- Arctic Reindeer Go Off the Circadian Clock
- Ear Infections Could Cause Long-Term ‘Lazy Ear’
- Brain Scans Depict Gulf War Syndrome Damage
- Half-Cocked? Hermaphrochickens Challenge Gender Determination
Posted: 11 Mar 2010 09:47 AM PST
"If you are being driven through a subjective day and night by an internal timer, you may be in 'night mode' when the optimal conditions for foraging are present." said biologist Karl-Arne Stokkan of the University of Tromsø in Norway, co-author of the study appearing Mar. 11 in Current Biology. "So it may be a disadvantage to have such a strong timer in such an environment."
Animals have a circadian clock is housed in the brain region called the hypothalamus and dictates when to rest and when to be active. In most animals, the clock resets every day on a roughly 24-hour schedule, said University of Massachusetts neurologist William Schwartz, who studies circadian biology, but was not involved in the study. The clock also determines the season, helping wildlife know to migrate in the fall or breed in the spring.
Though it's still a mystery exactly how the circadian clock orchestrates sleep and wakefulness, it works in part by driving periodic surges of melatonin and other hormones. Melatonin levels peak around dusk and drop sharply at sunrise.
"The general assumption is that clocks are ubiquitously present and that they are extremely important for the normal functioning of the organism," Stokkan said.
But nobody knew how circadian clocks would work in the Arctic extreme environments where there is no regular day-night cycle.
Stokkan's team looked at semi-domesticated reindeer native to Tromsø, Norway. Tromsø, which is just north of the Arctic circle, gets about two months of continuous daylight in summer, two months of darkness in winter, and only a few weeks of regular length days around the equinoxes. The researchers bought the reindeer from the indigenous Scandinavian people, called the Saami, who herd reindeer for a living.
The team took connective tissue cells from the reindeer and inserted a gene sequence into the reindeer DNA that triggers circadian clock genes. The sequence also included a reporter gene, which lit up every time the clock genes turned on, Stokkan said.
In other animals, this process leads cells to send out a burst of light roughly once every 24 hours, indicating that the clock genes turned on about once a day. The pattern persists even if the cells are in complete darkness or complete light.
But the clock genes in reindeer cells did not respond with this rhythmic on-off pattern, instead firing irregularly with a very low signal. The results suggest the reindeer have evolved to the weird Arctic environment by somehow turning off these genes.
The team also found melatonin levels rose in the darkness and dropped sharply in light, regardless of what the clock genes did. That suggests the animals respond to light cues alone, rather than their circadian clock.
Turning off the clock may help the reindeer keep to their non-stop schedule of grazing on grass, leaves, and lichen for a few hours, napping for few hours and then grazing some more, even in winter when the sun never rises, Stokkan said
"Because of their digestive system — something special to reindeer — they're not going to do well if they just eat at a certain time of day," Schwartz said. "They really have to be grazing every couple of hours."
It's still a mystery how these reindeer know the season without the help of circadian clock genes. Knowing the time of year is crucial for breeding, said University of Manchester biologist Andrew Loudon, co-author of the study. "Otherwise they'd give birth at the wrong time of year, or be trying to lay on fat when there's no food around."
One possibility is that the reindeer take breeding cues in fall and spring from fluctuations in melatonin, but don't use this hormonal signal to determine their day-t0-day nibbling schedule.
Stokkan is studying ptarmigan and other species of reindeer, and early results suggest turning off the clock may be a general pattern in other Arctic wildlife, Stokkan said.
Unfortunately, human Arctic dwellers don't have this adaptation and often have trouble sleeping in summer and get depressed in winter.
"To adapt your physiological mechanisms, you will have to go through a several-thousand-year-long exclusion of certain genes," Stokkan said. "We are pretty tropical animals that have come here very recently,we still carry a pretty strong timer in our genes."
Posted: 10 Mar 2010 06:32 PM PST
Some folks who don't seem to listen may just have a lazy ear. A new study in rats shows that short-term hearing impairments at any stage of life can lead to rewiring in the part of the brain that processes sounds, making the ear seem as if it is loafing on its duty to make sense from noise.
Ear infections and fluid buildup in the middle ear — a condition known as otitis media with effusion — can dampen incoming sound waves. These problems are extremely common in children and represent the top reason children go to the doctor. Such temporary hearing impairment can lead to lingering hearing deficits even after the infection or fluid clears up. The long-term difficulties result from a problem with how the brain adjusts to hearing changes rather than a malfunction in the ear's ability to detect sounds, researchers report in the March 11 Neuron.
An analogous problem in which the brain has trouble processing visual signals from a perfectly functional eye is often called "lazy eye." A lazy eye can often be retrained through practice in children up to about 8 years old.
Likewise, the new study shows that the brain's auditory cortex remains flexible enough that it can partially rewire itself even into adulthood. This gives hope that at least some ear "laziness" problems can be corrected in adults, say study coauthors Daniel Polley, a neuroscientist at the Massachusetts Eye and Ear Infirmary in Boston, and Maria Popescu of Vanderbilt University in Nashville.
Polley and Popescu's experiments with rats show that the brain has a number of critical windows for rewiring itself. The researchers surgically tied off the ear canal in one ear of infant, juvenile and adult rats to mimic the sound-deadening effects of fluid in the ear. After 60 days, the team measured activity of the rats' auditory cortex cells in response to sounds of various frequencies. Blocking sound to one ear produced different changes in the rats' brains, depending on the age when hearing was impaired, the team found.
In 2-week-old rats with blocked ears, more cells in the auditory cortex responded to low-frequency sounds and fewer cells responded to high-frequency sounds compared with rats with no ear blockage, suggesting a diminished range. The infant rats also had a strengthened response to sound signals from the open ear and a weakened response to signals from the closed ear — meaning that one side of the brain loses out in the competition to process sounds. Such losses in people could lead to subtle speech defects or other learning problems, says Takao Hensch, a neuroscientist at Children's Hospital Boston and Harvard University.
Juvenile rats whose ear canals were tied off at age 4 weeks didn't have more low-frequency–sensitive cells in their auditory cortex, indicating that the critical window for determining the low- and high-frequency range had already closed. But like the infant rats, the juvenile rats still showed a shift in which ear responded most to sound signals.
If the ear canal wasn't tied off until the rats were adults, the brain cells had a weakened response to the blocked ear but didn't strengthen the open ear's input. That result shows that as animals age, they lose the ability to boost signals from the open ear.
The new study "opens up quite a rich system to study brain plasticity," Hensch says. Researchers still don't yet know how long each of the critical rewiring periods last in rats or, assuming the system is similar in humans, in people. Also unclear is exactly what effect the brain rewiring would have on hearing in people.
While there's been little to no work done on how common lazy ear is in humans, the researchers think the new study could have important implications in medicine, especially for choosing how aggressively to treat childhood ear infections.
Since adults still retain some ability to rewire sound-processing centers, the researchers hope that just as a lazy eye can be retrained, lazy ears might also learn new work habits.
Posted: 10 Mar 2010 11:17 AM PST
SALT LAKE CITY — Nearly two decades after vets began returning from the Middle East complaining of Gulf War Syndrome, the federal government has yet to formally accept that their vague jumble of symptoms constitutes a legitimate illness. Here, at the Society of Toxicology annual meeting, yesterday, researchers rolled out a host of brain images — various types of magnetic-resonance scans and brain-wave measurements — that they say graphically and unambiguously depict Gulf War Syndrome.
Or syndromes. Because Robert Haley of the University of Texas Southwestern Medical Center in Dallas and the research team he heads have identified three discrete subtypes. Each is characterized by a different suite of symptoms. And the new imaging linked each illness with a distinct — and different — series of abnormalities in the brain.
Men with the same symptoms exhibited similar brain changes, features starkly different from healthy vets their age who had served in the same battalions. (That said, a few vets' symptoms seemed to encompass more than one syndrome. And in such instances, imaging confirmed their brains showed impairments that extended beyond those associated with a single syndrome.)
Since the early 1990s, some 175,000 U.S. troops have returned from service in the first Gulf War reporting a host of vague complaints, notes Richard Briggs, a physical chemist at UT Southwestern involved in the new imaging. Their symptoms ranged from mental confusion, difficulty concentrating, attacks of sudden vertigo and intense uncontrollable mood swings to extreme fatigue and sometimes numbness — or the opposite, constant body pain.
With funding from the Departments of Defense and Veterans Affairs, Haley has assembled a team of roughly 140 researchers. Many work with patients. Others are developing new animal, biochemical and genetic studies to identify the biological perturbations underlying Gulf War Illness. But the vast majority — two-thirds of these scientists — are now involved in brain imaging.
As a result of these studies, Briggs says, "In the last two years we have learned more about Gulf War Illness than we did in the previous 15."
What's emerged is evidence to suggest "that there are three major syndromes responsible for Gulf War Illness," he says. They appear loosely linked to at least three different types of agents to which many troops were exposed: sarin nerve gas, a nerve gas antidote (pyridostigmine bromide) that presented its own risks and military-grade pesticides to prevent illness from sand flies and other noxious pests. But Briggs acknowledges that no one knows for sure which combination of agents or environmental conditions might have conspired to trigger Gulf War illness.
What is clear, he says, is that "our data now clearly show, beyond a shadow of a doubt, that there are brain abnormalities — physiological differences — between ill veterans and normal ones." And from the new scans, "we can tell the ill veterans from the well veterans. And we can distinguish syndromes one, two and three from each other."
The new neuroimaging on a subset of 57 Gulf War vets was completed eight months ago. Yesterday's presentations represent an unveiling of the complex statistical analyses of data gleaned from those functional MRI scans (or fMRIs), brain-wave recordings and other magnetic resonance tools.
Some testing employed old-style technologies. For instance, about a dozen years ago, Haley's team performed magnetic resonance spectroscopy, also known as MRS, to study the chemical composition of various regions in the brains of Gulf War vets. And these tests uncovered the first solid indicators that there were physiological abnormalities in men complaining of Gulf War Illness. Such as a perturbation in the ratio of two chemicals active in the brain's basal ganglia: n-acetyl aspartate (or NAA) and creatine.
Don't know what that means? I didn't either. So Briggs explained.
"The basal ganglia is sort of the switching system of the brain. It's where a lot of communication between the left and right hemispheres occurs." Because it crosses the midbrain region, he says, "it's heavily involved in a lot of these decisionmaking and attention/inhibition networks" – processing centers that, if messed up, could explain many symptoms reported by sick vets.
NAA is a biomarker of healthy nerve cells. So any decrease is a bad sign. The concentration of creatine, which comprises the fuel for brain activities, tends to remain constant, Briggs says, so "it's often used as an internal standard" against which to compare things like NAA.
The Gulf War syndromes are each associated with a roughly 10 percent lower than normal NAA-to-creatine ratio in the left and right basal ganglia, Briggs says — "an indicator of either sick or dead neurons."
After Haley's team initially published evidence in the late '90s of the diminished NAA-to-creatine ratio in sick vets, two other labs confirmed this characteristic MRS feature in sick Gulf War veterans, Briggs notes. More recently, when one of those labs failed to reconfirm those changes during a followup study, the UT Southwestern team began to wonder whether it had erred the first time it had conducted the pioneering tests. Or whether the sick vets had simply gotten well over the past 10 years.
"Our new follow-up [MRS] tests now show our initial findings were right," Haley says, "and that the soldiers haven't gotten better with time."
Many of scans that his team unveiled here at SOT rely on a technology (fMRI) that was not available in the late '90s. So it provides new evidence of what sets sick vets apart.
This technology allows researchers to identify which areas are active as the brain works. Haley's multicenter team designed a series of fMRI tests that required subjects to look at threatening pictures of a battlefield, or imagine the theme behind two words to come up with a third ("desert" and "humps" might be the clues given to suggest "camel"), or to learn words and recall faces.
In healthy veterans, appropriate parts of the brain lit up as they thought, reasoned, viewed — even experienced extremes of temperature. But in men suffering from Gulf War Illness, Haley says, "a different part would often light up as their brain attempted to work around its damage."
Affected areas of the brain in each test varied. The thalamus, for example, is involved in attention and inhibition, Briggs explains. "It is activated differently in syndrome two versus controls," he notes. Not surprisingly, people with that particular syndrome have problems with those traits. The researchers also correlated what combinations of areas in the brain respond in concert during particular tasks. And sometimes, the collection of brain locales that lit up in sick vets differed markedly from those in healthy vets (see images above).
The background volume of blood flowing through the brain also varied substantially in sick vets, Haley notes, "which suggests decreased [brain] function." But even more importantly, blood flow varied in unpredictable ways when the sick Gulf War veterans were administered a drug meant to stimulate parts of the brain susceptible to chemical damage, such as nerve-gas-type agents.
In healthy vets and those suffering from syndrome one, blood flow to affected regions of the brain diminished, although not comparably; the drop in syndrome-one vets was about five times that in the healthy men. But among individuals suffering from Gulf War syndromes two and three, blood flow inappropriately spiked after administration of the drug.
Other tests probed for faults in the integrity of the circuitry connecting deep gray matter — where the brain performs unconscious calculations and processing — with the layer of white matter that performs conscious reasoning. In vets with syndrome two, the most seriously ill of the groups, a special form of scans showed signs that the insulating sheath covering the "wires" connecting the gray and white-matter regions was seriously impaired.
Concludes Briggs: "This tells us very clearly that in the syndrome twos — unlike either of the other syndromes, or the controls — their wiring is flawed."
The panoply of quantitative changes being revealed by brain imaging "is demystifying Gulf War Syndrome," says Haley. Indeed, before long, he predicts, "we're going to come up with tests whereby doctors can diagnose affected vets." And one day, he hopes, the information emerging from these images may actually point toward treatments.
Image: Healthy brain (left) shows response to pain from heat on the forearm. Different regions (right) respond to that heat in vets with Gulf War syndrome.
Posted: 10 Mar 2010 10:54 AM PST
Chicken sex doesn't work like ours. No, not that sex — but the process by which an embryo becomes a recognizably male or female animal.
Unlike mammals, it's not hormones that dictate a chicken's sex. It's a fundamental property of the cells themselves. But this only became apparent when biologists investigated several odd chickens that were half male and half female, as if a line were drawn down the center of their bodies.
"We assumed this was caused by one side of the body having some kind of sex chromosome anomaly," said Michael Clinton, a University of Edinburgh developmental biologist and co-author of the study, described March 10 in Nature. "But when we looked at them closely, they were composed of entirely normal cells. We realized that birds don't follow the mammalian model."
In mammals, there are two types of sex-determining chromosomes, X and Y. Each cell in an embryo has a pair of chromosomes, either XX or XY, but the cells are otherwise identical. Then, early in development, in response to some environmental cue, a group of cells that will someday become ovaries or testes start to produce hormones that cause other cells to develop in male- or female-specific ways. It's the hormones that matter: Exposed to lots of testosterone and deprived of estrogen, cells with female chromosomes will form masculine tissues, and vice versa.
There are a few oddball species such as the duck-billed platypus which has a whopping 10 sex chromosomes, making males XYXYXYXYXY. But the mammalian system was thought to represent a general rule among vertebrate species. And though birds have Z and W chromosomes rather than X and Y, and ZZ is male rather than female, they were thought to follow this rule, too.
That's why Clinton, along with fellow Edinburgh biologists Debiao Zhao and Derek McBrid, expected to find chromosomal malfunction in their half-female, half-male chickens, known as gynandromorphs. But the cells were perfectly normal. They just happened to be organized according to sex: cells with ZZ chromosomes on the male side, and cells with ZW chromosomes on the female side.
As cells on both sides of the body were exposed to the same hormones, it wasn't hormones that mattered to gender, as with mammals. Gender was a fundamental property of the cells.
"These funky chickens, oddities of nature that they are, will provide new perspectives on questions of sexual identity long thought to have been resolved," wrote Duke University cell biologists Lindsey Barske and Blanche Capel in a Nature commentary accompanying the findings.
About one in 10,000 birds is gynandromorphic, but biologists assumed the mammal model applied to all vertebrates, said Clinton.
To test the proposition, the researchers transplanted male cells into a female embryo, and female cells into a male embryo. In both cases, the cells continued to express their sex-specific hormones. Their fate was already set.
The findings expand on earlier research by University of California, Los Angeles biologist Arthur Arnold, who has studied the brains of gynandromorphic zebra finches. They also fit with long-established observations that heavy hormone doses can only change the sex of chicken embryos, but only as long as the dose is maintained. Take the hormones away, and the chickens revert to their intended form.
The big question is whether this kind of cell-based sexual identity will turn out to be a common sex-determining system in other vertebrates, write Barske and Capel.
Clinton suspects it will. "We believe now that certainly all birds, and possibly lower vertebrates, will have a cellular identity," he said. "Remnants of this cellular system may still exist in mammals, but it's overridden by the effects of hormones."
Images: 1) Gyandromorph chicken reflected in mirror; male side white, female side brown./Roslin Institute, University of Edinburgh. 2) Gyandromorph chicken./Roslin Institute, University of Edinburgh.
Thanks to Ed Yong for "half-cocked."
Citations: "Somatic sex identity is cell autonomous in the chicken." By D. Zhao, D. McBride, S. Nandi, H. A. McQueen, M. J. McGrew, P. M. Hocking, P. D. Lewis, H. M. Sang & M. Clinton. Nature, Vol. 464 No. 7285, March 11, 2010.
"An avian sexual revolution." By Lindsey A. Barske and Blanche Capel. Nature, Vol. 464 No. 7285, March 11, 2010.
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