Coaxing an animal into low-power mode on its own is a better solution. For some animals, natural states of lowered body temperature are commonplace. Hibernation is the obvious example. When bears, bats or other animals hibernate, they experience multiple bouts of a low-metabolism state called torpor for days at a time, punctuated by occasional periods of higher arousal. Mice enter a state known as daily torpor, lasting only hours, to conserve energy when food is scarce.
The mechanisms that control torpor and other hypothermic states—in which body temperatures drop below 37 degrees Celsius—are largely unknown. Two independent studies published in Nature on Thursday identify neurons that induce such states in mice when they are stimulated. The work paves the way toward understanding how these conditions are initiated and controlled. It could also ultimately help find methods for inducing hypothermic states in humans that will prove useful in medical settings. And more speculatively, such methods might one day approximate the musings about suspended animation that turn up in the movies.
One of the two studies was conducted by neuroscientist Takeshi Sakurai of the University of Tsukuba in Japan and his colleagues. It began with a paradoxical finding about a peptide called QRFP. The team showed that injecting it into animals actually increased their activity. But when the researchers switched on neurons that were making the peptide in mice, they got a surprise. “The mice stayed still and were very cold: the opposite to what they expected,” says Genshiro Sunagawa, of the RIKEN Center for Biosystems Dynamics Research in Japan, who co-led the study. The animals’ metabolic rate (measured by oxygen consumption), body temperature, heart rate and respiration all dropped.
QRFP itself was not involved in altering the mice’s metabolic rate. In fact, the lowered body temperature and other measures did not disappear when the gene for the peptide was deleted. But the gene appeared to serve as a landmark that could steer researchers to relevant metabolism-lowering neurons.
The QRFP peptide is found in many parts of the body, but it is especially prevalent in the hypothalamus, a brain region important for thermoregulation. Knowing this, the researchers used a technique known as chemogenetics—in which neurons are genetically modified so that they can be activated using a drug—to look for neurons in the hypothalamus responsible for the effect. They found that activating QRFP neurons indiscriminately produced a state that lasted for hours. And selectively activating neurons in specific parts of the hypothalamus sent the animals into a hibernationlike condition that lasted more than two days.
During this period, the mice’s metabolism remained properly regulated. And afterward, the rodents revived spontaneously—and unharmed, just as with hibernation. The team called these particular cells Q neurons and named the state the animals were in Q-neuron-induced hypothermia and hypometabolism (QIH). More simply, these properties describe torpor or hibernation.
The researchers conducted a similar experiment in rats, which do not naturally enter torpor, and saw the same effect. Even mice do not naturally hibernate for days at a time, as they did in these experiments. It is possible the animals’ reduced metabolism extended the effects of the drug, which normally wears off in around four hours. But Sunagawa favors another explanation: “Maybe it’s like pressing a switch. And after that, some other systems maintain the condition for a while,” he says. “We believe this system might exist in other mammals.”
The second study, led by neurobiologist Sinisa Hrvatin of Harvard Medical School, induced torpor in mice by depriving them of food. The team used chemogenetic tools to modify neurons that were active as the animals entered torpor, causing them to produce a receptor that could be turned on by a drug. It later injected these mice with the drug to reactivate the neurons and found that doing so induced a torporlike state even when food was available, which lowered the animals’ metabolism. “The question was: If we captured brain activity in torpor, then later restimulated those neurons, is that sufficient to induce torpor?” Hrvatin says. “We were amazed that the answer was yes.” The researchers showed that activating neurons in the same area in the hypothalamus where Sakurai and his colleagues found Q neurons was enough to initiate torpor. They also blocked the activity of these neurons, which disrupted the mice’s ability to enter torpor. “When you do a study like this, you’re out on a limb,” says neuroscientist Michael Greenberg, who was senior author of the second paper. “So when two studies come from such different perspectives and seem to unify something, it’s gratifying and a relief.”
The research provides new insight into a brain region known for its role in controlling basic bodily states. “We knew that the hypothalamus coordinates the majority of the body’s autonomic processes, like thermoregulation, circulation, body weight and energy balance,” says physiologist Gerhard Heldmaier of Philipps University of Marburg in Germany, who was not involved in the work. “From these studies, we learn that hypothalamic neurons guarantee not only stability but can also shift this control from life in the fast lane to life in the slow lane.”
A key next step will be to study more species. “It will be interesting to see how these cells differ between hibernators and nonhibernators,” Heldmaier says. “And if proper activation of them induces hibernation in nonhibernators.” A focus will be understanding how this biological system works. “What does it mean for a cell to be in torpor?” Hrvatin asks. “If you understand this at a molecular level, you may be able to protect the brain from ischemic injury, such as the most common type of stroke, or even neurodegenerative diseases.” Similar considerations apply to preserving organs for transplant.
Whether these states could be induced in humans remains to be seen. Small mammals have very different temperature-regulation systems than those of large mammals, so it is not clear if these neurons will have the same effect. “Is it possible to change the set point in a human? And by how much? I don’t know,” Hrvatin says. “There are a lot of unanswered questions.” Sunagawa dreams of intervals of “daily hibernation.” “If we could understand what sleep is doing, maybe we could combine sleeping and hibernation” and slow aging down, he says. Sunagawa’s group’s paper in Nature even includes a passage that speculates about inducing this quiescent state for astronauts going into deep space.