Research teams in the US and Japan have each discovered independently and by unrelated routes a population of hypothalamic neurons in mice that induce the low body temperature, reduced metabolism, and inactivity characteristic of hibernation and torpor. The two papers are published today (June 11) in Nature.
“Trying to pin down which neurons are involved with initiating torpor and hibernation . . . is certainly something that biologists have been interested in for several years now,” says biologist Steven Swoap of Williams College who was not involved in the research. “Both of [the teams] come at it from a different angle and almost end up in the same place, so they complement each other in that way, which is pretty nice,” he adds.
Hibernation and daily torpor are both forms of mammalian suspended animation and share a number of features. Both involve significant, but regulated, drops in body temperature, metabolism, heart rate, breathing rate, and activity, and both are thought to be ways of preserving energy when food is scarce. While hibernation lasts for weeks or months, however, daily torpor lasts several hours each day.
Why some mammals such as bears and certain primates and rodents have the ability to enter periods of dormancy while others don’t is unknown. But the diversity of hibernator species suggests that the biological mechanisms controlling such states may also be preserved, albeit unused, in non-hibernating species. This tantalizing possibility sparks ideas of sending dormant astronauts on extended space journeys as well as more down-to-earth notions of temporarily lowering body temperature and metabolism to preserve tissues in patients with, for example, traumatic injuries.
Before any such fantastic schemes can be considered, figuring out how hibernation works is essential. Much is understood about the physiological changes that occur during torpor and hibernation, but “what wasn’t known is how this process is centrally regulated by the brain,” says neurobiologist Sinisa Hrvatin, a postdoc at Harvard Medical School.
To investigate, Hrvatin and colleagues turned to laboratory mice because when these animals are deprived of food for 10 hours or so and housed at cold temperatures, they enter a state of torpor, Hrvatin explains.
Focusing on the hypothalamus—a region of the brain known to control, among other things, feeding, temperature, and sleep—the team used a “clever genetic trick,” says Swoap, to tag cells activated upon entry into torpor. Later, once the animals were fed and recovered, the genetic trickery enabled the team to reactivate those same neurons, sending the fed animals back into topor. “That’s a really pretty big, important finding,” Swoap says.
Single-cell RNA analysis of the torpor-activated neurons showed that the largest subset of such cells were those expressing the gene for pituitary adenylate cyclase-activating polypeptide (PACAP). Subsequent experiments in which only these PACAP-positive cells were activated in mice showed a similar induction of torpor. In contrast, inhibiting PACAP cells disrupted normal torpor in fasted mice.
Meanwhile in Japan, Genshiro Sunagawa of RIKEN, Takeshi Sakurai of the University of Tsukuba, and their colleagues were investigating the function of a tiny handful of hypothalamus cells that express a particular neuropeptide called pyroglutamylated RF-amide peptide (QRFP). Initially, the team did not suspect a role for the cells in hibernation or torpor, Sunagawa and Sukurai explain in an email to The Scientist.
“[QRFP] was thought to be involved in the regulation of feeding, behavior and sympathetic regulation as well as mood,” they write. So, when they stimulated the QRFP-producing cells, which they call Q neurons, in mice and found it induced an extended topor, the result “was totally unexpected,” they add. Inhibiting Q neurons impaired normal torpor, the team also showed.
Unlike normal torpor, which lasts a matter of hours, stimulation of the Q neurons induced a hypothermia lasting several days. “The torpor phenotype they see is stunning,” says physiologist and behaviorist Zackary Knight of the University of California, San Francisco, who was not involved in the study. “It really suggests that stimulation of these cells flips some kind of switch whereby the animal is in a long-term hypometabolic state.”
“Both papers . . . come up with a similar set of neurons located in about the same place in the mouse brain hypothalamus,” says neuroscientist Shaun Morrison of Oregon Health & Science University who was not involved in the research. “The big question is, are these the same neurons?”
“We found that some Q neurons express PACAP,” write Sunagawa and Sakurai, but many PACAP neurons do not express QRFP, they add, suggesting their Q neurons are a subset of the ones Hrvatin and colleagues found.
“It’s likely that, even if these are not the same neurons, they are certainly talking to each other,” says Swoap. The next step is to determine how such a conversation may occur, and what signals and factors influence it. Armed with this knowledge, “we speculate [hypothermia and hypometabolism] may also be induced in other non-hibernating mammals, including humans,” write Sunagawa and Sakurai.
S. Hrvatin et al., “Neurons that regulate mouse torpor,” Nature, doi:10.1038/s41586-020-2387-5, 2020.
T.M. Takahashi et al., “A discrete neuronal circuit induces a hibernation-like state in rodents,” Nature, doi:10.1038/s41586-020-2163-6, 2020.