Web-Crawling the Brain: 3-D Nanoscale Model of Neural Circuit Created

The brain is a black box. A complex circuitry of neurons fires information through channels, much like the inner workings of a computer chip. But while computer processors are regimented with the deft economy of an assembly line, neural circuits are impenetrable masses. Think tumbleweed.
Researchers in Harvard Medical School's Department of Neurobiology have developed a technique for unraveling these masses. Through a combination of microscopy platforms, researchers can crawl through the individual connections composing a neural network, much as Google crawls Web links.

"The questions that such a technique enables us to address are too numerous even to list," said Clay Reid, HMS professor of neurobiology and senior author on a paper reporting the findings in the March 10 edition of Nature.

The cerebral cortex is arguably the most important part of the mammalian brain. It processes sensory input, reasoning and, some say, even free will. For the past century, researchers have understood the broad outline of cerebral cortex anatomy. In the past decade, imaging technologies have allowed us to see neurons at work within a cortical circuit, to watch the brain process information.

But while these platforms can show us what a circuit does, they don't show us how it operates.

For many years, Reid's lab has been studying the cerebral cortex, adapting ways to hone the detail with which we can view the brain at work. Recently they and others have succeeded in isolating the activities of individual neurons, watching them fire in response to external stimuli.

The ultimate prize, however, would be to get inside a single cortical circuit and probe the architecture of its wiring.

Just one of these circuits, however, contains between 10,000 and 100,000 neurons, each of which makes about 10,000 interconnections, totaling upwards of 1 billion connections -- all within a single circuit. "This is a radically hard problem to address," Reid said.

Reid's team, which included Davi Bock, then a graduate student, and postdoctoral researcher Wei-Chung Allen Lee, embarked on a two-part study of the pinpoint-sized region of a mouse brain that is involved in processing vision. They first injected the brain with dyes that flashed whenever specific neurons fired and recorded the firings using a laser-scanning microscope. They then conducted a large anatomy experiment, using electron microscopy to see the same neurons and hundreds of others with nanometer resolution.

Using a new imaging system they developed, the team recorded more than 3 million high-resolution images. They sent them to the Pittsburgh Supercomputing Center at Carnegie Mellon University, where researchers stitched them into 3-D images. Using the resulting images, Bock, Lee and laboratory technician Hyon Suk Kim selected 10 individual neurons and painstakingly traced many of their connections, crawling through the brain's dense thicket to create a partial wiring diagram.

This model also yielded some interesting insights into how the brain functions. Reid's group found that neurons tasked with suppressing brain activity seem to be randomly wired, putting the lid on local groups of neurons all at once rather than picking and choosing. Such findings are important because many neurological conditions, such as epilepsy, are the result of neural inhibition gone awry.

"This is just the iceberg's tip," said Reid. "Within ten years I'm convinced we'll be imaging the activity of thousands of neurons in a living brain. In a visual circuit, we'll interpret the data to reconstruct what an animal actually sees. By that time, with the anatomical imaging, we'll also know how it's all wired together."

For now, Reid and his colleagues are working to scale up this platform to generate larger data sets.

"How the brain works is one of the greatest mysteries in nature," Reid added, "and this research presents a new and powerful way for us to explore that mystery."

This research was funded by the Center for Brain Science at Harvard University, Microsoft Research, and the NIH though the National Eye Institute. Researchers report no conflicts of interest.

Terror Bots Being Designed to Hunt You Down

A headless metal warrior stomps towards you, shooting. Fortunately, you've been training for a marathon and easily jet off to safety down an alleyway. But wait -– now a metal cheeta-bot is after you, racing faster than your puny legs can go. As the space between you and the galloping beast closes, you round a corner, see a door and dive through. It slams behind you. As you freeze, holding your breath, the robotic cat passes by outside with a wake of metallic echoes.

Relieved, you exhale into the dark. A fatal mistake -– outside, another robot has detected your breath and alerted the enemy to your location …

Waking up from this nightmare is a way to save yourself, for now, but in fact all three 'terror' bots it featured are based on actual prototypes being developed in California and Boston (though not with directly malicious intentions). Here's an introduction to the motley three.

ATLAS

A headless humanoid is being built by Boston Dynamics. Called Atlas, it has is a heel-to-toe gait. The designers want Atlas to be able to navigate over rough terrain as well as a human can, by resorting to a crawl or turning itself sideways as the situation necessitates. He (she?) also stays upright when pushed and can currently travel at 3.2 miles per hour. Atlas is the improved version of an earlier robo-person, Petman, that was designed to test the Army's chemical weapons suits, while mimicking human movement and physiology. Boston Dynamics recently won DARPA contracts to further develop Atlas and another robot named Cheetah.

CHEETAH

DARPA asked Boston Dynamics to build this robot-cat with a flexible spine, movable head and possibly even a tail. According to this IEEE Spectrum blog, the designers says Cheetah will sprint "faster than any existing legged robot and faster than the fastest human runners.” More than a speedy quadruped, Cheetah also has cat-like agility, able to turn corners and zig-zag with ease, as well as making lightning fast starts and stops.

COUGAR 20-H

A mini-surveillance robot more like Johnny 5 than a wildcat, the Cougar 20-H can park itself outside a building and detect activity inside from 65 feet away. The Army-funded rover, built by Orange County, Calif.-based TiaLinx, uses a low-power radar mounted on a tripod that can detect heartbeats and even breathing. As pointed out in Wired's Danger Room blog, this might actually make the Cougar 20-H well suited for search and rescue missions or for monitoring borders, since it can detect people through walls and underground.
Photo: Boston Dynamics

Dolphin-Baby Die-Off in Gulf Puzzles Scientists

This winter an alarmingly high number of young bottlenose dolphins in the Gulf of Mexico (map) have been washing up dead on U.S. shores, government scientists report.

The reason for the die-off is a mystery, and experts are urging caution in drawing any connections to last year's BP oil spill.

"Everybody wants to jump to that conclusion ... but at this point in time, it's too early to tell," said Blair Mase, coordinator of the Southeast Marine Mammal Stranding Network of the National Atmospheric and Oceanic Administration (NOAA).

Since January 1, 80 dead dolphins have been discovered along the coasts of Louisiana, Mississippi, Alabama, and Florida, according to the latest NOAA figures.

Forty-two of the dead were calves. Most of the juvenile dolphins are washing up in Mississippi and Alabama, because dolphins typically give birth and raise calves along the shallow shores of those states.

The normal gestation period for the dolphins is one year, and mothers usually give birth in March and April, so scientists think the affected calves are either being aborted, stillborn, or born prematurely.

"That's one part of the investigation that we're going to be looking at very carefully," Mase said.

"We'll methodically score each animal that has come ashore to determine if, in fact, it was an aborted calf or an animal born alive."

BP Oil Spill "a Factor We Need to Consider"

Dolphin die-offs—which scientists call unusual mortality events—occur every few years. But this one stands out, because young dolphins appear to be hardest hit, marine biologist Moby Solangi said.

"Usually in a stranding, you have a mixture of animals—males, females, adults, calves—but this one is distortedly focused on neonates," said Solangi, director of the Institute for Marine Mammal Studies (IMMS) in Gulfport, Mississippi, which is helping to investigate the deaths.

Also unusual: Only dolphins appear to be affected so far. No mass deaths of turtles, fish, or birds have been reported for this die-off.

Known causes of dolphin die-offs include unusually cold waters, ocean biotoxins, and diseases.

NOAA's Mase said scientists are investigating all of these factors and are not ruling out a possible connection to the BP oil spill.

"It's something that we are including in our investigation," Mase said.

IMMS's Solangi agreed that the BP oil spill "is a factor that we need to consider."

"The oil spill lasted several months, and it covered tens of thousands of square miles and much of the habitat of these animals."

IMMS scientists are currently performing necropsies on the dead dolphins to try to determine causes of death. The process—including analyzing tissue samples for signs of diseases, viral infections, and toxins—could take several weeks or months, Solangi said.

Oil Link Tough to Prove

While a link between last year's BP oil spill and this year's dolphin deaths is possible, it could be very difficult to prove, said Craig Matkin, a marine biologist at the North Gulf Oceanic Society in Alaska.

Matkin co-authored a study in 2008 that looked at the effects of the 1989 Exxon Valdez oil spill on killer whale populations in Alaska's Prince William Sound.

"I'm not overly optimistic that they're going to be able to find a link," he said.

One reason is that—unlike other environmental toxins, such as the pesticide DDT—the hydrocarbon molecules in oil are quickly processed by the body and do not persist in tissues, Matkin explained.

Scientists also don't have a good idea of how the spill might have affected dolphins still in the womb.

Oil is thought to affect marine animals through inhalation or direct and indirect ingestion—for example, by eating tainted fish. But the calves now showing up dead may not have even been conceived before or during the worst weeks of the spill and thus were not exposed to the oil directly.

Dolphin Die-offs Largely Cold Cases

In his 2008 study, Matkin's team concluded that the Exxon Valdez spill affected Alaskan killer whale populations for decades after the event. After inhaling oil vapors or eating oil-coated seals, for example, the whales experienced everything from "mild irritation" to instant death, the study days.

It's unknown how the 1989 spill affected calves. Killer whales tend to give birth in deep water, so dead calves are much less likely to wash ashore.

Matkin pointed out key differences between the two events.

"This is just not the same kind of situation," he said. "We were following individual animals for a period of time before the [Exxon Valdez] spill, so we knew who was missing, down to the individual.

"It's very different when you have a bunch of unknown animals stranded on a beach and you don't know anything about their history."

NOAA's Mase said it's possible that no satisfactory answer will ever be found for the dolphin-baby die-off.

"There have been 14 [unusual mortality events] since 1990," she said. "And of those 14, we've only been able to determine the causes for 6."

What If the Biggest Solar Storm on Record Happened Today?

On February 14 the sun erupted with the largest solar flare seen in four years—big enough to interfere with radio communications and GPS signals for airplanes on long-distance flights.

As solar storms go, the Valentine's Day flare was actually modest. But the burst of activity is only the start of the upcoming solar maximum, due to peak in the next couple of years.

"The sun has an activity cycle, much like hurricane season," Tom Bogdan, director of the Space Weather Prediction Center in Boulder, Colorado, said earlier this month at a meeting of the American Association for the Advancement of Science in Washington, D.C.

"It's been hibernating for four or five years, not doing much of anything." Now the sun is waking up, and even though the upcoming solar maximum may see a record low in the overall amount of activity, the individual events could be very powerful.

In fact, the biggest solar storm on record happened in 1859, during a solar maximum about the same size as the one we're entering, according to NASA.

That storm has been dubbed the Carrington Event, after British astronomer Richard Carrington, who witnessed the megaflare and was the first to realize the link between activity on the sun and geomagnetic disturbances on Earth.

During the Carrington Event, northern lights were reported as far south as Cuba and Honolulu, while southern lights were seen as far north as Santiago, Chile.
The flares were so powerful that "people in the northeastern U.S. could read newspaper print just from the light of the aurora," Daniel Baker, of the University of Colorado's Laboratory for Atmospheric and Space Physics, said at a geophysics meeting last December.

In addition, the geomagnetic disturbances were strong enough that U.S. telegraph operators reported sparks leaping from their equipment—some bad enough to set fires, said Ed Cliver, a space physicist at the U.S. Air Force Research Laboratory in Bedford, Massachusetts.

In 1859, such reports were mostly curiosities. But if something similar happened today, the world's high-tech infrastructure could grind to a halt.

"What's at stake," the Space Weather Prediction Center's Bogdan said, "are the advanced technologies that underlie virtually every aspect of our lives."

Solar Flare Would Rupture Earth's "Cyber Cocoon"

To begin with, the University of Colorado's Baker said, electrical disturbances as strong as those that took down telegraph machines—"the Internet of the era"—would be far more disruptive. Solar storms aimed at Earth come in three stages, not all of which occur in any given storm.

First, high-energy sunlight, mostly x-rays and ultraviolet light, ionizes Earth's upper atmosphere, interfering with radio communications. Next comes a radiation storm, potentially dangerous to unprotected astronauts.

Finally comes a coronal mass ejection, or CME, a slower moving cloud of charged particles that can take several days to reach Earth's atmosphere. When a CME hits, the solar particles can interact with Earth's magnetic field to produce powerful electromagnetic fluctuations. (Related: "Magnetic-Shield Cracks Found; Big Solar Storms Expected.")

"We live in a cyber cocoon enveloping the Earth," Baker said. "Imagine what the consequences might be."

Of particular concern are disruptions to global positioning systems (GPS), which have become ubiquitous in cell phones, airplanes, and automobiles, Baker said. A $13 billion business in 2003, the GPS industry is predicted to grow to nearly $1 trillion by 2017.

In addition, Baker said, satellite communications—also essential to many daily activities—would be at risk from solar storms.

"Every time you purchase a gallon of gas with your credit card, that's a satellite transaction," he said.

But the big fear is what might happen to the electrical grid, since power surges caused by solar particles could blow out giant transformers. Such transformers can take a long time to replace, especially if hundreds are destroyed at once, said Baker, who is a co-author of a National Research Council report on solar-storm risks.

The U.S. Air Force Research Laboratory's Cliver agrees: "They don't have a lot of these on the shelf," he said.

The eastern half of the U.S. is particularly vulnerable, because the power infrastructure is highly interconnected, so failures could easily cascade like chains of dominoes.

"Imagine large cities without power for a week, a month, or a year," Baker said. "The losses could be $1 to $2 trillion, and the effects could be felt for years."

Even if the latest solar maximum doesn't bring a Carrington-level event, smaller storms have been known to affect power and communications.

The "Halloween storms" of 2003, for instance, interfered with satellite communications, produced a brief power outage in Sweden, and lighted up the skies with ghostly auroras as far south as Florida and Texas.

Buffing Up Space-Weather Predictions

One solution is to rebuild the aging power grid to be less vulnerable to solar disruptions.

Another is better forecasting. Scientists using the new Solar Dynamics Observatory spacecraft are hoping to get a better understanding of how the sun behaves as it moves deeper into its next maximum and begins generating bigger storms.

These studies may help scientists predict when and where solar flares might appear and whether a given storm is pointed at Earth.

"Improved predictions will provide more accurate forecasts, so [officials] can take mitigating actions," said Rodney Viereck, a physicist at the Space Weather Prediction Center.

Even now, the center's Bogdan said, the most damaging emissions from big storms travel slowly enough to be detected by sun-watching satellites well before the particles strike Earth. "That gives us [about] 20 hours to determine what actions we need to take," Viereck said.

In a pinch, power companies could protect valuable transformers by taking them offline before the storm strikes. That would produce local blackouts, but they wouldn't last for long.

"The good news is that these storms tend to pass after a couple of hours," Bogdan added.

Meanwhile, scientists are scrambling to learn everything they can about the sun in an effort to produce even longer-range forecasts.

According to Vierick, space-weather predictions have some catching up to do: "We're back where weather forecasters were 50 years ago."

Engineered Viruses Boost Memory Recall in Mice

Memories fade with time, often to the annoyance of those who can’t recall important details. But scientists have now found a way to boost the recall of memories even after they’ve started to fade. Unfortunately, the method involves injecting an engineered virus directly into the brain, so those of us who are bad with names may want to wait a bit for the technique to be refined.

The work was done in rats, and the memories in question are associations between a specific taste — saccharine, for example — and an unpleasant stimulus, caused by injection of a nausea-inducing drug (the approach is called “conditioned taste aversion”). Unless the unpleasant association is reinforced, the memories will slowly fade with time, although the aversion doesn’t disappear entirely during the two-week period that the authors were looking at.

Two years ago, the same authors found that it was possible to radically accelerate this fading. By injecting a chemical that blocked a specific brain enzyme (protein kinase M ζ), the authors caused the rats to act as if they had never experienced the nausea, even if the memory manipulation took place 25 days after the conditioning. Most chemicals that interfere with memories tend to prevent them from being consolidated for long-term storage, but this chemical seemed to work even after the memory was firmly in place.

That’s potentially helpful, since some people have formed negative associations with harmless or even helpful items. Still, for most of us, it would be nice to think that fading memories could be resuscitated. Apparently, they can. The researchers have now done what’s effectively the converse experiment, and increased the activity of protein kinase M ζ. They did this by engineering a virus to express the gene for the kinase, and then infected specific areas of the brain involved in memory. All the infected cells had additional copies of the gene, and thus made more of its product.

The virus had exactly the effect that the authors would presumably have predicted. The virus was injected a week after the rats were given the aversion conditioning, when the memory would already be starting to fade, and the memory tests were done a week after that, yet rats showed a significantly improved retention of their memories. As the authors point out, the engineered virus boosted a memory that was formed before it was even present.

The memory molecule, PKMzeta, overexpressed in rat neurons. Red (left) shows PKMzeta while green (middle) is a fluorescent protein that shows nerve cells have been infected by viruses engineered to boost the memory molecule. Yellow (right) shows both the memory molecule and green fluorescent protein only overexpress at certain locations in the neuron. Weizmann Institute of Science/Science

Actually, you can make that memories, plural. The authors trained rats to avoid both saccharine and salty liquids over the course of three days, and then injected the virus a week after the last training. The memories of both of these trainings were enhanced by the presence of the viral protein kinase M ζ gene.

The authors can’t tell exactly what protein kinase M ζ is doing to increase the recall of memories, and suggest it could be either enhancing the association between taste and the unpleasant experience, or simply enhancing recall in general. Although they don’t mention it, their findings may also be limited to specific classes of memories, like the associations examined here.

That latter point makes the last sentence of the paper a bit over the top, as the authors suggest that a chemical that enhances protein kinase M ζ activity might make for a good treatment for memory disorders like amnesia and age-related decline. Until we have a clearer sense of how many types of memories it works for, that’s a bit premature. Fortunately, there are lots of ways to test the recall abilities of animals, many of which don’t involve negative associations. Hopefully, testing of the virus’ more general impact on memory is already underway.

Image: HIV (green dots), a member of the lentivirus genus. (C. Goldsmith/P. Feorino/E. L. Palmer/W. R. McManus/CDC)

Secret Space Plane Heading Back Into Orbit

The U.S. Air Force’s most mysterious spacecraft is headed back into orbit after a four-month hiatus. The second copy of the Boeing-built X-37 robotic space plane is slated for launch, atop an Atlas V rocket, from Cape Canaveral in Florida sometime on Friday. Forecasts of bad weather could push the launch to Saturday.

In any event, the blast-off is sure to revive speculation regarding the curious, 29-foot-long spacecraft that lands like an airplane — just like a miniature, unmanned space shuttle.

Nearly a year after the first X-37B launched on its 225-day, orbit-hopping inaugural mission, nobody outside of the Air Force knows exactly what the X-37 is for. That ambiguity has even sparked a minor space race as Russia and China at least threaten to build similar vehicles.

In the wake of the first X-37’s April launch, analysts listed all the things the X-37 is theoretically capable of. It could be a commando transport, a bomber or an orbital spy. It could launch, repair or reposition U.S. satellites in low orbit. It could sneak up and disable or steal enemy satellites. Its pickup-bed-sized payload bay is particularly enticing to observers.

“You can put sensors in there, satellites in there,” said Eric Sterner, from The Marshall Institute. “You could stick munitions in there, provided they exist.”

“I applaud the ingenuity and innovation of some reports,” Richard McKinney, the deputy undersecretary of the Air Force for space programs, joked during a December press conference. He insisted the 5-ton spacebot merely represents a “capability for a reusable and more effective way to test technology in space and return it for examination.”

“This is a test vehicle … pure and simple,” McKinney said.

But McKinney wouldn’t say what technologies the X-37 might be testing, and why the Air Force seems so attached to the idea of a self-landing, airplane-style space vehicle. After all, with the extra mass of its wings and landing gear, in some ways the X-37 is actually at a disadvantage compared to disposable spacecraft.

“Building this return capability into the space plane adds tons of extra mass compared to maneuvering spacecraft that are not designed to return to Earth,” Laura Grego and David Wright from the nonprofit Union of Concerned Scientists explained in a blog post. “That large mass penalty makes it more difficult and expensive to get a space plane and its payload into orbit and reduces the amount of maneuvering that it can do with a given amount of fuel.”

Everything the X-37 can apparently do, simpler spacecraft could do better and cheaper, Grego and Wright claimed. Even retrieving experimental items from space is better achieved using a simple capsule and parachute, they insisted.

Despite these criticisms, the Air Force is “really at the beginning of it” with the X-37B, McKinney crowed. The diminutive space bots are likely to stay very busy in coming years, leaving just two possible explanations.

One, the Air Force is stupid and doesn’t realize the X-37 is a second-rate vehicle for mucking about in space.

Or two, the X-37 is capable of something — or a mix of things — we outsiders haven’t yet imagined. Russia and China sure think so.

Oldest Objects in Solar System Indicate a Turbulent Beginning

Scientists have found that calcium, aluminum-rich inclusions (CAIs), some of the oldest objects in the solar system, formed far away from our sun and then later fell back into the mid-plane of the solar system. The findings may lead to a greater understanding of how our solar system and possibly other solar systems formed and evolved.
CAIs, roughly millimeter- to centimeter in size, are believed to have formed very early in the evolution of the solar system and had contact with nebular gas, either as solid condensates or as molten droplets. Relative to planetary materials, CAIs are enriched with the lightest oxygen isotope and are believed to record the oxygen composition of solar nebular gas where they grew. CAIs, at 4.57 billion years old, are millions of years older than more modern objects in the solar system, such as planets, which formed about 10-50 million years after CAIs.

Using Lawrence Livermore's NanoSIMS (nanometer-scale secondary-ion mass spectrometer) -- an instrument that can analyze samples with nanometer-scale spatial resolution -- LLNL scientists in conjunction with NASA Johnson Space Center, University of California, Berkeley and the University of Chicago measured the concentrations of oxygen isotopes found in the CAIs.

In the recent research, the team studied a specific CAI found in a piece of the Allende meteorite. Allende is the largest carbonaceous chondrite meteorite ever found on Earth. It fell to the ground in 1969 over the Mexican state of Chihuahua and is notable for possessing abundant CAIs.

Their findings imply that CAIs formed from several oxygen reservoirs, likely located in distinct regions of the solar nebula. CAIs travelled within the nebula by lofting outward away from the sun and then later falling back into the mid-plane of the solar system or by spiraling through shock waves around the sun.

Through oxygen isotopic analysis, the team found that rims surrounding the CAI show that late in the CAI's evolution, it was in a nebular environment distinct from where it originated and closer in composition to the environment in which the building materials of the terrestrial planets formed.

"Allende is this very unusual meteorite with all these wonderful inclusions (CAIs)," said Ian Hutcheon, one of the LLNL scientists on the team. "The isotopic measurements indicate that this CAI was transported among several different nebular oxygen isotopic reservoirs, arguably as it passed through into various regions of the protoplanetary disk."

A protoplanetary disk is an area of dense gas surrounding a newly formed star. In this case, the CAI formed when our star was quite young.

"It is particularly interesting in understanding the formation and dynamics of our solar system's protoplanetary disk (and protoplanetary disks in general)," said Justin Simon of NASA Johnson Space Center and lead author of a paper appearing in the March 4 issue of the journal Science.

The new observations, "support early and short-lived fluctuations of the environment in which CAIs formed, either due to transport of the CAIs themselves to distinct regions of the solar nebula or because of varying gas composition near the proto-sun," Hutcheon said.

Other Livermore researchers include Jennifer Matzel, Erick Ramon and Peter Weber.