Neuroscientists Demonstrate New Way to Control Prosthetic Device with Brain Signals

PASADENA, Calif.—Another milestone has been achieved in the quest to create prosthetic devices operated by brain activity. In the July 9 issue of the journal Science, California Institute of Technology neuroscientists Sam Musallam, Brian Corneil, Bradley Greger, Hans Scherberger, and Richard Andersen report on the Andersen lab's success in getting monkeys to move the cursor on a computer screen by merely thinking about a goal they would like to achieve, and assigning a value to the goal.

The research holds significant promise for neural prosthetic devices, Andersen says, because the "goal signals" from the brain will permit paralyzed patients to operate computers, robots, motorized wheelchairs—and perhaps someday even automobiles. The "value signals" complement the goal signals by allowing the paralyzed patients' preferences and motivations to be monitored continuously.

According to Musallam, the work is exciting "because it shows that a variety of thoughts can be recorded and used to control an interface between the brain and a machine."

The Andersen lab's new approach departs from earlier work on the neural control of prosthetic devices in that most previous results have relied on signals from the motor cortex of the brain used for controlling the limb. Andersen says the new study demonstrates that higher-level signals, also referred to as cognitive signals, emanating from the posterior parietal cortex and the high-level premotor cortex (both involved in higher brain functions related to movement planning), can be decoded for control of prosthetic devices.

The study involved three monkeys that were each trained to operate a computer cursor by merely "thinking about it," Andersen explains. "We have him think about positioning a cursor at a particular goal location on a computer screen, and then decode his thoughts. He thinks about reaching there, but doesn't actually reach, and if he thinks about it accurately, he's rewarded."

Combined with the goal task, the monkey is also told what reward to expect for correctly performing the task. Examples of variation in the reward are the type of juice, the size of the reward, and how often it can be given, Andersen says. The researchers are able to predict what each monkey expects to get if he thinks about the task in the correct way. The monkey's expectation of the value of the reward provides a signal that can be employed in the control of neural prosthetics.

This type of signal processing may have great value in the operation of prosthetic devices because, once the patient's goals are decoded, then the devices' computational system can perform the lower-level calculations needed to run the devices. In other words, a "smart robot" that was provided a goal signal from the brain of a patient could use this signal to trigger the calculation of trajectory signals for movement to be accomplished.

Since the brain signals are high-level and abstract, they are versatile and can be used to operate a number of devices. As for the value signals, Andersen says these might be useful in the continuous monitoring of the patients to know their preferences and moods much more effectively than currently possible.

"These signals could also be rapidly adjusted by changing parameters of the task to expedite the learning that patients must do in order to use an external device," Andersen says. "The result suggests that a large variety of cognitive signals could be interpreted, which could lead, for instance, to voice devices that operate by the patients' merely thinking about the words they want to speak."

Andersen is the Boswell Professor of Neuroscience at Caltech. Musallam and Greger are both postdoctoral fellows in biology at Caltech; Corneil is a former researcher in Andersen's lab who is now at the University of Western Ontario; and Scherberger, a former Caltech researcher, is now at the Institute of Neuroinformatics in Zurich, Switzerland.

Robert Tindol

"Minis" Have Mega Impact in the Brain

Embargoed: Not for Release Until 11:00 a.m. PDT Thursday, 24 June, 2004

PASADENA, Calif. — The brain is a maddeningly complex organ for scientists to understand. No assumption can remain unchallenged, no given taken as a given.

Take "minis" for example. That is, miniature excitatory synaptic events. The location where neurons communicate with each other is the synapse, the tiny gap between the ends of nerve fibers. That's where one nerve cell signals another by secreting special chemicals called neurotransmitters, which jump the gap. The synapse, and its ability to strengthen and wane, is thought to be at the heart of learning and memory. Minis, mere single, tiny packets of neurotransmitters, were always thought to have no biological significance, nothing more than "noise," or background chatter that played no role in the formation of a memory. Minis, it was thought, could be safely ignored.

Maybe not, says Mike Sutton, a postdoctoral scholar in the lab of Erin Schuman, an associate professor of biology at the California Institute of Technology, and an associate investigator for the Howard Hughes Medical Institute. Sutton, Schuman, and colleagues Nicholas Wall and Girish Aakalu report that on the contrary, minis may play an important role in regulating protein synthesis in the brain. Further, their work suggests the brain is a much more sensitive organ than originally perceived, sensitive to the tiniest of chemical signals. Their report appears in the June 25th issue of the journal Science.

Originally, Sutton et. al. weren't looking at minis at all, but at protein synthesis, the process through which cells assemble amino acids into proteins according to the genetic information contained within that cell's DNA. Proteins are the body's workhorses, and are required for the structure, function, and regulation of cells, tissues, and organs. Every protein has a unique function.

A neuron is composed of treelike branches that extend from the cell body. Numerous branches called dendrites contain numerous synapses that receive signals, while another single branch called an axon passes the signal on to another cell.

The original rationale behind the experiment was to examine how changes in synaptic activity regulate protein synthesis in a dendrite, says Sutton. His first experiment was a starting point to ask what happens when we first remove all types of activity from a cell, so he could then add it back later incrementally and observe how this affected protein synthesis in dendrites. "So we were going on the assumption that the spontaneous glutamate release--the minis--would have no impact, but we wanted to formally rule this out," he says.

Using several different drugs, Sutton first blocked any so-called action potentials, an electrical signal in the sending cell that causes the release of the neurotransmitter glutamate. Normally, a cell receives hundreds of signals each second. When action potentials are blocked, it receives only minis that arrive at about one signal each second. Next he blocked both the action potential and the release of any minis. "To our surprise, the presence or absence of minis had a very large impact on protein synthesis in dendrites," he says. It turned out that the minis inhibit protein synthesis, which increased when the minis were blocked. Further, says Sutton, "it appears the changes in synaptic activity that are needed to alter protein synthesis in dendrites are extremely small--a single package of glutamate is sufficient."

Sutton notes that it is widely accepted that synaptic transmission involves the release of glutamate packets. That is, an individual packet (called a vesicle) represents the elemental unit of synaptic communication. "This is known as the 'quantal' nature of synaptic transmission," he says, "and each packet is referred to as a quantum. The study demonstrates, then, the surprising point that protein synthesis in dendrites is extremely sensitive to changes in synaptic activity even when those changes represent a single neurotransmitter quantum.

"Because it's so sensitive," says Sutton, "there is the possibility that minis provide information about the characteristics of a given synapse (for example, is the signal big or small?), and that the postsynaptic or receiving cell might use this information to change the composition of that synapse. And it does this by changing the complement of proteins that are locally synthesized."

The ability to rapidly make more or fewer proteins at a synaptic site allows for quick changes in synaptic strength. Ultimately, he says, this ability may underlie long-term memory storage.

"It's amazing to us that these signals, long regarded by many as synaptic 'noise,' have such a dramatic impact on protein synthesis," says Schuman. "We're excited by the possibility that minis can change the local synaptic landscape. Figuring out the nature of the intracellular 'sensor' for these tiny events is now the big question."

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The Brain Can Make Errors in Reassembling the Color and Motion of Objects

PASADENA, Calif.—You're driving along in your car and catch a glimpse of a green SUV out of the corner of your eye. A few seconds later, you glance over, and to your surprise discover that the SUV is actually brown.

You may assume this is just your memory playing tricks on you, but new research from psychophysicists at the California Institute of Technology and the Helmholtz Institute in the Netherlands suggests that initial perceptions themselves can contain misassigned colors. This can happen in certain cases where the brain uses what it sees in the center of vision and then rearranges the colors in peripheral vision to match.

In an article appearing in this week's journal Nature, Caltech graduate student Daw-An Wu, Caltech professor of biology Shinsuke Shimojo, and Ryota Kanai of the Helmholtz Institute report that the color of an object can be misassigned even as observers are intently watching an ongoing event because of the way the brain combines the perceptions of motion and color. Because different parts of the brain are responsible for dealing with motion and color perception, mistakes in "binding" can occur, where the motion from one object is combined with the color of another object.

This is demonstrated when observers gaze steadily at a computer screen on which red and green dots are in upward and downward motion. In the center area of the screen, all the red dots are moving upward while all the green dots are moving downward.

Unknown to the observers, however, the researchers are able to control the motion of the red and green dots at the periphery of the screen. In other words, the red and green dots are moving in a certain direction in the center area of the screen, but their motion is partially or even wholly reversed on each side.

The observers show a significant tendency to mistake the motion of the red and green dots at the periphery. Even when the motion was completely reversed on the sides, the observers would see the same motion all across the screen.

According to Wu, the lead author of the paper, the design of the experiment exploits the fact that different parts of the brain are responsible for processing different visual features, such as motion and color. Further, the experiment shows that the brain can be tricked into binding the information back together incorrectly.

"This illusion confirms the existence of the binding problem the brain faces in integrating basic visual features of objects, " says Wu. "Here, the information is reintegrated incorrectly because the information in the center, where our vision is strongest, vetoes contradicting (but correct) information in the periphery."

The title of the article is "Steady-State Misbinding of Color and Motion."



Robert Tindol

Two Caltech Faculty Receive Franklin Medals

PASADENA—Two members of the California Institute of Technology faculty, chemist Harry Gray and biologist Seymour Benzer, are among this year's recipients of the prestigious Benjamin Franklin Medals.

The honor is bestowed annually by the Franklin Institute in Philadelphia to outstanding American scientists and technologists. Approaching its 180th anniversary, the Franklin Medal has been presented in the past to Albert Einstein, Samuel F. B. Morse, Alexander Graham Bell, Steven Hawking, Gordon Moore, Jane Goodall, and Noam Chomsky, among others. Past recipients have also won 103 Nobel Prizes through the years.

Gray, who is being recognized for his work in metalloproteins, is the Beckman Professor of Chemistry and founding director of the Beckman Institute at Caltech. A Caltech professor since 1966, he served as chair of the Division of Chemistry and Chemical Engineering from 1978 to 1984. He is a member of the National Academy of Sciences, received the National Medal of Science in 1986, and is also the recipient of the Wolf Prize and the Harvey Prize. Gray was named a foreign member of Great Britain's Royal Society, as well as a member of the American Philosophical Society.

Benzer is the Boswell Professor of Neuroscience, Emeritus, at Caltech, and a preeminent molecular biologist who has worked on phage genetics, nervous system development, and behavioral genetics of the fruit fly. He has been at Caltech since 1965. He is a member of the National Academy of Sciences. He received the National Medal of Science in 1983, and is also the recipient of the Lasker Award, the Wolf Prize, the Crafoord Prize, and the Harvey Prize. He is a member of the Royal Society and the American Philosophical Society.

Benzer and Gray will be honored in Philadelphia on April 29 at the annual Franklin Institute Awards Ceremony and Dinner, which is held in the Benjamin Franklin National Memorial.

Robert Tindol
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Researchers discover fundamental scaling rule that differentiates primate and carnivore brains

PASADENA, Calif.--Everybody from the Tarzan fan to the evolutionary biologist knows that our human brain is more like a chimpanzee's than a dog's. But is our brain also more like a tiny lemur's than a lion's?

In one previously unsuspected way, the answer is yes, according to neuroscientists at the California Institute of Technology. In the current issue of the Proceedings of the National Academy of Sciences (PNAS), graduate student Eliot Bush and his professor, John Allman, report their discovery of a basic difference between the brains of all primates, from lemurs to humans, and all the flesh-eating carnivores, such as lions and tigers and bears.

The difference lies in the way the percentage of frontal cortex mass increases as the species gets larger. The frontal cortex is the portion of brain just behind the forehead that has long been associated with reasoning and other "executive" functions. In carnivores, the frontal cortex becomes proportionately larger as the entire cortex of the individual species increases in size--in other words, a lion that has a cortex twice the size of another carnivore's also has a frontal cortex twice the size.

By contrast, primates like humans and apes tend to have a frontal cortex that gets disproportionately larger as the overall cortex increases in size. This phenomenon is known as "hyperscaling," according to Bush, the lead author of the journal article.

What this says about the human relationship to the tiny lemurs of Madagascar is that the two species likely share a developmental or structural quirk, along with all the other primates, that is absent in all the carnivores, Bush explains. "The fact that humans have a large frontal cortex doesn't necessarily mean that they are special; relatively large frontal lobes have developed independently in aye-ayes among the lemurs and spider monkeys among the New World monkeys."

Bush and Allman reached their conclusions by taking the substantial histological data from the comparative brain collection at the University of Wisconsin at Madison. The collection, accumulated over many years by neuroscientist Wally Welker, comprises painstaking data taken from well over 100 species.

Bush and Allman's innovation was taking the University of Wisconsin data and running it through special software that allowed for volume estimations of the various structures of the brain in each species. Their results compared 43 mammals (including 25 primates and 15 carnivores), which allowed them to make very accurate estimations of the hyperscaling (or the lack thereof) in the frontal cortex.

The results show that in primates the ratio of frontal cortex to the rest of the cortex is about three times higher in a large primate than in a small one. Carnivores don't have this kind of systematic variation.

The hyperscaling mechanism is genetic, and was presumably present when the primates first evolved. "Furthermore, it is probably peculiar to primates," says Allman, who is Hixon Professor of Neurobiology at Caltech.

The next step will be to look at the developmental differences between the two orders of mammals by looking at gene expression differences. Much of this data is already available through the intense efforts in recent years to acquire the complete genomes of various species. The human genome, for example, is already complete, and the chimp genome is nearly so.

"We're interested in looking for genes involved in frontal cortex development. Changes in these may help explain how primates came to be different from other mammals," Bush says.

At present, the researchers have no idea what the difference is at the molecular level, but with further study they should be able to make this determination, Allman says. "It's doable."

The article is titled "The scaling of frontal cortex in primates and carnivores." For a copy of the article, contact Jill Locantore, PNAS communications specialist, at 202-334-1310, or e-mail her at

The PNAS Web site is at

For more information on Bush and Allman's research, go to the Web site


Robert Tindol

Zombie Behaviors Are Part of Everyday Life, According to Neurobiologists

PASADENA, Ca.--When you're close to that woman you love this Valentine's Day, her fragrance may cause you to say to yourself, "Hmmm, Chanel No. 5," especially if you're the suave, sophisticated kind. Or if you're more of a missing link, you may even say to yourself, "Me want woman." In either case, you're exhibiting a zombie behavior, according to the two scientists who pioneered the scientific study of consciousness.

Longtime collaborators Christof Koch and Francis Crick (of DNA helix fame) think that "zombie agents"--that is, routine behaviors that we perform constantly without even thinking--are so much a central facet of human consciousness that they deserve serious scientific attention. In a new book titled The Quest for Consciousness: A Neurobiological Approach, Koch writes that interest in the subject of zombies has nothing to do with fiction, much less the supernatural. Crick, who for the last 13 years has collaborated with Koch on the study of consciousness, wrote the foreword of the book.

The existence of zombie agents highlights the fact that much of what goes on in our heads escapes awareness. Only a subset of brain activity gives rise to conscious sensations, to conscious feelings. "What is the difference between neuronal activity associated with consciousness and activity that bypasses the conscious mind?" asks Koch, a professor at the California Institute of Technology and head of the Computation and Neural Systems program.

Zombie agents include everything from keeping the body balanced, to unconsciously estimating the steepness of a hill we are about to climb, to driving a car, riding a bike, and performing other routine yet complex actions. We humans couldn't function without zombie agents, whose key advantage is that reaction times are kept to a minimum. For example, if a pencil is rolling off the table, we are quite able to grab it in midair, and we do so by executing an extremely complicated set of mental operations. And zombie agents might also be involved, by way of smell, in how we choose our sexual partners.

"Zombie agents control your eyes, hands, feet, and posture, and rapidly transduce sensory input into stereotypical motor output," writes Koch. "They might even trigger aggressive or sexual behavior when getting a whiff of the right stuff.

"All, however, bypass consciousness," Koch adds. "This is the zombie in you."

Zombie actions are but one of a number of topics that Koch and Crick have investigated since they started working together on the question of the brain basis of consciousness. Much of the book concerns perceptual experiments in normal people, patients, monkeys, and mice, that address the neuronal underpinnings of thoughts and actions.

As Crick points out in his foreword, consciousness is the major unsolved problem in biology. The Quest for Consciousness describes Koch and Crick's framework for coming to grips with the ancient mind-body problem. At the heart of their framework is discovering and characterizing the neuronal correlates of consciousness, the subtle, flickering patterns of brain activity that underlie each and every conscious experience.

The Quest for Consciousness: A Neurobiological Approach will be available in bookstores on February 27. For more information, see For review copies, contact Ben Roberts at Roberts & Company Publishers at (303) 221-3325, or send an e-mail to

Robert Tindol

Caltech Nobel Laureate Ed Lewisto be Feted at Campus Celebration

PASADENA—Edward Lewis, who pioneered the modern understanding of how genes regulate the development of specific regions of the body, will be honored at a special celebration on the California Institute of Technology campus at 4 p.m. Wednesday, February 4.

A member of the Caltech faculty, Lewis won the Nobel Prize in 1995 in physiology or medicine for his seminal work on fruit fly mutations, which led to a fundamental understanding of the relation between genes and embryonic development in humans as well as flies. Currently the Morgan Professor of Biology, Emeritus, Lewis continues an active fruit-fly research regimen that began when he was a high school student in the 1930s.

Guest lecturer Howard Lipshitz will present "From Fruit Flies to Fallout: Ed Lewis and His Science." A colleague of Lewis's for the last two decades, Lipshitz is editor of the new book Genes, Development, and Cancer: The Life and Work of Edward B. Lewis, which was published in the USA this month by Kluwer Academic Publishers in Norwell, Mass.

According to the publisher, Lewis's scientific research "is the bridge linking experimental genetics as conducted in the first half of the 20th century, and the powerful molecular genetic approaches that revolutionized the field in its last quarter." Much less widely known are Lewis's contributions to understanding the links between ionizing radiation and cancer, as well as the closely related issues concerning nuclear-weapons testing policy.

A native of Wilkes-Barre, Pennsylvania, Lewis earned his bachelor's degree at the University of Minnesota in 1939, and his Ph.D. at Caltech, where he has been on the faculty ever since, except as a U.S. Army Air Corps meteorologist in the Pacific theatre during World War II.

In the 1950s Lewis played a key role in discovering and explaining the role of homeotic genes--that is, genes that influence how the undifferentiated cells in a fertilized embryo separate into a head and a tail end, and how the eyes, legs, antennae, and other organs all form in their correct positions.

These genes are "highly conserved," as geneticists say, because the genes are similar in all organisms and play a role in the development of all animals, from fruit flies to mice to humans.

The lecture will be held in 119 Kerckhoff (the Norman Davidson Lecture Hall) on the west side of campus. Parking is available in the nearby parking structure on Wilson Avenue.

Robert Tindol

The length of the gaze affects human preferences, new study shows

PASADENA, Calif.—Beauty may be in the eye of the beholder, but a new psychophysical study from the California Institute of Technology suggests that the length of the beholding is important, too.

In an article appearing in the December 2003 issue of the journal Nature Neuroscience, Caltech biology professor Shinsuke Shimojo and his colleagues report that human test subjects asked to choose between two faces will spend increasingly more time gazing at the face that they will eventually choose as the one more attractive. Also, test subjects will typically choose the face that has been preferentially shown for a longer time by the experimenter. In addition, the results show that the effect of gaze duration on preference also holds true for choices between abstract geometric figures.

The findings show that human preferences may be more fundamentally tied to "feedback" between the very act of gazing and the internal, cognitive prototype of attractiveness than was formerly assumed. Earlier work by other researchers has relied on the "attractiveness template," which assumes that an individual's ideal conception of beauty has somehow been imprinted on his or her brain due to early exposures to other people's faces, such as the mother.

In fact, Shimojo says, the new results come from experiments especially designed to minimize the influence of earlier biases and existing preferences. Even when images of faces have been computer-processed to eliminate possible biases due to ethnic origins and even such trivial factors as hairstyles, the results still show strongly that the gaze is subconsciously oriented toward the eventual choice. This holds true even more strongly when a test subject is asked to choose between two abstract geometric figures, suggesting that the slightly lower tendency to fix the gaze on the eventual choice of two faces is influenced by existing selection biases that cannot be totally controlled.

The findings in Nature Neuroscience comprise two experiments. The first was the choice of the more attractive face, in which all the test subjects were asked to rate the faces from 1 (very unattractive) to 7 (very attractive). The average rating for each face was then calculated so that faces in pairs could be matched in different ways.

In the "face-attractiveness-easy task" the faces were paired according to gender, race, and neutrality of facial expressions, but comprised a choice of a "very unattractive" face with a "very attractive" face. Five test subjects were then shown 19 face pairs and were asked to choose the face they preferred. A video camera recorded the movements of their eyes as they directed their attention from one face on the screen to the other.

The results showed that the likelihood of gaze of the test subjects started from chance (50 percent) but rose above 70 percent of their time gazing at the face till they chose that face.

Even more striking was the difference in gaze devoted to the "face-attractiveness-difficult task," in which 30 pairs of faces were matched according to the closeness in which they had been ranked for attractiveness. In this experiment, the test subjects spent up to 83 percent of their time gazing at the face they would choose immediately before their decision response, suggesting that the gaze is even more important when there is little difference in the features of stimuli themselves.

The test subjects were also asked to choose the least attractive face, as well as the rounder face, and the results also showed that the length of the gaze was an important indicator of the eventual choice. In addition, the subjects were asked to choose between abstract geometric shapes, and the length of gaze also correlated highly with the eventual choice.

The second experiment is "gaze manipulation," in which the faces are not shown simultaneously, but in sequences of varying duration on the two sides of the computer screen. In other words, one face was shown for a longer time (900 milliseconds) than the other face (300 milliseconds), and as a control, the faces were also shown to other subjects in the center of the screen in an alternating sequence.

The results show that the face shown for a longer time tends to be chosen at chance level (50 percent) with only two repetitions of the sequence, but about 59 percent of the time with 12 repetitions. This suggests that the duration of the gaze can influence the choice. However, this manipulation did not work in the control experiment without gaze shift, as mentioned above, indicating that it is not mere exposure time, but rather active gaze shift, that made the differences.

In sum, the results indicate that active orienting by gaze shift is wired into the brain and that humans use it all the time, albeit subconsciously, Shimojo says. One example is our preference for good eye contact with people whom we are engaging in conversation.

"If I look directly into your eyes, then glance at your ears, you can immediately tell that I've broken eye contact, even if we're some distance apart," Shimojo explains. "This shows that there are subtle clues to what's in the mind."

In addition to Shimojo, the other authors are Claudiu Simion, a graduate student in biology at Caltech; Christian Scheier, a former postdoctoral researcher in Shimojo's lab; and Eiko Shimojo, of the School of Human Studies/Psychology at Bunkyo Gakuin University in Japan. Shinsuke Shimojo and Claudiu Simion contributed equally to the work. 

Robert Tindol

National Human Genome Research Institute awards $12 million, five-year grant to "WormBase"

PASADENA, Calif.— The Caltech-led WormBase project, an ongoing multi-institutional effort to make genetic information on the experimental animal known as C. elegans freely available to the world, has been augmented with a new $12 million grant from the National Human Genome Research Institute. The money will be distributed over five years for ongoing work on the genome database, which since its inception in 2000 has become a major resource for biomedical researchers as well as biologists attempting to better understand individual genes and how they interrelate. According to Caltech biology professor Paul Sternberg, leader of the project, WormBase has already succeeded in making available on-line the complete genome sequence (100.2 million base pairs) of the nematode, plus an almost complete sequence for the closely related organism C. briggsae, as well as genes for some 20 parasitic nematode species. In addition, the project makes available a huge amount of experimental data pertaining to the nematode.

The completed sequences will be vital for an emerging research effort that includes the new double-strand RNA interference technique for understanding a gene's function, and the fruits of the sequencing effort are already apparent. There are now 23,000 such experiments in WormBase, along with 280,000 DNA expression ("chip") microarray observations, as well as detailed information on the expression of more than 1,600 of the worm's 20,000 genes.

"For the future, researchers will look at interactions between genes, which means that there are 20,000-squared possibilities for the interactions of two genes alone," says Sternberg. "Also, our future effort will include working with similar databases of the genomes of other organisms, such as the mouse, fruit fly, and yeast, for shared software and shared conceptual vocabularies.

"The ultimate purpose is to allow medical researchers to get the information more easily," he adds.

The human-worm connection may seem tenuous to people outside biology, but it is known that the two organisms have similarity in about 40 percent of their genes. A very realistic motivation for the funding of genome sequencing of other organisms has been to provide data for comparisons of genes that are of interest in the quest to better understand human disease. Thus, a cancer researcher who discovers that a certain gene is expressed in cancer cells can use the WormBase to see if the gene exists in nematodes, and if so, what is known about the gene's function.

Exploring the fundamental relationships between genes from species separated by hundreds of millions of years of evolution is expected to be a cornerstone of 21st-century biological innovation. Improved knowledge of how a gene is expressed in one species--and as time goes on, how two or more genes interact--will provide new approaches for dealing with human disease and will almost certainly be the foundation for some important medical advances.

The role of WormBase in 21st-century medicine will continue to be as a resource for knowledge. Already the site is fully searchable in a number of ways, including by genes, cells (the nematodes have only 959, and all are clearly understood and clearly visible under a microscope), and biological processes, as well as by names of researchers.

Information in WormBase comes from teams at the two centers that sequence the C. elegans and C. briggsae genomes--a team at the Sanger Institute, in England, led by Richard Durbin, and one at Washington University, led by John Spieth. The innovative software used to display the information in WormBase was developed by Lincoln Stein of the Cold Spring Harbor Laboratory, where the WormBase Web server is located.

Fourteen individuals at Caltech are currently involved in the WormBase project, including nine biologists and three computer experts.

Robert Tindol

Why Fearful Animals Flee—or Freeze

PASADENA, Calif. –In most old-fashioned black-and-white horror flicks, it always seems there's some hapless hero or heroine who gets caught up in a life-threatening situation. Instead of making the obvious choice--to run like hell--he/she freezes in place. That decision, alas, leads to their ultimate demise.

While their fate was determined by bad scriptwriting, scientists already know that in real life, environment and experience influence defensive behaviors. Less understood are the neural circuits that determine such decisions. Now, in an article in the May 1 issue of the Journal of Neuroscience, researchers at the California Institute of Technology have developed an experimental model using mice that can map and manipulate the neural circuits involved in such innate behaviors as fear.

Raymond Mongeau, Gabriel A. Miller, Elizabeth Chiang, and David J. Anderson, in work performed at Caltech, manipulated either a flight or freeze reaction in mice through the use of an ultrasonic auditory stimulus, and further, were able to alter the mouse's behavior by making simple changes in the animal's environment. They also found that flight and freezing are negatively correlated, suggesting that a kind of competition exists between these alternative defensive motor responses. Finally, they have begun to map the potential circuitry in the brain that controls this competition.

"Fear and anxiety are important emotions, especially in this day and age," says Anderson, a Caltech professor of biology and an investigator with the Howard Hughes Medical Institute. "We know a lot about how the brain processes fear that is learned, but much less is known about innate or unlearned fear. Our results open the way to better understanding how the brain processes innately fearful stimuli, and how and where anxiety affects the brain to influence behavior."

Using the ultrasonic cue, the researchers were able to predict and manipulate the animal's reaction to a fearful situation. They found that mice exposed to the ultrasonic stimulus in their home cage (a familiar environment) predominantly displayed a flight response. Those placed in a new cage (an unfamiliar environment), or treated with foot shocks the previous day, primarily displayed freezing and less flight.

Anderson noted that in previous fear "conditioning" experiments, where mice learn to fear a neutral tone associated with a footshock, the animals show only freezing behavior and never flight, even though in the wild, flight is a normal and important fear response to predators. This suggests that the ultrasonic stimulus used by Anderson and colleagues is tapping into brain circuits that mediate natural, or innate, fear responses that include flight as well as freezing.

What causes the shift from flight to freezing behavior? Probably high anxiety and stress, say the authors, caused by an unfamiliar environment or the foot shocks. The researchers suggest that freezing requires a higher threshold level of anticipatory fear (the heroine inside a dark, spooky house) before it can be elicited by the ultrasound.

Most brain researchers believe the brain uses a hierarchy of neural systems to determine which defensive behaviors, like flight or freezing, to use. These range from an evolutionary older neural system that generates "quick and dirty" defensive strategies, to more evolved systems that produce slower but more sophisticated reactions. These systems are known to interact, but the neural mechanisms that decide which response wins out are not understood.

One of the goals of their work was to map the brain regions that control the behaviors triggered by the fear stimulus, to observe whether any change in brain activity correlated with the different defensive behaviors. They achieved this, all the way down to the resolution of a single neuron, by mapping the expression pattern of the c-FOS gene, a so-called "immediate early gene" that is turned on when neurons are excited. The switching on of the c-FOS gene can therefore be used as an indication of neuronal activation.

A map of the c-FOS expression patterns during flight vs. freezing revealed that mice displaying freezing behavior had neural activity in different regions of the brain than those that fled. Some of these regions were previously known to inhibit each other, providing a possible explanation for the apparent competition between flight and freezing observed in the intact animal.

Anderson notes that more work needs to be done to pin down where and how anxiety modifies defensive behavior. "This system may also provide a useful model for understanding the neural substrates of human fear disorders, like panic and anxiety," says Anderson, "as well as provide a model for developing drugs to treat them."

Contact: Mark Wheeler (626) 395-8733

Visit the Caltech Media Relations Website at




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