak Fried and Caltech neuroscientists Christof Koch and Gabriel Kreiman report on results obtained by questioning nine patients who had been fitted with brain sensors. The patients, all suffering from severe epilepsy uncontrolled with drugs, were being observed for a period of 1-2 weeks so that the regions of their brains responsible for their seizures could be identified and later surgically removed.

During their extended hospital stay, the patients were asked to look at photos of famous people such as President Clinton, pictures of animals, abstract drawings, and other images. While they were looking at the images, the researchers noted the precise neurons that were active.

Then, the subjects were instructed to close their eyes and vividly imagine the images. Again, the researchers took note of the neurons active at the time of visual imagery.

Analysis of the data showed that a subset of neurons in the hippocampus, amygdala, entorhinal cortex, and parahippocampal gyrus would fire both when the patient looked at the image, as well as when he or she imagined the image.

The results build upon previous work by Fried's group showing that single neurons in the human brain are involved in memory and can respond selectively to a wide variety of visual stimuli and stimulus features such as facial expression and gender.

According to Koch, a professor of computation and neural systems at Caltech, the study helps settle long-standing questions about the nature of human imagery. Particularly, the research sheds light on the process at work when humans see things with the "mind's eye."

"If you try to recall how many sunflowers there are in the Van Gogh painting, there is something that goes on in your head that gives rise to this visual image," Koch says. "There has been an ongoing debate about whether the brain areas involved in perception during 'vision with your eyes' are the same ones used during visual imagery."

The problem has been difficult to address because the techniques that yield very precise results in animals are generally not suitable for humans, and because the brain imaging techniques suitable for humans are not very precise, Koch says. Such techniques can image only large portions of the brain, each containing on the order of one million very diverse nerve cells.

"Recording the activity of single cells allows us to investigate the neuronal correlates of visual awareness at a detailed level of temporal and spatial resolution," says Kreiman.

The work was supported by the National Institutes of Health, the National Science Foundation, and the Center for Consciousness Studies at the University of Arizona.

Contact: Robert Tindol (626) 395-3631

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