Putting mice into hibernation causes a major loss of synapses - Ars Technica
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Our leading hypothesis for how our memories are stored is that when you learn something, the connections among neurons involved get stronger and physically larger, and that constitutes the memory. The trouble is that these connections significantly change over time—they’re plastic.
“If you compare the arrangement of these connections on day one with the same on day four or five, it’s very, very different,” says Kazumasa Tanaka, a neuroscientist at the Okinawa Institute of Science and Technology Graduate University in Japan. To learn how a memory that can last for years can sit on hardware that shifts every few days, Tanaka’s team made the shift a bit more dramatic. In a recent Science study, they induced a hibernation-like state in mice, which basically erased the state of more than half of their synapses. And yet the mice apparently have kept their memories.
Hibernation on demand
Hibernation is a specialty of squirrels, hamsters, and bears, but the neural circuit that triggers it is conserved across mammals, and is present in species that never hibernate in the wild—like mice. In June 2020, a team of researchers led by Takeshi Sakurai, a neuroscientist at the University of Tsukuba and a collaborator on Tanaka’s study, developed a technique to artificially activate this hibernation circuit. This can be done by activating a population called Q neurons in a region of the hypothalamus.
The result is a state dubbed QIH, for Q-neuron-induced hypothermia and hypometabolism.
“With our protocol, we can bring mice’s body temperature down to somewhere around 20° Celsius, and their heart rate and breathing rate decrease significantly as well,” Tanaka explains. Whether that counts as real hibernation depends on which hibernator serves as a reference. Bears in a hibernation state reduce their metabolic demand but don’t change their body temperature, which remains around 36° or 37° Celsius. On the other extreme, some species of squirrels enter super deep hibernation where their body temperature can go very close to freezing. “Artificial hibernation sits somewhere in the middle of that spectrum,” Tanaka says.
The most important thing about QIH, though, is that it can be switched on and off at will. In Tanaka’s experiments the mice spent 48 hours in the hibernation-like state and then woke up.
For their synapses, these 48 hours worked like Thanos’ snap.
Synaptic purge
To find out how many synapses are lost during QIH, Tanaka’s team implanted tetrodes, bundles of fine electrodes, into the hippocampus of freely moving mice. These let them record individual neurons firing. They found that activity dropped by about 70 percent once hibernation set in.
The brain tissues of some animals were imaged with a technique called serial block-face scanning electron microscopy before hibernation, during it, and days after returning to consciousness. It turned out the hibernation eradicated more than half of the synapses—in principle, this should erase most of the memories. “If you accept that memory traces reside in the efficacy of individual synapses, if you lose more than half of the synaptic connections, of course what you’d expect is impairment of the memory afterwards,” Tanaka says. But the team found no such impairment.
Before hibernation, the mice had been trained on two standard memory tasks. One was contextual fear conditioning, in which an animal learns to associate a particular box with a mild electric shock. The second was a plus-maze task in which the mouse learns to navigate its way to a reward. Performance in both tasks depends on memories stored in the hippocampus, which the team confirmed by creating a lesion in the region after training, which caused the memories to disappear.
When other mice, ones that were put into QIH, were aroused, though, they performed on these tasks just as well as the mice that did not hibernate. “What we found in these two different behavioral paradigms is the memory was completely intact,” Tanaka claims.
The survival of these memories through the purge of the synapses was also confirmed by brain activity recordings. Place cells, hippocampal neurons that fire when an animal occupies a particular spot, still fired in the same locations after arousal. And a decoder that read out the population activity could reconstruct where the mouse was just as accurately as before.
Returning synapses
Watching the same dendrites over eight days revealed that the synapses that...