During hibernation, the ground squirrel's brain loses many vital neural connections, but it has evolved a way to recuperate. Understanding that process might help scientists treat Alzheimer's
?| June 26, 2012?|
REBOUNDING BRAINS: Hibernating mammals offer scientists a unique way to study the brain's plasticity, as well as neurodegenerative diseases.
Image: Alan Vernon, via Wikimedia Commons
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Every September arctic ground squirrels in Alaska, Canada and Siberia retreat into burrows more than a meter beneath the tundra, curl up in nests built from grass, lichen and caribou hair, and begin to hibernate. As their lungs and hearts slow, the rivers of blood flowing through their bodies dwindle and their core body temperatures plummet, dipping below the freezing point of water. Electrical signals zipping along crisscrossing neural highways vanish in many areas of the brain. Seven months later the squirrels wake up and return to the surface?famished, eager to mate and perfectly healthy.
How hibernating mammals survive for so long at such low temperatures without any food or water beyond what they have stored in their own fat fascinates scientists for many reasons. Hibernation is an amazing biological feat and an opportunity to learn new ways of pushing the human body beyond its ostensible limits, as well as healing it when it breaks down. The arctic ground squirrel's brain, in particular, seems to be incredibly resilient. When ground squirrels hibernate their neurons shrink and many connections between neurons shrivel. But their brains periodically compensate for this loss with massive growth spurts, multiplying neural links beyond what existed before hibernation. Learning how the ground squirrel's brain recuperates could not only help scientists understand the brain's plasticity, but also suggest new ways to reverse or prevent cellular damage in neurodegenerative diseases. In particular, recent research on hibernating brains is changing the way some scientists think about misshapen tau proteins, which are a hallmark of Alzheimer's disease.
Brain freeze
Most small hibernating mammals?hamsters, hedgehogs, bats?turn down their body's thermostat during hibernation, relinquishing one of the defining features of all mammals: warm blood. Arctic ground squirrels are the most extreme example. In August 1987 Brian Barnes of the University of Alaska Fairbanks (U.A.F.) captured 12 arctic ground squirrels and implanted tiny temperature-sensitive radio transmitters in the animals' abdomens. He transported the squirrels to outdoor enclosures in Fairbanks?wire cages with borders reaching more than 1.2 meters belowground. By September the ground squirrels had dug burrows within the enclosures and begun to hibernate. Their body temperatures dropped to ?2.9 degrees Celsius, almost three degrees below the freezing point of freshwater and probably the lowest core body temperature ever recorded in a living mammal. Despite this, ground squirrel blood remains liquid, most likely through a phenomenon known as supercooling.
In laboratory experiments, Barnes also measured the temperature of various body parts as the squirrels hibernated in a chamber kept at ?4.3 degrees C. Although their colons, feet and bellies dropped below zero C, their necks never grew colder than 0.7 degree C, suggesting that the brain remains a little warmer than the rest of the body. Most mammals would die within hours if their brains were cooled so low, yet ground squirrel brains survived near freezing temperatures for weeks at a time. Every two to three weeks the squirrels shivered themselves back to their typical body temperature of 36.4 degrees C, which they maintained for 12 to 15 hours before becoming frozen pop-squirrels once more. Later, scientists would confirm that these intermittent periods of arousal are crucial to the ground squirrels' survival?without them their brains would wither long before spring's arrival.
Doom and bloom
Hibernation devastates the ground squirrel brain, wilting thousands if not millions of vital connections between brain cells, known as synapses. But its brain has evolved impressive resilience, repeatedly renewing itself at astonishing speeds, like a forest erupting through the scorched earth in a matter of days. Victor Popov of the Institute of Cell Biophysics in Russia discovered some of the earliest evidence of this plasticity. In the early 1990s Popov and his colleagues captured wild Siberian ground squirrels and kept them in temperature-controlled enclosures as they hibernated. The researchers sacrificed different animals at three distinct stages?during hibernation; two hours after one of the intermittent arousal periods; or one day after emerging from hibernation?and removed their brains to stain and examine the neurons within the hippocampus, an area crucial for memory. Neurons from squirrels that were in the middle of hibernation were shrunken and had far fewer dendrites?branches that receive signals from other neurons?compared with brain cells from fully awake and aroused squirrels. The dendrites in hibernating brains also had fewer dendritic spines, which jut out from the main branch like thorns on a rose stem and increase the number of possible synapses with nearby cells.
Whereas neurons in hibernating brains looked like barren tree limbs in the dead of winter, brain cells from squirrels that had just emerged from hibernation into a period of arousal sported dense crowns of overlapping dendrites. In only two hours the squirrels' brains had not only compensated for all the synapses lost during hibernation?their brain cells now boasted many more links than those of an active squirrel in the spring or summertime. One day later, however, their brains had pruned many of these ties, probably recognizing them as superfluous, much the way the developing mammalian brain shears its blooming neural forest.
Since Popov's study other researchers have observed similar loss and recovery of synapses in the brains of hibernating hamsters and hedgehogs. In a 2006 study Craig Heller of Stanford University discovered that the hibernating brain is incredibly plastic overall, not just in the hippocampus. Heller thinks that squirrels and similar hibernators lose dendrites during hibernation because their metabolism is too slow and their brains too cold and idle to keep those living wires in working condition.
Perhaps it's more efficient to let them shrivel, like a houseplant withering from neglect, and quickly nurse them back to life during those intermittent bouts of arousal. That way the mammals save as much energy as possible yet still preserve vital neural connections. Even so, researchers have estimated that many small hibernating mammals devote between 80 and 90 percent of all energy used during hibernation to keeping their brains alive.
Protective proteins?
Although scientists have documented structural changes to cells in the hibernating squirrel's brain, they do not yet understand what triggers the brain's recovery. Thomas Arendt of the University of Leipzig in Germany thinks the answer may involve a protein named tau. Normally, tau proteins help stabilize long, ropelike components of a cell's scaffolding called microtubules; tau keeps the many threads in the rope tightly bundled. When, for unknown reasons, tau proteins become hyperphosphorylated?that is, burdened with too many phosphate groups?they change shape and start clumping together inside neurons. As a result, microtubules grow slack and cells lose their shapes and stop functioning properly. Researchers know that misshapen tau proteins build up in the brain cells of people with various neurodegenerative disorders?notably Alzheimer's?but it is not yet clear whether distorted tau proteins in part cause such disorders or whether they are a side effect of the true causes.
Arendt and his colleagues discovered that hyperphosphorylated tau accumulates in the brains of hibernating European ground squirrels (Spermophilus citellus). The more synapses the rodents' brains lost during hibernation, the more hyperphosphorylated tau accrued in their neurons. Within a few hours of emerging from hibernation into a period of arousal, however, the squirrels somehow scoured tau from their brains. As one way of revealing this process Arendt stained slices of brain tissue from hibernating and aroused squirrels with a dye that binds specifically to tau proteins that carry extra phosphate groups. The difference was startling. Brain tissue from hibernating squirrels was generally dark and as black as ink in some areas, whereas tissue from aroused and non-hibernating animals was completely unblemished. Arendt thinks that hyperphosphorylated tau proteins accumulate during hibernation to prevent neurons from losing even more synapses than they do and, possibly, to play a role in the swift recovery of synapses during arousal. Hyperphosphorylated tau also accumulates in the developing mammalian brain, but largely disappears soon after birth, when the brain is pruning unnecessary connections. Perhaps, Arendt proposes, tau usually protects neurons, but malfunctions in the brains of people with Alzheimer's, analogous to an overreactive immune systems in people with autoimmune disorders.
Recently, Arendt and Barnes collaborated on a study that further investigated tau proteins in hibernating ground squirrels, hamsters and black bears. Clumps of hyperphosphorylated tau gathered in the bear brains during hibernation, even more reminiscent of the clusters of misshapen proteins observed in the neurons of people with Alzheimer's. Unlike ground squirrels and hamsters, black bears do not drop in body temperature much during hibernation nor do they enter periodic bouts of arousal. Rather, they remain in mild continuous hibernation all winter. Without intermittent arousals to clear hyperphosphorylated tau from their brains, Arendt proposes, hibernating black bears tiptoe perilously close to neurodegeneration, but somehow manage to reverse the damage when they wake up in the spring. Although these ideas about tau are controversial, Arendt and other scientists are pursuing related research because hibernating animals offer an opportunity to study Alzheimer's and related disorders in ways that would be unethical to replicate with the human brain.
Hibernating mammals may also give scientists a way to study the brain's untapped potential. Throughout history, neuroscientists have learned a lot about how typical brains work from brains that were unusual or damaged?organs that lacked the usual bridge of neural tissue between the two hemispheres or had large holes in a particular region. The hibernating brain, in contrast, reveals the extraordinary talents hidden in the typical mammalian brain. Some recent studies by Kelly Drew of U.A.F. and her colleagues suggest that even when a hibernating mammal is awake in the spring and summer its brain remains resistant to the kind of oxygen deprivation and neuronal damage that often result from heart attacks and stroke. When small mammals first evolved hibernation, their energy-hungry brains were put in an impossible situation: survive half the year with almost no oxygen or nutrition and emerge from the whole ordeal unscathed. Evidently, hibernation did not kill the brain?it only made it stronger.
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