Squirrel Hibernation May Help Stroke Survivors

squirrel hibernation red house tree eating

As winter approaches, squirrels collect nuts and bears gorge on food to gain weight. Animals of all sizes prepare for hibernation, in which they may sleep for up to seven months – something many of us would like to try. This process takes place without eating, drinking and even reduced breathing. How do animals hibernate, and what can squirrel hibernation teach us about new therapies in stroke patients?

Hibernation: The Long Nap

Winter in the wild isn’t a warm fireplace surrounded by hot food and great company. Far from it; winters are harsh periods with little food and an unforgiving environment. But some animals have found a way to improve their chances of survival by skipping winter altogether! Hibernation is the process of passing a period of time inactive, with reduced body temperature and metabolism.

True hibernation is observed in endotherms, also known as ‘warm-blooded’ animals. It is characterized by a suppression of metabolism to conserve energy, which results in decreased body temperature and inactivity. While cold-blooded animals like fish and reptiles may also experience periods of low activity, they cannot actively reduce their body temperature of metabolic rate. In the winter, many fish have to endure temperatures close to freezing and hence their metabolism naturally decreases.

brown bear hibernation squirrel forest big
One of the few large animals that hibernate, the brown bear. Mammals can maintain their body temperature as opposed to fish and reptiles, but at the cost of a higher metabolic rate.

Smaller animals like squirrels tend to have a higher metabolic rate, which means hibernation benefits them better as they will save more energy. A mouse’s metabolic rate, for example, is around 20 times higher than that of a sheep1. It is important to note that while hibernating, the animal itself is extremely vulnerable, therefore the benefits of hibernation have to be great; as a result, it is rare to find larger animals hibernating. Many species of bears love doing it anyway, but probably because few natural predators have evolved to attack them in their sleep.

Unlike bears, squirrels do not have huge fat stores and have to store their food outside their body. Squirrel hibernation is characterized by a frantic search of food, hoarding it away to prepare for the long nap. During their hibernation, their metabolism can drop to as little as 1% their active rate. Hibernation periods of animals vary from just a few days up to several months, depending on the area, temperature and species. Rodents like dormice can hibernate for around 6 months, sometimes even longer1.

More Complicated Than Just Going To Bed

The model animal to study hibernation has got to be alpine marmots, they can spend 9 months a year in this state. Their hibernation cycle consists of 4 different stages: entrance into hibernation, maintenance of deep hibernation, arousal and a euthermic period. In alpine marmots, each cycle lasts around 15 days and animals undergo 15 to 20 such cycles in a season.

alpine marmots squirrel hibernation fat looking furry creatures
‘What’s the matter, buddy – ain’t seen an alpine marmot before?’ (Source)

Entry into hibernation is characterized by a rapid decrease in metabolic rate, body temperature and heart rate. It is not fully understood how hibernation is triggered, but hibernating animals produce certain ‘hibernation chemicals’. Research into these may provide medical benefits – in preserving organs for transplant, for example2.

Following this comes sustaining the state of hibernation, which lasts several days. The heart rate decreases to a minimum while ventilation (breathing) also slows, leading to periods of apnea where the breathing mechanism is ‘paused’. During this time, the alpine marmot’s heart rate slows to five beats per minute and its breathing to 1–3 breaths per minute. Oxygen deficiency is not a problem for hibernators, which can consume it through their trachea without actually breathing.

Deep hibernation is terminated by the stage of arousal in which the animal wakes from its torpor. This is followed by the euthermic period lasting 1 to 2 days, to slowly warm up and return metabolism to normal levels. These stages require a lot of energy and time, also leaving the animal vulnerable to predation.

four stages squirrel bear mouse hibernation hibernate
The four stages of hibernation and the duration of each event, according to a studies carried out on alpine marmots.

These four stages are similar in all studied hibernators; however, some animals experience this on a daily cycle with the hibernation period around 12 hours a day. While still considered hibernation, this is known as daily torpor and is not restricted to the winter months. While hibernating saves around 90% of energy requirements, daily torpor saves 60 to 70%3.

Though physiological mechanisms and biochemical reactions are only partly known, some theories have already been established. One of the main features of hibernation is the decrease of adenosine triphosphate (ATP) synthesis and the inhibition of activities that require ATP.

This has been shown by reduced respiration in the mitochondria, a process that is responsible for the conversion of stored energy to ATP. Cellular processes like transcription and translation require large amounts of ATP to take place and are therefore inhibited to conserve energy3. Glycolysis (the metabolism of the sugar glucose) in the liver is reduced by inhibiting glycogen phosphorylase4.

Squirrel Hibernation and Brain Injuries

One of the most interesting properties of hibernation is the protection of organ function despite a lack of blood and oxygen supply. In studies of squirrels that had suffered head injuries, hibernating squirrels showed less brain damage than non-hibernating ones5. This discovery led to the idea that a hibernation-like state could be brought about for medical benefit.

Hypothermia and hibernation are physiologically similar, both characterized by decreased oxygen consumption, glycolysis and activity. This can be exploited as it reduces the body’s need for oxygen and blood supply after an event such as a stroke. There are several techniques to reach a hypothermia-induced hibernation state such as whole-body surface cooling with ice, or cooling the blood directly by infusing cold saline.

ice snow hibernation hypothermia cold cooling
Low temperatures can be used to induce hypothermia, which – like hibernation – reduces metabolic rate and oxygen demand.

Another option that is being researched is the use of phenothiazine-derived drugs. Many have already been approved by the FDA for the treatment of schizophrenia, such as chlorpromazine (Thorazine). As a side effect, some phenothiazine drugs are able to induce hypothermia with or without external cooling methods. While their reliability for this purpose has not yet been examined in clinical trials, these drugs definitely show promise6.

Related: How Drug Delivery Systems Are Transforming Neuromedicine

In patients who have just suffered a stroke, speed is crucial to prevent damage to brain tissue. As the brain requires a huge amount of oxygen, it is heavily reliant on having steady blood flow to keep its cells alive. A drug that induces ‘hibernation’ could be useful in preserving brain function, especially in such an event that immediate surgical treatment is not possible.

chlorpromazine drug antipsychotic induced hibernation
Chlorpromazine – an antipsychotic medicine. Note thiazine ring with a sulfur and nitrogen atom.

Many stroke survivors find themselves permanently disabled after medical intervention. By following in the (tiny) footsteps of squirrels, a hibernation-like state could provide a novel way to preserve brain tissue immediately after such an event.

References:

  1. Lyman C. P. (1982). Hibernation and Torpos in Mammals and Birds. Chapter 1, 1-10.
  2. Bolling, S. F., & Tramontini, N. L. (1997). Use of “natural” hibernation induction triggers for myocardial protection. The Annals of thoracic surgery64(3), 623-627.
  3. Heldmaier G., Ortmann S., Elvert R. (2004). Natural hypometabolism during hibernation and daily torpor in mammals. Respiratory Physiology & Neurobiology. Vol. 141, 317-329.
  4. Storey K. B. (1987). Regulation of Liver Metabolism by Enzyme Phosphorylation during Mammalian Hibernation. The Journal of Biological Chemistry. Vol. 262, Nr. 4, Issue of February 5, 1670-1673.
  5. Forreider B., Pozivilko D., Kawaji Q., Geng X., Ding Y. (2017). Hibernation-like neuroprotection in stroke by attenuating brain metabolic dysfunction. Progress in Neurobiology. Vol. 157, 174-187.
  6. Hopkin, D. B. (1956). Some Observations on the Use of the Phenothiazine Derivatives in Anæsthesia and Their Mode of Action, with Special Reference to Chlorpromazine. Canadian Medical Association Journal75(6), 473.

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