Neural circuits controlling hibernation-like behavior found in mice

Reviewed by Emily Henderson, B.Sc.June 11, 2020

The suspended animated dreams have long been captivating human imagination, reflected in countless works of myth and fiction, from King Arthur and the Sleeping Beauty to Captain America and Han Solo. By effectively suspending an individual’s time itself, the stasis condition promises to allow for the repair of fatal wounds, prolong life and enable travel to distant stars.

The interrupted animation may seem fancy, but a surprisingly diverse array of lives already realizes that version. Animals such as bears, frogs, and hummingbirds, through activities such as hibernation, are severely affected by severe winter, drought, food shortage, metabolism, heart rate, and slow biological stagnation by slow crawl and decrease in body temperature. You can survive the extreme conditions of.

Now, a neuroscientist at Harvard Medical School has discovered a group of hypothalamic neurons that control hibernation-like behavior or insomnia in mice, and for the first time reveals the neural circuits that control this condition.

Report in Nature On June 11, the team showed that when these neurons were stimulated, the mice could become insomnia and remain in that state for several days. When the activity of these neurons is blocked, natural insomnia is interrupted.

Another study published at the same time Nature Researchers from the University of Tsukuba in Japan have also identified a similar population of neurons in the hypothalamus.

With a better understanding of these processes in mice and other animal models, the authors imagine a possible future work towards inducing insomnia in humans-preventing brain damage during stroke, a new Potential outcomes with a variety of uses, including therapeutic potential For metabolic diseases or even help NASA send humans to Mars.

Imagination goes crazy when thinking about the possibilities of human hibernation. Can you really extend your life? Is this a way to send people to Mars? “

Sinisa Hrvatin, Neurobiology Instructor and Co-author of Research at the Brabatnik Institute at HMS

“To answer these questions, we must first study the basic biology of animal dormancy and hibernation,” Hrvatin said. “We and others are doing this-it’s not a science fiction.”

Many animals go to sleep in order to reduce their energy consumption in rare cases. Hibernation is an expanded seasonal form of this. Unlike sleep, coma is associated with systemic physiologic changes, especially a significant decrease in body temperature and suppression of metabolic activity. Although common in nature, the biological mechanisms underlying insomnia and hibernation are poorly understood.

In particular, the role of the brain remains largely unknown, driving the research efforts of researchers including Hrvatin and co-worker Senmiao Sun, a graduate student in the Harvard Program in Neuroscience, and senior author of the research, Michael Greenberg. It’s a problem. , Professor Nathan Marsh Puzy, and Chair of the Neurobiology Division of the Brabatnik Institute at HMS.

Nerve trap

Researchers have studied mice that do not hibernate, but experience insomnia when they lack food and are cold. When fed at 22 C (72 F), fasting mice had a sharp decrease in core body temperature, with a marked decrease in metabolic rate and exercise. In contrast, well-fed mice retained normal body temperature.

When mice began to enter Tororor, the team focused on a gene called Fos-previously shown by the Greenberg lab to be expressed in active neurons. By labeling the protein product of the Fos gene, we were able to identify which neurons were activated during the entire brain transition to insomnia.

This approach revealed extensive neuronal activity, including areas of the brain that regulate hunger, feeding, body temperature, and many other functions. To see if brain activity is sufficient to induce coma, the team combined two techniques (FosTRAP and chemogenetics) to genetically tag active neurons during coma .. These neurons can later be restimulated by adding chemicals.

Experiments show that re-stimulating neurons in this way after the mouse recovers from its first bout of inactivity can actually induce torpor, even in well-fed mice. confirmed.

However, because this approach labeled neurons throughout the brain, the researchers worked to narrow down specific areas controlling torture. To that end, they designed a virus-based tool and used it to selectively activate neurons only at the injection site.

The researchers conducted a series of painstaking experiments focusing on areas of the brain involved in regulating the hypothalamus, temperature, hunger, thirst, hormone secretion, and other functions. They systematically injected 54 animals with trace amounts of virus covering 226 different areas of the hypothalamus, then activated neurons only in the injected areas and looked for signs of insomnia.

Neurons in a specific area of ​​the hypothalamus, known as avMLPA, caused insomnia when activated. Stimulating neurons in other areas of the hypothalamus had no effect.

“When the first experiment went well, we knew there was something,” Greenberg said. “We can now use FosTRAP to control the toror in these mice, which allows us to identify a subset of cells involved in the process. An excellent demo showing how to study activity and behavioral states.”

Worthwhile goals

The team further analyzed the region-occupying neurons, using single-cell RNA sequences to examine approximately 50,000 individual cells representing 36 different cell types, and ultimately the neurotransmitter transporter gene Vglut2 and peptides. We identified a subset of Toror-Driveing ​​neurons marked by Adcyap1.

Stimulating only these neurons was sufficient to induce a rapid decrease in body temperature and locomotor activity, a major feature of coma. To confirm that these neurons are important for insomnia, researchers used another virus-based tool to suppress the activity of avMLPA-Vglut2 neurons. This prevented fasting mice from entering spontaneous insomnia, and in particular the associated reduction in core body temperature. In contrast, silencing these neurons in well-fed mice had no effect.

“In warm-blooded animals, body temperature is tightly controlled,” Sun said. “For example, in humans a few degrees of hypothermia can lead to hypothermia and can be fatal. However, insomnia circumvents this regulation and dramatically lowers body temperature. Insomnia in mice Studies will help us understand this warm and fascinating feature. Bloody animals may be manipulated through neural processes.”

The researchers warn that their experiments do not conclusively prove that a particular neuronal type controls dormancy, a complex behavior likely to involve many different cell types. I will. However, by identifying the specific brain regions and subsets of neurons involved in the process, scientists are at the door of efforts to better understand and control the state of mice and other animal models. Said the others.

They are now studying the long-term effects of torpor on mice, the role of other neuronal populations, and the underlying mechanisms and pathways that enable avMLPA neurons to regulate torror.

“Our findings open the door to a new understanding of what torture and hibernation are, and how they affect the cells, brain and body,” Hrvatin said. “We can now rigorously study how animals enter and leave these states, identify the underlying biology, and consider human applications. This study is important for this journey. It represents one of the steps.”

Even if it could cause human insomnia or hibernation one day, even if it could happen, its meaning would be profound.

“It’s too early to say if we can trigger this kind of condition in humans, but that might be a worthwhile goal,” Greenberg said. “It could lead to an understanding of interrupted animation, metabolic control, and perhaps extended lifespan. In particular, interrupted animation is a common theme in science fiction, perhaps our star-crossing theme. Ability will one day depend on it.”