Why Do We Sleep?

While we can more or less abstain from some basic biological urges—for food, drink, and sex—we can’t do the same for sleep. At some point, no matter how much espresso we drink, we just crash. And every animal that’s been studied, from the fruit fly to the frog, also exhibits some sort of sleep-like behavior. (Paul Sternberg, Morgan Professor of Biology, was one of the first to show that even a millimeter-long worm called a nematode falls into some sort of somnolent state.) But why do we—and the rest of the animal kingdom—sleep in the first place?

“We spend so much of our time sleeping that it must be doing something important,” says David Prober, assistant professor of biology and an expert on how genes and neurons regulate sleep. Yes, we snooze in order to rest and recuperate, but what that means at the molecular, genetic, or even cellular level remains a mystery. “Saying that we sleep because we’re tired is like saying we eat because we’re hungry,” Prober says. “That doesn’t explain why it’s better to eat some foods rather than others and what those different kinds of foods do for us.”

No one knows exactly why we slumber, Prober says, but there are four main hypotheses. The first is that sleeping allows the body to repair cells damaged by metabolic byproducts called free radicals. The production of these highly reactive substances increases during the day, when metabolism is faster. Indeed, scientists have found that the expression of genes involved in fixing cells gets kicked up a notch during sleep. This hypothesis is consistent with the fact that smaller animals, which tend to have higher metabolic rates (and therefore produce more free radicals), tend to sleep more. For example, some mice sleep for 20 hours a day, while giraffes and elephants only need two- to three-hour power naps.

Another idea is that sleep helps replenish fuel, which is burned while awake. One possible fuel is ATP, the all-purpose energy-carrying molecule, which creates an end product called adenosine when burned. So when ATP is low, adenosine is high, which tells the body that it’s time to sleep. While a postdoc at Harvard, Prober helped lead some experiments in which zebrafish were given drugs that prevented adenosine from latching onto receptor molecules, causing the fish to sleep less. But when given drugs with the opposite effect, they slept more. He has since expanded on these studies at Caltech.

Sleep might also be a time for your brain to do a little housekeeping. As you learn and absorb information throughout the day, you’re constantly generating new synapses, the junctions between neurons through which brain signals travel. But your skull has limited space, so bedtime might be when superfluous synapses are cleaned out.

And finally, during your daily slumber, your brain might be replaying the events of the day, reinforcing memory and learning. Thanos Siapas, associate professor of computation and neural systems, is one of several scientists who have done experiments that suggest this explanation for sleep. He and his colleagues looked at the brain activity of rats while the rodents ran through a maze and then again while they slept. The patterns were similar, suggesting the rats were reliving their day while asleep.

Of course, the real reason for sleep could be any combination of these four ideas, Prober says. Or perhaps only one of these hypotheses might have been true in the evolutionary past, but as organisms evolved, they developed additional uses for sleep.

Researchers in Prober’s lab look for the genetic and neural systems that affect zebrafish sleeping patterns by tweaking their genes and watching them doze off. An overhead camera records hundreds of tiny zebrafish larvae as they swim in an array of shallow square dishes. A computer automatically determines whether the fish are awake or not based on whether they’re moving or still, and whether they respond to various stimuli. Prober has identified about 500 drugs that affect their sleeping patterns, and now his lab is searching for the relevant genetic pathways. By studying the fish, the researchers hope to better understand sleep in more complex organisms like humans. “Even if we find only a few new genes, that’ll really open up the field,” he says. The future is promising, he adds, and for that, it’ll be well worth staying awake. 

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Marcus Woo
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David Anderson, Christof Koch Named Allen Distinguished Investigators

Two Caltech researchers have been named by the Paul G. Allen Family Foundation among the inaugural group of Allen Distinguished Investigators.

Caltech's David Anderson and Christof Koch are two of the seven investigators who were honored by the foundation as it launched a new program to advance important research in neuroscience and cellular engineering.

"A year ago, I started searching for programs with potential for major breakthroughs but which had struggled to find funding through traditional sources," says Paul G. Allen. "The inaugural Distinguished Investigators are working on some of the most exciting research in biology and neurology and I'm proud to be able to help keep that work going."

David Anderson, the Benzer Professor of Biology at Caltech and a Howard Hughes Medical Institute investigator, was granted $1.6 million over three years for a project designed to localize, identify, characterize, and turn on neurons in the hypothalamus associated with attack, and bring the study of aggression into the modern molecular era.

More specifically, Anderson's project will use powerful genetic tools to try to identify specific classes of neurons that control emotional behaviors. Identifying such neurons will greatly facilitate the study of how they are wired into the brain's circuitry, and how this circuitry is affected by genetic and environmental factors that influence emotional behavior. Such studies could potentially lead to the development of new treatments for emotional disorders.

Christof Koch, the Lois and Victor Troendle Professor of Cognitive and Behavioral Biology and professor of computation and neural systems at Caltech, will use his three-year, $600,000 award for a project entitled "Evaluating Connectomes Using Measures of Complexity and Synergy." A connectome is the complete set of connections among all processing elements of a particular nervous system. Koch's group will specifically analyze the locomotion network in the roundworm, Caenorhabditis elegans, with an eye toward assessing the information flow in the neural network that leads to a clearly measurable behavior.

Overall, Koch's group seeks to characterize the complexity of the connectome and its ability to integrate information using a combination of analysis and computation. The team proposes that integrated information—a measure that uses variables such as conditional entropy from information theory—is a critical property of nervous systems, and believes that evolution by natural selection gives rise to a systematic increase in the integrated information of brains. Koch and his colleagues propose to demonstrate this for both simulated artificial networks that evolve and/or learn as well as for extant neurobiological networks, such as the known locomotion network of C. elegans.

"One of the Foundation's goals is to support projects that create new knowledge about ourselves and our universe," says Susan M. Coliton, vice president of the Paul G. Allen Family Foundation. "Making investments in early stage, cutting-edge research leverages both our funding and the intellectual capital of talented scientists. We couldn't be more thrilled about the potential of this inaugural group of Allen Distinguished Investigators."

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Lori Oliwenstein
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Caltech Scientists Describe the Delicate Balance in the Brain that Controls Fear

Two different neural subtypes act like a seesaw to control the level of fear output from the brain's amygdala

PASADENA, Calif.—The eerie music in the movie theater swells; the roller coaster crests and begins its descent; something goes bump in the night. Suddenly, you're scared: your heart thumps, your stomach clenches, your throat tightens, your muscles freeze you in place. But fear doesn't come from your heart, your stomach, your throat, or your muscles. Fear begins in your brain, and it is there—specifically in an almond-shaped structure called the amygdala—that it is controlled, processed, and let out of the gate to kick off the rest of the fear response.

In this week's issue of the journal Nature, a research team led by scientists at the California Institute of Technology (Caltech) has taken an important step toward understanding just how this kickoff occurs by beginning to dissect the neural circuitry of fear. In their paper, these scientists—led by David J. Anderson, the Benzer Professor of Biology at Caltech and a Howard Hughes Medical Institute investigator—describe a microcircuit in the amygdala that controls, or "gates," the outflow of fear from that region of the brain.

The microcircuit in question, Anderson explains, contains two subtypes of neurons that are antagonistic—have opposing functions—and that control the level of fear output from the amygdala by acting like a seesaw.

"Imagine that one end of a seesaw is weighted and normally sits on a garden hose, preventing water—in this analogy, the fear impulse—from flowing through it," says Anderson. "When a signal that triggers a fear response arrives, it presses down on the opposite end of the seesaw, lifting the first end off the hose and allowing fear, like water, to flow." Once the flow of fear has begun, that impulse can be transmitted to other regions of the brain that control fearful behavior, such as freezing in place.

"Now that we know about this 'seesaw' mechanism," he adds, "it may someday provide a new target for developing more specific drugs for treating fear-based psychiatric illnesses like post-traumatic stress disorder, phobias, or anxiety disorders."

The key to understanding this delicate mechanism, Anderson says, was in uncovering "markers"—genes that would identify and allow for the scientists to discriminate between the different neuronal cell types in the amygdala. Anderson's group, led by postdoctoral fellow Wulf Haubensak, found its marker in a gene that encodes an enzyme known as protein kinase C-delta (PKCδ). PKCδ is expressed in about half the neurons within a subdivision of the amygdala's central nucleus, the part of the amygdala that controls fear output. 

Along with fellow postdocs Prabhat Kunwar and Haijiang Cai, Haubensak was able to fluorescently tag neurons in which the protein kinase is expressed; this allowed the researchers to map the connections of these neurons, as well as to monitor and manipulate their electrical activity. 

The studies, Anderson says, "revealed that PKCδ+ neurons form one end of a seesaw, by making connections with another population of neurons in the central nucleus that do not express the enzyme, which are called PKCδ- neurons." They also showed that the kinase-positive neurons inhibit outflow from the amygdala—proving that they act as the end of the seesaw that rests on the garden hose.

Still, a key question remained: What happens to the seesaw during exposure to a fear-eliciting signal? Anderson and his colleagues hypothesized that the fear signal would push down on the opposite end of the seesaw from the one formed by the PKCδ+ neurons, removing the crimp from the garden hose and allowing the fear signal to flow. But how to test this idea?

Enter neurophysiologist Andreas Lüthi and his student Stephane Ciocchi, from the Friedrich Miescher Institute in Basel, Switzerland. In work done independently from that of the Anderson lab, Lüthi and Ciocchi had managed to record electrical signals from the amygdala during exposure to fear-inducing stimuli. Interestingly, they had found two types of neurons that responded in opposite ways to the fear-inducing stimulus: one type increased its activity, while the other type decreased its activity. Like Anderson, they had begun to think that these neurons formed a seesaw that controls fear output from the amygdala.

And so the two teams joined forces to determine whether the cells Lüthi had been studying corresponded to the PKCδ+ and PKCδ- cells Anderson's lab had isolated. In what Anderson refers to as a "sophisticated experiment," the two teams performed electrophysiological recordings while simultaneously turning the PKCδ+ neurons on or off using a genetic method developed by Henry Lester, Caltech's Bren Professor of Biology.

The results of the experiment were "gratifyingly clear," says Anderson. The cells that decreased their activity in the face of fear-inducing stimuli clearly corresponded to the PKCδ+ neurons Anderson's lab had isolated, while those that increased their activity corresponded to the PKCδ-  neurons.

"These results supported the hypothesis that PKCδ+ neurons were indeed at the opposite end of the seesaw from the one that the fear signal 'presses down' on, consistent with the finding that PKCδ+ neurons crimp the 'fear hose,'" says Anderson.

The marriage of molecular biology and electrophysiology created by the collaboration between Anderson's and Lüthi's laboratories has revealed properties of the fear circuit that could not have been discovered in any other way, Anderson says. "The functional geography of the brain is organized like that of the world," he notes. "It's divided into continents, countries, states, towns and cities, neighborhoods and houses; the houses are analogous to the different types of neurons. Previously, it had only been possible to dissect the amygdala at the level of different towns, or of neighborhoods at best. Now, using these new genetic techniques, we are finally down to the level of the houses."

And that, he adds, is what will make it possible for us to fully understand the networks of communication that exist between neurons within a subdivision of the brain, as well as between subdivisions and different areas. "While these studies shed light on only a small part of the picture, they are an important step in that direction," Anderson says.

In addition to those previously mentioned, the other authors of the Nature paper, "Genetic dissection of an amygdala microcircuit that gates conditioned fear," are Nicholas Wall and Edward Callaway from the Salk Institute for Biological Studies; Ravikumar Ponnusamy, Michael Fanselow, Jonathan Biag, and Hong-Wei Dong from the University of California, Los Angeles; and Karl Deisseroth from Stanford University. Their work was funded by grants from the National Institutes of Health, Caltech, the Novartis Research Foundation, and the Howard Hughes Medical Institute, and by fellowships from the Human Frontier Science Program and the Jane Coffin Childs Memorial Fund for Medical Research.

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Lori Oliwenstein
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Controlling Individual Cortical Nerve Cells by Human Thought

PASADENA, Calif.—Five years ago, neuroscientist Christof Koch of the California Institute of Technology (Caltech), neurosurgeon Itzhak Fried of UCLA, and their colleagues discovered that a single neuron in the human brain can function much like a sophisticated computer and recognize people, landmarks, and objects, suggesting that a consistent and explicit code may help transform complex visual representations into long-term and more abstract memories.

Now Koch and Fried, along with former Caltech graduate student and current postdoctoral fellow Moran Cerf, have found that individuals can exert conscious control over the firing of these single neurons—despite the neurons' location in an area of the brain previously thought inaccessible to conscious control—and, in doing so, manipulate the behavior of an image on a computer screen.

The work, which appears in a paper in the October 28 issue of the journal Nature, shows that "individuals can rapidly, consciously, and voluntarily control neurons deep inside their head," says Koch, the Lois and Victor Troendle Professor of Cognitive and Behavioral Biology and professor of computation and neural systems at Caltech.

The study was conducted on 12 epilepsy patients at the David Geffen School of Medicine at UCLA, where Fried directs the Epilepsy Surgery Program. All of the patients suffered from seizures that could not be controlled by medication. To help localize where their seizures were originating in preparation for possible later surgery, the patients were surgically implanted with electrodes deep within the centers of their brains. Cerf used these electrodes to record the activity, as indicated by spikes on a computer screen, of individual neurons in parts of the medial temporal lobe—a brain region that plays a major role in human memory and emotion.

Prior to recording the activity of the neurons, Cerf interviewed each of the patients to learn about their interests. "I wanted to see what they like—say, the band Guns N' Roses, the TV show House, and the Red Sox," he says. Using that information, he created for each patient a data set of around 100 images reflecting the things he or she cares about. The patients then viewed those images, one after another, as Cerf monitored their brain activity to look for the targeted firing of single neurons. "Of 100 pictures, maybe 10 will have a strong correlation to a neuron," he says. "Those images might represent cached memories—things the patient has recently seen."

The four most strongly responding neurons, representing four different images, were selected for further investigation. "The goal was to get patients to control things with their minds," Cerf says. By thinking about the individual images—a picture of Marilyn Monroe, for example—the patients triggered the activity of their corresponding neurons, which was translated first into the movement of a cursor on a computer screen. In this way, patients trained themselves to move that cursor up and down, or even play a computer game.

But, says Cerf, "we wanted to take it one step further than just brain–machine interfaces and tap into the competition for attention between thoughts that race through our mind."

To do that, the team arranged for a situation in which two concepts competed for dominance in the mind of the patient. "We had patients sit in front of a blank screen and asked them to think of one of the target images," Cerf explains. As they thought of the image, and the related neuron fired, "we made the image appear on the screen," he says. That image is the "target." Then one of the other three images is introduced, to serve as the "distractor."

"The patient starts with a 50/50 image, a hybrid, representing the 'marriage' of the two images," Cerf says, and then has to make the target image fade in—just using his or her mind—and the distractor fade out. During the tests, the patients came up with their own personal strategies for making the right images appear; some simply thought of the picture, while others repeated the name of the image out loud or focused their gaze on a particular aspect of the image. Regardless of their tactics, the subjects quickly got the hang of the task, and they were successful in around 70 percent of trials.

"The patients clearly found this task to be incredibly fun as they started to feel that they control things in the environment purely with their thought," says Cerf. "They were highly enthusiastic to try new things and see the boundaries of 'thoughts' that still allow them to activate things in the environment."

Notably, even in cases where the patients were on the verge of failure—with, say, the distractor image representing 90 percent of the composite picture, so that it was essentially all the patients saw—"they were able to pull it back," Cerf says. Imagine, for example, that the target image is Bill Clinton and the distractor George Bush. When the patient is "failing" the task, the George Bush image will dominate. "The patient will see George Bush, but they're supposed to be thinking about Bill Clinton. So they shut off Bush—somehow figuring out how to control the flow of that information in their brain—and make other information appear. The imagery in their brain," he says, "is stronger than the hybrid image on the screen."

According to Koch, what is most exciting "is the discovery that the part of the brain that stores the instruction 'think of Clinton' reaches into the medial temporal lobe and excites the set of neurons responding to Clinton, simultaneously suppressing the population of neurons representing Bush, while leaving the vast majority of cells representing other concepts or familiar person untouched."

The work in the paper, "On-line voluntary control of human temporal lobe neurons," is part of a decade-long collaboration between the Fried and Koch groups, funded by the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the G. Harold & Leila Y. Mathers Charitable Foundation, and Korea's World Class University program.

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Kathy Svitil
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Two Caltech Scientists Named Among 2010 NIH Director's New Innovator Awardees

PASADENA, Calif.—As part of a National Institutes of Health (NIH) initiative to stimulate highly innovative research and support promising new scientific investigators, two scientists from the California Institute of Technology (Caltech) were named among the 2010 class of the NIH Director's New Innovator Award recipients.

Alexei Aravin, assistant professor of biology, and Changhuei Yang, associate professor of electrical engineering and bioengineering, were among those honored with the grants, which are meant to help new investigators take exceptional and innovative research ideas to the next level.

"NIH is pleased to be supporting early-stage investigators from across the country who are taking considered risks in a wide range of areas in order to accelerate research," says Francis S. Collins, director of the National Institutes of Health. "We look forward to the results of their work."

Yang and his research team will be pushing in a new research direction in biophotonics—the study of the interaction of time-reversed light with biological structures. When light hits the body's tissues, the light scatters, making visualizing structures under the skin extremely difficult. "A couple of years ago, my group experimentally demonstrated that it is possible to reduce tissue opacity"—make the tissues and their structures easier to see—"by time-reversing tissue light transmission," Yang explains. Put simply, they traced the paths of the scattered photons back through the tissues, showing that, by doing so, they could create images of what the light had encountered on its way in.

"We believe that this phenomenon holds a key to deep-tissue optical imaging and therapy," says Yang. "I am grateful for this New Innovator award, because it will allow my group to better understand the science and develop technologies that can capitalize on its advantages. If our work pans out well, it could lead the way to deep-tissue surgery without incision points, highly targeted optical-based cancer therapies, ultrasound imaging with chemical specificity, and better microscopy."

Yang received his BS, MS, and PhD from the Massachusetts Institute of Technology. He joined Caltech as an assistant professor of electrical engineering in 2003, became assistant professor of electrical engineering and bioengineering in 2004, and was named associate professor in 2009.

The research for which Aravin was singled out focuses on understanding the functions of small RNA—tiny snippets of ribonucleic acid that play a role in silencing genes through a pathway known as RNA interference. A few years ago, Aravin discovered a new class of small RNA that provides protection against a type of genomic parasite—the so-called transposable elements. He will use the New Innovator award to study the ways in which "small-RNA pathways can be programmed to modulate gene expression and cause heritable phenotypic changes"—changes to the proteins a cell makes, as well as to its other traits and characteristics. His goal? To use small RNA to develop tools and methodologies that can actively direct a cell down a particular developmental pathway.

"Achievement of these goals will be of great importance for both general science and medicine," says Aravin, "as it will provide insights into processes of development and lineage commitment and allow major advances to be made in medical applications such as stem cell technologies and anticancer therapies."

Aravin received his BS, MSc, and PhD from Moscow State University and joined the Caltech faculty in 2009.

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Lori Oliwenstein
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Addicted to Nicotine

The first pull on a cigarette should send you into convulsions. The brain proteins that nicotine affects are nearly identical to a receptor protein on muscle cells that tells them to contract, but nicotine doesn't affect your muscles. "Muscle proteins couldn't be very sensitive to nicotine," says chemist Dennis Dougherty. "Because if they were, smoking would be intolerable—every puff would activate every muscle in your body."

So Dougherty and biologist Henry Lester set out to discover why nicotine prefers brains over brawn. Their work may help explain why smoking is addictive, and it could enable the design of drugs to help you quit. Surprisingly, it might also lead to treatments for neurological diseases, including Parkinson's and schizophrenia. (There is no medical justification for smoking, but people who have smoked for 30 or more years are almost 50 percent less likely to develop Parkinson's disease than nonsmokers, and about 90 percent of schizophrenics smoke compared to 20 percent of the general population. It may be that nicotine helps counteract the attention and memory losses of schizophrenia.)

Nicotine hijacks a family of proteins that bind to acetylcholine, a neurotransmitter-of-all-trades. In the brain, acetylcholine is involved in learning and memory, in maintaining alertness, and in the sensation of pleasure. In the rest of your body, it's the intermediary between your nerve cells and your muscle cells, carrying commands across the synapses that separate them and setting your body in motion. So when you flex your pecs in the mirror and think to yourself, "Dang, I look good," that's acetylcholine at work.

The receptors loosely resemble molars, with five roots and a crown, and sit embedded in a cell wall like teeth in a jawbone. Each tooth has a cavity on one side of the crown—the binding site, into which the acetylcholine molecule fits perfectly. The act of binding opens a pore that runs down the center of the tooth like a root canal, allowing ions to flow and create an electrical current.

There are more than 20 known versions of the receptor. Each version is assembled from an assortment of five subunits, with each subunit running from a root up to its corresponding cusp, surrounding the root-canal pore. "The different receptors are siblings—more closely related than cousins—but not identical twins," Dougherty says. But while binding acetylcholine brings them together as a family, their different collections of subunits allow at least some of them to choose to bind various other molecules as well. This would not seem too surprising, except that other scientists had found that the actual binding site is identical: the same five amino acids arranged like the bottom and sides of a lidless box. "So this raises a fascinating question," says Dougherty. "We have two dozen different acetylcholine receptors with noticeably different pharmacologies. What's happening?"

Answering that question is a detective story 20 years in the making, complete with red herrings, cold trails, and undercover informants. There's even an unlikely hero—a frog whose unfertilized eggs can be persuaded to sprout a crop of receptor proteins on their surfaces.

It turns out that a single amino acid that's not even a part of the binding box holds the key. There's a critical spot, four amino acids away from the binding site, where changing one amino acid will allow an acetylcholine receptor to broaden its repertoire. Amino acids come in assorted sizes, and it appears that putting a bigger one at this particular spot nudges the binding box just enough to change its shape slightly. This altered shape, in turn, can accommodate other molecules—with who knows what other effects.

Read the full story at E&S online.

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Michael Torrice
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Fruit Flies Use Horizontal Landmarks for Altitude Control, Says Caltech Research Team

PASADENA, Calif.—Flies follow horizontal edges to regulate altitude, says a team of researchers from the California Institute of Technology (Caltech). This finding contradicts a previous model, which posited that insects adjust their height by visually measuring the motion beneath them as they fly.

This mechanism for controlling altitude—in which the insects use their eyes to track horizontal edges in their environment—is very similar to the strategy insects use to steer left and right, the researchers note. "For people interested in how the tiny brains of these creatures can control such sophisticated behaviors, it's intriguing to realize that the same circuits and mechanisms that underlie steering may also be used to control altitude," says Michael Dickinson, the Esther M. and Abe M. Zarem Professor of Bioengineering at Caltech.

The paper describing these experiments is being published in the online edition of Current Biology.

Altitude control is a critical component of flight; unlike us earthbound humans, insects and other flying creatures need to control their height above the ground, or risk flying too high above it—or crashing into it.

"Insects have to make their way through three dimensions," Dickinson notes. "We wanted to know how a fly chooses a particular altitude at which to fly, and why it isn't flying at some other height."

Insects, notes Dickinson—and fruit flies in particular—have long been used as a model for understanding the basic principles of vision and how it is used to control behavior. Thus, understanding how these tiny flies use visual cues—the images, and changes in those images, that appear on their retinas as they move around—to help them maneuver through a complex landscape is an important problem. Indeed, the results of such research are being used by engineers to control small flying robots.

The Caltech team was originally trying to test a model of altitude control in insects that had been put forth by a different group of scientists a few years earlier. This model proposed the idea that insects regulate their altitude based on the movement of the ground beneath them. The lower you fly, the more quickly the world moves underneath you; the higher up you are, the more slowly the world goes by. This effect is easily observed by looking through the window of an airplane as it changes altitude during takeoff or landing.

The idea, then, was that an insect could cruise at a particular altitude by rising up if the flow beneath it was too fast and descending when the flow beneath it was too slow.

To test this, the Caltech team used an automated flight chamber developed by Andrew Straw, senior research fellow in computation and neural systems at Caltech and the paper's first author. The system employs multiple cameras to "track the position of a fly as it flies within a simple virtual-reality environment," Straw explains. In the experiments at hand, this required the projection of a pattern of stripes on the floor of a specially designed chamber through which the flies can freely travel. As the flies flew through the chamber, the researchers presented them with different speeds of visual motion on the ground beneath them, in an attempt to elicit the expected changes in altitude.

The flies, however, did not respond as expected. "We couldn't elicit any altitude changes," says Straw. "We expected them to descend in the chamber when the motion below slowed, but they didn't descend; we expected them to ascend when the forward motion was rapid, but they didn't ascend."

In other words, the insects were not behaving as predicted by the model.

After a series of experiments designed to verify these results—"We spent an enormous amount of time trying to convince ourselves that the ground-flow model did not apply to our flies," says Dickinson—they began to consider other explanations for how the insects might regulate altitude.

"We already knew that flies steer toward objects with a prominent vertical edge," says Dickinson. "They will use that vertical edge as a visual landmark for navigation, steering left and right to keep it in their sights. Our idea was that maybe they use a similar strategy in altitude by tracking horizontal edges."

To test this idea, the team projected a series of horizontal edges (a black line with black above it, white below; or vice versa) on the walls of the chamber, watching how the flies' altitude changed—or didn't change—as the height of the edge moved. Indeed, says Dickinson, "The flies would quickly adjust their altitude to match the height of the visual landmark."

But the team wasn't completely convinced. After all, the horizontal lines were the only landmarks the flies had before them; maybe they were using the lines as a guide for want of any other kind of cue.

And so the team did another experiment, in which they combined the two types of cues: they moved a horizontal edge up and down the chamber's walls while simultaneously projecting a pattern of stripes on its floor.

The results were clear: the flies oriented themselves based on the horizontal landmarks given, and ignored the pattern on the chamber floor.

The experiments were possible in part because the team could collect its data very efficiently, Straw notes. "The data size used in these experiments was very large," he says. "The system was fully automated—every time a fly flew down the tunnel, the experiment automatically started—and so could run for many hours without human supervision." This, he says, allowed them to amass an amount of data large enough to leave no doubt about the experiment's conclusions.

What's next in the study of altitude control? "We're both excited about combining this technique with genetic approaches that are available in fruit flies," says Straw. "We want to determine which parts of the brain are responsible for these and other behaviors."

The Current Biology paper, "Visual Control of Altitude in Flying Drosophila," was coauthored by Straw, Dickinson, and Serin Lee, a Caltech postdoctoral scholar. Their work was funded by grants from the Air Force Office of Scientific Research and the Army Research Office.

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Lori Oliwenstein
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Two Caltech Scientists Receive 2010 NIH Director's Pioneer Awards

Michael Roukes, Pamela Bjorkman recognized for their "highly innovative approaches" to biomedical research

PASADENA, Calif.—Two scientists from the California Institute of Technology (Caltech) have been recognized by the National Institutes of Health (NIH) for their innovative and high-impact biomedical research programs.

Michael Roukes, professor of physics, applied physics, and bioengineering, and co-director of the Kavli Nanoscience Institute, and

Pamela Bjorkman, Caltech's Max Delbrück Professor of Biology and a Howard Hughes Medical Institute investigator, now join the 81 Pioneers—including Caltech researchers Rob Phillips and Bruce Hay—who have been selected since the program's inception in 2004.

"NIH is pleased to be supporting scientists from across the country who are taking considered risks in a wide range of areas in order to accelerate research," said NIH Director Francis S. Collins in announcing the awards. "We look forward to the result of their work."

According to its website, the program provides each investigator chosen with up to $500,000 in direct costs each year for five years to pursue what the NIH refers to as "high-risk research," and was created to "support individual scientists of exceptional creativity who propose pioneering—and possibly transforming—approaches to major challenges in biomedical and behavioral research."

For Roukes, that means using "nanoscale tools to push biomedical frontiers." Specifically, he plans to leverage advances in nanosystems technology, "an approach that coordinates vast numbers of individual nanodevices into a coherent whole," he explains.

The goal? To create tiny "chips" that can be used to rapidly identify which specific bacteria are plaguing an individual patient—quickly, at the patient's bedside, and without the need for culturing. Similar chips, he says, will be capable of "obtaining physiological 'fingerprints' from exhaled breath" for use in disease diagnostics.

Roukes says the chips will also provide new approaches to cancer research through the analysis of cell mechanics and motility, and will provide less-costly ways to screen libraries of therapeutic drug candidates. Roukes's highly collaborative efforts are aimed at jump-starting what he calls a "nanobiotech incubator" at Caltech.

Roukes received his PhD in physics in 1985 from Cornell University. He has been at Caltech since 1992, and was named founding director of the Kavli Nanoscience Institute in 2004.

Bjorkman's Pioneer project will focus on ways to improve the human immune response to HIV. "HIV/AIDS remains one of the most important current threats to global public health," she says. "Although humans can mount effective immune responses using antibodies against many other viruses, the antibody response to HIV in infected individuals is generally ineffective."

This, she believes, is the result of the "unusually low number and low density of spikes" on the surface membrane of the virus. Antibodies have two identical "arms" with which to attach to a virus or bacterium. In most cases, the density of spikes on a pathogen's surface is high enough that these arms can simultaneously attach to neighboring spikes. Not so with HIV; because its spikes are so few and far between, antibodies tend to bind with only one arm attaching to a single spike. Such binding is weak, says Bjorkman, "much like if you were hanging from a bar with only one arm," and is easily eliminated by viral mutations.

That is why Bjorkman is proposing "a new methodology, designed to screen for and produce novel anti-HIV binding proteins that can bind simultaneously to all three monomers in an HIV spike trimer." A trimer is a protein made of three identical macromolecules; if an antibody can bind to all three proteins at one time, it will "interact very tightly and render the low spike density of HIV and its high mutation rate irrelevant to effective neutralization," Bjorkman explains.

Bjorkman received her PhD in biochemistry and molecular biology in 1984 from Harvard University. She has been at Caltech since 1989, and was named the Delbrück Professor in 2004.

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Lori Oliwenstein
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Caltech Biologists Discover MicroRNAs that Control Function of Blood Stem Cells

Finding is important for diagnosis and treatment of cancer and anemia

PASADENA, Calif.—Hematopoietic stem cells provide the body with a constant supply of blood cells, including the red blood cells that deliver oxygen and the white blood cells that make up the immune system. Hematopoietic—or blood—stem cells must also make more copies of themselves to ensure that they are present in adequate numbers to provide blood throughout a person's lifetime, which means they need to strike a delicate balance between self-renewal and development into mature blood-cell lineages. Perturb that balance, and the result can be diseases such as leukemia and anemia.

One key to fighting these diseases is gaining an understanding of the genes and molecules that control the function of these stem cells. Biologists at the California Institute of Technology (Caltech) have taken a large step toward that end, with the discovery of a novel group of molecules that are found in high concentrations within hematopoietic stem cells and appear to regulate their production. 

When the molecules, tiny snippets of RNA known as microRNAs (miRNAs), are experimentally elevated to higher levels in the hematopoietic stem cells of laboratory mice, they "either impede or accelerate the function of these cells," says David Baltimore, Robert Andrews Millikan Professor of Biology, recipient of the 1975 Nobel Prize in Physiology or Medicine, and principal investigator on the research. 

A paper about the work was published July 26 in the early online edition of the Proceedings of the National Academy of Sciences (PNAS).

Intriguingly, the researchers found that one particular miRNA, miR-125b, plays a striking dual role. When miR-125b was mildly elevated,  it accelerated the production of mature blood cells by blood stem cells far better than any other miRNA. But when its expression was pushed to far higher levels, Baltimore says, "it led to a vicious cancer within 6 months." While the exact mechanism underlying this transformation event is presently unknown, it likely involves the inhibition by miR-125b of specific genes that normally suppress tumor formation.

"We were surprised to see that at high levels, miR-125b induced an aggressive myeloid leukemia in mice," says Caltech graduate student Aadel Chaudhuri, a coauthor on the paper. Myeloid leukemia results when normal blood cells—including red blood cells, blood-clotting platelets, and white blood cells—are systematically replaced by abnormal white blood cells that continue to grow uncontrollably, ultimately leading to death if untreated.

"These studies were performed in mice," says Caltech postdoctoral scholar Ryan O'Connell, the lead author of the PNAS paper, "but we also analyzed human blood stem cells and found that the same miRNAs are similarly enriched."

In addition, the researchers found that the expression of that key miRNA enhances the engraftment of human blood stem cells when they are transferred into mouse hosts, "indicating that the expression and function of these miRNAs has been conserved during evolution," O'Connell says.

That means, Chaudhuri says, "it is possible that certain human leukemias could be treated by targeting these newly identified stem-cell microRNAs."

"These findings, when combined with a similar report by physician–scientist David Scadden of the Massachusetts General Hospital and the Harvard Stem Cell Institute, show that miRNAs are important molecules that control the function of blood stem cells," he says. "These observations have important implications for both the diagnosis and treatment of cancer and anemia, which arise from defective blood stem cells. Blood stem cell transplantations have become a common form of therapy to treat cancer, autoimmunity, and even certain types of infectious diseases, and the exploitation of miRNA expression levels in blood stem cells through therapeutic targeting could be used to augment this approach." 

"These two studies add to the mounting evidence that miRNAs are critical controllers of the relative amounts of different types of blood cells made in the bone marrow of mice and people," Baltimore says. "In this work, we show that this is true for the stem cells, while earlier work from us and many others has shown that miRNA levels determine the concentrations of many types of mature blood cells. This knowledge offers the opportunity to therapeutically manipulate the levels of these blood cells," he says, "although targeting miRNAs therapeutically remains a great challenge to biotechnology."   

In addition to Baltimore, O'Connell, and Chaudhuri, the paper, "MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output," was also coauthored by Dinesh Rao, formerly of Caltech and currently of the David Geffen School of Medicine at UCLA; Caltech research technician William S. Gibson; and Caltech postdoctoral scholar Alejandro B. Balazs. The work was funded by the Cancer Research Institute; the National Heart, Lung, and Blood Institute; the National Science Foundation; and the National Cancer Institute.

David Baltimore is a director of Regulus Therapeutics, a company developing microRNA therapeutics, and chairman of its Scientific Advisory Board.

 

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Kathy Svitil
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Gain and Loss in Optimistic Versus Pessimistic Brains

PASADENA, Calif.—Our belief as to whether we will likely succeed or fail at a given task—and the consequences of winning or losing—directly affects the levels of neural effort put forth in movement-planning circuits in the human cortex, according to a new brain-imaging study by neuroscientists at the California Institute of Technology (Caltech). 

A paper about the research—led by Richard A. Andersen, the James G. Boswell Professor of Neuroscience at Caltech—appears in the August issue of PLoS Biology.

Research in Andersen's laboratory includes work to understand the neural mechanisms of action planning and decision-making. The lab is working toward the development of implanted neural prosthetic devices that would serve as an interface between severely paralyzed individuals' brain signals and artificial limbs—allowing their planned actions to control the limbs' movements.

 

In particular, Andersen's group focuses on a high-level area of the brain called the posterior parietal cortex (PPC), where sensory stimuli are transformed into movement plans.

In the current study, Andersen and his colleagues used a functional magnetic resonance imaging scanner to monitor activity in the PPC and other brain areas in subjects who were asked to perform a complex task. Using a trackball, they had to move a cursor to a number of memorized locations on a computer screen, in a predetermined order. 

"The subjects were given 1 second to memorize the sequence, 15 seconds to plan their movements in advance, and then only 10 seconds to finish the task," says Igor Kagan, a senior research fellow in biology in the Andersen lab, and a coauthor of the PLoS Biology paper. "We intentionally made the task hard—I couldn't do it myself," he says. 

The subjects received monetary compensation for participating in the experiment, with their earnings tied to their performance. The amount of money that would be gained (or lost) varied from trial to trial. In one trial, for example, success might net the participant $5, while failure would cause him to lose $1. In another trial, completing the task correctly would earn $1, while failure would cost $5. Alternatively, success and failure might produce an equivalent gain or loss (say, +$5 versus -$5). The subjects were told the stakes in advance of each trial.

Prior to receiving their earnings, the subjects reported—in a post-test questionnaire—how they perceived their performance. Interestingly, those perceptions did not correlate with their actual performance; individuals in the group who believed they had performed well were just as likely to have performed poorly, and vice versa for individuals in the group who believed they had done badly.

Furthermore, the researchers found that the pattern of brain activity in the PPC was linked to how well the subjects believed they had done on the tasks—that is, their subjective perception of their performance, rather than their actual performance—as well as by the monetary gain or loss they expected from success or failure. 

How hard an individual subject's brain "worked" at the task was dependent upon their personal approach. For example, Andersen says, "subjects who are 'optimists' and believe they are doing well will put out the most effort—and exhibit an increase in activity in their PPC—when they expect to earn a larger reward for being successful." Conversely, those individuals who believe they are doing poorly—the pessimists—show the most brain activity when there is a higher price for failure.

"They're trying harder to avoid losses and seem to care less about potential gains," Kagan adds.

"This study demonstrates that the process of planning and action is influenced by our subjective, but often incorrect, idea of how well we are doing, as well as by the potential gain or loss," Andersen says. The results suggest that the cortical areas involved in planning actions are also likely to be involved in decision-making, and take into account higher-order cognitive as well as subjective factors when deciding among potential actions.  

The paper, "Motor Preparatory Activity in Posterior Parietal Cortex is Modulated by Subjective Absolute Value," was also coauthored by former Caltech graduate student Asha Iyer, the first author of the study, now a resident at Mount Sinai Medical School, and former Caltech postdoctoral fellow Axel Lindner, now a group leader at the University of Tübingen. The research was funded by the Gordon and Betty Moore Foundation, the James G. Boswell Foundation, and the National Eye Institute.

 

Writer: 
Kathy Svitil
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